US008158152B2

(12) United States Patent (10) Patent No.: US 8,158,152 B2 Palepu (45) Date of Patent: Apr. 17, 2012

(54) LYOPHILIZATION PROCESS AND 6,884,422 B1 4/2005 Liu et al. PRODUCTS OBTANED THEREBY 6,900, 184 B2 5/2005 Cohen et al. 2002fOO 10357 A1 1/2002 Stogniew etal. 2002/009 1270 A1 7, 2002 Wu et al. (75) Inventor: Nageswara R. Palepu. Mill Creek, WA 2002/0143038 A1 10/2002 Bandyopadhyay et al. (US) 2002fO155097 A1 10, 2002 Te 2003, OO68416 A1 4/2003 Burgess et al. 2003/0077321 A1 4/2003 Kiel et al. (73) Assignee: SciDose LLC, Amherst, MA (US) 2003, OO82236 A1 5/2003 Mathiowitz et al. 2003/0096378 A1 5/2003 Qiu et al. (*) Notice: Subject to any disclaimer, the term of this 2003/OO96797 A1 5/2003 Stogniew et al. patent is extended or adjusted under 35 2003.01.1331.6 A1 6/2003 Kaisheva et al. U.S.C. 154(b) by 1560 days. 2003. O191157 A1 10, 2003 Doen 2003/0202978 A1 10, 2003 Maa et al. 2003/0211042 A1 11/2003 Evans (21) Appl. No.: 11/282,507 2003/0229027 A1 12/2003 Eissens et al. 2004.0005351 A1 1/2004 Kwon (22) Filed: Nov. 18, 2005 2004/0042971 A1 3/2004 Truong-Le et al. 2004/0042972 A1 3/2004 Truong-Le et al. (65) Prior Publication Data 2004.0043042 A1 3/2004 Johnson et al. 2004/OO57927 A1 3/2004 Warne et al. US 2007/O116729 A1 May 24, 2007 2004, OO63792 A1 4/2004 Khera et al. 2004/0092587 A1 5, 2004 Takada et al. (51) Int. C. 2004/O157789 A1 8, 2004 Geall et al. A6 IK 9/14 (2006.01) 2004O167173 A1 8/2004 Reddy et al. 2004/0176357 A1 9/2004 Dekemper (52) U.S. C...... 424/489: 514/35; 514/291; 514/192: 514/200: 514/282 (Continued) (58) Field of Classification Search ...... None See application file for complete search history. FOREIGN PATENT DOCUMENTS WO WO99-30688 6, 1999 (56) References Cited (Continued) U.S. PATENT DOCUMENTS OTHER PUBLICATIONS 4.959,215 A 9, 1990 Sauerbier et al. Jiang Guokun et al. Preparation of crystalline acyclovir Sodium for 5,206,025 A 4, 1993 Courteille et al. 5,336,669 A 8/1994 Palepu et al. injection, Chinese Journal of Pharmaceuticals, 2002, 33(2): 79-80). 5,418,223 A 5/1995 Palepu et al. 5,424,471 A 6/1995 Kennedy et al. Primary Examiner — Robert A Wax 5,561,121 A 10, 1996 Ku et al. Assistant Examiner — Hasan Ahmed 5,591,731 A 1/1997 Kennedy et al. 5,612,058 A 3, 1997 Schutz et al. (74) Attorney, Agent, or Firm — Frommer Lawerence & 5,631,023 A 5/1997 Kearney et al. Haug LLP; Sandra Kuzrnich, Esq.; Russell A. Garman 5,731,291 A 3, 1998 Sullivan et al. 5,882,684 A 3, 1999 Schutz et al. (57) ABSTRACT 5,955.488 A 9, 1999 Winterborn 6,010,719 A 1/2000 Remon et al. Alyophilization process which comprises dissolving a mate 6,063,802 A 5, 2000 Winterborn rial in one or more solvents for said material to form a solu 6,133,440 A 10/2000 Qiu et al. tion; forcing said material at least partially out of solution by 6,207456 B1 3, 2001 Baru et al. combining the Solution and a non-solvent for the material, 6,271,214 B1 8/2001 Qiu et al. which non-solvent is miscible with the solvent or solvents 6,384,259 B1 5/2002 Stogniew et al. 6,407.278 B2 6/2002 Stogniew et al. used and wherein said non-solvent is volatilizable under 6,436,679 B1 8/2002 Qiu et al. freeze-drying conditions. In addition, for hydrophobic and/or 6,440,414 B1 8, 2002 Kendricket al. lipophilic materials, the anti-solvent can be omitted, and the 6,489,312 B1 12/2002 Stogniew et al. 6,566,329 B1 5/2003 Meynet al. solution of the material in the solvent can be subjected 6,576,651 B2 6/2003 Bandyopadhyay et al. directly to freeze drying. The lyophilizates can then be recon 6,586,574 B1 7/2003 Hansen stituted with typical aqueous diluent in the case of hydro 6,589,554 B1 7/2003 Mizumoto et al. philic materials. Hydrophobic and or lipophilic materials can 6,641,526 B1 1 1/2003 Wakayama be initially reconstituted with propylene glycol and/or poly 6,670,384 B2 12/2003 Bandyopadhyay et al. 6,746,694 B1 6, 2004 Bhadra et al. ethyleneglycol to form a high concentration solution therein 6,770,678 B1 8, 2004 Kurz and this is further diluted for use with a diluent of Intralipid, 6,803,054 B2 10/2004 Mizumoto et al. plasma, serum, or even whole blood. 6,841,545 B2 1/2005 Stogniew et al. 6,869,618 B2 3/2005 Kiel et al. 46 Claims, No Drawings US 8,158,152 B2 Page 2

U.S. PATENT DOCUMENTS 2005, OO69584 A1 3/2005 Kiel et al. 2004/O197885 A1 10, 2004 Ueda 2005, OO84530 A1 4/2005 Rao 2004/0234593 A1 11, 2004 Kier1 et all 2005, 0100598 A1 5/2005 Mizumoto et al. 2004/0235903 Ai i??004 Khanna 2005/0137265 A1 6/2005 Haley 2005.0020509 A1 1/2005 Kiel et all 2005. O142190 A1 6/2005 Adin et al. 2005.002061.0 A1 1/2005 Zhang etal 2005/O148597 A1 7/2005 Kostanski et al. 2005.0020615 A1 1/2005 fE. 2005/O152962 A1 7/2005 Metselaar 2005/OO32775 A1 2, 2005 Gyollai et al. 2005/O152980 A1 7/2005 Ausborn et al. 2005/OO37O67 A1 2/2005 Hovdal et al. 2005/O152981 A1 7/2005 Gleeson et al. 2005.0049209 A1 3, 2005 Chen 2005, OO63912 A1 3/2005 Montgomery et al. FOREIGN PATENT DOCUMENTS 2005, OO69578 A1 3/2005 Balasubramanian et al. WO WO2004-039804 5, 2004 US 8,158,152 B2 1. 2 LYOPHILIZATION PROCESS AND freezing process. Depending upon the solvent or solvent com PRODUCTS OBTANED THEREBY bination used, there may be some liquid portion that does not freeze, but remains liquid and is distributed within the other CROSS-REFERENCE TO RELATED wise frozen mass. The application of Vacuum pressures then APPLICATIONS permits the removal of unfrozen liquids first, followed by the Sublimation of frozen liquid components, leaving behind a Not applicable. purer, dried product. In some techniques, the freezing process is done slowly so that crystallization takes place Substantially STATEMENT REGARDING before the solvent is frozen. In other techniques, the freezing 10 step is performed rapidly to freeze the solvent before appre FEDERALLY SPONSORED RESEARCHOR ciable crystallization has occurred. In still other techniques, DEVELOPMENT after freezing has taken place, addition of a small degree of heat to warm the frozen mass slightly permits the frozen Not Applicable liquid components to Sublimate more readily. These same 15 techniques may be applicable to situations when suspensions, FIELD OF THE INVENTION emulsions, and complex formulations are involved, except that the filtering step may not be suitable because it may The present invention relates to methods of preparing lyo remove active or other auxiliary components which are philizates, especially those free of undesired extra compo intended to be present. nents. The invention further relates to obtaining lyophilizates Unfortunately, the range of acceptable materials for use in of amorphous/crystalline Solids that are rapidly reconstitut pharmaceuticals that are intended for parenteral administra able. The invention further relates to the materials resulting tion, is not as large and not so accommodating. For example, from the novel lyophilization techniques presented herein. emulsions where the freeze-drying process leaves the emul sifier and/or the oil phase present in the lyophilizate would BACKGROUND OF THE INVENTION 25 generally not be acceptable from an intravenous injection point of view. Similarly, Suspending agents would also not be Freeze-drying or lyophilization has been widely used for a desirable. Thus, it is clear that an alternate lyophilization number of decades in pharmaceutical, food, and chemical procedure that could eliminate the use of undesirable auxil industries. Freeze-drying is particularly desirable in situa iary agents to a larger degree than is presently available is tions where a pharmaceutical or other material is required to 30 desirable and sought after. be dried or dehydrated or desolvated, but is sensitive to the Although the prior art is replete with references to freeze application of heat for the purpose of drying. Many com drying and lyophilization, most literature refers to the tech pounds, when exposed to the typically employed drying tem nique in a general manner Such as “the material is freeze-dried peratures of non-freeze drying techniques, decompose, as commonly practiced in the art” and other general State degrade, or Volatilize away, resulting in an undesirable prod 35 ments of similar description. Virtually all of the references uct. To recognize the large number of applications to which that do describe the details of the lyophilization process make freeze-drying has been adapted, one need only run a simple no mention of nor Suggestion of the use of an anti-solvent or search of the US Patent and Trademark Office patent data non-solvent. Most references refer to clear solutions, solvents bases for the term “freeze drying and/or “lyophilization', and co-solvents being used to obtain clarity or near clarity, which as of October 2005, returns over 3000 hits and covers 40 with the solution then being filtered. Most references involv a wide range of active agents and other materials. ing lyophilization, when discussing solvents, refer to aqueous In general, the freeze-drying or lyophilization technique is materials. to dissolve, Suspend, or emulsify a compound or formulation; Representative (non-exhaustive) patents and applications freeze the resultant solution, Suspension, or emulsion; and which are of note include the following, all of which are then to apply a vacuum thereto to Sublimate/evaporate the 45 incorporated herein in their entirety. U.S. 2005/0049209 dis Solvents and other liquids in the frozen mass used to dissolve, cusses freeze-drying of emulsions. U.S. Pat. No. 6,770,678 Suspend or emulsify the material. In many applications, the discusses that for freeze drying purposes it is desirable to have use of auxiliary agents to create Suitable solutions, Suspen the Solution concentration as high as possible, but often the sions, and emulsions is not of significant concern. This is high concentration leads to crystals forming during the cool especially So where the auxiliary agent is acceptable to be 50 ing step, which the reference states is undesirable. U.S. 2004/ present in the end product, as in the use of auxiliary food 0063792 mentions freeze-drying sertraline from a number of ingredients in freeze dried foods. Similarly, where pharma solvent/co-solvent combinations. U.S. 2004/0043042 dis ceuticals are intended for oral ingestion, a wide range of cusses micro-lyophilization. U.S. 2003/0229027 mentions auxiliary pharmaceutically acceptable agents may be used to freeze-drying canabinoids from solvent mixtures in the pres aid in the preparation of lyophilized active compounds or 55 ence of certain sugars. U.S. 2003/0202978 discusses spray formulations containing Such active compounds. In most freeze-drying. U.S. 2002/0010357: U.S. Pat. Nos. 6,384,259; freeze-drying processes, a clear Solution of the material to be 6,407.278; 6,841,545; and 6,489,312 all relate to amifostine freeze dried is obtained, if possible. This is then usually lyophilizates. U.S. Pat. No. 6,566,329 discusses precipitating filtered aseptically to remove any extraneous Solids and human growth hormone out of solution by adjusting the pH to microorganism, and the filtered solution is filled into glass 60 the isoelectric point and then freeze-drying the result. U.S. vials and cooled in a lyophilization chamber whereby the Pat. No. 5,731,291 discusses using a solvent (water) and a dissolved solids generally freeze together with the freezable second agent that Sublimates at -40°C. in a lyophilization liquid components, but may, depending upon concentration process. WO99/30688 discusses using an accelerant excipi and the rate of the freezing process, begin to come out of ent to enhance the rate of solvent sublimation. WO2004/ Solution during the process of cooling or freezing. For 65 0398.04 discusses freeze-drying moxifloxacin from water. example, if one were to prepare a solution at its Saturation The specification mentions that it can also be obtained by use concentration, the dissolved solid could precipitate during the of an anti-solvent followed by filtration, decantation, or cen US 8,158,152 B2 3 4 trifugation. There is no suggestion that the moxifloxacin rial in one or more solvents for said material to form a solu obtained from the solution by use of an anti-solvent then be tion; forcing said material at least partially out of solution by subjected to freeze drying. U.S. 2003/082236 discusses use of combining the Solution and a non-solvent for the material, a Supercritical anti-solvent. which non-solvent is miscible with the solvent or solvents used and wherein said non-solvent is volatilizable under OBJECTS OF THE INVENTION freeze-drying conditions or optionally seeding the Solution It is therefore an object of the invention whereby a hydro before or during the step of forcing it out of Solution; freezing philic or a hydrophobic material may be lyophilized using a the result thus far, and applying a vacuum to dry the frozen minimum number of auxiliary materials. result. For hydrophilic substances water is frequently the It is another object of the invention to preparelyophilizates 10 primary solvent and forms the frozen mass while any co of water sensitive materials. Solvent and the anti-solvent may or may not freeze during the It is still another object of the invention whereby an amor freezing step. For lipophilic or hydrophobic materials, water phous material may be recovered via lyophilization with or is frequently the anti-solvent and it is the solvent and potential without the use of auxiliary agents. co-solvent which may or may not freeze during the freezing Still another object of the invention is to provide a non 15 step. Either way, the dissolved material is forced out of solu aqueous lyophilization technique which includes several tion by the anti-solvent, the result subjected to freezing tem organic solvents which have not been previously known for peratures to form a frozen mass, and the frozen mass Sub use in the lyophilization process art. jected to vacuum pressures to result in a lyophilizate. In It is still another object of the invention whereby a crystal addition, for hydrophobic and/or lipophilic materials, the line hydrate and/or amorphous material may be recovered via anti-solvent can be omitted, and the solution of the material in lyophilization without the use of auxiliary agents while the solvent can be subjected directly to freeze drying. The simultaneously avoiding the use of ethanol. lyophilizates can then be reconstituted with typical aqueous An even further object of the invention is to provide a method of obtaining a substantially pure, readily reconstitut diluent in the case of hydrophilic materials. Hydrophobic and able hydrophilic or hydrophobic or lipophilic material sub or lipophilic materials can be initially reconstituted with pro stantially free of auxiliary materials. 25 pylene glycol and/or polyethyleneglycol to form a high con An even further object of the invention is to provide a centration solution therein and this is further diluted for use method of obtaining a substantially pure, readily reconstitut with a diluent of Intralipid, plasma, serum, or even whole able hydrophilic or hydrophobic or lipophilic material sub blood. stantially free of auxiliary materials which when reconstitutes with pharmaceutically acceptable diluent will result in either 30 DETAILED DESCRIPTION OF THE INVENTION a clear Solution or a micellar Solution or an emulsion or a Sub-micron Suspension. The present invention is directed to a method for freeze An even further object of the invention is to provide a drying or lyophilizing a material which may be (i) hydro method of obtaining a substantially pure, readily reconstitut philic or (ii) hydrophobic and/or lipophilic. Generally when able material containing a hydrophobic or lipophilic Sub 35 the material is hydrophilic, the material is also sensitive to the stance that further contains at least one of a solubilizer or a presence of moisture. The material is usually a substantially Surfactant or combinations thereof which material, upon pure compound, preferably a pure compound, but may also be reconstitution with pharmaceutically acceptable diluent will a simple or complex mixture. The material is dissolved in a result in either a clear Solution or a micellar solution or an solvent therefor, preferably without, but potentially with, one emulsion or a sub-micron Suspension. 40 or more co-solvents so as to obtain a Substantially clear, Yet another object of the invention is to provide a method preferably clear, solution of said material therein. Solvent for for obtaining an amorphous lyophilizate which is stable in the the material is one which can be removed in a freeze-drying presence of moisture. process, i.e., one that is volatile or Sublimates at the tempera An even further object of the invention is to provide a ture and pressure used in the primary drying step with any method of obtaining crystalline hydratelyophilizates that are 45 residual amount being removable during a secondary drying stable in the presence of moisture. step. If desired, the solution may be filtered aseptically before Yet another object of the invention is to prepare stable combining it with the anti-solvent which is also filtered asep lyophilizates of water sensitive materials from a lyophiliza tically, to remove any undesired (or undissolved) materials as tion process that includes water. well as microorganisms from the material containing Solution A further object of the invention is provide new, simplified 50 and anti-solvent. Alternatively, a pH adjustment can be lyophilization procedures for lipophilic and/or hydrophobic effected prior to the optional filtration in order to aid stability materials, with or without the use of anti-solvents. and/or solubility, and/or post filtration to aid stability. Prefer An even further object of the invention is to provide novel ably, a pH adjustment for stability purposes, when used, is lyophilizates of lipophilic and/or hydrophobic materials. conducted before the optional filtration step. The pH adjust Still a further object of the invention is to provide novel 55 ment can be accomplished by the addition of an acid or a base reconstitution methods for lyophilizates of lipophilic and/or or a buffer. Once the material to be lyophilized is in solution, hydrophobic materials. the solution is subjected to an anti-solvent for the material (or An even further object is to provide a rapidly dissolving a mixture of anti-solvents for the material). The anti-solvent end-used product that is suitable for use in delivering single for the material is volatile or sublimates under lyophilization unit dosages of in excess of hundreds of milligrams. 60 conditions (i.e., at the pressure and temperature used in the Still other objects of the invention will be apparent to those primary drying step). If the anti-solvent doesn’t freeze under of ordinary skill in the art. lyophilization conditions, special lyophilization techniques are adopted (such as the inclusion of a liquid nitrogen trap BRIEF SUMMARY OF THE INVENTION between the condenser and vacuum pump, and the like) to 65 remove the anti-solvent. The anti-solvent is not a solvent for These and other objects of the invention are Surprisingly the material and the material is essentially insoluble in the achieved by a process which comprises dissolving the mate anti-solvent but is miscible with the solvent used to dissolve US 8,158,152 B2 5 6 (and any co-solvent that is present to dissolve) the materialso parts water): “very slightly soluble” (1 part solute/1000 parts that upon its addition, a Substantial portion preferably Sub water to 1 part solute/10000 parts water); and “practically stantially all, most preferably all, of the material is forced out insoluble' or “insoluble” (1 part solute/>10000 parts water). of solution and forms a Suspension or slurry of Solid particu All of the designations “very soluble”, “freely soluble'. lates in the complex solvent/optional co-solvent/anti-solvent “soluble”, “sparingly soluble' and “slightly soluble' indicate mixture. Optionally before or during, preferably before or at materials which can be considered hydrophilic for the present the beginning of the step when the material is forced out of invention. The designations “very slightly soluble”, “practi solution, the solution may be seeded with a portion of the cally insoluble', and “insoluble' can be considered hydro material that is in the desired solid form to enhance formation phobic for purposes of the invention. The above classification of the appropriate form of the material. Optionally, if desired, 10 system is used detailed in Remington: The Science and Prac the result can then be filtered, decanted, etc. to separate a tice of Pharmacy 19" Ed., Mack Publishing co., Easton, Pa. portion of the solvent/optional co-solvent/anti-solvent mix 1995, Page 195, and is described in the United States Phar ture from the precipitated solids. When such a separation macopoeia. A second system is by a determination of the technique is used, the separated solids are still wet with the partition coefficient, P. defined as the ratio of the concentra solvent/optional co-solvent/anti-solvent mixture. Whether or 15 tion of a material in octanol to the concentration in waterin an not the post precipitation separation technique is used, the octanol/water system at equilibrium at 25°C. Generally, val resulting wet solids (Suspension, slurry, etc.) are then frozen ues for P are given as log P (see Handbook of Chemistry and and the frozen solid is dried by the application of vacuum to Physics 86' Ed. 2005-2006 at Pages 16-41 to 16-45 and remove the solvent, the co-solvent, and the anti-solvent. In Remington: The Science and Practice of Pharmacy 19" Ed., some embodiments, one or more (but not all) of the solvent/ Mack Publishing Co., Easton, Pa. 1995, Pages 158-159). optional co-solvent/anti-solvent of choice does not freeze at Values of P-31 (log P is negative) are clearly hydrophilic. the freezing step temperature allowed by the lyophilizer. Values of Pidd 1 are generally hydrophobic. However, since When this is the case, special anti-solvent removal conditions this measure is in the octanol/water system, it is not abso need to be used. These special removal conditions include the lutely controlling in the invention, but merely indicative of use of a liquid nitrogen trap and other similar techniques 25 whether a particular material is a likely hydrophilic or likely known in the art. hydrophobic one for initial consideration of the solvent, co The material may be selected from a wide range of com Solvent, and anti-solvent to use. Another guideline useful for pounds and compositions, but is preferably a substantially consideration of the hydrophilic or hydrophobic nature of the pure compound, most preferably a pure compound, where material is the hydrophilic-lipophilic balance (HLB) system. "pure' indicates as reasonably pure as can be obtained using 30 (See Remington above, pages 287-288). Although the HLB at least commercially reasonable standards and tolerances. system was developed for Surface active agents, it does give Thus, a product is “pure' for purposes of this invention if (in another guideline as to the hydrophilic nature or hydrophobic the context of pharmaceutical materials) it is Sufficiently pure nature of a material, with hydrophilic materials having an to meet Federal Food and Drug Administration purity stan HLB greater than about 10 and hydrophobic materials having dards. If the product in question is other than an end use 35 an HLB value generally below about 10. Once a potential pharmaceutical, the product is considered “pure' if it meets Solvent and potential anti-solvent are selected however, con the relevant industry standard for purity. Such industry stan firmation should be sought that the chosen anti-solvent does dards include Standards, such as “Reagent Grade', etc. substantially push the material out of solution in the chosen Compounds that can benefit from the present invention solvent or solvent/co-solvent mixture. The more efficiently include, but are not limited to, pharmaceutically active com 40 and completely the anti-solvent pushes the material out of pounds, Veterinary compounds, food materials, dyes, house solution, the better the invention should be expected to give hold and industrial chemicals, etc. Selected, non-limiting, the desired results. representative compounds include hydrophilic materials as Useful compounds which can be prepared in lyophilizate well as hydrophobic/lipophilic materials. Various hydrates formaccording to the invention (generally include, but are not and Solvates in various polymorphic forms of Such materials 45 limited to, end use acceptable salts, amides thereof. Sulfona are also suitable. Conversion from hydrophilic to hydropho mides thereof, carbamates thereof, esters thereof and phos bic materials may often be accomplished by a pH change phoesters thereof, hydrates and Solvates thereof, and crystal between a charged species and an uncharged one, Such as for line polymorphs and amorphous forms thereof, and example conversion between a free acid or base (less water racemates, enantiomers, and diastereomers thereof). In the soluble) and a salt thereof (more water soluble). If the solu 50 following exemplary list, most of the compounds are phar bility shifts sufficiently, the solvents/co-solvents for one form maceutically or veterinary acceptable compounds. Thus, the can become the anti-solvent for the other form and the anti salt or ester is preferably those that are acceptable in these solvents for the first form can become the solvents for the uses. However, if the lyophilizate will be further modified latter. Thus, the invention is applicable to free acids, free before being used as a pharmaceutical or veterinary material, bases, their salts, and Zwitterionic species where appropriate, 55 the salt or ester is not so limited. In addition, the following and those materials having a permanent charge such as more extensive list, lists one moiety for the free base, the free betains and Sultanes, and other quaternium compounds. A acid, and all salts thereof, so that the absence of a particular general guideline as to the hydrophilic VS hydrophobic nature salt or of the free acid or free base when another is present, of compounds can be gleaned from a variety of methods should be construed to include the listing of all such suitable known in the art. A simple system is the simple solubility of 60 forms. Similarly, not all pharmaceutically acceptable esters the compound in question in water and is designated by the are indicated, and again, the listing of a non-esterified form terms “very soluble' (1 part solute/less than 1 part water), should be deemed to include the suitable esterified counter “freely soluble' (1 part solute/1 part water to 1 part solute/10 parts. In addition, compounds having a quaternary ammo parts water); “soluble' 1 part solute/10 parts water to 1 part nium are listed only as the primary species without reference solute/30 parts water); “sparingly soluble” (1 part solute/30 65 to the counterion (i.e., benzalkonium, rather than benzalko parts water to 1 part solute/100 parts water); “slightly nium chloride, etc), but all suitable counterions are deemed to soluble” (1 part solute/100 parts water to 1 part solute/1000 be within the scope of the invention. US 8,158,152 B2 7 8 In light of the size of the more extensive list, the inventor acetazolamide, acetiamine, acetiromate, acetohexamide, presents his preferred compounds of interest, but this is only acetophenaZone, acetophenetidin, acetorphine, acetosulfone, in the interest of clarity and should not be taken as a limitation acetriozoic acid, acetylcysteine, acetyldigitoxin, acetylleu on the broader scope of the invention. Preferred compounds cine, acetyltributyl citrate, acetyltriethyl citrate, acevaltrate, for use as the material to be lyophilized according to the acexamin acid, acifran, acipimox, acitaZanolast, acitemate, invention include antibiotics (including penicillins, cepha acitretin, acivicin, alcantate, aclarubicin, aclatonium napa losporins, tetracyclines, macrollides, etc) Xanthines, anesthet disilate, acolbifene, aconiazide, aconitine, acotiamide, acox ics (including barbiturates, narcotics, and the "caines”), anti atrine, acreoZast, acridorex, acriflavine, acrihellin, acrisorcin, emetics, anti-cancer agents, etc. A specifically preferred acrivastine, acroinonide, acronine, actaplanin, actarit, actino group of compounds includes, but is not limited to, alfentanil 10 quinol, actisolide, actodigin, acyclovir, adafenoxate, (particularly the hydrochloride especially the monohydrate), adamexine, adapalene, adaprolol, adatanserin, adefovir, ade amifostine (particularly the amorphousand trihydrate forms), kalant, adelmidrol, ademitrionine, adenosine, adibendal, adi aminophyllin (particularly the dehydrate form), amoxicillin cillin, adimolol, adinazolam, adiphenine, aditeren, aditoprim, (particularly the trihydrate form), amplicillin (especially the adosopine, adoZelesin, adrafinil, adrenalone, adrogolide, trihydrate form), bupivacaine (especially the hydrochloride 15 afalanine, afeletecan, afloqualone, afovirsen, afurolol, agano salt and particularly the monohydrate form), caffeine (espe dine, aglepristone, agomelatine, aklomide, alacepril, alafos cially the monohydrate form), cefepime (especially the falin, alagebrium, alamecin, alamifovir, alanine, alanosine, hydrochloride salt and particularly the monohydrate form), alaproclate, alatrofloxacin, alazanine triclofenate, albacona ceftazidime (especially the pentahydrate form), ceftriaxone Zole, albendazole, albuterol, albutoin, alclofenac, alclometa (especially the 3.5 hydrate form), cephradine (particularly the Sone, alcloxa, alcuronium, aldioxa, aldosterone, alemcinal, mono and dihydrate forms), chromic chloride (especially the alendronic acid, alentemol, alepride, alestramustine, ale hexahydrate form), clindamycin (especially the monohydrate tamine, alexidine, alexitol, alexomycin, alfacalcidol, alfadex, form), codeine, cyclophosphamide, cysteine, dextrose, dox alfidalone, alfaprostol, alfatradiol, aldaxalone, alfentranil, apram (particularly the hydrochloride salt and especially the alfluZosin, algeldrate, algestone, alibendol, aliconazole, monohydrate form) doxycycline (especially the monohydrate 25 alifedrine, alifurane, alilusem, alimadol, alinastine, alinidine, form), edetate (especially the dihydrate form), hyoscyamine alipaminde, alliskiren, alitame, alitretinoin, alizapride, alle (especially the sulfate salt and the dihydrate form), levorpha torphine, allobarbitol, allocamide, allocupreide, allomethadi nol (especially as the dihydrate form), lidocaine (particularly one, allopurinol, allylestrenol, allylprodine, almecillin, alm as the hydrochloride Salt and especially as the monohydrate estrone, alminoprofen, almitrine, almokalant, almotriptan, form), lincomycin (particularly as the hydrochloride salt and 30 almoxatone, almurtide, alnespirone, alniditan, alonacic acid, especially in the monohydrate form), menadiol (particularly alonimid, aloracetam, alosetron, alovudine, aloxidone, alox as the sodium diphosphate salt and especially in the hexhy iprin, aloxistatin, alozafone, alpertine, alphameprodine, drate form), neropenam (especially as the trihydrate), meto alphamethadol, alphamethyldopa, alphaprodine, alpidem, clopramide (particularly as the hydrochloride salt and espe alpiropride, alprafenone, alprazolam, alprenolol, cially in the monohydrate form), morphine (particularly as 35 alprenoXime, alprostadil, alrestatin, altanserin, altapizone, the Sulfate salt and especially in the pentahydrate form), alteconazole, althiazide, altinicline, altoqualiine, altrenogast, nafcillin (particularly as the sodium salt and especially in the altretamine, alvemeline, alverine, alvimopan, alvocidib, ama monohydrate form), norepinephrine (particularly as the bitar dinone, amafalone, amanozine, amantadine, amantocillin, trate salt and especially in the monohydrate form), ambamustine, ambasilide, ambazone, ambenonium, ondansetron (particularly as the hydrochloride Salt and espe 40 ambenoxan, ambomycin, ambrisentan, ambroXol, ambruti cially in the dihydrate form), oxacillin (particularly as the cin, ambucaine, ambucetamide, ambuphylline, ambuside, Sodium salt and especially as the monohydrate), oxytetracy ambutonium, amcinafal, amcinafide, amcinonide, amdinocil cline (especially as the dihydrate), piperacillin (especially as lin, amdoxovir, ambucort, amedalin, amelometasone, amelt the monohydrate, Scopolamine (particularly as the hydrobro olide, amelubant, ameSergide, ametantrone, amethocaine, mide Salt and especially as trihydrate), spectinomycin (par 45 amezapine, amezinium, amfenac, amfepentorex, amfetami ticularly as the dihydrochloride and especially as the pentahy nil, amflutizole, amfonelic, amicarbalide, amicloral, amicy drate), Succinylcholine (particularly as the chloride salt), cline, anidantel, amidapsone, amidephrine, amiflamine, ami theophylline (especially as the monohydrate), thiothixene floverine, amifloxacin, amifostine, amiglumide, amikacin, (particularly as the dihydrochloride and especially as the amikhelline, amiloride, amiloxate, aminacrine, amindocate, dihydrate), tubocurarine (particularly as the hydrochloride 50 amineptine, aminoglutethimide, aminohippuric acid, ami salt and especially as the pentahydrate form), moxifloxacin, nolevulinic acid, aminometradine, aminopentamide, ami tacrolimus, itraconazole, argatroban, posaconazole, Vora nophenaZone, aminophylline, aminopromazine, aminop conazole, docetaxel, fludarabine, glatiramer acetate, gemcit terin, aminopyrine, aminoquinol, aminoquinuride, aminorex, abine, irinotecan, epoprostenol, and 7-ethyl-10-hydroxy aminosalicylic acid, aminothiazole, amiodarone, amiperone, camptothecin. 55 amphenazole, amipizone, amiprolose, amiquinsin, amisome A more complete list of compounds, most of which are tradine, amisulprode, amiterol, amithioZone, amitivir, ami pharmaceutical or veterinary, which can be utilized in the traz, amitriptyline, amitriptyinoxide, amixetrine, amlexanox, present invention includes, but is not limited to: abacavir, amlintide, amlodipine, amocarzine, amodiaquine, amol abamectin, abanoquil, abaperidone, abarelix, abecamil, abi anone, amonafide, amoproxan, amopyroquine, amorolfine, raterone, abitesartan, ablukast, abunidazole, acadesine, 60 amoscanate, amosulatol, amotoSalen, amotriphene, amoxap acamprosate, acaprazine, acebrochol, acebutolol, acecainide, ine, amoxecaine, amoxicillin, amoxydramine, amperozide, acecarbromal, aceclidine, aceclofenac, acedapsone, acedia anphechloral, amphenidone, amphetamine, amphomycin, Sulfone, acedoben, acefluranol, acefurtiamine, acefylline amphotalide, amphotericin, amplicillin, ampiroxicam, clofibrol, acefylline piperazine, aceglatone, aceglutaminde, amprenavir, amprolium, ampyrimine, ampyZine, amduinate, acemetacin, aceneuramicacid, acenocoumarol, acepeprone, 65 amrubicin, amsacrine. amtolimetin, amustaline, amylobar acepromazine, aceprometazine, acequinoline, acesulfame, bital, angestone, anagrelide, anakinra, anaritide, anastrozole, acetaminosalol, acetanilide, acetarSone, acetaminophen, anatibant, anaxirone, anazocine, anazolene, ancarolol, ancit US 8,158,152 B2 10 abine, andolast, androstenediol, androstenedione, andulafun Zocaine, benzoclidine, benzoctamine, benzodepa, gin, anecortave, anetholtrithion, angiotensin amide, andidox benzododecinium, benzonatate, benzopyrronium, benzo amine, anidulafungin, anilamate, anilleridine, anilopam, quinonium, benzotript, benzoxiquine, benzoxonium, ben anipamil, aniracetam, anirolate, anisacril, anisindione, Zoylpas, benzphetamine, benzpiperylon, benzpyrinium, ben anisopirol, anisotropine, anisperimus, anitraZafen, anpirto Zquercin, benzquinamide, benzthiazide, benztropine, line, ansoxetine, antafenite, antazoline, antazonite, anthelmy benzydamine, benzylhydrochlorothiazide, benzylpenicillin, cin, anthralin, anthramycin, antipyrine, antrafenine, apado benzylsulfamide, bepafant, beperidium, bephenium, bepias line, apafant, apalcillin, apaxafylline, apaziquone, apaZone, tine, bepridil, beractant, beraprost, berberine, berefrine, ber apicycline, aplindore, apomorphine, apovincamine, apra genin, berlafenone, bermoprofen, bertosamil, berupipam, clonidine, apramycin, aprepitant, aprakalim, aprindine, 10 bervastatin, berythromycin, besigomsin, besipirdine, beson aprinocarsine, apofene, aprosulate, aptazapine, aptiganel, prodil, besulpamide, besunide, beta carotene, betacetylmeth aptocaine, aranidipine, aranotin, arbaprosil, arbekacin, arb adol, betahistine, betaine, betameprodine, betamethadol, utamine, arclofenin, ardacin, ardeparin, arecoline, arfalasin, betamethasone, betamicin, betamipron, betaprodine, betax arfendazam, arformoterol, argatroban, argimeSna, argipres olol, betazole, bethanacol, bethanidine, betiatide, betox sin, argiprestocin, arlidone, arimoclomol, aripiprazole, 15 ycaine, bevantolol, bevonium, beXarotene, bexlosteride, armodafinil, arnolol, arofylline, artinolol, arprinocid, arpro bezafibrate, beztiramide, bialamicol, biapenem, bibeZonium, midine, arsanilic acid, arteflene, artemether, artemisinin, arte bibrocathol, bilcalutamide, bici fadine, bicoldil, biclofibrate, motil, artenimol, artesunate, articaine, artilide, arundic acid, biclotymol, bicoZamycin, bidimazium, bidisomide, arZoxifene, ascorbic acid, arsenapine, aseripide, asimadoline, bietamiverine, bietaserpine, bifemelane, bifepramide, asobamast, asocainol, asoprisnil, aspartame, aspartocin, bifeprofen, bifeprunox, bifluranol, bifonazole, bilastine, asperlin, aspirin, aspoxicillin, astemizole, astromicin, asula bimakalim, bimatoprost, bimoclomol, bimosiamose, bin crine, atameStane, ataprost, ataquimast, atavanavir, atenolol. darit, binedaline, binfloxacin, binfibrate, biniramycin, bini atevirdine, atibeprone, atilmotin, atipamezole, atipromod, Zolast, binodenosine, binospirone, bioallethrin, botin, bipen atiprosin, atizoram, atliprofen, atocalcitol, atolide, atomoxet amol, biperiden, biphenamine, biricodar, biriperone, ine, atorvastatin, atosiban, atovaquone, atracurium, atrasen 25 bisacodyl, bisantrene, bisaramil, bisbendazole, bisben tan, atraleuton, atrimustine, atrinositol, atromepane, atropine, tiamine, bisbutiamine, bisdequilinium, bisfenaZone, bisfenti atropine oxide, auranofin, aurothioglucose, avanafil, ava dine, bisnafide, bisorbin, bisoctriazole, bisoprolol, bisorcic, simibe, avicatonin, avalamycin, aviptadil, avitriptan, bisoxatin, bispyrithione, bithonol, bithionoloxide, butipa avizafone, avobenzone, azoparcin, avorelin, avridine, axam Zone, bitolterol, bitoscanate, bivalirudin, bizelesin, bleomy ozide, axitirome, axomadol, azabon, azabuperone, azaciti 30 cin, blonanserine, bluenSomycin, bofumustine, bolandiol. dine, azacitidine, azaclorzine, azaconazole, azacoSrterol, aza bolasterone, bolazine, boldenone, bolenol, bolmantalate, cyclonol, aZaftoZine, azalanstat, azalomycin, azaloxan, bometolol, bopindolol, bornaprine, bornaprolol, borelone, aZamethiphos, azamethonium, azamulin, azanator, azanida borocaptaine, bortezomib, bosentan, botiacrine, boxidine, Zole, azaperone, azapetine, azaquinzole, azaribine, azarole, brallobarbital, brasofensine, brazergoline, brefonalol, brema aZaserine, aZasetron, azaspirium, azastene, azatadine, aza 35 Zocine, brequinar, bretazenil, bretyllium, brifentanil, bri thioprine, azelaic acid, azelastine, aZelinnidipine, azepexole, monidine, brinaZaprone, brindoXime, brinzolamide, brivu azepindole, azetepa, aZetirelin, azidamfenicol, azidocillin, dine, brobactam, broclepride, brocrestine, brocrinat, azimexon, azimilide, azintamide, azipramide, azithromycin, brodimoprim, brofaromine, brofoxine, brolaconazole, brola aZlocillin, azlocillin, azolimine, azosemide, aztomycin, mfetamine, bromadoline, bromamid, bromazepam, bro aztreonam, aZumolene, bacampicillin, bacitracin, baclofen, 40 mchlorenone, bromebric acid, bromerguride, bromete bacmecillinam, bakeprofen, balaglitaZone, balaZipone, balo namine, bromfenac, brom hexene, bomindione, floxacin, balsalazide, bamaluzole, bamaquimast, bambermy bromisovalum, bromociclen, bromocriptine, bromodiphe cin, bambuterol, bamethan, bamifylline, bamipine, bamiras nylhydramine, bromofenfos, bromofos, bromopride, bro tine, bamidazole, banoxantrone, baduiloprim, barbexaclone, moxanide, bromperidol, brompheniramine, broparestrol, barbital, barixibat, barmastine, barnidipine, barucainide, 45 broperamol, bropirimine, broquinaldol, broSotaminde, bros barusiban, basifungin, batalbulin, batanopride, batebulast, tallicin, broSuximide, brotianide, brotizolam, brovanexine, batelapine, batilol, batimastat, batoprozine, baxitoizine, brovincamine, broxaldine, broXaterol, broxitalamide, broXu baZedoxifene, bazinaprine, becanthone, becatecarin, beclipar ridine, broxyquinoline, bucainide, bucetin, buciclovir, bucil cil, beclamide, becliconazole, beclobrate, beclomethasone, lamine, bucindolol, bucladesine, buclizine, buclosaminde, beclotiamine, befetupitant, befiperide, befloxatone, 50 bucloxic acid, bucolme, bucricaine, bucromarone, bucu befunolol, befuraline, bekanamycin, belaperidone, belariz molol, budesonide, budipine, budotitane, budralazine, ine, belfosdil, belotecan, beloxamide, beloxepin, bemar bufenadrine, bufeniode, bufetolol, bufexamac, bufezolac, inone, bemegride, bemesetron, bemetizide, beminafil, bemi buflomedil, bufogentin, buformin, bufrolin, bufuralol, bufyl parin, bemetradine, bemoradan, bemotrizinol, benactyzine, line, bullaquine, bumadizone, bumecaine, bumepidil, bumet benafentrine, benapry Zine, benaxibine, benazepril, ben 55 anide, bumetriazole, bunaftine, bunamidine, bunamiodyl, cianol, bencisteine, benclonidine, bencyclane, bendacalol, bunaprolast, bunaZosin, bunitrolol, bunolol, buparvaquone, bendamustine, bendazac, bendazol, benderizine, bendroflu bupicomide, bupivacaine, bupranolol, buprenorphine, bupro methazide, benethamine penicillin, benexate, benfluorex, pion, buquinerin, buquinolate, buquiterine, buramate, benfosformin, benfotiamine, benflurodil, benhepazone, beni burodiline, buserelin, buspirone, busulfan, butobarbital, dipine, benmoxin, benolizime, benorilate, benorterone, 60 butacaine, butacetin, butaclamol, butadiaZamide, butafosfan, benoxifos, benoxaprofen, benoximate, benpenolisin, benperi butalamine, butalbital, butamben, butamirate, butamisole, dol, benproperine, benrixate, bensalan, benserazide, bensul butamoxane, butanilicaine, butanserin, butantrone, butapera dazic acid, bentazepam, bentemazole, bentiamine, bentipi zine, butaprost, butaverine, butedronate, bytenafine, buteriz mine, bentiromide, bentoquatam, benurestat, benzalkonium, ine, butenamate, buthiazide, butibufen, butifrine, butikacin, benzarone, benzbromarone, benzestrol, benzethidine, benze 65 butilfenin, butinazocine, butinoline, butirosin, butixirate, thonium, benzetimide, benzilonium, benZindopyrine, ben butixocort, butobendine, butoconazole, butocrolol, butocta Ziodarone, benzmalecene, benznidazole, benzobarbital, ben mide, butofiolol, butonate, butopamine, butopiprine, buto US 8,158,152 B2 11 12 prozine, butopyrammonium, butorphanol, butoxamine, terol, choline alfoscerate, choline, chromic chloride, chromo butoxylate, butriptyline, butropium, butylscopolamine, nar, ciadox, ciaftalan, ciamexon, cianergoline, cianidanol, butynamine, buZepide, cabastine, cabergoline, cactinomycin, cianopramine, ciapilome, cicaprost, cicarperone, ciclactate, cadralazine, cadrofloxacin, cafaminol, cafedrine, caffeine, ciclafrine, ciclazindol, ciclesonide, cleletanine, cicliomenol, calcifediol, calciprotriene, calcitriol, calcobutrol, caldaret, ciclonicate, ciclonium, ciclopiroX, ciclopramine, ciclopro caldiamine, caloxetic acid, calteridol, clausterone, fen, cicloprolol, ciclosidomine, ciclotizolam, ciclotropium, camazepam, cambendazole, camaglibose, camiverine, camp cicloxilic acid, cicloxolone, cicortonide, cidofovir, cidox tothecin and its analogues such as 9-amino camptothecin, epin, cifenline, cifostodine, ciglitaZone, ciheptolane, cila 10-hydroxy camptothecin, 7-ethyl-10-hydroxy camptoth dopa, cilansertron, cilastatin, cilaZapril, cilengitide, cilexin, ecin, 9-nitro camptothecin and all other camptothecin ana 10 cilnidipine, cilobamine, cilobradine, cillofungin, cilomilast, logues with six, seven and eight membered lactone rings, cilostamide, cilostazol, ciluprevir, cilutazoline, cimaterol, camonagrel, camo.stat, camylofin, canbisol, candesartan, can cimemoxin, cimetidine, cimetropium, cimicoxib, dicidin, candocuronium, candoXatril, candoXatrilat, caner cimoxatone, cinacalcet, cinalukast, cinametic acid, tinib, canfosfaminde, cangrelor, cannabinol, canrenoate, can cinamolol, cinanserin, cinaproxen, cinchophen, cinecromen, renone, capectitabine, capobenate, capobenic acid, 15 cinepazet, cinepazide, cinfenine, cinfenoac, cinflumide, capravirine, capreomycin, capromorelin, caproxamine, cap cingestol, cinitapride, cinmetacin, cinnamaverine, cinnamed saicin, captamine, captodiame, captopril, capuride, caraber rine, cinnarizine, cinnofuradione, cinoctramide, cinodine, sat, caracemide, carafiban, caramiphen, carbachol, carbadox, cinolazepam, cinoquidox, cinoxacin, cinoxate, cinoXolone, carbamazepine, carbentel, carbasone, carbaspirin, carbaz cinoXopazide, cinperene, cinprazole, cinpropazide, cinprom eran, carbazochrome, carbazocine, cabenicillin, carbenox ide, cintaZone, cintriamide, cinuperone, cioteronel, cipamfyl olone, carbenzide, carbetapentane, carbetocin, carbidopa, line, cipemastat, ciprafamide, cipralisant, cipraZafone, carbimazole, carbinoxamine, carbiphene, carbofenotion, car ciprefadol, ciprocinonide, ciprofibrate, ciprofloxacin, boplatin, carboprost, carboquone, carbubarb, carburazepam, ciprokiren, cipropride, ciprocquaZone, ciprestene, ciramadol, carbutamide, carbuterol, carcainium, carebastine, carfenta cirazoline, cirolemycin, cisapride, cisatracurium, cincona nil, carfimate, cargutocin, cariporide, carisoprodol, carman 25 Zole, cismadinone, cisplatin, cistinexine, citalopram, tadine, carmofur, carmoterol, carmustine, carnidazole, car citatepine, citenamide, citenaZone, citicoline, citiolone, ciZo nitine, carocainide, caroverine, caroXaZone, carperidine, lirtine, cladribine, clamidoxic acid, clamikalant, clamox carperitide, carperone, carphenazine, carpindolol. ycuin, clanfenur, clanobutin, clantifen, clarithromycin, cla carpipramine, carpraZidil, carprofen, capronium, carsalam, Vulanate, claZolam, claZolimine, claZuril, clebopride, carsatirin, cartasteine, cartazolate, carteolol, carubicin, caru 30 clefamide, clemastine, clemeprol, clemizole, clenbuterol, monam, carvedilol, carvotroline, carZelesin, carZenide, cas clenpirin, clentiazem, cletoquine, clevidipine, clevudine, anthranol, casokefaminde, caspofungin, cathine, cathinone, clibucaine, clidafidine, clidanac, clindium, climazolam, cebaracetam, cedefingol, cefaclor, cefadroxil, cefalonium, climbazole, climiqualine, clinafloxacin, clindamycin, cli cefaloram, cefamandole, cefaparole, cefatriazine, cefazaflur, nofibrate, clinolamide, climprost, clioquinol, clioxanide, clip cefazedone, cefazolin, cefbuperaZone, cefanel, cefcapene, 35 rofen, cliropamine, clobazam, clobenoside, clobenzepam, cefclidin, cefdaloxime, cefdinir, cefditoren, cefedrolor, clobenorex, clobenztropine, clobetasol, clobetasone, clobuti cefempidone, cefepime, cefetamet, cefetecol, cefetriaole, nol, clobuZarit, clocanfamide, clocapramine, clociguanil, cefivtril, cefixime, cefimatilen, cefimenoxine, cefimepidium, clocinizine, clocortolone, clocoumarol, clodacaine, cefnetazole, ceminox, cefodizime, cefonicid, cefoperaZone, clodanolene, clodazon, clodoxopone, clodronate, clofara ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, 40 bine, clofazimine, clofenamic acid, clofeniclan, clofen cefoVecin, cefoxazole, cofoxitin, cefoZopran, cefpimizole, etamine, clofenoxyde, clofevine, clofexamine, clofeZone, cefpiramide, cefpodoxime, cefprozil, cefauinome, cefrotil, clofibrate, clofibric acid, clofibride, clofilium, clofucarba, cefroxadine, cefsulodin, cefsumide, ceftazidime, cefteram, clofoctol, cloforex, clofurac, clogestone, cloguanamil, clo ceftezole, ceftibuten, ceftioflur, ceftiolene, ceftioxide, ceft macrin, clomegestone, clometacin, clometherone, clomethia ioxime, ceftriaxone, cefuracetamime, cefuroxime, cefu 45 Zole, clometocillin, clomifenoxide, clominorex, clomiphene, Zonam, celecoxib, celgosivir, celiprolol, cemadotin, ceph clomipramine, clomocycline, clomoxir, clonazepam, clona acetrile, cephadrine, cephalexin, cephaloglycin. Zoline, clonidine, clonitazine, clonixeril, clonixin, clopam Cephaloridine, cephalothin, cephapirin, cepharanthine, ceph ide, clopenthixol, cloperastine, cloperidone, clopidogrel, clo radine, cericlamine, cerivastatin, ceronapril, ceruletide, ceta pidol, clopimozide, clopipazan, clopirac, cloponone, ben, cetalkonium, cetamolol, cetefloxacin, cethexonium, 50 cloprendol, cloprostenol, cloprothiazole, cloquinate, clo cethromycin, cetiedil, cetilistat, cetirizine, cetocycline, quinozine, cloracetadol, cloranolol, cloraZepate, cloraZepic cetopheincol, cetotiamine, cetoxime, cetraxate, cetrimo acid, clorethane, chlorexolone, clorfenvinos, clorgiline, clo nium, cetylpyridinium, cevimeline, chaulmosulfone, cheno ricromen, cloridarol, clorindanic acid, clorindione, clo diol, chinofon, chlofibrate, chlophendianol, chloracy Zine, rmecaine, cloroperone, clorophene, cloroqualone, clo chloralose, chlorambusil, chloramines-T, chloramphenicol, 55 rotepine, clorprenaline, clorSulon, clortermine, closantel, chlorazanil, chlorbenoxamine, chlorbetamide, chlorcycliz closiramine, clostebol, clothiapine, clothixamide, clotiaz ine, chlordantoin, chlordiazepoxide, chlordimorine, chlo epam, cloticaSone, clotioxone, clotixamide, clotrimazole, rhexidine, chlorindanol, chlorisondamine, chloramadione, clovoxamine, cloxacepride, cloxacillin, cloxazolam, clox chlormerodrin, chlormeZanone, chlormidazole, chlornaphaz estradiol, cloximate, cloXotestosterone, cloxypendyl, clox ine, chloroaZodin, chloroprednisone, chloroprocaine, chloro 60 ycuin, clozapine, cobalamide, cocaine, codeine, codoxime, pyramine, chloroquine, chloroserpidine, chlorothen, chlo cofistatin, cogaZocine, colchicines, colestolone, colfenamate, rothiazide, chlorotrianisene, chloroxine, chloroxylenol, colforsin, colfosceril, colimecycline, colterol, coluracetam, chlorphenesin, chlorpheniramine, chlorphenoctium, chlor conessine, congaZone, conivaptan, conorphone, cormetha phenoxamine, chlorphentermine, chlorproethazine, chlor Sone, corticorelin, cortisone, cortisuZol, cortivaZol, cortodox proguanil, chlorpromazine, chlorpropamide, chlorprothix 65 one, cotinine, cotriptyline, coumaphos, coumazolin, coumer ene, chlorpyrifos, chlortetracycline, chlorthalidone, mycin, coumetarol, creatinine, creatinolfosfate, cresotamide, chlorthenoxazine, chlorZoxazone, cholecalciferol, choles cridanimod, crilvastin, crisinatol, crobenetine, croconazole, US 8,158,152 B2 13 14 cromakalim, cromitrile, cromoglicate lisetil, cromolyn, cro dibenzothiophene, dibrompropamidine, bibromsalan, lom, cronidipine, cropropamide, crotamiton, crotetamide, dibrospidium, dibucaine, dibuprol, dibupyrone, dibusadol, crotoniazide, crotoxyfos, crufomate, cuprimyxin, cuproXo dicarbine, dicarfen, dichloralphenaZone, dichloramine, line, cyacetacide, cyamemazine, cyanocobalamine, cyclacil dichlorisone, dichlormeZanone, dichlorophen, dichlorphe lin, cyclamate, cyclamic acid, cyclandelate, cyclarbamate, narsine, dichloroxylenol, dichlorphenamide, dichlovos, dici cyclazocine, cyclazodone, cyclexanone, cyclindole, cyc ferron, dicirenone, diclaZuril, diclofenac, diclofenamide, liramine, cyclizine, cyclobarbital, cyclobendazole, cycloben diclofensine, diclofutrime, diclometide, diclonixin, diclo Zaprine, cyclobutoic acid, cyclobutyrol, cyclocumarol, ralurea, dicloxacillin, diclolinium, dicumrol, dicyclomine, cyclofenil, cycloguanil, cycloheximide, cyclomenol, cyclom didanosine, didrovaltrate, dieldrin, dienestrol, dienogest, ethycaine, cyclopentamine, cyclopenthiazide, cyclopento 10 diethadione, diethylphthalate, diethylcarbamazine, dietyl late, cyclophenazine, cyclophosphamide, cyclopregnol, propion, diethylstilbestrol, dethylthambutene, dietyltolua cyclopyrronium, cycloserine, cyclothiazide, cyclovalone, mide, dietifen, difebarbamate, difemerine, difemetorex, dife cycotiamine, cycrimine, cyfluthrin, cyhalothrin, cyhepta namizole, difencloxazine, difenoximide, difenoxin, mide, cyheptropine, cynarine, cypenamine, cypermethrin, difetarsone, difeterol, diflomotecan, diflorasone, difloxacin, cypothrin, cyprazepam, cyprenorphine, cyprodenate, cypro 15 difluanine, diflucortolone, diflumidone, diflunisal, diflupred heptadine, cyprolidol, cyproduinate, cyproterone, cyproxim nate, diftalone, digitalis, digitoxin, digoxin, dihexyverine, ide, cyromazine, cysteamine, cysteine, cystine, cytarabine, dihydralazine, dihydrocodeine, dihydroergotamine, dihy cythiolate, dabelotine, dabigatran, dabu Zalgron, dacarbazine, drostreptomycin, dihydrotachysterol, diisobutylaminoben dacemazine, dacinostat, dacisteine, dacopafant, dactinomy Zoyloxypropyl theophylline, diisopromine, diisopropanola cin, dacuronium, dagapamil, dagluril, dalbavancin, dalbrami mine, diisopropylamine, dilaZep, dilevalol, dilimefone, nol, dalcotidine, daledalin, dalfopristin, dalteparin, dal diloxanide, diltiazem, dimabefylline, dimadectin, dimecam troban, dalvastatin, dametralast, damotepine, danazol. ine, dimeclonium, dimecrotic acid, dimefadane, dimefline, daniquidone, danittracen, danofloxacin, danosteine, dan dimelazine, dimenhydrinate, dimenoxadol, dimepheptanol, thron, dantrolene, dapiprazole, dapitant, dapivirine, dapoxet dimepranol, dimepregnen, dimepropion, dimeproZan, dime ine, dapsone, daptomycin, darbufelone, darenzepine, dargli 25 Sna, dimesone, dimetacrine, dimetamfetamine, dimethadi taZone, darifenacin, darodipine, darunavir, darusentan, one, dimethazan, dimethisoquin, dimethisterone, dimetholiz dasantafil, datelliptium, daunorubicin, daxalipram, daZadrol, ine, dimethothizine, dimethoxanate, dimethylaminoethyl dazepinil, daZidamine, daZmegrel, dazolicine, dazopride, reserpilinate, dimethylthambutene, dimethyltubocurarinium, daZoquinast, daZOXiben, deboxament, debrisoquin, decame dimetipirium, dimetofrine, dimetridazole, diminaZene, thonium, decimemide, decitabine, decitropine, declenper 30 dimiracetam, dimoxamine, dimoxaprost, dimoxyline, one, declopramide, decloxizine, decominol, decoquinate, dimpylate, dinaline, dinaZafone, diniprofylline, dinitolmide, dectaflur, deditonium, deferasirox, deferiprone, deferoxam dinoprost, dinoprostone, dinsed, diohippuric acid, diosmin, ine, deflazacort, defosfamine, defoslimod, degarelix, dehy diotyrosine, dioxadrol, dioxamate, dioxaphetyl butyrate, droacetic acid, dehydrocholic acid, dehydroemetine, dioxation, dioxethedrin, dioxifedrine, dioxybenazone, dioxy delanterone, delapril, delavirdine, delquamine, deergotrile, 35 line, dipenine, diperodon, diphemanil, diphenadione, delfantrine, delfaprazine, Selmadinone, delmetacin, delimpi diphenan, diphenchloxazine, diphenhydramine, diphenidol. nol, delorazepam, deloXolone, delprostenate, delucemine, diphenoxylate, diphenylpiperidinomethyldioxolan, diphe dembrexine, demecarium, demeclocycline, demecolcine, nylpyraline, diphenoxazide, dipipanone, dipiproverine, demecycline, demegestone, demelverine, demexiptiline, dipivefrin, diprafenone, diprenorphine, diprobutine, dipro democonazole, demoxepam, demoxytocin, denatonium, 40 fene, diprogulic acid, diproleandomycin, diprofylline, dipro denaverine, denbufylline, denipride, denofungin, denopam qualone, diproteverine, diprotrizoate, diproxadol, dipy ine, denotivir, denpidaZone, denufosol, denZimol, depelestat, ridamole, dipyrithione, dipyrocetyl, dipyrone, diduafosol, depramine, depreotide, deprodone, deprostil, deptropine, dirithomycin, dirlotapide, disermolide, disquonium, disob dequalinium, deracoxib, deramciclane, deriglidole, derpan utamide, Sidofenin, Sdisogluside, disopyramide, disoxaril. icaine, derSalazine, desapidin, desciclovir, descinolone, 45 distigmine, disufenton, disulergine, disulfamide, disulfiram, deserpidine, desipramine, deeslanoside, desloratidine, disupraZoole, ditazole, ditekiren, ditercalinium, dithiaanine, deslorelin, desmeninol, desmethylmoramide, desmopressin, ditiocade, ditiocarb, ditiomustane, ditolamide, ditophal, div desocriptine, desogestrel, desmorphine, desonide, des abuterol, divalproex, divaplon, dixanthogen, dizatrifone, Oximetasone, desoxycorticosterone, desvenlafaxine, detaj dizcilpine, dobesilate, dobupride, dobutamide, dobutamine, mium, detanosal, deterenol, detirelix, detiviciclovir, detromi 50 docarpamine, docebenone, docetaxel, doconazole, doconex dine, detorubicin, detrothyronine, devapamil, devaZepide, ent, docosanol, docusate, dodeclonium, dodicin, dofamium, dexamethasone, dexamisole, dexbrompheniramine, dex dofecquidar, dolfetilide, dolasetron, doliracetam, domaZoline, budesonide, dexchlorpheniramine, dexclamol, dexecadotril, domiodol, domiphen, domipizone, domitroban, domopred dexefaroxan, dexetimide, dexetoZoline, dexfenfluramine, nate, domoxin, domperidone, donepezil, donetidine, doni dexfosfoserine, dexibuprofen, deximafen, dexindoprofen, 55 triptan, dopamantine, dopamine, dopexamine, dopropidil, dexivacaine, dexketoprofen, dexlofexidine, dexloxiglumide, doqualast, dorampimod, doramectin, doranidazole, doras dexmedetomidine, dexmethylphenidate, dexnafenodonee, tine, Soreptide, doretinel, doripenem, dorZolamide. dosergo dexniguldipine, dexnorgestrel, dexormaplatin, dexoxadrol, side, doSmalfate, dotarizine, dotefonium, dothiepin, doxacu dexpanthenol, dexpemedolac, dexpropranolol, dex.proxib rium, doxapram, doxaprost, doxazosin, doxefazepam, utene, dexraZoxane, dexsecoverine, dexSotalol, dextilidine, 60 doxenitoin, doxepine, doxergocalciferol, doxibetasol, doxi dextiopronin, dextofisopam, dextroamphetamine, dextro fluridine, doxofylline, doxorubicin, doxpicomine, doxycy femine, dextromethorphan, dextromoramide, dextrorphan, cline, doxylamine, draflazine, dramedilol, draquinolo, drazi dextrothyroxine, dexcerapimil, Sezaguanine, dezinamide, dox, dribendazolew, drimidene, drobuline, drocinonide, dezocine, diacerein, diacetamate, diacetolol, diamfenetide, droclidinium, drofenine, droloxifene, drometrizole, dromo diamocaine, diampromide, diamthiazole, diapamide, diar 65 stanolone, dronabinol, drinedarone, dropempine, droperidol. barone, diathymosulfone, diatrizoate, diaveridine, diazepam, droprenilamine, dropropizine, drospirenone, drotaverine, diaziquone, diaZOxide, dibekacin, dibemethine, dibenzepin, drotebanol, droxacin, droXicainide, droxicam, droxidopa, US 8,158,152 B2 15 16 droximavir, droxypropine, duaZomycin, dulofibrate, dulloxet Zole, etisomicin, etisulergine, etizolam, etocarlide, etoc ine, duloZafone, dumorelin, dumetacin, duoperone, duprac rylene, etodolac, etodroxizine, etofamide, etofenamate, etam, dutasteride, dyclonine, dyhydrogestrone, dymanthine, etofemprox, etofibrate, etofermin, etofuradine, etofylline, eto dyphylline, ebalZotan, ebastine, eberconazole, ebiratide, glucid, eorolex, etolotifen, etoloxamine, etomidate, etomido ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecalcidene, line, etomoxir, etomitaZene, etonogestrel, etoperidone, eto ecamsule, ecastolol, ecenofloxacin, echothiophate, eciprami poside, etoprindole, etoprine, etoricoxib, etorphine, dil, eclanamine, eclaZolast, ecomustine, econazole, ecopi etosalamide, etoxadrol, etoxeridine, etoZolin, etrabamine, pam, ecraprost, ectylurea, edaglitaZone, edaravone, edatrex etravirine, etretinate, etriciguat, etryptamine, etymemazine, ate, edelfosine, edetol, edifolone, edogestrone, edonentan, eucaine, eucalyptol, eugenol, euprocin, evandamine, evern edotecarin, edotreotide, edoxudine, edratide, edronocaine, 10 imicin, everolimus, evicromil, exalamide, exametazime, edrophonium, efaproxiral, efaroxan, efavirenz, efegatran, examorelin, exaprolol, exatecan, exemestane, exepanol, exi efepristin, efetozole, efletirizine, eflornithine, efloxate, eflu fone, exiprofen, exisulind, eZetimibe, eZlopitant, fadolmi cimibe, elfiumast, efonidipine, efrotomycin, eganoprost, dine, fadrozole, falecalcitriol, fallintolol, falipamil, eglumetad, egtazic acid, equalen, elacridar, elantrine, elan falnidamol, famciclovir, famirapinium, famotidine, famo Zepine, elaarofiban, elbanizine, eldacimibe, eletriptan, elf 15 tine, fampridine, famprofaZone, fampronil, fananserin, azepam, elgotipine, elinafide, eliprodil, elisartan, ellagic acid, fanapanel, fandofloxacin, fandoSentan, fanetizole, fantofar elliptinium, elmustine, elnadipine, elopiprazole, elsamitru one, fantridone, fargilitazar, fasidotril, fasiplon, fasoracetam, cin, eltanolone, eltenac, eltoprazine, elucaine, elvucitabine, faudil, fazadinium, fazarabine, febantel, febarbamate, febu elzasonan, elziverine, emakalim, emapunil, embramine, prol, febuverine, febuxostat, feclemine, feclobuzone, fedot embusartan, embutramide, emedastine, emepronium, emet ozine, fedrilate, felbamate, felbinac, felipyrine, felodipine, ine, emeglitate, emilium, emiteflur, emiverine, emodepside, feloprentan, fely pressin, femoxetine, fenabutene, fenace emopamil, emorfaZone, emitricitabine, emylcamate, enado tinol, fenaclon, fenadiazole, fenaftic acid, femalamide, femal line, enalapril, enalaprilat, enalkiren, enaZadrem, enbucrilate, comine, fenamifuril, fenamole, fenaperone, fenbendazole, encainide, enciprazine, enclomiphene, encyprate, endix fenbenicillin, fenbufen, fenbutreazate, fencamfamin, fenci aprine, endomide, endralazine, endrysone, enecadin, enefex 25 butirol, fencleXonium, fleclofenac, fenclonine, fenclorac, ine, enestebol, enfenamic acid, enfluvirtide, englitaZone, eni fenclozic acid, fendiline, fendizoate, fendosal, feneritrol, clobrate, enilconazole, eniloSpirone, eniluracil, eniporide, fenestrel, fenethazine, fenethylline, fenetradil, fenflumizole, enisoprost, enloplatin, enocitabine, enofelast, enolicam, fenfluramine, flenfluthrin, fengabine, fenharmane, fenimide, enoxacin, enoxamast, enoxaparin, enoXimone, enoXolone, feniodium, fenipentol, fenirfibrate, fenisorex, fenitrothion, enipiprazole, empiroline, enprazepine, enprofylline, enpro 30 fenleuton, fenmetoZole, fenmetraminde, fenobam, fenocinol, mate, enprostil, enramycin, enrasentan, enrofloxacin, fenocitimine, fenofibrate, fenoldopam, fenoprofen, fenot ensacillin, ensulizole, entacapone, entecavir, entSufon, envio erol, fenoerine, fenoxazoline, fenoxedil, fenozolone, fenpen mycin, enviradene, enviroxime, enZacamene, anZastaurin, tadiol, femperate, fenprpalone, fenpipramide, fenpiprane, fen epalrestat, epanolol, eperezolid, eperisone, eperVudine, ephe piverinium, fenprinast, fenproporex, fenprostalene, drine, epicainide, epicillin, epicriptine, epiestriol, epimestrol, 35 fenduiaone, fenretinide, fenspiride, fentanyl, fenthion, fen epinastine, epinephrine, epinepheryl, epipropidine, epirizole, tiazac, fenticlor, fenticonazolem, fentonium, fenvalerate, apiroprim, epirubicin, epitetracycline, epithiazide, epi fenyripol, fepentolic acid, fepitrizol, fepradinol, feprazone, tiostanol, eplerenone, elivanserin, epoprostenol, epostane, fepromide, feprosidnine, ferpifosate, fesoterodine, fetoxy eprazinone, eprinomectin, epristeride, eprobemide, eprosar late, fexicaine, fexinidazole, fexofenadine, fezatione, fezola tan, eprovafen, eproXindine, eprozinol, epsipranel, epalo 40 mine, fiacitabine, fialuridine, fibracillin, fidarestat, fidexaban, prost, eptapirone, eptaplatin, eptastigmine, eptazocin, eptifi fiduXosin, figopitant, filaminast, filenadol, filipin, finafloxa batide, equillin, erbulozole, erdosteine, ergocalciferol, cin, finasteride, fingolimod, fipamezole, fipexide, fipronil. ergonovine, ergotamine, eritoran, erizepine, erlotinib, ercain firocoxib, flavamine, flavodic acid, flavodilol, flavoxate, ide, ersentilide, ertapenem, ertiprotafib, erythrity tetrnitrate, flazalone, flecainide, flerobuterol, fleroxacin, flesinoxan, erythromycin, esafloxacin, esaprazole, esatenolol, escitalo 45 flestolol, fletazepam, flezelastine, flibanserin, flindokalner, pram, esculamine, eseridine, esflurbiprofen, esketamine, flocalcitriol, floctafenine, flomoxe?, floptopione, floranty escarbazepine, esmolol, esomeprazole, esonarimod, esorubi rone, flordipine, floredil, florfenicol, florifenine, flosatidil, cin, esoxybutynin, espatropate, esproquin, estazolam, estra flosequinan, flosulide, flotrenizine, floverine, floxacillin, diol, estramustine, estraZinol, estriol, estrofurate, estrone, floxacrine, floXuridine, flucizine, fluialamine, fluianisone, flu estropipaten esupone, esZopclone, etabenzarone, etacepride, 50 azacort, fluaZuron, flubanilate, flubendazole, flubepride, flu etafedrine, etafenone, etalocib, etamestrol, etaminile, etami carbril, flucetorex, flucindole, flucinprazine, flucloronide, phylline, etamocycline, etanidazole, etanterol, etaqualone, fluconazole, flucrylate, flucytosine, fludalanine, fludarabine, etarotene, etasuline, etazepine, etazolate, etebenecid, eter fludazonium, fludeoxyglucose, fludiazepam, fluidorex, flu obarb, etersalate, ethacridine, ethacrynic acid, ehtambutol, doxopone, fludrocortisone, flufenamic acid, flufenisal, flu ethamivan, ethamsylate, ethaverine, ethenZameide, ethiazide, 55 fosal, flufylline, flugestone, fluindarol, fluindione, flumaze ethinamate, ethinyl estradiol, ethionamide, ethisterone, etho nil, flimecinol, flumedroxone, flumequine, flumeridone, heptazine, ethomoxane, ethonam, ethopabate, ethopro flumethasone, flumethiazole, flumetramide, flumexadol, pazine, ethoSuximide, ethotoin, ethoxazene, ethoxazoruto flumeZapine, fluminorex, flumizole, flumoxonide, flunamine, side, ethoXZolamide, ethybenztropine, ethyl biscoumacetate, flunarizine, flunidazole, flunisolide, flunitrazepam, flunixin, ethyl carfluzepate, ethyl cartrizoate, ethyl dibunate, ethyl 60 flunoprost, flunoxaprofen, fluocinolone, fluocinonide, fluo dirazepate, ethyl loflazepate, ethylestrenol, ethylhydrocu cortin butyl, fluocortolone, fluorescein, fluoresone, fluoro preine, ethylmethylthiambutene, ethylmorphine, ethylnore dopa, fluorometholone, fluorosalan, fluorouracil, fluotracen, pinepherine, ethylstilbamine, ethylnerone, ethylnodil, fluoxetine, fluoxymesterone, fluparoxan, flupentiXol, flu ethypicone, etibendazole, eticlopride, eticyclidine, eti peramide, fluperlapine, fluperolone, flupheazine, flupi docaine, etidronate, etidronic acid, etifelmine, etifenin, eti 65 mazine, flupirtine, flupranone, fluprazine, fluprednidene, flu foXine, etilamfetamine, etillefrine, etilevodopa, etinidine, prednisolone, fluprofen, fluprofylline, fluproduaZone, etipirium, etiprendol, etiproston, etiracetam, etiroXate, etisa fluprostenol, fluquaZone, fluradoline, flurandrenolide, fluran US 8,158,152 B2 17 18 tel, flurazepam, flurbiprofen, fluretofen, flurithromycin, hexaprofen, hexapropymate, hexasonium, hexazole, hexe flurocitabine, flurofamide, flurogestone, flusoxolol, fluspip dine, hexestrol, hexetidine, hexobarbital, hexobendine, hexo erone, fluspirilene, flutamide, flutazolam, flutemazepam, flu cyclium, hexoprenaline, hexopyrronium, heylcaine, hista tiazin, fluticasone, flutizenol, flutomidate, flutonidine, fluto mine, histapyrrodine, histidine, homarylamine, homatropine, prazepam, flutrimazole, flutroline, flutropium, fluvastatin, homidium, homochlorcyclizine, homofenazine, fluvoxamine, fluzinamide, fluZoperine, fodipir, folic acid, homopipramol, homosalate, homprenorphine, hopantenic fomepizole, fomidacillin, fominoben, fomiversen, acid, hoquizil, hycanthone, hydracarbazine, hydralazine, fomocaine, fonazine, fondaparinux, fopiirtoline, forasartan, hydragaphen, hydrobentizide, hydrochlorothiazide, hydroc forfenimex, formebolone, formestane, formetorex, formini odone, hydrocortisone, hydroflumethiazide, hydromadinone, trazole, formocortal, formoterol, forodesine, foropafant, fos 10 hydromorphinol, hydromorphone, hydroquinone, hydroxy amprenavir, fosarilate, fosazepam, foSenazide, fosflucona indasate, hydroxyindasol, hydroxocobalamin, hydroxyam Zole, foSfocreatinine, fosfomycin, foSfonet, fosfosal, phetamine, hydroxychloroquin, hydroxydione, hydroxy fosfructose, fosinopril, fosinoprilat, foSmenic acid, fosmido pethidine, hydroxyphenamate, hydroxyprocaine, mycin, fosopamine, fosphenyloin, fospirate, fosquidone, hydroxyprogesterone, hydroxypyridine tartrate, hydroxys fostedil, foSrtriecin, fosveset, fotemustine, fortrenamine, 15 tenozole, hydroxyStilbamidine, hydroxytetracaine, hydrox fozivudine, frabuprofen, fradafiban, frakefamide, framycetin, yZine, hymecromone, hyoscyamine, ibafloxacin, ibandr frentizole, freselestat, fronepidil, fropenem, froVatriptan, onate, ibazocine, ibopamine, ibrolipim, ibrotamide, froxiprost, ftaxilide, ftivazide, formetazine, forpropazine, ibudalast, ibufenac, ibuprofen, ibuproxam, ibutamoren, fubrogonium, fudosteine, fuladectin, fulvestrant, fumagillin, ibuterol, ibutilide, ibuverine, icaridin, icatibant, iclaprim, fumoxicillin, fungimycin, fuprazole, furacrinic acid, furafyl icazepam, icodulinium, icofungipen, ifometaSone, icopezil, line, furalazine, furaltadone, furaprofen, furazabol, furazoli icosapent, icospiramide, icotidine, icrocaptide, idarubicin, done, furazolium, furbicillin, furcloprofen, furegrelate, fure idaverine, idazoxan, idebenone, idenast, idoxifene, idoxuri thidine, furfenorex, furidarone, furmethoxadone, furnidipine, dine, idralfidine, idramantone, idraparinux, idrapril, idiremci furobufen, furodazole, furofenac, furomazine, furomine, nal, idrociliamide, idronoxil, idropranolol, iferanserin, furosemide, furostilbestrol, fursalan, fursultiamine, fur 25 ifetroban, ifosfamide, ifoxetine, iganidipine, igmesine, igu terene, furtrethonium, fusafungine, fusidate, fusidic acid, ratimod, ilaprazole, ilatreotide, ilepcimide, iliparcil, ilmofos fuZlocillin, gabapentin, gabapexate, gaboxadol, gacyclidine, ine, illoomastat, illonidap, illoperidone, imafen, imanixil, ima gadobenate, gadobutrol, gadocolectic acid, gadodiamine, tinib, imaZodan, imcarbofos, imiclopazine, imidafenacin, gadofosveset, gadomelitol, gadopenamide, gadopentetate, imidapril, imidaprilat, imidocarb, imidoline, imidurea, imi gadoteric acid, gadoteridol, gadoversetamide, gadoxetate, 30 glitazar, imiloxan, iminophenimide, imipenem, imipramine, gadoxeticaicid, galamustine, galntamine, galarubicin, gala imipraminoxide, imiquimod, imirestat, imitrodast, imola somite, galdansetron, gallamine triethiodide, gallopamil, mine, imoxiterol, impacarzine, implitapide, impromidine, galocitabine, galosemide, galtifenin, gamfexine, gamolenic improSulfan, imuracetam, inamirone, inaperisone, incad acid, gamaXolone, ganciclovir, ganefromycin, ganglefene, ronic acid, indacaterol, indacrinone, indalpine, indanazoline, ganstigmine, gantacurium, gantofiban, gapicomine, gapro 35 indanidine, indanorex, indapamide, indatraline, indecainide, midine, garenoxacin, gatifloxacin, gavestinel, geclosporin, indeloxazine, indenolol, indibulin, indigotindisulfonate, gedocarnil, gefarnate, gefitinib, gemazocine, gemcabene, indinavir, indiplon, indisetron, indobufen, indocate, indocya gemcadiol, gemcitabine, gemeprost, genfibtrozil, gemifloxa nine green, indolapril, indolidan, indomethacin, indopanolol. cin, gemopatrilat, gentamicin, gepefrine, gepirone, gero indopine, indoprofen, indoramin, indorenate, indoxole, quinol, gestaclone, gestadienol, gestodene, gestonorone, 40 indriline, inecalcitol, ingliforib, inicarone, inocterone gestrinone, geVotroline, gimatecan, gimeracil, giparmen, acetate, inogatran, inosine, inositol, improquoone, intopli giracodazole, giractide, girisopam, gitaloxin, gitoformate, cine, intrazole, intriptyline, inulin, iobenguane, iobenzamic glafenine, glaspimod, glatiramer acetate. glemanserin, glen acid, iobitridol, iobutoic acid, icanlidic acid, iocarmic acid, vastatin, gliamilide, glibotnuride, glibutimine, glicaramide, iocetamic acid, iodamine, iodipamide, iodixanol, iodoantipy glicetanide, gliclazide, glicondamine, glidaZamide, gliflu 45 rine, iodocholesterol, iodohippurate, iodoquinol, iodothiou mide, glimepiride, glipalamide, glipizide, gliquidone, racil, idoxamic acid, iofetamine, ioflupane, iofratol, ioglicic glisamuride, glisentide, glisindamine, glisolamide, glisox acid, ioglucol, ioglunide, ioglycamic acid, iogulaamide, epide, gloxazone, gloXimonam, glucametacin, glucosamine, iohexol, iolidonic acid, iolixanic acid, iolopride, iomazenil. gluronolactone, glucuronamide, glunicate, glyburide, gly iomeglamic acid, iomeprol, iomethin, iometopane, iomorinic buthiazole, glubuzole, gycopyrrolate, glycylamide, glyhexa 50 acid, iopamidol, iopanoic acid, iopentol, iophendylate, iophe mide, glymidine, glyoctamide, glyparamide, glypinamide, noxic acid, iopromide, iopronic acid, iopydol, iopydone, iosa glyprothiazole, gly Sobuzole, goralatide, goserelin, gramici rcol, isofenamic acid, io.seric acid, iosimenol, iosimide, ioSu din, granisetron, grepafloxacin, griseofulvin, guabenXan, lamide, ioSumetic acid, iotasul, ioteric acid, iothalamate, guacetisal, guafecainol, guaiactamine, guaiapate, guaietolin, iothalamic acid, iotranic acid, iotriside, iotrizoic acid, iotro guaifenesin, guaimeSal, guaisteine, guaithylline, guanabenz, 55 lan, iotroXic acid, iotyrosine, iovesol, ioxabrolic acid, ioxa guanacline, guanadrel, guanaZodine, guanclofine, guancy glic acid, ioxilan, ioxitalamic acid, ioxotrizoic acid, ioZomic dine, guanethidine, guanfacine, guanisoquin, guanoclor, gua acid, ipamorelin, ipazilide, ipenoxazone, ipexidine, ipida noctine, guanoXabenz, guanoxan, guanoxyfen, gusperimus, crine, ipodate, iprgratine, ipramidil, ipratropium, ipra halazepam, halazone, halcinonide, halethazole, halobetasol, vacaine, iprazochrome, ipriflavone, iprindole, ipocinidine, halocortolone, halofantrine, halofenate, halofuginone, 60 iproclozide, iprocrodol, iprofenin, iproheptine, iproniazide, halometaSone, halonamine, halopemide, halopenium, halo ipronidazole, iproplatin, iprotiazem, iproxamine, iprozil peridol, halopredone, haloprogesterone, haloprogin, halox amine, ipsalazide, ipsapirone, iquindamine, iralukast, iram aZolam, haloxon, haloqionol, hamycin, hedaquinium, helio panel, irbesartan, irindalone, irinotecan, irloxacin, irofulven, mycin, hepronicate, heptabarbital, heptaverine, heptolamide, irolapride, iroXanadine, irsogladine, irtemazole, isalidole, hepzidine, heroin, hetacillin, hetaflur, heteronium, hexachlo 65 isalsteine, isamfaZone, isamoltan, isamoxole, isatoribine, rophene, hexacyclonate, hexacy prone, hexadiline, hexafluo isaxonine, isbogrel, isbufylline, ispamicin, isoamilinile, iso renium, hexamethonium, hexaminolevulinate, hexapradol, bromindione, isobucaine, isobutamben, isocarboxazid, iso US 8,158,152 B2 20 conazole, isocromil, isoetharine, isoflupredone, isof fen, losoxantrone, losulazine, loteprednol, lotrafiban, lot lurophate, isomazole, isomerol, isometamidium, rifen, lotucaine, lovastatin, loviride, loxanast, loxapine, isomethadone, isometheptene, isomolpan, isoamylamine, loxiglumide, loxoprofen, loxoribine, lozilurea, lubazodone, isoniazid, isonixin, isoprazole, isoprednidene, isoprofen, iso lubeluzole, lubiprostone, lucanthone, lucartamide, lucimy propamide, isopropicillin, isoproterenol, isoSrbide, isospa cin, lufenuron, lufironil, lufuradom, luliconazole, lumira glumic acid, isosulfan blue, isosulpride, isothipendyl, iso coxib, lupitidine, luprostiol, lurasidone, lurosetron, lurotote tiquimide, isotretinoin, isoxaprolol, isoxepac, isoxicam, can, lusaperidone, luxabendazole, lydimycin, lymecycline, isoXSuprine, isradipine, israpafant, istrdefylline, itameline, lynestrenol, lypressin, mabuprofen, mabuterol, madurami itanoXone, itasetron, itaZigrel, itopride, itraconazole, itriglu cin, mafenide, mafoprazine, mafosfamide, malathion, maley mide, itrocainide, itrocinonide, iturelix, ivbradine, ivarimod, 10 lsulfathiazole, malotilate, mangafodipir, manidipine, mani ivermectin, ivoqualine, ixabepilone, izonsteride, josamycin, faxine, mannomustine, manoZodil, mantabegron, kainic acid, kalafungin, kanamycin, kebuZone, keracyanin, mapinastine, maprotiline, maraviroc, marbofloxacin, marib ketamine, ketanserin, ketazocine, ketazolam, kethoxal, avir, maridomycin, marimastat, mariptiline, maropitant, mar ketipramine, ketobemidone, ketocaine, ketocainol, ketocona oxepin, masoprocol, maxacalcitol, maytansine, mazapertine, Zole, ketoprofen, ketorfanol, ketorolac, ketotifen, ketotrexate, 15 maZaticol, mazindol, maZipredone, maZokalim, mebanazine, khellin, khelloside, kitasamycin, labetalol, labradimil, mebendazole, menbenoside, mebeverine, mebeZonium, meb lachesine, lacidipine, lacosamide, lactalfate, lactilol, lactu hydrolin, mebiquine, mebolazine, mebrofenin, mebutamate, lose, ladirubicin, ladostigil, laflunimus, lafutine, laidlomycin mebutizide, mecamylamine, mecarbinate, mecetronium, propionate, lamifiban, lamivudine, lamotrigine, lamitidine, meciadanil, mecinarone, meclinertant, meclizine, meclocy lanatoside, landiolol, lanepitant, lanicemine, laniquidar, cline, meclofenamaic acid, meclofenoxate, meclonazepam, lanoconazole, lanperisone, lanproston, lanreotide, lanSopra mecloqualone, meclorisone dibutyrate, mecloxamine, meco Zole, lapatinib, lapisteride, laprafylline, lapyrium, lacquini balamin, medazepam, medazomide, medetomidine, mediba mod, lasalocid, lasinavir, lasofoxifene, latanoprost, lau Zine, medifoxamine, medorinone, medorubicin, dexium, laurcetium, laurocapram, lauroguadine, laurolinium, medrogestrone, medronic acid, medroxalol, medroxyproges lauryl isoquinolinium, lavoltidine, lazabemide, lecimibide, 25 terone acetate, medrylamine, medrysone, mefeclorazine, ledazerol, ledoxantrone, lefetamine, leflunomide, mefenamic acid, mefenidil, mefenidramium, mefenorex, lefradafiban, leiopyrrole, lemidosul, lemidipine, leminopra mefeserpine, mefexamide, mefloquine, mefruside, megalo Zole, lemoxinol, lemuteporfin, lanalidomine, lenampicillin, mycin, megestrol, megace, meglitinide, meglucycline, lenapenem, leniquisin, leuperone, leptacline, lercanidipine, meglumine, meglutol, meladrizine, melagatran, melarsom lergotrile, lerisetron, lesoptiron, lestaurtinib, leteprinim, lete 30 ine, melarsonyl, melarsoprol, meldonium, melengestrol prinim, letimide, letosteine, letraZuril, letrozole, leucino acetate, meletimide, melevodopa, melinamide, melitracen, caine, leucocianidol, leucovorin, leurubicin, levalbuterol, melizame, meloxicam, melperone, melphalan, melduinast, levallorphan, levamfetamine, levamisole, levcromakalim, meluadrine, mamantine, memotine, menabitan, menadiol. levcycloserine, levdobutamine, levemoamil, levetiracetam, menadione, menadoxime, menatetrenone, menbutone, men levisoprenaline, levlofexidine, levmetamfetamine, levobe 35 fegol, menglytate, menitrazepam, menoctone, menogaril. taxolol, levobunolol, levobupiacaine, levocabastine, levo menobentine, mepazine, mepenZolate, meperidine, mephen camitine, levodopa, levodropropizine, levofacetoperane, esin, mephenoxalone, mephentermine, mephenyloin, levofenfluramine, levofloxacin, levofluraltadone, levoleuco mephobarbital, mebaral, mepindolol, mepiperphenidol. Vorin, levomenol, levomepromazine, levomethadone, mepiprazole, mepiroXol, mepitioStane, mepivacaine, mepix levomethadyl acetate, levomethorphan, levometiomeprazine, 40 anox, mepramidil, meprednisone, meprobamate, meprochol, levomoprolol, levomoramide, levonantradol, levonordefrin, meproscillarin, meprotixol, meprylcaine, meptazinol, meduli levonorgestrel, levophenacylmorphan, levopropoxyphene, dox, meduinol, meduitamium, meduitazine, meradimqate, levopropylcilline, levopropuylhexedrine, levoprotiline, menthyl anthranilate, merafloxacin, meralein, meralluride, levorin, levormeloxifene, levorphanol, levosalbutamol, merbaphen, merbromin, mercaptomerin, mercaptopurine, levosemotiadil, levosimendan, levoSulpiride, levothyroxine, 45 mercuderamide, mercufenol, mercumatilin, mergocriptine, levotofisopam, levoxadrol, lexipafant, lexithromycin, lex meribendan, merimepodib, meropenem, mersalyl, mer ofenac, liarozole, libecillide, libenzapril, licarbazepine, tialide, mesabolone, mesalamine, meseclaZone, mesocarb, licofelone, licostinel, lidadronic acid, lidamine, lidanserin, mesoridazine, mesipiperone, mespirenone, mestanolone, lidocaine, lidoferin, lidorestat, lifariaine, lifibrate, lifibrol, mesterolone, mestranol, meSudipine, meSulergine, mesulfa lilopristone, limaprost, limazocic acid, linarotene, lincomy 50 mide, meSulfen, meSuprine, metabromsalan, met cin, lindane, linetastine, lineZolid, linogliride, linopirdine, butethamine, metabutoxycaine, metacetamol, meta linotroban, lisinidomine, lintitript, lintopride, liothyronine, clazepam, metacresol, metaglycodol, metahexamide, lipoic acid, liraglutide, liranaftate, lirequinil, lirexapride, lir metalkonium, metalol, metamelfalan, metamfaZone, metam imilast, liroldine, lisadimate, lisinopril, lisofylline, lisuride, fenpramone, metampicillin, metanixin, metapramine, metap litomeglovir, litoxetine, litracen, lividomycin, lixazinone, lix 55 roterenol, metaraminol, metaxalone, metaZamide, metazide, ivaptan, lobapolatin, lobeline, lobendazole, lobenzarit, lobu matazocine, metbufen, meteneprost, metergoline, metergota cavir, lobuprofen, locicortolone, lodaxaprine, lodaZecar, mine, metescufylline, metesculetol, metesind, metethohep lodelaben, lodenosine, Iodinixil, lodiperone, Iodoxamide, tazine, metformin, methacholine, methacycline, methadone, lofemizole, lofendazam, lofentanil, lofepramine, lofexidine, methadyl acetate, methallenestril, methallibure, methalthiaz loflucarban, lombazole, lomefloxacin, lomeguarib, lomeriZ 60 ide, methamphetamine, methandriol, methandrostenolone, ine, lometraline, lometrexol, lomevactone, lomifylline, lomo methaniazide, methantheline, methaphenilene, methapy fungin, lomustine, lonafarnib, lonapalene, lonaprofen, lona rilene, methaqualone, metharbital, methastyridone, meth Zolac, lonidamine, loperamide, lopinavir, lopirazepam, aZolamide, methdilazine, methenamine, methenolone, meth lopobutan, loprazolam, loracarbef, lorajmine, lorapride, eptazine, methestrol, methetoin, methikcillin, methimazole, lorazepam, lorbamate, lorcainide, lorcinadol, lorecleZole, 65 methiodal, methiomeprazine, methionine, methisaZone, lorglumide, lormetazepam, lornoxicam, lopiprazole, lorta methitural, methixene, methocarbamol, methocidin, metho lamine, lorZafone, losartan, losigamone, losindole, loSmipro hexital, methopholone, methoprene, methoserpidine, meth US 8,158,152 B2 21 22 otrexate, methotrimeprazine, methoxamine, methoXSalen, nafronyl, naftalofos, naftaZone, naftifine, naftopidil, naftox methoxyphedrine, methoxyphenamine, methoxypromazine, ate, naftypamide, naglivan, nalbuphine, malfurafine, nalidixic methScopolamine, methSuximide, methyclothiazide, methyl acid, nalmefene, nalmexone, nalorphine, naloxone, naltrex aminolevulinate, methyl palmoxirate, methyl salicylate, one, naminidil, naminterol, namirotene, namoXyrate, nana methylatropine, methylbenactyzium, methylbenzethonium, frocin, nandrolone, nanterinone, nantradol, napactadine, methylcromone, methyldesorphine, methyldihydromor napamezole, naphazaoline, naphthonone, napirimus, napi phine, methyldopa, methylene blie, methylephedrine, meth tane, naproxime, naproxen, naproXol, napsagatran, naranol, ylergometrine, methylergonovine, methyllparaben, meth narasin, naratriptan, nardetoterol, naroparcil, natamycin, ylphenidate, methylprednisolone, methyltestosterone, nateglinide, navuridine, naxagolide, naxaprosteine, naxifyl methylthiouracil, methynodiol, methyprylon, methysergide, 10 line, nealbarbital, nebantan, nebidrazine, nebivolol, metiamide, metiapine, metiazinic acid, metibride, meticrane, neboglamine, nebracetam, nebramycin, necopidem, nedapl metildigoxin, metindizate, metioprim, metioxate, metipirox, atin, nedocromil, nefazodone, nefiracetam, neflumozide, metiprenaline, metitepine, metizoline, metkephamid, nefopam, nelarabine, neldaZosin, neleZaprine, nelfinavir, metochalcone, metocinium, metoclopramide, metocurine, neltenexine, nelZarabine, nemadectin, nemaZoline, nemi metofenazate, metogest, metolaZone, metomidate, metopi 15 fitide, nemonapride, memorubicin, neocinchophen, neomy mazine, metopon, metoprine, metoprolol, metoquizine, cin, neostigmine, nepadutant, nepafenac, nepaprazole, nepi metoserpate, metostilenol, metoxepin, metrafazoline, metral castat, nepinalone, nequinate, neramexane, neraminol, indole, metrazifone, metrenperone, metribolone, metri nerbacadol, neridronic acid, nerisopam, nesapidil, nesiritide, fonate, metrifudil, metrizamide, metrizoate, metronidiazole, nesosteine, nestifylline, neticonazole, netilmicin, netivudine, meturedepa, metyrapone, metyrosine, mevastatin, mexafyl netobimin, netoglitaZone, netupitant, neutramycin, nevi line, mexazolam, mexenone, mexiletine, mexiprosil, mexo parine, nexeridine, nexopamil, niacin, niacinamide, niala profen, mexrenoate, meZacopride, meZepine, mezilamine, mide, niaprazine, nibroxane, nicafenine, nicainoprol, nica meZlocillin, miaanserin, mibefradil, mibolerone, miboplatin, metane, nicanartine, nicaraven, nicarbazin, nicardipine, micafungin, miconazole, micronomicin, midaflur, midafotel, nicergoline, niceritol, niceverine, niclofolan, niclosamide, midaglizole, midamaline, midaxifylline, midazogrel, mida 25 nicoboxil, nicoclonate, nicocodine, nicocortonide, nicocido Zolam, midecamycin, midestein, midodrine, midostaurin, dine, nicoduozide, nicofibrate, nicofuranose, nifurate, mifentidine, mifepristone, mifobate, miglitol, miglustat, nicogrelate, nicomol, nicomorphine, nicopholine, nicorac mikamycin, milacainide, millacemide, milameline, milataxel, etam, nicorandil, nicothiaZone, nicotredole, nicoXamat, nic milemperone, milfasartan, millipertine, miloxacin, milrinone, tiazem, nictindole, nidroxy Zone, nifedipine, nifekalant, nife miltefosine, milverine, mimbane, minalrestat, minamestane, 30 malol, nifenaZone, niflumic acid, nifungin, nifiradene, minaprine, minaxolone, mindodilol, mindoperone, minepen nifuraldezone, nifuralide, nifuratel, nifuratrone, nifurdazil, tate, minocromil, minocycline, minodronic acid, minopafant, nifurethaZone, nifurfoline, nifurimide, nifurizone, nifurma minoxidil, mioflaazine, mipitroban, mipragoside, miproX Zole, nifurmerone, nifuroquine, nifuroxazide, nifuroxime, ifene, mirfentanil, mirincamycin, miripirium, miriplatin, nifurpipone, nifurpirinol, nifirprazine, nifurquinazol. mirisetron, miristalkonium, miroprofen, mirosamicin, 35 nifursemizone, nifursol, nifurthiazole, nifurtimox, nifurtoi mirostipen, mirtazapine, misonidazole, misoprostol, mitem nol, nifurvidine, nifurzide, nigludipine, nihydraZone, cinal, mitiglinide, mitindomine, mitobronitol, mitocarcin, nikethamide, nileprost, nilprazole, niludipine, nilutamide, mitoclomine, mitocromin, mitoflaxone, mitogillin, mitogua nilvadipine, nimaZone, nimeSulide, nimetazepam, nimidane, Zone, mitolactol, mitomalcin, mitomycin, mitonafide, mito nimodipine, nimorazole, nimustane, neometacin, niperoti podozide, mitoquidone, mitosper, mitolane, mitotenamine, 40 dine, nipradillol, niprofaZone, nitavoline, nirdazole, nis mitoxantrone, mitoZolomide, mitradipide, mivacurium, buterol, nisobamate, nisoldipine, nisoxetine, nisterime, nitar mivobulin, mivotilate, mixidine, mizolastine, mizoribine, Sone, nitaZoxanide, nitecapone, nithiamide, nitisinone, mobecarb, mobenzoxamine, mocimycin, mociprazine, nitracrine, nitrafudan, nitralamine, nitramisole, nitradua moclonemide, moctamide, modafinil, modaline, modecain Zone, nitrazepam, nitrefazole, nitrendipine, nitrocefin, nitro ide, modipafant, moexipril, moexiprilat, mofarotene, 45 clofene, nitrocycline, nitrodan, nitrofurantoin, nitrofuraZone, mofebtaZone, mofegiline, mofeZolac, mofloverine, mofoX nitromersol, nitromide, nitromifene, nitroscanate, nitrovin, ine, mofuisteine, molfarnate, molinaZone, molindone, mol nitroXinil, nitroxoline, nivaZol. nivimedone, nizatidine, racetam, molsidomine, mometaSone, monalaZone, nizofenone, noberastine, nocloprost, nocodazole, nofecain monatepil, monesin, monobenzone, monoctanoin, ide, nogalamycin, nolatrexed, nolinium, nolomirole. nolpi monometacrine, monophosphothiamine, monoxerutin, mon 50 tantium, nomegestrol, nomelidine, nomifensine, nonabine, telukast, monterelin, moperone, mopidamol, mopidralazine, nonaperone, nonapyrimine, nonathymulin, nonivamide, moprolol, moquizone, morantel, moraZone, morclofone, noracymethadol, norbolethone, norbudroine, norcholestenol, morforex, moricizine, morinamide, momiflumate, moro norclostebol, norcodeine, nordazepam, nordefrin, nordinone, cromen, moroxydine, morpheridine, morphine, morSuxim norelgestromin, norepinepherine, norethandrolone, noethin ide, mosapramine, mosapride, motapizone, motexafin, 55 drone, norethynodrel, noreximide, norfenefrine, norfloxacin, motrazepam, motrtinide, moveltipril, moxadolen, moxalac norgesterone, norgestimate, norgestomet, norgestrel, norg tam, moxaprindine, moXastine, moXaverine, moxazocine, estrieneone, norletimol, norlevorphenol, normethadone, nor moxestrol, moxicoumone, moxidectin, moxifloxacin, moxi morphine, norpipanone, nortetrazepam, nortopixantrone, lubant, moxipraquine, moxirapine, moxisylate, moXnida nortriptyline, norvinisterone, nosantine, noscapine, nosihep Zole, moXonidine, moZavaptan, moZenavir, mubritnib, mupi 60 tide, novobiocin, noxiptiline, noxytiolin, nuclomedone, rocin, murabutide, muraglitazar, mureletecan, murocainide, nuclotixene, nufenoXole, nupafant, nuvenZepine, nylestriol, muZolimine, mycophenolic acid, my fadol, myrophine, nylidrin, nystatin, obidoxime, ocaperidone, ocfentanil, ocilt myrtecaine, nabaZenil, nabilone, nabitan, naboctate, nabume ide, ocinaplon, octacaine, octafonium, octamoxin, octapinol, tone, nacartocin, nadide, nadiofloxacin, nadolol, nadoxolol. octatine, octaverine, octaZamide, octenidine, Octicizer, nafagrel, nafamo.stat, nafarelin, nafazatrom, nafcaproic acid, 65 octimibate, octinoxate, octisalate, octocrylene, octodrine, nafcillin, nafenodone, nafenopin, nafetolol, nafimidone, octopamine, octotiamine, octreotide, octriptyline, octriazole, nafiverine, naflocort, nafomine, nafoxadol, nafoxidine, odalprofen, odapipam, odiparcil, ofloxacin, oftomine, oftas US 8,158,152 B2 23 24 ceine, oglu fanide, olaflur, olamufloxacin, olanexidine, olan tigetide, pentisomicin, pentisomeide, pentizidone, pentobar Zapine, olaquindox, olcegepant, oleandomycin, oletimol, bital, pentolinium, pentolonium, pentomone, pentopril, pen olmesartan, olopatadine, olpadronic acid, olpimedone, torex, pentosalen, pentostatin, pentoxifylline, pentoxyverine, olprinone, olradipine, olsalazine, oltipraz, olvanil, omaciclo pentrinitrol, pentylenetetraZol, peplomycin, pepstatin, pera Vir, omapartrilat, omeprazole, omidoline, omigapil, omilox clopone, peradoxime, perafensine, peralopride, peramivir, etine, omoconazole, omonasteine, onapristone, ondansetron, peraquisin, perastine, peratizole, perazine, perbufylline, per ontazolast, ontianil, opanixil, opaviraline, opiniazide, fomedil, perfosfamide, pegolide, perhexiline, periciazine, opipramol, opratonium, oraZamide, oraZipone, orbofiban, perifosine, perimetazine, perindopril, perindoprilat, orbutopril, orconazole, orientiparcin, oritavancin, orlistat, perisoxal, perlapine, permethrin, peroSpirone, perphenazine, ormaplatin, ormeloxifene, ormetoprin, ornidazole, orni 10 persilic acid, perZinfotel, petrichloral, peXantel, phanquone, preessin, ornithine, ornoprostil, orotic acid, orotirelin, orpan phenacaine, phenacemide, phenacetin, phenactropinium, oxin, orphenadrine, ortataxel, orteteamine, osanetant, osater phenadoxone, phenaglycodol, phenamaZoline, phenampro one, oseltamivir, osemoZotan, osmadizone, ospennifene, mide, phenaphthazine, phenarsone, phenazocine, ostreogrycin, OSutidine, otamixaban, otenZepad, oteracil, phenaZopyridine, phenbutaZone, phencarbamide, phencycli otilonium, otimerate, ouabain, oxabolon, oxabrexine, 15 dine, phendimetrazine, phenelzine, pheneridine, phenethicil oxaceprol, oxacillin, oxadimedine, oxafloZane, oxaflu lin, pheneturide, phenylglutarimide, phenicarbazide, phenin mazine, oxagrelate, oxalinast, oxaliplatin, oXamarin, oxam damine, phenindione, pheniprazine, pheniramine, etacin, oxamisole, oxaminiquinem oxanamide, Oxandrolone, phenisonone, phenmetrazine, phenobarbital, phenobutiodil, oxantel, oxapadol, oxapium, Oxaprazine, oxaprotiline, phenomorphan, phenothiazine, phenothrin, phenoxyben oxaprozin, oXcarbazole, oxatomide, oxazafone, oxazepam, Zamine, phenoxypropazine, phenprobamate, phenprocou oxazidone, oxazolam, oxazorone, oXcarbazepine, oxdrala mon, phenpromethamine, phensuXimide, phentermine, phen Zine, Oxeclosporin, oxedrine, Oxeglitazar, OXeladin, oxen tolamine, phenyl aminosalicylic acid, phenylalanine, dolone, oxepinac, oxetacillin, oxethazine, oxetorone, phenylbutaZone, phenylephrine, phenylpropanolamine, phe oxfendazole, Oxfenicine, Oxibendazole, oxibetaine, oxiconi nylthiolone, phenyltoloxamine, phenyracillin, phenyramidol. Zole, oxidapamine, oxidronic acid, Oxfentorex, oxifungin, 25 phenyloin, pnetharbital, pholcodine, pholedrine, phoxim, oxigluttione, oxilofrine, OXilorphan, oXimonam, OXindanac, phthalofyne, phthylsulfacetamide, phthalylsulfamethiazole, oxiniacic acid, Oxperomide, oxiracetam, oxiramide, oxiso phthalylsulfathiazole, physostigmine. Phytic acid, phytona pred. Oxisuran, oxitefonium, oxitriptan, oxitriptyline, oXtri dione, pibaxizine, pibecarb, piberaline, piboserod, pibroZe ponium, OXmetidine, oxodipine, oxogestone, oxolamine, lesin, pibutidien, picafibrate, picartamide, picenadol, picil oXolinic acid, oXomermazine, oXonazine, Oxophenarsine, 30 orex, piclaimilast, piclonidine, piclopastine, picloxydine, Oxoprostol, oxpheneridine, oXprenoate, oXprenolol, Oxtriph picobenzide, picodralazine, picolamine, piconol, picoperine, yline, oxbenzone, oxybutynin, oxychlorosene, oxycin picoplatin, picoprazole, picotamide, picotrin, picumast, picu chophen, oxyclipine, oxyclozanide, oxycodone, oxydipento meterol, pidobenzone, pidolacetamol, pidolicaica, pidoti nium, oxyfedrine, Oxymesterone, Oxymetazoline, mod, pifarnine, pifinate, pifexole, piflutiXol, piketoprofen, oxymethalone, oxymorphone, oxypendyl, oxypertine, 35 pildralazine, pilocarpine, pilsicainide, pimagedine, pime oxyphenbutaZone, oxyphencyclimine, oxyphenisatin, clone, pimecrolimus, pimefylline, pimelautide, pimetacin, oxyphenonium, oxypurinol, oxypurronium, oxyquinoline, pimethixene, pimetine, imetremide, pimilprost, piminodine, oxyridazine, oxysonium, oxytetracycline, oxytocin, oZagrel, pimobendan, pimonidazole, pimozide, pinacidil, pinadoline, oZagamicin, oZolindone, paclitaxel, pacrindolol, pactimibe, pinafide, pinaverium, pinazepam, pincainide, pindolol. padimate A, padimate Q, pafenolol, pagoclone, paldimycin, 40 pinokalant, pinolcaine, pinoxepine, pioglitaZone, pipacy palinavir, paliperidone, palmidrol, palmoxirate, palonid cline, pipamazine, pipamperone, pipazethate, pipebuZone, ipine, palonosertron, palosuran, pamabron, pamaqueside, pipecuronium, pipemidicacid, pipendoxifene, pipenzolate, pamaquin, pamicogrel, pamidronic acid, panadiplon, pan pipequaline, piperacetazine, piperacillin, piperamide, piperi amesine, pancopride, pancuronium, panipenem, panomifene, dolate, piperilate, piperocaine, piperonyl butoxide, piper pantenicate, pantethine, panthenol, pantoprazole, 45 oxan, piperphenidol, piperylone, pipobroman, pipoctanone, panuramine, papverine, papveroline, parachlorphenol, pipofezine, piposulfan, pipotiazine, pipoxizine, pipoxolan, paraflutizide, paramethadione, paramethasone acetate, pipradimadol, pipradrol, pipramadol, pipratecol, piprinhydri paranitrosulfathiazole, paranyline, parapenzolate, para nate, pipocurarium, piprofurol, piprozolin, piquindone, propamol, pararosaniline, paraxaZone, parbendazole, parc piquizil, piracetam, pirandamine, pirarubicin, piraxelate, etasal, parconazole, parecoxib, pareptide, parethoxycaine, 50 pirzmonam, piraZolac, pirbenicillin, pirbuterol, pirdonium, pargeverine, pargolol, pargyline, paricalcitol, paridocaine, pirenoxine, piremperone, pirezepine, pirepolol, piretanide, parodilol, paromomycin, paroxetine, paroxypropione, pirfenidone, pirbendil, piridicillin, piridocaine, piridoxilate, parsalmide, particin, parvaquone, pasiniazid, pasireotide, piridironic acid, pirifibrate, pirimiphos-ethyl, pirindazole, patamostat, patupilone, paulomycin, paxamate, paZelliptine, pirinixic acid, pirinixil, piriprost, piriqualone, piriSudanol, paZinaclone, paZoxide, paZufloxacin, pecilocin, pecocycline, 55 piritramide, piritrexin, pirlimycin, pirlindole, pirmagrel, pir pefloxocin, pelanserin, peldesine, peliomycin, pelitinib, peli menol, pirnabine, piroctone, pirodavir, priodomast, pirog trexol, pelretin, pelrinone, pelubiprofen, pemedolac, liride, piroheptine, pirolate, pirolazamide, piromidic acid, pemerid, pemetrexed, pemirolast, pemoline, penamecillin, piroXantrone, piroXicam, piroxicillin, piroXimone, pirozadil, penbutolol, penciclovir, pendecamine, pendetide, penfluri pirprofen, pirquinozol, pirralkonium, pirsidomine, pirteni dol, penflutizide, pengitoxin, penicillamine, penicillin G, 60 dine, pitenodil, pitofenone, pituxate, pivagabine, pivampicil penicillin V, penimepicycline, penimocycline, penirolol, pen lin, pivenfrine, pivopril, pivoxazepam, pixantrone, pizoty mesterol, penoctonium, penprostene, pentabamate, penta line, plafbride, plaunotol, plauracin, pleconaril, pleuromulin, cynium, pentfluranol, pentagastrin, pentagestrone, pentala plevitrexed, plicamuycin, plomestane, pobilukast, podilfen, mide, pentamethonium, pentamidine, pentamorphone, podofilox, poldine, polymixin, polythiazide, pomisartan, pentamoxane, pentamustine, pentapiperide, pentapiperium, 65 ponalrestat, ponaZuril, ponfibrate, porfiromycin, posacona pentaquine, pentazocine, pentetic acid, pentreotide, Zole, posatirelin, posiZolid, poskine, practolol, pradolfoxa penthienate, penthrichloral, pentiapine, pentifylline, pen cin, prajmalium, pralatrexate, pralidoxime, prailmorelin, pral US 8,158,152 B2 25 26 nacasan, pramipexole, pramiracetam, pramoxine, prampine, tazar, relcovaptan, relomycin, remacemide, remifentanil, pranazepide, pranidipine, prankulast, pranolium, pranopro remikiren, remiprostol, remoxipride, renanolone, rentiapril, fen, pranosal, prasterone, praSugrel, pratosartan, pravadoline, renzapride, repaglinide, reparixin, repinotan, repirinast, pravastatin, praxadine, praZarelix, prazepam, prazepine, repromicin, reproterol, rescimetol, rescinnamine, resequinil, praziquantel, praZitone, prazocillin, prazosin, preclamol. reserpine, residuimod, resocortol butyrate, resorantel, resor prednazate, prednazoline, prednicarbate, prednimustine, cinol, retapamulin, retelliptine, retigabine, retinol, revapra prednisolamate, prednisolone, prednisone, prednival, pred Zan, revatropate, revenast, reviparin, revizinone, revospirone, nylidene, pregabalin, pregnadiol, pregnenolone, premafloxa ribavirin, riboflavin, riboprine, ribostamuycin, ricasetron, cin, premazepam, prenalterol, prenisteine, prenoverine, ridazolol, ridogrel, rifabutin, rifalazil, rifametane, rifamexil, prenoxdiazine, prenylamine, pretamazium, pretiadoil, preza 10 rifamide, rifampin, rifapentine, rifaximin, rilapine, ril tide, pribecaine, pridefine, prideperone, pridinol, prifelone, makalim, rilmazafone, rillmenidine, rilopirox, riloZarone, pri?inium, prifuroline, pilocalne, primaperone, primaquine, rillpovorine, riluzole, rimantadine, rimazolium, rimcazole, primidolol, primidone, primycin, prinomastat, prinomide, rimexolone, rimiterol, rimonabant, rimoprogin, riodipine, prinoXodan, pristinol, pristinamycin, prizidilol, proadifen, rioprostil, ripazepam, ripisartan, risarestat, risedronicacid, probarbital, probenecid, probicromil, probucol, procaina 15 risocaine, risotilide, rispenzepine, risperidone, ristianol, ris mide, procaine, procarbazine, procaterol, prochlorperazine, tocetin, ritanserin, ritometan, ritipenem, ritobegron, rito procinolol, procinonide, proclonol, procromil, procyclidine, drine, ritolukast, ritonavir, ritropirronium, ritrosulfan, rivar procymate, prodeconium, prodilidine, prodipine, prodolic Oxaban, rivastigmine, rivoglitaZone, rizatriptan, robalZotan, acid, profadol, profexalone, proflavine, proflazepam, proga robenidine, rocastine, rocepafant, rociclovir, rocuronium, bide, progesterone, proglumetacin, proglumide, prohep rodocaine, rodorubicin, rofecoxib, rofelodine, rofileponide, tazine, proligestone, praline, prolintane, prolonium, pro roflumilast, rogletimide, rokitamycin, rollafagrel, roletamide, mazine, promegestone, promestriene, promethazine, rolgamidine, rolicyclidine, rolicyprine, rolipram, rollitetracy promolate, promoxolane, prontalol, propacetamol, pro cline, rolodine, rolziracetam, romazarit, romergoline, pafenone, propagermanium, propamidine, propanidid, pro romifenone, romifidine, romurtide, ronactolol, ronidazole, panocaine, propantheline, proparacaine, propatyl nitrate, 25 ronifibrate, ronipamil, runnel, ropinirole, ropitoin, ropiv propazolamide, propenidazole, proprintofylline, propen acaine, ropizine, roquinimex, rosaprostol, rosaramicin, rose Zolate, properidine, propetamide, propetamfos, propetandrol, bengal, rosiglitaZone, roSoxacin, rostafuroxin, rostaporfin, propicillin, propikacin, propinetidine, propiomazine, propi rosterolone, rosuvastatin, rotamicillin, rotigotine, rotoxam ocaine, propiram, propisergide, propiverine, propizepine, ine, rotaxate, roXadimate, roXarsone, roXatidine acetate, roxi propofol, propoxate, propoXur, propoxycaine, pro 30 bolone, roxifiban, roXindole, roXithromycin, roXolonium, poxyphene, propranolol, propyl docetrizoate, propyl gallate, roXoperone, rubitecan, ruboxistaurin, rufinamide, rufloxacin, propylhexedrine, propyliodone, propylthiouracil, propyper rupatadine, rupintrivir, rutamycin, ruvazone, ruzadolane, one, propyphenaZone, propyromazine, produaZone, pro Sabarubicin, sabcomeline, sabeluzole, Sabiporide, Saccharin, quinolate, prorenoate, proroXan, prScillardin, prospidium, Safingol, Safirinol, Sagandipine, salacetamide, Salafibrate, sal prostalene, proSulpride, prosultiamine, proterguride, pro 35 antel, Salazodine, Salazosulfadimidine, Salazosulfamide, theobromine, prothipendyl, prothixene, protiofate, protiona salaZoSulfathiazole, Salcaprozoic acid, Salcolex, Salethamide, mide, protirelin, protizinic acid, protokylol, protoporphyrin, Salflucerine, Salicylalcohol, salicylamide, salicylic acid, Sali protriptyline, proXZole, proxibarbal, proxibutene, proxicro nazid, salinomycin, Salmefamol, salmeterol, salmisteine, sal mil, proxifeZone, proXorphan, proxymetacaine, proxyphyl nacedin, Salprotoside, Salsalate, Sameridine, Samixogrel, line, proZapine, prucalopride, prulifloxacin, pruvanserin, 40 Sampatrilat, Sampirtine, Sancycline, Sanfetrinem, sangui pseudoephedrine, pumafentrine, pumaprazole, pumitepa, narium, Saperconazole, saprisartan, sapropterin, saquinavir, pumosetrag, puromycin, pyrabrom, pyrantel, pyrathiazine, Sarafloxacin, Sarakalim, Saralasin, sarcolysin, Sardomozide, pyrazinamide, pyrazofurin, pyricarbate, pyridarone, pyridi saredutant, Saripedem, sarizotan, Sarmazenil, Samoxicillin, nol, pyridofylline, pyridostigmine, pyridoxal, pyridoxamine, Sarpicillin, Sarpogrelate, saterinone, satigrel, satranidazole, pyridoxine, pyrilamine, pyrimethamine, pyrimate, pyrino 45 satraplatin, saviprazole, Savoxepin, scopafungin, scopinast, line, pyrithione, pyrithyldione, pyritidium, pyritinol, Scopolamine, Secalciferol, seclaZone, secnidazole, secobar pyrophenindane, pyrovalerone, pyroxamine, pyrrobutamine, bital, securinine, Sedecamycin, Sedoxantrone, Seganserin, pyrrocaine, pyrrolifene, pyrroliphene, pyrrolnitrin, pyrroX segesterone, Seglitide, Selamectin, Selgiline, selfotel, Solde ane, pyrvinium, pytamine, quadazocine, quadrosilan, noson, selprazine, Sampimod, sematilide, Semaxanib, semdu quatacaine, quaZepam, quaZinone, quaZodine, quaZolast, 50 ramicin, Semorphone, semotiadil, semustine, SenaZodan, Seo quetiapine, quifenadine, quiflapon, quillifoline, quiloStig calcitol, sepazonium, Seperidol, sepimostat, Seprilose, mine, quinacainol, quinacillin, quinacrine, quinagolide, seproxetine, sequifenadine, Seratrodast, Serazapine, serfi quinaldine blue, quinapril, quinaprilat, quinazosin, qui brate, Sergolexole, Sermetacin, sertindole, Sertraline, setast bolone, quincarbate, quindecamine, quindonium, quindoxin, ine, Setzindol, Setipafant, Setiptiline, Setoperone, Sevitropium, quinelorane, quinestradol, quinestrol, quinethaZone, quineto 55 sevopramide, Sezalamide, Sagoside, sibenadet. Sibopirdine, late, quineZamide, quinfamide, quingestanol acetate, Sibrafiban, Sibutramine, siccanin, sifrprazine, SiguaZodan, quingestrone, quinidine, quinine, quinotolast, quinpirole, silandrone, sildenafil. Silibinin, Silcristin, sildianin, silodosin, quinterenol, quitiofos, quinuclium, quinupramine, quinupris silodrate, silperisone, siltenZepine, Simendan, simetride, sim tin, quipazine, quisultazine, rabeprazole, raclopride, racto fibrate, simtraZene, simvastatin, sincalide, sinefungin, sini pamine, radafaxine, rafoxanide, ragaglitazar, ralitoline, ral 60 trodil. Sintropium, sipatrigine, siramesine, Siratiazem, siroli oxifene, raltitrexed, raluridine, ramatroban, ramciclane, mus, Sisomicin, sitafloxacin, Sitalidone, Sitamaquine, ramelteon, ramifenaZone, ramipril, ramiprilat, ramixotidine, sitaxentan, sitofibrate, sitoglusoide, sivelestat, Soblidotin, ramnodigin, ramnoplanin, ramorelix, ramosetron, ranelic Sobuzoxane, Solabegron, Solifenasin, Solimastat, Solpecainol, acid, ranimustine, ranimycin, ranirestat, ranitidine, ranolaine, Solypertine. Somatadine, Soneclosan, Sonepiprazole, Sopi rapacuronium, rasagiline, rasburicase, rathyronine, ravu 65 tazine, Sopromidine, Soquinolol, Sorafenib, Soraprazan, Sorb conazole, raZaxaban, razinodil, raZobazam, razoxane, rebim inicate, Sorbinil, Sorivudine, Sornidipine, Sotalol, Soterenol, astat, reboxetine, recainam, reclazepam, regadenoson, regli spaglumic acid, sparfloxacin, sparfosate, sparsomycin, US 8,158,152 B2 27 28 sparteine, spectinomycin, spiclamine, spiperone, spiradoline, Zole, tendamistat, tenidap, tenilapine, teniloxazine, spiramide, spiramycin, spirapril, spiraprilat, spirendolol. tenilsetam, teniposide, tenivastatin, tenocyclidine, tenofovir, spirgetine, spirilene, spiriprostil, spirofylline, spirogerma tenofovir disoproxil, tenonitrozole, tenosal, tenosiprol, nium, Spiroglumide, Spiromustine, spironolactone, spiropl tenoxicam, tenylidone, teoprantil, teoprolol, tepirindole, tep atin, spirorenone, spirotriazine, spiroXasone, SpiroXatrine, oxalin, teprenone, teprotide, teraZosin, terbequinil, terbin spiroXepin, Spizofurone, Sprodiamine, squalamine, squalane, afine, terbogrel, terbucromil, terbufirol, terbuficin, terbuprol, Stacofylline, stillimycin, Stannsoprfin, stanolone, stanoaolol. terbutaline, terciprazine, terconazole, terdecamycin, teeres stavudine, Stearylsulfamide, Steffimycin, Stenbolone, strpro tigmine, terfeadine, terflavoxate, terfluranol, terguride, teri nin, Stercuronium, Stevaladil, Stibamine, Stilbophen, stilbami flunomide, terikalant, terizidone, terlakiren, terlipressin, dine, stilbazium, stilonium, Strimazole, Stiripentol, stirocain 10 ternidazole, terodiline, terofenamate, teroxalene, teroxirone, ide, stirofos, Streptomycin, Streptonicozid, Streptonigrin, tertatolol, tesaglitazar, tesicam, tesimide, tesimilifene, streptozocin, styramine, SubathiaZone, Subendazole. Succi tesofensine, testolactone, testosterone, tetomilst, tetrabar nylcholine, Succinylsulfathiazole, Succisulfone, Suclofenide, bital, tetrabenazine, tetracaine, tetracycline, tetrahydrozo Sucralfate. Sucralose. Sucrose octaacetate. Sucrosulfate, Sudex line, tetramethrin, tetramisole, tetraxetan, tetrazepam, tetra anox, Sudoxicam, Sufenatil, Sufotidine, Sufugolix, Sugamma 15 Zolast, tetriprofen, tetrofosmin, tetronasin, tetroquinone, dex, Sulamserod, Sulazepam, SulaZuril, Sulbactam, Sulbenicil tetroxoprin, tetrydamine, teverelix, texacromil, tezacitabine, lin, Sulbenox, Sulbentine, Sulbutiamine, Sulclamine, tezosentan, thalidomide, thebacon, thenalidine, thenium, the Sulconazole, Sulfabenz, Sulfabenzamide, SulfabromomethaZ nyldiamine, theobromine, theodrenaline, theofibrate, theo ine, Sulfacarbamide, Sulfacecole, Sulfacetamide, Sulfachlo phylline, thiabendazole, thiacetarsamide, thialbarbital, thia rpyridazine, Sulfachrysoidine, Sulfaclomide, Sulfaclorazole, mazole, thiamine, thiamiprine, thiamphenicol, thamylal, Sulfaclozine, Sulfacytine, Sulfadiazine, Sulfadimethoxine, thiazesim, thiazinamium, thiazolsulfone, thiethyperazine, Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanole, Sul thihexinol ethylbromide, thimerfonate, thimerosal, thio falene, Sulfaloxic acid, SulfamaZone, Sulfamerazine, Sulfame colchicoside, thioctic acid, thiofuradene, thioguanine, thio ter, Sulfamethazine, Sulfamethizole, Sulfamethoxazole, Sul hexamide, thioinosine, thiopental, thiophanate, thiopro famethoxypyridazine, Sulfametmidline, sulfametrole, 25 pazate, thioproperazine, thioridazine, thiosalan, thiostrpton, Sulfamonomethoxine, Sulfamoxole, Sulfanilamide, Sulfa thiotepa, thiotetrabarbital, thiothixene, thiphenamil, thiphen nilate, Sulfaanitran, Sulfaperin, Sulfaphenazole, Sulfaproxy cillin, thiram, thonzonium, thonZylamine, thoZalinone, threo line, Sulfapyridine, Sulfaquinoxaline, Sulfarsphenamine, Sul nine, thymocartin, thymoctonan, thymol, thymopentin, thy fasalazine, Sulfasomizole, SulfaSuccinamide, Sulfasymazine, motrinan, thyromedan, thyropropic acid, thyroxin, tiacrilast, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfatroxazole, 30 tiadenol, tiafibrate, tiagabine, tiamenidine, tiametomnium, Sulfatrozole, Sulfazamet, Sulfinaolol, Sulfinpyrazone, Sul tiamulin, tianafac, tianeptine, tiapamil, tiapirinol, tiapride, firam, sulfisomidine, sulfisoxazole, sulfobromophthalein, tiaprofenic acid, tiaprost, tiaramide, tiazofurin, tiaZuril, tia Sulfonterol, Sulforidazine, Sulfosalicylic acid, Sulfoxone, Sul balosin, tibeglisene, tibenelast, tibenzate, tibeZonium, crinat, Sulindac, Sulisatin, Sulisobenzone, Sulmarin, Sulma tibolone, tibric acid, tibrofan, ticabesine, ticalopride, ticarbo Zole, Sulmepride, Sulnidazole, Sulocarbilate, Suloctidil, Sulo 35 dine, ticarcillin, ticlatone, ticlopidine, ticolubant, ticrynafen, dexide, Sulofenur, Sulopenem, Sulosemide, Sulotroban, tidembersat, tidiacic acid, tiemonium, tienocarbine, tieno Suloxifen, Sulpiride, Sulprosal, Sulprostone, Sultamicillin, Sul pramine, tienoxolol, tifemoxone, tifenaZoxide, tiflamizole, tiame, Sultopride, Sultosilic acid, Sultroponium, Sulukast, Sul tiflorex, tifluadom, tiflucarbine, tiformin, tifurac, tigecycline, Verapride, Sumacetamol, Sumanirole, Sumarotene, Sumatrip tigemonam, tigestol, tigloidine, tillargenine, tiletamine, tili tan, Sumetizide, Sunagrel, Suncillin, Sunepitron, Supidimide, 40 dine, tiliquinol, tilisolol, tilmacoxib, tilmicosin, tilnoprofen, Supalast, Suproclone, Suprofen, Suramin, Suricainide, Suri tilomisole, tillorone, tilozepine, tilsuprost, tiludonic acid, tim clone, SuritoZole, Suronacrine, Susalimod, SuXemerid, Sux codar, timefurone, timegadine, timelotem, timepidium, timi ethonium, SuXibuZone, Symclosene, Synetine, tabilautide, perone, timirdine, timobesone acetate, timofibrate, timolol. tabimorelin, tacalcitol, tacapenem, tacedinaline, taclamine, timonacic, timoprazole, tinabinol, tinazoline, tinidazole, tacrine, tacrolimus, tadalafil, tafluposide, taglutamine, tago 45 tinisulpride, tinofedrine, tinoridine, tiocarlide, tioclomarol, rizine, talampanel, talampicillin, talaporfin, talastine, talb tioconazole, tioctilate, tiodaZosin, tiodonium, tiomergine, utal, taleranol, talibegron, talinolol, talipexole, talisomycin, tiomesterone, tioperidone, tiopinate, tiopronin, tiopropam tallimustine, talmetacin, talmetoprim, talnetant, talniflumate, ine, tioSpirone, tiotidine, tiotropium, tioxacin, tioXamast, talopram, talsalate, toloXimine, talsaclidine, talsupram, tioxaprofen, tioxidazole, tioXolone, tipentosin, tipepidine, taltirelin, taltobulin, taltrimide, taludipine, talviraline, 50 tipetropium, tipifarnib, tipindole, tipranavir, tipredane, tipre tameridone, tameticillin, tametraline, tamibarotene, tamiti nolol, tiprinast, tiprodil, tiprostanide, tiportimod, tiqueside, nol, tanolarizine, tamoxifen, tampramine, tamsulosin, tiquinamide, tiquizium, tiracizine, tirapazamine, tiratricol, tanaproget, tandamine, tandospirone, tandutinib, taniplon, tirilazad, tirofiban, tiropramine, tisartan, tisocalcitate, tanomastat, tapentadol, taprizosin, taprostene, tarazepide, tisocromide, tisopurine, tisoquone, tivanidazole, tiviciclovir, tariquindar, tasosartan, tasuldine, taurolidine, tauromustine, 55 tivirapine, tixadil, tixanox, tiXocortol, tiZabrin, tizanidine, tauroselcholic acid, taurosteine, tazadolene, tazanolast, taZ tizolemide, tizoprolic acid, tobicillin, toborinone, tobramy arotene, taZaSubrate, tazeprofen, tazifylline, taZiprinone, cin, tocainide, tocamphyl, tocladesine, tocofenoxate, tocofi taZobactam, tazofelone, tazolol, tazometime, tebanicline, brate, tocophersolan, todralazine, tofenacin, tofetridine, tebatizole, tebipenem, tebufelone, tebuquine, tecadenoson, tofimilast, tofisoline, tofisppam, tolafentrine, tolamolol. tecalcet, tecastemizole, teclthiazide, teclozan, tedisamil, tefa 60 tolaZamide, tolboxane, tolbutamide, tolvapone, tolciclate, Zoline, tefenperate, teflufazine, teflutiXol, tegafur, tegaserod, toldimfos, tolfamide, tolfenamic acid, tolgabide, tolimidone, teglicar, teicopamin, telavancin, telbivudine, telenzepine, tolindate, toliodium, toliprolol, tolmesoxide, tometin, tolnaf telinavir, tellithromycin, telmesteine, telmisartan, teloX tate, tolnapersine, tolnidamine, toloconium, tolonidine, tolo antrone, teludipine, temafloxacin, temarotene, tematropium, nium, toloxatone, toloxychlorinol, tolpadol, tolpentamide, temazepam, temefos, temelastine, temiverine, temocapril, 65 tolperisone, tolpiprazole, tolpronine, tolpropamide, tolpyrra temocaprilat, temocillin, temodox, temoporfin, temozolo mide, tolduinzole, tolrestat, tolterodine, toltraZuril, tolu mide, temisirolimus, temurtide, tenamfetamine, tenatopra fazepam, tolvaptan, tolycaine, tomeglovir, tomelukast, tomo US 8,158,152 B2 29 30 glumide, tomoxiprole, tonabersat, tonazocine, topilutamide, ViroXime, Visnadine, Visnafylline, Vofopiitant, Voglibose, topiramate, topixantrone, topotecan, toprilidine, topterone, Volazocine, Volpristin, Voriconazole, Vorozole, Voxergolide, toquizine, torbafylline, torcetrapib, torcitabine, toremifene, Xaliproden, Xamoterol, Xanomeline, Xanoxic acid, Xanthinol, toripristone, torsemide, tosagestin, tosifen, toSufloxacin, Xantifibrate, Xantocillin, Xanto?yl palmitate, Xemilofiban, to Sulur, trabectedin, traboXopine, tracazolate, tradecamide, Xenalipin, Xenazoic acid, Xenbucin, Xenipentone, Xenothio tralonide, tramadol, tramaZoline, trandolapril, trandolaprilat, rate, Xenygloxal, Xenylhexenicacid, Xenylropium, Xibenolol. tranexamic acid, tranilast, transcainide, trantelinium, trany Xibornol, Xidecaflur, Xilobam, Ximelagatran, Ximoprofen, cypromine, trapencaine, trapidil, travoprost, traXanox, traXo Xinidamine, Xinomiline, sipamide, Xipranolol. Xorphanol, prodil, traZitiline, trazium, traZodone, traZolopride, treben Xylamidine, Xylazine, Xylocoumarol. Xylometazoline, Xylox Zomine, trecadrine, trecetilide, trefentanil, trelnarizine, 10 emine, yohimbic acid, Zabicipril, Zabiciprilat, Zacopride, treloxinate, trenbolone, trengestone, trenizine, treosulfan, Zafirlukast, Zafiuleptine, Zalcitabine, Zalderide, Zaleplon, trepibutone, trepipam, trepirium, treprostinil, treptilamine, Zalospirone, Zalitidine, Zaltoprofen, Zamifenacin, Zanamivir, terquisin, tresperimus, trestolone, trethinium, trethocanoic Zanapezil, Zankiren, Zanoterone, Zapizolam, Zaprinast, Zard acid, tretinoin, tretinoin tocoferil, tretoquinol, triacetin, tri averine, Zatebradine, Zatosetron, Zelandopam, Zenarestat, afungin, triamcinolone, triamcinolone acetonide, triamcino 15 Zenazocine, Zeniplatin, Zepastine, Zeranol, Zetidoline, Zidapa lone benetonide, triamcinolone furetonide, triampyZine, tri mide, Zidometacin, Zidovudine, Zifrostilone, Zilantel, Zilas amternem triaziquone, triazolam, tribendilol, tribenoside, corb, Zileuton, Zilpaterol, Zimeldine, Zimidoben, Zindotrine, tribromsalan, tribuZone, tricaprilin, tricetamide, trichlorfon, Zindoxifene, Zinconazole, Zinostatin, Zinterol, ZinviroXime, trichlormethiazide, trichlomethine, triciribine, triclabenda Zipeprol, Ziprsidone, Zocainone, Zofenopril. Zofenoprilat, Zole, triclacetamol, triclazate, triclobisonium, triclocarban, Zoficonazole, Zolamine, Zolasartan, Zolazepam, Zolendronic triclodazol, triclofenol, triclofos, triclofyllin, triclonide, tri acid, Zolenzepine, Zollertine, Zolimidine, Zoliprofen, Zolmi closan, tricyclamol, tridihexethyl, tridolgosir, trientine, tri triptan, Zoloperone, Zolpidem, Zomebazam, Zomepirac, ethylenemelamine, trifenagrel, trifezolac, triflocin, trifluba Zometapine, Zonampanel, ZonicleZole, Zoniporide, Zonisa Zam, triflumidate, triflomeprazine, trifluperazine, mide, Zopiclone, Zopolrestat, Zorbamycin, Zorubicin, ZoSu trifluperidol, triflupromazine, trifluidine, triflusal, trifosmin, 25 quidar, Zotepine, Zoticasone, Zoxazolamine, Zucapsaicin, trigeVolol, trihexylpheidyl, triletide, triloStane, trimaZosin, Zuclomiphene, Zuclopenthixol, and Zylofuramine. trimebutine, trimecain, trimedoxime, trimegestone, trimep The solvent, as mentioned, can be any liquid in which the eridine, trimeprazine, trimetazidine, trimethadone, trimetha material dissolves; the solvent can be a single Substance or a mide, trimethaphan, trimethidinium, trimethobenzamide, tri mixture of co-solvents, the important point being that the methoprim, trimetozine, trimetrexZate, trimexiline, 30 material to be lyophilized goes into solution. Solvents useful trimipramine, trimoprostil, trimoxamine, trioxifene, triox in the invention include materials that are liquid at room salen, tripalmitin, tripamide, triparanol, tripelennamine, tri temperature, dissolve the material, and are volatilizable or platin, triprolidine, triptorelin, tritoqualine, trixolane, tri Sublimatable at the temperature and pressure conditions of Zoxime, trocimine, troclosene, trodusquemine, trofosfamide, the primary drying step discussed below. Since not all sol troglitaZone, troleandomycin, tromanttadine, tropabazate, 35 vents dissolve all materials, some of the potential solvents tropanserin, tropapride, tropatepine, tropenZiline, tropicam will not be solvents in particular cases. Those of ordinary skill ide, tropigline, tropirine, tropisetron, tropodifene, troquida will know which liquids are suitable as solvents once the Zole, trospectomycin, trospium, trovafloxacin, troVirdine, material to be lyophilized has been selected, by reference to troxacitabine, troXerutin, troXipide, troXolamide, troXonium, standard texts in the field or by the conduct of simple disso troxypyrrolium, truXicurium, truXipicurium, tryparsamide, 40 lution testing of the material with the potential solvent. The tubocurarine, tubulozole, tucaresol, tuclazepam, tulathromy chosen solvent will either alone dissolve the material or cin, tulobuterol, tulopafant, turosteride, tuvatidine, tybamate, together with a co-solvent will dissolve the material in ques tylosin, tymazolin, tyropanoate, tyrosine, tyrothricin, uben tion. Co-solvents are selected from the same class as solvents, imex, ubidecarenone, ubisindine, ufenamate, ufiprazole, are miscible with the chosen solvent, and generally aid the uldazepam, ulifloxacin, uliprisnil, umespirone, undecylenic 45 dissolution of the material in the solvent. Once the material in acid, unoprostone, upenazime, upidosin, uracil, uracil mus question is selected and the solvent and any co-solvent is tard, urapidil, uredepa, uredofos, urefibrate, ursodiol. selected, the anti-solvent is also selected from the same set of urulcholic acid, utibapril, utibaprilat, Vadocaine, Valaciclovir, Substances, but limited to those which do not significantly Valconazole, Valdecoxib, Valdetamide, Valdipromide, Vale dissolve the material, preferably do not dissolve the material thamate, vlaganiciclovir, Valine, Valnemulin, Vlanoctamide, 50 at all, and yet are miscible with the chosen solvent/optional valofane, Valomaciclovir, Valperinol, Valproate, Vlaproicacid, co-solvent system previously selected. For purposes of the valpromide, Valrocemide, valrubicin, Valsartan, Valorcitab present invention, solubility of the material in the solvent or ine, Valtrate, Vamicamide, Vancomycin, Vandetanib, Vanep solvent/cosolvent mixture is critical only in that the material rim, Vanitiolide, VanoXerine, Vanyldisulfamide, Vapiprost, needs to be dissolved. The concentration of the material in the Vapreotide, Vardenfanil, Varenicline, Varespladib, Vatalanib, 55 Solvent or solvent/co-solvent mixture is only of concern in Vatanidipine, Vebufloxacin, Vecuronium, Vedaclidine, certain situations. For example, in pharmaceutical injectable Vedaprofen, Velaresol, Velnacrine, Venlafaxine, Venritidine, formulations, where the material is lyophilized in containers Verodoline, Veralipride, Verapamil, Verazide, Verilopam, Ver that, once reconstituted in the container contain unit dosage of lukast, Verofylline, versetamide, Verteporfin, Vesnarinone, the material for administration, materials requiring a small vestipitant, Vetrabutine, Vidarabine, vigabatrin, VilaZodone, 60 unit dose may utilize a significant volume of “solvent in the Vildaglipin, Viloxazine, vinbarbital, vinblastine, vinburnine, lyophilization procedure. However, where the material Vincamine, Vincanol, Vincofos, Vinconate, Vincristine, Vinde requires a large unit dose, the liquid chosen as the Solvent burnol, Vindesine, Vinpidine, Vinflunine, Vinformide, VinfoS must necessarily be a much better solvent for the materialso iltine, Vinglycinate, Vinleucinol, Vinleurosine, Vinmegallate, that the amount of solvent needed to dissolve the unit dose is Vinorelbine, Vinpocetine, Vinpoline, Vinrosidine, Vintiamol. 65 amenable to being placed in the lyophilization container for Vintoperol, Vintriptol, vinylbital, Vinzolidine, Viomycin, processing economically. While these same concerns are Viprostol, Vicqualine, Vicquidil, Virginiamycin, viridofulvin, important to bulk lyophilization procedures as well, they are US 8,158,152 B2 31 32 less stringent than where the lyophilization containers are the primary solvent so as to effect dissolution of the material. intended as the reconstitution container having unit doses. Such co-solvents should be used as minimally as possible so Thus, the choice of a liquid as a solvent or a co-solvent not as to avoid unnecessarily complicating the solid product (po only depends upon the intrinsic ability to dissolve the material tentially mixed solvate crystal forms or mixed solvent amor in question, but on its relationship to the amount of the solu phous associations, etc.), but there is no other reason to avoid tion that can be placed in the lyophilization container them and their use is within the scope of the present invention. intended to have a specific amount of endlyophilizate. Those Where a co-solvent is utilized, it must also be one that is of ordinary skill in the art will appreciate these concerns and Volatile or Sublimates under the primary drying step condi be able to readily modify their particular choices to accom tions. modate these concerns. Similar concerns apply to the choice 10 If desired, the solution pH may be adjusted within a range of anti-solvent. either to facilitate the solubility of the compound or to provide The lyophilization procedures herein can also be used to a particular pH environment for optimum stability that is prepare rapidly disintegrating tablets that dissolve in the compatible with the end use of the lyophilizate. Thus, for mouth without the need for water to Swallow the tablet. Cur product that will be reconstituted with water for injection, rently available rapidly dissolving tablets (technology owned 15 with or without tonicity modifiers therein, the pH should be by Zydus) is only applicable to hydrophilic molecules having Such that on reconstitution, a physiologically tolerated com a low unit dose requirement (generally less than about 15 mg patible pH is achieved. This is less of concern with materials per dose) which do not require taste-masking. The current that will be incorporated into more complex formulations or invention, on the other hand, permits creating a lyophilizate in that will be used as reagents for further reactions. In these a tablet mold so that the lyophilizate takes the shape of a latter situations, the pH of the lyophilizate does not necessar tablet. Since the present lyophilization method can omit vir ily correlate with its end pH so that a larger latitude of pH tually all auxiliary materials if the drug doesn’t require taste values in the lyophilizate are acceptable. masking, it is applicable to materials having a high unit dose In one embodiment of the invention, once the solution is amount (hundreds to more than 1 gram per unit dose), as well obtained (and any desired pH adjustment and any desired as to those having Small unit dosage amounts. Furthermore, 25 filtration pre-material precipitation has taken place), the solu while the Zydus technology is available only with respect to tion can be added to an anti-solvent for the material or can hydrophilic materials, the present invention is applicable to have such anti-solvent added to it. The purpose of this step is both hydrophilic and hydrophobic materials. to force the material out of solution in a manner which will Suitable, non-limiting, liquids for use as solvents, co-sol permit recovery of the desired form of the material. The vents, or anti-solvents, depending on the circumstances as 30 anti-solvent is a substance which is not a solvent for the outlined elsewhere in this specification include, but are not material, but is miscible with the solvent and, if present, any limited to water, 5-7 membered heteroring systems (the het co-solvent, used. The anti-solvent must also be a substance eroring systems having 1-3 heteroatoms, where the heteroa that can be removed in the context of the freeze-drying itself. toms are oxygen or Sulfur, the Sulfur atoms being unsubsti Thus, it is a substance which is volatile or sublimes at the tuted or further carrying one or two oxygen Substituents, 35 temperature and pressure used in the primary drying step of except that two oxygen atoms cannot be in adjacent ring the freeze-drying process. As stated above, the anti-solvent is positions, for example tetrahydrofuran (THF), tetrahydropy selected from the same group of liquids set forth above, ran, dioxane, trioxane and other cyclic mono-, di- and tri except that for use as an anti-solvent, the liquid must adhere to ethers), lower alkanols (such as ethanol, propanol, isopro the constraints of this paragraph with respect to the particular panol, sec-butanol, t-butyl alcohol, and n-butyl alcohol), or 40 material/solvent/optional co-solvent system in question. other organic solvents that freeze in the range of a lower In another embodiment of the invention, in which the mate temperature of about -100° C., preferably -90° C., more rial is hydrophobic or lipophilic, the solvent is selected from, preferably -80° C., and an upper temperature of not more 5-7 membered heteroring systems (the heteroring systems than about 25°C., preferably not more than about 20°C., even having 1-3 heteroatoms, where the heteroatoms are oxygen or more preferably not more than about 15° C., still more pref 45 sulfur, the sulfur atoms being unsubstituted or further carry erably not more than about 10°C. In addition, PEG 600-6000 ing one or two oxygen Substituents, except that two oxygen and tocopherol Succinate and acetate can also be used. atoms cannot be in adjacent ring positions, for example tetra Preferably, the solvent is water, especially for hydrophilic hydrofuran (THF), tetrahydropyran, dioxane, trioxane and materials. Water is preferred in the context of pharmaceuti other cyclic mono-, di- and tri-ethers). The use of these liq cals, Veterinary products, and foodstuffs because any residual 50 uids as solvents in the lyophilization process is new to the Solvent that remains with the Solid is innocuous once the lyophilization art. In addition, in the lyophilization of hydro lyophilizate is reconstituted with water. In applications in phobic or lipophilic materials according to the invention, industries other than the above or where the freeze dried lower alkanols (methanol, ethanol, propanol, isopropanol, product is desired as a reactant in further reactions, other n-butanol, sec-butanol, or t-butanol), liquid ketones, liquid solvents, both within and beyond those set forth above may be 55 (oxygen or Sulfur) ethers, liquid (oxygen or Sulfur) ketones, preferred as well and will be well within the ordinary skill of liquid (oxygen or Sulfur) esters or thioesters may also be used those in the art. Nonetheless, the solvent must be one that is as the liquid solvent. In these embodiments, in addition to Volatile or Sublimates under the primary drying step condi utilizing the anti-solvent as indicated above, the system can tions. Other preferable liquids for use in the invention as the omit the anti-solvent and directly lyophilize the solution of Solvent or as the co-solvent or as the anti-solvent as dictated 60 the material in these liquids, in a manner completely analo by the particulars of the material in question include ethanol, gously to completely aqueous lyophilization techniques. tetrahydrofuran, and dioxane. When omitting the anti-solvent, the preferred solvents are the If desired, a co-solvent may be used to aid in the dissolution heteroring solvents discussed above. The lyophilizate here as of the material in the solvent. As stated above, such co with the resultant lyophilizate of hydrophobic and lipophilic Solvents are selected from the same group of liquids above, as 65 embodiments when using the anti-solvent process above do, long as the co-solvent is different from the solvent in question however, require different reconstitution techniques than in the particular embodiment in question and miscible with those for the hydrophilic materials. US 8,158,152 B2 33 34 Again, it should be noted that for any given material, not all anti-solvent to solvent/co-solvent utilized as well as the speed of the liquids listed above will be solvents for the specific of the addition when adding anti-solvent to the solvent/co material, however, a mere solubility test will determine if the Solvent/material Solution as well as freezing conditions. The particular solvent is suitable for a particular material. If the reverse addition of solvent/co-solvent/material to anti-sol material is soluble in the particular liquid, then the liquid is vent results in a very rapid precipitation since the ratio of suitable as a solvent and/or co-solvent. If the material is not anti-solvent to solvent/co-solvent is always very high during soluble in the liquid, then that is a potential anti-solvent for the addition. that system if and only if it is also miscible with the solvent or Once the precipitation is effected (or once the dissolution is Solvent/co-solvent system being used. Suppose a material has effected in the embodiments that omit the anti-solvent), the a solubility in a liquid A of 1000 mg/ml, in liquid B of 100 10 mixture is frozen in a cooling step that is typically over a mg/ml, in liquid C of 10 mg/ml, and in liquid D of 0.01 period of about 30 minto 10 hours, preferably about 1 our to mg/ml. Further, Suppose that the material has a unit adult dose about 8 hours, more preferably about 2 hours to about 7 hours, of 300 mg, a unit pediatric dose of 60 mg, and an infant unit typically about 4 to about 6 hours to result in a frozen mass. A dose of 12 mg. To prepare a suitable adult dose of the inven quick freezing generally favors amorphous product, while a tion, one would use liquid A (and possibly liquid B) as the 15 slow cooling generally favors a more crystalline product; Solvent. Liquid D is an clearly Suitable as an anti-solvent, but however, this is only a general guideline, and particular liquid C might also be suitable as the anti-solvent. To prepare results can vary depending on a number of conditions. If a Suitable pediatric unit dose of the invention, one might use desired, prior to freezing, the mixture can be filtered so that liquidA, but liquid B might be a better choice depending upon the bulk of the solvent/co-solvent/anti-solvent is removed/ available equipment precision. Liquid C, while it can be used recovered leaving behind a precipitate wet with some of the as the anti-solvent, since it can still dissolve an appreciable solvent/co-solvent/anti-solvent mixture, which is then sub amount of the unit dose amount, it is preferably not so used, jected to the freezing step. (This procedure applies especially and the better choice as the anti-solvent is liquid D. In pre when preparing sterile bulk, not unit dose vials for parenteral paring a Suitable infant unit dosage of the invention, liquid C administration). is not only not suitable as the anti-solvent (since it is capable 25 Once frozen, the mass is subjected to a vacuum pressure of dissolving virtually the entire unit dosage amount, but whereby a Substantial portion, if not all of the remaining precisely because of this, it might actually be suitable for use solvent/co-solvent/anti-solvent is volatilized off during pri as the solvent while liquid D would be the anti-solvent. Thus, mary drying. Remaining residual amounts of one or more of given the particulars of the individual situation of the various Solvent and/or co-solvent and/or anti-solvent are removed in solubilities in the various liquids as potential solvent and 30 a secondary drying step. Generally, during the primary drying anti-solvents, and the specifics of the unit dosage amounts the product temperature is maintained below 0°C while in the needed to be in the lyophilized product, a single liquid may be secondary drying the product temperature will be maintained a solvent in Some cases and yet an anti-solvent in others even at about 25 to 40°C., although other primary and secondary for the same material intending to be lyophilized. Thus, while drying temperatures may be suitably found in the ordinary Some testing is necessary to determine the specifics of the 35 course by those of ordinary skill in the art. systems within the invention, such is well within the abilities The lyophilizates prepared according to the invention can of one of ordinary skill in the art. Generally, liquids that are be prepared in situ in the container that will be used for suitable as solvent or co-solvents for hydrophilic materials reconstitution; in molds (or blister packs) for preparing rap are likely to be anti-solvents for hydrophobic or lipophilic idly dissolving tablets; or can be prepared in bulk for use in materials, while anti-solvents for hydrophilic materials are 40 any other processes or reactions as desired. Thus, bulk chemi likely to be solvents and co-solvents for hydrophobic and/or cals can be prepared and packaged for blending with other lipophilic materials. Similarly, liquids that are solvents and/or components at a user's convenience or need. Similarly Small co-solvents for hydrophobic and/or lipophilic materials are portions of lyophilizates of the invention may be prepared in likely to be anti-solvents for hydrophilic materials, while unit of use containers and packed with dissolution media in carriers that are anti-solvents for hydrophobic and/or lipo 45 Suitable kits for ease of preparing single units of use. philic materials are likely to solvents or co-solvents for In one particularly preferred embodiment, amifostine (a hydrophilic materials. highly water soluble material) is the hydrophilic material, The material/solvent/co-solvent (if present)/anti-solvent water is selected as the solvent, and tetrahydrofuran is (if present) system is then frozen and the frozen product is selected as the anti-solvent. Also, tetrahydropyran, dioxane, subjected to vacuum to sublimate or volatilize the solvent, 50 trioxane and the other liquid heteroring compounds men so-solvent/anti-solvent components. tioned in paragraphs 0034-0036 can be used as anti-solvents In general, in the embodiments in which anti-solvent is for amifostine when water is the solvent. Of the aforemen utilized, once the solution of the material is formed in the tioned solvents, dioxane offers special advantages over other solvent or solvent/co-solvent mixture, the solution is mixed organic solvents. Dioxane freezes below 15°C and subli with anti-solvent in a proportion in the range of about 5:1 to 55 mates rapidly under vacuum. Use of dioxane as an anti about 1:5, preferably about 4:1 to about 1:4, more preferably Solvent does not require any solvent trap and can be lyo about 3:1 to about 1:3; even more preferably about 2:1 to philized similar to completely aqueous lyophilization. about 1:2, still more preferably about 1.5:1 to about 1:1.5, still Similarly trioxane also has a low meting point and can be even more preferably about 1:1 on a volume/volume basis of easily removed during the lyophilization. Optionally, the pH (solvent and/or-solvent): (anti-solvent). 60 can be adjusted to into the range of about 7 to about 8 prior to The addition of the anti-solvent causes thematerial to come adding the anti-solvent. out of solution. This precipitation can be allowed to continue In another preferred embodiment, a slurry is made using for as long as desired before the freezing step takes place, but ceftazadime and water. The pH is adjusted to about 5 to about the slower the precipitation, the greater the likelihood that the 7 using NaOH to facilitate the dissolution of ceftazidime. precipitated material will adopt a crystalline conformation. 65 Once solution is effected, an anti-solvent, such as THF, diox The speed of precipitation and thus the degree of crystallinity ane or one of the other liquid heteroring compounds is added or amorphous character can be controlled by the ratio of to precipitate the ceftazadime, which is then frozen and dried. US 8,158,152 B2 35 36 In this embodiment, lower alkanols. Such as ethanol, n- or product will have the non-acceptable material removed prior iso-propanol, or n-, sec-, or t-butanol may also be used as the to that product being used). Bulking agents that are generally anti-solvent. The same procedure is generally applicable to Suitable are those which raise the glass transition temperature other cephalosporins, especially to ceftrioxone and cephra of the material being lyophilized. For pharmaceuticals these dine. generally include, but are not limited to, saccharides (such as In another embodiment, a slurry of cefapime is made in fructose, Sucrose, lactose, trehalose, and others), polyvi water. The pH is adjusted to about 1 to about 3 with HCl (or nylpyrrolidone, and cyclodextrins, the saccharides being pre other Suitable inorganic acid) to facilitate dissolution. Once ferred, and trehalose being a particularly Suitable material. dissolved, anti-solvent (liquid herteroring compounds) is Complexing/solubilizing agents include niacinamide and added to precipitate the cefapime, and the result is freeze 10 other cyclic amide, gentisic acid, cyclodextrins and Surfac dried. tants with HLB values ranging from 1 to 16. Nonetheless, in In a further embodiment, cyclophosphamide (sparingly most instances, the invention permits the omission of the soluble in water but highly soluble in ethanol) is dissolved in bulking agent, and the absence of bulking agent is a preferred one or more of the liquid hetero-ring compounds and/or lower embodiment. For pharmaceutical purposes, buffers can be, alkanols to form a concentrated solution. Water is then added 15 but are not limited to, amino acids, inorganic buffers, mono as an anti-solvent to precipitate the crystalline cyclophospha and di-carboxylic acid buffers, hydroxyl-mono- and di-car mide monohydrate or anhydrate. The result is then freeze boxylic acid buffers, amines, and Sulfonamides. The antioxi dried. dants include, but are not limited to, different class of In another particularly preferred embodiment, itraconazole bisulfites, ascorbic acid, disodium- and tetrasodium EDTA, is the hydrophobic/lipophilic material and a non-aqueous citrates as metalion chelators, BHA, BHT, sulfoxylates, pro liquid is selected as a solvent to dissolve it. An anti-solvent is pyl gallate, amino acids containing thio group Such as not needed to lyophilize the hydrophobic/lipophilic mol methionine, and thiols as well as other antioxidants listed in ecule. The non-aqueous solvents to dissolve lipophilic mol the FDA website for inactive ingredients used in pharmaceu ecules are listed in paragraph 0034-0036. In addition ethanol tical dosage forms. and PEG 600-6000 and tocopherol succinate and acetate can 25 Lyophilizates of the present invention have significantly also be used as solvents to solubilize lipophilic materials. improved stability over materials prepared without lyo Once the material is dissolved in the non-aqueous solvent, it philization or prepared via currentlyophilization techniques is filtered asceptically to remove any undesired components other than those of the invention. For example, a completely and microorganisms and filled into vials and lyophilized water lyophilization of amifostine results in a material that either using the conventional lyophilization procedures or 30 degrades to 80% of its initial amifostine amount in 30 days, special procedures depending on the nature and amount of when stored at 40°C. Amorphousamifostine lyophilizate of non-aqueous solvents used to dissolve the material. The lyo the invention using water as the solvent and tetrahydrofuran philizate can be reconstituted with minimum volume of phar as the anti-solvent, stored under the same conditions, results maceutically acceptable solvent (typically polyethylene gly in degrading to only 98% of its initial amount in 30 days and color liquid PEGs) to prepare a liquid concentrate. The liquid 35 to 90% of its initial amount in 90 days. concentrate is further diluted to a desirable concentration in a The lyophilizates of the present invention (when limited to special diluent or commercially available Intralipid fat emul pharmaceutical and veterinary active agents, as previously sions, or plasma or serum or in whole blood prior to admin discussed, can be utilized in the preparation of injectable final istering to patients. One aspect of the novelty of this embodi products as well as in rapidly dissolving oral dosage forms. In ment of the invention is that patient’s blood can be used to 40 addition, they can be utilized in the preparation of other oral dilute the liquid concentrate and administer back into the dosage forms (tablets, capsules, powders, etc) for ingestion as patients blood stream. Since these molecules are lipophilic, is or for rapid dissolution in liquids for ingestion. Still further, they will partition into the lipid layer of the fat emulsion or the lyophilizates can be applied topically as is to wet or blood. “weeping? oozing Surfaces for administration. These In a still further embodiment, itraconazole is dissolved in 45 include, without limitation topical application to open or non-aqueous liquid such as THF at a very high concentration. oozing wounds, as well as to mucous membranes. Inhalation Itraconazole is generally considered soluble in methylene of lyophilizate powder for application to the nose and bron chloride only. We Surprisingly found that high concentrations chial tree, as well as instillation of the powder to the eye, oral of itraconazole can be dissolved in the non-aqueous solvents mucosa, rectum, vaginal, uterine, urethral, and urinary blad listed in the paragraph 0034-0036 in the presence of small 50 der tissues are contemplated by the present invention. In quantities of HC1. The itraconazole thus dissolved in the non addition, the lyophilzates can be rapidly dissolved in appro aqueous solvent is lyophilized. The lyophilizate is reconsti priate liquid media for administration to these tissues as well. tuted to 100 mg/ml Solution using pharmaceutically accept able solvent, typically propylene glycol. The liquid concen EXAMPLES trate is further diluted with 25 ml or more of 10% Intralipid fat 55 emulsion. The aqueous and oil phase of the emulsion is sepa Example 1 rated by using an ultracentrifuge and it is observed that all the itraconazole is partitioned into the fat layer of the emulsion. A sufficient amount of amifostine is dissolved in water to While some embodiments seek to eliminate auxiliary com resultina concentration in the range of 100 to 500 mg/ml. The ponents in the lyophilization process, not all auxiliaries need 60 solution is asceptically filtered through a 0.2 micron filter be eliminated. Thus, as desired, the solution prepared prior to (Pall filter membrane Nylon 66 or any compatible filter). any precipitation of the material and prior to any freezing step Separately, tetrahydrofuran is asceptically filtered using a can have Suitable auxiliary materials such as building agents, Pall filter membrane Nylon 66.2 ml of the filtered amifostine buffers, and anti-oxidizing agents. Each of the auxiliary solution is placed in a 5 ml USP type 1 pre-sterilized and agents must be compatible with the end use or be capable of 65 depyrogenated flint vial and 1 ml of the filtered THF is added being removed prior to use (as when the lyophilizate is being thereto. The vial contents become cloudy. The vials having used in further reactions or where the subsequently purified the amifostine, water, and THF are placed onto a lyophiliza US 8,158,152 B2 37 38 tion tray, which is then introduced into a lyophilization cham Example 8 ber. The chamber temperature is set to -30° C. When the product temperature reaches -25°C., the condenser is turned A sufficient amount of itraconazole is dissolved in acidified on at a setting of -50° C. or below. When the condenser tetrahydrofuranto resultina concentration in the range of 100 temperature reaches -40°C., the vacuum pump is turned on to 500 mg/ml. The solution is asceptically filtered through a and the vacuum monitor gauge is adjusted to 200 microns. 0.2 micron filter (Pall filter membrane Nylon 66 or any com When the vacuum reaches 200 microns, the shelf temperature patible filter). Separately, water is asceptically filtered using a is set to -5°C. and the product is dried for 12 hours. At the Pall filter membrane Nylon 66 (or any compatible filter).2 ml conclusion of the 12 hours, the shelf temperature is reset to of the filtered itraconazole solution is placed in a 5 ml USP 30° C. and the product is dried for an additional 15 hours. The 10 type 1 pre-sterilized and depyrogenated flint vial and 1 ml of equipment is bleeded with nitrogen to bring the pressure back the filtered water is added thereto. The vial contents become to atmospheric pressure, the vials are stoppered, and sealed cloudy. The vials having the itraconazole, water, and THF are with aluminum caps. placed onto a lyophilization tray, which is then introduced into a lyophilization chamber. The chamber temperature is set Example 2 15 to -30°C. When the product temperature reaches -25°C., the condenser is turned on at a setting of -50° C. or below. When Example 1 is repeated with the following variations as set the condenser temperature reaches -40° C., the vacuum forth in Table I pump is turned on and the vacuum monitor gauge is adjusted TABLE I

AMIFOSTINE THF FREEZE PRIMARY SECONDARY SAMPLE AMOUNT AMOUNT TEMP DRYTIME DRYTIME A. 100 mg 0.1 m -40 2 HOURS 2 HOURS B 200 mg 0.1 m -40° 20 HOURS 20 HOURS C 300 mg 0.1 m -40 2 HOURS 2 HOURS D 400 mg 0.1 m -40 2 HOURS 2 HOURS E 500 mg 0.1 m -40 2 HOURS 2 HOURS 100 mg O.25 m -30° SHOURS SHOURS G 200 mg O.25 m -30° SHOURS SHOURS H 300 mg O.25 m -2O 8 HOURS SHOURS I 400 mg O.25 m -2O 8 HOURS SHOURS J 500 mg O.25 m -40° 20 HOURS SHOURS K 100 mg O.5 m -35° 2OHOURS SHOURS 200 mg O.S in -350 4 HOURS 8 HOURS M 300 mg O.5 m -2O 4 HOURS 8 HOURS N 400 mg O.5 m -25 3 HOURS 8 HOURS O 500 mg O.5 m -25 3 HOURS 8 HOURS C 100 mg 1 m -2O 2 HOURS 8 HOURS Q 200 mg 1 m -30° SHOURS SHOURS R 300 mg 1 m -30° SHOURS SHOURS S 400 mg 1 m -2O 8 HOURS SHOURS T 500 mg 1 m -2O 8 HOURS SHOURS U 100 mg 2 m -40° 20 HOURS SHOURS V 200 mg 2 m -35° 2OHOURS SHOURS W 300 mg 2 m -350 4 HOURS 8 HOURS X 400 mg 2 m -2O 4 HOURS 8 HOURS Y 500 mg 2 m -25 3 HOURS 8 HOURS

45 whereby suitable lyophilizates can be obtained. to 200 microns. When the vacuum reaches 200 microns, the shelf temperature is set to -5°C. and the product is dried for Example 3 12 hours. At the conclusion of the 12 hours, the shelf tem perature is reset to 30° C. and the product is dried for an Example 2 is repeated using dioxane as the anti-solvent, 50 additional 15 hours. The equipment is bleeded with nitrogen whereby suitable lyophilizates can be obtained. to bring the pressure back to atmospheric pressure, the vials are stoppered, and sealed with aluminum caps. Examples 4-7 Example 9 Examples 2-3 are repeated except that amifostine is 55 replaced (a) with ceftazadine with the water having a pH of 5-7 (Examples 4-5) or (b) with cefapine with the water having Example 8 is repeated with the following variations as set a pH of 1-3, whereby suitable lyophilizates can be obtained. forth in Table II TABLE II

INTRACONAZOLE THF FREEZE PRIMARY SECONDARY SAMPLE AMOUNT AMOUNT TEMP DRY TIME DRY TIME

A. 100 mg 1 ml -40 12 HOURS 12 HOURS B 200 mg 2 ml -40 2OHOURS 2OHOURS C 300 mg 3 ml -40 12 HOURS 12 HOURS US 8,158,152 B2 39 40 TABLE II-continued

INTRACONAZOLE THF FREEZE PRIMARY SECONDARY SAMPLE AMOUNT AMOUNT TEMP DRY TIME DRY TIME D 400 mg 4 m -40 2 HOURS RS E 500 mg 5 m -40 2 HOURS RS 100 mg 1 m -30° SHOURS RS G 200 mg 2 m -30° SHOURS RS H 300 mg 3 m -20 8 HOURS RS I 400 mg 4 m -20 8 HOURS RS J 500 mg 5 m -40 2OHOURS RS K 100 mg 1 m -350 2OHOURS RS 200 mg 2 m -350 4 HOURS RS M 300 mg 3 m -20 4 HOURS RS N 400 mg 4 m -25 3 HOURS RS O 500 mg 5 m -25 3 HOURS RS C 100 mg 1 m -20 2 HOURS RS Q 200 mg 2 m -30° SHOURS RS R 300 mg 3 m -30° SHOURS RS S 400 mg 4 m -20 8 HOURS RS 500 mg 5 m -20 8 HOURS RS U 100 mg 1 m -40 2OHOURS RS V 200 mg 2 m -350 2OHOURS RS W 300 mg 3 m -350 4 HOURS RS X 400 mg 4 m -20 4 HOURS RS Y 500 mg 5 m -25 3 HOURS RS whereby suitable lyophilizates can be obtained. 25 lipophilic non-solvents of step (b) to yield a frozen result, the frozen result comprising a frozen portion; and Example 10 (d) vacuum drying the frozen result of step (c) to yield a lyophilizate. Example 9 is repeated using dioxane as the solvent w 2. The method of claim 1 wherein the hydrophilic pharma whereby suitable lyophilizates can be obtained. 30 ceutical compound is crystalline. 3. The method of claim 1 wherein the hydrophilic pharma Examples 11-12 ceutical compound is amorphous. Examples 9-10 are repeated except that the water anti 4. The method of claim 1 wherein the lyophilizate is crys talline. solvent is omitted, whereby suitable lyophilizates can be 35 obtained. 5. The method of claim 1 wherein the lyophilizate is amor phous. Example 13-17 6. The method of claim 1, further comprising at least one of (i) aseptically filtering the Solution of step (a) prior to the Example 9 is repeated using ethanol (Example 13), tetrahy 40 addition of the lipophilic non-solvent thereto; and (ii) asepti dropyrane (Example 14), isopropanol (Example 15), toco cally filtering the lipophilic non-solvent prior to the addition pherol acetate (Example 16), or tocopherol Succinate (EX of the lipophilic non-solvent to the solution of step (a). ample 17) as the solvent whereby suitable lyophilizates can 7. The method of claim 1 wherein the hydrophilic solvent be obtained. is water. 45 8. The method of claim 1 wherein the hydrophilic solvent I claim: is a lower alkanol. 1. A method of lyophilizing a hydrophilic pharmaceutical 9. The method of claim 8 wherein the lower alkanol is compound comprising: ethanol, propanol, isopropanol, sec-butanol, t-butyl alcohol, (a) dissolving the hydrophilic pharmaceutical compound or n-butyl alcohol. in one or more hydrophilic solvents to form a solution, 50 wherein the one or more hydrophilic solvents is a liquid 10. The method of claim 1 wherein the lipophilic non in which the hydrophilic pharmaceutical compound dis Solvent is a cyclic mono-, di-, or tri-ether. 11. The method of claim 10 wherein the cyclic mono-, di-, Solves; or tri-ether is tetrahydrofuran, tetrahydropyran, dioxane, or (b) adding one or more lipophilic non-solvents for the trioxane. hydrophilic pharmaceutical compound to the solution, 55 wherein: 12. The method of claim 1, further comprising adding a (i) the one or more lipophilic non-solvents is a liquid in co-solvent to the hydrophilic solvent. which the hydrophilic pharmaceutical compound is 13. The method of claim 12 wherein the co-solvent is essentially insoluble, selected from the group consisting of polyethylene glycol (ii) the one or more lipophilic non-solvents is miscible 60 600-6000. with the one or more hydrophilic solvents, 14. The method of claim 1, further comprising adding a (iii) the one or more lipophilic non-solvents is volatiliz bulking agent. able under freeze-drying conditions, and 15. The method of claim 14 wherein the bulking agent is (iv) the hydrophilic pharmaceutical compound at least selected from the group consisting of a saccharide, polyvi partially precipitates; 65 nylpyrrolidone, a cyclodextrin, and trehalose. (c) freezing the hydrophilic pharmaceutical compound, the 16. The method of claim 1, further comprising adding a one or more hydrophilic solvents and the one or more solubilizer, a surfactant or a combination thereof. US 8,158,152 B2 41 42 17. The method of claim 16 wherein the solubilizer is 28. The method of claim 24 wherein the lyophilizate is selected from the group consisting of a cyclic amide, gentisic amorphous. acid, and a cyclodextrin. 29. The method of claim 24, further comprising at least one of (i) aseptically filtering the solution of step (a) prior to the 18. The method of claim 16, wherein the surfactant com addition of the hydrophilic non-solvent thereto; and (ii) asep prises a hydrophilic-lipophilic balance (HLB) value ranging tically filtering the hydrophilic non-solvent prior to the addi from 1 to 16. tion of the lipophilic non-solvent to the solution of step (a). 19. The method of claim 1, further comprising adding a 30. The method of claim 24 wherein the hydrophilic non buffer. solvent is water. 20. The method of claim 19, wherein the buffer is selected 31. The method of claim 24 wherein the hydrophilic non from the group consisting of an amino acid, an inorganic 10 Solvent is a lower alkanol. buffer, a mono- or di-carboxylic acid buffer, a hydroxyl 32. The method of claim 31 wherein the lower alkanol is mono- or di-carboxylic acid buffer, an amine, and a Sulfona ethanol, propanol, isopropanol, sec-butanol, t-butyl alcohol, mide. or n-butyl alcohol. 21. The method of claim 1, further comprising adding an 15 33. The method of claim 24 wherein the lipophilic solvent antioxidant. is a cyclic mono-, di-, or tri-ether. 22. The method of claim 21 wherein the antioxidant is 34. The method of claim 33 wherein the cyclic mono-, di-, selected from the group consisting of a bisulfite, ascorbic or tri-ether is tetrahydrofuran, tetrahydropyran, dioxane, or acid, disodium- or tetrasodium ethylenediaminetetraacetic trioxane. acid, a citrate as metalion chelator, butylated hydroxyanisole, 35. The method of claim 24, further comprising adding a butylated hydroxytoluene, a Sulfoxylate, propyl gallate, an co-solvent to the lipophilic solvent. amino acid containing a thio group, and a thiol. 36. The method of claim 35 wherein the co-solvent is 23. The method of claim 1 wherein the frozen result further selected from the group consisting of polyethylene glycol 600-6000. comprises an unfrozen portion. 37. The method of claim 24, further comprising adding a 24. A method of lyophilizing a lipophilic pharmaceutical 25 compound comprising: bulking agent. (a) dissolving the lipophilic pharmaceutical compound in 38. The method of claim 37 wherein the bulking agent is one or more lipophilic solvents to form a solution, selected from the group consisting of a saccharide, polyvi wherein the one or more lipophilic Solvents is a liquid in nylpyrrolidone, a cyclodextrin, and trehalose. which the lipophilic pharmaceutical compound dis 30 39. The method of claim 24, further comprising adding a solubilizer, a surfactant or a combination thereof. Solves; 40. The method of claim 39 wherein the solubilizer is (b) adding one or more hydrophilic non-solvents for the selected from the group consisting of a cyclic amide, gentisic lipophilic pharmaceutical compound to the solution, acid, and a cyclodextrin. wherein: 41. The method of claim 39, wherein the surfactant com (i) the one or more hydrophilic non-solvents is a liquid in 35 prises a hydrophilic-lipophilic balance (HLB) value ranging which the lipophilic pharmaceutical compound is from 1 to 16. essentially insoluble, 42. The method of claim 24, further comprising adding a (ii) the one or more hydrophilic non-solvents is miscible buffer. with the one or more lipophilic solvents, 43. The method of claim 42, wherein the buffer is selected (iii) the one or more hydrophilic non-solvents is volatil 40 from the group consisting of an amino acid, an inorganic izable under freeze-drying conditions, and buffer, a mono- or di-carboxylic acid buffer, a hydroxyl (iv) the lipophilic pharmaceutical compound at least mono- or di-carboxylic acid buffer, an amine, and a Sulfona partially precipitates; mide. (c) freezing the lipophilic pharmaceutical compound, the 44. The method of claim 24, further comprising adding an one or more lipophilic solvents and the one or more 45 antioxidant. hydrophilic non-solvents of step (b) to yield a frozen 45. The method of claim 44 wherein the antioxidant is result, the frozen result comprising a frozen portion; and selected from the group consisting of a bisulfite, ascorbic (d) vacuum drying the frozen result of step (c) to yield a acid, disodium- or tetrasodium ethylenediaminetetraacetic lyophilizate. acid, a citrate as metalion chelator, butylated hydroxyanisole, 25. The method of claim 24 wherein the lipophilic phar 50 maceutical compound is crystalline. butylated hydroxytoluene, a Sulfoxylate, propyl gallate, an 26. The method of claim 24 wherein the lipophilic phar amino acid containing a thio group, and a thiol. maceutical compound is amorphous. 46. The method of claim 24 wherein the frozen result 27. The method of claim 24 wherein the lyophilizate is further comprises an unfrozen portion. crystalline. k k k k k