Food and Drug Administration, HHS Pt. 4
440.107e Ampicillin trihydrate-probenecid 440.180g Penicillin G potassium tablets for capsules. solution. 440.108 Bacampicillin hydrochloride dosage forms. Subpart C—Injectable Dosage Forms 440.108a Bacampicillin hydrochloride tab- lets. 440.201 Sterile azlocillin sodium. 440.108b Bacampicillin hydrochloride for 440.202 Sterile amdinocillin. oral suspension. 440.207 Sterile ampicillin trihydrate for sus- 440.111 Carbencillin indanyl sodium tablets. pension. 440.115 Cloxacillin sodium monohydrate 440.209 Ampicillin sodium injectable dosage oral dosage forms. forms. 440.115a Cloxacillin sodium monohydrate 440.209a Sterile ampicillin sodium. capsules. 440.209b Sterile ampicillin sodium and 440.115b Cloxacillin sodium monohydrate sulbactam sodium. for oral solution. 440.210 Benzylpenicilloyl-polylysine injec- tion. 440.117 Cyclacillin oral dosage forms. 440.213 Sterile carbenicillin disodium. 440.117a Cyclacillin tablets. 440.219 Dicloxacillin sodium monohydrate 440.117b Cyclacillin for oral suspension. injectable dosage forms. 440.119 Dicloxacillin sodium monohydrate 440.219a Sterile dicloxacillin sodium oral dosage forms. monohydrate. 440.119a Dicloxacillin sodium monohydrate 440.219b Dicloxacillin sodium monohydrate capsules. for injection. 440.119b Dicloxacillin sodium monohydrate 440.229 Hetacillin potassium injectable dos- for oral suspension. age forms. 440.125 Hetacillin oral dosage forms. 440.229a Sterile hetacillin potassium. 440.125a Hetacillin chewable tablets. 440.229b Hetacillin potassium for injection. 440.125b Hetacillin for oral suspension. 440.236 Methicillin sodium monohydrate for 440.129 Hetacillin potassium capsules. injection. 440.141 Nafcillin sodium monohydrate oral 440.237 Sterile mezlocillin sodium dosage forms. monohydrate. 440.141a Nafcillin sodium monohydrate tab- 440.241 Nafcillin sodium injectable dosage lets. forms. 440.141b Nafcillin sodium monohydrate cap- 440.241a Nafcillin sodium monohydrate for sules. injection. 440.141c Nafcillin sodium monohydrate for 440.241b Nafcillin sodium injection. oral solution. 440.249 Oxacillin sodium injectable dosage 440.149 Oxacillin sodium monohydrate oral forms. dosage forms. 440.249a Oxacillin sodium monohydrate for 440.149a Oxacillin sodium monohydrate cap- injection. sules. 440.249b Oxacillin sodium injection. 440.149b Oxacillin sodium monohydrate for 440.255 Penicillin G benzathine injectable oral solution. dosage forms. 440.155 Penicillin G benzathine oral dosage 440.255b Sterile penicillin G benzathine sus- forms. pension. 440.155a—440.155b [Reserved] 440.255c Sterile penicillin G benzathine-pen- 440.155c Penicillin G benzathine oral sus- icillin G procaine suspension. pension. 440.255d Sterile penicillin G benzathine for 440.155d Penicillin G benzathine tablets. suspension. 440.171 Penicillin V oral dosage forms. 440.274 Penicillin G procaine injectable dos- 440.171a Penicillin V capsules. age forms. 440.171b Penicillin V for oral suspension. 440.274a Sterile penicillin G procaine with 440.171c Penicillin V tablets. aluminum stearate suspension. 440.173 Penicillin V potassium oral dosage 440.274b Sterile penicillin G procaine sus- forms. pension. 440.173a Penicillin V potassium capsules. 440.274c Sterile penicillin G procaine for 440.173b Penicillin V potassium chewable suspension. tablets. 440.280 Penicillin G potassium injectable 440.173c Penicillin V potassium tablets. dosage forms. 440.173d Penicillin V potassium for oral so- 440.280a Sterile penicillin G potassium. lution. 440.280b Penicillin G potassium for injec- 440.180 Penicillin G potassium oral dosage tion. forms. 440.280c Penicillin G potassium injection. 440.180a Penicillin G potassium tablets. 440.281 Penicillin G sodium injectable dos- 440.180c Penicillin G potassium capsules. age forms. 440.180f Penicillin G potassium for oral so- 440.281a Sterile penicillin G sodium. lution. 440.281b Penicillin G sodium for injection.
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440.283 Sterile piperacillin sodium. (vii) It gives a positive identity test 440.290 Ticarcillin disodium injectable dos- for azlocillin. age forms. (2) Labeling. It shall be labeled in ac- 440.290a Sterile ticarcillin disodium. 440.290b Sterile ticarcillin disodium and cordance with the requirements of clavulanate potassium. § 432.5 of this chapter. 440.290c Ticarcillin disodium and (3) Requests for certification; samples. clavulanate potassium injection. In addition to complying with the re- quirements of § 431.1 of this chapter, Subparts D–J—[Reserved] each such request shall contain: Subpart K—Bulk Drug Formulations for (i) Results of tests and assays on the Repacking or for Manufacturing Use batch for potency, sterility, pyrogens, moisture, pH, specific rotation, and 440.1080a Sterile penicillin G potassium identity. buffered. (ii) Samples, if required by the Direc- 440.1081a Sterile penicillin G sodium, buffered. tor, Center for Drug Evaluation and Research: AUTHORITY: Sec. 507 of the Federal Food, (a) If it is packaged for repacking or Drug, and Cosmetic Act (21 U.S.C. 357). for use in the manufacture of another drug: Subpart A—Bulk Drugs (1) For all tests except sterility: 10 § 440.1a Sterile azlocillin sodium. packages, each containing approxi- mately 300 milligrams; and 5 packages, (a) Requirements for certification—(1) each containing approximately 1 gram. Standards of identity, strength, quality, (2) For sterility testing: 20 packages, and purity. Sterile azlocillin sodium is each containing approximately 300 mil- the sodium salt of 4-thia-1- ligrams. azabicyclo[3.2.0]heptane-2-carboxylic (b) If it is packaged for dispensing: acid, 3,3-dimethyl-7-oxo-6-[[[[(2-oxo-1- (1) For all tests except sterility: A imidazolidinyl)carbonyl] minimum of 15 immediate containers. amino]phenylac-etyl]amino]-[2S- [2α,5α,6β(S*)]]-. It is so purified and (2) For sterility testing: 20 immediate dried that: containers, collected at regular inter- (i) If the azlocillin sodium is not vals throughout each filling operation. packaged for dispensing, its azlocillin (b) Tests and methods of assay—(1) Po- content is not less than 859 micrograms tency. Proceed as directed in and not more than 1,000 micrograms of § 442.40(b)(1)(ii) of this chapter, except: azlocillin per milligram on an anhy- (i) Dilute Brij 35 solution. In lieu of the drous basis. If the azlocillin sodium is hydroxylamine hydrochloride solution packaged for dispensing, its azlocillin described in § 442.40(b)(1)(ii)(b)(1) of this content is not less than 859 micrograms chapter, use dilute Brij 35 solution in and not more than 1,000 micrograms of the reference channel. Prepare dilute azlocillin per milligram on an anhy- Brij 35 solution as follows: Place 1 mil- drous basis and also, each container liliter of Brij 35, 30 percent solution, contains not less than 90 percent and into a 1-liter volumetric flask contain- not more than 115 percent of the num- ing 900 milliliters of distilled water. ber of milligrams of azlocillin that it is Swirl gently and dilute to volume slow- represented to contain. ly with distilled water. Mix well. (ii) It is sterile. (ii) Buffer. In lieu of the buffer de- (iii) It is nonpyrogenic. scribed in § 442.40(b)(1)(ii)(b)(2) of this (iv) Its moisture content is not more chapter, use the buffer prepared as fol- than 2.5 percent. lows: Dissolve 200 grams of primary (v) Its pH in an aqueous solution con- standard tris (hydroxymethyl) taining 100 milligrams of azlocillin per aminomethane in sufficient distilled milliliter is not less than 6.0 and not water to make 1 liter. Filter before use. more than 8.0. (iii) Preparation of working standard (vi) Its specific rotation in an aque- solution. Dissolve and dilute an accu- ous solution containing 10 milligrams rately weighed portion of the azlocillin of azlocillin per milliliter is ∂170° to working standard with sufficient dis- ∂200°. tilled water to obtain a concentration 492
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of 1.0 milligram of azlocillin per milli- (b) Calculate the azlocillin content of liter. the single-dose vial as follows: (iv) Preparation of sample solutions— (a) Product not packaged for dispensing A× P × d Milligrams of azlocillin per vial = u s (micrograms of azlocillin per milligram). × Dissolve and dilute an accurately As 1, 000 weighed portion of the sample with suf- where: ficient distilled water to obtain a stock Au=Absorbance of sample solution; solution of 1.0 milligram of azlocillin Ps=Potency of working standard solution per milliliter (estimated). in micrograms per milliliter; (b) Product packaged for dispensing. As=Absorbance of working standard solu- Determine both micrograms of tion; and azlocillin per milligram of the sample d=Dilution factor of the sample. and milligrams of azlocillin per con- (2) Sterility. Proceed as directed in tainer. Use separate containers for § 436.20 of this chapter, using the meth- preparation of each sample solution as od described in paragraph (e)(1) of that described in paragraphs (b)(1)(iv)(b)(1) section. and (2) of this section. (3) Pyrogens. Proceed as directed in (1) Micrograms of azlocillin per milli- § 436.32(b) of this chapter, using a solu- gram. Dissolve and dilute an accurately tion containing 100 milligrams of weighed portion of the sample with suf- azlocillin per milliliter. ficient distilled water to obtain a stock (4) Moisture. Proceed as directed in solution of 1.0 milligram of azlocillin § 436.201 of this chapter, using the titra- per milliliter (estimated). tion procedure and calculations de- (2) Milligrams of azlocillin per con- scribed in paragraph (e)(2) of that sec- tainer. Reconstitute as directed in the tion and preparing the sample as fol- labeling using distilled water in lieu of lows: Weigh the vial. Rapidly transfer a the reconstituting fluid. Then, using a portion of the powder into the titration suitable hypodermic needle and sy- vessel, add the Karl Fischer reagent ringe, remove all of the withdrawable and restopper the vial immediately. contents if it is represented as a single- Reweigh the vial to obtain the sample dose container; or, if the labeling speci- weight. A nitrogen purged glove bag or fies the amount of potency in a given glove box should be used for preparing volume of the resultant preparation, the sample. remove an accurately measured rep- (5) pH. Proceed as directed in § 436.202 resentative portion from each con- of this chapter, using an aqueous solu- tainer. Dilute with distilled water to tion containing 100 milligrams of obtain a stock solution of convenient azlocillin per milliliter. concentration. Further dilute an ali- (6) Specific rotation. Proceed as di- quot of the stock solution with dis- rected in § 436.210 of this chapter, using tilled water to a concentration of 1.0 an aqueous solution containing 10 mil- milligram of azlocillin per milliliter ligrams of azlocillin per milliliter and (estimated). a 1.0-decimeter polarimeter tube. Cal- (v) Calculations—(a) Calculate the culate the specific rotation on an anhy- micrograms of azlocillin per milligram drous basis. of sample as follows: (7) Identity. Proceed as directed in § 436.336 of this chapter. Micrograms of AP× ×100 azlocillin per = u s [47 FR 53348, Nov. 26, 1982, as amended at 50 × × ( ) milligram of sample ACs u100− m FR 1504, Jan. 11, 1985; 55 FR 11582, Mar. 29, 1990] where:
Au=Absorbance of sample solution; § 440.2a Sterile amdinocillin. Ps=Potency of working standard solution (a) Requirements for certification—(1) in micrograms per milliliter; Standards of identity, strength, quality, As=Absorbance of working standard solu- tion; and purity. Sterile amdinocillin is 4- Cu=Milligrams of sample per milliliter of thia-1-azabicyclo[3.2.0]heptane-2-car- sample solution; and boxylic acid, 6-[[(hexahydro-1H-azepin- m=Percent moisture in sample. 1-yl)-methylene]amino]-3,3-dimethyl-7-
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oxo-, [2S-2α,5α,6β)]-. It is so purified and (2) For sterility testing: 25 immediate dried that: containers, collected at regular inter- (i) If the amdinocillin is not vals throughout each filling operation. packaged for dispensing, its (b) Tests and methods of assay—(1) amdinocillin potency is not less than Amdinocillin potency and container con- 950 micrograms and not more than 1,050 tent. Proceed as directed in § 436.353 of micrograms of amdinocillin per milli- this chapter, using ambient tempera- gram on an anhydrous basis. If the ture, an ultraviolet detection system amdinocillin is packaged for dispens- operating at a wavelength of 220 ing, its amdinocillin potency is not less nanometers, a column packed with than 950 micrograms and not more microparticulate (3 to 10 micrometers than 1,050 micrograms of amdinocillin in diameter) reversed phase packing per milligram on an anhydrous basis material such as octadecyl hydro- and also, each container contains not carbon bonded silicas, e.g., a Whatman less than 90 percent and not more than ODS–3 column (25-centimeter column 120 percent of the number of milli- having an inside diameter of 4.6 milli- grams of amdinocillin that it is rep- meters and 5 micrometer particle size resented to contain. or equivalent), a flow rate of 1.0 milli- (ii) It is sterile. liter per minute, and an injection vol- (iii) It is nonpyrogenic. ume of 20 microliters. Reagents, work- (iv) Its moisture content is not more ing standard and sample solutions, sys- than 0.5 percent. tem suitability requirements, and cal- (v) Its pH in an aqueous solution con- culations are as follows: taining 100 milligrams of amdinocillin (i) Reagents—(a) Buffer solution 0.01M per milliliter is not less than 4.0 and pH 5.0. Transfer 1.36 grams of not more than 6.2. monobasic potassium phosphate in suf- (vi) It is crystalline. ficient water to make 1,000 milliliters of solution. Adjust the pH to 5.0 ± 0.1 (vii) It gives a positive identity test with 18N phosphoric acid or 10N sodium for amdinocillin. hydroxide. (2) Labeling. It shall be labeled in ac- (b) Mobile phase. Mix acetonitrile cordance with the requirements of (high-pressure liquid chromatography § 432.5 of this chapter. grade): 0.01M pH 5.0 phosphate buffer (3) Requests for certification; samples. (15:85). In addition to complying with the re- (ii) Working standard and sample solu- quirements of § 431.1 of this chapter, tions—(a) Preparation of working stand- each such request shall contain: ard solution. Prepare the working (i) Results of tests and assays on the standard solution fresh before injection batch for amdinocillin potency, and if by dissolving an accurately weighed packaged for dispensing, amdinocillin portion of the amdinocillin working potency and container content, steril- standard with sufficient distilled water ity, pyrogens, moisture, pH, crystallin- to obtain a stock solution containing ity, and identity. approximately 100 micrograms of (ii) Samples, if required by the Direc- amdinocillin per milliliter. tor, Center for Drug Evaluation and (b) Preparation of sample solutions—(1) Research: Product not packaged for dispensing (a) If it is packaged for repacking or (micrograms of amdinocillin per milli- for use in the manufacture of another gram). Dissolve an accurately weighed drug: portion of the sample with sufficient (1) For all tests except sterility: 10 distilled water to obtain a solution packages, each containing approxi- containing 100 micrograms of mately 300 milligrams. amdinocillin per milliliter (estimated). (2) For sterility testing: 20 packages, (2) Product packaged for dispensing. each containing approximately 300 mil- Determine both micrograms of ligrams. amdinocillin per milligram of the sam- (b) If it is packaged for dispensing: ple and milligrams of amdinocillin per (1) For all tests except sterility: A container. Use separate containers for minimum of 15 immediate containers. preparation of each sample solution as
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described in paragraphs (b)(1)(ii)(b)(2) Ps=Amdinocillin activity in the amdinocillin (i) and (ii) of this section. working standard solution in (i) Micrograms of amdinocillin per milli- micrograms per milliliter; gram. Dissolve an accurately weighed Cu=Milligrams of sample per milliliter of sample solution; and portion of the sample with sufficient m=Percent moisture content of the sample. distilled water to obtain a solution containing 100 micrograms of (b) Calculate the amdinocillin con- amdinocillin per milliliter (estimated). tent of the container as follows: (ii) Milligrams of amdinocillin per con- A× P × d tainer. Reconstitute the sample as di- Milligrams of amdinocillin = u s rected in the labeling. Then, using a per container × suitable hypodermic needle and sy- As 1, 000 ringe, remove all of the withdrawable where: contents if it is represented as a single- Au=Area of the amdinocillin peak in the dose container; or, if the labeling speci- chromatogram of the sample (at a reten- tion time equal to that observed for the fies the amount of potency in a given standard); volume of the resultant preparation, As=Area of the amdinocillin peak in the remove an accurately measured rep- chromatogram of the amdinocillin work- resentative portion from each con- ing standard: tainer. Dilute the solution thus ob- Ps=Amdinocillin activity in the amdinocillin tained with sufficient distilled water to working standard solution in obtain a solution containing 100 micrograms per milliliter; and micrograms of amdinocillin per milli- d=Dilution factor of the sample. liter (estimated). (2) Sterility. Proceed as directed in (iii) System suitability requirements—(a) § 436.20 of this chapter, using the meth- Tailing factor. The tailing factor (T) is od described in paragraph (e)(1) of that satisfactory if it is not more than 2.5 at section. 5 percent of peak height: (3) Pyrogens. Proceed as directed in (b) Efficiency of the column. The effi- § 436.32(a) of this chapter, using a solu- ciency of the column (n) is satisfactory tion containing 40 milligrams of if it is greater than 1,500 theoretical amdinocillin per milliliter. plates. (4) Moisture. Proceed as directed in (c) Resolution factor. The resolution § 436.201 of this chapter. factor (R) between the peak for (5) pH. Proceed as directed in § 436.202 amdinocillin and its nearest eluting of this chapter, using an aqueous solu- impurity is satisfactory if it is not less tion containing 100 milligrams of than 2.5. amdinocillin per milliliter. (d) Coefficient of variation. The coeffi- (6) Crystallinity. Proceed as directed cient of variation (SR in percent) of five in § 436.203(a) of this chapter. replicate injections is satisfactory if it (7) Identity. Proceed as directed in is not more than 2.0 percent. § 436.211 of this chapter, using a potas- sium bromide disc containing 1 milli- If the system suitability parameters gram of amdinocillin in 300 milligrams have been met, then proceed as de- of potassium bromide, prepared as de- scribed in § 436.353(b) of this chapter. scribed in paragraph (b)(l) of that sec- (iv) Calculations. (a) Calculate the tion. micrograms of amdinocillin per milli- gram of sample as follows: [50 FR 7765, Feb. 26, 1985; 50 FR 10220, Mar. 14, 1985; 50 FR 18243, Apr. 30, 1985; 55 FR 11582, Mar. 29, 1990] Micrograms of A× P × 100 = u s amdinocillin per § 440.3 Amoxicillin trihydrate. AC× ×()100 − m milligram s u (a) Requirements for certification— (1) where: Standards of identity, strength, quality, Au=Area of the amdinocillin peak in the and purity. Amoxicillin trihydrate is chromatogram of the sample (at a reten- the trihydrate form of D( ) -amino-p- tion time equal to that observed for the ¥ a standard); hydroxybenzyl penicillin. It is so puri- fied and dried that: As=Area of the amdinocillin peak in the chromatogram of the amdinocillin work- (i) Its potency is not less than 900 ing standard; micrograms and not more than 1,050
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micrograms of amoxicillin per milli- amoxicillin content, concordance, crys- gram on an anhydrous basis. tallinity, and identity. (ii) [Reserved] (ii) Samples required: 12 packages, (iii) Its moisture content is not less each containing approximately 500 mil- than 11.5 percent and not more than ligrams. 14.5 percent. (b) Tests and methods of assay—(1) Po- (iv) Its pH in an aqueous solution tency. Use any of the following meth- containing 2 milligrams per milliliter ods; however, the results obtained from is not less than 3.5 and not more than the iodometric assay shall be conclu- 6.0. sive: (v) Its amoxicillin content is not less (i) Microbiological agar diffusion assay. than 90 percent on an anhydrous basis. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay (vi) The acid-base titration concord- as follows: Dissolve an accurately ance is such that the difference be- weighed portion of the sample in suffi- tween the percent amoxicillin content cient sterile distilled water to give a when determined by nonaqueous acid stock solution containing 1.0 milligram titration and by nonaqueous base titra- of amoxicillin per milliliter (esti- tion is not more than 6. The potency- mated). Further dilute an aliquot of acid titration concordance is such that the stock solution with solution 3 to the difference between the potency the reference concentration of 0.1 value divided by 10 and the percent microgram of amoxicillin per milliliter amoxicillin content of the sample de- (estimated). termined by the nonaqueous acid titra- (ii) Iodometric assay. Proceed as di- tion is not more than 6. The potency- rected in § 436.204 of this chapter, ex- base titration concordance is such that cept in paragraph (d) of that section, the difference between the potency add 3 drops of 1.2N hydrochloric acid to value divided by 10 and the percent both the sample and working standard amoxicillin content of the sample de- solutions after the addition of 0.01N io- termined by the nonaqueous base titra- dine solution. tion is not more than 6. (iii) Hydroxylamine colorimetric assay. (vii) It is crystalline. Proceed as directed in § 436.205 of this (viii) It gives a positive identity test chapter. for amoxicillin trihydrate. (2) [Reserved] (2) Labeling. In addition to the label- (3) Moisture. Proceed as directed in ing requirements of § 432.5 of this chap- § 436.201 of this chapter. ter, each package shall bear on its out- (4) pH. Proceed as directed in § 436.202 side wrapper or container and the im- of this chapter, using an aqueous solu- mediate container the following state- tion containing 2 milligrams per milli- ment: ‘‘For use in the manufacture of liter. nonparenteral drugs only’’. (5) Amoxicillin content. Proceed as di- (3) Requests for certification; samples. rected in § 436.213 of this chapter using In addition to complying with the re- both the titration procedures described quirements of § 431.1 of this chapter, in paragraphs (e) (1) and (2) of that sec- each such request shall contain: tion. Calculate the percent amoxicillin (i) Results of tests and assays on the content as follows: batch for potency, moisture, pH, (i) Acid titration.
(A− B)(normality of lithium methoxide reagent) (365.4)(100)(100) Percent amoxicillin content = (Weight of sample in milligrams )(100 − m )
where: B=Milliliters of lithium methoxide reagent A=Milliliters of lithium methoxide reagent used in titrating the blank. used in titrating the sample. m=Percent moisture content of the sample.
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Calculate the difference between the po- (ii) Base titration. tency and the amoxicillin content as follows:
Potency in micrograms per milligram percent Difference = − amoxicillin 10 content
(A− B)(normality of perchloric acid reagent) (365.4)(100)(100) Percent amoxicillin content = (Weight of sample in milligrams )(100 − m )
where: (vi) The acid-base titration concord- A=Milliliters of perchloric acid reagent ance is such that the difference be- used in titrating the sample. tween the percent ampicillin content B=Milliliters of perchloric acid reagent used in titrating the blank. when determined by nonaqueous acid m=Percent moisture content of the sample. titration and by nonaqueous base titra- Calculate the difference between the po- tion is not more than six. The potency- tency and the amoxicillin content as follows: acid titration concordance is such that the difference between the potency Potency in micrograms value divided by 10 and the percent am- per milligram percent Difference = − amoxicillin picillin content of the sample deter- 10 content mined by the nonaqueous acid titration (6) Crystallinity. Proceed as directed is not more than six. The potency-base in § 436.203(a) of this chapter. titration concordance is such that the (7) Identity. Proceed as directed in difference between the potency value § 436.211 of this chapter, using a 0.5 per- divided by 10 and the percent ampi- cent potassium bromide disc prepared cillin content of the sample determined as described in paragraph (b)(1) of that by the nonaqueous base titration is not section. more than six. [39 FR 34032, Sept. 23, 1974, as amended at 46 (vii) It is crystalline. FR 16682, Mar. 13, 1981; 49 FR 3458, Jan. 27, (viii) It gives a positive identity test 1984; 50 FR 19918, May 13, 1985] for ampicillin. (2) Labeling. In addition to the label- § 440.5 Ampicillin. ing requirements prescribed by (a) Requirements for certification—(1) § 432.5(b) of this chapter, each package Standards of identity, strength, quality, shall bear on its outside wrapper or and purity. Ampicillin is 6-[D-a- container and the immediate container aminobenzyl] penicillin. It is a white the following statement, ‘‘For use in powder. It is so purified and dried that: the manufacture of nonparenteral (i) It contains not less than 900 drugs only’’. micrograms and not more than 1,050 (3) Requests for certification; samples. micrograms of ampicillin per milli- In addition to complying with the re- gram on an anhydrous basis. quirements of § 431.1 of this chapter, (ii) [Reserved] (iii) Its loss on drying is not more each such request shall contain: than 2.0 percent. (i) Results of tests and assays on the (iv) Its pH in an aqueous solution batch for potency, loss on drying, pH, containing 10 milligrams per milliliter ampicillin content, concordance, crys- is not less than 3.5 and not more than tallinity, and identity. 6.0. (ii) Samples required: 10 packages, (v) Its ampicillin content is not less each containing approximately 300 mil- than 90 percent on an anhydrous basis. ligrams.
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(b) Tests and methods of assay—(1) Po- cept in paragraph (d) of that section, tency. Assay for potency by any of the add 3 drops of 1.2N hydrochloric acid to following methods; however, the re- both the sample and working standard sults obtained from the micro- solutions after the addition of 0.01N io- biological agar diffusion assay shall be dine solution. conclusive. (iii) Hydroxylamine colorimetric assay. (i) Microbiological agar diffusion assay. Proceed as directed in § 436.205 of this Proceed as directed in § 436.105 of this chapter. chapter, preparing the sample for assay (2) [Reserved] as follows: Dissolve an accurately (3) Loss on drying. Proceed as directed weighed portion of the sample in suffi- in § 436.200(a) of this chapter. cient sterile distilled water to give a (4) pH. Proceed as directed in § 436.202 stock solution containing 0.1 milligram of this chapter, using an aqueous solu- of ampicillin per milliliter (estimated). tion containing 10 milligrams per mil- Further dilute an aliquot of the stock liliter. solution with 0.1M potassium phos- (5) Ampicillin content. Proceed as di- phate buffer, pH 8.0 (solution 3), to the rected in § 436.213 of this chapter, using reference concentration of 0.1 both the titration procedures described microgram of ampicillin per milliliter in paragraphs (e) (1) and (2) of that sec- (estimated). tion. Calculate the percent ampicillin (ii) Iodometric assay. Proceed as di- content as follows: rected in § 436.204 of this chapter, ex- (i) Acid titration.
(A− B)(normality of lithium methoxide reagent) (349.4)(100)(100) Percent ampicillin content = (Weight of sample in milligrams )(100 − m )
where: A=Milliliters of lithium methoxide reagent Potency in micrograms percent used in titrating the sample; per milligram − B=Milliliters of lithium methoxide reagent Difference = ampicillin used in titrating the blank; 10 content m=Percent moisture content of the sample. (ii) Base titration. Calculate the difference between the po- tency and the ampicillin content as follows:
(A− B)(normality of perchloric acid reagent) (349.4)(100) Percent ampicillin content = (Weight of sample in milligrams )(100 − m )
where: A=Milliliters of perchloric acid reagent Potency in micrograms used in titrating the samples; percent B=Milliliters of perchloric acid reagent per milligram Difference = − ampicillin used in titrating the blank; 10 m=Percent moisture content of the sample. content Calculate the difference between the po- (6) Crystallinity. Proceed as directed tency and the ampicillin content as follows: in § 436.203(a) of this chapter. (7) Identity. Proceed as directed in § 436.211 of this chapter, using a 0.5 per- cent potassium bromide disc, prepared
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as described in paragraph (b)(1) of that (3) Requests for certification; samples. section. In addition to complying with the re- quirements of § 431.1 of this chapter, [39 FR 18976, May 30, 1974, as amended at 41 FR 42649, Sept. 28, 1976; 46 FR 16682, Mar. 13, each such request shall contain: 1981; 49 FR 3458, Jan. 27, 1984; 50 FR 19918, (i) Results of tests and assays on the May 13, 1985] batch for potency, loss on drying, pH, ampicillin content, concordance, crys- § 440.7 Ampicillin trihydrate. tallinity, and identity. (a) Requirements for certification—(1) (ii) Samples required: 10 packages Standards of identity, strength, quality, each containing approximately 300 mil- and purity. Ampicillin trihydrate is the ligrams. trihydrate form of D(¥)a-amino-benzyl (b) Tests and methods of assay—(1) Po- penicillin. It is so purified and dried tency. Use any of the following meth- that: ods; however, the results obtained from (i) It contains not less than 900 the microbiological agar diffusion micrograms and not more than 1,050 assay shall be conclusive. micrograms of ampicillin per milli- (i) Microbiological agar diffusion assay. gram on an anhydrous basis. Proceed as directed in § 436.105 of this (ii) [Reserved] chapter, preparing the sample for assay (iii) Its loss on drying is not less than as follows: Dissolve an accurately 12 percent and not more than 15 per- weighed portion of the sample in suffi- cent. cient sterile distilled water to give a (iv) Its pH in an aqueous solution stock solution containing 0.1 milligram containing 10 milligrams per milliliter of ampicillin per milliliter (estimated). is not less than 3.5 and not more than Further dilute an aliquot of the stock 6.0. solution with 0.1M potassium phos- (v) Its ampicillin content is not less phate buffer, pH 8.0 (solution 3), to the than 90 percent on an anhydrous basis. reference concentration of 0.1 (vi) The acid-base titration concord- microgram of ampicillin per milliliter ance is such that the difference be- (estimated). tween the percent ampicillin content when determined by nonaqueous acid (ii) Iodometric assay. Proceed as di- titration and by nonaqueous base titra- rected in § 436.204 of this chapter, ex- tion is not more than 6. The potency- cept in paragraph (d) of that section, acid titration concordance is such that add 3 drops of 1.2N hydrochloric acid to the difference between the potency both the sample and working standard value divided by 10 and the percent am- solutions after the addition of 0.01N io- picillin content of the sample deter- dine solution. mined by the nonaqueous acid titration (iii) Hydroxylamine colorimetric assay. is not more than 6. The potency-base Proceed as directed in § 436.205 of this titration concordance is such that the chapter. difference between the potency value (2) [Reserved] divided by 10 and the percent ampi- (3) Loss on drying. Proceed as directed cillin content of the sample determined in § 436.200(a) of this chapter. by the nonaqueous base titration is not (4) pH. Proceed as directed in § 436.202 more than 6. of this chapter, using an aqueous solu- (vii) It is crystalline. tion containing 10 milligrams per mil- (viii) It gives a positive identity test liliter. for ampicillin trihydrate. (5) Ampicillin content. Proceed as di- (2) Labeling. In addition to the label- rected in § 436.213 of this chapter, using ing requirements prescribed by both the titration procedures described § 432.5(b) of this chapter, this drug shall in paragraphs (e) (1) and (2) of that sec- be labeled ‘‘ampicillin’’ and each pack- tion. Calculate the percent ampicillin age shall bear on its outside wrapper or content as follows: container and the immediate container (i) Acid titration. the following statement ‘‘For use in the manufacture of nonparenteral Percent ampicillin content=[(A¥B) (nor- drugs only’’. mality of lithium methoxide reagent) (349.4)
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(100) (100)]/[(Weight of sample in milligrams) is not less than 3.5 and not more than (100¥m)], 6.0. where: (vii) Its ampicillin content is not less A=Milliliters of lithium methoxide reagent than 90 percent on an anhydrous basis. used in titrating the sample; (viii) The acid-base titration con- B=Milliliters of lithium methoxide reagent cordance is such that the difference be- used in titrating the blank; tween the percent ampicillin content m=Percent moisture content of the sample. when determined by nonaqueous acid Calculate the difference between the po- titration and by nonaqueous base titra- tency and the ampicillin content as follows: tion is not more than 6. The potency- Difference=(Potency in micrograms per mil- acid titration concordance is such that ligram/10)¥percent ampicillin content. the difference between the potency value divided by 10 and the percent am- (ii) Base titration. picillin content of the sample deter- Percent ampicillin content=[(A¥B) (normal- mined by the nonaqueous acid titration ity of perchloric acid reagent) (349.4) (100) is not more than 6. The potency-base (100)]/[(Weight of sample in milligrams) titration concordance is such that the (100¥m)], difference between the potency value where: divided by 10 and the percent ampi- A=Milliliters of perchloric acid reagent used cillin content of the sample determined in titrating the samples; by the nonaqueous base titration is not B=Milliliters of perchloric acid reagent used more than 6. in titrating the blank; (ix) It is crystalline. m=Percent moisture content of the sample. (x) It gives a positive identity test Calculate the difference between the po- for ampicillin trihydrate. tency and the ampicillin content as follows: (2) Labeling. In addition to the label- Difference=(Potency in micrograms per mil- ing requirements prescribed by ligram/10)¥percent ampicillin content. § 432.5(b) of this chapter, this drug shall (6) Crystallinity. Proceed as directed be labeled ‘‘ampicillin.’’ in § 436.203(a) of this chapter. (3) Requests for certification; samples. (7) Identity. Proceed as directed in In addition to complying with the re- § 436.211 of this chapter, using an 0.5 quirements of § 431.1 of this chapter, percent potassium bromide disc, pre- each such request shall contain: pared as described in paragraph (b)(1) (i) Results of tests and assays on the of that section. batch for potency, sterility, pyrogens, loss on drying, pH, ampicillin content, [39 FR 18976, May 30, 1974, as amended at 46 concordance, crystallinity, and iden- FR 16683, Mar. 13, 1981; 49 FR 3458, Jan. 27, tity. 1984; 50 FR 19918, May 13, 1985] (ii) Samples required: (a) For all tests except sterility: 10 § 440.7a Sterile ampicillin trihydrate. packages, each containing approxi- (a) Requirements for certification—(1) mately 300 milligrams. Standards of identity, strength, quality, (b) For sterility testing: 20 packages, and purity. Ampicillin trihydrate is the each containing approximately 300 mil- trihydrate form of D(-)α-aminobenzyl ligrams. penicillin. It is so purified and dried (b) Tests and methods of assay—(1) Po- that: tency. Use any of the following meth- (i) It contains not less than 900 ods; however, the results obtained from micrograms and not more than 1,050 the microbiological agar diffusion micrograms of ampicillin per milli- assay shall be conclusive: gram on an anhydrous basis. (i) Microbiological agar diffusion assay. (ii) It is sterile. Proceed as directed in § 436.105 of this (iii) It is nonpyrogenic. chapter, preparing the sample for assay (iv) [Reserved] as follows: Dissolve an accurately (v) Its loss on drying is not less than weighed portion of the sample in suffi- 12 percent and not more than 15 per- cient sterile distilled water to give a cent. stock solution containing 0.1 milligram (vi) Its pH in an aqueous solution of ampicillin per milliliter. Further di- containing 10 milligrams per milliliter lute an aliquot of the stock solution
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with 0.1M potassium phosphate buffer, (i) Acid titration. pH 8.0 (solution 3) to the reference con- Percent ampicillin content=[(A¥B) (normal- centration of 0.1 microgram of ampi- ity of lithium methoxide reagent) (349.4) cillin per milliliter (estimated). (100) (100)]/[(Weight of sample in milli- (ii) Iodometric assay. Proceed as di- grams) (100¥m)]. rected in § 436.204 of this chapter, ex- where: cept in paragraph (d) of that section, A=Milliliters of lithium methoxide reagent add 3 drops of 1.2N hydrochloric acid to used in titrating the sample; both the sample and working standard B=Milliliters of lithium methoxide reagent used in titrating the blank; solutions after the addition of 0.01N io- m=Percent moisture content of the sample. dine solution. Calculate the difference between the po- (iii) Hydroxylamine colorimetric assay. tency and the ampicillin content as follows: Proceed as directed in § 436.205 of this Difference=(Potency in micrograms per mil- chapter. ligram/10)¥percent ampicillin content. (2) Sterility. Proceed as directed in § 436.20 of this chapter, using the meth- (ii) Base titration. od described in paragraph (e)(1) of that Percent ampicillin content=[(A¥B) (normal- section, except in lieu of paragraph ity of perchloric acid reagent) (349.4) (100) (e)(1)(i)(a), prepare the sample for test (100)]/[(Weight of sample in milligrams) (100 m)]. as follows: From each of 10 immediate ¥ containers, aseptically transfer ap- where: proximately 300 milligrams of sample A=Milliliters of perchloric acid reagent used in titrating the samples; into a sterile 500-milliliter Erlenmeyer B=Milliliters of perchloric acid reagent flask containing approximately 400 used in titrating the blank; milliliters of diluting fluid D. Add at m=Percent moisture content of the sample. least 200,000 Levy units 1 of penicillin- Calculate the difference between the po- ase. Repeat the process using 10 addi- tency and the ampicillin content as follows: tional containers. Swirl both of the Difference=(Potency in micrograms per mil- stoppered flasks to completely solu- ligram/10)¥percent ampicillin content. bilize the suspension prior to filtration (8) Crystallinity. Proceed as directed and proceed as directed in paragraph in § 436.203(a) of this chapter. (e)(1)(ii) of that section. (9) Identity. Proceed as directed in (3) Pyrogens. Proceed as directed in § 436.211 of this chapter, using a 0.5 per- § 436.32(f) of this chapter, using a solu- cent potassium bromide disc, prepared tion containing 20 milligrams of ampi- as described in paragraph (b)(1) of that cillin per milliliter. section. (4) [Reserved] [39 FR 18976, May 30, 1974, as amended at 46 (5) Loss on drying. Proceed as directed FR 16683, Mar. 13, 1981; 49 FR 3458, Jan. 27, in § 436.200(a) of this chapter. 1984; 50 FR 19918, May 13, 1985] (6) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solu- § 440.8 Bacampicillin hydrochloride. tion containing 10 milligrams per mil- (a) Requirements for certification—(1) liliter. Standards of identity, strength, quality, (7) Ampicillin content. Proceed as di- and purity. Bacampicillin hydro- rected in § 436.213 of this chapter, using chloride is the hydrochloride salt of both the titration procedures described the 1–ethoxycarbonyloxyethyl ester of in paragraph (e)(1) and (2) of that sec- ampicillin. It is a white powder. It is so tion. Calculate the ampicillin content purified and dried that: (i) Its potency is not less than 623 as follows: micrograms and not more than 727 micrograms of ampicillin per milli- 1 One Levy unit of penicillinase inactivates gram on an ‘‘as is’’ basis. 59.3 units of penicillin G in 1 hour at 25° C. (ii) [Reserved] and at a pH of 7.0 in a phosphate buffered so- (iii) Its moisture content is not more lution of a pure alkali salt of penicillin G than 1.0 percent. when the substrate is in sufficient con- (iv) Its pH in an aqueous solution centration to maintain a zero order reaction. containing 20 milligrams per milliliter
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is not less than 3.0 and not more than (4) pH. Proceed as directed in § 436.202 4.5. of this chapter, using an aqueous solu- (v) It passes the identity test. tion containing 20 milligrams per mil- (2) Labeling. It shall be labeled in ac- liliter. cordance with the requirements of (5) Identity. Proceed as directed in § 432.5 of this chapter. § 436.330 of this chapter. (3) Requests for certification; samples. [46 FR 25603, May 8, 1981, as amended at 50 In addition to complying with the re- FR 19918, May 13, 1985] quirements of § 431.1 of this chapter, each such request shall contain: § 440.9a Sterile ampicillin sodium. (i) Results of tests and assays on the (a) Requirements for certification— (1) batch for potency, moisture, pH, and Standards of identity, strength, quality, identity. and purity. Sterile ampicillin sodium is (ii) Samples required: 10 packages, the sodium salt of D(-)a-aminobenzyl each containing approximately 300 mil- penicillin. It is so purified and dried ligrams. that: (b) Tests and methods of assay—(1) Po- (i) Its potency is not less than 845 tency. Use either of the following meth- micrograms and not more than 988 ods; however, the results obtained from micrograms of ampicillin per milli- the iodometric assay shall be conclu- gram on an anhydrous basis. If it is sive. packaged for dispensing, it contains (i) Hydroxylamine colorimetric assay. not less than 90 percent and not more Proceed as directed in § 442.40(b)(1)(ii) than 115 percent of the number of milli- of this chapter, except: grams of ampicillin that it is rep- (a) Buffer. In lieu of the buffer de- resented to contain. scribed in § 442.40(b)(1)(ii) (b)(2) of this (ii) It is sterile. chapter, use the buffer prepared as fol- (iii) It is nonpyrogenic. lows: Dissolve 200 grams of primary (iv) [Reserved] standard tris (hydroxymethyl) (v) Its moisture content is not more aminomethane in sufficient distilled than 2 percent. water to make 1 liter. Filter before use. (vi) Its pH in an aqueous solution (b) Preparation of working standard so- containing 10 milligrams per milliliter lution. Use the ampicillin working is not less than 8.0 and not more than standard. Dissolve and dilute an accu- 10.0. rately weighed portion of the ampi- (vii) Its ampicillin content is not less cillin working standard in sufficient than 84.5 percent, except if the high- distilled water to obtain a concentra- performance liquid chromatographic tion of 1.25 milligrams of ampicillin per (HPLC) assay method is used, then the milliliter. ampicillin content standard is not ap- (c) Preparation of sample solution. Dis- plicable. solve and dilute an accurately weighed (viii) The potency-base titration con- portion of the sample with sufficient cordance is such that the difference be- distilled water to obtain a concentra- tween the potency value divided by 10 tion of 1.25 milligrams of ampicillin per and the percent ampicillin content of milliliter (estimated). the sample determined by the nonaque- (d) Calculations. Calculate the ampi- ous base titration is not more than 6, cillin content in micrograms per milli- except if the HPLC assay method is gram as follows: used, then the concordance standard is not applicable. Ampicillin content in AP× = u a (ix) It is crystalline. micrograms per milligram AW× (x) It passes the identity test for am- s u picillin sodium. (ii) Iodometric assay. Proceed as di- (2) Labeling. It shall be labeled in ac- rected in § 436.204 of this chapter, ex- cordance with the requirements of cept use the ampicillin working stand- § 432.5 of this chapter. ard. (3) Requests for certification; samples. (2) [Reserved] In addition to complying with the re- (3) Moisture. Proceed as directed in quirements of § 431.1 of this chapter, § 436.201 of this chapter. each such request shall contain:
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(i) Results of tests and assays on the ent to give a stock solution as specified batch for potency, sterility, pyrogens, above. moisture, pH, ampicillin content, con- (ii) Assay procedure. Use any of the cordance, crystallinity, and identity. following methods; however, the re- (ii) Samples required: sults obtained from the micro- (a) If the batch is packaged for re- biological agar diffusion assay shall be packing or for use in manufacturing conclusive. another drug: (a) Microbiological agar diffusion (1) For all tests except sterility: 10 assay. Proceed as directed in § 436.105 of packages, each containing approxi- this chapter, diluting an aliquot of the mately 300 milligrams. stock solution with 0.1M potassium (2) For sterility testing: 20 packages phosphate buffer, pH 8.0 (solution 3), to each containing approximately 300 mil- the reference concentration of 0.1 ligrams. microgram of ampicillin per milliliter (b) If the batch is packaged for dis- (estimated). pensing: (b) Iodometric assay. Proceed as di- (1) For all tests except sterility: A rected in § 436.204 of this chapter, ex- minimum of 15 immediate containers cept in paragraph (d) of that section, or if each vial contains 250 milligrams add 3 drops of 1.2N hydrochloric acid to or less of ampicillin a minimum of 24 both the sample and working standard vials. solutions after the addition of 0.01N io- (2) For sterility testing: 20 immediate dine solution. containers, collected at regular inter- vals throughout each filling operation. (c) Hydroxylamine colorimetric assay. (b) Tests and methods of assay—(1) Po- Proceed as directed in § 436.205 of this tency—(i) Sample preparation. Dissolve chapter. an accurately weighed sample in suffi- (d) HPLC assay. Proceed as directed cient sterile distilled water to give a in § 436.216 of this chapter, using ambi- stock solution containing 0.1 milligram ent temperature, an ultraviolet detec- of ampicillin per milliliter (estimated), tion system operating at a wavelength for the microbiological agar diffusion of 254 nanometers, a 4-millimeter X 5- assay and in 1.0 percent potassium centimeter guard column containing phosphate buffer, pH 6.0 (solution 1), 40- to 60-micrometer diameter packing for the iodometric assay or for the hy- material as described for the analytical droxylamine colorimetric assay to give column, a 4-millimeter X 30-centimeter a stock solution of convenient con- analytical column packed with micro- centration. For the high-performance particulate (3 to 10 micrometers in di- liquid chromatographic assay (HPLC), ameter) reversed phase packing mate- transfer an accurately weighed portion rial such as octadecyl hydrocarbon of ampicillin, equivalent to about 100 bonded silica, and a flow rate of about milligrams of anhydrous ampicillin, to 2.0 milliliters per minute. Separately a 100-milliliter volumetric flask. Add inject equal volumes (about 20 micro- about 75 milliliters of diluent (prepared liters) of the working standard prepa- as described in paragraph ration and the sample solution into the (b)(1)(ii)(d)(1)(ii) of this section), shake chromatograph, record the chromato- and sonicate, if necessary, to achieve gram, and measure the responses for complete dissolution. Also, if it is the major peaks. Reagents, working packaged for dispensing, reconstitute standard and resolution test solution, as directed in the labeling. Then using system suitability requirements, and a suitable hypodermic needle and sy- calculations are as follows: ringe, remove all of the withdrawable (1) Reagents—(i) Mobile phase. Prepare contents if it is represented as a single- a suitably filtered and degassed mix- dose container, or if the labeling speci- ture of water, acetonitrile, 1.0M fies the amount of potency in a given monobasic potassium phosphate, and volume of the resultant preparation, 1.0N acetic acid (909:80:10:1). remove an accurately measured rep- (ii) Diluent. Mix 10 milliliters of 1.0M resentative portion from each con- monobasic potassium and 1 milliliter tainer. Dilute with either sterile dis- of 1.0N acetic acid, dilute with water to tilled water, solution 1, or HPLC dilu- make 1,000 milliliters, and mix.
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(2) Preparation of working and internal (4) Calculations. Calculate the standard solutions—(i) Working standard micrograms of ampicillin per milli- solution. Dissolve a portion of ampi- gram of sample as follows: cillin working standard, accurately weighed, in the diluent to obtain a so- Micrograms of × × APu s 100 lution having a known concentration ampicillin per = × × − of about 1 milligram per milliliter. milligram As C u ()100 m Shake and sonicate, if necessary, to where: achieve complete dissolution. Use this Au=Area of the ampicillin peak in the chro- solution promptly after preparation. matogram of the sample (at a retention (ii) Resolution test solution. Dissolve time equal to that observed for the caffeine in working standard solution standard); As=Area of the ampicillin peak in the chro- to obtain a solution containing about 1 matogram of the ampicillin working milligram per milliliter. standard; (3) System suitability requirements—(i) Ps=Ampicillin activity in the ampicillin Tailing factor. The tailing factor (T) is working standard solution in satisfactory if it is not more than 1.4 at micrograms per milliliter; Cu=Milligrams of sample per milliliter of 5 percent of peak height. sample solution; and (ii) Resolution. The resolution (R) be- m=Percent moisture content of the sample. tween the caffeine and the ampicillin (2) Sterility. Proceed as directed in peaks is satisfactory if it is not less § 436.20 of this chapter, using the meth- than 2.0. The relative retention times od described in paragraph (e)(1) of that are about 2.0 for caffeine and 1.0 for section. ampicillin. (3) Pyrogens. Proceed as directed in (iii) Coefficient of variation (relative § 436.32(b) of this chapter, using a solu- standard deviation). The coefficient of tion containing 20 milligrams of ampi- variation (SR in percent) of 5 replicate cillin per milliliter. injections is satisfactory if it is not (4) [Reserved] more than 2.0 percent. (5) Moisture. Proceed as directed in If the system suitability requirements § 436.201 of this chapter. have been met, then proceed as de- (6) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solu- scribed in § 436.216(b) of this chapter. tion containing 10 milligrams of ampi- Alternate chromatographic conditions cillin per milliliter. are acceptable provided reproducibility (7) Ampicillin content. Proceed as di- and resolution are comparable to the rected in § 436.213 of this chapter, using system. However, the sample prepara- the titration procedure described in tion described in paragraph (b)(1)(i) of paragraph (e)(2) of that section. Cal- this section should not be changed. culate the ampicillin content as follow
(A− B)(normality of perchloric acid reagent) (174.7)(100)(100) Percent ampicillin content = (Weight of sample in milligrams)(100− m )
where: m=Percent moisture content of the sample. A=Milliliters of perchloric acid reagent Calculate the difference between the po- used in titrating the sample; tency and the ampicillin content as follows: B=Milliliters of perchloric acid reagent used in titrating the blank;
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Potency in micrograms per milligram Difference = − percent ampicillin content 10
(8) Crystallinity. Proceed as directed Lysine content—(a) Equipment. Amino in § 436.203(a) of this chapter. acid analyzer capable of: (9) Identity. Proceed as directed in (1) Separating the hydrolysis prod- § 436.211 of this chapter, using the ucts of benzylpenicilloyl polylysine method described in paragraph (b)(2) of into discrete components by means of that section. an ion-exchange column. [39 FR 18976, May 30, 1974, as amended at 41 (2) Mixing the separated amino acid FR 10886, Mar. 15, 1976; 41 FR 42649, Sept. 28, components with a ninhydrin reagent 1976; 42 FR 59857, Nov. 22, 1977; 46 FR 16683, and promoting the reaction in a coil at Mar. 13, 1981; 49 FR 3458, Jan. 27, 1984; 50 FR elevated temperatures. 19918, May 13, 1985; 52 FR 42288, Nov. 4, 1987; (3) Quantitating the ninhydrin posi- 52 FR 45281, Nov. 25, 1987; 54 FR 47204, Nov. 13, tive materials by means of a suitable 1989] colorimeter and recorder. § 440.10 Benzylpenicilloyl-polylysine (b) Reagents—(1) Citrate buffer: Dis- concentrate. solve and dilute 19.69 grams of sodium (a) Requirements for certification— (1) citrate dihydrate, 16.5 milliliters of hy- Standards of identity, strength, quality, drochloric acid, 0.1 milliliter of and purity. Benzylpenicilloyl- pentachlorophenol, 5 milliliters of polylysine concentrate is a pale yellow thiodiglycol in 900 milliliters of dis- to dark yellow aqueous solution of tilled water; adjust to a pH of 2.2 and benzylpenicilloyl e substituted poly-L- dilute to 1 liter with distilled water. lysine. It contains one or more suitable (2) Calibration mixture: Dissolve and and harmless buffers. It is so purified dilute equal molar amounts of ammo- that: nia, and the L form of lysine in the cit- (i) It contains not less than 50 per- rate buffer to result in final concentra- cent and not more than 70 percent tions of 2.5 × 10¥ 4M for each. benzylpenicilloyl substitution on the (c) Preparation of standard and sample polylysine. solutions—(1) Standard solution (ii) The benzylpenicilloyl concentra- (standard lysine solution (2.5× 10¥4 M)). tion is not less than 1.25×10¥ 2M and Transfer an accurately weighed portion not more than 2.0×10¥ 2M. of 54.8 milligrams of lysine (iii) The penamaldate concentration dihydrochloride to a 100-milliliter volu- is not more than 6.0×10¥ 4M. metric flask. Dissolve and dilute to (iv) The penicillenate concentration mark with citrate buffer. Make an ac- is not more than 2.0×10¥ 4M. curate tenfold dilution of this solution (v) Its pH is not less than 6.5 and not with citrate buffer. The resulting more than 8.5. standard solution is 2.5×10¥4 M with re- (2) Labeling. It shall be labeled in ac- spect to lysine. cordance with the requirements of (2) Sample solution. Dilute 1 milliliter § 432.5 of this chapter. of the benzylpenicilloyl-polylysine con- (3) Requests for certification; samples. centrate to 10 milliliters with distilled In addition to complying with the re- water. Mix 1 milliliter of the diluted quirements of § 431.1 of this chapter, solution with 1.5 milliliters of 6.0N hy- each such request shall contain: drochloric acid and seal in an ampule (i) Results of tests and assays on the under nitrogen. Hydrolyze the solution batch for percent benzylpenicilloyl for 22 hours at 110° C. Transfer the con- substitution, benzylpenicilloyl content, tents of the ampule quantitatively into penamaldate content, penicillenate a 50-milliliter round bottom flask and content, and pH. dry by rotary evaporation. Wash the (ii) Samples required: 2 vials, each contents and evaporate to dryness containing not less than 5 milliliters. three times using 5-milliliter portions (b) Tests and methods of assay—(1) Per- of distilled water. Dissolve the hydrol- cent benzylpenicilloyl substitution—(i) ysate in 10 milliliters of citrate buffer.
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(d) Procedure. Standardize the proce- dure for use of the amino acid analyzer Molar benzyl - (A −A ) × 500 = 1 2 with the calibration mixture. Apply 0.5 penicilloyl content milliliter of the lysine standard solu- 22,325 tion to the amino acid analyzer and de- where: termine the area of the lysine peak. A1=The highest absorbance at 282 nanometers Apply 0.5 milliliter of the sample solu- A2=The initial absorbance at 282 tion to the amino acid analyzer and de- nanometers termine the area of the lysine peak. 22,325=The molar absorptivity of the (e) Calculations. Calculate the lysine penamaldate formed by the reaction of content by the following formula: the benzylpenicilloyl moiety with the mercuric chloride at a pH of 7.6. Molar concentration of lysine A × 2. 5 Percent benzylpenicilloyl substi- in the benzylpenicilloyl - = tution=(Molar benzylpenicilloyl content × 100)/Molar lysine content polylysine concentrate BC× (2) Penicillenate and penamaldate con- where: tent. Dilute 1 milliliter of the A=The area of the lysine peak of the sam- benzylpenicilloyl-polylysine con- ple solution. centrate to 50 milliliters with saline B=The area of the lysine peak of the stand- ard solution. phosphate buffer, pH 7.6. Using a suit- C=The percent purity of the lysine able spectrophotometer and the saline dihydrochloride. phosphate buffer, pH 7.6, as a blank, de- termine the absorbance at 322 and 282 (ii) Benzylpenicilloyl content—(a) Re- nanometers. Calculate the agents. (1) Mercuric chloride solution: penicillenate content by the following Dissolve 35 milligrams of mercuric formula: chloride in 500 milliliters of distilled water. Absorbance at 322 × (2) Saline phosphate buffer, pH 7.6: Molar penicillenate = nanometers 50 Dissolve 9 grams of sodium chloride content and 1.38 grams monobasic sodium phos- 26, 600 phate in 900 milliliters of distilled where: water, adjust to pH 7.6 and dilute to 1 26,600=Molar absorptivity of the liter with distilled water. penicillenate moiety at 322 nanometers at a pH of 7.6 (b) Preparation of sample solution. Calculate the penamaldate content by the Transfer 1 milliliter of the following formula: benzylpenicilloyl-polylysine con- centrate into a 500-milliliter volu- Absorbance at 282 × metric flask and dilute to volume with Molar penamaldate = nanometers 50 saline phosphate buffer, pH 7.6. content (c) Procedure. Transfer 3 milliliters of 22,325 the sample solution into a where: spectrophotometric cell. Using a suit- 22,325=Molar absorptivity of the able spectrophotometer and the saline penamaldate moiety at 282 nanometers at a pH of 7.6. phosphate buffer, pH 7.6, as a blank, de- termine the initial absorbance at 282 (3) pH. Proceed as directed in § 436.202 nanometers. Thereafter, react the di- of this chapter, using the undiluted luted benzylpenicilloyl-polylysine solu- sample. tion with 0.02-milliliter portions of the [39 FR 35346, Oct. 1, 1974; 39 FR 38370, Oct. 31, mercuric chloride solution. Determine 1974; 39 FR 39871, Nov. 12, 1974; 39 FR 40946, the absorbance at 282 nanometers at 1 Nov. 22, 1974] and 3 minutes after each addition of mercuric chloride solution. The in- § 440.11 Carbenicillin indanyl sodium. creased absorbance at 282 nanometers (a) Requirements for certification— (1) is used in calculating the Standards of identity, strength, quality, benzylpenicilloyl content. Calculate and purity. Carbenicillin indanyl so- the benzylpenicilloyl content by means dium is the monosodium salt of N-(2- of the following formula: carboxy-3,3-dimethyl-7-oxo-4-thia-1-
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azabicyclo [3.2.0] hept-6-yl)-2-phenyl- benzylpenicillin. It is so purified and malonamic acid, 1-(5-indanyl) ester. It dried that: is so purified and dried that: (i) It contains not less than 770 (i) Its potency is not less than 659 micrograms of carbenicillin per milli- micrograms and not more than 769 gram on an anhydrous basis. If it is micrograms of carbenicillin per milli- packaged for dispensing, its gram on an anhydrous basis at the carbenicillin content is not less than 90 time of certification, and not less than percent and not more than 120 percent 630 micrograms of carbenicillin per of the number of milligrams of milligram on an anhydrous basis at carbenicillin that it is represented to any time during the expiration period. contain. (ii) [Reserved] (ii) It is sterile. (iii) Its moisture content is not more (iii) It is nonpyrogenic. than 2.0 percent. (iv) [Reserved] (iv) Its pH in an aqueous solution (v) Its moisture content is not more containing 100 milligrams per milliliter than 6 percent. is not less than 5.0 nor more than 8.0. (vi) Its pH in an aqueous solution (v) It gives a positive result to the containing 10 milligrams of identity test for carbenicillin indanyl carbenicillin per milliliter (or if sodium. packaged for dispensing, after recon- (2) Labeling. It shall be labeled in ac- stitution as directed in the labeling) is cordance with the requirements of not less than 6.0 and not more than 8.0. § 432.5 of this chapter. (vii) It gives a positive identity test (3) Requests for certification; samples. for carbenicillin disodium. In addition to complying with the re- (2) Labeling. It shall be labeled in ac- quirements of § 431.1 of this chapter, cordance with the requirements of each such request shall contain: § 432.5 of this chapter. (i) Results of tests and assays on the (3) Requests for certification; samples. batch for potency, moisture, pH, and In addition to the requirements of identity. § 431.1 of this chapter, each such re- (ii) Samples required: Five packages, quest shall contain: each containing approximately 1.0 (i) Results of tests and assays on the gram and one package containing ap- batch for potency, sterility, pyrogens, proximately 2.5 grams. moisture, pH, and identity. (b) Tests and methods of assay—(1) Po- (ii) Samples required: tency. Proceed as directed in § 436.300 of (a) If the batch is packaged for re- this chapter. packing or for use in the manufacture of another drug: (2) [Reserved] (1) For all tests except sterility: 10 (3) Moisture. Proceed as directed in packages, each containing approxi- § 436.201 of this chapter. mately 300 milligrams; and 5 packages, (4) pH. Proceed as directed in § 436.202 each containing approximately 1 gram. of this chapter, using an aqueous solu- (2) For sterility testing: 20 packages, tion containing 100 milligrams per mil- each containing approximately 300 mil- liliter. ligrams. (5) Identity. Proceed as directed in (b) If the batch is packaged for dis- § 436.211 of this chapter, using the 0.5- pensing: percent potassium bromide disc pre- (1) For all tests except sterility: A pared as described in paragraph (b)(1) minimum of 15 immediate containers. of that section. (2) For sterility testing: 20 immediate [39 FR 18976, May 30, 1974, as amended at 50 containers, collected at regular inter- FR 19918, May 13, 1985] vals throughout each filling operation. (b) Tests and methods of assay—(1) Po- § 440.13a Sterile carbenicillin tency. Proceed as directed in § 436.105 of disodium. this chapter, preparing the sample for (a) Requirements for certification— (1) assay as follows: Dissolve an accu- Standards of identity, strength, quality, rately weighed sample in sufficient 1.0 and purity. Carbenicillin disodium is percent potassium phosphate buffer, pH the disodium salt of α-carboxy- 6.0 (solution 1), to give a stock solution
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of convenient concentration; and also (i) Its potency is not less than 825 if it is packaged for dispensing, recon- micrograms of cloxacillin per milli- stitute as directed in the labeling. gram. Then, using a suitable hypodermic nee- (ii) [Reserved] dle and syringe, remove all of the (iii) Its moisture content is not less withdrawable contents if it is rep- than 3 percent and not more than 5 per- resented as a single–dose container; or cent. if the labeling specifies the amount of (iv) Its pH in an aqueous solution potency in a given volume of the re- containing 10 milligrams per milliliter sultant preparation, remove an accu- is not less than 4.5 nor more than 7.5. rately measured representative portion (v) Its cloxacillin content is not less from each container. If it is a single than 82.5 percent. dose container, use a separate needle (vi) It passes the identity test. and syringe for each container. Dilute (vii) It is crystalline. with sufficient solution 1 to give a (2) Labeling. It shall be labeled in ac- stock solution of convenient con- cordance with the requirements of centration. Further dilute the stock § 432.5 of this subchapter. solution with solution 1 to the ref- (3) Requests for certification; samples. erence concentration of 20.0 In addition to complying with the re- micrograms of carbenicillin per milli- quirements of § 431.1 of this subchapter, liter (estimated). each such request shall contain: (2) Sterility. Proceed as directed in (i) Results of tests and assays on the § 436.20 of this chapter, using the meth- batch for potency, moisture, pH, od described in paragraph (e)(1) of that cloxacillin content, identity, and crys- section. tallinity. (3) Pyrogens. Proceed as directed in (ii) Samples required: 10 packages, § 436.32(b) of this chapter, using a solu- each containing approximately 300 mil- tion containing 200 milligrams of ligrams. carbenicillin per milliliter. (b) Tests and methods of assay—(1) Po- (4) [Reserved] tency. Use any of the following meth- (5) Moisture. Proceed as directed in ods; however, the results obtained from § 436.201 of this chapter. the microbiological agar diffusion assay shall be conclusive. (6) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solu- (i) Microbiological agar diffusion assay. tion containing 10 milligrams of Proceed as directed in § 436.105 of this chapter, preparing the sample for assay carbenicillin per milliliter (or if as follows: Dissolve an accurately packaged for dispensing, use a solution weighed portion of the sample in suffi- prepared as directed for reconstitution cient 1 percent potassium phosphate in the labeling). buffer, pH 6.0 (solution 1), to give a (7) Identity. Proceed as directed in stock solution of convenient con- § 436.211 of this chapter, using a 0.5 per- centration. Further dilute an aliquot of cent potassium bromide disc prepared the stock solution with solution 1 to as directed in paragraph (b)(1) of that the reference concentration of 5 section. micrograms of cloxacillin per milliliter [39 FR 18976, May 30, 1974, as amended at 42 (estimated). FR 59857, Nov. 22, 1977; 45 FR 22921, Apr. 4, (ii) Iodometric assay. Proceed as di- 1980; 50 FR 19918, May 13, 1985; 51 FR 27532, rected in § 436.204 of this subchapter. Aug. 1, 1986] (iii) Hydroxylamine colorimetric assay. Proceed as directed in § 436.205 of this § 440.15 Cloxacillin sodium subchapter. monohydrate. (2) [Reserved] (a) Requirements for certification—(1) (3) Moisture. Proceed as directed in Standards of identity, strength, quality, § 436.201 of this subchapter. and purity. Cloxacillin sodium is the (4) pH. Proceed as directed in § 436.202 monohydrate sodium salt of 5-methyl- of this subchapter, using an aqueous 3-(o- chlorophenyl)-4-isoxazolyl penicil- solution containing 10 milligrams per lin. It is so purified and dried that: milliliter.
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(5) Cloxacillin content. Accurately tractives and dilute to 100 milliliters weigh approximately 100 milligrams of with carbon dioxide-free water. Treat a the sample and dissolve in sufficient 5N portion of the cloxacillin working sodium hydroxide to give a total vol- standard in the same manner. Using a ume of 25 milliliters. Place in a boiling suitable spectrophotometer, determine water bath for 30 minutes. Cool, acidify the absorbance of the solution in a 1- 1 milliliter with 1 milliliter of dilute centimeter cell at the absorption peaks sulfuric acid (1 in 2), add 8 milliliters of at 257±3 nanometers and at 282±3 water, and extract with two 25-milli- nanometers compared with a reagent liter portions of ethyl ether. Combine blank. Determine the percent the ether extractives and extract with cloxacillin in the sample by means of 25-milliliter portions of 0.1N sodium hydroxide. Combine the alkaline ex- the following calculation:
× A1 weight of standard in milligrams, on an "as is" basis× percent cloxacillin in the standard Percent cloxacillin = × A2 weight of sample in milligrams on an "as is" basis ×100
where: is not less than 4.0 and not more than A1=Difference in absorbance for the sample 6.5. between 257 nanometers and 282 (v) Its cyclacillin content is not less nanometers: than 90 percent on an anhydrous basis. A2=Difference in absorbance for the cloxacillin working standard, similarly (vi) The acid-base titration concord- treated. ance is such that the difference be- tween the percent cyclacillin content (6) Identity. Proceed as directed in when determined by nonaqueous acid § 436.211 of this subchapter, using the titration and nonaqueous base titra- 0.5 percent potassium bromide disc de- tion is not more than six. The potency- scribed in paragraph (b)(1) of that sec- acid titration concordance is such that tion. the difference between the potency (7) Crystallinity. Proceed as directed value divided by 10 and the percent in § 436.203 of this subchapter. cyclacillin content of the sample deter- [39 FR 18976, May 30, 1974, as amended at 42 mined by the nonaqueous acid titration FR 59857, Nov. 22, 1977; 50 FR 19918, May 13, is not more than six. The potency base 1985] titration concordance is such that the difference between the potency value § 440.17 Cyclacillin. divided by 10 and the percent (a) Requirements for certification—(1) cyclacillin content of the sample deter- Standards of identity, strength, quality, mined by the nonaqueous base titra- and purity. Cyclacillin is 6-(1- tion is not more than six. aminocyclohexanecarboxamido)-3,3-di- (vii) It is crystalline. methyl-7-oxo-4-thia-1-azabicyclo[3.2.0] (viii) It gives a positive identity test heptane-2-carboxylic acid. It is a white for cyclacillin. to off-white powder. It is so purified (2) Labeling. In addition to the label- and dried that: ing requirements of § 432.5 of this chap- (i) It contains not less than 900 ter, each package shall bear on its out- micrograms and not more than 1,050 side wrapper or container and the im- micrograms of cyclacillin per milli- mediate container the following state- gram. ment, ‘‘For use in the manufacture of (ii) [Reserved] nonparenteral drugs only.’’ (iii) Its moisture content is not more (3) Requests for certification; samples. than 1.0 percent. In addition to complying with the re- (iv) Its pH in an aqueous solution quirements of § 431.1 of this chapter, containing 10 milligrams per milliliter each such request shall contain:
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(i) Results of tests and assays on the reference concentration of 1.0 batch for potency, moisture, pH, microgram of cyclacillin per milliliter cyclacillin content, concordance, crys- (estimated). tallinity, and identity. (ii) Iodometric assay. Proceed as di- (ii) Samples required: 10 packages, rected in § 436.204 of this chapter. each containing approximately 500 mil- (iii) Hydroxylamine colorimetric assay. ligrams. Proceed as directed in § 436.205 of this (b) Tests and methods of assay—(1) Po- chapter. tency. Assay for potency by any of the (2) [Reserved] following methods; however, the re- (3) Moisture. Proceed as directed in sults obtained from the iodometric assay shall be conclusive. § 436.201 of this chapter. (i) Microbiological agar diffusion assay. (4) pH. Proceed as directed in § 436.202 Proceed as directed in § 436.105 of this of this chapter, using an aqueous solu- chapter, preparing the sample for assay tion containing 10 milligrams per mil- as follows: Dissolve an accurately liliter. weighed portion of the sample in suffi- (5) Cyclacillin content. Proceed as di- cient sterile distilled water to give a rected in § 436.213 of this chapter, using stock solution containing 1 milligram both the titration procedures described of cyclacillin per milliliter (estimated). in paragraph (e)(1) and (2) of that sec- Further dilute an aliquot of the stock tion. Calculate the percent cyclacillin solution with 0.1M potassium phos- content as follows: phate buffer, pH 8.0 (solution 3), to the (i) Acid titration.
Percent cyclacillin (A− B)(normality of perchloric acid reagent)(341.4)(100) = content (Weight of sample in milligrams)(100 − m)
where: A=Milliliters of lithium methoxide reagent Potency in micrograms percent used in titrating the sample; per milligram B=Milliliters of lithium methoxide reagent Difference = − cyclacillin used in titrating the blank; 10 content m=Percent moisture content of the sample. (ii) Base titration. Calculate the difference between the po- tency and the cyclacillin content as follows:
Percent cyclacillin (A− B)(normality of perchloric acid reagent) (341.4)(100)(100) = content (Weight of sample in milligrams)(100− m )
where: m=Percent moisture content of the sample. A=Milliliters of perchloric acid reagent Calculate the difference between the po- used in titrating the sample; tency and the cyclacillin content as follows: B=Milliliters of perchloric acid reagent used in titrating the blank;
Potency in micrograms per milligrams Difference = − percent cyclacillin content 10
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(6) Crystallinity. Proceed as directed ganic chlorine content, free chloride in § 436.203(a) of this chapter. content, crystallinity, and identity. (7) Identity. Proceed as directed in (ii) Samples required: 10 containers, § 436.211 of this chapter, using a 1-per- each containing not less than 500 milli- cent potassium bromide disc prepared grams. as described in paragraph (b)(1) of that (b) Tests and methods of assay—(1) Po- section. tency. Use any of the following meth- [46 FR 2981, Jan. 13, 1981; 46 FR 15880, Mar. 10, ods; however, the results obtained from 1981, as amended at 50 FR 19918, May 13, 1985] the microbiological agar diffusion assay shall be conclusive. § 440.19 Dicloxacillin sodium (i) Microbiological agar diffusion assay. monohydrate. Proceed as directed in § 436.105 of this (a) Requirements for certification—(1) chapter, preparing the sample for Standards of identity, strength, quality, assay, as follows: Dissolve an accu- and purity. Dicloxacillin sodium rately weighed portion of the sample in monohydrate is the monohydrated so- sufficient 1 percent potassium phos- dium salt of 5-methyl-3-(2,6- phate buffer, pH 6.0 (solution 1), to give dichlorophenyl)-4-isoxazolyl penicillin. a stock solution of convenient con- It is so purified and dried that: centration. Further dilute an aliquot of (i) Its potency is not less than 850 the stock solution with solution 1 to micrograms of dicloxacillin per milli- the reference concentration of 5 gram. micrograms of dicloxacillin per milli- (ii) [Reserved] liter (estimated). (iii) Its moisture content is not less (ii) Iodometric assay. Proceed as di- than 3 percent nor more than 5 percent. rected in § 436.204 of this chapter. (iv) Its pH in an aqueous solution (iii) Hydroxylamine colorimetric assay. containing 10 milligrams per milliliter Proceed as directed in § 436.205 of this is not less than 4.5 nor more than 7.5. chapter. (v) Its organic chlorine content is not (2) [Reserved] less than 13.0 percent nor more than (3) Moisture content. Proceed as di- 14.2 percent. rected in § 436.201 of this chapter. (vi) Its free chloride content is not (4) pH. Proceed as directed in § 436.202 more than 0.5 percent. of this chapter, using an aqueous solu- (vii) It is crystalline. tion containing 10 milligrams per mil- (viii) It gives a positive identity test liliter. for dicloxacillin sodium monohydrate. (5) Organic chlorine content—(i) Re- (2) Labeling. It shall be labeled in ac- agents. (a) o- Chlorobenzoic acid of cordance with the requirements of known purity. § 432.5 of this chapter. (b) 0.01N Silver nitrate solution. (3) Requests for certification; samples. Store in brown glass reagent bottle. In addition to complying with the re- Standardize against an accurately quirements of § 431.1 of this chapter, weighed sample of 20 to 25 milligrams each such request shall contain: of o- chlorobenzoic acid using the pro- (i) Results of tests and assays on the cedure described in paragraph (b)(5)(ii) batch for potency, moisture, pH, or- of this section.
Percent purity of the o-chlorobenzoic acid × milligrams of o-chlorobenzoic acid Normality (N ) = 15, 657 × milliliters of silver nitrate consumed
(c) 0.1N Sodium hydroxide solution. (ii) Total chlorine. (Caution—The ana- (d) 1:1 Nitric acid solution: Mix 1 vol- lyst should wear safety glasses and use ume of concentrated nitric acid with 1 a suitable shield between himself and volume of distilled water. the apparatus. The glassware must be scrupulously clean.) Accurately weigh
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20 to 25 milligrams of the sample and the stopper, and hold the stopper firm- place it on the center of a piece of ha- ly in place. If the ignition is carried lide-free filter paper measuring about 4 out in a closed system, the inversion of centimeters square (this is specially the flask may be omitted. After com- cut paper with a fuse strip attached to bustion is completed, shake the flask the area that holds the sample), and vigorously, add a small amount of dis- fold the paper to enclose it. Place 10 tilled water to the collar to insure an milliliters of 0.1N sodium hydroxide air tight seal, and allow to stand for into an oxygen combustion flask not less than 10 minutes with intermit- (Schoniger flask), and flush the air tent shaking. Transfer to a suitable ti- from the flask with a stream of rapidly tration vessel, heat on a steam bath for flowing oxygen. Place the sample into the platinum sample holder and ignite 20 to 30 minutes, cool to room tempera- the fuse strip by suitable means. If the ture, add 5 milliliters of nitric acid so- strip is ignited outside the flask, im- lution, and titrate potentiometrically mediately plunge the stopper into the with 0.01N silver nitrate, using one sil- flask, invert so that the sodium hy- ver electrode and one silver/silver chlo- droxide solution makes a seal around ride electrode.
N ×milliliters of silver nitrate × 3545. 7 Percent total chlorine = Milligrams of sample
(iii) Free chloride. Accurately weigh bath 20 to 30 minutes. Cool to room 100 to 150 milligrams of sample directly temperature, add 5 milliliters of 1:1 ni- into a titration flask, dissolve in 10 tric acid solution and titrate milliliters of 0.1N sodium hydroxide, potentiometrically with 0.01N silver ni- and add about 20 milliliters of distilled trate using one silver electrode and one water, heat this solution on the steam silver/silver chloride electrode.
N ×milliliters of silver nitrate × 3545. 7 Percent free chloride = Milligrams of sample
(iv) Organic chlorine. Percent organic dium salt of 5-methyl-3-(2,6-dichloro- chlorine=Percent total chlo- phenyl)-4-isoxazolyl penicillin. It is so rine¥percent free chloride. purified and dried that: (6) Crystallinity. Proceed as directed (i) Its potency is not less than 850 in § 436.203(a) of this chapter. micrograms of dicloxacillin per milli- (7) Identity. Proceed as directed in gram. If it is packaged for dispensing, § 436.211 of this chapter, using the 1 per- its potency is satisfactory if it con- cent potassium bromide disc described tains not less than 90 percent and not in paragraph (b)(1) of that section. more than 120 percent of the number of milligrams of dicloxacillin that it is [39 FR 18976, May 30, 1974, as amended at 42 represented to contain. FR 59857, Nov. 22, 1977; 44 FR 10378, Feb. 20, 1979; 50 FR 19918, May 13, 1985] (ii) It is sterile. (iii) It is nonpyrogenic. § 440.19a Sterile dicloxacillin sodium (iv) [Reserved] monohydrate. (v) Its moisture content is not less (a) Requirements for certification—(1) than 3 percent and not more than 5 per- Standards of identity, strength, quality, cent. and purity. Sterile dicloxacillin sodium (vi) Its pH in an aqueous solution monohydrate is the monohydrated so- containing 10 milligrams per milliliter
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or when reconstituted as directed in hypodermic needle and syringe, remove the labeling, if it is packaged for dis- all of the withdrawable contents if it is pensing is not less than 4.5 nor more represented as a single-dose container, than 7.5. or if the labeling specifies the amount (vii) Its organic chlorine content is of potency in a given volume of the re- not less than 13.0 percent and not more sultant preparation, remove an accu- than 14.2 percent. rately measured representative portion (viii) Its free chloride content is not from each container. Dilute with either more than 0.5 percent. solution 1 or distilled water, as speci- (ix) It is crystalline. fied above, to give a stock solution of (x) It gives a positive identity test convenient concentration. for dicloxacillin sodium monohydrate. (ii) Assay procedures. Use any of the (2) Labeling. If this drug is packaged following methods; however, the re- for dispensing, in addition to the label- sults obtained from the micro- ing requirements of § 432.5 of this chap- biological agar diffusion assay shall be ter, this drug shall be labeled ‘‘sterile conclusive. dicloxacillin sodium’’. (a) Microbiological agar diffusion (3) Requests for certification; samples. assay. Proceed as directed in § 436.105 of In addition to complying with the re- this chapter, diluting an aliquot of the quirements of § 431.1 of this chapter, stock solution with solution 1 to the each such request shall contain: reference concentration of 5 (i) Results of tests and assays on the micrograms of dicloxacillin per milli- batch for potency, sterility, pyrogens, liter (estimated). moisture, pH, organic chlorine content, free chloride content, crystallinity, (b) Iodometric assay. Proceed as di- and identity. rected in § 436.204 of this subchapter. (ii) Samples required: (c) Hydroxylamine colorimetric assay. (a) If the batch is packaged for re- Proceed as directed in § 436.205 of this packing or for use in the manufacture subchapter. of another drug: (2) Sterility. Proceed as directed in (1) For all tests except sterility: 10 § 436.20 of this chapter, using the meth- packages, each containing approxi- od described in paragraph (e)(1) of that mately 500 milligrams. section. (2) For sterility testing: 20 packages, (3) Pyrogens. Proceed as directed in each containing approximately 300 mil- § 436.32(a) of this chapter, using a solu- ligrams. tion containing 20 milligrams of (b) If the batch is packaged for dis- dicloxacillin per milliliter. pensing: (4) [Reserved] (1) For all tests except sterility: A (5) Moisture. Proceed as directed in minimum of 15 immediate containers. § 436.201 of this chapter. (2) For sterility testing: 20 immediate (6) pH. Proceed as directed in § 436.202 containers, collected at regular inter- of this subchapter, using an aqueous vals throughout each filling operation. solution containing 10 milligrams per (b) Tests and methods of assay—(1) Po- milliliter (or using a solution reconsti- tency. Use any of the following meth- tuted as directed in the labeling if it is ods; however, the results obtained from packaged for dispensing). the microbiological agar diffusion (7) Organic chlorine content. Proceed assay shall be conclusive. as directed in § 440.19(b)(5). (i) Sample preparation. Dissolve an ac- (8) Crystallinity. Proceed as directed curately weighed sample in sufficient 1 in § 436.203(a) of this chapter. percent potassium phosphate buffer, pH 6.0 (solution 1), for the microbiological (9) Identity. Proceed as directed in agar diffusion assay and the hydroxyl- § 436.211 of this chapter, using a 1 per- amine colorimetric assay or in distilled cent potassium bromide disc prepared water for the iodometric assay, to give as directed in paragraph (b)(1) of that a stock solution of convenient con- section. centration; and also if it is packaged [39 FR 18976, May 30, 1974, as amended at 42 for dispensing, reconstitute as directed FR 59857, Nov. 22, 1977; 50 FR 19918, May 13, in the labeling. Then, using a suitable 1985]
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§ 440.25 Hetacillin. (5) Hetacillin content—(i) Reagents—(a) (a) Requirements for certification—(1) Hydrochloric acid-acetone solution. Di- Standards of identity, strength, quality, lute 8.5 milliliters of concentrated hy- and purity. Hetacillin is 6-(2,2-Di- drochloric acid to 1 liter with acetone methyl-5-oxo-4-phenyl-1- and mix well. Use for 1 day only. imidazolidinyl)-3,3-dimethyl-7-oxo-4- (b) p-Dimethylaminocinnamalde- hyde thia-1-azabicyclo[3.2.0]heptane-2-car- solution. Dissolve 0.5 gram of p- boxylic acid. It occurs as a fine, white dimethylaminocinnamaldehyde in suf- to off-white powder. It is so purified ficient hydrochloric acid-acetone solu- and dried that: tion to a final volume of 100 milliliters (i) Its potency is not less than 810 and shake well, filtering if necessary. micrograms of ampicillin per milli- Prepare immediately before use. gram. (ii) Preparation of standard solutions. (ii) [Reserved] Transfer about 100 milligrams of the (iii) Its moisture content is not more hetacillin working standard, accu- than 1.0 percent. rately weighed, to a 200-milliliter volu- (iv) Its pH in an aqueous solution metric flask. Add 150 milliliters of re- containing 10 milligrams per milliliter frigerated distilled water and 20 milli- is not less than 2.5 nor more than 5.5. liters of 1N hydrochloric acid, shake, (v) Its hetacillin content is not less dilute to volume with distilled water, than 90 and not more than 105 percent. and mix well. Transfer 0.5, 1.0, and 2.0 (vi) It gives a positive identity test milliliters into three respective 25-mil- for hetacillin. liliter volumetric flasks. Add 1.5 and (vii) It is crystalline. 1.0 milliliters of 0.1N hydrochloric acid (2) Labeling. It shall be labeled in ac- respectively to the first and second cordance with the requirements of flasks to bring the volume in each to § 432.5(b) of this chapter. 2.0 milliliters. (3) Requests for certification; samples. (iii) Blank. Use 2.0 milliliters of 0.1N In addition to complying with the re- hydrochloric acid in a 25-milliliter vol- quirements of § 431.1 of this chapter, umetric flask. each such request shall contain: (iv) Preparation of sample solutions. (i) Results of tests and assays on the Using a mortar and pestle, grind the batch for potency, moisture, pH, sample to a fine powder. Transfer an hetacillin content, identity, and crys- accurately weighed portion of about 100 tallinity. milligrams to a 200-milliliter volu- (ii) Samples required: 10 packages, metric flask. Add 150 milliliters of re- each containing approximately 300 mil- frigerated distilled water and 20 milli- ligrams. liters of 1N hydrochloric acid, shake, (b) Tests and methods of assay—(1) Po- dilute to volume with distilled water, tency. Proceed as directed for ampi- and mix well. Transfer 1.0 milliliter to cillin in § 436.105 of this chapter, using a 25-milliliter volumetric flask, add 1.0 the ampicillin working standard as the milliliter of 0.1N hydrochloric acid, and standard of comparison and preparing mix. the sample for assay as follows: Dis- (v) Procedure. To each of the flasks solve an accurately weighed sample in containing standards, blank, and sam- sufficient 0.1M potassium phosphate ple, add 15 milliliters of hydrochloric buffer, pH 8.0 (solution 3), to give a acid-acetone solution and mix. Then stock solution of convenient con- add 3 milliliters of p- dimeth- centration. Further dilute the stock ylaminocinnamaldehyde solution to solution with solution 3 to the ref- each and mix. Add 3 milliliters of 0.1N erence concentration of 0.1 microgram hydrochloric acid to each, dilute to of ampicillin per milliliter (estimated). volume with hydrochloric acid-acetone (2) [Reserved] solution, mix well, and allow to stand (3) Moisture. Proceed as directed in at 25° C. for exactly 30 minutes. (Filter § 436.201 of this chapter. the sample solutions, if necessary, to (4) pH. Proceed as directed in § 436.202 remove any turbidity.) Using a suitable of this chapter, using an aqueous solu- spectrophotometer, read the tion containing 10 milligrams per mil- absorbance values of standard and sam- liliter. ple solutions at a wavelength of 515
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nanometers against the blank. Plot the (i) Results of tests and assays on the absorbance values of the standards ver- batch for potency, moisture, pH, sus their concentrations and read the hetacillin content, identity, and crys- sample concentration from this stand- tallinity. ard response line. (ii) Samples required: 10 packages, (vi) Calculations. each containing approximately 300 mil- ligrams. CP×5, 000 × (b) Tests and methods of assay—(1) Po- Percent hetacillin = Weight of sample tency. Proceed as directed for ampi- cillin in § 436.105 of this chapter, using in milligrams the ampicillin working standard as the where: standard of comparison and preparing C=Concentration in milligrams of hetacillin the sample for assay as follows: Dis- per milliliter of the final solution of the solve an accurately weighed sample in sample obtained from the standard re- sufficient 0.1M potassium phosphate sponse line. P=Hetacillin content of the hetacillin work- buffer pH 8.0 (solution 3), to give a ing standard in percent. stock solution of convenient con- centration. Further dilute the stock (6) Identity. Proceed as directed in solution with solution 3 to the ref- § 436.211 of this chapter, using a 1 per- erence concentration of 0.1 microgram cent potassium bromide disc prepared of ampicillin per milliliter (estimated). as directed in paragraph (b)(1) of that (2) [Reserved] section. (3) Moisture. Proceed as directed in (7) Crystallinity. Proceed as directed § 436.201 of this chapter. in § 436.203(a) of this chapter. (4) pH. Proceed as directed in § 436.202 [39 FR 18976, May 30, 1974, as amended at 42 of this chapter, using an aqueous solu- FR 59857, Nov. 22, 1977; 44 FR 10379, Feb. 20, tion containing 10 milligrams per mil- 1979; 50 FR 19918, May 13, 1985] liliter. (5) Hetacillin content. Proceed as di- § 440.29 Hetacillin potassium. rected in § 440.25(b)(5), except use about (a) Requirements for certification—(1) 110 milligrams of sample and calculate Standards of identity, strength, quality the hetacillin content as follows: and purity. Hetacillin potassium is the potassium salt of hetacillin. It occurs CP×5, 000 × Percent hetacillin = as a fine, white to light buff powder. It Weight of sample is so purified and dried that: (i) Its potency is not less than 735 in milligrams micrograms of ampicillin per milli- where: gram. C=Concentration in milligrams of hetacillin (ii) [Reserved] per milliliter of the final solution of the (iii) Its moisture content is not more sample obtained from the standard re- sponse line. than 1.0 percent. P=Hetacillin content of the hetacillin work- (iv) Its pH in an aqueous solution ing standard in percent. containing 10 milligrams per milliliter is not less than 7.0 and not more than (6) Identity. Proceed as directed in 9.0. § 436.211 of this chapter, using a 1 per- (v) Its hetacillin content is not less cent potassium bromide disc prepared than 82 percent and not more than 95.5 as directed in paragraph (b)(1) of that percent. section. (vi) It gives a positive identity test (7) Crystallinity. Proceed as directed for hetacillin potassium. in § 436.203(a) of this chapter. (vii) It is crystalline. [39 FR 18976, May 30, 1974, as amended at 42 (2) Labeling. It shall be labeled in ac- FR 59857, Nov. 22, 1977; 44 FR 10379, Feb. 20, cordance with the requirements of 1979; 50 FR 19918, May 13, 1985] § 432.5(b) of this chapter. (3) Requests for certification; samples. § 440.29a Sterile hetacillin potassium. In addition to complying with the re- (a) Requirements for certification— (1) quirements of § 431.1 of this chapter, Standards of identity, strength, quality, each such request shall contain: and purity. Hetacillin potassium is the
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potassium salt of hetacillin. It occurs (2) For sterility testing: 20 immediate as a fine, white to light buff powder. It containers, collected at regular inter- is so purified and dried that: vals throughout each filling operation. (i) Its potency is not less than 735 (b) Tests and methods of assay—(1) Po- micrograms of ampicillin per milli- tency. Proceed as directed for ampi- gram. If it is packaged for dispensing, cillin in § 436.105 of this chapter, using its potency is satisfactory if it con- the ampicillin working standard as the tains not less than 90 percent and not standard of comparison and preparing more than 120 percent of the number of the sample for assay as follows: Dis- milligrams of ampicillin that it is rep- solve an accurately weighed sample in resented to contain. sufficient 0.1M potassium phosphate (ii) It is sterile. buffer, pH 8.0 (solution 3), to give a (iii) It is nonpyrogenic. stock solution of convenient con- (iv) [Reserved] centration; and also if it is packaged (v) Its moisture content is not more than 1.0 percent. for dispensing, reconstitute as directed (vi) Its pH in an aqueous solution in the labeling. Then, using a suitable containing 10 milligrams per milliliter hypodermic needle and syringe, remove (or when reconstituted as directed in the withdrawable contents from each the labeling, if it is packaged for dis- container represented as a single-dose pensing) is not less than 7.0 and not container; or if the labeling specifies more than 9.0. the amount of potency in a given vol- (vii) Its hetacillin content is not less ume of the resultant preparation, with- than 82 percent and not more than 95.5 draw an accurately measured rep- percent. resentative portion from each con- (viii) It gives a positive identity test tainer. Dilute the sample thus obtained for hetacillin potassium. with sufficient solution 3 to give a (ix) It is crystalline. stock solution of convenient con- (2) Labeling. It shall be labeled in ac- centration. Further dilute the stock cordance with the requirements of solution with solution 3 to the ref- § 432.5 of this chapter. erence concentration of 0.1 microgram (3) Requests for certification; samples. of ampicillin per milliliter (estimated). In addition to complying with the re- (2) Sterility. Proceed as directed in quirements of § 431.1 of this chapter, § 436.20 of this chapter, using the meth- each such request shall contain: od described in paragraph (e)(1) of that (i) Results of tests and assays on the section. batch for potency, sterility, pyrogens, (3) Pyrogens. Proceed as directed in moisture, pH, hetacillin content, iden- tity, and crystallinity. § 436.32(a) of this chapter using a solu- (ii) Samples required: tion containing the equivalent of 18 (a) If the batch is packaged for re- milligrams of ampicillin per milliliter. packing or for use in the manufacture (4) [Reserved] of another drug: (5) Moisture. Proceed as directed in (1) For all tests except sterility: 10 § 436.201 of this chapter. packages, each containing approxi- (6) pH. Proceed as directed in § 436.202 mately 300 milligrams. of this chapter, using an aqueous solu- (2) For sterility testing: 20 packages, tion containing 10 milligrams per mil- each containing approximately 300 mil- liliter (or using a solution reconsti- ligrams. tuted as directed in the labeling, if it is (b) If the batch is packaged for dis- packaged for dispensing). pensing: (7) Hetacillin content. Proceed as di- (1) For all tests except sterility: A rected in § 440.25(b)(5), except use about minimum of 10 immediate containers, 110 milligrams of sample and calculate except if each contains less than 450 the potassium hetacillin content as fol- milligrams, a minimum of 16 imme- lows: diate containers.
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moisture, pH, methicillin content, CP×5, 000 × Percent hetacillin = crystallinity, and identity. Weight of sample (ii) Samples required: in milligrams (a) For all tests except sterility: 10 packages, each containing approxi- where: mately 300 milligrams, plus one pack- C=Concentration in milligrams of hetacillin age containing approximately 2 grams. per milliliter of the final solution of the sample obtained from the standard re- (b) For sterility testing: 20 packages, sponse line. each containing approximately 600 mil- P=Hetacillin content of the hetacillin work- ligrams. ing standard in percent. (b) Tests and methods of assay—(1) Po- tency. Use any of the following meth- (8) Identity. Proceed as directed in ods; however, the results obtained from § 436.211 of this chapter, using a 1 per- the microbiological agar diffusion cent potassium bromide disc prepared assay shall be conclusive. as directed in paragraph (b)(1) of that (i) Microbiological agar diffusion assay. section. Proceed as directed in § 436.105 of this (9) Proceed as directed Crystallinity. chapter, preparing the sample for assay in § 436.203(a) of this chapter. as follows: Dissolve an accurately [39 FR 19876, May 30, 1974, as amended at 42 weighed portion of the sample in suffi- FR 59857, Nov. 22, 1977; 43 FR 2393, Jan. 17, cient 1 percent potassium phosphate 1978; 44 FR 10379, Feb. 20, 1979; 50 FR 19918, buffer, pH 6.0 (solution 1), to give a May 13, 1985] stock solution of convenient con- centration. Further dilute an aliquot of § 440.36a Sterile methicillin sodium monohydrate. the stock solution with solution 1 to the reference concentration of 10 (a) Requirements for certification— (1) micrograms of methicillin per milli- Standards of identity, strength, quality, liter (estimated). and purity. Methicillin sodium (ii) Iodometric assay. Proceed as di- monohydrate is the monohydrated so- rected in § 436.204 of this subchapter. dium salt of (2,6-dimethoxyphenyl) (iii) Hydroxylamine colorimetric assay. penicillin. It is so purified and dried Proceed as directed in § 436.205 of this that: subchapter. (i) It contains not less than 815 (2) Sterility. Proceed as directed in in micrograms of methicillin per milli- § 436.20 of this subchapter, using the gram. method described in paragraph (e)(1) of (ii) It is sterile. that section. (iii) It is nonpyrogenic. (3) Pyrogens. Proceed as directed in (iv) [Reserved] § 436.32(a) of this chapter, using a solu- (v) Its moisture content is not less tion containing 60 milligrams of than 3 percent and not more than 6 per- methicillin per milliliter. cent. (4) [Reserved] (vi) Its pH in an aqueous solution (5) Moisture. Proceed as directed in containing 10 milligrams per milliliter § 436.201 of this subchapter. is not less than 5.0 and not more than (6) pH. Proceed as directed in § 436.202 7.5. of this subchapter, using an aqueous (vii) Its methicillin content is not solution containing 10 milligrams per less than 81.5 percent. milliliter. (viii) It is crystalline. (7) Methicillin content. Dissolve an ac- (ix) It passes the identity test. curately weighed portion of the sample (2) Labeling. It shall be labeled in ac- in a sufficient accurately measured cordance with the requirements of volume of distilled water to obtain a § 432.5 of this subchapter. concentration of 0.2 milligram of (3) Requests for certification; samples. methicillin per milliliter (estimated). In addition to complying with the re- Treat a portion of the methicillin quirements of § 431.1 of this subchapter, working standard in the same manner. each such request shall contain: Using a suitable spectrophotometer (i) Results of tests and assays on the equipped with a 1-centimeter quartz batch for potency, sterility, pyrogens, cell and distilled water as the blank,
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determine the absorbance at 280 solution containing 10 milligrams per nanometers. If a recording 100 milliliters) at the 280-nanometer spectrophotometer is used, record the absorption peak. (The exact position of ultraviolet absorption spectrum from the peak should be determined for the 250 nanometers to 300 nanometers. If a particular instrument used.) Calculate nonrecording spectrophotometer is as follows: used, determine the absorbance (on a
Absorbance of sample× weight of working standard × volume of sample solution× percent methicillin in working standard Percent methicillin = Absorbance of standard× weight of sample ×volume of standard solution
(8) Crystallinity. Proceed as directed (iv) [Reserved] in § 436.203(a) of this subchapter. (v) Its moisture content is not more (9) Identity. Using the sample solu- than 6.0 percent. tion prepared as described in paragraph (vi) Its pH in an aqueous solution (b)(7) of this section, determine the containing 100 milligrams per milliliter absorbancies at the absorption maxi- is not less than 4.5 and not more than mum at 280 nanometers and at the ab- 8.0. sorption minimum at 264 nanometers. (vii) The specific rotation in an aque- The ratio of the two ous solution containing 10 milligrams of mezlocillin per milliliter at 25° C is A A 280/ 264 185°±10°. should be not less than 1.30 and not (viii) It gives a positive identity test more than 1.45. for mezlocillin. (2) Labeling. It shall be labeled in ac- [39 FR 18976, May 30, 1974, as amended at 40 cordance with the requirements of FR 15089, Apr. 4, 1975; 42 FR 59858, Nov. 22, § 432.5 of this chapter. 1977; 50 FR 19918, May 13, 1985] (3) Requests for certification; samples. § 440.37a Sterile mezlocillin sodium In addition to complying with the re- monohydrate. quirements of § 431.1 of this chapter, each such request shall contain: (a) Requirements for certification—(1) (i) Results of tests and assays on the Standards of identity, strength, quality, batch for potency, sterility, pyrogens, and purity. Sterile mezlocillin sodium moisture, pH, specific rotation, and monohydrate is the monohydrate so- identity. dium salt of (2S, 5R, 6R)-3,3-dimethyl-6- (ii) Samples required: [(R)-2-[3-(methylsulfonyl)-2-oxo-1- (a) If it is packaged for repacking or imidazolidine-carboxamido]-2- for use in the manufacture of another phenylacetamido]-7-oxo-4-thia-1- drug: azabicyclo[3.2.0] heptane-2-carboxylic (1) For all tests except sterility: 10 acid. It is so purified and dried that: packages, each containing approxi- (i) It contains not less than 838 mately 300 milligrams; and 5 packages, micrograms and not more than 978 each containing approximately 1 gram. micrograms of mezlocillin per milli- (2) For sterility testing: 20 packages, gram on an anhydrous basis. If it is each containing approximately 300 mil- packaged for dispensing, its mezlocillin ligrams. content is not less than 90 percent and (b) If it is packaged for dispensing: not more than 115 percent of the num- (1) For all tests except sterility: A ber of milligrams of mezlocillin that it minimum of 15 immediate containers. is represented to contain. (2) For sterility testing: 20 immediate (ii) It is sterile. containers, collected at regular inter- (iii) It is nonpyrogenic. vals throughout each filling operation.
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(b) Tests and methods of assay—(1) Po- Wu=Milligrams of sample per milliliter of tency. Use either of the following meth- sample solution. ods; however, the results obtained from (2) Calculate the mezlocillin content the hydroxylamine colorimetric assay of the single-dose vial as follows: shall be conclusive. × × (i) Hydroxylamine colorimetric assay. Milligrams of mezlocillin Au P a d Proceed as directed in § 442.40(b)(1)(ii) = per single-dose vial × of this chapter, except: As 1, 000 (a) Buffer. In lieu of the buffer de- where: scribed in § 442.40(b)(1)(ii)(b)(2) of this A =Absorbance of sample solution; chapter, use the buffer prepared as fol- u Pa=Potency of working standard solution lows: Dissolve 200 grams of primary in micrograms per milliliter; standard tris (hydroxymethyl) As=Absorbance of working standard solu- aminomethane in sufficient distilled tion; water to make 1 liter. Filter before use. d=Dilution factor of the sample. (b) Preparation of working standard so- (3) Calculate the mezlocillin content lution. Dissolve and dilute an accu- of the multiple-dose vial as follows: rately weighed portion of the mezlocillin working standard with suf- × × Milligramsof mezlocillin Au P a d ficient distilled water to obtain a con- = per multiple-dose vial × × centration of 2.0 milligrams of As 1, 000 n mezlocillin per milliliter. where: (c) Preparation of sample solution. Dis- solve an accurately weighed portion of Au=Absorbance of sample solution; Pa=Potency of working standard solution the sample with sufficient distilled in micrograms per milliliter; water to obtain a stock solution of con- As=Absorbance of working standard solu- venient concentration; also, if tion; packaged for dispensing, reconstitute d=Dilution factor of the sample; as directed in the labeling using dis- n=Volume of sample solution assayed. tilled water in lieu of the reconstitut- (ii) Iodometric assay. Proceed as di- ing fluid. Then using a suitable hypo- rected in § 436.204 of this chapter. dermic needle and syringe, remove all (2) Sterility. Proceed as directed in of the withdrawable contents if it is § 436.20 of this chapter, using the meth- represented as a single-dose container; od described in paragraph (e)(1) of that or, if the labeling specifies the amount section. of potency in a given volume of the re- (3) Pyrogens. Proceed as directed in sultant preparation, remove an accu- § 436.32(b) of this chapter, using a solu- rately measured representative portion tion containing 100 milligrams of from each container. Dilute with dis- mezlocillin per milliliter. tilled water to obtain a stock solution (4) [Reserved] of convenient concentration. Further (5) Moisture. Proceed as directed in dilute an aliquot of the stock solution § 436.201 of this chapter. with distilled water to a concentration (6) pH. Proceed as directed in § 436.202 of 2.0 milligrams of mezlocillin per mil- of this chapter, using an aqueous solu- liliter (estimated). tion containing 100 milligrams of (d) Calculations—(1) Calculate the mezlocillin per milliliter. mezlocillin content in micrograms per (7) Specific rotation. Dilute an accu- milligram as follows: rately weighed sample with sufficient distilled water to obtain a concentra- Micrograms of mezlocillin per AP× = u a tion of approximately 10 milligrams of milligram of sample AW× mezlocillin per milliliter. Proceed as s u directed in § 436.210 of this chapter, where: using a 1-decimeter polarimeter tube. (8) Identity. Proceed as directed in Au=Absorbance of sample solution; § 436.311 of this chapter, diluting the Pa=Potency of working standard solution in micrograms per milliliter; sample with distilled water to a con-
As=Absorbance of working standard solu- centration of 4 milligrams of tion; mezlocillin per milliliter, except:
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(i) Use the mezlocillin working (b) Tests and methods of assay—(1) Po- standard and dilute with distilled tency. Use any of the following meth- water to a concentration of 4 milli- ods: however, the results obtained from grams of mezlocillin per milligram; the microbiological agar diffusion (ii) In lieu of the ninhydrin spray so- assay shall be conclusive. lution, after the plate is dried with a (i) Microbiological agar diffusion assay. current of warm air, expose the plate Proceed as directed in § 436.105 of this to iodine vapors for about 30 seconds; chapter, preparing the sample for assay and as follows: Dissolve an accurately (iii) Mezlocillin has an Rf value of weighed portion of the sample in suffi- about 0.67. cient 1 percent potassium phosphate buffer, pH 6.0 (solution 1), to give a [46 FR 58298, Dec. 1, 1981, as amended at 50 stock solution of convenient con- FR 19918, 19919, May 13, 1985] centration. Further dilute an aliquot of § 440.41 Nafcillin sodium the stock solution with solution 1 to monohydrate. the reference concentration of 2 micrograms of nafcillin per milliliter (a) Requirements for certification— (1) (estimated). Standards of identity, strength, quality, (ii) Iodometric assay. Proceed as di- and purity. Nafcillin sodium rected in § 436.204 of this chapter. monohydrate is the monohydrated so- (iii) Hydroxylamine colorimetric assay. dium salt of 6-(2-ethoxy-1- Proceed as directed in § 436.205 of this naphthamido) penicillanic acid. It is so chapter. purified and dried that: (2) [Reserved] (i) It contains not less than 820 (3) Moisture. Proceed as directed in micrograms of nafcillin per milligram. § 436.201 of this chapter. (ii) [Reserved] (4) pH. Proceed as directed in § 436.202 (iii) Its moisture content is not less of this chapter, using an aqueous solu- than 3.5 percent and not more than 5.3 tion containing 30 milligrams per mil- percent. liliter. (iv) Its pH in an aqueous solution (5) Crystallinity. Proceed as directed containing 30 milligrams per milliliter in § 436.203(b) of this chapter. is not less than 5.0 and not more than (6) Nafcillin content. Dissolve an accu- 7.0. rately weighed portion of the sample in (v) It is crystalline. a sufficient accurately measured vol- (vi) Its nafcillin content is not less ume of distilled water to obtain a con- than 82.0 percent. centration of 0.05 milligram of nafcillin (vii) It gives a positive identity test per milliliter (estimated). Treat a por- for nafcillin. tion of the nafcillin working standard (2) Labeling. It shall be labeled in ac- in the same manner. Using a suitable cordance with the requirements of spectrophotometer equipped with § 432.5(b) of this chapter. quartz cells and distilled water as a (3) Requests for certification; samples. blank, scan the absorption spectra of In addition to complying with the re- the sample and the nafcillin working quirements of § 431.1 of this chapter, standard solutions between the wave- each such request shall contain: lengths of 245 nanometers and 340 (i) Results of tests and assays on the nanometers. Determine the absorbance batch for potency, moisture, pH, crys- of the sample and working standard so- tallinity, nafcillin content, and iden- lutions at the absorption maximum at tity. 280±3 nanometers. (The exact position (ii) Samples required: 10 packages, of the maximum should be determined each containing approximately 300 mil- for the particular instrument used.) ligrams. Calculate as follows:
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Absorbanceof sample× weight in milligrams of standard × volume of samplesolution× nafcillin content of standard in percent Percent nafcillin = Absorbanceof standard× weight in milligrams of sample ×volume of standardsolution
(7) Identity. The absorption spectrum (b) For sterility testing: 20 packages, of the sample determined as directed in each containing approximately 300 mil- paragraph (b)(6) of this section com- ligrams. pares qualitatively with that of the (b) Tests and methods of assay—(1) Po- nafcillin working standard. tency. Use any of the following meth- [39 FR 18976, May 30, 1974, as amended at 42 ods: however, the results obtained from FR 59858, Nov. 22, 1977; 46 FR 16683, Mar. 13, the microbiological agar diffusion 1981; 50 FR 19918, 19919, May 13, 1985] assay shall be conclusive. (i) Microbiological agar diffusion assay. § 440.41a Sterile nafcillin sodium Proceed as directed in § 436.105 of this monohydrate. chapter, preparing the sample for assay (a) Requirements for certification— (1) as follows: Dissolve an accurately Standards of identity, strength, quality, weighed portion of the sample in suffi- and purity. Sterile nafcillin sodium cient 1 percent potassium phosphate monohydrate is the monohydrated so- buffer, pH 6.0 (solution 1), to give a dium salt of 6-(2-ethoxy-1- stock solution of convenient con- naphthamido) penicillanic acid. It is so centration. Further dilute an aliquot of purified and dried that: the stock solution with solution 1 to (i) It contains not less than 820 the reference concentration of 2 micrograms of nafcillin per milligram. micrograms of nafcillin per milliliter (ii) It is sterile. (estimated). (iii) It is nonpyrogenic. (ii) Iodometric assay. Proceed as di- (iv) [Reserved] rected in § 436.204 of this chapter. (v) Its moisture content is not less (iii) Hydroxylamine colorimetric assay. than 3.5 nor more than 5.3 percent. Proceed as directed in § 436.205 of this (vi) Its pH in an aqueous solution chapter. containing 30 milligrams per milliliter (2) Sterility. Proceed as directed in is not less than 5.0 and not more than § 436.20 of this chapter, using the meth- 7.0. od described in paragraph (e)(1) of that (vii) It is crystalline. section. (viii) Its nafcillin content is not less (3) Proceed as directed in than 82.0 percent. Pyrogens. § 436.32(a) of this chapter, using a solu- (ix) It gives a positive identity test for nafcillin. tion containing 80 milligrams of nafcillin per milliliter. (2) Labeling. It shall be labeled in ac- cordance with the requirements of (4) [Reserved] § 432.5(b) of this chapter. (5) Moisture. Proceed as directed in (3) Requests for certification; samples. § 436.201 of this chapter. In addition to complying with the re- (6) pH. Proceed as directed in § 436.202 quirements of § 431.1 of this chapter, of this chapter, using an aqueous solu- each such request shall contain: tion containing 30 milligrams per mil- (i) Results of tests and assays on the liliter. batch for potency, sterility, pyrogens, (7) Crystallinity. Proceed as directed moisture, pH, crystallinity, nafcillin in § 436.203(b) of this chapter. content, and identity. (8) Nafcillin content. Proceed as di- (ii) Samples required: rected in § 440.41(b)(6). (a) For all tests except sterility: 10 (9) Identity. The absorption spectrum packages, each containing approxi- of the sample determined as directed in mately 300 milligrams.
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paragraph (b)(8) of this section com- chapter, preparing the sample for assay pares qualitatively with that of the as follows: Dissolve an accurately nafcillin working standard. weighed portion of the sample in suffi- cient 1.0 percent potassium phosphate [39 FR 18976, May 30, 1974, as amended at 42 FR 59858, Nov. 22, 1977; 45 FR 16474, Mar. 14, buffer, pH 6.0 (solution 1), to give a 1980; 45 FR 22921, Apr. 4, 1980; 50 FR 19918, stock solution of convenient con- 19919, May 13, 1985] centration. Further dilute an aliquot of the stock solution with solution 1 to § 440.49 Oxacillin sodium the reference concentration of 5.0 monohydrate. micrograms of oxacillin per milliliter (a) Requirements for certification—(1) (estimated). Standards of identity, strength, quality, (ii) Iodometric assay. Proceed as di- and purity. Oxacillin sodium rected in § 436.204 of this chapter. monohydrate is the monohydrated so- (iii) Hydroxylamine colorimetric assay. dium salt of 5-methyl-3-phenyl-4- Proceed as directed in § 436.205 of this isoxazolyl penicillin. It is so purified chapter. and dried that: (2) [Reserved] (i) It contains not less than 815 and (3) Moisture. Proceed as directed in not more than 950 micrograms of § 436.201 of this chapter. oxacillin per milligram. (4) pH. Proceed as directed in § 436.202 (ii) [Reserved] of this chapter, using a solution con- (iii) Its moisture content is not less taining 30 milligrams per milliliter. than 3.5 and not more than 5.0 percent. (5) Oxacillin content. Place approxi- (iv) Its pH in an aqueous solution mately 60 milligrams of sample, accu- containing 30 milligrams per milliliter rately weighed, into a 100-milliliter is not less than 4.5 and not more than volumetric flask. Dissolve and fill to 7.5. volume with distilled water. Pipette a (v) Its oxacillin content is not less 5.0-milliliter aliquot of the sample so- than 81.5 percent and not more than lution into a 22- by 200-millimeter test 95.0 percent. tube, and add 5 milliliters of 10 N (vi) It is crystalline. NaOH. Mix the solution, and place the (vii) It gives a positive identity test tube in a boiling water bath for 60 min- for the oxacillin moiety. utes. Cool the tube, carefully add 10 (2) Labeling. It shall be labeled in ac- milliliters of 6 N HCl, mix, and replace cordance with the requirements of the tube in the boiling water bath for § 432.5 of this chapter. 10 minutes. Position the tube in the (3) Requests for certification; samples. bath so that the liquid level in the tube In addition to complying with the re- is the same as the liquid level in the quirements of § 431.1 of this chapter, bath. After heating, remove the tube each such request shall contain: from the bath, carefully agitate the (i) Results of tests and assays on the contents of the tube, and cool to room batch for potency, moisture, pH, temperature. Quantitatively transfer oxacillin content, crystallinity, and the contents of the tube to a 250-milli- identity. liter volumetric flask. Add approxi- (ii) Samples required: 10 packages, mately 200 milliliters of freshly boiled each containing approximately 300 mil- and cooled distilled water, then 4.0 mil- ligrams. liliters of 7.5 N NH4OH, and dilute to (b) Tests and methods of assay—(1) Po- volume with freshly boiled and cooled tency. Assay for potency by any of the distilled water. Treat a sample of the following methods; however, the re- oxacillin working standard in the same sults obtained from the micro- manner. Determine the absorbance of biological agar diffusion assay shall be the sample and working standard solu- conclusive. tions on a suitable spectrophotometer (i) Microbiological agar diffusion assay. at 235 nanometers against a reagent Proceed as directed in § 436.105 of this blank, and calculate as follows:
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Absorbance of sample× Weight in milligrams of standard ×oxacillin content of standard in percent Percent oxacillin = Absorbance of standard× Weight in milligrams of sample
(6) Crystallinity. Proceed as directed (a) For all tests except sterility: 10 in § 436.203(a) of this chapter. packages, each containing approxi- (7) Identity. Use the sample solution mately 300 milligrams, plus one pack- prepared as described in paragraph age containing approximately 2 grams. (b)(5) of this section and record the ul- (b) For sterility testing: 20 packages, traviolet spectrum between 230 each containing approximately 600 mil- nanometers and 260 nanometers. It ligrams. should be basically identical to that of (b) Tests and methods of assay—(1) Po- the standard similarly treated. tency. Assay for potency by any of the [39 FR 18976, May 30, 1974, as amended at 42 following methods; however, the re- FR 59858, Nov. 22, 1977; 49 FR 5096, Feb. 10, sults obtained from the micro- 1984; 50 FR 19918, 19919, May 13, 1985] biological agar diffusion assay shall be § 440.49a Sterile oxacillin sodium conclusive. monohydrate. (i) Microbiological agar diffusion assay. (a) Requirements for certification— (1) Proceed as directed in § 436.105 of this Standards of identity, strength, quality, chapter, preparing the sample for assay and purity. Sterile oxacillin sodium as follows: Dissolve an accurately monohydrate is the monohydrated so- weighed portion of the sample in suffi- dium salt of 5-methyl-3-phenyl-4- cient 1.0 percent potassium phosphate isoxazolyl penicillin. It is so purified buffer, pH 6.0 (solution 1), to give a and dried that: stock solution of convenient con- (i) It contains not less than 815 and centration. Further dilute an aliquot of not more than 950 micrograms of the stock solution with solution 1 to oxacillin per milligram. the reference concentration of 5.0 (ii) It is sterile. micrograms of oxacillin per milliliter (iii) It is nonpyrogenic. (estimated). (iv) [Reserved] (ii) Iodometric assay. Proceed as di- (v) Its moisture content is not less rected in § 436.204 of this chapter. than 3.5 and not more than 5.0 percent. (iii) Hydroxylamine colorimetric assay. (vi) Its pH in an aqueous solution Proceed as directed in § 436.205 of this containing 30 milligrams per milliliter chapter. is not less than 4.5 and not more than (2) Sterility. Proceed as directed in 7.5. (vii) Its oxacillin content is not less § 436.20 of this chapter, using the meth- than 81.5 percent and not more than od described in paragraph (e)(1) of that 95.0 percent. section. (viii) It is crystalline. (3) Pyrogens. Proceed as directed in (ix) It gives a positive identity test § 436.32(a) of this chapter, using a solu- for the oxacillin moiety. tion containing 20 milligrams of (2) Labeling. It shall be labeled in ac- oxacillin per milliliter. cordance with the requirements of (4) [Reserved] § 432.5 of this chapter. (5) Moisture. Proceed as directed in (3) Requests for certification; samples. § 436.201 of this chapter. In addition to complying with the re- (6) pH. Proceed as directed in § 436.202 quirements of § 431.1 of this chapter, of this chapter, using a solution con- each such request shall contain: taining 30 milligrams per milliliter. (i) Results of tests and assays on the (7) Oxacillin content. Proceed as di- batch for potency, sterility, pyrogens, rected in § 440.49(b)(5). moisture, pH, oxacillin content, crys- (8) Crystallinity. Proceed as directed tallinity, and identity. in § 436.203(a) of this chapter. (ii) Samples required:
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(9) Identity. Proceed as directed in ods; however, the results obtained from § 440.49(b)(7). the iodometric assay shall be conclu- sive. [39 FR 18976, May 30, 1974, as amended at 42 FR 59858, Nov. 22, 1977; 50 FR 19918, 19919, (i) Microbiological agar diffusion assay. May 13, 1985] Proceed as directed in § 436.105 of this chapter, preparing the sample for assay § 440.55a Sterile penicillin G as follows: Dissolve an accurately benzathine. measured representative portion of the (a) Requirements for certification— (1) sample in sufficient absolute methyl Standards of identity, strength, quality, alcohol to give a solution of convenient and purity. Penicillin G benzathine is concentration. Immediately, further the N,N′- dibenzylethylenediamine salt dilute with 1 percent potassium phos- of penicillin G. It is so purified and phate buffer, pH 6.0 (solution 1), to the dried that: reference concentration of 1.0 unit of (i) Its potency is not less than 1,090 penicillin G per milliliter (estimated). units and not more than 1,272 units per (ii) Iodometric assay. Proceed as di- milligram. rected in § 436.204 of this chapter. (ii) It is sterile. (2) Sterility. Proceed as directed in (iii) It is nonpyrogenic. § 436.20 of this chapter, using the meth- (iv) [Reserved] od described in paragraph (e)(2) of that (v) Its moisture content is not less section, except use medium C in lieu of than 5.0 percent and not more than 8 medium A, medium F in lieu of me- percent. dium E, and during the period of incu- (vi) Its pH in a 1:1 mixture of abso- bation shake the tubes at least once lute ethyl alcohol and water contain- daily. ing 0.5 milligram per milliliter is not (3) Pyrogens. Proceed as directed in less than 4.0 and not more than 6.5. § 436.32(d) of this chapter, using a solu- (vii) Its penicillin G content is not tion containing 4,000 units of penicillin less than 57.9 percent and not more G per milliliter. than 71.6 percent. (viii) It is crystalline. (4) [Reserved] (2) Labeling. It shall be labeled in ac- (5) Moisture. Proceed as directed in cordance with the requirements of § 436.201 of this chapter. § 432.5 of this chapter. (6) pH. Proceed as directed in § 436.202 (3) Requests for certification; samples. of this chapter, except prepare the In addition to complying with the re- sample as follows: Dissolve 50 milli- quirements of § 431.1 of this chapter, grams of sample with 50 milliliters of each such request shall contain: absolute ethyl alcohol. Add 50 milli- (i) Results of tests and assays on the liters of distilled water and mix well. batch for potency, sterility, pyrogens, (7) Penicillin G content. Accurately moisture, pH, penicillin G content, and weigh approximately 50 milligrams of crystallinity. the sample, dissolve in absolute methyl (ii) Samples required: alcohol, and dilute to 100 milliliters (a) For all tests except sterility: 10 with absolute methyl alcohol. Treat a packages, each containing approxi- portion of the working standard in the mately 300 milligrams. same manner. Using a suitable (b) For sterility testing: 20 packages, spectrophotometer equipped with a each containing approximately 600 mil- quartz cell and absolute methyl alcohol ligrams. as the blank, determine the absorbance (b) Tests and methods of assay—(1) Po- at 263 nanometers. Calculate the per- tency. Use either of the following meth- cent penicillin G as follows:
Absorbance of sample× weight in milligrams of standard × percent penicillin G in standard Percent penicillin G = Absorbance of standard× weight in milligrams of sample
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(8) Crystallinity. Proceed as directed (b) Tests and methods of assay— (1) Po- in § 436.203(a) of this chapter. tency. Assay for potency by any of the following methods; however, the re- [42 FR 59858, Nov. 22, 1977, as amended at 45 FR 16472, Mar. 14, 1980; 49 FR 6092, Feb. 17, sults obtained from the bioassay meth- 1984; 50 FR 19918, 19919, May 13, 1985] od shall be conclusive. (i) Microbiological agar diffusion assay. § 440.71 Penicillin V. Proceed as directed in § 436.105 of this (a) Requirements for certification—(1) chapter, preparing the sample for assay Standards of identity, strength, quality, as follows: Dissolve an accurately and purity. Penicillin V is 3,3-dimethyl weighed sample (approximately 30 mil- - 7-oxo-6-(2-phenoxyacetamido)-4-thia- ligrams) in 2.0 milliliters of absolute 1-azabicyclo[3.2.0]heptane-2-carboxylic methyl alcohol. Further dilute an ali- acid. It is so purified and dried that: quot of this solution with sufficient 1 (i) Its potency is not less than 1,525 percent potassium phosphate buffer, pH units nor more than 1,780 units per mil- 6.0 (solution 1), to the reference con- ligram. centration of 1.0 unit of penicillin V (ii) [Reserved] per milliliter (estimated). (iii) Its moisture content is not more (ii) Iodometric assay. Proceed as di- than 2.0 percent. rected in § 436.204 of this chapter. (iv) Its pH in a saturated aqueous so- (iii) Hydroxylamine colorimetric assay. lution is not less than 2.5 and not more Proceed as directed in § 436.205 of this than 4.0. chapter. (v) Its penicillin V content is not less (2) [Reserved] than 90 percent and not more than 105 (3) Moisture. Proceed as directed in percent. § 436.201 of this chapter. (vi) It is crystalline. (4) pH. Proceed as directed in § 436.202 (2) Labeling. In addition to the label- of this chapter, using a saturated aque- ing requirements of § 432.5 of this chap- ous solution prepared by adding ap- ter, each package shall bear on its out- proximately 30 milligrams per milli- side wrapper or container and the im- liter. mediate container the statement ‘‘For (5) Penicillin V content. Accurately use in the manufacture of nonparen- weigh approximately 20 milligrams of teral drugs only.’’ the sample, dissolve in absolute meth- (3) Requests for certification; samples. anol, and make to 100 milliliters with In addition to complying with the re- absolute methyl alcohol. Treat a por- quirements of § 431.1 of this chapter, tion of the working standard in the each such request shall contain: same manner. Using a suitable (i) Results of tests and assays on the spectrophotometer equipped with a batch for potency, moisture, pH, peni- quartz cell and absolute methyl alcohol cillin V content, and crystallinity. as the blank, determine the absorbance (ii) Samples required: 10 packages, of the peak at 276 nanometers. Cal- each containing approximately 300 mil- culate the percent penicillin V as fol- ligrams. lows:
Absorbance of sample× weight in milligrams of standard × Percent penicillin V in standard Percent penicillin V = Absorbance of standard× Weight in milligrams of sample
(6) Crystallinity. Proceed as directed § 440.73 Penicillin V potassium. in § 436.203(a) of this chapter. (a) Requirements for certification—(1) [42 FR 59859, Nov. 22, 1977, as amended at 50 Standards of identity, strength, quality, FR 19918, 19919, May 13, 1985] and purity. Penicillin V potassium is the potassium salt of 3,3-dimethyl-7- oxo-6-(2-phenoxyacetamido) - 4 -thia - 1
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- azabicyclo[3.2.0]heptane - 2 - car- (i) Microbiological agar diffusion assay. boxylic acid. It is so purified and dried Proceed as directed in § 436.105 of this that: chapter, preparing the sample for assay (i) Its potency is not less than 1,380 as follows: Dissolve an accurately units nor more than 1,610 units per mil- weighed sample in sufficient 1 percent ligram. potassium phosphate buffer, pH 6.0 (so- (ii) [Reserved] lution 1), to obtain a stock solution of (iii) Its loss on drying is not more convenient concentration. Further di- than 1.5 percent. lute an aliquot of the stock solution (iv) Its pH in an aqueous solution with solution 1 to the reference con- containing 30 milligrams per milliliter centration of 1.0 unit of penicillin V is not less than 4.0 and not more than 7.5. per milliliter (estimated). (v) Its penicillin V content is not less (ii) Iodometric assay. Proceed as di- than 81.2 percent and not more than rected in § 436.204 of this chapter. 94.7 percent. (iii) Hydroxylamine colorimetric assay. (vi) It is crystalline. Proceed as directed in § 436.205 of this (2) Labeling. In addition to the label- chapter. ing requirements of § 432.5 of this chap- (2) [Reserved] ter, each package shall bear on its out- (3) Loss on drying. Proceed as directed side wrapper or container and the im- in § 436.200(b) of this chapter. mediate container the statement ‘‘For (4) pH. Proceed as directed in § 436.202 use in the manufacture of nonparental of this chapter, using an aqueous solu- drugs only.’’ tion containing 30 milligrams per mil- (3) Requests for certification; samples. liliter. In addition to complying with the re- (5) Penicillin V content. Dissolve and quirements of § 431.1 of this chapter, each such request shall contain: dilute approximately 20 milligrams of (i) Results of tests and assays on the the sample, accurately weighed to 100 batch for potency, loss on drying, pH, milliliters with 0.1N sodium hydroxide penicillin V content, and crystallinity. solution. Treat a portion of the penicil- (ii) Samples required: 10 packages, lin V working standard in the same each containing approximately 300 mil- manner. Using a suitable ligrams. spectrophotometer equipped with a (b) Tests and methods of assay—(1) Po- quartz cell and 0.1N sodium hydroxide tency. Assay for potency by any of the solution as the blank, determine the following methods; however, the re- absorbance of the peak at 275 sults obtained from the iodometric nanometers. Calculate the percent pen- assay shall be conclusive. icillin V as follows:
Absorbance of sample× Weight in milligrams of standard × Percent penicillin V in standard Percent penicillin V = Absorbance of standard× Weight in milligrams of sample
(6) Crystallinity. Proceed as directed azabicyclo [3.2.0]heptane-2-carboxylic in § 436.203(a) of this chapter. acid 2-(diethylamino) ethyl p- aminobenzoate compound (1:1). It is so [42 FR 59859, Nov. 22, 1977, as amended at 50 FR 19918, 19919, May 13, 1985] purified and dried that: (i) Its potency is not less than 900 § 440.74a Sterile penicillin G procaine. units and not more than 1,050 units per (a) Requirements for certification—(1) milligram. Standards of identity, strength, quality, (ii) It is sterile. and purity. Penicillin G procaine is 3,3 (iii) It is nonpyrogenic. - dimethyl - 7 - oxo - 6 - (2 - (iv) [Reserved] phenylacetamido) - 4 - thia - 1 -
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(v) Its moisture content is not less contains lecithin, use diluting fluid D than 2.8 percent and not more than 4.2 in lieu of A. percent. (3) Pyrogens. Proceed as directed in (vi) Its pH in a saturated aqueous so- § 436.32(h) of this chapter, using a solu- lution (about 300 milligrams per milli- tion containing 2,000 units of penicillin liter) is not less than 5.0 and not more G per milliliter. than 7.5. (4) [Reserved] (vii) Its penicillin G content is not (5) Moisture. Proceed as directed in less than 51.0 percent and not more § 436.201 of this chapter. than 59.6 percent. (6) pH. Proceed as directed in § 436.202 (viii) It is crystalline. of this chapter, using a saturated solu- (2) Labeling. It shall be labeled in ac- tion prepared by suspending 300 milli- cordance with the requirements of grams of sample per milliliter. § 432.5 of this chapter. (7) Penicillin G content. Proceed as di- (3) Requests for certification; samples. rected in § 436.316 of this chapter. In addition to complying with the re- (8) Crystallinity. Proceed as directed quirements of § 431.1 of this chapter, in § 436.203(a) of this chapter. each such request shall contain: (i) Results of tests and assays on the [42 FR 59860, Nov. 22, 1977, as amended at 45 batch for potency, sterility, pyrogens, FR 16472, Mar. 14, 1980; 45 FR 22921, Apr. 4, 1980; 50 FR 19918, 19919, May 13, 1985] moisture, pH, penicillin G content, and crystallinity. § 440.80 Penicillin G potassium. (ii) Samples required: (a) For all tests except sterility: 10 (a) Requirements for certification—(1) packages, each containing approxi- Standards of identity, strength, quality mately 300 milligrams. and purity. Penicillin G potassium is potassium 3,3-dimethyl-7-oxo-6-(2- (b) For sterility testing: 20 packages, phenylacetamido)-4-thia-1- each containing approximately 600 mil- azabicyclo[3.2.0]heptane-2-carboxylate. ligrams. It is so purified and dried that: (b) Tests and methods of assay—(1) Po- (i) Its potency is not less than 1,440 tency. Use any of the following meth- units and not more than 1,680 units per ods; however, the results obtained from milligram. the iodometric assay shall be conclu- sive. (ii) Its loss on drying is not more (i) Microbiological agar diffusion assay. than 1.5 percent. Proceed as directed in § 436.105 of this (iii) The pH of an aqueous solution chapter, preparing the sample for assay containing 60 milligrams per milliliter as follows: Dissolve an accurately is not less than 5.0 and not more than weighed sample in sufficient 1 percent 7.5. potassium phosphate buffer, pH 6.0 (so- (iv) Its penicillin G content is not lution 1), to give a stock solution of less than 80.8 percent and not more convenient concentration. Further di- than 94.3 percent. lute an aliquot of the stock solution (v) It is crystalline. with solution 1 to the reference con- (2) Labeling. It shall be labeled in ac- centration of 1.0 unit of penicillin G cordance with the requirements of per milliliter (estimated). § 432.5 of this chapter. (ii) Iodometric assay. Proceed as di- (3) Requests for certification; samples. rected in § 436.204 of this chapter. In addition to complying with the re- (iii) Hydroxylamine colorimetric assay. quirements of § 431.1 of this chapter, Proceed as directed § 436.205 of this each such request shall contain: chapter. (i) Results of test and assays on the (2) Sterility. Proceed as directed in batch for potency, loss on drying, pH, § 436.20 of this chapter, using the meth- penicillin G content, and od described in paragraph (e)(1) of that crystrallinity. section, except add sufficient penicil- (ii) Samples, if required by the Cen- linase to diluting fluid A and swirl the ter for Drug Evaluation and Research: flask to completely solubilize the sam- 10 packages, each containing approxi- ple before filtration. If the product mately 300 milligrams.
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(b) Test and methods of assay—(1) Po- (a) If the batch is packaged for re- tency. Proceed as directed in packing or for use in the manufacture § 440.80a(b)(1). of another drug: (2) Loss on drying. Proceed as directed (1) For all tests except sterility: 10 in § 436.200(b) of this chapter. packages, each containing approxi- (3) pH. Proceed as directed in § 436.202 mately 300 milligrams. of this chapter, using an aqueous solu- (2) For sterility testing: 20 packages, tion containing 60 milligrams per mil- each containing approximately 600 mil- liliter. ligrams. (4) Penicillin G content. Proceed as di- (b) If the batch is packaged for dis- rected in § 436.316 of this chapter. pensing: (5) Crystallinity. Proceed as directed (1) For all tests except sterility: A in § 436.203(a) of this chapter. minimum of 10 immediate containers. (2) For sterility testing: 20 immediate [55 FR 38674, Sept. 20, 1990] containers, collected at regular inter- § 440.80a Sterile penicillin G potas- vals throughout each filling operation. sium. (b) Tests and methods of assay—(1) Po- tency—(i) Sample preparation. Dissolve (a) Requirements for certification—(1) an accurately weighed portion of the Standards of identity, strength, quality, sample in sufficient 1 percent potas- and purity. Penicillin G potassium is sium phosphate buffer, pH 6.0 (solution potassium 3,3-dimethyl-7-oxo-6-(2- 1), to give a stock solution of conven- phenylacetamido)-4-thia-1-azabicyclo ient concentration; also, if it is [3.2.0] heptane-2-carboxylate. It is so packaged for dispensing, reconstitute purified and dried that: as directed in the labeling. Then using (i) Its potency is not less than 1,440 a suitable hypodermic needle and sy- units and not more than 1,680 units per ringe, remove all of the withdrawable milligram. If it is packaged for dispens- contents if it is represented as a single- ing, its potency is satisfactory if it is dose container; or if the labeling speci- not less than 90 percent and not more fies the amount of potency in a given than 115 percent of the number of units volume of the resultant preparation, of penicillin G that it is represented to remove an accurately measured rep- contain. resentative portion from each con- (ii) It is sterile. tainer. Dilute with solution 1 to give a (iii) It is nonpyrogenic. stock solution of convenient con- (iv) [Reserved] centration. (v) Its loss on drying is not more (ii) Assay procedures. Use any of the than 1.5 percent. following methods; however, the re- (vi) Its pH in an aqueous solution sults obtained from the iodometric containing 60 milligrams per milliliter assay shall be conclusive. is not less than 5.0 and not more than (a) Microbiological agar diffusion 7.5. assay. Proceed as directed in § 436.105 of (vii) Its penicillin G content is not this chapter, diluting an aliquot of the less than 80.8 percent and not more stock solution with solution 1 to the than 94.3 percent. reference concentration of 1.0 unit of (viii) It is crystalline. penicillin G per milliliter (estimated). (2) Labeling. It shall be labeled in ac- (b) Iodometric assay. Proceed as di- cordance with the requirements of rected in § 436.204 of this chapter, dilut- § 432.5 of this chapter. ing an aliquot of the stock solution (3) Requests for certification; samples. with solution 1 to the prescribed con- In addition to complying with the re- centration. quirements of § 431.1 of this chapter, (c) Hydroxylamine colorimetric assay. each such request shall contain: Proceed as directed in § 436.205 of this (i) Results of tests and assays on the chapter. batch for potency, sterility, pyrogens, (2) Sterility. Proceed as directed in loss on drying, pH, penicillin G con- § 436.20 of this chapter, using the meth- tent, and crystallinity. od described in paragraph (e)(1) of that (ii) Samples required: section.
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(3) Pyrogens. Proceed as directed in (i) Results of tests and assays on the § 436.32(b) of this chapter, using a solu- batch for potency, sterility, pyrogens, tion containing 20,000 units of penicil- loss on drying, pH, penicillin G con- lin G per milliliter. tent, crystallinity, and heat stability. (4) [Reserved] (ii) Samples required: (5) Loss on drying. Proceed as directed (a) If the batch is packaged for re- in § 436.200(b) of this chapter. packing or for use in the manufacture (6) pH. Proceed as directed in § 436.202 of another drug: of this chapter, using an aqueous solu- (1) For all tests except sterility: 10 tion containing 60 milligrams per mil- packages, each containing approxi- liliter. mately 300 milligrams. (7) Penicillin G content. Proceed as di- (2) For sterility testing: 20 packages, rected in § 436.316 of this chapter. each containing approximately 600 mil- (8) Crystallinity. Proceed as directed ligrams. in § 436.203(a) of this chapter. (b) If the batch is packaged for dis- [42 FR 59860, Nov. 22, 1977, as amended at 45 pensing: FR 16472, Mar. 14, 1980; 45 FR 22922, Apr. 4, (1) For all tests except sterility: A 1980; 50 FR 19918, 19919, May 13, 1985] minimum of 10 immediate containers. (2) For sterility testing: 20 immediate § 440.81a Sterile penicillin G sodium. containers, collected at regular inter- (a) Requirements for certification—(1) vals throughout each filling operation. Standards of identity, strength, quality, (b) Tests and methods of assay—(1) Po- and purity. Penicillin G sodium is so- tency—(i) Sample preparation. Dissolve dium 3,3-dimethyl-7-oxo-6-(2 - an accurately weighed portion of the phenylacetamido) - 4 - thia - 1 - sample in sufficient 1 percent potas- azabicyclo [3.2.0] heptane-2- sium phosphate buffer, pH 6.0 (solution carboxylate. It is so purified and dried 1), to give a stock solution of conven- that: ient concentration; also, if it is (i) Its potency is not less than 1,500 packaged for dispensing, reconstitute units and not more than 1,750 units per as directed in the labeling. Then using milligram. If it is packaged for dispens- a suitable hypodermic needle and sy- ing, its content is satisfactory if it is ringe, remove all of the withdrawable not less than 90 percent and not more contents if it is represented as a single- than 115 percent of the number of units dose container; or if the labeling speci- of penicillin G that it is represented to fies the amount of potency in a given contain. volume of the resultant preparation, (ii) It is sterile. remove an accurately measured rep- (iii) It is nonpyrogenic. resentative aliquot from each con- (iv) [Reserved] tainer. Dilute with solution 1 to give a (v) Its loss on drying is not more stock solution of convenient con- than 1.5 percent. centration. (vi) Its pH in an aqueous solution (ii) Assay procedures. Use any of the containing 60 milligrams per milliliter following methods; however, the re- is not less than 5.0 and not more than sults obtained from the iodometric 7.5. assay shall be conclusive. (vii) Its penicillin G content is not (a) Microbiological agar diffusion less than 84.5 percent and not more assay. Proceed as directed in § 436.105 of than 98.5 percent. this chapter, diluting an aliquot of the (viii) It is crystalline. stock solution with solution 1 to the (ix) It passes the test for heat stabil- reference concentration of 1.0 unit of ity if it does not show a loss of more penicillin G per milliliter (estimated). than 10 percent of its original potency. (b) Iodometric assay. Proceed as di- (2) Labeling. It shall be labeled in ac- rected in § 436.204 of this chapter, dilut- cordance with the requirements of ing an aliquot of the stock solution § 432.5 of this chapter. with solution 1 to the prescribed con- (3) Requests for certification; samples. centration. In addition to complying with the re- (c) Hydroxylamine colorimetric assay. quirements of § 431.1 of this chapter, Proceed as directed in § 436.205 of this each such request shall contain: chapter.
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(2) Sterility. Proceed as directed in quirements of § 431.1 of this chapter, § 436.20 of this chapter, using the meth- each such request shall contain: od described in paragraph (e)(1) of that (i) Results of tests and assays on the section. batch for potency, sterility, pyrogens, (3) Pyrogens. Proceed as directed in moisture, and pH. § 436.32(b) of this chapter, using a solu- (ii) Samples required: tion containing 20,000 units of penicil- (a) If it is packaged for repacking or lin G per milliliter. for use in the manufacture of another (4) [Reserved] drug: (5) Loss on drying. Proceed as directed (1) For all tests except sterility: 10 in § 436.200(b) of this chapter. packages, each containing approxi- (6) pH. Proceed as directed in § 436.202 mately 300 milligrams; and 5 packages, of this chapter, using an aqueous solu- each containing approximately 1 gram. tion containing 60 milligrams per mil- (2) For sterility testing: 20 packages, liliter. each containing approximately 300 mil- (7) Penicillin G content. Proceed as di- ligrams. rected in § 436.316 of this chapter. (b) If it is packaged for dispensing: (1) For all tests except sterility: A (8) Crystallinity. Proceed as directed minimum of 15 immediate containers. in § 436.203(a) of this chapter. (2) For sterility testing: 20 immediate (9) Heat stability. Proceed as directed containers, collected at regular inter- in § 436.214 of this chapter. vals throughout each filling operation. [42 FR 59861, Nov. 22, 1977, as amended at 45 (b) Tests and methods of assay—(1) Po- FR 22922, Apr. 4, 1980; 50 FR 19918, 19919, May tency. Proceed as directed in § 436.334 of 13, 1985] this chapter. (2) Sterility. Proceed as directed in § 440.83a Sterile piperacillin sodium. § 436.20 of this chapter, using the meth- (a) Requirements for certification—(1) od described in paragraph (e)(1) of that Standards of identity, strength, quality, section. and purity. Sterile piperacillin sodium (3) Pyrogens. Proceed as directed in is the sodium salt of (2S,5R, 6R)-6-[(R)- § 436.32(a) of this chapter, using a solu- 2-(4-ethyl-2,3-dioxo-1-piperazine- tion containing 150 milligrams of carboxamido)-2-phenylacetamido]-3,3- piperacillin per milliliter. dimethyl-7-oxo-4-thia-1-azabicyclo- (4) [Reserved] [3.2.0]heptane-2-carboxylate. It is so pu- (5) Moisture. Proceed as directed in rified and dried that: § 436.201 of this chapter, using the sam- (i) Its potency is not less than 863 ple preparation method described in micrograms and not more than 1,007 paragraph (d)(4) of that section. micrograms of piperacillin per milli- (6) pH. Proceed as directed in § 436.202 gram on an anhydrous basis. If it is of this chapter, using an aqueous solu- packaged for dispensing, it contains tion containing 400 milligrams per mil- not less than 90.0 percent and not more liliter than 120.0 percent of the number of [47 FR 15769, Apr. 13, 1982, as amended at 50 grams of piperacillin that it is rep- FR 19918, 19919, May 13, 1985] resented to contain. (ii) It is sterile. § 440.90a Sterile ticarcillin disodium. (iii) It is nonpyrogenic. (a) Requirements for certification—(1) (iv) [Reserved] Standards of identity, strength, quality, (v) Its moisture content is not more and purity. Sterile ticarcillin disodium than 1.0 percent. is 6-[(carboxy-3-thienylacetyl)] amino - (vi) Its pH in an aqueous solution 3, 3-dimethyl - 7 - oxo - 4 - thia - 1 - containing 400 milligrams per milliliter azabicyclo[3.2.0]heptane-2-carboxylic is not less than 5.5 and not more than acid disodium salt. It is so purified and 7.5. dried that: (2) Labeling. It shall be labeled in ac- (i) It contains not less than 800 cordance with the requirements of micrograms of ticarcillin per milli- § 432.5 of this chapter. gram on an anhydrous basis. If it is (3) Requests for certification; samples. packaged for dispensing, its ticarcillin In addition to complying with the re- content is not less than 90 percent and
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not more than 115 percent of the num- withdrawable contents if it is rep- ber of milligrams of ticarcillin that it resented as a single-dose container; or is represented to contain. if the labeling specifies the amount of (ii) It is sterile. potency in a given volume of the re- (iii) It is nonpyrogenic. sultant preparation, remove an accu- (iv) [Reserved] rately measured representative portion (v) Its moisture content is not more from each container. If it is a single- than 6.0 percent. dose container, use a separate needle (vi) Its pH in an aqueous solution and syringe for each container. Dilute containing 10 milligrams of ticarcillin with sufficient solution 1 to give a per milliliter (or if packaged for dis- stock solution of convenient con- pensing after reconstitution as directed centration. Further dilute an aliquot of in the labeling) is not less than 6.0 and the stock solution with solution 1 to not more than 8.0. the reference concentration of 5.0 (vii) It gives a positive identity test micrograms of ticarcillin per milliliter for ticarcillin. (estimated). (viii) Its ticarcillin content is not (2) Sterility. Proceed as directed in less than 80 percent and not more than § 436.20 of this chapter, using the meth- 94 percent on an anhydrous basis. od described in paragraph (e)(1) of that (2) Labeling. It shall be labeled in ac- section. cordance with the requirements of (3) Pyrogens. Proceed as directed in § 432.5 of this chapter. § 436.32(b) of this chapter, using a solu- (3) Requests for certification; samples. tion containing 100 milligrams of In addition to complying with the re- ticarcillin per milliliter. quirements of § 431.1 of this chapter, (4) [Reserved] each such request shall contain: (5) Moisture. Proceed as directed in (i) Results of tests and assays on the § 436.201 of this chapter. batch for potency, sterility, pyrogens, (6) pH. Proceed as directed in § 436.202 moisture, pH, identity, and ticarcillin of this chapter, using an aqueous solu- content. tion containing 10 milligrams of (ii) Samples required: ticarcillin per milliliter (or if packaged (a) If it is packaged for repacking or for dispensing, use a solution prepared for use in the manufacture of another as directed for reconstitution in the la- drug: beling). (1) For all tests except sterility: 10 (7) Identity and ticarcillin content. packages, each containing approxi- Transfer an accurately weighed portion mately 300 milligrams; and 5 packages, of approximately 40 milligrams of the each containing approximately 1 gram. sample to a 100-milliliter volumetric (2) For sterility testing: 20 packages, flask. Dissolve and dilute to volume each containing approximately 300 mil- with distilled water. Transfer 5.0 milli- ligrams. liters of this solution to another 100- (b) If it is packaged for dispensing: milliliter volumetric flask and dilute (1) For all tests except sterility: A to volume with 0.1N methanolic hydro- minimum of 15 immediate containers. chloric acid (prepared by diluting 0.8 (2) For sterility testing: 20 immediate milliliter of 12N hydrochloric acid to containers, collected at regular inter- 100 milliliters with methyl alcohol). vals throughout each filling operation. Treat a portion of the ticarcillin stand- (b) Tests and methods of assay—(1) Po- ard in the same manner. Using a suit- tency. Proceed as directed in § 436.105 of able spectrophotometer equipped with this chapter, preparing the sample for a 1.0-centimeter quartz cell and 0.1N assay as follows: Dissolve an accu- methanolic acid as a blank, scan the rately weighed sample in sufficient 1.0 absorption spectrum of the methanolic percent potassium phosphate buffer, pH solution of the sample and the stand- 6.0 (solution 1), to give a stock solution ard between the wavelengths of 300 and of convenient concentration; and also, 200 nanometers. Determine the if it is packaged for dispensing, recon- absorbance of each solution at the stitute as directed in the labeling. maxima, at approximately 230 Then using a suitable hypodermic nee- nanometers. The spectrum of the sam- dle and syringe, remove all the ples should compare qualitatively with
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that of the ticarcillin working stand- ard. Determine the percent ticarcillin as follows:
Absorbance of sample× Weight in milligrams of standard × Potency of standard in micrograms per milligram× 10 Percent ticarcillin = Absorbance of standard× weight in milligrams of sample× (100 − m)
where: m=Percent moisture in the sample. rected in § 436.355 of this chapter using [42 FR 14093, Mar. 15, 1977, as amended at 50 the equipment, conditions, reagents, FR 19918, 19919, May 13, 1985] and system suitability requirements as described in § 440.290b(b), except use the § 440.91 Ticarcillin monosodium resolution test solution to determine monohydrate. resolution in lieu of the working stand- (a) Requirements for certification—(1) ard solution. Prepare the working Standards of identity, strength, quality, standard solution, sample solution, and and purity. Ticarcillin monosodium resolution test solution and calculate monohydrate is 6-[(carboxy-3- the micrograms of ticarcillin per milli- thienylacetyl)] amino-3,3-dimethyl-7- grams as follows: oxo-4-thia-1-azabicyclo [3.2.0] heptane- (i) Preparation of working standard, 2-carboxylic acid monosodium salt sample, and resolution test solutions—(A) monohydrate. It is so purified and Working standard solution. Accurately dried that: weigh a quantity of the ticarcillin (i) Its ticarcillin potency is not less working standard containing the equiv- than 890 micrograms of ticarcillin per alent of approximately 90 milligrams of milligram calculated on an anhydrous ticarcillin activity and transfer to a basis. 100-milliliter volumetric flask. Dis- (ii) Its moisture content is not less solve and dilute to volume with diluent than 4.0 and not more than 6.0 percent. pH 6.4 phosphate buffer prepared as de- (iii) The pH of an aqueous solution scribed in § 440.290b(b)(1)(i)(c). containing 10 milligrams of ticarcillin (B) Sample solution. Dissolve an accu- per milliliter is not less than 2.5 and rately weighed portion of the sample not more than 4.0. with diluent pH 6.4 buffer as prepared (iv) It gives a positive identity test in § 440.290b(b)(1)(i)(c) to obtain a solu- for ticarcillin. tion containing 0.9 milligram of (v) It is crystalline. ticarcillin activity per milliliter (esti- (2) Labeling. It shall be labeled in ac- mated). cordance with the requirements of (C) Resolution test solution. Accurately § 432.5 of this chapter. weigh a quantity of the ticarcillin (3) Requests for certification; samples. working standard containing the equiv- In addition to complying with the re- alent of approximately 90 milligrams of quirements of § 431.1 of this chapter, ticarcillin activity and transfer to a each such request shall contain: 100-milliliter volumetric flask. Prepare (i) Results of tests and assays on the a solution of the clavulanic acid work- batch for potency, moisture, pH, iden- ing standard containing the equivalent tity, and crystallinity. of 30 milligrams of clavulanic acid ac- (ii) Samples, if required by the Cen- tivity in a 100-milliliter volumetric ter for Drug Evaluation and Research: flask. Dissolve and dilute to volume 10 packages, each containing approxi- with diluent. Transfer 10 milliliters of mately 300 milligrams. this solution into the flask containing (b) Tests and methods of assay—(1) the ticarcillin standard. Dilute the Ticarcillin potency. Determine the combined standard solution to volume micrograms of ticarcillin activity per with diluent and mix. Use within 8 milligram of sample. Proceed as di- hours of preparation.
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(ii) Calculations. Calculate the to the standards prescribed by micrograms of ticarcillin per milli- § 440.3(a)(1). gram as follows: (2) Labeling. In addition to the label- ing requirements prescribed by § 432.5 Milligrams of ACV× × × 0. 5 of this chapter, this drug shall be la- amoxicillin or clavulanic = u beled ‘‘amoxicillin capsules’’. acid per milliliter As (3) Requests for certification; samples. In addition to complying with the re- where: quirements of § 431.1 of this chapter, Au=Area of the ticarcillin peak in the chro- matogram of the sample (at a retention each such request shall contain: time equal to that observed for the (i) Results of tests and assays on: standard); (a) The amoxicillin trihydrate used As=Area of the ticarcillin peak in the chro- in making the batch for potency, mois- matogram of the ticarcillin working ture, pH, amoxicillin content, concord- standard; ance, crystallinity, and identity. Ps=Ticarcillin activity in the ticarcillin working standard solution in (b) The batch for potency, moisture, micrograms per milliliter; and identity.
Cu=Milligrams of ticarcillin sample per mil- (ii) Samples required: liliter of sample solution; and (a) The amoxicillin trihydrate used m=Percent moisture content of the sample. in making the batch: 12 packages, each containing approximately 300 milli- (2) Moisture. Proceed as directed in grams. § 436.201 of this chapter. (b) The batch: A minimum of 30 cap- (3) pH. Proceed as directed in § 436.202 sules. of this chapter, using an aqueous solu- tion containing 10 milligrams of (b) Tests and methods of assay—(1) Po- ticarcillin per milliliter. tency. Assay for potency by either of (4) Identity. Proceed as directed in the following methods; however, the re- § 440.90a(b)(7). sults obtained from the iodometric assay shall be conclusive: (5) Crystallinity. Proceed as directed in § 436.203 of this chapter. (i) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of this [55 FR 5839, Feb. 20, 1990] chapter, preparing the sample for assay as follows: Place a representative num- Subpart B—Oral Dosage Forms ber of capsules into a high-speed glass blender jar containing sufficient 0.1M § 440.103 Amoxicillin oral dosage potassium phosphate buffer, pH 8.0 (so- forms. lution 3), to give a stock solution of convenient concentration. Blend for 3 § 440.103a Amoxicillin trihydrate cap- to 5 minutes. Remove an aliquot and sules. further dilute with solution 3 to the (a) Requirements for certification—(1) reference concentration of 0.1 Standards of identity, strength, quality, microgram of amoxicillin per milliliter and purity. Amoxicillin trihydrate cap- (estimated). sules are composed of amoxicillin tri- (ii) Iodometric assay. Proceed as di- hydrate with or without one or more rected in § 436.204 of this chapter, ex- suitable and harmless lubricants, cept in paragraph (d) of that section, diluents, and drying agents, enclosed in add 3 drops of 1.2N hydrochloric acid to a gelatin capsule. Each capsule con- both the sample and working standard tains amoxicillin trihydrate equivalent solutions after the addition of 0.01N io- to 250 milligrams or 500 milligrams of dine solution. Prepare the sample as amoxicillin. Its potency is satisfactory follows: Place the contents of a rep- if it is not less than 90 percent and not resentative number of capsules into a more than 120 percent of the number of high-speed glass blender jar and add milligrams of amoxicillin that it is sufficient distilled water to give a con- represented to contain. Its moisture venient concentration. Blend for 3 to 5 content is not more than 14.5 percent. minutes. Further dilute an aliquot It passes the identity test. The with distilled water to the prescribed amoxicillin trihydrate used conforms concentration.
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(2) Moisture. Proceed as directed in (a) The amoxicillin trihydrate used § 436.201 of this chapter. in making the batch: 12 packages, each (3) Identity. Proceed as directed in containing approximately 300 milli- § 436.311 of this chapter, preparing the grams. sample solution as follows: Dissolve an (b) The batch: A minimum of six im- accurately weighed portion of the mediate containers. amoxicillin capsule contents in 0.1N (b) Tests and methods of assay—(1) Po- hydrochloric acid to give a solution tency. Assay for potency by either of containing 4 milligrams of amoxicillin the following methods; however, the re- per milliliter. sults obtained from the iodometric [39 FR 34033, Sept. 23, 1974, as amended at 49 assay shall be conclusive: FR 3458, Jan. 27, 1984; 50 FR 19919, May 13, (i) Microbiological agar diffusion assay. 1985] Proceed as directed in § 436.105 of this chapter, preparing the sample for assay § 440.103b Amoxicillin trihydrate for as follows: Reconstitute the drug as di- oral suspension. rected in the labeling. Place an accu- (a) Requirements for certification—(1) rately measured representative portion Standards of identity, strength, quality, of the sample into a suitable volu- and purity. Amoxicillin trihydrate for metric flask and dilute to volume with oral suspension is a mixture of 0.1M potassium phosphate buffer, pH amoxicillin trihydrate with one or 8.0 (solution 3), to give a stock solution more suitable and harmless colorings, of convenient concentration. Mix well. flavorings, buffers, sweetening ingredi- Further dilute an aliquot with solution ents, preservatives, stabilizers, and 3 to the reference concentration of 0.1 suspending agents. When reconstituted microgram of amoxicillin per milliliter as directed in the labeling, it contains (estimated). amoxicillin trihydrate equivalent to ei- (ii) Iodometric assay. Proceed as di- ther 25 or 50 milligrams of amoxicillin rected in § 436.204 of this chapter, ex- per milliliter. Its potency is satisfac- cept in paragraph (d) of that section, tory if it is not less than 90 percent and add 3 drops of 1.2N hydrochloric acid to not more than 120 percent of the num- both the sample and working standard ber of milligrams of amoxicillin that it solutions after the addition of 0.01N io- is represented to contain. Its moisture dine solution. Prepare the sample as content is not more than 3.0 percent. follows: Reconstitute the drug as di- Its pH, when reconstituted as directed rected in the labeling. Place an accu- in the labeling, is not less than 5.0 and rately measured aliquot (usually a sin- not more than 7.5. It passes the iden- gle dose) into an appropriately sized tity test. The amoxicillin trihydrate volumetric flask and dilute to volume used conforms to the standards pre- with distilled water. Mix well. Further scribed by § 440.3(a)(1). dilute with distilled water to the pre- (2) Labeling. In addition to the label- scribed concentration. ing requirements prescribed by § 432.5 (2) Moisture. Proceed as directed in of this chapter, this drug shall be la- § 436.201 of this chapter. beled ‘‘amoxicillin for oral suspen- (3) pH. Proceed as directed in § 436.202 sion’’. of this chapter, using the suspension (3) Requests for certification; samples. reconstituted as directed in the label- In addition to complying with the re- ing. quirements of § 431.1 of this chapter, (4) Identity. Proceed as directed in each such request shall contain: § 436.311 of this chapter, preparing the (i) Results of tests and assays on: sample solution as follows: From an al- (a) The amoxicillin trihydrate used iquot of suspension prepared in accord- in making the batch for potency, mois- ance with the label, make either a ture, pH, amoxicillin content, concord- 6.25:1 dilution for the 25-milligrams- ance, crystallinity, and identity. per-milliliter dosage; or a 12.5:1 dilu- (b) The batch for potency, moisture, tion for the 50-milligrams-per-milli- pH, and identity. liter dosage, with 0.1N hydrochloric (ii) Samples required: acid. The slight dilution of the acid
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does not have a significant effect on ber of tablets into a high-speed glass the test. blender jar with sufficient 0.1M potas- sium phosphate buffer, pH 8.0 (solution [39 FR 34033, Sept. 23, 1974, as amended at 49 FR 3458, Jan. 27, 1984; 50 FR 19919, May 13, 3), to obtain a stock solution of con- 1985; 54 FR 47351, Nov. 14, 1989] venient concentration. Blend for 3 to 5 minutes. Remove an aliquot and dilute § 440.103c Amoxicillin trihydrate with solution 3 to the reference con- chewable tablets. centration of 0.1 microgram of (a) Requirements for certification— (1) amoxicillin per milliliter (estimated). Standards of identity, strength, quality, (ii) Iodometric assay. Proceed as di- and purity. Amoxicillin trihydrate rected in § 436.204 of this chapter, pre- chewable tablets are composed of paring the sample as follows: Place a amoxicillin trihydrate with or without representative number of tablets into a one or more suitable lubricants, high-speed glass blender jar containing diluents, preservatives, drying agents, sufficient 1 percent potassium phos- flavorings, and colorings. Each tablet phate buffer, pH 6.0 (solution 1), to give contains amoxicillin trihydrate equiva- a stock solution of convenient con- lent to either 125 or 250 milligrams of centration. Blend for 5 minutes. Fur- amoxicillin. Its potency is satisfactory ther dilute with solution 1 to the pre- if it contains not less than 90 percent scribed concentration. and not more than 120 percent of the (2) Moisture. Proceed as directed in number of milligrams of amoxicillin § 436.201 of this chapter. that it is represented to contain. Its (3) Identity. Proceed as directed in moisture content is not more than 6.0 § 436.311 of this chapter, preparing the percent. It passes the identity test. The sample as follows: Using a mortar and amoxicillin trihydrate used conforms pestle, grind a representative number to the standards prescribed by of tablets into a fine powder. Dissolve § 440.3(a)(1). an accurately weighed amount of this (2) Labeling. In addition to the label- powder in 0.1N hydrochloric acid to ing requirements prescribed by give a solution containing 4 milligrams of amoxicillin per milliliter. § 432.5 of this chapter, this drug shall be labeled ‘‘amoxicillin tablets.’’ [45 FR 64569, Sept. 30, 1980, as amended at 50 (3) Requests for certification; samples. FR 19919, May 13, 1985] In addition to the requirements of §431.1 of this chapter, each such request § 440.103d Amoxicillin trihydrate and clavulanate potassium tablets. shall contain: (i) Results of tests and assay on: (a) Requirements for certification—(1) (a) The amoxicillin trihydrate used Standards of identity, strength, quality, in making the batch for potency, mois- and purity. Amoxicillin trihydrate and ture, pH, amoxicillin content, concord- clavulanate potassium tablets are com- ance, crystallinity, and identity. posed of amoxicillin trihydrate and (b) The batch for potency, moisture, clavulanate potassium with or without and identity. one or more suitable lubricants, (ii) Samples required: diluents, and binders. Each tablet con- (a) The amoxicillin trihydrate used tains amoxicillin trihydrate equivalent in making the batch: 12 packages, each to either 250 or 500 milligrams of containing approximately 300 milli- amoxicillin and clavulanate potassium grams. equivalent to 125 milligrams of (b) The batch: A minimum of 30 tab- clavulanic acid. Its amoxicillin tri- lets. hydrate content is satisfactory if it (b) Tests and methods of assay—(1) Po- contains not less than 90 percent and tency. Assay for potency by either of not more than 120 percent of the num- the following methods; however, the re- ber of milligrams of amoxicillin that it sults obtained from the iodometric is represented to contain. Its assay shall be conclusive. clavulanate potassium content is satis- (i) Microbiological agar diffusion assay. factory if it contains not less than 90 Proceed as directed in § 436.105 of this percent and not more than 120 percent chapter, preparing the sample for assay of the number of milligrams of as follows: Place a representative num- clavulanic acid that it is represented to
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contain. Its moisture content is not ed silica. Reagents, working standard more than 7 percent if it contains 250 and sample solutions, system suit- milligrams of amoxicillin and not more ability requirements, and calculations than 10 percent if it contains 500 milli- for amoxicillin or clavulanic acid con- grams of amoxicillin. It passes the dis- tent are as follows: solution test if the quantity Q, at 30 (i) Reagents—(a) 0.5M Sodium phos- minutes, is 85 percent or greater if it phate buffer solution, pH 4.4. Transfer contains 250 milligrams of amoxicillin 7.8 grams of monobasic sodium phos- and 75 percent or greater if it contains phate to a 1-liter volumetric flask and 500 milligrams of amoxicillin. The dissolve in 900 milliliters of distilled amoxicillin trihydrate conforms to the water. Adjust the pH to 4.4 ± 0.1 with standards prescribed by § 440.3(a)(1). 18N phosphoric acid or 10N sodium hy- The clavulanate potassium conforms to droxide. Dilute to volume with dis- the standards prescribed by tilled water. Mix well. § 455.15(a)(1) of this chapter. (b) Mobile phase. Mix methanol: 0.05M (2) Labeling. In addition to the label- sodium phosphate buffer solution, pH ing requirements prescribed by § 432.5 4.4 (5:95 v/v) and ultrasonicate for no of this chapter, this drug shall be la- less than 2 minutes. Degas by passing beled ‘‘amoxicillin and clavulanate potas- through a 0.5-micron filter with vacu- sium tablets’’. um. The mobile phase may be sparged (3) Requests for certification; samples. with the helium through a 2-microm- In addition to the requirements of eter metal filter for the duration of the § 431.1 of this chapter, each such re- analysis. Adjust the ratio of methanol quest shall contain: to aqueous buffer as necessary to ob- (i) Results of tests and assays on: tain satisfactory retention of the (a) The amoxicillin trihydrate used peaks. in making the batch for potency, mois- (ii) Working standard and sample solu- ture, pH, amoxicillin content, concord- tions—(a) Preparation of working stand- ance, crystallinity, and identity. ard solution. Accurately weigh and (b) The clavulanate potassium used in making the batch for clavulanic acid transfer into a 200-milliliter volu- content, moisture, pH, identity, and metric flask approximately 100 milli- clavam-2-carboxylate content. grams of amoxicillin working standard (c) The batch for amoxicillin content, and approximately 50 milligrams of the clavulanic acid content, moisture, and clavulanic acid working standard. Dis- dissolution rate. solve and dilute to volume with dis- (ii) Samples, if required by the Direc- tilled water. Use within 8 hours after tor, Center for Drug Evaluation and preparation. Research: (b) Preparation of sample solution. To (a) The amoxicillin trihydrate used obtain a concentration of 0.5 milligram in making the batch: 12 packages, each of amoxicillin per milliliter, dissolve a containing approximately 300 milli- representative number of tablets in grams. water with the aid of a magnetic stir- (b) The clavulanate potassium used rer or ultrasonication. Filter a small in making the batch: 12 packages, each aliquot through Whatman #42 filter containing approximately 300 milli- paper or equivalent, discarding the grams. first 10 milliliters of filtrate. Alter- (c) The batch: A minimum of 100 tab- natively, a suitable membrane filter lets. may be used. Prepare samples not more (b) Tests and methods of assay—(1) than 1 hour before the Amoxicillin and clavulanic acid contents. chromatographic injection. Proceed as directed in § 436.351 of this (iii) System suitability requirements— chapter, using ambient temperature, (a) Tailing factor. The tailing factor (T) an ultraviolet detection system operat- is satisfactory if it is not more than ing at a wavelength between 220 and 230 1.5. nanometers, and a column packed with (b) Efficiency of the column. The effi- microparticulate (3 to 10 micrometers ciency of the column (n) is satisfactory in diameter) reversed phase packing if it is greater than 550 theoretical material such as octadecyl silane bond- plates.
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(c) Resolution factor. The resolution constituted as directed in the labeling, factor (R) between the clavulanic acid each milliliter contains either and amoxicillin peaks is satisfactory if amoxicillin trihydrate equivalent to 25 it is not less than 3.5. milligrams of amoxicillin with (d) Coefficient of variation. The coeffi- clavulanate potassium equivalent to cient of variation (SR in percent) is sat- 6.25 clavulanic acid or amoxicillin tri- isfactory if it is not more than 2.0 per- hydrate equivalent to 50 milligrams of cent. amoxicillin with clavulanate potas- sium equivalent to 12.5 milligrams of If the system suitability requirements clavulanic acid. Its amoxicillin tri- have been met, then proceed as de- hydrate content is satisfactory if it is scribed in § 436.351(b) of this chapter. not less than 90 percent and not more (iv) Calculations. Calculate the milli- than 120 percent of the number of milli- grams of amoxicillin or clavulanic acid grams of amoxicillin that it is rep- content per tablet as follows: resented to contain. Its clavulanate po- Milligrams of tassium content is satisfactory if it is ACV× × not less than 90 percent and not more amoxicillin = u s than 125 percent of the number of milli- or clavulanic acid × grams of clavulanic acid that it is rep- ANs per tablet resented to contain. The moisture con- where: tent of the dry powder is not more than Au=Response of the amoxicillin or clavulanic 7.5 percent when the reconstituted so- acid peak in the chromatogram of the lution is to contain 25 milligrams of sample (at a retention time equal to that amoxicillin per milliliter and not more observed for the standard); than 8.5 percent when the reconsti- As=Response of the amoxicillin or clavulanic acid peak in the chromatogram of the tuted solution is to contain 50 milli- amoxicillin or clavulanic acid working grams of amoxicillin per milliliter. standard; When reconstituted as directed in the Cs=Concentration of standards in milligrams labeling, its pH is not less than 4.8 and of amoxicillin or clavulanic acid per mil- not more than 6.6. The amoxicillin tri- liliter of the standard solution; hydrate used conforms to the standards V=Volume of sample solution (milliliters); prescribed by § 440.3(a)(1). The and clavulanate potassium conforms to the N=Number of tablets taken for assay. standards prescribed by § 455.15(a)(1) of (2) Moisture. Proceed as directed in this chapter. § 436.201 of this chapter. (2) Labeling. In addition to the label- (3) Dissolution. Proceed as directed in ing requirements prescribed by § 432.5 § 436.215 of this chapter. Dissolution of this chapter, this drug shall be la- rate is determined by dissolution of the beled ‘‘amoxicillin and clavulanate potas- amoxicillin component using the high- sium for oral suspension’’. performance liquid chromatographic (3) Requests for certification; samples. assay described in this section. In addition to the requirements of [49 FR 39672, Oct. 10, 1984, as amended at 50 § 431.1 of this chapter, each such re- FR 19919, May 13, 1985; 55 FR 11582, Mar. 29, quest shall contain: 1990] (i) Results of tests and assays on: (a) The amoxicillin trihydrate used § 440.103e Amoxicillin trihydrate and in making the batch for potency, mois- clavulanate potassium for oral sus- ture, pH, amoxicillin content, concord- pension. ance, crystallinity, and identity. (a) Requirements for certification—(1) (b) The clavulanate potassium used Standards of identity, strength, quality, in making the batch for clavulanic acid and purity. Amoxicillin trihydrate and content, moisture, pH, identity, and clavulanate potassium for oral suspen- clavam-2-carboxylate content. sion is a dry mixture of amoxicillin tri- (c) The batch for amoxicillin content, hydrate and clavulanate potassium clavulanic acid content, moisture, and with one or more suitable and harmless pH. colorings, flavorings, buffers, sweeten- (ii) Samples, if required by the Direc- ing ingredients, preservatives, stabiliz- tor, Center for Drug Evaluation and ers, and suspending agents. When re- Research:
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(a) The amoxicillin trihydrate used in the labeling. Immediately transfer in making the batch: 12 packages, each an appropriate aliquot to a suitable containing approximately 300 milli- volumetric flask to obtain an approxi- grams. mate amoxicillin concentration of 0.5 (b) The clavulanate potassium used milligram per milliliter and dilute to in making the batch: 12 packages, each volume with distilled water. Mix well containing approximately 300 milli- for 10 minutes using a magnetic stirrer. grams. Filter an aliquot through Whatman #42 (c) The batch: A minimum of 6 imme- or equivalent filter paper. Alter- diate containers. natively, a suitable membrane filter (b) Tests and methods of assay—(1) may be used. Samples should be pre- Amoxicillin content or clavulanic acid pared just prior to chromatographic in- content. Proceed as directed in § 436.351 jection. Inject the sample solution of this chapter, using ambient tem- within 1 hour after the addition of perature, an ultraviolet detection sys- water. tem operating at a wavelength between (iii) System suitability requirements— 220 and 230 nanometers, and a column (a) Tailing factor. The tailing factor (T) packed with microparticulate (3 to 10 is satisfactory if it is not more than micrometers in diameter) reversed 1.5. phase packing material such as octa- (b) Efficiency of the column. The effi- decyl silane bonded silica. Reagents, ciency of the column (n) is satisfactory working standard and sample solu- if it is greater than 550 theoretical tions, system suitability requirments, plates. and calculations for amoxicillin and (c) Resolution factor. The resolution clavulanic acid content are as follows: factor (R) between the clavulanic acid (i) Reagents—(a) 0.05M Sodium phos- and amoxicillin peaks is satisfactory if phate buffer solution, pH 4.4. Transfer it is not less than 3.5. 7.8 grams of monobasic sodium phos- (d) Coefficient of variation. The coeffi- phate to a 1-liter volumetric flask and cient of variation (SR in percent) is sat- dissolve in 900 milliliters of distilled isfactory if it is not more than 2.0 per- water. Adjust to pH 4.4 ± 0.1 with 18N cent. phosphoric acid or 10N sodium hydrox- If the system suitability requirements ide. Dilute to volume with distilled have been met, then proceed as de- water. Mix well. scribed in § 436.351(b) of this chapter. (b) Mobile phase. Mix methanol:0.05M (iv) Calculations. Calculate the quan- sodium phosphate buffer solution, pH tity of amoxicillin or clavulanic acid 4.4 (5:95 v/v) and mix or ultrasonicate content in milligrams per milliliter of for no less than 2 minutes. Degas by the oral suspension as follows: passing through a 0.5-micron filter with vacuum. The mobile phase may be Milligrams of sparged with helium through a 2-mi- A× C × V × 0.5 amoxicillin = u crometer metal filter for the duration or clavulanic acid per of the analysis. Adjust the ratio of As methanol to aqueous buffer as nec- milliliter essary to obtain satisfactory retention Where: of the peaks. Au=Response of the amoxicillin or clavulanic (ii) Working standard and sample solu- acid peaks in the sample chromatogram; tions—(a) Preparation of working stand- As=Response of the amoxicillin or clavulanic acid peaks in the standard chromato- ard solution. Accurately weigh and gram; transfer into a 200-milliliter volu- C=Concentration of the standard (milligrams metric flask approximately 100 milli- per milliliter of amoxicillin X potency of grams of amoxicillin working standard amoxicillin standard or milligrams per and approximately 50 milligrams of the milliliter of clavulanate X potency of clavulanate working standard. Dissolve clavulanate standard); and and dilute to volume with distilled V=Dilution volume in milliliters. water. Use within 8 hours after prepa- (2) Moisture. Proceed as directed in ration. § 436.201 of this chapter. (b) Preparation of sample solution. Re- (3) pH. Proceed as directed in § 436.202 constitute the suspension as directed of this chapter, using the suspension
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reconstituted as directed in the label- content, moisture, pH, identity, and ing. clavam-2-carboxylate content. [49 FR 39673, Oct. 10, 1984, as amended at 50 (c) The batch for amoxicillin content, FR 19919, May 13, 1985; 55 FR 11582, Mar. 29, clavulanic acid content, moisture, and 1990] dissolution rate. (ii) Samples, if required by the Direc- § 440.103f Amoxicillin trihydrate- tor, Center for Drug Evaluation and clavulanate potassium chewable Research: tablets. (a) The amoxicillin trihydrate used (a) Requirements for certification—(1) in making the batch: 12 packages, each Standards of identity, strength, quality, containing approximately 300 milli- and purity. Amoxicillin trihydrate- grams. clavulanate potassium chewable tab- (b) The clavulanate potassium used lets are composed of amoxicillin tri- in making the batch: 12 packages, each hydrate and clavulanate potassium containing approximately 300 milli- with or without one or more suitable grams. lubricants, diluents, flavorings, and (c) The batch: A minimum of 100 tab- binders. Each tablet contains lets. amoxicillin trihydrate equivalent to ei- ther 125 or 250 milligrams of (b) Tests and methods of assay—(1) amoxicillin and clavulanate potassium Amoxicillin and clavulanic acid contents. equivalent to 31.25 or 62.5 milligrams of Proceed as directed in § 436.351 of this clavulanic acid. Its amoxicillin tri- chapter, using ambient temperature, hydrate content is satisfactory if it an ultraviolet detection system operat- contains not less than 90 percent and ing at a wavelength between 220 and 230 not more than 120 percent of the num- nanometers, and a column packed with ber of milligrams of amoxicillin that it microparticulate (3 to 10 micrometers is represented to contain. Its in diameter) reversed phase packing clavulanate potassium content is satis- material such as octadecyl hydro- factory if it contains not less than 90 carbon bonded silicas. Reagents, work- percent and not more than 120 percent ing standard and sample solutions, sys- of the number of milligrams of tem suitability requirements, and cal- clavulanic acid that it is represented to culations for amoxicillin or clavulanic contain. Its moisture content is not acid content are as follows: more than 6 percent. It passes the dis- (i) Reagents—(a) 0.05M Sodium phos- solution test if the quantity Q, of phate buffer solution, pH 4.4. Transfer amoxicillin at 30 minutes, is 85 percent 7.8 grams of sodium monobasic phos- or greater. The amoxicillin trihydrate phate to a 1-liter volumetric flask and conforms to the standards prescribed dissolve in 900 milliliters of distilled by § 440.3(a)(1). The clavulanate potas- water. Adjust the pH to 4.4±0.1 with 18N sium conforms to the standards pre- phosphoric acid or 10N sodium hydrox- scribed by § 455.15(a)(1) of this chapter. ide. Dilute to volume with distilled (2) Labeling. In addition to the label- water. Mix well. ing requirements prescribed by § 432.5 (b) Mobile phase. Mix methanol: 0.05M of this chapter, this drug shall be la- sodium phosphate buffer solution, pH beled ‘‘amoxicillin-clavulanate potassium 4.4 (5:95 v/v) and ultrasonicate for no chewable tablets’’. less than 2 minutes. Degas by passing (3) Requests for certification; samples. through a 0.5-micron filter with vacu- In addition to the requirements of um. The mobile phase may be sparged § 431.1 of this chapter, each such re- with the helium through a 2-microm- quest shall contain: eter metal filter for the duration of the (i) Results of tests and assays on: analysis. Adjust the ratio of methanol (a) The amoxicillin trihydrate used to aqueous buffer as necessary to ob- in making the batch for potency, safe- tain satisfactory retention of the ty, moisture, pH, amoxicillin content, peaks. concordance, crystallinity, and iden- (ii) Working standard and sample solu- tity. tions—(a) Preparation of working stand- (b) The clavulanate potassium used ard solution. Dissolve and dilute accu- in making the batch for clavulanic acid rately weighed portions each of the
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amoxicillin trihydrate working stand- Cs=Concentration of standards in milligrams ard and the clavulanate lithium work- of amoxicillin or clavulanic acid per mil- ing standard with water to obtain a so- liliter of the standard solution; lution containing 0.5 milligram of V=Volume of sample solution (milliliters); amoxicillin and 0.25 milligram of and N=Number of tablets taken for assay. clavulanic acid per milliliter. Use with- in 1 hour after preparation or within 4 (2) Moisture. Proceed as directed in hours if stored under refrigeration. § 436.201 of this chapter. (b) Preparation of sample solution. To (3) Dissolution. Proceed as directed in obtain a concentration of 0.5 milligram § 436.215 of this chapter. Dissolution of amoxicillin per milliliter, dissolve a rate is determined by dissolution of the representative number of tablets in amoxicillin component using the high- water with the aid of a magnetic stir- performance liquid chromatographic rer or ultrasonication. Filter an ali- assay described in this section. quot through Whatman #42 filter paper or equivalent, discard the first 10 milli- [50 FR 42933, Oct. 25, 1985; 50 FR 47367, Nov. liters of filtrate, and use the remaining 17, 1985, as amended at 55 FR 11582, Mar. 29, portion as the sample solution. Alter- 1990] natively, a suitable membrane filter § 440.105 Ampicillin oral dosage forms. may be used. Prepare samples not more than 1 hour before the § 440.105a Ampicillin tablets. chromatographic injection. (iii) System suitability requirements— (a) Requirements for certification—(1) (a) Tailing factor. The tailing factor (T) Standards of identity, strength, quality, is satisfactory if it is not more than and purity. Ampicillin tablets are com- 1.5. posed of ampicillin with one or more (b) Efficiency of the column. The effi- suitable and harmless diluents and lu- ciency of the column (n) is satisfactory bricants. Each tablet contains 250 or if it is greater than 1,000 theoretical 500 milligrams of ampicillin. Its po- plates in a 30-centimeter column for tency is satisfactory if it is not less each active component. than 90 percent and not more than 120 (c) Resolution. The resolution (R) be- percent of the number of milligrams of tween the clavulanic acid and ampicillin that it is represented to amoxicillin peaks is satisfactory if it is contain. Its loss on drying is not more not less than 3.5. than 4 percent. The tablets disinte- (d) Coefficient of variation. The coeffi- grate within 15 minutes. The ampicillin cient of variation (SR in percent) of five used conforms to the standards pre- replicate injections is satisfactory if it scribed by § 440.5(a)(1). is not more than 2.0 percent. (2) Labeling. It shall be labeled in ac- If the system suitability requirements cordance with the requirements of have been met, then proceed as de- § 432.5 of this chapter. scribed in § 436.351(b) of this chapter. (3) Requests for certification; samples. (iv) Calculations. Calculate the milli- In addition to complying with the re- grams of amoxicillin or clavulanic acid quirements of § 431.1 of this chapter, content per tablet as follows: each such request shall contain: (i) Results of tests and assays on: Milligrams of × × (a) The ampicillin used in making amoxicillin or = ACVu s the batch for potency, loss on drying, clavulanic acid per AN× pH, ampicillin content, concordance, tablet s crystallinity, and identity. where (b) The batch for potency, loss on Au=Response of the amoxicillin or clavulanic drying, and disintegration time. acid peak in the chromatogram of the (ii) Samples required: sample (at a retention time equal to that (a) The ampicillin used in making observed for the standard); the batch: 10 packages, each containing As=Response of the amoxicillin or clavulanic acid peak in the chromatogram of the approximately 300 milligrams. amoxicillin or clavulanic acid working (b) The batch: A minimum of 36 tab- standard; lets.
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(b) Tests and methods of assay—(1) Po- of this chapter, this drug shall be la- tency. Use either of the following meth- beled ‘‘ampicillin tablets’’. ods; however, the results obtained from (3) Requests for certification; samples. the microbiological agar diffusion In addition to complying with the re- assay shall be conclusive. quirements of § 431.1 of this chapter, (i) Microbiological agar diffusion assay. each such request shall contain: Proceed as directed in § 436.105 of this (i) The results of tests and assays on: chapter, preparing the sample for assay (a) The ampicillin used in making as follows: Place a representative num- the batch for potency, loss on drying, ber of tablets into a high-speed glass pH, ampicillin content, concordance, blender jar with sufficient 0.1M potas- sium phosphate buffer, pH 8.0 (solution crystallinity, and identity. 3), to give a stock solution of conven- (b) The batch for potency and loss on ient concentration. Blend for 3 to 5 drying. minutes. Remove an aliquot and fur- (ii) Samples required: ther dilute with solution 3 to the ref- (a) The ampicillin used in making erence concentration of 0.1 microgram the batch: 10 packages, each containing of ampicillin per milliliter (estimated). approximately 300 milligrams. (ii) Iodometric assay. Proceed as di- (b) The batch: A minimum of 30 tab- rected in § 436.204 of this chapter, ex- lets. cept in paragraph (d) of that section, (b) Tests and methods of assay—(1) Po- add 3 drops of 1.2N hydrochloric acid to tency. Use either of the following meth- both the sample and working standard ods; however, the results obtained from solutions after the addition of 0.01N io- the microbiological agar diffusion dine solution. Prepare the sample as assay shall be conclusive. follows: Place a representative number (i) Microbiological agar diffusion assay. of tablets in a high-speed glass blender Proceed as directed in § 436.105 of this jar and add sufficient distilled water to chapter, preparing the sample for assay give a convenient concentration. Blend as follows: Place a representative num- for 3 to 5 minutes. Further dilute an al- ber of tablets into a high-speed glass iquot with distilled water to the pre- blender jar with sufficient 0.1M potas- scribed concentration. sium phosphate buffer, pH 8.0 (solution (2) Loss on drying. Proceed as directed 3), to give a stock solution of conven- in § 436.200(a) of this chapter. ient concentration. Blend for 3 to 5 (3) Disintegration time. Proceed as di- minutes. Remove an aliquot and fur- rected in § 436.212 of this chapter, using ther dilute with solution 3 to the ref- the procedure described in paragraph (e)(1) of that section. erence concentration of 0.1 microgram of ampicillin per milliliter (estimated). [39 FR 18976, May 30, 1974, as amended at 49 (ii) Iodometric assay. Proceed as di- FR 3458, Jan. 27, 1984; 50 FR 19919, May 13, rected in § 436.204 of this chapter, ex- 1985] cept in paragraph (d) of that section, § 440.105b Ampicillin chewable tablets. add 3 drops of 1.2N hydrochloric acid to both the sample and working standard (a) Requirements for certification—(1) solutions after the addition of 0.01N io- Standards of identity, strength, quality, dine solution. Prepare the sample as and purity. Each ampicillin chewable follows: Blend a representative number tablet contains 125 milligrams or 250 of tablets in a high-speed blender with milligrams of ampicillin with suitable sufficient distilled water to give a binders, lubricants, flavorings, and stock solution of convenient con- colorings. Its potency is satisfactory if centration. Blend for 3 to 5 minutes. it is not less than 90 percent and not Further dilute an aliquot of the stock more than 120 percent of the number of solution with distilled water to the milligrams of ampicillin that it is rep- prescribed concentration. resented to contain. Its loss on drying is not more than 3 percent. The ampi- (2) Loss on drying. Proceed as directed cillin used conforms to the standards in § 436.200(a) of this chapter. prescribed by § 440.5(a)(1). [39 FR 18976, May 30, 1974, as amended at 43 (2) Labeling. In addition to the label- FR 9800, Mar. 10, 1978; 49 FR 3458, Jan. 27, ing requirements prescribed by § 432.5 1984; 50 FR 19919, May 13, 1985]
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§ 440.105c Ampicillin capsules. (ii) Iodometric assay. Proceed as di- rected in § 436.204 of this chapter, ex- (a) Requirements for certification— (1) cept in paragraph (d) of that section, Standards of identity, strength, quality, add 3 drops of 1.2N hydrochloric acid to and purity. Ampicillin capsules are both the sample and working standard composed of ampicillin with or without solutions after the addition of 0.01N io- one or more buffer substances, dine solution. Prepare the sample as diluents, binders, lubricants, vegetable follows: Place the contents of a rep- oils, colorings, and flavorings, enclosed resentative number of capsules into a in a gelatin capsule. Each capsule con- high-speed glass blender jar and add tains 125 milligrams, 250 milligrams, or sufficient distilled water to give a con- 500 milligrams of ampicillin. Its po- venient concentration. Blend for 3 to 5 tency is satisfactory if it is not less minutes. Filter through Whatman No. than 90 percent and not more than 120 2 filter paper. Further dilute an aliquot percent of the number of milligrams of of the filtrate with distilled water to ampicillin that it is represented to the prescribed concentration. contain. The loss on drying is not more (2) Loss on drying. Proceed as directed than 4.0 percent. The ampicillin used in § 436.200(a) of this chapter. conforms to the standards prescribed by § 440.5(a)(1). [39 FR 18976, May 30, 1974, as amended at 49 (2) Labeling. It shall be labeled in ac- FR 3458, Jan. 27, 1984; 50 FR 19919, May 13, cordance with the requirements of 1985] § 432.5 of this chapter. § 440.105d Ampicillin for oral suspen- (3) Requests for certification; samples. sion. In addition to complying with the re- (a) Requirements for certification—(1) quirements of § 431.1 of this chapter, Standards of identity, strength, quality, each such request shall contain: and purity. Ampicillin for oral suspen- (i) Results of tests and assays on: sion is a mixture of ampicillin with one (a) The ampicillin used in making or more suitable and harmless color- the batch for potency, loss on drying, ings, flavorings, buffer substances, pH, ampicillin content, concordance, sweetening ingredients, and preserva- crystallinity, and identity. tives. When reconstituted as directed (b) The batch for potency and loss on in the labeling, it contains either 25 drying. milligrams, 50 milligrams, or 100 milli- (ii) Samples required: grams of ampicillin per milliliter. Its (a) The ampicillin used in making potency is satisfactory if it is not less the batch: 10 packages, each containing than 90 percent and not more than 120 approximately 300 milligrams. percent of the number of milligrams of (b) The batch: A minimum of 30 cap- ampicillin that it is represented to sules. contain. Its moisture content is not (b) Tests and methods of assay—(1) Po- more than 2.5 percent. When reconsti- tency. Assay for potency by either of tuted as directed in the labeling, its pH the following methods; however, the re- is not less than 5.0 and not more than sults obtained from the micro- 7.5. The ampicillin used conforms to biological agar diffusion assay shall be the standards prescribed by § 440.5(a)(1). conclusive. (2) Labeling. It shall be labeled in ac- (i) Microbiological agar diffusion assay. cordance with the requirements of Proceed as directed in § 436.105 of this § 432.5 of this chapter. chapter, preparing the sample for assay (3) Requests for certification; samples. as follows: Place a representative num- In addition to complying with the re- ber of capsules into a high-speed glass quirements of § 431.1 of this chapter, blender jar with sufficient 0.1M potas- each such request shall contain: sium phosphate buffer, pH 8.0 (solution (i) Results of tests and assays on: 3), to give a convenient concentration. (a) The ampicillin used in making Blend for 3 to 5 minutes. Remove an al- the batch for potency, loss on drying, iquot and further dilute with solution 3 pH, ampicillin content, concordance, to the reference concentration of 0.1 crystallinity, and identity. microgram of ampicillin per milliliter (b) The batch for potency, moisture, (estimated). and pH.
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(ii) Samples required: cillin trihydrate with or without one or (a) The ampicillin used in making more suitable diluents, lubricants, pre- the batch: 10 packages, each containing servatives, and flavorings. Each tablet approximately 300 milligrams. contains ampicillin trihydrate equiva- (b) The batch: A minimum of 6 imme- lent to 125 or 250 milligrams of ampi- diate containers. cillin. Its potency is satisfactory if it (b) Tests and methods of assay—(1) Po- contains not less than 90 percent and tency. Assay for potency by either of not more than 120 percent of the num- the following methods; however, the re- ber of milligrams of ampicillin that it sults obtained from the micro- is represented to contain. Its moisture biological agar diffusion assay shall be content is not more than 5.0 percent. conclusive. The ampicillin trihydrate used con- (i) Microbiological agar diffusion assay. forms to the standards prescribed by Proceed as directed in § 436.105 of this § 440.7(a)(1). chapter, preparing the sample for assay (2) Labeling. In addition to the label- as follows: Reconstitute the drug as di- ing requirements prescribed by § 432.5 rected in the labeling. Place an accu- of this chapter, this drug shall be la- rately measured representative portion beled ‘‘ampicillin tablets.’’ of the sample into a suitable volu- (3) Requests for certification; samples. metric flask and dilute to volume with In addition to complying with the re- 0.1M potassium phosphate buffer, pH quirements of § 431.1 of this chapter, 8.0 (solution 3), to give a convenient each such request shall contain: concentration. Mix well. Further dilute (i) Results of tests and assays on: an aliquot with solution 3 to the ref- (a) The ampicillin trihydrate used in erence concentration of 0.1 microgram making the batch for potency, loss on of ampicillin per milliliter (estimated). drying, pH, ampicillin content, con- (ii) Iodometric assay. Proceed as di- cordance, crystallinity, and identity. rected in § 436.204 of this chapter, ex- (b) The batch for potency and mois- cept in paragraph (d) of that section, ture. add 3 drops of 1.2N hydrochloric acid to (ii) Samples required: both the sample and working standard (a) The ampicillin trihydrate used in solutions after the addition of 0.01N io- making the batch: 10 packages, each dine solution. Prepare the sample as containing approximately 300 milli- follows: Reconstitute the drug as di- grams. rected in the labeling. Place an accu- (b) The batch: A minimum of 30 tab- rately measured aliquot (usually a sin- lets. gle dose) into an appropriately sized (b) Tests and methods of assay—(1) Po- volumetric flask and dilute to volume tency. Use either of the following meth- with distilled water. Mix well. Further ods; however, the results obtained from dilute with distilled water to the pre- the microbiological agar diffusion scribed concentration. assay shall be conclusive. (2) Moisture. Proceed as directed in (i) Microbiological agar diffusion assay. § 436.201 of this chapter. Proceed as directed in § 436.105 of this (3) pH. Proceed as directed in § 436.202 chapter, preparing the sample for assay of this chapter, using the drug recon- as follows: Place a representative num- stituted as directed in the labeling. ber of tablets into a high-speed glass blender jar with sufficient 0.1M potas- [39 FR 18976, May 30, 1974, as amended at 49 sium phosphate buffer, pH 8.0 (solution FR 3458, Jan. 27, 1984; 50 FR 19919, May 13, 1985] 3), to give a stock solution of conven- ient concentration. Blend for 3 to 5 § 440.107 Ampicillin trihydrate oral minutes. Remove an aliquot and fur- dosage forms. ther dilute with solution 3 to the ref- erence concentration of 0.1 microgram § 440.107a Ampicillin trihydrate of ampicillin per milliliter (estimated). chewable tablets. (ii) Iodometric assay. Proceed as di- (a) Requirements for certification—(1) rected in § 436.204 of this chapter, ex- Standards of identity, strength, quality, cept in paragraph (d) of that section, and purity. Ampicillin trihydrate add 3 drops of 1.2N hydrochloric acid to chewable tablets are composed of ampi- both the sample and working standard
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solutions after the addition of 0.01N io- (b) Tests and methods of assay—(1) Po- dine solution. Prepare the sample as tency. Assay for potency by either of follows: Place a representative number the following methods; however, the re- of tablets into a high-speed glass blend- sults obtained from the micro- er jar containing sufficient distilled biological agar diffusion assay shall be water to give a convenient concentra- conclusive. tion. Blend for 5 minutes. Further di- (i) Microbiological agar diffusion assay. lute with distilled water to the pre- Proceed as directed in § 436.105 of this scribed concentration. chapter, preparing the sample for assay (2) Moisture. Proceed as directed in as follows: Place a representative num- § 436.201 of this chapter. ber of capsules into a high-speed glass [39 FR 18976, May 30, 1974, as amended at 49 blender jar with sufficient 0.1M potas- FR 3459, Jan. 27, 1984; 50 FR 19919, May 13, sium phosphate buffer, pH 8.0 (solution 1985] 3), to give a convenient concentration. Blend for 3 to 5 minutes. Remove an al- § 440.107b Ampicillin trihydrate cap- iquot and further dilute with solution 3 sules. to the reference concentration of 0.1 (a) Requirements for certification—(1) microgram of ampicillin per milliliter Standards of identity, strength, quality, (estimated). and purity. Ampicillin trihydrate cap- (ii) Iodometric assay. Proceed as di- sules are composed of ampicillin tri- rected in § 436.204 of this chapter, ex- hydrate with or without one or more cept in paragraph (d) of that section, buffer substances, diluents, binders, lu- add 3 drops of 1.2N hydrochloric acid to bricants, vegetable oils, colorings, and both the sample and working standard flavorings enclosed in a gelatin cap- solutions after the addition of 0.01N io- sule. Each capsule contains ampicillin dine solution. Prepare the sample as trihydrate equivalent to 250 milligrams follows: Place the contents of a rep- or 500 milligrams of ampicillin. Its po- resentative number of capsules into a tency is satisfactory if it contains not high-speed glass blender jar and add less than 90 percent and not more than sufficient distilled water to give a con- 120 percent of the number of milli- venient concentration. Blend for 3 to 5 grams of ampicillin that it is rep- minutes. Filter through Whatman No. resented to contain. Its loss on drying 2 filter paper. Further dilute an aliquot is not less than 10 percent and not of the filtrate with distilled water to more than 15 percent. The ampicillin the prescribed concentration. trihydrate used conforms to the stand- (2) Loss on drying. Proceed as directed ards prescribed by § 440.7(a)(1). in § 436.200(a) of this chapter. (2) Labeling. In addition to the label- ing requirements prescribed by § 432.5 [39 FR 18976, May 30, 1974, as amended at 49 of this chapter, this drug shall be la- FR 3459, Jan. 27, 1984; 50 FR 19919, May 13, beled ‘‘ampicillin capsules’’. 1985] (3) Requests for certification; samples. In addition to complying with the re- § 440.107c Ampicillin trihydrate for oral suspension. quirements of § 431.1 of this chapter, each such request shall contain: (a) Requirements for certification—(1) (i) Results of tests and assays on: Standards of identity, strength, quality, (a) The ampicillin trihydrate used in and purity. Ampicillin trihydrate for making the batch for potency, loss on oral suspension is a mixture of ampi- drying, pH, ampicillin content, con- cillin trihydrate with one or more suit- cordance, crystallinity, and identity. able and harmless colorings, flavorings, (b) The batch for potency and loss on buffers, sweetening ingredients, and drying. preservatives. When reconstituted as (ii) Samples required: directed in the labeling, it contains (a) The ampicillin trihydrate used in ampicillin trihydrate equivalent to ei- making the batch: 10 packages, each ther 25, 50, or 100 milligrams of ampi- containing approximately 300 milli- cillin per milliliter. Its potency is sat- grams. isfactory if it is not less than 90 per- (b) The batch: A minimum of 30 cap- cent and not more than 120 percent of sules. the number of milligrams of ampicillin
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that it is represented to contain. Its erence concentration of 0.1 microgram moisture content is: of ampicillin per milliliter (estimated). (i) Not more than 2.5 percent if it (ii) Iodometric assay. Proceed as di- contains sugar and is intended to con- rected in § 436.204 of this chapter, ex- tain the equivalent of 25 or 50 milli- cept in paragraph (d) of that section, grams of ampicillin per milliliter when add 3 drops of 1.2N hydrochloric acid to reconstituted as directed in the label- both the sample and working standard ing; or solutions after the addition of 0.01N io- (ii) Not more than 5 percent if it con- dine solution. Prepare the sample as tains sugar and is intended to contain follows: Reconstitute the drug as di- the equivalent of 100 milligrams of am- rected in the labeling. Place an accu- picillin per milliliter when reconsti- rately measured aliquot (usually a sin- tuted as directed in the labeling; or gle dose) into an appropriately sized volumetric flask and dilute to volume Its pH, when reconstituted as directed with distilled water. Mix well. Further in the labeling, is not less than 5.0 and dilute with distilled water to the pre- is not more than 7.5. The ampicillin scribed concentration. trihydrate used conforms to the stand- ards prescribed by § 440.7(a)(1). (2) Moisture. Proceed as directed in § 436.201 of this chapter. (2) Labeling. In addition to the label- (3) pH. Proceed as directed in § 436.202 ing requirements prescribed by § 432.5 of this chapter, using the drug recon- of this chapter, this drug shall be la- stituted as directed in the labeling. beled ‘‘ampicillin for oral suspension.’’ (3) Requests for certification; samples. [39 FR 18976, May 30, 1974, as amended at 49 In addition to complying with the re- FR 3459, Jan. 27, 1984; 49 FR 5096, Feb. 10, quirements of § 431.1 of this chapter, 1984; 50 FR 19919, May 13, 1985] each such request shall contain: (i) Results of tests and assays on: § 440.107d Ampicillin trihydrate- probenecid for oral suspension. (a) The ampicillin trihydrate used in making the batch for potency, loss on (a) Requirements for certification—(1) drying, pH, ampicillin content, con- Standards of identity, strength, quality, cordance, crystallinity, and identity. and purity. Ampicillin trihydrate and (b) The batch for potency, moisture, probenecid for oral suspension is a dry and pH. mixture of ampicillin trihydrate and (ii) Samples required: probenecid with suitable flavorings, lu- (a) The ampicillin trihydrate used in bricants, colorings, and suspending making the batch: 10 packages, each agents packaged in a single-dose con- containing approximately 300 milli- tainer. When reconstituted as directed grams. in the labeling, each single dose will (b) The batch: A minimum of six im- contain ampicillin trihydrate equiva- mediate containers. lent to 3.5 grams of ampicillin and 1.0 (b) Tests and methods of assay—(1) Po- gram of probenecid. Its ampicillin con- tency. Assay for potency by either of tent is satisfactory if it is not less than the following methods; however, the re- 90 percent and not more than 120 per- sults obtained from the micro- cent of the number of grams of ampi- biological agar diffusion assay shall be cillin that it is represented to contain. conclusive. Its probenecid content is satisfactory if (i) Microbiological agar diffusion assay. it is not less than 90 percent and not Proceed as directed in § 436.105 of this more than 110 percent of the number of chapter, preparing the sample for assay grams of probenecid that it is rep- as follows: Reconstitute the drug as di- resented to contain. Its moisture con- rected in the labeling. Place an accu- tent is not more than 5.0 percent. When rately measured representative portion reconstituted as directed in the label- of the sample into a suitable volu- ing, its pH is not less than 5.0 and not metric flask and dilute to volume with more than 7.5. The ampicillin tri- 0.1M potassium phosphate buffer, pH hydrate used conforms to the standards 8.0 (solution 3), to give a convenient prescribed by § 440.7(a)(1). The concentration. Mix well. Further dilute probenecid used conforms to the stand- an aliquot with solution 3 to the ref- ards prescribed by the U.S.P.
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(2) Labeling. In addition to the label- probenecid reference standard, accu- ing requirements prescribed by § 432.5 rately weighed, to a 25-milliliter volu- of this chapter, this drug shall be la- metric flask. Dissolve and dilute to beled ‘‘ampicillin-probenecid for oral volume with 1 percent aqueous sodium suspension’’. carbonate solution. (3) Requests for certification, samples. (ii) Preparation of sample solution. Re- In addition to complying with the re- constitute the sample as directed in quirements of § 431.1 of this chapter, the labeling and mix well. Drain the each such request shall contain: suspension from the bottle for 30 sec- (i) Results of tests and assays on: onds into a 1,000-milliliter volumetric (a) The ampicillin trihydrate used in flask. Dilute to volume with 1 percent making the batch for potency, loss on aqueous sodium carbonate solution, drying, pH, ampicillin content, con- shake well, and filter through cordance, crystallinity, and identity. Whatman No. 6 filter paper. Discard (b) The probenecid used in making the first 10-milliliter portion. the batch for all U.S.P. specifications. (iii) Procedure. Transfer 2.0 milliliters (c) The batch for ampicillin content, of the clear filtrate to a 125-milliliter probenecid content, moisture, and pH. separatory funnel and add 8.0 milli- (ii) Samples required: liters of 1.0N hydrochloric acid. Extract (a) The ampicillin trihydrate used in the solution with four 20-milliliter por- making the batch: 10 packages, each tions of chloroform, filtering each ex- containing approximately 300 milli- tract through a glass wool pledget into grams. a 100-milliliter volumetric flask. Wash (b) The batch: A minimum of 10 im- the pledget with chloroform, dilute to mediate containers. volume with chloroform and mix. Treat (b) Tests and methods of assay—(1) Am- 2.0 milliliters of the standard solution picillin content—(i) Sample preparation. in the same manner. Using a suitable Reconstitute as directed in the labeling spectrophotometer equipped with a 1- and mix well. Drain the suspension centimeter cell and chloroform washed from the bottle for 30 seconds into a with 1 percent aqueous sodium carbon- high-speed glass blender jar containing ate solution as a blank, determine the sufficient sterile distilled water to ob- absorbance of the sample and standard tain a total volume of 500 milliliters. solutions at the peak near 257 Blend for 10 minutes. nanometers. (ii) Assay procedures. Use any of the (iv) Calculations. Calculate the following methods; however, the re- probenecid content as follows: sults obtained from the micro- Grams probenecid per con- biological agar diffusion assay shall be tainer=(Absorbance of sample×weight of conclusive. standard in milligrams×percent purity of (a) Microbiological agar diffusion standard)/(Absorbance of stand- assay. Proceed as directed in § 436.105 of ard×25×100) this chapter, diluting an aliquot of the (3) Moisture. Proceed as directed in aqueous solution with 0.1M potassium § 436.201 of this chapter. phosphate buffer, pH 8.0 (solution 3), to (4) pH. Proceed as directed in § 436.202 the reference concentration of 0.1 of this chapter, using the drug recon- microgram of ampicillin per milliliter stituted as directed in the labeling. (estimated). [39 FR 18976, May 30, 1974, as amended at 40 (b) Iodometric assay. Proceed as di- FR 49083, Oct. 21, 1975; 49 FR 3459, Jan. 27, rected in § 436.204 of this chapter, ex- 1984; 50 FR 19919, May 13, 1985] cept in paragraph (d) of that section, add 3 drops of 1.2N hydrochloric acid to § 440.107e Ampicillin trihydrate- both the sample and working standard probenecid capsules. solutions after the addition of 0.01N io- (a) Requirements for certification—(1) dine solution. Dilute an aliquot of the Standards of identity, strength, quality, aqueous solution to the prescribed con- and purity. Ampicillin trihydrate- centration. probenecid capsules are composed of (2) Probenecid content—(i) Preparation ampicillin trihydrate and probenecid of standard solution. Transfer approxi- with or without one or more buffer sub- mately 25 milligrams of U.S.P. stances, diluents, binders, lubricants,
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vegetable oils, colorings, and ient concentration. Blend for 8 to 10 flavorings enclosed in a gelatin cap- minutes. Remove an aliquot and fur- sule. Each capsule contains ampicillin ther dilute with solution 3 to the ref- trihydrate equivalent to 389 milligrams erence concentration of 0.1 microgram of ampicillin and 111 milligrams of of ampicillin per milliliter (estimated). probenecid. Its ampicillin content is (ii) Iodometric assay. Proceed as di- satisfactory if it is not less than 90 per- rected in § 436.204 of this chapter, ex- cent and not more than 120 percent of cept in paragraph (d) of that section, the number of milligrams of ampicillin add 3 drops of 1.2N hydrochloric acid to that it is represented to contain. Its both the sample and working standard probenecid content is satisfactory if it solutions after the addition of 0.01N io- is not less than 90 percent and not dine solution. Prepare the sample as more than 110 percent of the number of follows: Place the contents of a rep- milligrams of probenecid that it is rep- resentative number of capsules into a resented to contain. Its loss on drying high-speed glass blender jar with suffi- is not less than 8.5 percent and not cient distilled water to give a conven- more than 13.0 percent. The ampicillin ient concentration. Blend for 8 to 10 trihydrate used conforms to the stand- minutes. Filter through Whatman No. ards prescribed by § 440.7(a)(1). The 2 filter paper. Further dilute an aliquot probenecid used conforms to the stand- of the filtrate with distilled water to ards prescribed by the U.S.P. the prescribed concentration. (2) Labeling. In addition to the label- (2) Probenecid content—(i) Preparation ing requirements prescribed by § 432.5 of standard solution. Transfer approxi- of this chapter, this drug shall be la- mately 25 milligrams of probenecid ref- beled ‘‘ampicillin-probenecid cap- erence standard U.S.P., accurately sules’’. weighed, to a 25-milliliter volumetric (3) Requests for certification; samples. flask. Dissolve and dilute to volume In addition to complying with the re- with 1 percent aqueous sodium carbon- quirements of § 431.1 of this chapter, ate solution. each such request shall contain: (i) Results of tests and assays on: (ii) Preparation of sample solution. (a) The ampicillin trihydrate used in Place the contents of a representative making the batch for potency, loss on number of capsules into a high-speed drying, pH, ampicillin content, con- glass blender jar with 100 milliliters of cordance, crystallinity, and identity. 1 percent aqueous sodium carbonate so- (b) The probenecid used in making lution for each capsule. Blend for 8 to the batch for all U.S.P. specifications. 10 minutes. Filter a portion through (c) The batch for ampicillin content, Whatman No. 2 filter paper, discarding probenecid content, and loss on drying. the first 10-milliliter portion of the fil- (ii) Samples required: trate. (a) The ampicillin trihydrate used in (iii) Procedure. Transfer 2.0 milliliters making the batch: 10 packages, each of the clear filtrate to a 125-milliliter containing approximately 300 milli- separatory funnel and add 8.0 milli- grams. liters of 1.0N hydrochloric acid. Extract (b) The batch: A minimum of 30 cap- the solution with four 20-milliliter por- sules. tions of chloroform, filtering each ex- (b) Tests and methods of assay—(1) Am- tract into a 100-milliliter volumetric picillin content. Use any of the following flask through a glass wool pledget and methods; however, the results obtained 6 grams of chloroform-washed anhy- from the microbiological agar diffusion drous sodium sulfate. Wash the pledget assay shall be conclusive. and sodium sulfate with chloroform, di- (i) Microbiological agar diffusion assay. lute to volume with chloroform and Proceed as directed in § 436.105 of this mix. Treat 2.0 milliliters of the stand- chapter, preparing the sample for assay ard solution in the same manner. Using as follows: Place a representative num- a suitable spectrophotometer equipped ber of capsules into a high-speed glass with a 1-centimeter cell and chloro- blender jar with sufficient 0.1M potas- form washed with 1 percent aqueous so- sium phosphate buffer, pH 8.0 (solution dium carbonate solution as a blank, de- 3), to give a stock solution of conven- termine the absorbance of the sample
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and standard solutions at the peak (b) Tests and methods of assay—(1) Po- near 257 nanometers. tency. Use either of the following meth- (iv) Calculations. Calculate the ods; however, the results obtained from probenecid content as follows: the iodometric assay shall be conclu- sive. Milligrams probenecid per capsule = (i) Hydroxylamine colorimetric assay. (Absorbance of sample × weight of stand- ard in milligrams × percent purity of Proceed as directed in § 440.8(b)(1)(i) of standard)/(Absorbance of standard × 25) this chapter, except prepare the sample solution and calculate the potency of (3) Loss on drying. Proceed as directed the sample as follows: in § 436.200(a) of this chapter. (a) Preparation of sample solution. [40 FR 58288, Dec. 16, 1975, as amended at 45 Place one tablet into a high-speed glass FR 16474, Mar. 14, 1980; 49 FR 3459, Jan. 27, blender jar with sufficient distilled 1984; 50 FR 19919, May 13, 1985] water to obtain a concentration of 1.25 milligrams of ampicillin per milliliter § 440.108 Bacampicillin hydrochloride (estimated). Blend for 3 to 5 minutes. dosage forms. Filter before using. (b) Calculations. Calculate the ampi- § 440.108a Bacampicillin hydrochloride cillin content in milligrams per tablet tablets. as follows: (a) Requirements for certification—(1) Standards of identity, strength, quality, × × Milligrams of Au P a d and purity. Bacampicillin hydro- = cyclacillin per tablet × chloride tablets are composed of As 1, 000 bacampicillin hydrochloride with one where: or more suitable and harmless diluents Au=Absorbance of sample solution; and lubricants. Each tablet contains Pa=Potency of working standard in bacampicillin hydrochloride equivalent micrograms per milliliter; to either 280 or 560 milligrams of ampi- As=Absorbance of working standard solution; cillin. Its potency is satisfactory if it is d=Dilution factor of the sample. not less than 90 percent and not more (ii) Iodometric assay. Proceed as di- than 125 percent of the number of milli- rected in § 436.204 of this chapter, ex- grams of ampicillin that it is rep- cept use the ampicillin working stand- resented to contain. Its moisture con- ard. Prepare the sample as follows: Dis- tent is not more than 2.5 percent. It solve and dilute a representative num- passes the dissolution test. The ber of tablets with distilled water to bacampicillin hydrochloride used con- the prescribed concentration. forms to the standards prescribed by (2) Moisture. Proceed as directed in § 440.8(a)(1). § 436.201 of this chapter. (2) Labeling. It shall be labeled in ac- (3) Dissolution. Proceed as directed in cordance with the requirements of § 436.215 of this chapter, except in lieu § 432.5 of this chapter. of paragraph (d) of that section use the (3) Requests for certification; samples. interpretation described in the United In addition to complying with the re- States Pharmacopeia XX dissolution quirements of § 431.1 of this chapter, test. The quantity, Q (the amount of each such request shall contain: ampicillin dissolved) is 85 percent at 30 (i) Results of tests and assays on: minutes. (a) The bacampicillin hydrochloride [46 FR 25604, May 8, 1981. Redesignated at 47 used in making the batch for potency, FR 23711, June 1, 1982, and amended at 48 FR moisture, pH, and identity. 51293, 51294, Nov. 8, 1983; 50 FR 19919, May 13, (b) The batch for potency, moisture, 1985] and dissolution. (ii) Samples required: § 440.108b Bacampicillin hydro- (a) The bacampicillin hydrochloride chloride for oral suspension. used in making the batch: 10 packages, (a) Requirements for certification—(1) each containing approximately 300 mil- Standards of identity, strength, quality, ligrams. and purity. Bacampicillin hydro- (b) The batch: A minimum of 100 tab- chloride for oral suspension is a mix- lets. ture of bacampicillin hydrochloride
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with one or more suitable and harmless milliliters of a solvent mixture of 95 buffers, diluents, sweetening ingredi- percent ethanol and 0.1M phosphoric ents, suspending agents, flavorings, acid (8:2). Shake for 30 minutes on a and colorings. When reconstituted as wrist action shaker and dilute to vol- directed in the labeling, it contains ume with the solvent mixture. Cen- bacampicillin hydrochloride equivalent trifuge a portion of the sample solution to 17.5 milligrams of ampicillin per for 10 minutes at 6,000 rpm. Use the milliliter. Its potency is satisfactory if clear supernatant without further dilu- it is not less than 90 percent and not tion. more than 125 percent of the number of (2) Loss on drying. Proceed as directed milligrams of ampicillin that it is rep- in § 436.200(b) of this chapter. resented to contain. Its loss on drying (3) pH. Proceed as directed in § 436.202 is not more than 2.0 percent. When re- of this chapter, using the drug recon- constituted as directed in the labeling, stituted as directed in the labeling. its pH is not less than 6.5 and not more (4) Identity. Proceed as directed in than 8.0. It gives a positive identity § 436.330 of this chapter, except prepare test for bacampicillin hydrochloride. the sample as follows: Reconstitute as The bacampicillin hydrochloride con- directed in the labeling. Place 8.0 milli- forms to the standards prescribed by liters of the sample into a 100-milliliter § 440.8(a)(1). volumetric flask, add 70 milliliters of (2) Labeling. It shall be labeled in ac- 95 percent ethyl alcohol and shake for cordance with the requirements of 30 minutes. Dilute to volume with 95 § 432.5 of this chapter. percent ethyl alcohol. (3) Requests for certification; samples. [47 FR 23711, June 1, 1982, as amended at 50 In addition to complying with the re- FR 19919, May 13, 1985] quirements of § 431.1 of this chapter, each such request shall contain: § 440.111 Carbenicillin indanyl sodium (i) Results of tests and assays on: tablets. (a) The bacampicillin used in making (a) Requirements for certification— (1) the batch for potency, moisture, pH, Standards of identity, strength, quality, and identity. and purity. Carbenicillin indanyl so- (b) The batch for potency, loss on dium tablets are composed of drying, pH, and identity. carbenicillin indanyl sodium and one (ii) Samples required: or more suitable and harmless diluents, (a) The bacampicillin used in making binders, lubricants, colorings, and the batch: 10 packages, each containing coating substances. Each tablet con- approximately 300 milligrams. tains carbenicillin indanyl sodium (b) The batch: A minimum of 6 imme- equivalent to 382 milligrams of diate containers. carbenicillin. Its potency is satisfac- (b) Tests and methods of assay—(1) Po- tory if it contains not less than 90 per- tency. Proceed as directed in § 436.204 of cent and not more than 120 percent of this chapter, except: the number of milligrams of (i) Use the ampicillin working stand- carbenicillin that it is represented to ard as the standard of comparison; contain. Its moisture content is not (ii) Use 4.0 milliliters of sample solu- more than 2.0 percent. It gives a posi- tion in lieu of the 2.0 milliliters speci- tive identity test for carbenicillin fied in paragraph (c)(1) of that section; indanyl sodium. The tablets shall dis- and integrate within 1 hour. The (iii) Calculate the potency of the carbenicillin indanyl sodium used con- sample as follows: forms to the standards prescribed by × × § 440.11(a)(1). Milligrams of = Vu F d (2) Labeling. It shall be labeled in ac- ampicillin per dose n× 4 , 000 cordance with the requirements of § 432.5 of this chapter. Prepare the sample as follows: Recon- (3) Requests for certification; samples. stitute the drug as directed in the la- In addition to complying with the re- beling. Place an accurately measured quirements of § 431.1 of this chapter, portion equivalent to one dose into a each such request shall contain: 250-milliliter volumetric flask. Add 200 (i) Results of tests and assays on:
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(a) The carbenicillin indanyl sodium (3) Identity. Proceed as directed in used in making the batch for potency, § 436.301 of this chapter, preparing the moisture, pH, and identity. sample as follows: Using a mortar and (b) The batch for potency, moisture, pestle, grind a representative number identity, and disintegration time. of tablets into a fine powder. Dissolve a (ii) Samples required: weighed amount of this powder in suffi- (a) The carbenicillin indanyl sodium cient extraction solvent (described in used in making the batch: Five pack- § 436.301(b)(1) of this chapter) to give 10 ages, each containing approximately 1 milligrams of carbenicillin per milli- gram and one package containing ap- liter. Shake the mixture for 5 minutes proximately 2.5 grams. and promptly dilute an aliquot in ex- (b) The batch: A minimum of 36 tab- traction solvent to obtain a final con- lets. centration of 1 milligram carbenicillin (b) Tests and methods of assay—(1) Po- per milliliter. tency. Proceed as directed in § 436.300 of (4) Disintegration time. Proceed as di- this chapter, except: rected in § 436.212 of this chapter, using (i) Preparation of the sample. Accu- the procedure described in paragraph rately weigh 20 tablets and determine (e)(2) of that section. the average tablet weight. Using a mortar and pestle, grind the tablets to [39 FR 18976, May 30, 1974, as amended at 50 a fine powder. Accurately weigh a por- FR 19919, May 13, 1985] tion of the powder approximately equivalent to the weight of one tablet § 440.115 Cloxacillin sodium and transfer it into a 100-milliliter vol- monohydrate oral dosage forms. umetric flask. Add approximately 70 milliliters of distilled water and shake § 440.115a Cloxacillin sodium monohydrate capsules. the flask for 5 minutes. Dilute to vol- ume and mix well. Transfer a 5-milli- (a) Requirements for certification— (1) liter aliquot of the stock solution to a Standards of identity, strength, quality, 50-milliliter glass-stoppered centrifuge and purity. Cloxacillin sodium tube. (The solution will be slightly monohydrate capsules are composed of turbid.) Add 15 milliliters of phosphate- cloxacillin sodium and one or more citrate buffer and 20 milliliters of 4- suitable and harmless diluents and lu- methyl-2-pentanone to the tube. Stop- bricants. Each capsule contains per the tube and shake it for 10 sec- cloxacillin sodium monohydrate equiv- onds. Centrifuge at 2,000 revolutions alent to 125 milligrams, 250 milligrams, per minute to separate the phases. Re- or 500 milligrams of cloxacillin. Its po- move about 15 milliliters of the upper tency is satisfactory if it is not less phase and proceed as directed in than 90 percent and not more than 120 § 436.300(e) of this chapter. percent of the number of milligrams of (ii) Calculations. Calculate the cloxacillin that it is represented to carbenicillin content (potency) of the contain. Its moisture content is not tablets as follows: more than 5 percent. The cloxacillin sodium monohydrate used conforms to Milligrams of carbenicillin per tab- the standards prescribed by let=(Degrees of rotation of sample solu- tion × weight of working standard × aver- § 440.15(a)(1). age tablet weight × 100 × micrograms of (2) Labeling. In addition to the label- carbenicillin in each milligram of the ing requirements of § 432.5 of this chap- working standard)/(Degrees of rotation of ter, this drug shall be labeled working standard×weight of sample × 25 × ‘‘cloxacillin sodium capsules’’. 1,000) (3) Requests for certification; samples. where: In addition to complying with the re- 100 and 25=The volume of the sample and quirements of § 431.1 of this subchapter, working standard solutions, respec- each such request shall contain: tively; (i) Results of tests and assays on: 1,000=Factor to correct micrograms to mil- (a) The cloxacillin sodium ligrams. monohydrate used in making the batch (2) Moisture. Proceed as directed in for potency, moisture, pH, cloxacillin § 436.201 of this chapter. content, identity, and crystallinity.
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(b) The batch for potency and mois- tent is not more than 1 percent. When ture. reconstituted as directed in its label- (ii) Samples required: ing, its pH is not less than 5.0 nor more (a) The cloxacillin sodium than 7.5. The cloxacillin sodium monohydrate used in making the monohydrate used conforms to the batch: 10 packages, each containing ap- standards prescribed by § 440.15(a)(1). proximately 300 milligrams. (2) Labeling. In addition to the label- (b) The batch: A minimum of 30 cap- ing requirements of § 432.5 of this chap- sules. ter, this drug shall be labeled (b) Tests and methods of assay—(1) Po- ‘‘cloxacillin sodium for oral solution’’. tency—(i) Sample preparation. Place a representative number of capsules into (3) Requests for certification; samples. a high-speed glass blender jar contain- In addition to complying with the re- ing sufficient 1 percent potassium quirements of § 431.1 of this subchapter, phosphate buffer, pH 6.0 (solution 1), to each such request shall contain: give a stock solution of convenient (i) Results of tests and assays on: concentration. Blend for 3 to 5 min- (a) The cloxacillin sodium utes. monohydrate used in making the batch (ii) Assay procedure. Use either of the for potency, moisture, pH, cloxacillin following methods; however, the re- content, identity, and crystallinity. sults obtained from the micro- (b) The batch for potency, moisture, biological agar diffusion assay shall be and pH. conclusive. (ii) Samples required: (a) Microbiological agar diffusion (a) The cloxacillin sodium assay. Proceed as directed in § 436.105 of monohydrate used in making the this chapter, diluting an aliquot of the batch: 10 packages, each containing ap- stock solution with solution 1 to the proximately 300 milligrams. reference concentration of 5 micrograms of cloxacillin per milliliter (b) The batch: A minimum of six im- (estimated). mediate containers. (b) Iodometric assay. Proceed as di- (b) Tests and methods of assay—(1) Po- rected in § 436.204 of this subchapter, di- tency—(i) Sample preparation. Reconsti- luting an aliquot of the stock solution tute the sample as directed in the la- with solution 1 to the prescribed con- beling. Dilute an accurately measured centration. representative aliquot of the sample (2) Moisture. Proceed as directed in with sufficient 1 percent potassium § 436.201 of this subchapter. phosphate buffer, pH 6.0 (solution 1), to [39 FR 18976, May 30, 1974, as amended at 42 give a stock solution of convenient FR 59861, Nov. 22, 1977; 50 FR 19919, May 13, concentration. 1985] (ii) Assay procedures. Use either of the following methods; however, the re- § 440.115b Cloxacillin sodium sults obtained from the micro- monohydrate for oral solution. biological agar diffusion assay shall be (a) Requirements for certification—(1) conclusive. Standards of identity, strength, quality, (a) Microbiological agar diffusion and purity. Cloxacillin sodium assay. Proceed as directed in § 436.105 of monohydrate for oral solution is a mix- this chapter, diluting an aliquot of the ture of sodium cloxacillin with one or stock solution with solution 1 to the more suitable and harmless colorings, reference concentration of 5 flavorings, buffer substances, and pre- servatives. When reconstituted as di- micrograms of cloxacillin per milliliter rected in the labeling, each milliliter (estimated). contains the equivalent of 25 milli- (b) Iodometric assay. Proceed as di- grams or 50 milligrams of cloxacillin. rected in § 436.204 of this chapter, dilut- Its potency is satisfactory if it is not ing an aliquot of the stock solution less than 90 percent and not more than with solution 1 to the prescribed con- 120 percent of the number of milli- centration. grams of cloxacillin that it is rep- (2) Moisture. Proceed as directed in resented to contain. Its moisture con- § 436.201 of this subchapter.
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(3) pH. Proceed as directed in § 436.202 sium phosphate buffer, pH 8.0 (solution of this subchapter, using the drug re- 3), to give a stock solution of conven- constituted as directed in its labeling. ient concentration. Blend for 3 to 5 minutes. Remove an aliquot and fur- [39 FR 18976, May 30, 1974, as amended at 42 FR 59861, Nov. 22, 1977; 43 FR 9800, Mar. 10, ther dilute with solution 3 to the ref- 1978; 50 FR 19919, May 13, 1985] erence concentration of 1.0 microgram of cyclacillin per milliliter (estimated). § 440.117 Cyclacillin oral dosage forms. (ii) Iodometric assay. Proceed as di- rected in § 436.204 of this chapter, pre- § 440.117a Cyclacillin tablets. paring the sample solution as follows: (a) Requirements for certification—(1) Place a representative number of tab- Standards of identity, strength, quality, lets in a high-speed glass blender jar and purity. Cyclacillin tablets are com- and add sufficient distilled water to posed of cyclacillin with one or more give a convenient concentration. Blend suitable and harmless diluents, lubri- for 3 to 5 minutes. Further dilute an al- cants, colorings, and disintegrants. iquot with distilled water to the pre- Each tablet contains 250 or 500 milli- scribed concentration. grams of cyclacillin. Its potency is sat- (iii) Hydroxylamine colorimetric assay. isfactory if it is not less than 90 per- Proceed as directed in § 442.40(b)(1)(ii) cent and not more than 120 percent of of this chapter, except prepare the the number of milligrams of cyclacillin working standard and sample solutions that it is represented to contain. Its and calculate the potency of the sam- moisture content is not more than 5 ple as follows: percent. The tablets disintegrate with- (a) Preparation of working standard so- in 15 minutes. It gives a positive iden- lution. Dissolve and dilute an accu- tity test for cyclacillin. The cyclacillin rately weighed portion of the used conforms to the standards pre- cyclacillin working standard in suffi- scribed by § 440.17(a)(1). cient distilled water to obtain a con- (2) Labeling. It shall be labeled in ac- centration of 1.25 milligrams of cordance with the requirements of cyclacillin per milliliter. § 432.5 of this chapter. (b) Preparation of sample solution. (3) Requests for certification; samples. Place one tablet into a high-speed glass In addition to complying with the re- blender jar and add sufficient distilled quirements of § 431.1 of this chapter, water to obtain a concentration of 1.25 each such request shall contain: milligrams of cyclacillin per milliliter. (i) Results of tests and assays on: Blend for 3 to 5 minutes. Filter, if nec- (a) The cyclacillin used in making essary. the batch for potency, moisture, pH, (c) Calculations. Calculate the cyclacillin content, concordance, crys- cyclacillin content in milligrams per tallinity, and identity. tablet as follows: (b) The batch for potency, moisture, A× P × d disintegration time, and identity. Milligrams of cyclacillin = u a (ii) Samples required: per 5 milliliters of sample × (a) The cyclacillin used in making As 1, 000 the batch: 10 packages, each containing where: approximately 500 milligrams. Au=Absorbance of sample solution; (b) The batch: A minimum of 36 tab- Pa=Potency of working standard in lets. micrograms per milliliter; (b) Tests and methods of assay—(1) Po- As=Absorbance of working standard solu- tency. Use any of the following meth- tion; ods; however, the results obtained from d=Dilution factor of the sample. the iodometric assay shall be conclu- (2) Moisture. Proceed as directed in sive. § 436.201 of this chapter. (i) Microbiological agar diffusion assay. (3) Disintegration time. Proceed as di- Proceed as directed in § 436.105 of this rected in § 436.212 of this chapter, using chapter, preparing the sample for assay the procedure in paragraph (e)(1) of as follows: Place a representative num- that section, except do not use discs. ber of tablets into a high-speed glass (4) Identity. Proceed as directed in blender jar with sufficient 0.1M potas- § 436.327 of this chapter, preparing the
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sample as follows: Dissolve a represent- sults obtained from the iodometric ative portion of finely powdered tablets assay shall be conclusive. with sufficient 0.1N sodium hydroxide (i) Microbiological agar diffusion assay. to obtain a solution containing 1 milli- Proceed as directed in § 436.105 of this gram of cyclacillin per milliliter. chapter, preparing the sample for assay Allow the sample solution to stand for as follows: Reconstitute the drug as di- 15 minutes before using. rected in the labeling. Place an accu- rately measured representative portion [46 FR 2985, Jan. 13, 1981; 46 FR 15880, Mar. 10, 1981, as amended at 50 FR 19919, May 13, 1985] of the sample into a suitable volu- metric flask and dilute to volume with § 440.117b Cyclacillin for oral suspen- 0.1M potassium phosphate buffer, pH sion. 8.0 (solution 3), to give a convenient concentration. Mix well. Further dilute (a) Requirements for certification—(1) an aliquot with solution 3 to the ref- Standards of identity, strength, quality, erence concentration of 1.0 microgram and purity. Cyclacillin for oral suspen- sion is a mixture of cyclacillin with of cyclacillin per milliliter (estimated). one or more suitable and harmless (ii) Iodometric assay. Proceed as di- colorings, flavorings, buffer substances, rected in § 436.204 of this chapter, pre- sweetening ingredients, preservatives, paring the sample as follows: Reconsti- and suspending agents. When reconsti- tute the drug as directed in the label- tuted as directed in the labeling, it ing. Place an accurately measured rep- contains either 25 milligrams, 50 milli- resentative portion of the sample into grams, or 100 milligrams of cyclacillin an appropriate-sized volumetric flask per milliliter. Its potency is satisfac- and dilute to volume with 1 percent po- tory if it is not less than 90 percent and tassium phosphate buffer, pH 6.0 (solu- not more than 120 percent of the num- tion 1). Mix well. Further dilute with ber of milligrams of cyclacillin that it solution 1 to the prescribed concentra- is represented to contain. Its moisture tion. content is not more than 1.5 percent. (iii) Hydroxylamine colorimetric assay. When reconstituted as directed in the Proceed as directed in § 442.40(b)(1)(ii) labeling, its pH is not less than 4.5 and of this chapter, except prepare the not more than 6.5. It gives a positive working standard and sample solutions identity test for cyclacillin. The and calculate the potency of the sam- cyclacillin used conforms to the stand- ple as follows: ards prescribed by § 440.17(a)(1). (a) Preparation of working standard so- (2) Labeling. It shall be labeled in ac- lution. Dissolve and dilute an accu- cordance with the requirements of rately weighed portion of the § 432.5 of this chapter. cyclacillin working standard in suffi- (3) Requests for certification; samples. cient distilled water to obtain a con- In addition to complying with the re- centration of 1.25 milligrams of quirements of § 431.1 of this chapter, cyclacillin per milliliter. each such request shall contain: (b) Preparation of sample solution. Re- (i) Results of tests and assays on: constitute the sample as directed in the labeling. Place an accurately meas- (a) The cyclacillin used in making the batch for potency, moisture, pH, ured aliquot of the sample into an ap- cyclacillin content, concordance, crys- propriate-sized volumetric flask and di- tallinity, and identity. lute to volume with distilled water to yield a concentration of 1.25 milli- (b) The batch for potency, moisture, grams of cyclacillin per milliliter. Mix pH, and identity. well. Filter, if necessary. (ii) Samples required: (c) Calculations. Calculate the (a) The cyclacillin used in making cyclacillin content as follows: the batch: 10 packages, each containing approximately 500 milligrams. Milligrams of A× P × d (b) The batch: A minimum of seven cyclacillin per = u a immediate containers. × (b) Tests and methods of assay—(1) Po- 5 milliliters of sample As 1, 000 tency. Assay for potency by any of the where: following methods; however, the re- Au=Absorbance of sample solution; 553
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Pa=Potency of working standard in (b) The batch for potency and mois- micrograms per milliliter; ture. As=Absorbance of working standard solu- (ii) Samples required: tion; (a) The dicloxacillin sodium d=Dilution factor of the sample. monohydrate used in making the (2) Moisture. Proceed as directed in batch: 10 containers, each containing § 436.201 of this chapter. not less than 500 milligrams. (3) pH. Proceed as directed in § 436.202 (b) The batch: A minimum of 30 cap- of this chapter, using the drug recon- sules. stituted as directed in the labeling. (b) Tests and methods of assay—(1) Po- (4) Identity. Proceed as directed in tency—(i) Sample preparation. Place a § 436.327 of this chapter, preparing the representative number of capsules into sample as follows: Dilute an accurately a high-speed glass blender jar contain- measured representative portion of the ing sufficient 1 percent potassium reconstituted suspension with 0.1N so- phosphate buffer, pH 6.0 (solution 1), to dium hydroxide to obtain a solution give a stock solution of convenient containing 1 milligram of cyclacillin concentration. Blend for 3 to 5 min- per milliliter. Allow the sample solu- utes. Remove an aliquot and further di- tion to stand 45 minutes before using. lute with solution 1 to the reference concentration of 5.0 micrograms of [46 FR 2985, Jan. 13, 1981; 46 FR 15880, Mar. 10, 1981, as amended at 50 FR 19919, May 13, 1985] dicloxacillin per milliliter (estimated) for the microbiological agar diffusion § 440.119 Dicloxacillin sodium assay and to the prescribed concentra- monohydrate oral dosage forms. tion for the iodometric assay. (ii) Assay procedure. Assay for po- § 440.119a Dicloxacillin sodium tency by either of the following meth- monohydrate capsules. ods; however, the results obtained from (a) Requirements for certification—(1) the microbiological agar diffusion Standards of identity, strength, quality, assay shall be conclusive. and purity. Dicloxacillin sodium (a) Microbiological agar diffusion monohydrate capsules are composed of assay. Proceed as directed in § 436.105 of dicloxacillin sodium monohydrate and this chapter. one or more suitable diluents and lu- (b) Iodometric assay. Proceed as di- bricants. Each capsule contains rected in § 436.204 of this chapter. dicloxacillin sodium monohydrate (2) Moisture. Proceed as directed in equivalent to 62.5, 125, 250, or 500 milli- § 436.201 of this chapter. grams of dicloxacillin. Its potency is [39 FR 18976, May 30, 1974, as amended at 42 satisfactory if it is not less than 90 per- FR 59861, Nov. 22, 1977; 43 FR 2393, Jan. 17, cent and not more than 120 percent of 1978; 44 FR 10379, Feb. 20, 1979; 50 FR 19919, the number of milligrams of May 13, 1985] dicloxacillin that it is represented to contain. The moisture content is not § 440.119b Dicloxacillin sodium more than 5 percent. The dicloxacillin monohydrate for oral suspension. sodium monohydrate conforms to the (a) Requirements for certification—(1) requirements of § 440.19(a)(1). Standards of identity, strength, quality, (2) Labeling. In addition to the label- and purity. Dicloxacillin sodium ing requirements of § 432.5 of this chap- monohydrate for oral suspension is a ter, this drug shall be labeled mixture of dicloxacillin sodium ‘‘dicloxacillin sodium capsules’’. monohydrate with one or more suitable (3) Requests for certification; samples. colorings, flavorings, buffer substances, In addition to complying with the re- and preservatives. When reconstituted quirements of § 431.1 of this chapter, as directed in the labeling, it contains each such request shall contain: the equivalent of 12.5 or 25 milligrams (i) Results of tests and assays on: of dicloxacillin per milliliter. Its po- (a) The dicloxacillin sodium tency is satisfactory if it is not less monohydrate used in making the batch than 90 percent and not more than 120 for potency, moisture, pH, organic percent of the number of milligrams of chlorine content, free chloride content, dicloxacillin that it is represented to crystallinity, and identity. contain. Its moisture content is not
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more than 2 percent. The pH of the sus- (a) Microbiological agar diffusion pension, when reconstituted as directed assay. Proceed as directed in § 436.105 of in the labeling, is not less than 4.5 nor this chapter. more than 7.5. The dicloxacillin sodium (b) Iodometric assay. Proceed as di- monohydrate used conforms to the re- rected in § 436.204 of this chapter. quirements of § 440.19(a)(1). (2) Moisture. Proceed as directed in (2) Labeling. In addition to the label- § 436.201 of this chapter. ing requirements of § 432.5 of this chap- (3) pH. Proceed as directed in § 436.202 ter, this drug shall be labeled of this chapter, using the drug recon- ‘‘dicloxacillin sodium for oral suspen- stituted as directed in the labeling. sion’’. [39 FR 18976, May 30, 1974, as amended at 42 (3) Requests for certification; samples. FR 59861, Nov. 22, 1977; 50 FR 19919, May 13, In addition to complying with the re- 1985] quirements of § 431.1 of this chapter, § 440.125 Hetacillin oral dosage forms. each such request shall contain: (i) Results of tests and assay on: § 440.125a Hetacillin chewable tablets. (a) The dicloxacillin sodium (a) Requirements for certification— (1) monohydrate used in making the batch Standards of identity, strength, quality, for potency, moisture, pH, organic and purity. Each hetacillin chewable chlorine content, free chloride content, tablet contains an amount of hetacillin crystallinity, and identity. equivalent to 112.5 milligrams of ampi- (b) The batch for potency, moisture, cillin with suitable buffers, preserva- and pH. tives, binders, flavorings, colorings, (ii) Samples required: and sweetening ingredients. Its po- (a) The dicloxacillin sodium tency is satisfactory if it contains not monohydrate used in making the less than 90 percent and not more than batch: 10 containers, each containing 120 percent of the number of milli- not less than 500 milligrams. grams of ampicillin that it is rep- (b) The batch: A minimum of 6 imme- resented to contain. The moisture con- diate containers. tent is not more than 2.0 percent. The (b) Tests and methods of assay—(1) Po- hetacillin used conforms to the re- tency—(i) Sample preparation. Reconsti- quirements of § 440.25(a)(1). tute the sample as directed in the la- (2) Labeling. It shall be labeled in ac- beling. Place an accurately measured cordance with the requirements of aliquot of the sample containing an es- § 432.5 of this chapter. (3) Requests for certification; samples. timated 125 milligrams of dicloxacillin In addition to complying with the re- into a 100-milliliter volumetric flask. quirements of § 431.1 of this chapter, Add 20 milliliters of each such request shall contain: dimethylformamide and shake me- (i) Results of tests and assays on: chanically for 30 minutes. Dilute to (a) The hetacillin used in making the volume with 1 percent potassium phos- batch for potency, moisture, pH, phate buffer, pH 6.0 (solution 1). The hetacillin content, identity, and crys- addition of dimethylformamide may be tallinity. omitted if complete solution can be ob- (b) The batch for potency and mois- tained with solution 1. Further dilute ture. an aliquot with sufficient solution 1 to (ii) Samples required. the reference concentration of 5.0 (a) The hetacillin used in making the micrograms of dicloxacillin per milli- batch: 10 packages, each containing ap- liter (estimated) for the micro- proximately 300 milligrams. biological agar diffusion assay and to (b) The batch: A minimum of 30 tab- the prescribed concentration for the lets. iodometric assay. (b) Tests and methods of assay—(1) Po- (ii) Assay procedure. Assay for po- tency. Proceed as directed for ampi- tency by either of the following meth- cillin in § 436.105 of this chapter, using ods; however, the results obtained from the ampicillin working standard as the the microbiological agar diffusion standard of comparison and preparing assay shall be conclusive. the sample for assay as follows: Place a
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representative number of tablets in a (b) Tests and methods of assay—(1) Po- high-speed glass blender with sufficient tency. Proceed as directed for ampi- 0.1M potassium phosphate buffer, pH cillin in § 436.105 of this chapter, pre- 8.0 (solution 3), to give a stock solution paring the sample for assay as follows: of convenient concentration. Blend for Reconstitute the sample as directed in 3 to 5 minutes. Further dilute an ali- the labeling. Remove an accurately quot of the stock solution with solu- measured representative portion with a tion 3 to the reference concentration of suitable syringe and hypodermic needle 0.1 microgram of ampicillin per milli- and place into a suitable volumetric liter (estimated). flask. Dilute to volume with 0.1M po- (2) Moisture. Proceed as directed in tassium phosphate buffer, pH 8.0 (solu- § 436.201 of this chapter. tion 3). Further dilute an aliquot with solution 3 to the reference concentra- [39 FR 18976, May 30, 1974, as amended at 50 tion of 0.1 microgram of ampicillin per FR 19919, May 13, 1985] milliliter (estimated). § 440.125b Hetacillin for oral suspen- (2) Moisture. Proceed as directed in sion. § 436.201 of this chapter. (3) pH. Proceed as directed in § 436.202 (a) Requirements for certification— (1) of this chapter, using the sample after Standards of identity, strength, quality, reconstituting as directed in the label- and purity. Hetacillin for oral suspen- ing. sion is a mixture of hetacillin with one or more suitable preservatives, sus- [39 FR 18976, May 30, 1974, as amended at 50 pending agents, sweetening ingredi- FR 19919, May 13, 1985] ents, flavorings, and colorings. When § 440.129 Hetacillin potassium cap- reconstituted as directed in the label- sules. ing, it contains the equivalent of 22.5, 45, or 112.5 milligrams of ampicillin per (a) Requirements for certification—(1) milliliter. Its potency is satisfactory if Standards of identity, strength, quality, it contains not less than 90 percent and and purity. Hetacillin potassium cap- not more than 120 percent of the num- sules are composed of potassium ber of milligrams of ampicillin that it hetacillin with or without one or more is represented to contain. Its moisture suitable diluents, lubricants, and dry- content is not more than 2.0 percent. ing agents. Each capsule contains an The pH of the suspension, when recon- amount of potassium hetacillin equiva- stituted as directed in its labeling, is lent to 112.5, 225, or 450 milligrams of not less than 2.0 and not more than 5.0. ampicillin. Its potency is satisfactory The hetacillin used conforms to the re- if it contains not less than 90 percent quirements of § 440.25(a)(1). and not more than 120 percent of the number of milligrams of ampicillin (2) Labeling. It shall be labeled in ac- that it is represented to contain. The cordance with the requirements of moisture content is not more than 3 § 432.5 of this chapter. percent. The potassium hetacillin used (3) Requests for certification; samples. conforms to the requirements of In addition to complying with the re- § 440.29(a)(1). quirements of § 431.1 of this chapter, (2) Labeling. It shall be labeled in ac- each such request shall contain: cordance with the requirements of (i) Results of tests and assays on: § 432.5 of this chapter. (a) The hetacillin used in making the (3) Requests for certification; samples. batch for potency, moisture, pH, In addition to complying with the re- hetacillin content, identity, and crys- quirements of § 431.1 of this chapter, tallinity. each such request shall contain: (b) The batch for potency, moisture, (i) Results of tests and assays on: and pH. (a) The hetacillin potassium used in (ii) Samples required: making the batch for potency, mois- (a) The hetacillin used in making the ture, pH, hetacillin content, identity, batch: 10 packages, each containing ap- and crystallinity. proximately 300 milligrams. (b) The batch for potency and mois- (b) The batch: A minimum of six im- ture. mediate containers. (ii) Samples required:
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(a) The hetacillin potassium used in quirements of § 431.1 of this chapter, making the batch: 10 packages, each each such request shall contain: containing approximately 300 milli- (i) Results of tests and assays on: grams. (a) The nafcillin sodium (b) The batch: A minimum of 30 cap- monohydrate used in making the batch sules. for potency, moisture, pH, crystallin- (b) Tests and methods of assay—(1) Po- ity, nafcillin content, and identity. tency. Proceed as directed for ampi- (b) The batch for potency, moisture, cillin in § 436.105 of this chapter, using and disintegration time. the ampicillin working standard as the (ii) Samples required: standard of comparison and preparing (a) The nafcillin sodium the sample for assay as follows: Place a monohydrate used in making the representative number of capsules in a batch: 10 packages, each containing ap- high-speed glass blender with sufficient proximately 300 milligrams. 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to give a stock solution (b) The batch: A minimum of 36 tab- of convenient concentration. Blend for lets. 3 to 5 minutes. Further dilute an ali- (b) Tests and methods of assay—(1) Po- quot of the stock solution with solu- tency—(i) Sample preparation. Place a tion 3 to the reference concentration of representative number of tablets into a 0.1 microgram of ampicillin per milli- high-speed glass blender jar containing liter (estimated). sufficient 1 percent potassium phos- (2) Moisture. Proceed as directed in phate buffer, pH 6.0 (solution 1), to give § 436.201 of this chapter. a stock solution of convenient con- centration. Blend for 3 to 5 minutes. [39 FR 18976, May 30, 1974, as amended at 42 (ii) Assay procedures. Assay for po- FR 59861, Nov. 22, 1977; 50 FR 19919, May 13, 1985] tency by any of the following methods; however, the results obtained from the § 440.141 Nafcillin sodium microbiological agar diffusion assay monohydrate oral dosage forms. shall be conclusive. (a) Microbiological agar diffusion § 440.141a Nafcillin sodium assay. Proceed as directed in § 436.105 of monohydrate tablets. this chapter, diluting an aliquot of the (a) Requirements for certification— (1) stock solution with solution 1 to the Standards of identity, strength, quality, reference concentration of 2.0 and purity. Nafcillin sodium micrograms of nafcillin per milliliter monohydrate tablets are composed of (estimated). nafcillin sodium monohydrate with one (b) Iodometric assay. Proceed as di- or more suitable buffers, binders, rected in § 436.204 of this chapter, dilut- disintegrants, diluents, and lubricants. ing an aliquot of the stock solution Each tablet contains nafcillin sodium with solution 1 to the prescribed con- monohydrate equivalent to 500 milli- centration. grams of nafcillin. Its potency is satis- (c) Hydroxylamine colorimetric assay. factory if it is not less than 90 percent Proceed as directed in § 436.205 of this and not more than 120 percent of the number of milligrams of nafcillin that chapter. it is represented to contain. Its mois- (2) Moisture. Proceed as directed in ture content is not more than 5 per- § 436.201 of this chapter. cent. It shall disintegrate within 20 (3) Disintegration time. Proceed as di- minutes. The nafcillin sodium rected in § 436.212 of this chapter, using monohydrate used conforms to the the method described in paragraph standards prescribed by § 440.41(a)(1). (e)(1) of that section, except use dis- (2) Labeling. In addition to the label- tilled water in lieu of simulated gastric ing requirements of § 432.5 of this chap- fluid as the immersion fluid. ter, this drug shall be labeled [39 FR 18976, May 30, 1974, as amended at 42 ‘‘nafcillin sodium tablets’’. FR 59862, Nov. 22, 1977; 50 FR 19919, May 13, (3) Requests for certification; samples. 1985] In addition to complying with the re-
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§ 440.141b Nafcillin sodium ods; however, the results obtained from monohydrate capsules. the microbiological agar diffusion (a) Requirements for certification— (1) assay shall be conclusive. Standards of identity, strength, quality, (a) Microbiological agar diffusion and purity. Nafcillin sodium assay. Proceed as directed in § 436.105 of monohydrate capsules are composed of this chapter. nafcillin sodium monohydrate and one (b) Iodometric assay. Proceed as di- or more suitable and harmless buffer rected in § 436.204 of this chapter. substances and lubricants. Each cap- (2) Moisture. Proceed as directed in sule contains nafcillin sodium § 436.201 of this chapter. monohydrate equivalent to 250 milli- [39 FR 18976, May 30, 1974, as amended at 42 grams of nafcillin. The potency is sat- FR 59862, Nov. 22, 1977; 50 FR 19919, May 13, isfactory if it is not less than 90 per- 1985] cent and not more than 120 percent of the number of milligrams of nafcillin § 440.141c Nafcillin sodium that it is represented to contain. The monohydrate for oral solution. moisture content is not more than 5.0 (a) Requirements for certification—(1) percent. The nafcillin sodium Standards of identity, strength, quality, monohydrate conforms to the stand- and purity. Nafcillin sodium ards prescribed by § 440.41(a)(1). monohydrate for oral solution is a (2) Labeling. In addition to the label- packaged combination of one imme- ing requirements of § 432.5 of this chap- diate container of nafcillin sodium ter, this drug shall be labeled monohydrate and one immediate con- ‘‘nafcillin sodium capsules’’. tainer of an aqueous diluent containing (3) Requests for certification; samples. one or more suitable and harmless In addition to complying with the re- colorings, flavoring, buffers, quirements of § 431.1 of this chapter, dispersants, diluents, and preserva- each such request shall contain: tives. When reconstituted as directed (i) Results of tests and assays on: in the labeling, each milliliter contains (a) The nafcillin sodium the equivalent of 50 milligrams of monohydrate used in making the batch nafcillin. Its potency is satisfactory if for potency, moisture, pH, crystallin- it is not less than 90 percent and not ity, nafcillin content, and identity. more than 120 percent of the number of (b) The batch for potency and mois- milligrams of nafcillin that it is rep- ture. resented to contain. Its moisture con- (ii) Samples required: tent is not more than 5 percent. When (a) The nafcillin sodium reconstituted as directed in the label- monohydrate used in making the ing, its pH is not less than 5.5 and not batch: 10 packages, each containing ap- more than 7.5. The nafcillin sodium proximately 300 milligrams. monohydrate used conforms to the (b) The batch: A minimum of 30 cap- standards prescribed by § 440.41(a)(1). sules. (2) Labeling. In addition to the label- (b) Tests and methods of assay—(1) Po- ing requirements of § 432.5 of this chap- tency—(i) Sample preparation. Place a ter, this drug shall be labeled representative number of capsules into ‘‘nafcillin sodium for oral solution’’. a high-speed glass blender jar contain- (3) Requests for certification; samples. ing sufficient 1 percent potassium In addition to complying with the re- phosphate buffer, pH 6.0 (solution 1), to quirements of § 431.1 of this chapter, give a stock solution of convenient each such request shall contain: concentration. Blend for 3 to 5 min- (i) Results of tests and assays on: utes. Remove an aliquot and further di- (a) The nafcillin sodium lute with solution 1 to the reference monohydrate used in making the batch concentration of 2.0 micrograms of for potency, moisture, pH, crystallin- nafcillin per milliliter (estimated) for ity, nafcillin content, and identity. the microbiological agar diffusion (b) The batch for potency, moisture, assay and to the prescribed concentra- and pH. tion for the iodometric assay. (ii) Samples required: (ii) Assay procedures. Assay for po- (a) The nafcillin sodium tency by either of the following meth- monohydrate used in making the
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batch: 10 packages, each containing ap- monohydrate used conforms to the proximately 300 milligrams. standards prescribed by § 440.49(a)(1). (b) The batch: A minimum of 6 imme- (2) Labeling. In addition to the label- diate containers. ing requirements of § 432.5 of this chap- (b) Tests and methods of assay—(1) Po- ter, this drug shall be labeled tency—(i) Sample preparation. Reconsti- ‘‘oxacillin sodium capsules’’. tute as directed in the labeling. Place (3) Requests for certification; samples. an accurately measured representative In addition to complying with the re- aliquot of the sample into a 250-milli- quirements of § 431.1 of this chapter, liter volumetric flask and dilute to vol- each such request shall contain: ume with 1 percent potassium phos- (i) Results of tests and assays on: phate buffer, pH 6.0 (solution 1). Mix well. Further dilute an aliquot with so- (a) The oxacillin sodium lution 1 to the reference concentration monohydrate used in making the batch of 2.0 micrograms of nafcillin per milli- for potency, moisture, pH, oxacillin liter (estimated) for the micro- content, crystallinity, and identity. biological agar diffusion assay and to (b) The batch for potency and mois- the prescribed concentration for the ture. iodometric assay. (ii) Samples required: (ii) Assay procedures. Assay for po- (a) The oxacillin sodium tency by either of the following meth- monohydrate used in making the ods; however, the results obtained from batch: 10 packages, each containing ap- the microbiological agar diffusion proximately 300 milligrams. assay shall be conclusive. (b) The batch: A minimum of 30 cap- (a) Microbiological agar diffusion sules. assay. Proceed as directed in § 436.105 of (b) Tests and methods of assay—(1) Po- this chapter. tency—(i) Sample preparation. Place a (b) Iodometric assay. Proceed as di- representative number of capsules into rected in § 436.204 of this chapter. a high-speed glass blender jar contain- (2) Moisture. Proceed as directed in § 436.201 of this chapter. ing sufficient 1 percent potassium (3) pH. Proceed as directed in § 436.202 phosphate buffer, pH 6.0 (solution 1), to of this chapter, using the drug recon- give a stock solution of convenient stituted as directed in the labeling. concentration. Blend for 3 to 5 min- utes. [39 FR 18976, May 30, 1974, as amended at 42 (ii) Assay procedures. Use either of the FR 59862, Nov. 22, 1977; 50 FR 19919, May 13, 1985] following methods; however, the re- sults obtained from the micro- § 440.149 Oxacillin sodium biological agar diffusion assay shall be monohydrate oral dosage forms. conclusive. (a) Microbiological agar diffusion § 440.149a Oxacillin sodium assay. Proceed as directed in § 436.105 of monohydrate capsules. this chapter, diluting an aliquot of the (a) Requirements for certification— (1) stock solution with solution 1 to the Standards of identity, strength, quality, reference concentration of 5 and purity. Oxacillin sodium micrograms of oxacillin per milliliter monohydrate capsules are composed of (estimated). oxacillin sodium monohydrate with or (b) Iodometric assay. Proceed as di- without one or more diluents and lubri- cants, enclosed in a gelatin capsule. rected in § 436.204 of this chapter, dilut- Each capsule contains oxacillin sodium ing an aliquot of the stock solution monohydrate equivalent to 125, 250, or with solution 1 to the prescribed con- 500 milligrams of oxacillin. Its potency centration. is satisfactory if it is not less than 90 (2) Moisture. Proceed as directed in percent and not more than 120 percent § 436.201 of this chapter. of the number of milligrams of [39 FR 18976, May 30, 1974, as amended at 42 oxacillin that it is represented to con- FR 59862, Nov. 22, 1977; 50 FR 19919, May 13, tain. Its moisture content is not more 1985] than 6.0 percent. The oxacillin sodium
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§ 440.149b Oxacillin sodium biological agar diffusion assay shall be monohydrate for oral solution. conclusive. (a) Requirements for certification— (1) (a) Microbiological agar diffusion Standards of identity, strength, quality, assay. Proceed as directed in § 436.105 of and purity. Oxacillin sodium this chapter, diluting an aliquot of the monohydrate for oral solution is a mix- stock solution with solution 1 to the ture of oxacillin sodium monohydrate reference concentration of 5 with one or more suitable colorings, micrograms of oxacillin per milliliter flavorings, buffer substances, stabiliz- (estimated). ers, and preservatives. When reconsti- (b) Iodometric assay. Proceed as di- tuted as directed in the labeling, each rected in § 436.204 of this chapter, dilut- milliliter contains the equivalent of ei- ing an aliquot of the stock solution ther 25 or 50 milligrams of oxacillin. Its with solution 1 to the prescribed con- potency is satisfactory if it is not less centration. than 90 percent and not more than 120 (2) Moisture. Proceed as directed in percent of the number of milligrams of § 436.201 of this chapter. oxacillin that it is represented to con- (3) pH. Proceed as directed in § 436.202 tain. Its moisture content is not more than 1.0 percent. When reconstituted as of this chapter using the drug reconsti- directed in its labeling, the pH of the tuted as directed in the labeling. solution is not less than 5.0 and not [39 FR 18976, May 30, 1974, as amended at 42 more than 7.5. The oxacillin sodium FR 59862, Nov. 22, 1977; 50 FR 19919, May 13, monohydrate used conforms to the 1985] standards prescribed by § 440.49(a)(1). (2) Labeling. In addition to the label- § 440.155 Penicillin G benzathine oral ing requirements of § 432.5 of this chap- dosage forms. ter, this drug shall be labeled ‘‘oxacillin sodium for oral solution’’. §§ 440.155a—440.155b [Reserved] (3) Requests for certification; samples. In addition to complying with the re- § 440.155c Penicillin G benzathine oral suspension. quirements of § 431.1 of this chapter, each such request shall contain: (a) Requirements for certification—(1) (i) Results of tests and assays on: Standards of identity, strength, quality, (a) The oxacillin sodium and purity. Penicillin G benzathine oral monohydrate used in making the batch suspension contains penicillin G for potency, moisture, pH, oxacillin benzathine with one or more suitable content, crystallinity, and identity. dispersing agents, buffer substances, (b) The batch for potency, moisture, preservatives, colorings, and and pH. flavorings. Each milliliter contains (ii) Samples required: penicillin G benzathine equivalent to (a) The oxacillin sodium 30,000 units or 60,000 units of penicillin monohydrate used in making the G. Its potency is satisfactory if it is batch: 10 packages, each containing ap- not less than 90 percent and not more proximately 300 milligrams. than 120 percent of the number of units (b) The batch: A minimum of six im- of penicillin G that it is represented to mediate containers. contain. Its pH is not less than 6.0 and (b) Tests and methods of assay—(1) Po- not more than 7.0. The penicillin G tency—(i) Sample preparation. Reconsti- benzathine used conforms to the stand- tute as directed in the labeling. Place an accurately measured representative ards prescribed by § 440.55a(a)(1), except aliquot of the sample into an appro- sterility and pyrogens. priate-sized volumetric flask with suf- (2) Labeling. It shall be labeled in ac- ficient 1 percent potassium phosphate cordance with the requirements of buffer, pH 6.0 (solution 1), to give a § 432.5 of this chapter. stock solution of convenient con- (3) Requests for certification; samples. centration. In addition to complying with the re- (ii) Assay procedures. Use either of the quirements of § 431.1 of this chapter, following methods; however, the re- each such request shall contain: sults obtained from the micro- (i) Results of tests and assays on:
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(a) The penicillin G benzathine used ards prescribed by § 440.55a(a)(1), except in making the batch for potency, mois- sterility and pyrogens. ture, pH, penicillin G content, and (2) Labeling. It shall be labeled in ac- crystallinity. cordance with the requirements of (b) The batch for potency and pH. § 432.5 of this chapter. (ii) Samples required: (3) Requests for certification; samples. (a) The penicillin G benzathine used In addition to complying with the re- in making the batch: 10 packages, each quirements of § 431.1 of this chapter, containing approximately 300 milli- each such request shall contain: grams. (i) Results of tests and assays on: (b) The batch: A minimum of 5 imme- (a) The penicillin G benzathine used diate containers. in making the batch for potency, mois- (b) Tests and methods of assay—(1) Po- ture, pH, penicillin G content, and tency. Use either of the following meth- crystallinity. ods; however, the results obtained from (b) The batch for potency, moisture, the iodometric assay shall be conclu- and disintegration time. sive. (ii) Samples required: (i) Microbiological agar diffusion assay. (a) The penicillin G benzathine used Proceed as directed in § 436.105 of this in making the batch: 10 packages, each chapter, preparing the sample for assay containing approximately 300 milli- as follows: Dissolve an accurately grams. measured representative volume of the (b) The batch: A minimum of 36 tab- sample in sufficient absolute methyl lets. alcohol to give a solution of convenient (b) Tests and methods of assay—(1) Po- concentration. Immediately further di- tency. Using the penicillin G working lute with 1 percent potassium phos- standard as the standard of compari- phate buffer, pH 6.0 (solution 1), to the son, assay for potency by either of the reference concentration of 1.0 unit of following methods; however, the re- penicillin G per milliliter (estimated). sults obtained from the iodometric (ii) Iodometric assay. Proceed as di- assay shall be conclusive. rected in § 436.204 of this chapter, using (i) Microbiological agar diffusion assay. a representative aliquot of the drug Proceed as directed in § 436.105 of this prepared for assay as described in para- chapter, preparing the sample for assay graph (b)(2) of that section. as follows: Place a representative num- (2) pH. Proceed as directed in § 436.202 ber of tablets into a high-speed glass of this chapter, using the undiluted blender jar containing 200 milliliters of sample. absolute methyl alcohol. Blend for 1 [42 FR 59862, Nov. 22, 1977, as amended at 50 minute. Add an additional 300 milli- FR 19919, May 13, 1985] liters of absolute methyl alcohol and blend again for 2 to 3 minutes. Imme- § 440.155d Penicillin G benzathine tab- diately further dilute an aliquot with 1 lets. percent potassium phosphate buffer, pH (a) Requirements for certification—(1) 6.0 (solution 1), to the reference con- Standards of identity, strength, quality, centration of 1.0 unit of penicillin G and purity. Penicillin G benzathine tab- per milliliter (estimated). lets contain penicillin G benzathine (ii) Iodometric assay. Proceed as di- with one or more suitable and harmless rected in § 436.204 of this chapter, pre- diluents, binders, lubricants, colorings, paring the sample as follows: Weigh and flavorings. Each tablet contains and finely powder six tablets. Transfer penicillin G benzathine equivalent to two accurately weighed portions of the 200,000 units of penicillin G. Its potency tablets, each equivalent to 200,000 units is satisfactory if it is not less than 90 of penicillin G, to two separate 100-mil- percent and not more than 120 percent liliter volumetric flasks. Dilute one of the number of units of penicillin G flask, which is to be used as the blank, that it is represented to contain. Its to volume with 1 percent potassium moisture content is not more than 8.0 phosphate buffer, pH 6.0 (solution 1), percent. The tablets shall disintegrate and proceed as directed in § 436.204(d) of within 1 hour. The penicillin G this chapter. In lieu of directions in benzathine used conforms to the stand- § 436.204(e) (1), (2), and (3), to the other
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flask add 10 milliliters of 1.0N NaOH ing sufficient absolute methyl alcohol and mix well. Allow to stand for 15 to give a solution of convenient con- minutes, then add 10 milliliters of 1.2N centration. Blend for 3 to 5 minutes. HC1, and dilute to volume with dis- (ii) Assay procedures. Use either of the tilled water. Pipette a 2.0-milliliter ali- following methods; however, the re- quot into a 125-milliliter glass- sults obtained from the iodometric stoppered Erlenmeyer flask and pro- assay shall be conclusive. ceed as directed in § 436.204(c)(4) of this (a) Microbiological agar diffusion chapter. assay. Proceed as directed in § 436.105 of (2) Moisture. Proceed as directed in this chapter. Immediately dilute an al- § 436.201 of this chapter. iquot of the methyl alcohol solution (3) Disintegration time. Proceed as di- with 1 percent potassium phosphate rected in § 436.212 of this chapter. buffer, pH 6.0 (solution 1), to the ref- [42 FR 59862, Nov. 22, 1977, as amended at 50 erence concentration of 1.0 unit of pen- FR 19919, May 13, 1985] icillin V per milliliter (estimated). (b) Iodometric assay. Proceed as di- § 440.171 Penicillin V oral dosage rected in § 436.204 of this chapter, dilut- forms. ing an aliquot of the methyl alcohol with solution 1 to the prescribed con- § 440.171a Penicillin V capsules. centration. (a) Requirements for certification—(1) (2) Moisture. Proceed as directed in Standards of identity, strength, quality, § 436.201 of this chapter. and purity. Penicillin V capsules are composed of penicillin V with one or [42 FR 59863, Nov. 22, 1977, as amended at 50 more suitable and harmless lubricants. FR 19919, May 13, 1985] Each capsule contains either 125 milli- § 440.171b Penicillin V for oral suspen- grams (200,000 units) or 250 milligrams sion. (400,000 units) of penicillin V. Its po- tency is satisfactory if it is not less (a) Requirements for certification—(1) than 90 percent and not more than 120 Standards of identity, strength, quality, percent of the number of milligrams or and purity. Penicillin V for oral suspen- units of penicillin V that it is rep- sion is composed of penicillin V with or resented to contain. Its moisture con- without one or more suitable and tent is not more than 2 percent. The harmless suspending agents, colorings, penicillin V used conforms to the flavorings, and buffer substances. When standards prescribed by § 440.71(a)(1). reconstituted as directed in the label- (2) Labeling. It shall be labeled in ac- ing, each millilter contains 25 milli- cordance with the requirements of grams (40,000 units), 50 milligrams § 432.5 of this chapter. (80,000 units) or 208.3 milligrams (3) Requests for certification; samples. (333,333 units) of penicillin V. Its po- In addition to complying with the re- tency is satisfactory if it is not less quirements of § 431.1 of this chapter, than 90 percent and not more than 120 each such request shall contain: percent of the number of milligrams or (i) Results of tests and assays on: units of penicillin V that it is rep- (a) The penicillin V used in making resented to contain. Its moisture con- the batch for potency, moisture, pH, tent is not more than 1 percent. When penicillin V content, and crystallinity. reconstituted as directed in the label- (b) The batch for potency and mois- ing, its pH is not less than 2.0 and not ture. more than 4.0. The penicillin V used (ii) Samples required: conforms to the standards prescribed (a) The penicillin V used in making by § 440.71(a)(1). the batch: 10 packages, each containing (2) Labeling. It shall be labeled in ac- approximately 300 milligrams. cordance with the requirements of (b) The batch: A minimum of 30 cap- §432.5 of this chapter. sules. (3) Requests for certification; samples. (b) Tests and methods of assay—(1) Po- In addition to complying with the re- tency—(i) Sample preparation. Place a quirements of §431.1 of this chapter, representative number of capsules into each such request shall contain: a high-speed glass blender jar contain- (i) Results of tests and assays on:
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(a) The penicillin V used in making less than 90 percent and not more than the batch for potency, moisture, pH, 120 percent of the number of milli- penicillin V content, and crystallinity. grams or units of penicillin V that it is (b) The batch for potency, moisture, represented to contain. Its moisture and pH. content is not more than 3 percent. It (ii) Samples required: shall disintegrate within 1 hour. The (a) The penicillin V used in making penicillin V used conforms to the the batch: 10 packages, each containing standards prescribed by § 440.71(a)(1). approximately 300 milligrams. (2) Labeling. It shall be labeled in ac- (b) The batch: A minimum of 6 imme- cordance with the requirements of diate containers. § 432.5 of this chapter. (b) Tests and methods of assay—(1) Po- (3) Requests for certification; samples. tency. Use either of the following meth- In addition to complying with the re- ods; however, the results obtained from quirements of § 431.1 of this chapter, the iodometric assay shall be conclu- each such request shall contain: sive. (i) Results of tests and assays on: (i) Microbiological agar diffusion assay. (a) The penicillin V used in making Proceed as directed in § 436.105 of this the batch for potency, moisture, pH, chapter, preparing the sample for assay penicillin V content, and crystallinity. as follows: Reconstitute as directed in (b) The batch for potency, moisture, the labeling. Dissolve an accurately and disintegration time. measured representative volume of the sample in sufficient absolute methyl (ii) Samples required: alcohol to give a solution of convenient (a) The penicillin V used in making concentration. Immediately further di- the batch: 10 packages, each containing lute an aliquot with 1 percent potas- approximately 300 milligrams. sium phosphate buffer, pH 6.0 (solution (b) The batch: A minimum of 36 tab- 1), to the reference concentration of 1.0 lets. unit of penicillin V (estimated). (b) Tests and methods of assay—(1) Po- (ii) Iodometric assay. Proceed as di- tency—(i) Sample preparation. Place a rected in § 436.204 of this chapter, pre- representative number of tablets into a paring the sample as follows: Reconsti- high-speed glass blender jar containing tute as directed in the labeling. Dis- sufficient absolute methyl alcohol to solve an accurately measured rep- give a stock solution of convenient resentative portion of the sample in ab- concentration. Blend for 2 to 5 min- solute methyl alcohol and dilute with utes. 1.0 percent potassium phosphate buffer, (ii) Assay procedures. Use either of the pH 6.0 (solution 1) to the prescribed following methods; however, the re- concentration. sults obtained from the iodometric (2) Moisture. Proceed as directed in assay shall be conclusive. § 436.201 of this chapter. (a) Microbiological agar diffusion (3) pH. Proceed as directed in § 436.202 assay. Proceed as directed in § 436.105 of of this chapter, using the sample recon- this chapter. Immediately dilute an al- stituted as directed in the labeling. iquot of the methyl alcohol solution with 1 percent potassium phosphate [42 FR 59863, Nov. 22, 1977, as amended at 50 buffer, pH 6.0 (solution 1), to the ref- FR 19919, May 13, 1985] erence concentration of 1.0 unit of pen- § 440.171c Penicillin V tablets. icillin V per milliliter (estimated). (b) Iodometric assay. Proceed as di- (a) Requirements for certification—(1) rected in § 436.204 of this chapter, dilut- Standards of identity, strength, quality, ing an aliquot of the methyl alcohol so- and purity. Penicillin V tablets are lution with solution 1 to the prescribed composed of penicillin V with or with- concentration. out one or more suitable and harmless diluents, binders, lubricants, and color- (2) Moisture. Proceed as directed in ings. Each tablet contains 125 milli- § 436.201 of this chapter. grams (200,000 units), 300 milligrams (3) Disintegration time. Proceed as di- (500,000 units), or 500 milligrams rected in § 436.212 of this chapter. (800,000 units) of penicillin V. Its po- [42 FR 59864, Nov. 22, 1977, as amended at 50 tency is satisfactory if it contains not FR 19919, May 13, 1985]
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§ 440.173 Penicillin V potassium oral (a) Microbiological agar diffusion dosage forms. assay. Proceed as directed in § 436.105 of this chapter, diluting an aliquot of the § 440.173a Penicillin V potassium cap- stock solution with solution 1 to the sules. reference concentration of 1.0 unit of (a) Requirements for certification— (1) penicillin V per milliliter (estimated). Standards of identity, strength, quality, (b) Iodometric assay. Proceed as di- and purity. Penicillin V potassium cap- rected in § 436.204 of this chapter, dilut- sules are composed of penicillin V po- ing an aliquot of the stock solution tassium and one or more suitable lubri- with solution 1 to the prescribed con- cants and fillers. Each capsule contains centration. penicillin V potassium equivalent to (2) Loss on drying. Proceed as directed 250 milligrams (400,000 units) or 500 mil- in § 436.200(b) of this chapter. ligrams (800,000 units) of penicillin V. [42 FR 59864, Nov. 22, 1977, as amended at 50 The potency is satisfactory if it is not FR 19919, May 13, 1985] less than 90 percent and more than 115 percent of the number of milligrams or § 440.173b Penicillin V potassium units of penicillin V that it is rep- chewable tablets. resented to contain. Its loss on drying (a) Requirements for certification— (1) is not more than 2.0 percent. The peni- Standards of identity, strength, quality, cillin V potassium used conforms to and purity. Penicillin V potassium the standards prescribed by chewable tablets are composed of peni- § 440.73(a)(1). cillin V potassium with suitable (2) Labeling. It shall be labeled in ac- diluents, binders, buffers, colorings, cordance with the requirements of and flavorings. Each tablet contains § 432.5 of this chapter. penicillin V potassium equivalent to (3) Requests for certification; samples. 125 milligrams (200,000 units) or 250 mil- In addition to complying with the re- ligrams (400,000 units) of penicillin V. quirements of § 431.1 of this chapter, Its potency is satisfactory if it con- each such request shall contain: tains not less than 90 percent and not (i) Results of tests and assays on: more than 125 percent of the number of (a) The penicillin V potassium used milligrams or units of penicillin V that in making the batch for potency, loss it is represented to contain. The loss on drying, pH, crystallinity, penicillin on drying is not more than 1.5 percent. V content. The penicillin V potassium used con- (b) The batch for potency and loss on forms to the standards prescribed by drying. § 440.73(a) (1). (ii) Samples required: (2) Labeling. In addition to the label- (a) The penicillin V potassium used ing requirements prescribed by § 432.5 in making the batch: 10 packages, each of this chapter, this drug shall be la- containing approximately 300 milli- beled ‘‘penicillin V potassium tablets’’. grams. (3) Requests for certification; samples. (b) The batch: A minimum of 30 cap- In addition to complying with the re- sules. quirements of § 431.1 of this chapter, (b) Tests and methods of assay—(1) Po- each such request shall contain: tency—(i) Sample preparation. Place a (i) Results of tests and assays on: representative number of capsules into (a) The penicillin V potassium used a high-speed glass blender jar contain- in making the batch for potency, loss ing sufficient 1 percent potassium on drying, pH, penicillin V content, phosphate buffer, pH 6.0 (solution 1), to and crystallinity. give a stock solution of convenient (b) The batch for potency and loss on concentration. Blend for 3 to 5 min- drying. utes. (ii) Samples required: (ii) Assay procedures. Using the peni- (a) The penicillin V potassium used cillin V working standard as the stand- in making the batch: 10 packages, each ard of comparison, assay by either of containing approximately 300 milli- the following methods; however, the re- grams. sults obtained from the iodometric (b) The batch: A minimum of 30 tab- assay shall be conclusive. lets.
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(b) Tests and methods of assay—(1) Po- (i) Results of tests and assays on: tency—(i) Sample preparation. Place a (a) The penicillin V potassium used representative number of tablets into a in making the batch for potency, loss high-speed glass blender jar containing on drying, pH, penicillin V content and sufficient 1 percent potassium phos- crystallinity. phate buffer, pH 6.0 (solution 1), to give (b) The batch for potency, loss on a stock solution of convenient con- drying, and disintegration time. centration. Blend for 3 to 5 minutes. (ii) Samples required: (ii) Assay procedures. Use either of the (a) The penicillin V potassium used following methods; however, the re- in making the batch: 10 packages, each sults obtained from the iodometric containing approximately 300 milli- assay shall be conclusive. grams. (a) Microbiological agar diffusion (b) The batch: A minimum of 36 tab- assay. Proceed as directed in § 436.105 of lets. this chapter, diluting an aliquot of the (b) Tests and methods of assay—(1) Po- stock solution with solution 1 to the tency—(i) Sample preparation. Place a reference concentration of 1.0 unit of representative number of tablets into a penicillin V per milliliter (estimated). high-speed glass blender jar containing (b) Iodometric assay. Proceed as di- sufficient 1 percent potassium phos- rected in § 436.204 of this chapter, dilut- phate buffer, pH 6.0 (solution 1), to give ing an aliquot of the stock solution a stock solution of convenient con- with solution 1 to the prescribed con- centration. Blend for 3 to 5 minutes. centration. (2) Loss on drying. Proceed as directed (ii) Assay procedures. Use either of the in § 436.200(b) of this chapter. following methods; however, the re- sults obtained from the iodometric [42 FR 59864, Nov. 22, 1977, as amended at 50 assay shall be conclusive. FR 19919, May 13, 1985] (a) Microbiological agar diffusion assay. Proceed as directed in § 436.105 of § 440.173c Penicillin V potassium tab- lets. this chapter, diluting an aliquot of the stock solution with solution 1 to the (a) Requirements for certification— (1) reference concentration of 1.0 unit of Standards of identity, strength, quality, penicillin V per milliliter (estimated). and purity. Penicillin V potassium tab- (b) Iodometric assay. Proceed as di- lets are composed of penicillin V potas- rected in § 436.204 of this chapter, dilut- sium with or without one or more suit- ing an aliquot of the stock solution able and harmless buffer substances, with solution 1 to the prescibed con- diluents, binders, lubricants, colorings, centration. and flavorings. Each tablet contains (2) Loss on drying. Proceed as directed penicillin V potassium equivalent to in § 436.200(b) of this chapter. 125 milligrams (200,000 units), 250 milli- (3) Disintegration time. Proceed as di- grams (400,000 units), or 500 milligrams rected in § 436.212 of this chapter. (800,000 units) of penicillin V. Its po- tency is satisfactory if it contains not [42 FR 59865, Nov. 22, 1977, as amended at 50 less than 90 percent and not more than FR 19919, May 13, 1985] 120 percent of the number of milli- grams or units of penicillin V that it is § 440.173d Penicillin V potassium for represented to contain. Its loss on dry- oral solution. ing is not more than 1.5 percent. It (a) Requirements for certification— (1) shall disintegrate within 1 hour. The Standards of identity, strength, quality, penicillin V potassium used conforms and purity. Penicillin V potassium for to the standards prescribed by oral solution is composed of penicillin § 440.73(a)(1). V potassium with or without one or (2) Labeling. It shall be labeled in ac- more suitable and harmless suspending cordance with the requirements of agents, colorings, flavorings, buffer § 432.5 of this chapter. substances, and preservatives. When re- (3) Requests for certification; samples. constituted as directed in the labeling, In addition to complying with the re- each milliliter contains penicillin V quirements of § 431.1 of this chapter, potassium equivalent to either 25 milli- each such request shall contain: grams (40,000 units) or 50 milligrams
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(80,000 units) of penicillin V. Its po- (3) pH. Proceed as directed in § 436.202 tency is satisfactory if it contains not of this chapter, using the sample when less than 90 percent and not more than reconstituted as directed in the label- 135 percent of the number of milli- ing. grams or units of penicillin V that it is [42 FR 59865, Nov. 22, 1977, as amended at 50 represented to contain. Its moisture FR 19919, May 13, 1985] content is not more than 1 percent. When reconstituted as directed in the § 440.180 Penicillin G potassium oral labeling, its pH is not less than 5.0 and dosage forms. not more than 7.5. The penicillin V po- tassium used conforms to the stand- § 440.180a Penicillin G potassium tab- ards prescribed by § 440.73(a)(1). lets. (2) Labeling. It shall be labeled in ac- (a) Requirements for certification—(1) cordance with the requirements of Standards of identity, strength, quality, § 432.5 of this chapter. and purity. Penicillin potassium tablets (3) Requests for certification; samples. are composed of penicillin G potassium In addition to complying with the re- with or without one or more suitable quirements of § 431.1 of this chapter, and harmless buffer substances, each such requests shall contain: diluents, binders, lubricants, colorings, (i) Results of tests and assays on: and flavorings. Each tablet contains (a) The penicillin V potassium used penicillin G potassium equivalent to in making the batch for potency, loss 100,000 units, 200,000 units, 250,000 units, on drying, pH, penicillin V content, 400,000 units, 500,000 units, 800,000 units and crystallinity. or 1,000,000 units of penicillin G. Its po- (b) The batch for potency, moisture, tency is satisfactory if it is not less and pH. than 90 percent and not more than 120 percent of the number of units of peni- (ii) Samples required: cillin G that it is represented to con- (a) The penicillin V potassium used tain. Its loss on drying is not more in making the batch: 10 packages, each than 1 percent. The tablets shall dis- containing approximately 300 milli- integrate within 1 hour. The penicillin grams. G potassium used conforms to the (b) The batch: A minimum of 6 imme- standards prescribed by § 440.80a(a)(1), diate containers. except sterility and pyrogens. (b) Tests and methods of assay—(1) Po- (2) Labeling. It shall be labeled in ac- tency—(i) Sample preparation. Reconsti- cordance with the requirements of tute as directed in the labeling. Dilute § 432.5 of this chapter. an accurately measured representative (3) Requests for certification; samples. portion of the suspension with 1 per- In addition to complying with the re- cent potassium phosphate buffer, pH 6.0 quirements of § 431.1 of this chapter, (solution 1), to give a stock solution of each such request shall contain: convenient concentration. (i) Results of tests and assays on: (ii) Assay procedures. Use either of the (a) The penicillin G potassium used following methods; however, the re- in making the batch for potency, loss sults obtained from the iodometric on drying, pH, penicillin G content, assay shall be conclusive. and crystallinity. (a) Microbiological agar diffusion (b) The batch: assay. Proceed as directed in § 436.105 of (1) If the person who requests certifi- this chapter, diluting an aliquot of the cation is the manufacturer of the stock solution with solution 1 to the batch: Potency, loss on drying, and dis- reference concentration of 1.0 unit of integration time of tablets collected penicillin V per milliliter (estimated). during the time of tableting the batch; (b) Iodometric assay. Proceed as di- and, unless the tablets are packaged rected in § 436.204 of this chapter, dilut- into dispensing-size containers imme- ing an aliquot of the stock solution diately after they are compressed or with solution 1 to the prescribed con- the manufacturer has submitted to the centration. Commissioner, and it has been accept- (2) Moisture. Proceed as directed in ed, information adequate to prove that § 436.201 of this chapter. such tests are not necessary, loss on
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drying of the tablets collected during (b) Iodometric assay. Proceed as di- each day of packaging the batch. rected in § 436.204 of this chapter, dilut- (2) If the person who requests certifi- ing an aliquot of the stock solution cation is not the manufacturer of the with solution 1 to the prescribed con- batch: Potency, loss on drying, and dis- centration. integration time of tablets collected (2) Loss on drying. Proceed as directed during each day the tablets are being in § 436.200(b) of this chapter. packaged into dispensing-size contain- (3) Disintegration time. Proceed as di- ers. rected in § 436.212 of this chapter. (ii) Samples required: [42 FR 59865, Nov. 22, 1977; 43 FR 3705, Jan. 27, (a) The penicillin G potassium used 1978, as amended at 50 FR 19919, May 13, 1985] in making the batch: 10 packages, each containing approximately 300 milli- § 440.180c Penicillin G potassium cap- grams. sules. (b) The batch: (a) Requirements for certification— (1) (1) If the person who requests certifi- Standards of identity, strength, quality, cation is the manufacturer of the and purity. Penicillin G potassium cap- batch: A minimum of 36 tablets. If, sules are composed of penicillin G po- after tableting, such person packaged tassium and a suitable and harmless the batch into dispensing-size contain- diluent. Each capsule contains penicil- ers: 20 tablets, collected at equal inter- lin G potassium equivalent to 250,000 vals during each day the tablets are units or 400,000 units of penicillin G. Its being packaged, except that this sam- potency is satisfactory if it is not less ple is not required if the tablets are than 90 percent and not more than 120 packaged immediately after they are percent of the number of units of peni- compressed or if the manufacturer has cillin G that it is represented to con- been exempted by the Commissioner tain. Its loss on drying is not more from such requirement. than 1.5 percent. The penicillin G po- (2) If the person who requests certifi- tassium used conforms to the stand- cation is not the manufacturer of the ards prescribed by § 440.80a(a)(1), except batch (for the purposes of certification, sterility and pyrogens. a batch shall be that number of tablets (2) Labeling. It shall be labeled in ac- filled by such person into dispensing- cordance with the requirements of size containers during each day’s pack- § 432.5 of this chapter. aging operations): A minimum of 36 (3) Requests for certification; samples. tablets collected by taking single tab- In addition to complying with the re- lets at such intervals throughout each quirements of § 431.1 of this chapter, day of packaging the tablets so that each such request shall contain: the quantities packaged during the in- (i) Results of tests and assays on: tervals are approximately equal. (a) The penicillin G potassium used (b) Tests and methods of assay—(1) Po- in making the batch for potency, loss tency—(i) Sample preparation. Place a on drying, pH, penicillin G content, representative number of tablets into a and crystallinity. high-speed glass blender jar containing (b) The batch: sufficient 1 percent potassium phos- (1) If the person who requests certifi- phate buffer, pH 6.0 (solution 1), to give cation is the manufacturer of the a stock solution of convenient con- batch: Potency and loss on drying of centration. Blend for 3 to 5 minutes. capsules collected during the time of (ii) Assay procedures. Use either of the encapsulating the batch; and, unless following methods; however, the re- the capsules are packaged into dispens- sults obtained from the iodometric ing-size containers immediately after assay shall be conclusive. they are encapsulated or the manufac- (a) Microbiological agar diffusion turer has submitted to the Commis- assay. Proceed as directed in § 436.105 of sioner, and it has been accepted, infor- this chapter, diluting an aliquot of the mation adequate to prove that such stock solution with solution 1 to the tests are not necessary, loss on drying reference concentration of 1.0 unit of of capsules collected during each day of penicillin G per milliliter (estimated). packaging the batch.
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(2) If the person who requests certifi- with solution 1 to the prescribed con- cation is not the manufacturer of the centration. batch: Potency and loss on drying of (2) Loss on drying. Proceed as directed capsules collected during each day the in § 436.200(b) of this chapter. capsules are being packaged into dis- pensing-size containers. [42 FR 59866, Nov. 22, 1977, as amended at 50 FR 19919, May 13, 1985] (ii) Samples required: (a) The penicillin G potassium used § 440.180f Penicillin G potassium for in making the batch: 10 packages, each oral solution. containing approximately 300 milli- grams. (a) Requirements for certification— (1) (b) The batch: Standards of identity, strength, quality, Penicillin G potassium for (1) If the person who requests certifi- and purity. cation is the manufacturer of the oral solution contains penicillin G po- batch: A minimum of 30 capsules. If tassium and one or more suitable and after encapsulating, such person harmless buffers, colorings, flavorings, packaged the batch into dispensing- diluents, and preservatives. Each milli- size containers: 20 capsules collected at liter contains penicillin G potassium equal intervals during each day the equivalent to 20,000 units, 25,000 units, capsules are being packaged, except 40,000 units, 50,000 units, 80,000 units, or that this sample is not required if the 100,000 units of penicillin G. Its potency capsules are packaged immediately is satisfactory if it is not less than 90 after they are filled or if the manufac- percent and not more than 130 percent turer has been exempted by the Com- of the number of units of penicillin G missioner from such requirement. that it is represented to contain. Its moisture content is not more than 1 (2) If the person who requests certifi- cation is not the manufacturer of the percent. When reconstituted as di- batch (for the purposes of certification, rected in the labeling, its pH is not less a batch shall be that number of cap- than 5.5 and not more than 7.5. The sules filed by such person into dispens- penicillin G potassium used conforms ing-size containers during each day’s to the standards prescribed by packaging operations): A minimum of § 440.80a(a)(1), except sterility and 30 capsules collected by taking single pyrogens. capsules at such intervals throughout (2) Labeling. It shall be labeled in ac- each day of packaging the capsules cordance with the requirements of that the quantities packaged during § 432.5 of this chapter. the intervals are approximately equal. (3) Requests for certification; samples. (b) Tests and methods of assay—(1) Po- In addition to complying with the re- tency—(i) Sample preparation. Place a quirements of § 431.1 of this chapter, representative number of capsules into each such request shall contain: a high-speed glass blender jar contain- (i) Results of tests and assays on: ing sufficient 1 percent potassium (a) The penicillin G potassium used phosphate buffer, pH 6.0 (solution 1), to in making the batch for potency, loss give a stock solution of convenient on drying, pH, penicillin G content, concentration. Blend for 3 to 5 min- and crystallinity. utes. (b) The batch for potency, moisture, (ii) Assay procedures. Use either of the and pH. following methods; however, the re- (ii) Samples required: sults obtained from the iodometric (a) The penicillin G potassium used assay shall be conclusive. in making the batch: 10 packages, each (a) Microbiological agar diffusion containing approximately 300 milli- assay. Proceed as directed in § 436.105 of grams. this chapter, diluting an aliquot of the (b) The batch: A minimum of 6 imme- stock solution with solution 1 to the diate containers. reference concentration of 1.0 unit of (b) Tests and methods of assay—(1) Po- penicillin G per milliliter (estimated). tency—(i) Sample preparation. Reconsti- (b) Iodometric assay. Proceed as di- tute as directed in the labeling. Trans- rected in § 436.204 of this chapter, dilut- fer an accurately measured representa- ing an aliquot of the stock solution tive portion into a suitable volumetric
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flask and dilute to volume with 1 per- (1) If the person who requests certifi- cent potassium phosphate buffer, pH 6.0 cation is the manufacturer of the (solution 1). batch: Potency and loss on drying of (ii) Assay procedures. Use either of the tablets collected during the time of following methods; however, the re- tableting the batch; and, unless the sults obtained from the iodometric tablets are packaged into dispensing- assay shall be conclusive. size containers immediately after they (a) Microbiological agar diffusion are compressed, or the manufacturer assay. Proceed as directed in § 436.105 of has submitted to the Commissioner, this chapter, diluting an aliquot of the and it has been accepted, information stock solution with solution 1 to the adequate to prove that such tests are reference concentration of 1.0 unit of not necessary, loss on drying of the penicillin G per milliliter (estimated). tablets collected during each day of (b) Iodometric assay. Proceed as di- packaging the batch. rected in § 436.204 of this chapter, dilut- (2) If the person who requests certifi- ing an aliquot of the stock solution cation is not the manufacturer of the with solution 1 to the prescribed con- batch: Potency and loss on drying of centration. the tablets collected during each day (2) Moisture. Proceed as directed in the tablets are being packaged into dis- § 436.201 of this chapter. pensing-size containers. (3) pH. Proceed as directed in § 436.202 (ii) Samples required: of this chapter, using the solution ob- (a) The penicillin G potassium used tained after reconstituting the drug as in making the batch: 10 packages, each directed in the labeling. containing approximately 300 milli- [42 FR 59866, Nov. 22, 1977, as amended at 50 grams. FR 19919, May 13, 1985] (b) The batch: (1) If the person who requests certifi- § 440.180g Penicillin G potassium tab- cation is the manufacturer of the lets for solution. batch: A minimum of 30 tablets. If, (a) Requirements for certification— (1) after tableting, such person packaged Standards of identity, strength, quality, the batch into dispensing-size contain- and purity. Penicillin G potassium tab- ers: 20 tablets collected at equal inter- lets for solution are composed of peni- vals during each day the tablets are cillin G potassium. Each tablet con- packaged, except that this sample is tains penicillin G potassium equivalent not required if the tablets are packaged to 100,000 units, 200,000 units, or 250,000 immediately after they are compressed units of penicillin G. The potency is or if the manufacturer has been ex- satisfactory if it is not less than 90 per- empted by the Commissioner from such cent and not more than 120 percent of requirement. the number of units of penicillin G that (2) If the person who requests certifi- it is represented to contain. Its loss on cation is not the manufacturer of the drying is not more than 1 percent. The batch (for the purposes of certification, penicillin G potassium used conforms a batch shall be that number of tablets to the standards prescribed by filed by such person into dispensing- § 440.80a(a)(1), except sterility and size containers during each day’s pack- pyrogens. aging operations): A minimum of 30 (2) Labeling. It shall be labeled in ac- tablets collected by taking single tab- cordance with the requirements of lets at such intervals throughout each § 432.5 of this chapter. day of packaging the tablets that the (3) Requests for certification; samples. quantities packaged during the inter- In addition to complying with the re- vals are approximately equal. quirements of § 431.1 of this chapter, (b) Tests and methods of assay—(1) Po- each such request shall contain: tency—(i) Sample preparation. Place a (i) Results of tests and assays on: representative number of tablets into a (a) The penicillin G potassium used high-speed glass blender jar containing in making the batch for potency, loss sufficient 1 percent potassium phos- on drying, pH, penicillin G content, phate buffer, pH 6.0 (solution 1), to give and crystallinity. a stock solution of convenient con- (b) The batch: centration. Blend for 3 to 5 minutes.
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(ii) Assay procedures. Use either of the used conforms to the standards pre- following methods; however, the re- scribed by § 440.7a(a)(1) of this chapter. sults obtained from the iodometric (2) Labeling. In addition to the label- assay shall be conclusive. ing requirements prescribed by § 432.5 (a) Microbiological agar diffusion of this chapter, this drug shall be la- assay. Proceed as directed in § 436.105 of beled ‘‘sterile ampicillin for suspen- this chapter, diluting an aliquot of the sion.’’ stock solution with solution 1 to the (3) Requests for certification; samples. reference concentration of 1.0 unit of In addition to complying with the re- penicillin G per milliliter (estimated). quirements of § 431.1 of this chapter, (b) Iodometric assay. Proceed as di- each such request shall contain: rected in § 436.204 of this chapter, dilut- (i) Results of tests and assays on: ing an aliquot of the stock solution (a) The ampicillin trihydrate used in with solution 1 to the prescribed con- making the batch for potency, loss on centration. drying, pH, ampicillin content, con- (2) Loss on drying. Proceed as directed cordance, crystallinity, and identity. in § 436.200(b) of this chapter. (b) The batch for potency, sterility, [42 FR 59867, Nov. 22, 1977, as amended at 50 pyrogens, loss on drying, and pH. FR 19919, May 13, 1985] (ii) Samples required: (a) The ampicillin trihydrate used in Subpart C—Injectable Dosage making the batch: 10 packages, each Forms containing approximately 300 milli- grams. § 440.201 Sterile azlocillin sodium. (b) The batch: The requirements for certification (1) For all tests except sterility: A and the tests and methods of assay for minimum of 12 immediate containers. sterile azlocillin sodium packaged for (2) For sterility testing: 20 immediate dispensing are described in § 440.1a. containers, collected at regular inter- vals throughout each filling operation. [47 FR 53349, Nov. 26, 1982] (b) Tests and methods of assay—(1) Po- § 440.202 Sterile amdinocillin. tency—(i) Sample preparation. Reconsti- tute as directed in the labeling. Using The requirements for certification a suitable hypodermic needle and sy- and the tests and methods of assay for ringe, remove all of the withdrawable sterile amdinocillin packaged for dis- contents if it is represented as a single- pensing are described in § 440.2a. dose container, or, if the labeling speci- [50 FR 7766, Feb. 26, 1985] fies the amount of potency in a given volume of the resultant preparation, § 440.207 Sterile ampicillin trihydrate remove an accurately measured rep- for suspension. resentative portion from each con- (a) Requirements for certification—(1) tainer. Dilute the resultant solution Standards of identity, strength, quality, with 0.1M potassium phosphate buffer, and purity. Sterile ampicillin tri- pH 8.0 (solution 3), for the micro- hydrate for suspension is a dry mixture biological agar diffusion assay, or dis- of ampicillin trihydrate and one or tilled water for the iodometric assay, more suitable and harmless buffer sub- to give a stock solution of convenient stances, stabilizers, suspending agents, concentration. and preservatives. Its potency is satis- (ii) Assay procedures. Use either of the factory if it is not less than 90 percent following methods; however, the re- and not more than 120 percent of the sults obtained from the micro- number of milligrams of ampicillin biological agar diffusion assay shall be that it is represented to contain. It is conclusive. sterile. It is nonpyrogenic. Its loss on (a) Microbiological agar diffusion drying is not less than 11.4 percent and assay. Proceed as directed in § 436.105 of not more than 14.0 percent. When re- this chapter, diluting an aliquot of the constituted as directed in the labeling, stock solution with solution 3 to the its pH is not less than 5.0 and not more reference concentration of 0.1 than 7.0. The ampicillin trihydrate microgram of ampicillin per milliliter.
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(b) Iodometric assay. Proceed as di- sterile ampicillin sodium packaged for rected in § 436.204 of this chapter, ex- dispensing are described in § 440.9a. cept in paragraph (d) of that section, [39 FR 18976, May 30, 1974, as amended at 42 add 3 drops of 1.2N hydrochloric acid to FR 59867, Nov. 22, 1977. Redesignated at 52 FR both the sample and working standard 42288, Nov. 4, 1987] solutions after the addition of 0.01N io- dine solution. Dilute an aliquot of the § 440.209b Sterile ampicillin sodium stock solution with distilled water to and sulbactam sodium. the prescribed concentration. (a) Requirements for certification—(1) (2) Sterility. Proceed as directed in Standards of identity, strength, quality, § 436.20 of this chapter, using the meth- and purity. Ampicillin sodium and od described in paragraph (e)(1) of that sulbactam sodium is a dry mixture of section, except in lieu of (e)(1)(i)(a), ampicillin sodium and sulbactam so- prepare the sample for test as follows: dium in which the ratio of ampicillin From each of 10 immediate containers, to sulbactam is 2:1. Its ampicillin po- aseptically transfer approximately 300 tency is not less than 563 micrograms milligrams of sample into a sterile 500- of ampicillin per milligram on an an- milliliter Erlenmeyer flask containing hydrous basis. It contains not less than approximately 400 milliliters of dilut- 280 micrograms of sulbactam per milli- ing fluid D. Add at least 200,000 Levy gram on an anhydrous basis. Its ampi- units 1 of penicillinase. Repeat the cillin sodium content is satisfactory if process using 10 additional containers. it contains not less than 90 percent and Swirl both of the stoppered flasks to not more than 115 percent of the num- completely solubilize the suspension ber of milligrams of ampicillin that it prior to filtration and proceed as di- is represented to contain. Its rected in paragraph (e)(1)(ii) of that sulbactam sodium content is satisfac- section. If the formulation cannot be tory if it contains not less than 90 per- filtered, proceed as directed in cent and not more than 115 percent of § 436.20(e)(2) of this chapter, except use the number of milligrams of sulbactam medium B in lieu of medium A. that it is represented to contain. It is (3) Pyrogens. Proceed as directed in sterile. It is nonpyrogenic. Its moisture § 436.32(f) of this chapter, using a solu- content is not more than 2.0 percent. tion containing 20 milligrams of ampi- The pH of an aqueous solution contain- cillin per milliliter. ing 10 milligrams of ampicillin and 5 milligrams of sulbactam per milliliter (4) [Reserved] is not less than 8.0 and not more than (5) Loss on drying. Proceed as directed 10.0. It passes the identity test for am- in § 436.200(a) of this chapter. picillin and sulbactam. The ampicillin (6) pH. Proceed as directed in § 436.202 sodium content conforms to the stand- of this chapter, using the solution ob- ards prescribed by § 440.9a(a)(1) of this tained when the product is reconsti- chapter. The sulbactam content con- tuted as directed in the labeling. forms to the standards prescribed by [39 FR 18976, May 30, 1974, as amended at 49 § 455.82a(a)(1) of this chapter. FR 3459, Jan. 27, 1984; 50 FR 19918, 19919, May (2) Labeling. It shall be labeled in ac- 13, 1985] cordance with the requirements of § 432.5 of this chapter. § 440.209 Ampicillin sodium injectable (3) Requests for certification; samples. dosage forms. In addition to the requirements of § 431.1 of this chapter, each such re- § 440.209a Sterile ampicillin sodium. quest shall contain: The requirements for certification (i) Results of tests and assays on: and the tests and methods of assay for (A) The ampicillin sodium used in making the batch for potency, steril- ity, pyrogens, moisture, pH, crystallin- 1 One Levy unit of penicillinase inactivates ity, and identity. 59.3 units of pencillin G in 1 hour at 25° C. and at a pH of 7.0 in a phosphate buffered so- (B) The sulbactam sodium used in lution of a pure alkali salt of penicillin G making the batch for potency, steril- when the substrate is in sufficient con- ity, pyrogens, moisture, crystallinity, centration to maintain a zero order reaction. and identity.
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(C) The batch for ampicillin potency, (ii) Preparation of working standard sulbactam potency, sterility, pyrogens, and sample solutions—(A) Working stand- moisture, pH, and identity. ard solution. Accurately weigh a por- (ii) Samples, if required by the Direc- tion of the ampicillin working standard tor, Center for Drug Evaluation and containing the equivalence of approxi- Research: mately 75 milligrams of ampicillin ac- (A) The ampicillin sodium used in tivity and transfer into a 25-milliliter making the batch: 12 packages, each volumetric flask. Accurately weigh a containing approximately 300 milli- portion of the sulbactam working grams. standard containing 35 milligrams of (B) The sulbactam sodium used in sulbactam and transfer into the 25-mil- making the batch: 12 packages, each liliter volumetric flask containing the containing approximately 300 milli- ampicillin. Dissolve and dilute to vol- grams. ume with mobile phase. Further dilute (C) The batch: 5 milliliters to 25 milliliters with mo- (1) For all tests except sterility: A bile phase. minimum of 10 immediate containers. (B) Sample solution. Dissolve an accu- (2) For sterility testing: A minimum rately weighed sample in sufficient mo- of 20 immediate containers collected at bile phase to give a stock solution con- regular intervals throughout each fill- taining 1 milligram of sample per mil- ing operation. liliter (estimated); and, also, if it is (b) Tests and methods of assay—(1) Am- packaged for dispensing, reconstitute picillin and sulbactam content. Proceed as directed in the labeling. Then using as directed in § 436.216 of this chapter, a suitable hypodermic needle and sy- operating isothermally at 25 °C, using ringe, remove all of the withdrawable an ultraviolet detection system operat- contents if it is represented as a single- ing at a wavelength of 230 nanometers, dose container, or if the labeling speci- a column packed with microparticulate fies the amount of potency in a given (3 to 10 micrometers in diameter) re- volume of the resultant preparation, versed phase packing material such as remove an accurately measured rep- octadecyl hydrocarbon bonded silica, a resentative portion from each con- flow rate of 2.0 milliliters per minute, tainer. Dilute with mobile phase to and a known injection volume of 10 yield a solution containing about 0.30 microliters. Reagents, working stand- milligram sulbactam and about 0.60 ard and sample solutions, system suit- milligram ampicillin per milliliter. ability requirements, and calculations (iii) System suitability requirements— are as follows: (A) Tailing factor. The tailing factor (T) (i) Reagents—(A) 1.0M Phosphoric acid. is satisfactory if it is not more than 1.5 Prepare by diluting 67.5 milliliters of at 10 percent of peak height in lieu of reagent grade phosphoric acid (85 per- 5 percent of peak height. cent) in distilled water to 1 liter. (B) Efficiency of the column. The effi- (B) 0.005M Tetrabutylammonium hy- ciency of the column (n) is satisfactory droxide. Dilute 6.6 milliliters of if it is greater than 3,500 theoretical tetrabutylammonium hydroxide (40 plates for sulbactam for a 30-centi- percent) to 1,800 milliliters with dis- meter column. tilled water. Adjust the pH to 5.0 with (C) Resolution. Dissolve 17.5 milli- 1.0M phosphoric acid and dilute with grams of sulbactam in 50 milliliters of distill water to 2 liters. 0.01N sodium hydroxide and let stand (C) Mobile phase. Mix 350 milliliters of for 30 minutes. Adjust the pH of the so- acetonitrile with 1,650 milliliters of lution to 5.0 with concentrated phos- 0.005M tetrabutylammonium hydrox- phoric acid. Transfer a 5-milliliter ali- ide. Filter and degas the mobile phase quot of the resulting solution to a 25- just prior to its introduction into the milliliter volumetric flask, add 4.25 chromatograph pumping system. milliliters of acetonitrile, and dilute to (Slight adjustments in pH and/or aceto- volume with 0.005M nitrile content may be made to achieve tetrabutylammonium hydroxide as de- the system suitability parameters de- scribed in paragraph (b)(1)(i)(B) of this fined in paragraph (b)(1)(iii) of this sec- section. Transfer 2 milliliters of this tion.) solution to a 50-milliliter flask, add 30
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milligrams of ampicillin potency, dis- Ps=Ampicillin or sulbactam activity in the solve and dilute to volume with mobile ampicillin-sulbactam working standard phase. Use this solution to determine solution in micrograms per milliliter; the resolution factor. The resolution and d=Dilution factor of the sample. (R) between the peaks for ampicillin and sulbactam alkaline degradation (2) Sterility. Proceed as directed in product is satisfactory if it is not less § 436.20 of this chapter, using the meth- than 1.2. od described in paragraph (e)(1) of that (D) Coefficient of variation (relative section. standard deviation). The coefficient of (3) Pyrogens. Proceed as directed in variation (SR in percent) of 5 replicate § 436.32(b) of this chapter, using a solu- injections is satisfactory if it is not tion containing 20 milligrams of more than 2.0 percent. sulbactam and 40 milligrams of ampi- cillin per milliliter. If the system suitability requirements (4) Moisture. Proceed as directed in have been met, then proceed as de- § 436.201 of this chapter. scribed in § 436.216(b) of this chapter. (5) pH. Proceed as directed in § 436.202 Alternate chromatographic conditions of this chapter, using an aqueous solu- are acceptable provided reproducibility tion containing 10 milligrams of ampi- and resolution are comparable to the cillin and 5 milligrams of sulbactam system. However, the sample prepara- per milliliter. tion described in paragraph (b)(1)(ii)(b) (6) Identity. The high-performance of this section should not be changed. liquid chromatogram of the sample de- (iv) Calculations. (A) Calculate the termined as directed in paragraph micrograms of ampicillin or sulbactam (b)(1) of this section compares quali- per milligram of sample as follows: tatively to that of the ampicillin- Micrograms of sulbactam working standard. × × [52 FR 42288, Nov. 4, 1987, as amended at 54 ampicillin or APu s 100 = FR 47205, Feb. 20, 1989; 55 FR 11582, Mar. 29, sulbactam per A× C ×()100 − m 1990] milligram s u where: § 440.210 Benzylpenicilloyl-polylysine injection. Au=Area of the ampicillin or sulbactam peak in the chromatogram of the sample (at a (a) Requirements for certification— (1) retention time equal to that observed for Standards of identity, strength, quality, the standard); and purity. Benzylpenicilloyl- As=Area of the ampicillin or sulbactam peak polylysine injection is an aqueous solu- in the chromatogram of the ampicillin or sulbactam working standard; tion of benzylpenicilloyl-polylysine. It contains one or more suitable and Ps=Ampicillin or sulbactam activity in the ampicillin-sulbactam working standard harmless buffers. Its benzylpenicilloyl solution in micrograms per milliliter; content is satisfactory if it is not less ¥ 5 Cu=Milligrams of sample per milliliter of than 5.4×10 M and not more than sample solution; and 7.0×10¥ 5M, except that for the issuance m=Percent moisture content of the sample. of a certificate for a batch, the (B) Calculate the ampicillin or benzylpenicilloyl content must be not sulbactam content of the container as less than 6.4×10¥ 5M. It is sterile. It is follows: nonpyrogenic. Its pH is not less than 6.5 and not more than 8.5. The benzylpenicilloyl-polylysine con- Milligrams of A× P × d ampicillin or sulbactam = u s centrate used conforms to the stand- A ×1, 000 ards prescribed by § 440.10(a)(1). per container s (2) Labeling. It shall be labeled in ac- where: cordance with the requirements of Au=Area of the ampicillin or sulbactam peak § 432.5 of this chapter. in the chromatogram of the sample (at a (3) Requests for certification; samples. retention time equal to that observed for the standard); In addition to complying with the re- quirements of § 431.1 of this chapter, As=Area of the ampicillin or sulbactam peak in the chromatogram of the ampicillin or each such request shall contain: sulbactam working standard; (i) Results of tests and assays on:
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(a) The benzylpenicilloyl-polylysine § 440.219 Dicloxacillin sodium concentrate used in making the batch monohydrate injectable dosage for percent benzylpenicilloyl substi- forms. tution, benzylpenicilloyl content, penamaldate content, penicillenate § 440.219a Sterile dicloxacillin sodium monohydrate. content, and pH. (b) The batch for benzylpenicilloyl The requirements for certification content, sterility, pyrogens, and pH. and the tests and methods of assay for sterile dicloxacillin sodium (ii) Samples required: monohydrate packaged for dispensing (a) The benzylpenicilloyl-polylysine are described in § 440.19a. concentrate used in making the batch: 2 vials, each containing not less than 5 [39 FR 18976, May 30, 1974, as amended at 42 milliliters. FR 59867, Nov. 22, 1977] (b) The batch: § 440.219b Dicloxacillin sodium (1) For all tests except sterility: A monohydrate for injection. minimum of 60 immediate containers. (a) Requirements for certification— (1) (2) For sterility testing: 20 immediate Standards of identity, strength, quality, containers, collected at regular inter- and purity. Dicloxacillin sodium vals throughout each filling operation. monohydrate for injection is a dry mix- (b) Tests and methods of assay—(1) ture of dicloxacillin sodium Benzylpenicilloyl content. Proceed as di- monohydrate and lidocaine hydro- rected in § 440.10(b)(1)(ii) except in lieu chloride packaged for dispensing. Its of § 440.10(b)(1)(ii)(b) prepare the sample potency is satisfactory if it is not less solution as follows: Pool contents of 16 than 90 percent and not more than 115 immediate containers. Dilute a 3.0-mil- percent of the number of milligrams of liliter aliquot to 10 milliliters with sa- dicloxacillin that it is represented to line phosphate buffer, pH 7.6. contain. It is sterile. It is (2) Sterility. Proceed as directed in nonpyrogenic. Its moisture content is § 436.20 of this chapter, using the meth- not more than 5 percent. When recon- od described in paragraph (e)(1) of that stituted as directed in the labeling, its section. pH is not less than 4.5 and not more (3) Pyrogens. Proceed as directed in than 7.5. The dicloxacillin sodium monohydrate used conforms to the § 436.32(a) of this chapter, preparing the standards prescribed by § 440.19a(a)(1). sample solution as follows: Pool the (2) Labeling. In addition to the label- contents of at least 8 vials to obtain a ing requirements of § 432.5 of this chap- minimum of 1.5 milliliters of the origi- ter, this drug shall be labeled nal preparation. Dilute the 1.5 milli- ‘‘dicloxacillin sodium for injection’’. liters to 50 milliliters with diluent 2. (3) Requests for certification; samples. (4) [Reserved] In addition to complying with the re- (5) pH. Proceed as directed in § 436.202 quirements of § 431.1 of this chapter, of this chapter, using the undiluted so- each such request shall contain: lution. (i) Results of tests and assays on: [39 FR 35347, Oct. 1, 1974, as amended at 42 FR (a) The dicloxacillin sodium 14094, Mar. 15, 1977; 50 FR 19918, 19919, May 13, monohydrate used in making the batch 1985] for potency, moisture, pH, organic chlorine content, free chloride content, § 440.213 Sterile carbenicillin crystallinity, and identity. disodium. (b) The batch for potency, sterility, pyrogens, moisture, and pH. The requirements for certification (ii) Samples required: and the tests and methods of assay for (a) The dicloxacillin sodium sterile carbenicillin disodium packaged monohydrate used in making the for dispensing are described in § 440.13a. batch: 10 packages, each containing ap- [39 FR 18976, May 30, 1974, as amended at 42 proximately 500 milligrams. FR 59867, Nov. 22, 1977] (b) The batch:
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(1) For all tests except sterility: A (6) pH. Proceed as directed in § 436.202 minimum of 15 immediate containers. of this chapter, using the product re- (2) For sterility testing: 20 immediate constituted as directed in the labeling. containers, collected at regular inter- [39 FR 18976, May 30, 1974, as amended at 42 vals throughout each filling operation. FR 59867, Nov. 22, 1977; 50 FR 19918, 19919, (b) Tests and methods of assay—(1) Po- May 13, 1985] tency—(i) Sample preparation. Reconsti- tute as directed in the labeling. Using § 440.229 Hetacillin potassium injectable dosage forms. a suitable hypodermic needle and sy- ringe remove all of the withdrawable § 440.229a Sterile hetacillin potassium. contents if it is represented as a single- The requirements for certification dose container; or, if the labeling speci- and the tests and methods of assay for fies the amount of potency in a given sterile hetacillin potassium packaged volume of the resultant preparation, for dispensing are described in § 440.29a. remove an accurately measured rep- resentative portion from each con- [39 FR 18976, May 30, 1974, as amended at 42 tainer. Dilute the sample thus obtained FR 59867, Nov. 22, 1977] with sufficient 1.0 percent potassium § 440.229b Hetacillin potassium for in- phosphate buffer, pH 6.0 (solution 1), jection. for the microbiological agar diffusion (a) Requirements for certification— (1) assay or in distilled water for the Standards of identity, strength, quality, iodometric assay and hydroxylamine and purity. Hetacillin potassium for in- colorimetric assay, to give a stock so- jection is a dry mixture of hetacillin lution of convenient concentration. potassium and lidocaine hydrochloride. (ii) Assay procedure. Use any of the Its potency is satisfactory if it con- following methods; however, the re- tains not less than 90 percent and not sults obtained from the micro- more than 120 percent of the number of biological agar diffusion assay shall be milligrams of ampicillin that it is rep- conclusive. resented to contain. It is sterile and (a) Microbiological agar diffusion nonpyrogenic. Its moisture content is assay. Proceed as directed in § 436.105 of not more than 1.0 percent. When recon- this chapter, diluting an aliquot of the stituted as directed in its labeling, its stock solution with solution 1 to the pH is not less than 7.0 and not more reference concentration of 5 than 9.0. The hetacillin potassium used micrograms of dicloxacillin per milli- conforms to the requirements of liter (estimated). § 440.29a(a)(1). (b) Iodometric assay. Proceed as di- (2) Labeling. It shall be labeled in ac- rected in § 436.204 of this chapter, dilut- cordance with the requirements of ing an aliquot of the stock solution § 432.5 of this chapter. with distilled water to the prescribed (3) Requests for certification; samples. concentration. In addition to complying with the re- (c) Hydroxylamine colorimetric assay. quirements of § 431.1 of this chapter, Proceed as directed in § 436.205 of this each such request shall contain: chapter, except dilute an aliquot of the (i) Results of tests and assays on: stock solution with distilled water to (a) The hetacillin potassium used in the prescribed concentration. making the batch for potency, mois- ture, pH, hetacillin content, identity, (2) Sterility. Proceed as directed in and crystallinity. § 436.20 of this chapter, using the meth- (b) The batch for potency, sterility, od described in paragraph (e)(1) of that pyrogens, moisture, and pH. section. (ii) Samples required: (3) Pyrogens. Proceed as directed in (a) The hetacillin potassium used in § 436.32(a) of this chapter, using a solu- making the batch: 10 packages, each tion containing 20 milligrams of containing approximately 300 milli- dicloxacillin per milliliter. grams. (4) [Reserved] (b) The batch: (5) Moisture. Proceed as directed in (1) For all tests except sterility: A § 436.201 of this chapter. minimum of 10 immediate containers,
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except if each contains less than 450 cent by weight of its total solids (such milligrams of ampicillin, a minimum sodium citrate conforms to the stand- of 16 immediate containers. ards prescribed therefor by the U.S.P.). (2) For sterility testing: 20 immediate Its potency is satisfactory if it is not containers collected at regular inter- less than 90 percent and not more than vals throughout each filling operation. 115 percent of the number of milli- (b) Tests and methods of assay—(1) Po- grams of methicillin that it is rep- tency. Proceed as directed for ampi- resented to contain. It is sterile. It is cillin in § 436.105 of this chapter, using nonpyrogenic. Its pH in an aqueous so- the ampicillin working standard as the lution containing 10 milligrams per standard of comparison and preparing milliliter is not less than 6.0 and not the sample for assay as follows: Recon- more than 8.5. Its moisture content is stitute as directed in the labeling. not more than 6.0 percent. The Using a suitable hypodermic needle and methicillin sodium monohydrate used syringe, remove the withdrawable con- conforms to the standards prescribed tents from each container represented by § 440.36a(a)(1). as a single-dose container; or, if the la- (2) Labeling. In addition to the label- beling specifies the amount of potency ing requirements of § 432.5 of this chap- in a given volume of the resultant ter, this drug shall be labeled preparation, withdraw an accurately ‘‘methicillin sodium for injection’’. measured representative portion from (3) Requests for certification; samples. each container. Dilute the sample thus In addition to complying with the re- obtained with sufficient 0.1M potas- quirements of § 431.1 of this subchapter, sium phosphate buffer, pH 8.0 (solution each such request shall contain: 3), to give a stock solution of conven- (i) Results of tests and assays on: ient concentration. Further dilute the (a) The methicillin sodium stock solution with solution 3 to the monohydrate used in making the batch reference concentration of 0.1 for potency, moisture, pH, methicillin microgram of ampicillin per milliliter content, crystallinity, and identity. (estimated). (b) The batch for potency, sterility, (2) Sterility. Proceed as directed in pyrogens, pH, and moisture. § 436.20 of this chapter, using the meth- od described in paragraph (e)(1) of that (ii) Samples required: section. (a) The methicillin sodium (3) Pyrogens. Proceed as directed in monohydrate used in making the § 436.32(a) of this chapter, using a solu- batch: 10 packages, each containing ap- tion containing the equivalent of 18 proximately 300 milligrams, plus one milligrams of ampicillin per milliliter. package containing approximately 2 (4) [Reserved] grams. (5) Moisture. Proceed as directed in (b) The batch: § 436.201 of this chapter. (1) For all tests except sterility: A (6) pH. Proceed as directed in § 436.202 minimum of 10 immediate containers. of this chapter, using the product re- (2) For sterility testing: 20 immediate constituted as directed in the labeling. containers, collected at regular inter- [39 FR 18976, May 30, 1974, as amended at 42 vals throughout each filling operation. FR 59867, Nov. 22, 1977; 50 FR 19918, 19919, (b) Tests and methods of assay—(1) Po- May 13, 1985] tency—(i) Sample preparation. Reconsti- tute as directed in the labeling. Using § 440.236 Methicillin sodium a suitable hypodermic needle and sy- monohydrate for injection. ringe, remove all of the withdrawable (a) Requirements for certification—(1) contents if it is represented as a single- Standards of identity, strength, quality, dose container; or, if the labeling speci- and purity. Methicillin sodium fies the amount of potency in a given monohydrate for injection is volume of the resultant preparation, methicillin sodium monohydrate with remove an accurately measured rep- or without one or more suitable and resentative portion from each con- harmless preservatives and the buffer tainer. Dilute the portion thus ob- sodium citrate in a quantity not less tained with 1 percent potassium phos- than 4 percent and not more than 5 per- phate buffer, pH 6.0 (solution 1), to give
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a stock solution of convenient con- tency is satisfactory if it is not less centration. than 90 percent and not more than 120 (ii) Assay procedure. Use either of the percent of the number of milligrams of following methods; however, the re- nafcillin that it is represented to con- sults obtained from the micro- tain. It is sterile. It is nonpyrogenic. biological agar diffusion assay shall be Its moisture content is not less than 3.5 conclusive. and not more than 5.3 percent. When (a) Microbiological agar diffusion reconstituted as directed in the label- assay. Proceed as directed in § 436.105 of ing, the pH is not less than 6.0 and not this subchapter, diluting an aliquot of more than 8.5. The nafcillin sodium the stock solution with solution 1 to monohydrate used conforms to the re- the reference concentration of 10 quirements of § 440.41a(a)(1). micrograms of methicillin per milli- (2) Labeling. In addition to the label- liter (estimated). ing requirements of § 432.5 of this chap- (b) Iodometric assay. Proceed as di- ter, this drug shall be labeled rected in § 436.204 of this subchapter, di- ‘‘nafcillin sodium for injection’’. luting an aliquot of the stock solution with solution 1 to the prescribed con- (3) Requests for certification; samples. centration. In addition to complying with the re- (2) Sterility. Proceed as directed in quirements of § 431.1 of this chapter, § 436.20 of this subchapter, using the each such request shall contain: method described in paragraph (e)(1) of (i) Results of tests and assays on: that section. (a) The nafcillin sodium (3) Pyrogens. Proceed as directed in monohydrate used in making the batch § 436.32(a) of this chapter, using a solu- for potency, moisture, pH, crystallin- tion containing 60 milligrams of ity, nafcillin content, and identity. methicillin per milliliter. (b) The batch for potency, sterility, (4) [Reserved] pyrogens, moisture, and pH. (5) pH. Proceed as directed in § 436.202 (ii) Samples required: of this chapter, using an aqueous solu- (a) The nafcillin sodium tion containing 10 milligrams per monohydrate used in making the millilter. batch: 10 packages, each containing ap- (6) Moisture. Proceed as directed in proximately 300 milligrams. § 436.201 of this subchapter. (b) The batch: [39 FR 18976, May 30, 1974, as amended at 40 (1) For all tests except sterility: A FR 15089, Apr. 4, 1975; 42 FR 59868, Nov. 22, minimum of 12 immediate containers. 1977; 49 FR 5096, Feb. 10, 1984; 50 FR 19918, (2) For sterility testing: 20 immediate 19919, May 13, 1985] containers, collected at regular inter- § 440.237 Sterile mezlocillin sodium vals throughout each filling operation. monohydrate. (b) Tests and methods of assay—(1) Po- The requirements for certification tency—(i) Sample preparation. Reconsti- and the tests and methods of assay for tute as directed in the labeling. Using sterile mezlocillin sodium a suitable hypodermic needle and sy- monohydrate packaged for dispensing ringe, remove all of the withdrawable are described in § 440.37a. contents if it is represented as a single- dose container; or, if the labeling speci- [46 FR 58299, Dec. 1, 1981] fies the amount of potency in a given § 440.241 Nafcillin sodium injectable volume of the resultant preparation re- dosage forms. move an accurately measured rep- resentative portion from each con- § 440.241a Nafcillin sodium tainer. Dilute the sample thus obtained monohydrate for injection. with 1 percent potassium phosphate (a) Requirements for certification— (1) buffer, pH 6.0 (solution 1), to the ref- Standards of identity, strength, quality, erence concentration of 2.0 micrograms and purity. Nafcillin sodium of nafcillin per milliliter (estimated) monohydrate for injection is a dry mix- for the microbiological agar diffusion ture of nafcillin sodium monohydrate assay and to the prescribed concentra- and a suitable buffer substance. Its po- tion for the iodometric assay.
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(ii) Assay procedures. Assay for po- quirements of § 431.1 of this chapter, tency by either of the following meth- each such request shall contain: ods; however, the results obtained from (i) Results of tests and assays on: the microbiological agar diffusion (A) The nafcillin sodium assay shall be conclusive. monohydrate used in making the batch (a) Microbiological agar diffusion for potency, moisture, pH, crystallin- assay. Proceed as directed in § 436.105 of ity, nafcillin content, and identity. this chapter. (B) The batch for nafcillin content, (b) Iodometric assay. Proceed as di- sterility, pyrogens, and pH. rected in § 436.204 of this chapter. (ii) Samples, if required by the Cen- (2) Sterility. Proceed as directed in ter for Drug Evaluation and Research: § 436.20 of this chapter, using the meth- (A) The nafcillin sodium od described in paragraph (e)(1) of that monohydrate used in making the section. batch: 10 packages, each containing ap- (3) Pyrogens. Proceed as directed in proximately 300 milligrams. § 436.32(a) of this chapter, using a solu- (B) The batch: tion containing 80 milligrams of (1) For all tests except sterility: A nafcillin per milliliter. minimum of 10 immediate containers. (4) [Reserved] (2) For sterility testing: 20 immediate (5) Moisture. Proceed as directed in containers, collected at regular inter- § 436.201 of this chapter. vals throughout each filling operation. (6) pH. Proceed as directed in § 436.202 (b) Tests and methods of assay. Thaw of this chapter, using the solution ob- the sample as directed in the labeling. tained when the product is reconsti- The sample solution used for testing tuted as directed in the labeling. must be at room temperature. (1) Nafcillin content. Proceed as di- [39 FR 18976, May 30, 1974, as amended at 42 FR 59868, Nov. 22, 1977; 45 FR 22922, Apr. 4, rected in § 440.241a(b)(1), except use the 1980; 47 FR 22515, May 25, 1982; 50 FR 19919, thawed solution. May 13, 1985. Redesignated at 55 FR 277, Jan. (2) Sterility. Proceed as directed in 4, 1990] § 436.20 of this chapter, using the meth- od described in paragraph (e)(1) of that § 440.241b Nafcillin sodium injection. section. (a) Requirements for certification—(1) (3) Pyrogens. Proceed as directed in Standards of identity, strength, quality, § 436.32(a) of this chapter, except inject and purity. Nafcillin sodium injection a sufficient volume of the undiluted so- is a frozen, aqueous, iso-osmatic solu- lution to deliver 80 milligrams of tion of nafcillin sodium which may nafcillin per kilogram. contain one or more suitable and harm- (4) pH. Proceed as directed in § 436.202 less buffer substances and a tonicity of this chapter, using the undiluted so- adjusting agent. Each milliliter con- lution. tains nafcillin sodium equivalent to 20 [55 FR 277, Jan. 4, 1990] or 40 milligrams of nafcillin. Its nafcillin content is satisfactory if it is § 440.249 Oxacillin sodium injectable not less than 90 percent and not more dosage forms. than 120 percent of the number of milli- grams of nafcillin that it is represented § 440.249a Oxacillin sodium to contain. It is sterile. It is monohydrate for injection. nonpyrogenic. Its pH is not less than (a) Requirements for certification— (1) 6.0 and not more than 8.5. The nafcillin Standards of identity, strength, quality, sodium monohydrate used conforms to and purity. Oxacillin sodium the standards prescribed by monohydrate for injection is a dry mix- § 440.41(a)(1). ture of oxacillin sodium monohydrate (2) Labeling. it shall be labeled in ac- and one or more buffer substances, cordance with the requirements of with or without trisodium ethylene- § 432.5 of this chapter. In addition, this diamine tetraacetic acid, and with or drug shall be labeled ‘‘nafcillin sodium without one or more suitable and injection.’’ harmless preservatives. Its potency is (3) Requests for certification; samples. satisfactory if it is not less than 90 per- In addition to complying with the re- cent and not more than 115 percent of
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the number of milligrams of oxacillin (a) Microbiological agar diffusion that it is represented to contain. It is assay. Proceed as directed in § 436.105 of sterile. It is nonpyrogenic. Its moisture this chapter, diluting an aliquot of the content is not more than 6.0 percent. stock solution with solution 1 to the Its pH in an aqueous solution contain- reference concentration of 5 ing 30 milligrams per milliliter is not micrograms of oxacillin per milliliter less than 6.0 and not more than 8.5. The (estimated). oxacillin sodium monohydrate used (b) Iodometric assay. Proceed as di- conforms to the standards prescribed rected in § 436.204 of this chapter, dilut- by § 440.49a(a)(1). ing an aliquot of the stock solution (2) Labeling. In addition to the label- with solution 1 to the prescribed con- ing requirements of § 432.5 of this chap- centration. ter, this drug shall be labeled (2) Sterility. Proceed as directed in ‘‘oxacillin sodium for injection’’. § 436.20 of this chapter, using the meth- (3) Requests for certification; samples. od described in paragraph (e)(1) of that In addition to complying with the re- section. quirements of § 431.1 of this chapter, (3) Pyrogens. Proceed as directed in each such request shall contain: § 436.32(a) of this chapter, using a solu- (i) Results of tests and assays on: tion containing 20 milligrams of (a) The oxacillin sodium oxacillin per milliliter. monohydrate used in making the batch (4) [Reserved] (5) Moisture. Proceed as directed in for potency, moisture, pH, oxacillin § 436.201 of this chapter. content, crystallinity, and identity. (6) pH. Proceed as directed in § 436.202 (b) The batch for potency, sterility, of this chapter, using an aqueous solu- pyrogens, moisture, and pH. tion containing 30 milligrams per mil- (ii) Samples required: liliter. (a) The oxacillin sodium monohydrate used in making the [39 FR 18976, May 30, 1974, as amended at 42 batch: 10 packages, each containing ap- FR 59868, Nov. 22, 1977; 50 FR 19918, 19919, May 13, 1985. Redesignated at 55 FR 279, Jan. proximately 300 milligrams. 4, 1990] (b) The batch: (1) For all tests except sterility: A § 440.249b Oxacillin sodium injection. minimum of 10 immediate containers. (a) Requirements for certification—(1) (2) For sterility testing: 20 immediate Standards of identity, strength, quality, containers, collected at regular inter- and purity. Oxacillin sodium injection vals throughout each filling operation, is a frozen aqueous, iso-osmotic solu- or 40 immediate containers if each con- tion of oxacillin sodium which may tains less than 600 milligrams. contain one or more suitable and harm- (b) Tests and methods of assay—(1) Po- less buffer substances and a tonicity tency—(i) Sample preparation. Reconsti- adjusting agent. Each milliliter con- tute as directed in the labeling. Then tains oxacillin sodium equivalent to 20 using a suitable hypodermic needle and or 40 milligrams of oxacillin. Its syringe, remove all of the oxacillin content is satisfactory if it is withdrawable contents if it is rep- not less than 90 percent and not more resented as a single-dose container, or, than 115 percent of the number of milli- if the labeling specifies the amount of grams of oxacillin that it is rep- potency in a given volume of the re- resented to contain. It is sterile. It is sultant preparation, remove an accu- nonpyrogenic. Its pH is not less than rately measured representative portion 6.0 and not more than 8.5. The oxacillin from each container. Dilute with 1 per- sodium monohydrate used conforms to cent potassium phosphate buffer, pH 6.0 the standards prescribed by (solution 1), to give a stock solution of § 440.49(a)(1), except that the pH of an convenient concentration. aqueous solution containing 30 milli- (ii) Assay procedures. Use either of the grams per milliliter is not less than 4.0 following methods; however, the re- and not more than 7.0. sults obtained from the micro- (2) Labeling. It shall be labeled in ac- biological agar diffusion assay shall be cordance with the requirements of conclusive. § 432.5 of this chapter. In addition, this
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drug shall be labeled ‘‘oxacillin sodium and preservatives. Each container or injection’’. each milliliter contains penicillin G (3) Requests for certification: samples. benzathine equivalent to not less than In addition to complying with the re- 300,000 units of penicillin G. Its potency quirements of § 431.1 of this chapter, is satisfactory if it is not less than 90 each such request shall contain: percent and not more than 115 percent (i) Results of tests and assays on: of the number of units of penicillin G (A) The oxacillin sodium that it is represented to contain. It is monohydrate used in making the batch sterile. It is nonpyrogenic. Its pH is not for potency, moisture, pH, oxacillin less than 5.0 and not more than 7.5. The content, crystallinity, and identity. penicillin G benzathine used conforms (B) The batch for oxacillin content, to the standards prescribed by sterility, pyrogens, and pH. § 440.55a(a)(1). (ii) Samples, if required by the Cen- (2) Labeling. It shall be labeled in ac- ter for Drug Evaluation and Research: cordance with the requirements of (A) The oxacillin sodium § 432.5 of this chapter. monohydrate used in making the (3) Requests for certification; samples. batch: 10 packages, each containing ap- In addition to complying with the re- proximately 300 milligrams. quirements of § 431.1 of this chapter, (B) The batch: each such request shall contain: (1) For all tests except sterility: A (i) Results of tests and assays on: minimum of 10 immediate containers. (a) The penicillin G benzathine used (2) For sterility testing: 20 immediate in making the batch for potency, mois- containers, collected at regular inter- ture, pH, penicillin G content, and vals throughout each filling operation. crystallinity. (b) Tests and methods of assay. Thaw (b) The batch for potency, sterility, the sample as directed in the labeling. pyrogens, and pH. he sample solution used for testing (ii) Samples required: must be at room temperature. (1) Oxacillin content. Proceed as di- (a) The penicillin G benzathine used rected in § 440.249a(b)(1), except use the in making the batch: 10 packages, each thawed solution. containing approximately 300 milli- (2) Sterility. Proceed as directed in grams. § 436.20 of this chapter, using the meth- (b) The batch: od described in paragraph (e)(1) of that (1) For all tests except sterility: A section. minimum of 10 immediate containers. (3) Pyrogens. Proceed as directed in (2) For sterility testing: 20 immediate § 436.32(a) of this chapter, except inject containers, collected at regular inter- a sufficient volume of the undiluted so- vals throughout each filing operation. lution to deliver 20 milligrams of (b) Tests and methods of assay—(1) Po- oxacillin per kilogram. tency. Use either of the following meth- (4) pH. Proceed as directed in § 436.202 ods; however, the results obtained from of this chapter, using the undiluted so- the iodometric assay shall be conclu- lution. sive. (i) Microbiological agar diffusion assay. [55 FR 279, Jan. 4, 1990; 55 FR 2481, Jan. 24, 1990] Proceed as directed in § 436.105 of this chapter, preparing the sample for assay § 440.255 Penicillin G benzathine as follows: Using a suitable hypodermic injectable dosage forms. needle and syringe, remove all of the withdrawable contents if it is rep- § 440.255b Sterile penicillin G resented as a single-dose container; or, benzathine suspension. if the labeling specifies the amount of (a) Requirements for certification—(1) potency in a given volume, remove an Standards of identity, strength, quality, accurately measured representative and purity. Sterile penicillin G portion from each container. Dilute the benzathine suspension is an aqueous portion thus obtained with sufficient suspension of penicillin G benzathine absolute methyl alcohol to give a solu- and one or more suitable suspending or tion of convenient concentration. Im- dispersing agents, buffer substances, mediately further dilute with 1 percent
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potassium phosphate buffer, pH 6.0 (so- resented to contain. It is sterile. It is lution 1), to the reference concentra- nonpyrogenic. Its pH is not less than tion of 1.0 unit of penicillin G per milli- 5.0 and not more than 7.5. The penicil- liter (estimated). lin G benzathine used conforms to the (ii) Iodometric assay. Using a suitable standards prescribed by § 440.55a (a)(1). hypodermic needle and syringe, remove The penicillin G procaine used con- all of the withdrawable contents if it is forms to the standards prescribed by represented as a single-dose container; § 440.74a(a)(1). or if the labeling specifies the amount (2) Labeling. It shall be labeled in ac- of potency in a given volume, remove cordance with the requirements of an accurately measured representative § 432.5 of this chapter. portion from each container. Using the (3) Requests for certification; samples. sample thus obtained, proceed as di- In addition to complying with the re- rected in § 436.204(b)(2) of this chapter. quirements of § 431.1 of this chapter, (2) Sterility. Proceed as directed in each such request shall contain: § 436.20 of this chapter, using the meth- (i) Results of tests and assays on: od described in paragraph (e)(2) of that (a) The penicillin G benzathine used section, except use medium C in lieu of in making the batch for potency, mois- medium A, and medium F in lieu of ture, pH, penicillin G content, and medium E. During the period of incuba- crystallinity. tion, shake the tubes at least once (b) The penicillin G procaine used in daily. making the batch for potency, mois- (3) Pyrogens. Proceed as directed in ture, pH, penicillin G content, and § 436.32(d) of this chapter, using a solu- crystallinity. tion containing 4,000 units of penicillin (c) The batch for penicillin G G per milliliter. benzathine content, penicillin G pro- (4) [Reserved] caine content, sterility, pyrogens, and (5) pH. Proceed as directed in § 436.202 pH. of this chapter, using the undiluted (ii) Samples required: sample. (a) The penicillin G benzathine used [42 FR 59868, Nov. 22, 1977, as amended at 43 in making the batch: 10 packages, each FR 9799, Mar. 10, 1978; 50 FR 19918, 19919, May containing approximately 500 milli- 13, 1985] grams. (b) The penicillin G procaine used in § 440.255c Sterile penicillin G making the batch: 10 packages, each benzathine-penicillin G procaine containing approximately 500 milli- suspension. grams. (a) Requirements for certification— (1) (c) The batch: Standards of identity, strength, quality, (1) For all tests except sterility: A and purity. Sterile penicillin G minimum of 10 immediate containers. benzathine-penicillin G procaine sus- (2) For sterility testing: 20 immediate pension is an aqueous mixture of peni- containers, collected at regualr inter- cillin G benzathine and penicillin G vals throughout each filling operation. procaine with or without suitable and (b) Tests and methods of assay—(1) Po- harmless buffer substances, suspending tency—(i) Total potency. Assay for total agents, and preservatives. Each con- potency by either of the following tainer or each milliliter contains peni- methods; however, the results obtained cillin G benzathine and penicillin G from the iodometric assay shall be con- procaine each equivalent to not less clusive. than 150,000 units of penicillin G. Its (a) Microbiological agar diffusion penicillin G benzathine content is sat- assay. Proceed as directed in § 436.105 of isfactory if it is not less than 90 per- this chapter, preparing the sample for cent and not more than 115 percent of assay as follows: Using a suitable hypo- the number of units of penicillin G that dermic needle and syringe, place one it is represented to contain. Its penicil- dose of the drug in a 100-milliliter volu- lin G procaine content is satisfactory if metric flask and add sufficient methyl it is not less than 90 percent and not alcohol to dissolve the benzathine peni- more than 115 percent of the number of cillin G. Dilute to volume with 1 per- units of penicillin G that it is rep- cent potassium phosphate buffer, pH 6.0
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(solution 1), and shake well. Imme- utes. Add 1 milliliter of 1.2N HC1 for diately further dilute an aliquot with each 2 milliliters of 0.5N NaOH, mix, solution 1 to the reference concentra- and dilute with distilled water to ob- tion of 1.0 unit of penicillin G per milli- tain a concentration of 60 units of peni- liter (estimated). cillin G procaine per milliliter. Trans- (b) Iodometric assay. Proceed as di- fer a 3.0-milliliter aliquot of this solu- rected in § 436.204 of this chapter, pre- tion to a 50-milliliter volumetric flask paring the sample as follows: Using a and add 2 milliliters of water to give a suitable hypodermic needle and sy- volume of 5 milliliters. ringe, withdraw 2 one-dose portions of (c) Procedure. Transfer respectively, sample. Place one portion into an ap- 1.0, 2.0, 3.0, 4.0, and 5.0 milliliters of the propriate-sized volumetric flask and standard procaine solution to each of add 20 milliliters of 0.5N NaOH for each five 50-milliliter volumetric flasks and 300,000 units of benzathine penicillin G, transfer 5.0 milliliters of distilled mix well, being sure that all penicillin water to a sixth 50-milliliter volu- is in solution, and allow to stand for 15 metric flask. Add 4.0, 3.0, 2.0, and 1.0 minutes. Add 1 milliliter of 1.2N HCl milliliters of water to the first four for each 2 milliliters of 0.5N NaOH, flasks, respectively, to give each a vol- mix, and dilute with distilled water to ume of 5 milliliters. To each flask of obtain a concentration of 2,000 units the standard and sample solutions, add per milliliter. Dilute the other portion, 0.5 milliliter of 4N HC1, 1.0 milliliter of which is to be used as the blank solu- sodium nitrite solution, 1.0 milliliter of tion, with 1 percent potassium phos- ammonium sulfamate solution, and 1.0 phate buffer, pH 6.0 (solution 1), to give milliliter of N-(1-naphthyl)-ethylene- a concentration of approximately 2,000 diamine solution. Mix and wait two units per milliliter. minutes after each addition. Dilute (ii) Penicillin G procaine content—(a) each flask to volume with distilled Reagents—(1) Sodium nitrite solution. water. Using a suitable photoelectric Dissolve 0.1 gram of sodium nitrite in colorimeter, determine the absorbancy 100 milliliters of distilled water. Pre- of each solution at 550 nanometers. The pare a fresh solution every week and instrument is balanced so that the zero store under refrigeration. concentration reads 0 absorbancy. Plot (2) Ammonium sulfamate solution. Dis- the standard curve on coordinate graph solve 0.5 gram of ammonium sulfamate paper. Obtain the procaine penicillin in 100 milliliters of distilled water and content of the solution for assay di- store under refrigeration. rectly from the point on the standard (3) N-(1-naphthyl)-ethylenediamine so- curve corresponding to its absorbancy. lution. Dissolve 0.1 gram of N-(1- naphthyl) - ethylenediamine (iii) Penicillin G benzathine content. dihydrochloride in 100 milliliters of dis- The sum of the penicillin G procaine tilled water. Prepare fresh solutions content determined as directed in para- every week and store under refrigera- graph (b)(1)(ii) of this section sub- tion. tracted from the total potency deter- (4) Standard procaine solution. Prepare mined as directed in paragraph (b)(1)(i) a standard solution containing 27.55 of this section represents the penicillin milligrams of procaine hydrochloride G benzathine content. U.S.P. in a liter of distilled water (each (2) Sterility. Proceed as directed in milliliter of the standard solution is § 436.20 of this chapter, using the meth- equivalent to 60 units of penicillin G od described in paragraph (e)(2) of that procaine). section, except use medium C in lieu of (b) Preparation of sample solution. medium A, medium F in lieu of me- Using a suitable hypodermic needle and dium E, and during the period of incu- syringe, withdraw a one-dose portion of bation, shake the tubes at least once the sample and place it into an appro- daily. priate-sized volumetric flask. Add 20 (3) Pyrogens. Proceed as directed in milliliters of 0.5N NaOH for each 300,000 § 436.32(d) of this chapter, using a solu- units of penicillin G benzathine, mix tion containing 4,000 units of penicillin well, being sure that all penicillin is in G per milliliter. solution, and allow to stand for 15 min- (4) [Reserved]
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(5) pH. Proceed as directed in § 436.202 (2) If the batch is packaged for dis- of this chapter, using the undiluted pensing: aqueous suspension. (i) For all tests except sterility: A [42 FR 59868, Nov. 22, 1977, as amended at 43 minimum of 10 immediate containers. FR 9799, Mar. 10, 1978; 50 FR 19918, 19919, May (ii) For sterility testing: 20 imme- 13, 1985] diate containers, collected at regular intervals throughout each filling oper- § 440.255d Sterile penicillin G ation. benzathine for suspension. (b) Tests and methods of assay—(1) Po- (a) Requirements for certification—(1) tency. Use either of the following meth- Standards of identity, strength, quality, ods; however, the results obtained from and purity. Sterile penicillin G the iodometric assay shall be conclu- benzathine for suspension is a dry mix- sive. ture of penicillin G benzathine and one (i) Microbiological agar diffusion assay. or more suitable suspending or dispers- Proceed as directed in § 436.105 of this ing agents, and with or without one or chapter, preparing the sample for assay more suitable preservatives and buffer as follows: Reconstitute as directed in substances. Its potency is satisfactory the labeling. Using a suitable hypo- if it is not less than 90 percent and not dermic needle and syringe, remove all more than 115 percent of the number of of the withdrawable contents if it is units of penicillin G that it is rep- represented as a single–dose container; resented to contain. It is sterile. It is or, if the labeling specifies the amount nonpyrogenic. Its moisture content is not less than 5.0 percent and not more of potency in a given volume of the re- than 8.0 percent. When reconstituted as sultant preparation, remove an accu- directed in the labeling, its pH is not rately measured representative portion less than 5.0 and not more than 7.5. The from each container. Dissolve the por- penicillin G benzathine used conforms tion thus obtained with sufficient abso- to the standards prescribed by lute methyl alcohol to give a solution § 440.55a(a)(1). of convenient concentration. Imme- (2) Labeling. It shall be labeled in ac- diately, further dilute with 1 percent cordance with the requirements of potassium phosphate buffer, pH 6.0 (so- § 432.5 of this chapter. lution 1), to the reference concentra- (3) Requests for certification; samples. tion of 1.0 unit of penicillin G per milli- In addition to complying with the re- liter (estimated). quirements of § 431.1 of this chapter, (ii) Iodometric assay. Proceed as di- each such request shall contain: rected in § 436.204 of this chapter, pre- (i) Results of tests and assays on: paring the sample as follows: Reconsti- (a) The penicillin G benzathine used tute as directed in the labeling. Using in making the batch for potency, mois- a suitable hypodermic needle and sy- ture, pH, penicillin G content, and ringe, remove all of the withdrawable crystallinity. contents if it is represented as a single- (b) The batch for potency, sterility, dose container; or, if the labeling speci- pyrogens, moisture, and pH. fies the amount of potency in a given (ii) Samples required: volume of the resultant preparation, (a) The penicillin G benzathine used remove an accurately measured rep- in making the batch: 10 packages, each resentative portion from each con- containing approximately 300 milli- tainer. Using the sample thus obtained, grams. proceed as directed in § 436.205(b)(2) of (b) The batch: this chapter. (1) If the batch is packaged for re- (2) Sterility. Proceed as directed in packing: § 436.20 of this chapter, using the meth- (i) For all tests except sterility: 10 od described in paragraph (e)(2) of that packages, each containing approxi- section, except use medium C in lieu of mately 300 milligrams. medium A, and medium F in lieu of (ii) For sterility testing: 20 packages, medium E. During the period of incuba- each containing approximately 600 mil- tion shake the tubes at least once ligrams. daily.
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(3) Pyrogens. Proceed as directed in (ii) Samples required: § 436.32(d) of this chapter, using a solu- (a) The penicillin G procaine used in tion containing 4,000 units of penicillin making the batch: 10 packages, each G per milliliter. containing approximately 300 milli- (4) [Reserved] grams. (5) Moisture. Proceed as directed in (b) The batch: § 436.201 of this chapter. (1) For all tests except sterility: A (6) pH. Proceed as directed in § 436.202 minimum of 5 immediate containers. of this chapter, using the suspension (2) For sterility testing: 20 immediate obtained when the product is reconsti- containers, collected at regular inter- tuted as directed in the labeling. vals throughout each filling operation. (b) Tests and methods of assay—(1) Po- [42 FR 59869, Nov. 22, 1977, as amended at 50 tency. Proceed as directed in § 436.105 of FR 19918, 19919, May 13, 1985] this chapter, preparing the sample for § 440.274 Penicillin G procaine assay as follows: Place an accurately injectable dosage forms. measured representative portion of the sample or the entire contents of a sin- § 440.274a Sterile penicillin G procaine gle-dose container into a 50-milliliter with aluminum stearate suspension. volumetric flask. Add 4 milliliters of (a) Requirements for certification—(1) chloroform and mix thoroughly. Dilute Standards of identity, strength, quality, to volume with absolute ethyl alcohol. and purity. Sterile penicillin G pro- Mix well. Immediately further dilute caine with aluminum stearate suspen- with sufficient 1.0 percent potassium sion is penicillin G procaine in a re- phosphate buffer, pH 6.0 (solution 1), to fined vegetable oil with one or more the reference concentration of 1 unit of suitable and harmless dispersing penicillin G per milliliter (estimated). agents and hardening agents. Each mil- (2) Sterility. Proceed as directed in liliter contains penicillin G procaine § 436.20 of this chapter, using the meth- equivalent to 300,000 units of penicillin od described in paragraph (e)(2) of that G. Its potency is satisfactory if it is section, except use medium B in lieu of not less than 90 percent and not more medium A. than 115 percent of the number of units (3) Moisture. Proceed as directed in of penicillin G that it is represented to § 436.201 of this chapter. contain. It is sterile. Its moisture con- [42 FR 59870, Nov. 22, 1977, as amended at 50 tent is not more than 1.4 percent. The FR 19919, May 13, 1985] penicillin G procaine used conforms to the standards prescribed by § 440.274b Sterile penicillin G procaine § 440.74a(a)(1). If the hardening agent is suspension. a refined hydrogenated and deodorized (a) Requirements for certification—(1) peanut oil, it is free from rancidity; it Standards of identity, strength, quality, has an iodine value of not more than and purity. Sterile penicillin G pro- 10; its free fatty acid content as oleic caine suspension is an aqueous mixture acid is not more than one-tenth of 1 of penicillin G procaine and one or percent and its melting point is 64° C±2° more suitable suspending or dispersing C. agents, buffer substances, and preserv- (2) Labeling. It shall be labeled in ac- atives. It may contain procaine hydro- cordance with the requirements of chloride in a concentration not exceed- § 432.5 of this chapter. ing 2.0 percent and one or more suit- (3) Requests for certification; samples. able stabilizing agents. Each container In addition to complying with the re- or each milliliter contains penicillin G quirements of § 431.1 of this chapter, procaine equivalent to not less than each such request shall contain: 300,000 units of penicillin G. Its potency (i) Results of tests and assays on: is satisfactory if it is not less than 90 (a) The penicillin G procaine used in percent and not more than 115 percent making the batch for potency, of the number of units of penicillin G pyrogens, moisture, pH, penicillin G that it is represented to contain. It is content, and crystallinity. sterile. It is nonpyrogenic. Its pH is not (b) The batch for potency, sterility, less than 5.0 and not more than 7.5. The and moisture. penicillin G procaine used conforms to
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the standards prescribed by gle-dose container; or, if the labeling § 440.74a(a)(1). specifies the amount of potency in a (2) Labeling. It shall be labeled in ac- given volume, remove an accurately cordance with the requirements of measured representative portion from § 432.5 of this chapter. each container. Dissolve and dilute the (3) Requests for certification; samples. sample thus obtained with 1 percent In addition to complying with the re- potassium phosphate buffer, pH 6.0 (so- quirements of § 431.1 of this chapter, lution 1), to the prescribed concentra- each such request shall contain: tion. (i) Results of tests and assays on: (2) Sterility. Proceed as directed in (a) The penicillin G procaine used in § 436.20 of this chapter, using the meth- making the batch for potency, mois- od described in paragraph (e)(1) of that ture, pH, penicillin G content, and section, except add sufficient penicil- crystallinity. linase to diluting fluid A and swirl the (b) The batch for potency, sterility, flask to completely solubilize the pro- pyrogens, and pH. caine penicillin before filtration. If the (ii) Samples required: product contains lecithin, use diluting (a) The penicillin G procaine used in fluid D in lieu of diluting fluid A. If the making the batch: 10 packages, each product contains sodium containing approximately 300 milli- carboxymethylcellulose, add sufficient grams. sterile carboxymethylcellulase to di- (b) The batch: luting fluid A or D to completely solu- (1) For all tests except sterility: A bilize the sodium minimum of 10 immediate containers. carboxymethylcellulose before filtra- (2) For sterility testing: 20 immediate tion. If the preparation contains ho- containers, collected at regular inter- mogenizers or suspending agents that vals throughout each filling operation. prevent solubilization, proceed as di- (b) Tests and methods of assay—(1) Po- rected in paragraph (e)(2) of that sec- tency. Use either of the following meth- tion, except use medium B in lieu of ods; however, the results obtained from medium A. the iodometric assay shall be conclu- (3) Pyrogens. Proceed as directed in sive. § 436.32(h) of this chapter, using a solu- (i) Microbiological agar diffusion assay. tion containing 2,000 units of penicillin Proceed as directed in § 436.105 of this G per milliliter. chapter, preparing the sample for assay (4) [Reserved] as follows: Using a suitable hypodermic (5) pH. Proceed as directed in § 436.202 needle and syringe, remove all of the of this chapter, using the undiluted withdrawable contents, if it is rep- drug. resented as a single-dose container; or, if the labeling specifies the amount of [42 FR 59870, Nov. 22, 1977, as amended at 43 potency in a given volume, remove an FR 9799, Mar. 10, 1978; 45 FR 22922, Apr. 4, accurately measured representative 1980; 50 FR 19918, 19919, May 13, 1985] portion from each container. Dissolve the sample thus obtained in 50 to 100 § 440.274c Sterile penicillin G procaine milliliters of absolute methyl alcohol for suspension. and add sufficient 1 percent potassium (a) Requirements for certification—(1) phosphate buffer, pH 6.0 (solution 1), to Standards of identity, strength, quality, give a stock solution of convenient and purity. Sterile penicillin G pro- concentration. Immediately further di- caine for suspension is a dry mixture of lute an aliquot of the stock solution penicillin G procaine and one or more with solution 1 to the reference con- suitable suspending or dispersing centration of 1.0 unit of penicillin G agents, buffer substances, and preserv- per milliliter (estimated). atives. Its potency is satisfactory if it (ii) Iodometric assay. Proceed as di- is not less than 90 percent and not rected in § 436.204 of this chapter, pre- more than 115 percent of the number of paring the sample as follows: Using a units of penicillin G that it is rep- suitable hypodermic needle and sy- resented to contain. It is sterile. It is ringe, remove all of the withdrawable nonpyrogenic. Its moisture content is contents, if it is represented as a sin- not less than 2.8 and not more than 4.2
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percent. When reconstituted as di- the labeling. Then using a suitable rected in the labeling, its pH is not less hypodermic needle and syringe, remove than 5.0 and not more than 7.5. The all of the withdrawable contents, if it penicillin G procaine used conforms to is represented as a single-dose con- the standards prescribed by tainer; or, if the labeling specifies the § 440.74a(a)(1). amount of potency in a given volume of (2) Labeling. It shall be labeled in ac- the resultant preparation, remove an cordance with the requirements of accurately measured representative § 432.5 of this chapter. portion from each container. Dissolve (3) Requests for certification; samples. the sample thus obtained in 50 to 100 In addition to complying with the re- milliliters of absolute methyl alcohol quirements of § 431.1 of this chapter, and add sufficient 1 percent potassium each such request shall contain: phosphate buffer, pH 6.0 (solution 1), to (i) Results of tests and assays on: give a stock solution of convenient (a) The penicillin G procaine used in concentration. Immediately further di- making the batch for potency, mois- lute an aliquot of the stock solution ture, pH, penicillin G content, and with solution 1 to the reference con- crystallinity. centration of 1.0 unit of penicillin G (b) The batch for potency, sterility, per milliliter (estimated). pyrogens, moisture, and pH. (ii) Iodometric assay. Proceed as di- (ii) Samples required: rected in § 436.204 of this chapter, pre- (a) The penicillin G procaine used in paring the sample as follows: If it is making the batch: 10 packages, each packaged for repacking, dissolve and containing approximately 300 milli- dilute an accurately weighed sample, grams. equivalent to one dose, with 1 percent (b) The batch: (1) If the batch is packaged for re- potassium phosphate buffer, pH 6.0 (so- packing: lution 1), to the prescribed concentra- (i) For all tests except sterility: 10 tion. If it is packaged for dispensing, packages, each containing approxi- reconstitute as directed in the labeling. mately 300 milligrams. Then using a suitable hypodermic nee- (ii) For sterility testing: 20 packages, dle and syringe, remove all of the each containing approximately 600 mil- withdrawable contents, if it is rep- ligrams. resented as a single-dose container; or, (2) If the batch is packaged for dis- if the labeling specifies the amount of pensing: potency in a given volume, remove an (i) For all tests except sterility: A accurately measured representative minimum of 10 immediate containers. portion from each container. Dissolve (ii) For sterility testing: 20 imme- and dilute the sample thus obtained diate containers, collected at regular with 1 percent potassium phosphate intervals throughout each filling oper- buffer, pH 6.0 (solution 1), to the pre- ation. scribed concentration. (b) Tests and methods of assay—(1) Po- (2) Sterility. Proceed as directed in tency. Use either of the following meth- § 436.20 of this chapter, using the meth- ods; however, the results obtained from od described in paragraph (e)(1) of that the iodometric assay shall be conclu- section, except add sufficient penicil- sive. linase to diluting fluid A and swirl the (i) Microbiological agar diffusion assay. flask to completely solubilize the pro- Proceed as directed in § 436.105 of this caine penicillin before filtration. If the chapter, preparing the sample for assay product contains lecithin, use diluting as follows: If it is packaged for repack- fluid D in lieu of diluting fluid A. If the ing, dissolve an accurately weighed product contains sodium sample, equivalent to one dose, in 50 to carboxymethylcellulose, add sufficient 100 milliliters of absolute methyl alco- sterile carboxymethylcellulase to di- hol and add sufficient 1 percent potas- luting fluid A or D to completely solu- sium phosphate buffer, pH 6.0 (solution bilize the sodium 1), to give a stock solution of conven- carboxymethylcellulose before filtra- ient concentration. If it is packaged for tion. If the preparation contains ho- dispensing, reconstitute as directed in mogenizers or suspending agents that
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prevent solubilization, proceed as di- to the standards prescribed by the rected in paragraph (e)(2) of that sec- U.S.P. tion, except use medium B in lieu of (2) Labeling. It shall be labeled in ac- medium A. cordance with the requirements of (3) Pyrogens. Proceed as directed in § 432.5 of this chapter. § 436.32(h) of this chapter, using a solu- (3) Requests for certification; samples. tion containing 2,000 units of penicillin In addition to complying with the re- G per milliliter. quirements of § 431.1 of this chapter, (4) [Reserved] each such request shall contain: (5) Moisture. Proceed as directed in (i) Results of tests and assays on: § 436.201 of this chapter. (a) The penicillin G potassium used (6) pH. Proceed as directed in § 436.202 in making the batch for potency, loss of this chapter, using the suspension on drying, pH, penicillin G content, obtained when reconstituted as di- and crystallinity. rected in the labeling. (b) The batch for potency, sterility, pyrogens, loss on drying, and pH. [42 FR 59871, Nov. 22, 1977, as amended at 45 (ii) Samples required: FR 22922, Apr. 4, 1980; 50 FR 19918, 19919, May (a) The penicillin G potassium, 13, 1985] buffered, used in making the batch: 10 packages, each containing approxi- § 440.280 Penicillin G potassium injectable dosage forms. mately 300 milligrams. (b) The batch: § 440.280a Sterile penicillin G potas- (1) For all tests except sterility: A sium. minimum of 10 immediate containers. (2) For sterility testing: 20 immediate The requirements for certification containers, collected at regular inter- and the tests and methods of assay for vals throughout each filling operation. sterile penicillin G potassium packaged (b) Tests and methods of assay—(1) Po- for dispensing are described in § 440.80a. tency—(i) Sample preparation. Reconsti- [39 FR 18976, May 30, 1974, as amended at 42 tute as directed in the labeling. Then, FR 59871, Nov. 22, 1977] using a suitable hypodermic needle and syringe, remove all of the § 440.280b Penicillin G potassium for withdrawable contents if it is rep- injection. resented as a single-dose container; or, (a) Requirements for certification— (1) if the labeling specifies the amount of Standards of identity, strength, quality, potency in a given volume of the re- and purity. Penicillin G potassium for sultant preparation, remove or expel injection is a dry mixture of penicillin an accurately measured representative G potassium and the buffer sodium cit- portion from each container. Dilute rate in a quantity not less than 4.0 per- with solution 1 to give a stock solution cent and not more than 5.0 percent by of convenient concentration. weight of its total solids. It may con- (ii) Assay procedures. Assay for po- tain citric acid in a quantity not more tency by any of the following methods; than 0.15 percent of its total solids in however, the results obtained from the place of a corresponding amount of so- iodometric assay shall be conclusive. dium citrate. Its potency is satisfac- (a) Microbiological agar diffusion tory if it is not less than 90 percent and assay. Proceed as directed in § 436.105 of not more than 120 percent of the num- this chapter, diluting an aliquot of the ber of units of penicillin G that it is stock solution with solution 1 to the represented to contain. It is sterile. It reference concentration of 1.0 unit of is nonpyrogenic. Its loss on drying is penicillin G per milliliter (estimated). not more than 1.5 percent. Its pH is not (b) Iodometric assay. Proceed as di- less than 6.0 and not more than 8.5. If rected in § 436.204 of this chapter, dilut- penicillin G potassium buffered is used, ing an aliquot of the stock solution it conforms to the standards prescribed with solution 1 to the prescribed con- by § 440.1080(a)(1). If penicillin G potas- centration. sium is used, it conforms to the stand- (c) Hydroxylamine colorimetric assay. ards prescribed by § 440.80a(a)(1) and the Proceed as directed in § 436.205 of this sodium citrate and citric acid conforms chapter, diluting an aliquot of the
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stock solution with solution 1 to the on drying, pH, penicillin G content, prescribed concentration. and crystallinity. (2) Sterility. Proceed as directed in (B) The batch for penicillin G con- § 436.20 of this chapter, using the meth- tent, sterility, pyrogens, and pH. od described in paragraph (e)(1) of that (ii) Samples, if required by the Cen- section. ter for Drug Evaluation and Research: (3) Pyrogens. Proceed as directed in (A) The penicillin G potassium used § 436.32(b) of this chapter, using a solu- in making the batch: 10 packages, each tion containing 20,000 units of penicil- containing approximately 300 milli- lin G per milliliter. grams. (4) [Reserved] (B) The batch: (5) Loss on drying. Proceed as directed (1) For all tests except sterility: A in § 436.200(b) of this chapter. minimum of 10 immediate containers. (6) pH. Proceed as directed in § 436.202 (2) For sterility testing: 20 immediate of this chapter, using an aqueous solu- containers, collected at regular inter- tion containing 60 milligrams per mil- vals throughout each filling operation. liliter or, if the diluent is included in a (b) Tests and methods of assay. Thaw disposable syringe combination, use the sample as directed in the labeling. the solution obtained when the drug is The sample solution used for testing reconstituted as directed in the label- must be at room temperature. ing. (1) Penicillin G content. Proceed as di- rected in § 440.280b(b)(1) of this chapter, [42 FR 59871, Nov. 22, 1977, as amended at 43 except use the thawed solution. FR 9799, Mar. 10, 1978; 45 FR 22922, Apr. 4, (2) Sterility. Proceed as directed in 1980; 50 FR 19918, 19919, May 13, 1985] § 436.20 of this chapter, using the meth- § 440.280c Penicillin G potassium in- od described in paragraph (e)(1) of that jection. section. (3) Pyrogens. Proceed as directed in (a) Requirements for certification—(1) § 436.32(a) of this chapter, except inject Standards of identity, strength, quality, a sufficient volume of the undiluted so- and purity. Penicillin G potassium in- lution to deliver 20,000 units of penicil- jection is a frozen, aqueous, iso-os- lin G per kilogram. motic solution of penicillin G potas- (4) pH. Proceed as directed in § 436.202 sium which may contain one or more of this chapter, using the undiluted so- suitable and harmless buffer sub- lution. stances and a tonicity adjusting agent. Each milliliter contains penicillin G [55 FR 38675, Sept. 20, 1990] potassium equivalent to 20,000, 40,000, or 60,000 units of penicillin G. Its peni- § 440.281 Pencillin G sodium injectable cillin G content is satisfactory if it is dosage forms. not less than 90 percent and not more § 440.281a Sterile penicillin G sodium. than 115 percent of the number of units of penicillin G that it is represented to The requirements for certification contain. It is sterile. It is and the tests and methods of assay for nonpyrogenic. Its pH is not less than sterile penicillin G sodium packaged 5.5 and not more than 8.0. The penicil- for dispensing are described in § 440.81a. lin G potassium used conforms to the [42 FR 59872, Nov. 22, 1977] standards prescribed by § 440.80(a)(1). (2) Labeling. It shall be labeled in ac- § 440.281b Penicillin G sodium for in- cordance with the requirements of jection. § 432.5 of this chapter. In addition, this (a) Requirements for certification—(1) drug shall be labeled ‘‘penicillin G po- Standards of identity, strength, quality, tassium injection’’. and purity. Penicillin G sodium for in- (3) Requests for certification; samples. jection is a dry mixture of penicillin G In addition to complying with the re- sodium and the buffer sodium citrate quirements of § 431.1 of this chapter, in a quantity not less than 4.0 percent each such request shall contain: and not more than 5.0 percent by (i) Results of tests and assays on: weight of its total solids. It may con- (A) The penicillin G potassium used tain citric acid in a quantity not more in making the batch for potency, loss than 0.15 percent of its total solids in
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place of a corresponding amount of so- reference concentration of 1.0 unit of dium citrate. Its potency is satisfac- penicillin G per milliliter (estimated). tory if it is not less than 90 percent and (b) Iodometric assay. Proceed as di- not more than 120 percent of the num- rected in § 436.204 of this chapter, dilut- ber of units of penicillin G that it is ing an aliquot of the stock solution represented to contain. It is sterile. It with solution 1 to the prescribed con- is nonpyrogenic. Its loss on drying is centration. not more than 1.5 percent. Its pH is not (c) Hydroxylamine colorimetric assay. less than 6.0 and not more than 7.5. The Proceed as directed in § 436.205 of this penicillin G sodium, buffered, used con- chapter, diluting an aliquot of the forms to the standards prescribed by stock solution with solution 1 to the § 440.1081a(a)(1). prescribed concentration. (2) Labeling. It shall be labeled in ac- (2) Sterility. Proceed as directed in cordance with the requirements of § 436.20 of this chapter, using the meth- § 432.5 of this chapter. od described in paragraph (e)(1) of that (3) Requests for certification; samples. section. In addition to complying with the re- (3) Pyrogens. Proceed as directed in quirements of § 431.1 of this chapter, § 436.32(b) of this chapter, using a solu- each such request shall contain: tion containing 20,000 units of penicil- (i) Results of tests and assays on: lin G per milliliter. (a) The penicillin G sodium, buffered, (4) [Reserved] used in making the batch for potency, (5) Loss on drying. Proceed as directed loss on drying, pH, penicillin G con- in § 436.200(b) of this chapter. tent, crystallinity, and heat stability. (6) pH. Proceed as directed § 436.202 of (b) The batch for potency, sterility, this chapter, using an aqueous solution pyrogens, loss on drying, and pH. containing 60 milligrams per milliliter. (ii) Samples required: (a) The penicillin G sodium, buffered, [42 FR 59872, Nov. 22, 1977; 43 FR 2393, Jan. 17, 1978, as amended at 45 FR 22922, Apr. 4, 1980; used in making the batch: 10 packages, 50 FR 19918, 19919, May 13, 1985] each containing approximately 60 mil- ligrams. § 440.283 Sterile piperacillin sodium. (b) The batch: The requirements for certification (1) For all tests except sterility: A and the tests and methods of assay for minimum of 10 immediate containers. sterile piperacillin sodium packaged (2) For sterility testing: 20 immediate for dispensing are described in § 440.83a containers, collected at regular inter- vals throughout each filling operation. [47 FR 15770, Apr. 13, 1982] (b) Tests and methods of assay—(1) Po- tency—(i) Sample preparation. Reconsti- § 440.290 Ticarcillin disodium tute as directed in the labeling. Then injectable dosage forms. using a suitable hypodermic needle and § 440.290a Sterile ticarcillin disodium. syringe, remove all of the withdrawable contents if it is rep- The requirements for certification resented as a single-dose container; or, and the tests and methods of assay for if the labeling specifies the amount of sterile ticarcillin disodium packaged potency in a given volume of the re- for dispensing are described in § 440.90a. sultant preparation, remove an accu- [43 FR 9800, Mar. 10, 1978. Redesignated at 50 rately measured representative portion FR 33518, Aug. 20, 1985] from each container. Dilute with solu- tion 1 to give a stock solution of con- § 440.290b Sterile ticarcillin disodium venient concentration. and clavulanate potassium. (ii) Assay procedures. Assay for po- (a) Requirements for certification—(1) tency by any of the following methods; Standards of identity, strength, quality, however, the results obtained from the and purity. Ticarcillin disodium and iodometric assay shall be conclusive. clavulanate potassium is a dry mixture (a) Microbiological agar diffusion of ticarcillin disodium and clavulanate assay. Proceed as directed in § 436.105 of potassium, in which the ratio of this chapter, diluting an aliquot of the ticarcillin to clavulanic acid is 15:1 or stock solution with solution 1 to the 30:1. Its ticarcillin potency is not less
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than 755 micrograms of ticarcillin per containing approximately 300 milli- milligram on an anhydrous basis if the grams. ratio is 30:1 and 733 micrograms of (c) The batch: ticarcillin per milligram on an anhy- (1) For all tests except sterility: A drous basis if the ratio is 15:1. Its minimum of 10 immediate containers. ticarcillin disodium content is satisfac- (2) For sterility testing: A minimum tory if it contains not less than 90 per- of 20 immediate containers collected at cent and not more than 115 percent of regular intervals throughout each fill- the number of milligrams of ticarcillin ing operation. that it is represented to contain. Its (b) Tests and methods of assay—(1) clavulanate potassium content is satis- Ticarcillin and clavulanic acid contents. factory if it contains not less than 85 Determine micrograms of ticarcillin percent and not more than 120 percent per milligram of sample and milli- of the number of milligrams of grams of both ticarcillin and clavulanic acid that it is represented to clavulanic acid per container. Proceed contain. It is sterile. It is as directed in § 436.355 of this chapter, nonpyrogenic. Its moisture content is using ambient temperature, an ultra- not more than 4.2 percent. Its pH of an violet detection system operating at a aqueous solution containing 100 milli- wavelength between 220 and 230 grams per milliliter is not less than 5.5 nanometers, and a column packed with and not more than 7.5. The ticarcillin microparticulate (3 to 10 micrometers disodium conforms to the standards in diameter) reversed phase packing prescribed by § 440.90a(a)(1) except that it contains not less than 840 material such as octadecyl silane bond- micrograms of ticarcillin per milli- ed silicas. Reagents, working standard gram on an anhydrous basis. The and sample solutions, system suit- clavulanate potassium conforms to the ability requirements, and calculations standards prescribed by § 455.15a(a)(1) of for ticarcillin or clavulanic acid con- this chapter. tent are as follows: (2) Labeling. It shall be labeled in ac- (i) Reagents—(a) 0.1M Monobasic so- cordance with the requirements of dium phosphate buffer solution, pH 4.3. § 432.5 of this chapter. Transfer 13.8 grams of monobasic so- (3) Requests for certification; samples. dium phosphate monohydrate to a 1- In addition to the requirements of liter volumetric flask and dissolve in § 431.1 of this chapter, each such re- 900 milliliters of distilled water. Adjust quest shall contain: the pH to 4.3±0.1 with 18N phosphoric (i) Results of tests and assays on: acid or 10N sodium hydroxide. Dilute to (a) The ticarcillin disodium used in volume with distilled water. Mix well. making the batch for potency, steril- (b) Mobile phase. Mix acetonitrile: ity, pyrogens, moisture, pH, and iden- 0.1M monobasic sodium phosphate buff- tity. er solution, pH 4.3 (5:95 v/v) and mix for (b) The clavulanate potassium used no less than two minutes. Degas by in making the batch for potency, ste- passing through a 0.5-micrometer filter rility, pyrogens, moisture, pH, iden- with vacuum. The mobile phase may be tity, and clavam-2-carboxylate con- sparged with the helium through a 2- tent. micrometer metal filter for the dura- (c) The batch for ticarcillin potency, tion of the analysis. Adjust the ratio of ticarcillin content, clavulanic acid acetonitrile to aqueous buffer as nec- content, sterility, pyrogens, moisture, essary to obtain satisfactory separa- and pH. tion of the peaks. (ii) Samples, if required by the Direc- (c) Diluent. 0.05M monobasic sodium tor, Center for Drug Evaluation and phosphate buffer solution, pH 6.4 Research: Transfer 6.9 grams of monobasic so- (a) The ticarcillin disodium used in dium phosphate to a 1-liter volumetric making the batch: 12 packages, each flask and dissolve in 900 milliliters of containing approximately 300 milli- water. Adjust the pH to 6.4 with sodium grams. hydroxide (10N). Dilute to volume with (b) The clavulanate potassium used distilled water. Mix well. Use this dilu- in making the batch: 12 packages, each ent to prepare the working standard
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and sample solutions described in para- (c) Resolution factor. The resolution graph (b)(1)(ii) of this section. factor (R) between the clavulanic acid (ii) Working standard and sample solu- and ticarcillin peaks is satisfactory if tions)—(a) Preparation of working stand- it is not less than 5.0. ard solution. Accurately weigh a quan- (d) Coefficient of variation. The coeffi- tity of the ticarcillin working standard cient of variation (SR in percent) is sat- containing the equivalent of approxi- isfactory if it is not more than 2.0 per- mately 90 milligrams of ticarcillin ac- cent. tivity and transfer into a 100-milliliter volumetric flask. Prepare a solution of If the system suitability requirements the clavulanic acid working standard have been met, then proceed as de- containing the equivalent of 30 milli- scribed in § 436.355(b) of this chapter. grams or 60 milligrams of clavulanic (iv) Calculations. (a) Calculate the acid activity in a 100-milliliter volu- micrograms of ticarcillin per milli- metric flask. Dissolve and dilute to gram as follows: volume with diluent. Transfer 10 milli- liters of this solution into the flask Micrograms of AP× containing the ticarcillin standard. Di- ticarcillin per = u s lute the combined standard solution to × milligram ACs u volume with diluent. Mix. Use within 8 hours after preparation. where: (b) Preparation of sample solutions—(1) Au=Area of the ticarcillin peak in the chro- Ticarcillin potency (micrograms of matogram of the sample (at a retention ticarcillin per milligram). Accurately time equal to that observed for the standard); weigh the total contents of a container As=Area of the ticarcillin peak in the chro- and dissolve with sufficient diluent to matogram of the ticarcillin working obtain a stock solution containing ap- standard;
proximately 30 milligrams of Ps=Ticarcillin activity in the ticarcillin ticarcillin per milliliter. Further dilute working standard solution in this solution with diluent to obtain a micrograms of anhydrous ticarcillin free final concentration of 0.9 milligrams of acid per milliliter; and ticarcillin per milliliter (estimated). Cu=Milligrams of sample per millilter of (2) Ticarcilin and clavulanic acid con- sample solution. tent (milligrams of ticarcillin and (b) Calculate the ticarcillin or clavulanic acid per container). Reconsti- clavulanic acid anhydrous free acid tute the container with an appropriate content of the container as follows: volume of distilled water. Using a suit- able hypodermic syringe, remove all of Milligrams of anhydrous A× P × d the withdrawable contents. Dilute with ticarcillin or clavulanic acid = u s diluent to obtain a stock solution con- free acid per container A ×1, 000 taining approximately 30 milligrams of s ticarcillin per milliliter and 1 or 2 mil- where:
ligrams of clavulanic acid per milli- Au=Area of the ticarcillin or clavulanic acid liter. Further dilute this solution with peak in the chromatogram of the sample the diluent to obtain a final concentra- (at a retention time equal to that ob- tion of 0.9 milligram of ticarcillin per served for the standard); milliliter. The final solution will con- As=Area of the ticarcillin or clavulanic acid peak in the chromatogram of the tain either 0.03 or 0.06 milligram of ticarcillin or clavulanic acid working clavulanic acid per milliliter (esti- standard; mated) depending on the initial Ps=Anhydrous ticarcillian or clavulanic free ticarcillin to clavulanic acid ratio. acid activity in the ticarcillin-clavulanic (iii) System suitability requirements— acid working standard solution in (a) Tailing factor. The tailing factor (T) micrograms per milliliter; and is satisfactory if it is not more than d=Dilution factor of the sample. 2.0. (2) Sterility. Proceed as directed in (b) Efficiency of the column. The effi- § 436.20 of this chapter, using the meth- ciency of the column (n) is satisfactory od described in paragraph (e)(1) of that if it is greater than 1,000 theoretical section. plates in a 25-centimeter column.
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(3) Pyrogens. Proceed as directed in (A) The ticarcillin monosodium § 436.32(b) of this chapter, using a solu- monohydrate used in making the batch tion containing 100 milligrams of for potency, moisture, pH, identity, ticarcillin per milliliter. and crystallinity. (4) Moisture. Proceed as directed in (B) The clavulanate potassium used § 436.201 of this chapter. in making the batch for potency, mois- (5) pH. Proceed as directed in § 436.202 ture, pH, identity, and clavam-2- of this chapter, using a solution con- carboxylate content. taining 100 milligrams per milliliter. (C) The batch for ticarcillin content, [50 FR 34418, Aug. 20, 1985; 50 FR 42156, Oct. clavulanic acid content, sterility, 18, 1985; 50 FR 43384, Oct. 25, 1985; 50 FR 45403, pyrogens, pH, and identity. Oct. 31, 1985, as amended at 55 FR 11582, Mar. (ii) Samples, if required by the Cen- 29, 1990] ter for Drug Evaluation and Research: (A) The ticarcillin monosodium § 440.290c Ticarcillin disodium and clavulanate potassium injection. monohydrate used in making the batch: 12 packages, each containing ap- (a) Requirements for certification—(1) proximately 300 milligrams. Standards of identity, strength, quality, (B) The clavulanate potassium used and purity. Ticarcillin disodium and clavulanate potassium injection is a in making the batch: 12 packages, each frozen, aqueous, isoosmotic solution of containing approximately 300 milli- ticarcillin disodium and clavulanate grams. potassium with one or more suitable (C) The batch: and harmless buffer substances. The (1) For all tests except sterility: A ratio of ticarcillin to clavulanic acid is minimum of 10 immediate containers. 30:1. Each milliliter contains ticarcillin (2) For sterility testing: 20 immediate disodium equivalent to 30 milligrams containers, collected at regular inter- of ticarcillin and clavulanate potas- vals throughout each filling operation. sium equivalent to 1 milligram of (b) Tests and methods of assay. Thaw clavulanic acid. Its ticarcillin content the sample as directed in the labeling. is satisfactory if it is not less than 90 The sample solution used for testing percent and not more than 115 percent must be at room temperature. of the number of milligrams of (1) Ticarcillin and clavulanic acid con- ticarcillin that it is represented to con- tents. Proceed as directed in tain. Its clavulanate potassium content § 440.290b(b)(1), except use the thawed is satisfactory if it contains not less solution and prepare the sample solu- than 85 percent and not more than 120 tion and calculate the ticarcillin and percent of the number of milligrams of clavulanic acid content as follows: clavulanic acid that it is represented to (i) Preparation of sample solution. contain. It is sterile. It is nonpyrogenic. Its pH is not less than Using a suitable hypodermic needle and 5.5 and not more than 7.5. It passes the syringe, remove an accurately meas- identity test. The ticarcillin mono- ured representative portion from each sodium monohydrate used conforms to container immediately after thawing the standards prescribed by and reaching room temperature. Dilute § 440.91(a)(1). The clavulanate potas- with diluent (described in sium used conforms to the standards § 440.290b(b)(1)(i)(c)) to obtain a solution prescribed by § 455.15(a)(1) of this chap- containing approximately 0.9 milli- ter. gram of ticarcillin activity per milli- (2) Labeling. It shall be labeled in ac- liter (estimated). This solution will cordance with the requirements of contain approximately 0.03 milligram § 432.5 of this chapter. of clavulanic acid per milliliter. Intro- (3) Requests for certification; samples. duce the sample into the chro- In addition to complying with the re- matograph in a timely manner. quirements of § 431.1 of this chapter, (ii) Calculations. Calculate the each such request shall contain: ticarcillin or clavulanic acid con- (i) Results of tests and assays on: centration as follows:
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must conform to all U.S.P. specifica- Milligrams of ticarcillin × × tions. It is so purified and dried that: Au P s d or clavulanic acid = (i) Its potency is not less than 1,355 activity per milliliter × As 1, 000 units and not more than 1,595 units per where: milligram. (ii) It is sterile. Au=Area of the ticarcillin or clavulanic acid peak in the chromatogram of the sample (iii) It is nonpyrogenic. (at a retention time equal to that ob- (iv) [Reserved] served for the standard); (v) Its loss on drying is not more As=Area of the ticarcillin or clavulanic acid than 1.5 percent. peak in the chromatogram of the (vi) Its pH is not less than 6.0 and not ticarcillin or clavulanic acid working more than 8.5. standard; (vii) Its penicillin G content is not Ps=Ticarcillin or clavulanic acid activity in the ticarcillin-clavulanic acid working less than 76.3 percent and not more standard solution in micrograms per mil- than 89.8 percent. liliter; and (viii) It is crystalline. d=Dilution factor of the sample. (2) Labeling. It shall be labeled in ac- cordance with the requirements of (2) Sterility. Proceed as directed in § 432.5 of this chapter. § 436.20 of this chapter, using the meth- (3) Requests for certification; samples. od described in § 436.20(e)(1). In addition to complying with the re- (3) Pyrogens. Proceed as directed in quirements of § 431.1 of this chapter, § 436.32(a) of this chapter, except inject each such request shall contain: a sufficient volume of the undiluted so- (i) Results of tests and assays on the lution to deliver 100 milligrams of batch for potency, sterility, pyrogens, ticarcillin per kilogram. loss on drying, pH, penicillin G con- (4) pH. Proceed as directed in § 436.202 tent, and crystallinity. of this chapter, using the undiluted so- (ii) Samples required: lution. (a) For all tests except sterility: 10 (5) Identity. The high-performance packages, each containing approxi- liquid chromatogram of the sample de- mately 300 milligrams. termined as directed in paragraph (b) For sterility testing: 20 packages, (b)(1) of this section compares quali- each containing approximately 600 mil- tatively to that of the ticarcillin and ligrams. clavulanic acid working standard. (b) Tests and methods of assay—(1) Po- [55 FR 5840, Feb. 20, 1990] tency—(i) Sample preparation. Dissolve an accurately weighed sample in suffi- [ ] cient 1.0 percent potassium phosphate Subparts D–J— Reserved buffer, pH 6.0 (solution 1), to give a stock solution of convenient con- Subpart K—Bulk Drug Formulations centration. for Repacking or for Manufac- (ii) Assay procedures. Assay for po- turing Use tency by any of the following methods; however, the results obtained from the § 440.1080a Sterile penicillin G potas- iodometric assay shall be conclusive. sium buffered. (a) Microbiological agar diffusion (a) Requirements for certification—(1) assay. Proceed as directed in § 436.105 of Standards of identity, strength, quality, this chapter, diluting an aliquot of the and purity. Penicillin G potassium, stock solution with solution 1 to the buffered, is a dry mixture of penicillin reference concentration of 1.0 unit of G potassium and the buffer sodium cit- penicillin G per milliliter (estimated). rate in a quantity not less than 4.0 per- (b) Iodometric assay. Proceed as di- cent and not more than 5.0 percent by rected in § 436.204 of this chapter, dilut- weight of its total solids. It may con- ing an aliquot of the stock solution tain citric acid in a quantity not more with solution 1 to the prescribed con- than 0.15 percent of its total solids in centration. place of a corresponding amount of so- (c) Hydroxylamine colorimetric assay. dium citrate. The sodium citrate and Proceed as directed in § 436.205 of this citric acid used in making the batch chapter, diluting an aliquot of the
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stock solution with solution 1 to the (2) Labeling. It shall be labeled in ac- prescribed concentration. cordance with the requirements of (2) Sterility. Proceed as directed in § 432.5 of this chapter. § 436.20 of this chapter, using the meth- (3) Requests for certification; samples. od described in paragraph (e)(1) of that In addition to complying with the re- section. quirements of § 431.1 of this chapter, (3) Pyrogens. Proceed as directed in each such request shall contain: § 436.32(b) of this chapter, using a solu- (i) Results of tests and assays on the tion containing 20,000 units of penicil- batch for potency, sterility, pyrogens, lin G per milliliter. loss on drying, pH, penicillin G con- (4) [Reserved] (5) Loss on drying. Proceed as directed tent, crystallinity, and heat stability. in § 436.200(b) of this chapter. (ii) Samples required: (6) pH. Proceed as directed in § 436.202 (a) For all tests except sterility: 10 of this chapter, using an aqueous solu- packages, each containing approxi- tion containing 60 milligrams per mil- mately 300 milligrams. liliter. (b) For sterility testing: 20 packages, (7) Penicillin G content. Proceed as di- each containing approximately 600 mil- rected in § 436.316 of this chapter. ligrams. (8) Crystallinity. Proceed as directed (b) Tests and methods of assay—(1) Po- in § 436.203(a) of this chapter. tency—(i) Sample preparation. Dissolve [42 FR 59872, Nov. 22, 1977, as amended at 45 an accurately weighed sample in suffi- FR 22922, Apr. 4, 1980; 50 FR 19918, 19919, May cient 1.0 percent potassium phosphate 13, 1985] buffer, pH 6.0 (solution 1), to give a stock solution of convenient con- § 440.1081a Sterile penicillin G sodium, centration. buffered. (ii) Assay procedures. Assay for po- (a) Requirements for certification—(1) tency by any of the following methods; Standards of identity, strength, quality, however, the results obtained from the and purity. Penicillin G sodium, iodometric assay shall be conclusive. buffered, is a dry mixture of penicillin (a) Microbiological agar diffusion G sodium and the buffer sodium citrate in a quantity not less than 4.0 percent assay. Proceed as directed in § 436.105 of and not more than 5.0 percent by this chapter, diluting an aliquot of the weight of its total solids. It may con- stock solution with solution 1 to the tain citric acid in a quantity not more reference concentration of 1.0 unit of than 0.15 percent of its total solids in penicillin G per milliliter (estimated). place of a corresponding amount of so- (b) Iodometric assay. Proceed as di- dium citrate. The sodium citrate and rected in § 436.204 of this chapter, dilut- citric acid used in making the batch ing an aliquot of the stock solution must conform to all U.S.P. specifica- with solution 1 to the prescribed con- tions. It is so purified and dried that: centration. (i) Its potency is not less than 1,420 (c) Hydroxylamine colorimetric assay. units and not more than 1,667 units per Proceed as directed in § 436.205 of this milligram. chapter, diluting an aliquot of the (ii) It is sterile. stock solution with solution 1 to the (iii) It is nonpyrogenic. prescribed concentration. (iv) [Reserved] (2) Sterility. Proceed as directed in (v) Its loss on drying is not more § 436.20 of this chapter, using the meth- than 1.5 percent. od described in paragraph (e)(1) of that (vi) Its pH is not less than 6.0 and not more than 7.5. section. (vii) Its penicillin G content is not (3) Pyrogens. Proceed as directed in less than 80 percent and not more than § 436.32(b) of this chapter, using a solu- 93.8 percent. tion containing 20,000 units of penicil- (viii) It is crystalline. lin G per milliliter. (ix) It passes the test for heat stabil- (4) [Reserved] ity if it does not show a loss of more (5) Loss on drying. Proceed as directed than 10 percent of its original potency. in §436.200(b) of this chapter.
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(6) pH. Proceed as directed in § 436.202 imipenem per milliliter at 25 °C is ∂85° of this chapter, using an aqueous solu- to ∂95° on an anhydrous basis. tion containing 60 milligrams per mil- (vi) It gives a positive identity test. liliter. (vii) It is crystalline. (7) Penicillin G content. Proceed as di- (2) Labeling. It shall be labeled in ac- rected in § 436.316 of this chapter. cordance with the requirements of (8) Crystallinity. Proceed as directed § 432.5 of this chapter. in § 436.203(a) of this chapter. (3) Requests for certification; samples. (9) Heat stability. Proceed as directed In addition to complying with the re- in § 436.214 of this chapter. quirements of § 431.1 of this chapter, [42 FR 59873, Nov. 22, 1977; 43 FR 2393, Jan. 17, each such request shall contain: 1978, as amended at 45 FR 22922, Apr. 4, 1980; (i) Results of tests and assays on the 50 FR 19918, 19919, May 13, 1985] batch for potency, sterility, pyrogens, loss on drying, specific rotation, iden- PART 441—PENEM ANTIBIOTIC tity, and crystallinity. DRUGS (ii) Samples, if required by the Direc- tor, Center for Drug Evaluation and Subpart A—Bulk Drugs Research: (a) For all tests except sterility: 10 Sec. 441.20a Sterile imipenem monohydrate. packages, each containing approxi- mately 500 milligrams. Subpart B—[Reserved] (b) For sterility testing: 20 packages, each containing equal portions of ap- Subpart C—Injectable Dosage Forms proximately 300 milligrams. 441.220 Imipenem monohydrate-cilastatin (b) Tests and methods of assay—(1) Po- sodium injectable dosage forms. tency. Proceed as directed in § 436.216 of 441.220a Sterile imipenem monohydrate- this chapter, using a column heater cilastatin sodium. which will maintain a 50 °C column 441.220b Imipenem monohydrate-cilastatin temperature, and ultraviolet detection sodium for injection. system operating at a wavelength of AUTHORITY: Sec. 507 of the Federal Food, 254 nanometers, a column packed with Drug, and Cosmetic Act (21 U.S.C. 357). microparticulate (3 to 10 micrometers in diameter) reversed phase packing Subpart A—Bulk Drugs material such as octyl or octadecyl hy- drocarbon bonded silicas, a flow rate of § 441.20a Sterile imipenem 2.0 milliliters per minute, and a known monohydrate. injection volume of 10 microliters. Re- (a) Requirements for certification—(1) agents, working standard and sample Standards of identity, strength, quality, solutions, system suitability require- and purity. Imipenem monohydrate is ments, and calculations are as follows: the monohydrate form of [5R-[5α, 6α, (i) Reagents—(a) Phosphate buffer, (R*)]]-6-(1-hydroxyethyl)-3-[[2- 0.001M. Dissolve 272 milligrams of [(iminomethyl) amino]ethyl]thio]-7- monobasic potassium phosphate in oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-car- 1,800 milliliters of deionized water. Ad- boxylic acid. It is a white to tan col- just the pH to 6.8 with 0.5N sodium hy- ored powder. It is so purified and dried droxide or dilute phosphoric acid. Di- that: lute to 2,000 milliliters with deionized (i) Its potency is not less than 900 water and filter prior to use. micrograms and not more than 1,050 (b) Mobile phase. Dissolve 2.0 grams of micrograms of imipenem per milligram 1-hexanesulfonic acid, sodium salt in on an anhydrous basis. 800 milliliters of phosphate buffer, (ii) It is sterile. 0.001M. Adjust the pH to 6.8 with 0.5N (iii) It is nonpyrogenic. sodium hydroxide or dilute phosphoric (iv) Its loss on drying is not less than acid and dilute to 1,000 milliliters with 5.0 percent and not more than 8.0 per- phosphate buffer, 0.001M. Filter and cent. degas the mobile phase just prior to its (v) Its specific rotation in an aqueous introduction into the chromatograph solution containing 5 milligrams of pumping system.
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