United States Patent (19) (11) 4,092,315 Bianco 45) May 30, 1978 (54) NOVEL CRYSTALLINE FORMS OF PRAZOSN HYDROCHLORDE OTHER PUBLICATIONS Weissberger, A. Ed., "Technique of Organic Chem.", (75) Inventor: Ernest J. Bianco, Niantic, Conn. vol. III, Interscience N.Y., N.Y., (1950). 73 Assignee: Pfizer Inc., New York, N.Y. Primary Examiner-Alton D. Rollins Assistant Examiner-D. B. Springer (21) Appl. No.: 662,937 Attorney, Agent, or Firm-Connolly and Hutz 22 Filed: Mar. 1, 1976 57 ABSTRACT The invention relates to novel and valuable crystalline 51) Int. C.’...... CO7D 239/94 forms of the hypotensive agent prazosin hydrochloride. 52 U.S. C...... 544/291; 424/251 The anhydrous a-form is preferred because it is rela 58 Field of Search ...... 260/256.4 Q; 424/251 tively non-hygroscopic and hence possesses important (56) References Cited advantages in handling and formulation. The polyhy drate form of prazosin hydrochloride is preferred be U.S. PATENT DOCUMENTS cause of its low, uniform rate of dissolution. 3,635,979 1/1972 Hess ...... 260/256.4 Q 3,663,706 5/1972 Hess ...... 424/251 4 Claims, 6 Drawing Figures U.S. Patent May 30, 1978 Sheet 1 of 6 4,092,315

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U. S. Patent May 30, 1978 Sheet 3 of 6 4,092,315

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U. S. Patent May 30, 1978 Sheet 5 of 6 4,092,315

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4,092,315 1. 2 NOVEL CRYSTALLINEHYDROCHLORIDE FORMS OF PRAZOSN weigh, weigh, weigh, BACKGROUND OF THE INVENTION 5 33 2: g 1. Field of the Invention 3. The invention pertains to the novel, relatively non- 612 846 11.90 hygroscopic, crystalline a-form of the valuable hypo- : S. tensive agent prazosin hydrochloride of the formula: 654 525 133 10 6.75 9.60 13.87 6,81 9.85 13.95 CHO 29: 10,02 14.82 3 N w n-N N-C HC 21 N v O So 1s Another object of this inventionv . 0 is to provide a new CHO crystalline anhydrous form of prazosin hydrochloride 3 NH, which is relatively non-hygroscopic and stable. Yet another object of the invention is to provide the and processes for preparing said crystalline ot-form, as novel crystalline hydrates of 2-4-(furoyl)piperazin-1- well as the novel, crystalline polyhydrate form of 20 yl)-4-amino-6,7-dimethoxyquinazoline hyrochloride prazosin hydrochloride which has a low, uniform rate characterized by the infrared spectrum in potassium of dissolution. bromide having the following absorption bands: 2. Description of the Prior Art U.S. Pat. Nos. 3,511,836, 3,635,979 and 3,663,706 Wavelength, Wavelength, Wavelength, disclose 2-4-(2-furoyl)piperazin-1-yl)-4-amino-6,7- 25 Microns Microns Microns dimethoxyquinazoline. The first of these U.S. Patents 2.98 7.80 10.15 3.14 7.95 10.66 specifically claims this compound and its acid addition 6.04 8.08 11.10 salts and U.S. Pat. No. 3,663,706 claims the use of the 6.14 8.27 11.31 compound and its pharmaceutically acceptable acid 6.30 8.40 11.70 30 6.53 8.75 11.90 addition salts as valuable hypotensive agents. Pharma 6.72 8.96 12.00 cological studies on 2-4-(2-furoyl)piperazin-1-yl)-4- 6.95 9.17 13.10 7.15 9.33 13.27 amino-6,7-dimethoxyquinazoline hydrochloride, here 7.21 9.85 13.57 inafter designated by its generic name, prazosin hydro 7.73 10.03 14.05 chloride, were reported by Scriabine et al., Experientia, 35 24, 1150(1968), and by Constantine et al., in "Hyperten and further characterized by containing from about 8 to sion: Mechanisms and Management”, Onesti et al., edi 15% by weight of water. tors, Grune and Stratton, Inc., 1973, p. 429-444. Prelim Still another object of the invention is to provide a inary clinical studies on prazosin hydrochloride were process for producing a hypotensive effect which com reported by Cohen, J. Clin. Pharmacol, 10, 408(1970). prises administering to a hypertensive host a hypoten Side effects due to initial doses of prazosin have been sive effective amount of said hydrate of prazosin hydro reported by Bendall et al., Brit. Med. Jour, 2, chloride. 727(1975). DETAILED DESCRIPTION OF THE DESCRIPTION OF THE DRAWINGS INVENTION FIG. I is the infrared spectrum of the a-form of 45 The present invention is based on the discovery of prazosin hydrochloride in KBr. two novel, crystalline forms of the valuable hypoten FIG. II is the infrared spectrum of prazosin hydro sive agent prazosin hydrochloride which have decided chloride polyhydrate in KBr. advantages over other forms of this drug. The first of FIG.III is representative infrared spectra of various so these novel crystalline forms of prazosin hydrochloride crystalline modifications of prazosin hydrochloride. is an anhydrous form herein designated as the "a-form'. FIG. IV is representative X-ray diffractograms of The ot-form has been found to be relatively non-hygro various crystalline modifications of prazosin hydrochlo scopic and stable. It thus possesses important advan ride. tages in handling, storing and formulation. Other crys FIG. V is the powder dissolution profile of various 55 talline, anhydrous, unsolvated forms of prazosin hydro crystalline modifications of prazosin hydrochloride in chloride disclosed herein are designated, for conve water at 25 C. nience, the "g-form', the "y-form' and "anhydrate'. FIG.VI is the powder dissolution profiles of prazosin Also disclosed is the solvate, prazosin hydrochloride hydrochloride, a-form and polyhydrate in simulated methanolate. gastric juice at 25 C. As used herein the term "relatively non-hygro SUMMARY scopic' means that a sample, initially containing not more than about 0.5% water, when exposed to a tem It is an object of this invention to provide a novel perature of about 37° C. and a relative humidity of crystalline polymorph of 2-4-(2-furoyl)piperazin-1-yl)- about 75% for a period of about 30 days, contains not 4-amino-6,7-dimethoxyquinazoline hydrochloride 65 materially in excess of 1.5% water. Prazosin hydrochlo herein designated as the ot-form of prazosin hydrochlo ride having up to but not materially in excess of about ride, characterized by the infrared spectrum in potas 1.5% water is considered to be anhydrous within the sium bromide having the following absorption bands: context of this invention. 4,092,315 3 4. The second novel crystalline form of prazosin hydro 2-methyl-3-pentanol, 4-methyl-1-pentanol, 2-methyl-3- chloride which has decided advantage over otherforms hexanol, 2-methyl-2-hexanol, cycloheptanol and the of this drug is herein designated as the "polyhydrate'. It like. Especially preferred for producing the a-form of has now been found that when any of the other forms of prazosin hydrochloride is isoamyl alcohol, also known prazosin hydrochloride are crystallized from an aque 5 as 3-methyl-1-butanol, because of its ready availability ous medium or mixtures of water and organic solvents, and efficiency in forming the desired crystalline poly followed by drying until the water content of the result morph of prazosin hydrochloride. For convenience, the ing crystals is in the range of about 8 to 15% by weight preferred temperature for formation of the a-form as determined by the well-known Karl Fischer method when isoamyl alcohol is employed is about 132 C. for determination of water, prazosin hydrochloride 10 which is the boiling point of this alcohol at atmospheric polyhydrate is obtained. At the lower end of this range pressure. of water content, that is at about 8% water by weight, In carrying out the process to prepare the a-form of the stiochiometry corresponds to a dihydrate of prazosin hydrochloride it is preferred to use an amount prazosin hydrochloride having about two moles of of alcoholic solvent sufficient to effect at least a partial water per mole of prazosin hydrochloride. Said dihy 15 solution of prazosin hydrochloride when the mixture is drate is within the scope and purview of this invention. heated to a temperature within the preferred range of Especially preferred, however, is prazosin hydrochlo temperature. Ordinarily, from about 4 to 25 ml. of such ride polyhydrate having from about 12 to 15% water by alcohol per gram of prazosin hydrochloride will suffice, weight because it is more readily obtained and has less although, more or less than this amount of alcohol may tendency to absorb water than other hydrates of 20 be employed in some instances with satisfactory results. prazosin hydrochloride. The heating time required to effect substantially con The polyhydrate may be prepared, for example, by plete formation of the a-form of prazosin hydrochloride crystallization of prazosin hydrochloride from hot by the above process can vary from as little as a few water or from mixtures of water and organic solvents minutes to about 6 hours or more. The optimal time followed by filtering and drying the crystals until the 25 required in a given instance will vary with several fac moisture content is in the desired range of about 8 to tors such as the precise temperature and the particular 15% by weight. When mixtures of water and organic alcohol used as solvent. When the process is carried out solvents are employed, suitable organic solvents are in refluxing isoamyl alcohol the time required to effect water miscible organic solvents such as methanol, etha substantially complete formation of the desired at-form nol, isopropanol, acetone, methyl ethyl ketone, and the 30 is ordinarily about 2-3 hours. The extent of formation of like as well as mixtures of such water miscible organic the ot-form of prazosin hydrochloride may be conve solvents with water inniscible organic solvents such as niently monitored by removal of a sample, cooling to dichloromethane, chloroform, hexane, benzene, toluene room temperature, isolating the precipitate by filtration and the like. An alternate method for preparing and obtaining an infrared spectrum in potassium bro prazosin hydrochloride polyhydrate is by trituration of 35 mide of the precipitate. As shown below, each of the anhydrous prazosin hydrochloride with water followed non-hydrated forms of prazosin hydrochloride has a by drying the resulting crystals to the desired moisture characteristic infrared spectrum. content. When the starting prazosin hydrochloride employed As mentioned above, the water content of the is a solvate such as the methanolate or one of the hy polyhydrate can vary from about 8 to about 15% or 40 drates, it is preferable, although not essential, to remove more. From X-ray diffraction data, presented below, it the molecules of solvation or hydration by distilling off, appears that only up to two molecules of water per e.g., methanol or water during the heating period re molecule of prazosin hydrochloride are bound in the quired to obtain the a-form of prazosin hydrochloride crystal lattice. The remaining water is free interstitial by the above process. Water. 45 If, in carrying out the above process, the prazosin When a sample of prazosin hyrochloride polyhydrate hydrochloride is heated in an alcoholic solvent such as containing from about 12 to 15% water by weight is isoamyl alcohol but at a temperature somewhat below further exposed to drying conditions, such as storage in about 125 C., or even when heated at a higher tempera a desiccator or heating in a vacuum oven, moisture loss ture, within the above-mentioned preferred range of occurs until the dihydrate containing about 8.0% mois 50 temperature for preparing the d-form of prazosin hy ture is obtained. Heating at 100° C. in a vacuum oven or drochloride, but for an insufficient length of time, the vacuum desiccator will ordinarily suffice. Further heat resulting product will be either the crystalline poly ing will, in turn, provide the monohydrate containing morph of prazosin hydrochloride herein designated as about 4.1% moisture. Still further heating leads to the the y-form, or a mixture of a-form and y-form. formation of prazosin hydrochloride anhydrate. 55 The methanolate of prazosin hydrochloride may be The preferred, novel and valuable a-form of prazosin obtained by slurrying any of the essentially anhydrous hydrochloride is readily and reproducibly obtained by forms of prazosin hydrochloride in methanol. At room heating any of the forms of prazosin hydrochloride, temperature, ordinarily, about 3 hours is sufficient. The including the hydrates and solvate in the presence of a methanolate may be formed more rapidly by heating at suitable organic solvent at a temperature in the range of 60 a higher temperature. For example, at the boiling point about 100 to 200 C. and preferably in the presence of of methanol, solvate formation is complete in about 10 an alcoholic solvent at a temperature in the range of minutes. The product is isolated by standard methods. about 125-160 C. Preferred alcoholic solvents are the Elemental analysis of the methanolate reveals that the aliphatic and alicyclic alcohols having from about 5 to prazosin hydrochloride and methanol are combined in a 7 carbon atoms. Examples of such alcohols are isoamyl 65 1:1 mole ratio. alcohol, n-pentanol, 2-methyl-1-butanol, cyclopentanol, The g-form of prazosin hydrochloride is obtained 1-methylcyclopentanol, 2-methylcyclopentanol, cyclo when the above methanolate is exposed to temperatures hexanol, 1-methylcyclohexanol, 3-methylcyclohexanol, sufficient to remove the solvate molecule. For example, 4,092,315 5 6 heating the methanolate at 135 C. for about 12 hours or 110' C. for about 24 hours. Removal of methanol is TABLE II-continued facilitated by carrying out the above thermal exposure Form of Prazosin. HCl Characteristic Peaks, degrees 20 23'; sharp bands at 9.3' and at reduced pressure, e.g., in a vacuum oven. 27.5°. f sharp bands at 11.3', 22.5, CHARACTERIZATION OF THE VARIOUS 23.6 FORMS OF PRAZOSN HYDROCHLORDE y band groupings at 10.5, 16.7" 24.8 Infrared Spectra Polyhydrate/dihydrate sharp bands at 8.05", 12.2; doublet at 25.2 The infrared spectra of the three anhydrous crystal Monohydrate sharp bands at 10.5, 12.0", 16.9 10 doublets at 24.5', 26.5 line forms of prazosin hydrochloride, the methanolate, Anhydrate not significantly different than the hydrates and the amorphous dehydrate when ob the monohydrate tained by standard methods either as a KBr pellet or Methanolate sharp bands at 10.5", 17.3, Mujol mull, provide a rapid and convenient method for 23.9, 25.5° The diffractogram for the polyhydrate containingabout 15% water is not signifi characterizing these forms. However, infrared spectros 15 cantly differentthan that obtained for the dihydrate. Thisindicates that only two copy did not discriminate the various hydrated forms molecules of water permolecule of prazosin hydrochloride are actuallybound in the from one another. The characteristic infrared spectrum crystal lattice, the remaining water in the polyhydrate is free interstitial water. of the a-form of prazosin hydrochloride is shown in FIG. I. The infrared spectrum of FIG. II was obtained The X-ray diffractograms further confirmed the dif with a sample of prazosin hydrochloride polyhydrate ferences between the a-, f-, y- and anhydrate forms of (12% moisture). The infrared spectrum together with 20 prazosin hydrochloride. The combination of X-ray the water content of the sample can be used to charac analysis and moisture determination also provides a terize the polyhydrate. The infrared spectra (KBr) of method for characterizing the various hydrates. the a-, 3- and y-polymorphs, the polyhydrate, the an hydrate and the methanolate of prazosin hydrochloride Differential Scanning Calorimetry (DSC) are compared in FIG.III. The spectra are representa 25 Samples (1-2 mg) were analyzed on a Mettler DTA tive of those obtained on a Perkin-Elmer Model 21 2000 thermal analyzer at a range of 50 microvolts or 100 recording infrared spectrophotometer employing potas microvolts and at a heating rate of 5 per minute. Re sium bromide pellets prepared by intimately grinding in sults obtained are summarized in Tables III and IV. a mortar and pestle 1 mg. of the appropriate sample 30 TABLE II with 300 mg. of KBr. The mixture is then placed in a Summary of DSC Data on Samples Perkin Elmer die press model No. 1860025 and the die of Various Forms of Prazosin Hydrochloride subjected to 15,000 p.s. i., under vacuum for one minute. (Heating rate, 5' per minute; Samples intro Characteristic infrared absorption bands which may duced at about 40; Temperatures in C.) a-Form Single endotherm at 279 be used for differentiating the various forms of prazosin 35 y-Form Partially resolved endothermic hydrochloride from one another are listed in Table I. doublet at 270' (medium) and 278 (strong) TABLE Polyhydrate Broad endotherm from about 60 to 160 with peak at Form of Characteristic Bands 10, weak endotherm at Prazosin. HC1 cm comment 183, medium exotherm at O- 795 12.6 sharp 195, strong endotherm at 265. A- 770 13 sharp Methanolate Broad endotherm at 137, y- 770, 743 13, 13.4 doublet sharp medium endotherm at 167 Hydrates 1260 7.95 sharp p strong endotherm at 755 13.3 broad 1000 10 doublet Anhydrate 260 7.95 sharp 755 13.3 45 1005 9.95 triplet TABLE IV *The infrared spectra of the monohydrate (4.1% HO), dihydrate (7.9% HO) and Summary of DSC Data on Samples of Crystalline polyhydrate were identical. Polymorphs of Prazosin Hydrochloride (Heating rate, 5 per minute; Samples introduced When samples of the a-, 3- and y- polymorphs are at about 250; Temperatures in C.) 50 a-Form Unresolved endothermic doublet triturated with water the resulting product in each case at 263 A-Form Partially resolved endothermic is found to give an infrared spectrum identical to that of doublet at 263 (strong) and the prazosin hydrochloride hydrates. 263.5' (medium) y-Form Partially resolved endothermic X-ray Diffractometry doublet at 261.5' (strong) and X-ray powder diffraction patterns were obtained on a 55 262.5 (medium) Siemens diffractomer equipped with nickel-filtered cop per radiation and a scintillation counter detector. Beam Interpretation of the differential scanning calorimetry intensity as a function of the angle 26 was recorded at a data is complicated by decomposition that occurs dur scanning rate of 1 per minute. ing fusion. No sign of polymorphic conversion was Characteristic diffractograms of each of the modifica observed by DSC, which indicates that the polymor tions of prazosin hydrochloride examined are shown in phic forms are solvent-induced and that their conver FIG. IV. The peaks (expressed in "degrees 20”) which sion points are beyond their decomposition tempera may be used to distinguish one form from another are tures. Although each of the forms of prazosin hydro summarized below in Table II. chloride appeared to have unique DSC behavior, the 65 characteristics of each are heavily dependent upon test TABLE I ing conditions. Adjustments in instrumental parameters Form of Prazosin. HCl Characteristic Peaks, degrees 20 were found capable of inducing different DSC patterns Oslo 1:3:3:1 quartet centered at for a given polymorph or solvate. The doublet pattern 4,092,315 7 8 of the y-Form of prazosin hydrochloride, for example, tained at 50 C., and others were stored at 25 C. while was found to vary as a function of heating rate, starting exposing them to sunlight, temperature and sample size. All samples were stored in clear glass bottles. After Methanol could only be removed from the methano such storage for 6 weeks and again at 12 weeks the late between about 130' and 140 C. well above its boiling point of 65° C. This suggests that strong bonding samples were observed for any visual or chemical forces exist in this solvate between methanol and changes. All samples were found to have good chemical prazosin hydrochloride. By contrast, the polyhydrate stability. However, the sample of polyhydrate that was loses water rapidly at temperatures approaching the exposed to sunlight exhibited some photodegradation as boiling point of free water, indicating that at least some 10 evidenced by visible color change from white to yel of the water present was unbound and occupied only an low-pink at 6 weeks and to orange at 12 weeks. The interstitial position within the dihydrate lattice. other forms of prazosin hydrochloride were stable to sunlight throughout the test period. Hygroscopicity When samples of prazosin hydrochloride polyhy Since moisture uptake affects integrity of a drug 15 drate are stored in ambler glass bottles at 25 C. while form, the a-, 3- and y- crystalline polymorphs of exposing them to sunlight, no changes are evident after prazosin hydrochloride were compared for their rela 12 weeks. tive hygroscopicity. Samples of each polymorph were placed in an open beaker and stored in a chamber main Dissolution Studies tained at 37° C. and 75% relative humidity, Portions 20 To measure the rate of dissolution of the powdered were withdrawn periodically and their water content drug in water, 100 mg. offine powder was added to 50 determined by the Karl Fischer method. Results are mi. of water contained in a 100 ml. volumetric flask. listed in Table V. The stoppered flask was shaken in a wrist-action shaker TABLE V in a 25 C. water bath. Samples were withdrawn period Water Content of Samples Exposed to 37 C, 75% RH. 25 ically, filtered through a Millipore filter (0.45m pore Water Content, % by Weight size), then analyzed spectrophotometrically on a Beck Exposure Time, Prazosin Hydrochloride Days ot-Form As-Form y-Form man Acta III spectrophotometer. The slopes of Beer's 5 0.32 0.59 0.16 law plots for prazosin hydrochloride at 246 mm. and 330 12 0.85 1.18 4.61 nm. were used to calculate solubility of the powders. 25 1.18 4.66 9.47 30 FIG. V depicts the powder dissolution profiles in water 34 154 6.06 905 of the a-form, 6-form, y-form, the methanolate and polyhydrate of prazosin hydrochloride. While the data As the above data indicates, the ot-form of prazosin for polyhydrate is uniform throughout the 4 days of the hydrochloride is relatively non-hydroscopic when com experiment, the other forms of prazosin hydrochloride pared with the B- and y-forms. Changes in the infrared 35 spectrum (KBr pellet) of a sample of the y-form of each show greater initial solubility with gradual decline prazosin hydrochloride after such exposure to moisture in solubility to that of the polyhydrate. confirmed the formation of a hydrate. FIG. VI summarizes the results of the powder disso Samples of prazosin hydrochloride polyhydrate, ini lution data obtained in the same manner as described tially containing 13.7% water were exposed at 37 C. above, except that 200 mg. of solute in 50 ml. of USP and 75% relative humidity. After 10 and 23 days the simulated gastric juice (SGJ) was used in each case. The water content was 13.2 and 13.4%, respectively. A ot-form of prazosin hydrochloride attained maximum sample, initially containing 13.5% water upon exposure solubility in about 5 minutes and solubility declined at room temperature and 20% relative humidity was gradually throughout the experiment, finally approach found to contain 13.0% water after 18 days and 13.1% 45 ing that of the polyhydrate. The polyhydrate also water after 35 days. reached its maximum solubility in a few minutes, but at a much lower level, and that level remained constant Microscopy throughout the experiment. Upon examination with a light microscope at 200X Compressed disc dissolution studies were carried out magnification, the ot-form and the methanolate of 50 by means of the procedure developed by Hamlin et al., prazosin hydrochloride are found to be comprised of J. Pharm, Sci, 51,432(1962). A 300 mg. sample of pow rod-like crystals, with those of the methanolate being der was compressed against a flat surface at 3000 psi. for much larger in size. The 3-form consisted of dark, mon 2 minutes into a flat round disc using a tablet die of 7/16 oclinic crystals, while the y-form and polyhydrate are inch diameter. The die holding the compressed disc was both needle-like crystals. 55 When a drop of water is added to each of the three stoppered at the open end and placed into a plastic microscope slides containing a-, 3-, and y-forms of holder. This assembly was then placed into a jar con prazosin hydrochloride, sharp needle-like crystals of taining 1000 ml. of water equilibrated at 37° C. The hydrate grew and joined together to form a spectacular, stirring rate of a teflon paddle centered in the jar was hair-like nematic array, characteristic of a liquid crystal 60 maintained at 150 revolutions per minute. The solution line phase. This is in agreement with the above men was pumped continuously through a Millipore filter tioned change in the infrared spectra of the a-, 3-, y (0.45 mL pore size) into a flow cell of a Beckman Acta polymorphs to that of the hydrates of prazosin hydro II spectrophotometer which automatically recorded chloride upon trituration of each of the crystalline poly any absorbance changes at 246 mm. morphs with water. Stability Studies 65 Table VI compares the intrinsic dissolution rates of Stability studies were carried out on bulk lots of the various forms of prazosin hydrochloride. The rates ot-form, 3-form, y-form and the polyhydrate of prazosin were determined from the slopes of the compressed disc hydrochloride. Samples were stored in an oven main dissolution profiles between 4 and 10 minutes. 4,092,315 9 10 TABLE VI starch, alginic acid and certain complex silicates to Intrinsic Dissolution Rates of Various Forms of gether with lubricating agents such as magnesium stea Prazosin Hydrochloride in Water at 37 C. Dissolution Rate rate, sodium lauryl sulfate and talc are often used. For Form (ig/liter sec.) oral administration in capsules, excipients such as lac O- 3.25 tose and high molecular weight polyethylene glycols A- 3.36 2.35 may be added. When aqueous suspensions are desired, ethanolate 2.68 the active ingredient is combined with emulsifying and Polyhydrate 2.57 /or suspending agents. Diluents such as ethanol, propy Anhydrate 2.35 lene glycol, glycerine and various combinations of dilu 10 ents are employed. For parenteral administration, solu From the above characterization studies on the vari ous forms of prazosin hydrochloride it is apparent that tion of the a-form or polyhydrate of prazosin hydro the ot-form has several important advantages over the chloride in combination with other solutes such as glu other forms. It is the only crystalline, anhydrous form cose or saline are used. Such aqueous solutions should which is non-hygroscopic, and is stable to storage con 15 be suitably buffered, if necessary, to render them iso ditions normally encountered, including exposure to tonic. sunlight. Also it is readily and reproducibly prepared by It should be noted that in dosage forms containing a methods described herein. molar excess of water the anhydrous a-form of prazosin The polyhydrate form of prazosin hydrochloride is hydrochloride becomes hydrated, as shown above. also readily prepared by methods described herein. It is 20 The dosage required to reduce blood pressure in stable to normal storage conditions when stored in con hypertensive subjects will be determined by the nature tainers which protect it from sunlight. Examples of such and the extent of the hypertension. Generally, small containers are screw-capped amber glass bottles or dosages will be administered initially with a gradual screw-capped opaque plastic bottles which are well increase in dosage until the optimum level is deter known in the art. A further advantage of the polyhy 25 mined. It will generally be found that when the compo drate form of prazosin hydrochloride is its low and sition is administered orally, larger quantities of the uniform rate of dissolution, from which it may be con cluded that it will provide smoother, more gradual and active ingredient will be required to produce the same longer lasting blood levels per unit dose than other level of blood pressure reduction as produced by a forms of this valuable hypotensive agent since it is 30 smaller quantity administered parenterally. In general, known in the art that dissolution rate of a drug corre from about 0.02 to 10 milligrams of active ingredient lates with its bioavailability. Furthermore, by providing per kilogram of body weight administered in single or such smooth blood levels of prazosin hydrochloride by multiple dosage units effectively reduces blood pressure administering the polyhydrate form of this valuable in hypertensive subjects. Tablets containing 0.5 to 5 hypotensive agent, certain side effects sometimes asso 35 milligrams of active ingredient are particularly useful. ciated with initial doses of the drug should be mini The following examples are given by way of illustra mized. tion and are not to be construed as limiting the invention Since, as noted above, the ot-form of prazosin hydro in any way. Many variations of the invention are possi chloride is converted to the polyhydrate by contacting ble within the spirit of the invention. it with an excess of water, the attainment of the same smooth blood levels will be realized with formulations EXAMPLE 1. containing the a-form if exposed to an aqueous medium Prazosin Hydrochloride Methanolate for sufficient time prior to administration of the drug or during its administration but prior to absorption into the To 1000 ml. of isoamyl alcohol are added 65.4 g. blood. 45 (0.272 mole) of 2-chloro-4-amino-6,7-dimethox The methanolate form of prazosin hydrochloride youinazoline and 54.0 g (0.30 mole) of 1-(2-furoyl)pip suffers the disadvantage of containing the toxic metha erazine. The mixture was heated at reflux for 3 hours nol molecule which is likely to have adverse effects if then allowed to stir while cooling to room temperature administered to hypotensive subjects. and stirring continued for an additional 16 hours at The 6-form of prazosin hydrochloride is hygroscopic 50 ambient temperature. The reaction mixture is cooled to and is more difficult to prepare than the preferred a form and polyhydrate. The y-form is more hygroscopic 15 C., filtered, the cake washed with acetone and air then the 3-form. dried to obtain 107.2 g of crude material, M.P. The monohydrate and anhydrate forms of prazosin 272-276(dec.). This is slurried in 1400 ml. of methanol, hydrochloride are less desirable than the preferred a 55 heated at reflux temperature for 3 hours, then allowed and polyhydrate forms because they must be prepared to cool to room temperature. The solid is isolated by from the polyhydrate by extended drying at relatively filtration, washed with methanol, then with ether and high temperatures and have been found to revert to air dried to afford 110 g. of the title compound as large polyhydrate upon exposure to moist air. rod-like crystals, M.P. 276-278 C. (dec.). The preferred a- and polyhydrate forms of prazosin Analysis: Calc'd for CHN30HCL. CH-OH (per hydrochloride are administered to hypertensive sub cent): C, 53.15; H, 5.80; N, 15.50; C1, 7.85. Found: C, jects either alone or in combination with pharmaceuti 53.02; H, 5.77; N, 15.47; C1, 7.79 cally acceptable carriers. The proportion of active in Thermogravimetric analysis carried out on a DuPont gredient depends upon the chosen route for administra Thermogravimetric Analyzer at a heating rate of 20 tion and standard pharmaceutical practice. For exam 65 C/minute shows a weight loss of 7% occurs at 135 C. ple, they may be administered in tablet form with such This corresponds to a 1:1 methanol: prazosin hydro excipients as lactose, sodium citrate, calcium carbonate chloride stoichiometry, in agreement with the above and dicalcium phosphate. Various disintegrants such as elemental analysis. 4,092,315 11 12 EXAMPLE 2 -continued Prazosin Hydrochloride, As-Form Alcohol Temperature, C. 2-Methylbutanol 125 Cyclopentanol 140 Ten grams of prazosin hydrochloride methanolate, s Cyclohexanol 60 obtained in Example 1 was placed in an oven and held 2-Methyl-3-pentanol 128 at 110' C., for 24 hours, then cooled to room tempera 4-Methyl-1-pentanol 160 n-Butanol 130 ture. The resulting material consisted of monoclinic (in pressure reactor) crystals, M.P. 278-280 C. 2-Methyl-3-hexanol 142 5-Methyl-3-hexanol 47 Analysis: Calc'd, for CHNOHCL (percent): C, 10 2-Methyl-2-hexanol 140 54.34; H, 5.28; N, 16.68; C1, 8.44. Found: C, 54.21; H, Cycloheptanol 160 5.26; N, 16.60; C1, 8.37. EXAMPLE 3 EXAMPLE 5 Prazosin Hydrochloride, y-Form 15 Conversion of Prazosin Hydrochloride, 3-Form to the 2-(1-Piperazinyl)-4-amino-6,7-dimethoxyquinazoline ol-Form (57.8 g., 0.20 mole) was dissolved in 1000 ml of chloro form and 30.2 g (0.20 mole) of 2-furoyl chloride was Five grams of the g-form of prazosin .HCl obtained added slowly at ambient temperature. When the addi in Example 2 was stirred with 50 ml. of isoamyl alcohol tion was completed the resulting slurry was stirred for 20 while heating at reflux for 2 hours. The mixture was 15 minutes after which 1000 ml. of isoamyl alcohol was then allowed to cool to room temperature, washed with added. To the resulting mixture was then added suffi chloroform and air dried overnight to afford rod-like cient 10% (w/w) aqueous sodium hyroxide solution to crystals. The infrared spectrum (KBr) was identical to effect the solution of the solid material, about 200 ml. that of the a-form of prazosin hydrochloride. was ordinarily required, while maintaining the mixture 25 EXAMPLE 6 at room temperature. The aqueous layer was separated and the organic phase was washed with 250 ml. of wa Conversion of Prazosin Hydrochloride, y-Form to the ter. The organic layer was dried over anhydrous ot-Form MgSO, filtered and the filtrate cooled to 0°C. Anhy When the above procedure was repeated with 5g of drous hydrogen chloride was passed through the solu 30 the y-form of prazosin .HCl obtained in Example 3, the tion at 0-5 C. until the solution was acidic to moist rod shaped crystals of the a-form were also obtained. ened test paper (pH about 2-2.5), about 45 minutes was Again the infrared spectrum (KBr) was superimposible required for the addition. The chloroform was then with that of an authentic specimen of Prazosin hydro evaporated at reduced pressure while warming gently chloride, a-form. to about 45' at 20-30 mm Hg. The vacuum was then 35 released and the solution heated to about 100 C. to EXAMPLE 7 remove the last traces of chloroform. The mixture was Conversion of Prazosin Hydrochloride Methanolate to then allowed to cool to room temperature. The product the ol-Form was recovered by filtration, washed with chloroform A5 g. sample of the methanolate obtained in Example and dried in the vacuum oven at 50-60 C. to afford 40 1 is refluxed for 3 hours in 100 ml. of 2-methylbutanol. 73.9 g, of needle-like crystals, M.P. 277-279 C. (dec.) of the title polymorph. The mixture is allowed to cool to room temperature, When a sample of the g-form of prazosin hydrochlo washed with dichloromethane, and air dried to afford ride obtained in Example 2 was recrystallized from the a-form of prazosin hydrochloride. isoamyl alcohol by heating to about 115 C. then cool 45 EXAMPLE 8 ing to room temperature, the y-form was also obtained. Prazosin Hydrochloride Hydrates and Anhydrate EXAMPLE 4 Prazosin hydrochloride, 180 g, was dissolved in a Prazosin Hydrochloride, a-Form mixture of 3 liters methanol, 3 liters chloroform and 50 1200 m. water. The solution was filtered, then concen The procedure of Example 3 was repeated, except trated at atmospheric pressure to 1100 ml. volume. that after evaporating the bulk of the chloroform the After cooling to room temperature, the precipitated isoamyl alcohol slurry was heated at reflux (130-132 solids were collected by filtration, the cake washed C.) for 2 hours. The mixture was then allowed to cool to with ethanol, then with hexane, and dried for 3 hours at room temperature, filtered, washed with chloroform 55 60° C. to afford 176 g. of needle-like crystals, M.P. and dried in the vacuum oven at 50-60C. The result 265-268 C. (dec.), water by Karl Fisher method: ing rod-like crystals melted at 280°-282 (dec.). 11.96%. Upon thin-layer chromatography it was found Anal: Calc'd, for CHNOHCl (M.W. 419.87); C, to be identical with an authentic sample of prazosin 54,35; H, 5.28; N, 16.68; C1, 8.44 Found: C, 54.38; H, hydrochloride. Other samples exposed to high humidity 5.56; N, 16.71; C1, 8.41. contained up to 15% moisture. This compound was When the above procedure is repeated but employing designated prazosin hydrochloride polyhydrate. one of the alcohols listed below in place of isoamyl Upon drying the above polyhydrate in a vacuum alcohol and heating at the indicated temperature, the desicator at 100 C. for 30 minutes the moisture content results are substantially the same. was reduced to 7.9% which corresponds to prazosin hydrochloride dihydrate. Alcohol Temperature, C. When a sample of prazosin hydrochloride polyhy n-Pentanol 138 drate was dried in the vaccum desiccator at 100 C. for a-Hexanol 56 about 60 minutes, the moisture content was reduced to 4,092,315 13 14 4.1% which corresponds to prazosin hydrochloride capsules containing 0.25, 0.5, 1, 2.5 and 5 mg. of active monohydrate. ingredients. Drying in the vacuum desiccator at 100° C. for 12-15 hours afforded the anhydrate form of prazosin hydro EXAMPLE 13 chloride, containing about 1% water. 5 Injectable Preparation When samples of the anhydrate and monohydrate are stored at room temperature and 75% relative humidity One thousand grams of the a-form of 2-4-(2-furoyl)- they absorb moisture rapidly to form the dihydrate (8% piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline hy water) in about 24 hours. The dihydrate continues to drochloride is intimately mixed and ground with 2500 absorb water at a slower rate until an equilibrium water 10 grams of sodium ascorbate. The dry mixture is filled content of 13.5% is obtained after 4 days. into vials, sterilized with ethylene oxide and the vials sterilely stoppered. For intravenous administration suf EXAMPLE 9 ficient water is added to the vials to form a solution Conversion of the ol-Form of Prazosin to the containing 1.0 mg. of active ingredient per milliliter. Polyhydrate 15 EXAMPLE 14 To 500 ml. of water, 50 g. of the a-form of prazosin hydrochloride was added and the mixture stirred and Suspension heated to 95" C. for 2 hours. After cooling to about 50' A suspension of the polyhydrate of 2-4-(2-furoyl)pip C. the slurry was filtered, washed with water and dried erazin-1-yl)-4-amino-6,7-dimethoxyquinazoline hydro in air for 48 hours to obtain 50.5 g. of prazosin hydro chloride is prepared with the following composition: chloride polyhydrate containing 12.4% water. The infrared spectrum obtained with a KBr disc was identi Effective ingredient 2.50 g cal to that shown in FIG. I. 70% Aqueous sorbitol 714.29 g Glycerine, U.S.P. 185.35 EXAMPLE 10 25 Gum acacia (10% solution) 100.00 ml Polyvinylpyrrolidone 0.50 g Conversion of Prazosin Hydrochloride Dihydrate to Water, distilled, to make 1 liter the a-Form When a sample of prazosin hydrochloride dihydrate To this suspension, various sweetening and flavoring was slurried with isoamyl alcohol, then refluxed for 3 30 agents may be added by choice. The suspension con hours, cooled and filtered, the rod-like crystals obtained tains approximately 2.5 mg. of hypotensive agent per were identified as the a-form by comparison of the milliliter. infrared spectrum (KBr) with that of an authentic sam What is claimed is: ple of the a-form as shown in FIG. I. 1. The crystalline a-form of 2-4-(2-furoyl)piperazin EXAMPLE 11 35 1-yl)-4-amino-6,7-dimethoxyquinazoline hydrochloride characterized by the infrared spectrum in potassium Tablets bromide having the following absorption bands: A tablet base is prepared by blending the following ingredients in the proportion by weight indicated: Wavelength, Wavelength, Wavelength, 40 Microns Microns Microns Sucrose, U.S.P. 2.95 7.30 10.67 Tapioca starch 3.10 7.81 11.05 Magnesium stearate 3.25 8,08 11.30 3.50 8.28 11.66 6.12. 8.40 1.90 6.26 8.70 12.60 Into this base there is blended a sufficient amount of 45 6.39 9.02 13.10 the a-form of 2-4-(2-furoyl)piperazin-1-yl)-4-amino 6.54 9.25 13.31 6,7-dimethoxyquinazoline hydrochloride to provide 6.75 9.60 13.87 6.8 9.85 13.95 tablets containing 0.5, 1, 2 and 5 mg. of active ingredi 7.02 10,02 14.82 ent. 50 7.22 EXAMPLE 12 Capsules 2-4-(2-furoyl)piperazin-1-yl)-4-amino-6,7-dimethox2. The process for preparing the crystalline a-form of A blend is prepared containing the following ingredi yquinazoline hydrochloride of claim 1 which comprises ents: 55 precipitationfuroyl)piperazin-1-yl)-4-amino-6,7-dimethoxyquinazo of said a-form after heating 2-4-(2- Calcium carbonate, U.S.P. line hydrochloride, a hydrate or methanolate thereof, in Dicalcium phosphate the presence of an alkanol or cycloalkanol solvent hav Magnesium trisilicate, U.S.P. Lactose, U.S.P. ing from about 5 to 7 carbon atoms at a temperature in Potato starch the range of about 125 to 160 C., until formation of Magnesium stearate A said crystalline a-form is substantially complete. Magnesium stearate B 3. The process of claim 2 whrein said alcoholic sol vent is isoamyl alcohol. To this blend is added a sufficient amount of the 4. The process of claim 3 wherein said isoamyl alco polyhydrate of 2-4-(2-furoyl)piperazin-1-yl)-4-amino- 65 hol is heated at a temperature of about 132 C. 6,7-dimethoxyquinazoline hydrochloride to provide k k