Title of Invention

A PROCESS FOR PREPARATION OF CRYSTALLINE POLYMORPHIC FORM B OF BENAZEPRIL HYDROCHLORIDE

Abstract

The present invention relates to a process for preparation of crystalline polymorph B of 3-[[(18)-1-( ethoxy-carbonyl)-3-phenylpropyl] amino ]-2,3,4,5- tetrahydro-2-oxo-l H-l-benzazepine-l -acetic acid monohydrochloride comprising the step of adding an aqueous solution of hydrochloride to a solution of the free base 3-[[(18)-1-( ethoxy-carbonyl)- 3 -phenylpropyljamino]- 2,3,4,5- tetrahydro-2-oxO-lH-l-benzazePine-l-aceticacid monohydrochloride in an organic solvent.

Full Text

The present invention is directed to a process for the preparation of crystalline polymorphic form B of Benazepril hydrochloride. The present invention relates to a new crystalline form of Benazepril hydrochloride. Benazepril hydrochloride Is known by the chemical name: 3-[I(1S)-1-(ethoxy-carbonyl)-3-phenylpropyl]amlnol-2,3,4,5-tetrahydro-2-oxo-1 H-1 -benzazepine-1 -acetic acid monohydrochloride. Benazepril has the foitowing formula: Benazepril Is an orally-active ACE-lnhibitor, mari The processes described in the publications mentioned above result in the isolation of Benazepril hydrochloride in one defined crystalline form, herein designated as Form A. However, It is known that pharmaceutical substances can exhibit polymorphism. Polymorphism is commonly defined as the ability of any substance to have two or more different crystal strctures. Drug substances may also encapsulate solvent molecules when crystallized. These solvates or hydrates are referred to as pseudopolymorphs. It is also possible that the amorphous form is encountered. Different polymorphs, pseudopolymorphs or the amorphous form differ in their physical properties such as melting point, solubility etc. These can appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. It is also economically desirable that the product is stable for extended periods of time without the need for specialised storage conditions. It is therefore important to evaluate polymorphism of drug substances. We now have surprisingly found a novel crystalline form of Benazepril hydrochloride, herein designated as fomi B, with improved stability as well as the amorphous form of Benazepril hydrochloride. Accordingly, the present invention is directed to the polymorphic Form B, the amorphous form of Benazepril hydrochloride, processes for the preparation of Fonm B and the amorphous form of Benazepril hydrochloride, as well as novel processes for the preparation of Form A. One object of the present invention is a crystalline polymorph of 3-[[(1S)-1-(ethoxy-carbonyl)- 3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1 -benzazepine-1 -acetic acid monohydrochloride which exhibits a characteristic X-ray powder diffraction pattern with characteristic peal 13.2 (vs), 10.7 (s). 8.8 (m), 6.4 (m), 5.87 (s), 5.75 (m), 5.35 (m), 5.26 (m), 4.87 (m), 4.66 (s), 4.40 (m), 3.86 (m), 3.79 (m). 3.66 (m), 3.60 (m), 3.57 (m), 3.52 (m), 3.45 (m), 3.40 (m), 3.36 (m), 3.27 (m), 3.18 (m), 2.95 (m), 2.72 (m), 2.65 (m); herein designated as Form B. Here and in the following the abbreviations in brackets mean: (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity; (w) = weak intensity; and (vw) = very weak intensity. Small changes in the experimental details can cause small deviation in the d-values of characteristic peaks in the X-ray powder diffraction patterns, see Figures 2 and 3 which are X-ray powder diffraction patterns for Form B. A discussion of the theory of X-ray powder diffraction patterns can be found in "X-ray diffraction procedures" by H.P. Klug and L.E. Alexander, J. Wiley, New York (1974). Furthermore, the present invention is directed to processes for the preparation of Form B of Benazepril hydrochloride. Form B can generally be prepared by addition of an aqueous solution of hydrochloride (HCI) to a solution of the free base of Benazepril in an organic solvent. Examples of such organic solvents are ketones, for example acetone or methyl ethyl ketone; acetates, for example ethylacetate or isopropylacetate; nitriles. for example acetonitrile; alcohols, for example isopropylalcohol; or ethers, for example methyl-tert.butyl ether or THF. Preferred as organic solvents are C3-C10ketones, C3-Cioacetates, C2-C10nitriles, C1 Cioalcohols or C3-C10ethers, especially C3-C10ketones, C3-C10acetates or CrCioethers. Highly preferred is ethyl acetate. The weight ratio of the organic solvent to the aqueous solution of HCI is preferably 1:1 to 500:1, especially 1:1 to 100:1. Highly preferred is a weight ratio of 5:1 to 100:1. The process can, for example, be carried out at temperatures of from 10 to 60oC. Preferably, the process is carried out at ambient temperature. If desired, during the preparation process seeding with Form B can be carried cut. Form B can be isolated by filtration and dried in air or in vacuum. Form B can also be prepared by stirring a suspension of Form A or the amorphous form of Benazepril hydrochloride in an organic solvent. Examples of such organic solvents are ketones, acetates, nitriles, alcohols or ethers. For these organic solvents the preferences given above apply. Highly preferred are tert-butyl methyl ether, acetone, tetrahydrofuran. The process can, for example, be carried out at temperatures of from 10 to 60oC. Form B can be isolated by filtration and dried in air or in vacuum. It is preferred that the organic solvent contains small amounts of water. The amount of water is preferably about 0.1 to 15%, most preferably about 0.5 to 10%, especially about 1 to 5% by volume of the suspension. If desired, during the preparation process seeding with Form B can be carried out. Form B can also be prepared by stirring a suspension of Form A or the amorphous form in water. Form B can be isolated by filtration and dried in air or in vacuum. If desired, during the preparation process seeding with Form B can be carried out. Another object of the present invention are the amorphous form of Benazepril hydrochloride and processes for the preparation thereof. The amorphous form of Benazepril hydrochloride is characterised by a powder X-ray diffraction pattern substantially as depicted in Figure 4. The amorphous form of Benazepril hydrochloride can generally be prepared by evaporation of a solution of Benazepril hydrochloride in an organic solvent or water. Preferably by evaporation of a solution of Benazepril hydrochloride in one of the above organic solvents, especially in a C2-C10ketone, like acetone. According to another preferred embodiment evaporation of a solution of Benazepril hydrochloride in water is carried out. The evaporation is preferably carried out in vacuum at ambient temperature. It is also possible, to carry out evaporation at elevated temperatures. Furthermore, the present invention is directed to processes for the preparation of Form A of Benazepril hydrochloride. Form A can generally be prepared by mixing of a solution of Benazepril hydrochloride (preferably a concentrated solution of Benazepril hydrochloride) in an organic solvent, like Ci-Cioaicohols, N-methylpyrrolidone (NMF) or N,N-dimethylformamide (DMF), with a non-solvent like alkanes or acetates, especially C4-C12alkanes or C1-C10acetates, especially hexane or ethyl acetate. Preferred organic solvents are C1-C4alcohols, like methanol and preferably ethanol. It is preferred to add an alcoliolic solution of Benazepril hydrochloride to the non-solvent, especially to heptane or ethyl acetate. If desired, during the preparation process seeding with Form A can be carried out. Form A is preferably prepared in a waterfree medium. Another object of the present invention are pharmaceutical compositions comprising an effective amount of crystalline polymorphic B, or the amorphous form, and a pharmaceuticaily acceptable carrier. The polymorphic Form B may be used as single component or as mixtures with Form A or the amorphous form. As to the novel polymorphic form of Benazepril hydrochloride it is preferred that these contain 25-100% by weight, especially 50-100% by weight of the novel form, based on the total amount of Benazepril hydrochloride. Preferably, such an amount of the novel polymorphic form of Benazepril hydrochloride is 75-100% by weight, especially 90-100% by weight. Highly preferred is an amount of 95-100% by weight. The compositions of the invention include powders, granulates, aggregates and other solid compositions comprising crystalline polymorphic B or the amorphous form. In addition, the compositions that are contemplated by the present invention may further include diluents, such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyimethyi cellulose, carboxymethyl. cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents like calcium carbonate and calcium diphosphate and other diluents known to the pharmaceutical industry. Yet other suitable diluents include waxes, sugars and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin. Further excipients that are within the contemplation of the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes. Excipients that also may be present in the solid compositions further include disintegrants like sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others. In addition, excipients may include tableting lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and giidants such as silicon dioxide. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. Dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and losenges as well as liquid suspensions and elixirs. While the description is not intended to be limiting, the invention is also not intended to pertain to true solutions of Benazepril hydrochloride whereupon the properties that distinguish the solid forms of Benazepril hydrochloride are lost. However, the use of the novel forms to prepare such solutions is considered to be within the contemplation of the invention. Capsule dosages, of course, will contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material. Tablets and powders may be coated. Tablets and powders may be coated with an enteric coating. The enteric coated powder forms may have coatings comprising phthaiic acid cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plastlcizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating. Preferred unit dosages of the pharmaceutical compositions of this invention typically contain from 0.5 to 100 mg of the novel Benazepril hydrochloride forms or mixtures thereof with each other or other forms of Benazepril hydrochloride. More usually, the combined weight of the Benazepril hydrochloride forms of a unit dosage are from 2.5 mg to 80 mg, for example 5, 10, 20 or 40 mg. The following Examples illustrate the invention in more detail. Temperatures are given in degrees Celsius. Example 1: Preoaration of polvmorphic Form B 100 mg of Benazepril hydrochloride Form A was suspended in a mixture of 2 ml tert-butyl methyl ether and 0.1 ml water. This suspension was stirred for 14 hours at 20""C. 78 mg of Benazepril hydrochloride Form B was obtained after filtration and dried in vacuum at 30°C. The obtained Form B was characterized by X-ray powder diffraction, see Fig 2. Example 2: Preparation of polvmonjhic Form B 161 mg Benazepril hydrochloride Form A was suspended in 3 ml acetone and stirred for 20 hours at 20°C. This suspension was filtered and dried in air at 30°C. X-ray powder diffraction showed the product to be polymorphic Form B, see Fig 3. Example 3: Preparation of Dolvmorphic Form B 160 mg Benazepril hydrochloride Form A was suspended in 2 ml THF. This suspension was stirred at ambient temperatures for 5 hours. This suspension was filtered and dried in air at 30°C. X-ray powder diffraction showed the product to be polymorphic Form B. Example 4: Preparation of polvmonjhic Form B 86 mg Benazepril free base was dissolved in 3 ml ethyl acetate. Then 0.1 ml of an aqueous 2 molar solution of HCI was added. After adding an additional 3 ml of ethyl acetate and stirring for 3 hours, the product was obtained by filtration and dried in air at ambient temperature. X-ray powder diffraction showed the product to be polymorphic Form B. Example 5: Preparation of polvmorohic Form A Reference example: 2.4 gram Benazepril free base was dissolved in 60 ml diethyl ether. This solution was stirred for 20 minutes under a gentle stream of HCI gas. The white suspension was stirred for an aditional 15 minutes and then filtered. The white solid was dried in vacuum at 40""C (35 mbar). The product (2.3 gram) was characterized by X-ray powder diffraction, see Fig 1. Example 6: Preparation of polvmorohic Form A 111 mg Benazepril hydrochloride was dissolved in 0.8 ml water-free ethanol. This solution was rapidly added to 10 ml heptane at 20°C. While stirring, the suspension was slowly cooled to 5°C. Then the white precipitate was filtered and dried in vacuum. X-ray powder diffraction showed the product to be polymorphic Form A. Example 7: Preparation of the amorphous form 1 DO mg Benazepril hydrochloride was dissolved in 2 ml water. The solution was filtered and the obtained clear solution was evaporated to dryness at 50°C in vacuum (300 mbar). The obtained white powder was characterized by DSC (Tg = 76°C) and X-ray powder diffraction, see Fig 4. Brief description of the drawings Figure 1 is a characteristic X-ray powder diffraction pattern for Form A. Figure 2 is a characteristic X-ray powder diffraction pattern for Form B. Figure 3 is another characteristic X-ray powder diffraction pattern for Form B. Figure 4 is a characteristic X-ray powder diffraction pattern for the amorphous form. We claim: 1. A process for the preparation of a crystalline polymorph B of 3-[[(lS)-l-(ethoxy- carbonyl)-3-phenylpropyl]amino]-2,3,4,5- tetrahydro-2-oxo-l H- 1-benzazepine-l -acetic acid monohydrochloride which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d values (A) at 13.2 (vs), 10.7 (s), 8.8 (m), 6.4 (m), 5.87 (s), 5.75 (m), 5.35 (m), 5.26 (m), 4.87 (m), 4.66 (s), 4.40 (m), 3.86 (m), 3.79 (m), 3.66 (m), 3.60 (m), 3.57 (m), 3.52 (m),3.45 (m), 3.40 (m), 3.36 (m), 3.27 (m), 3.18 (m), 2.95 (m), 2.72 (m), 2.65 (m); wherein (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity, comprising the step of adding an aqueous solution of hydrochloride to a solution of the free base 3-[[(lS)-l-(ethoxy-carbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepine-l-aceticacid monohydrochloride in an organic solvent. 2. The process as claimed in claim 1, wherein the organic solvent is a C3-C10 ketone, C3-C10 acetate, C2-C10 nitrile, C1-C10 alcohol or C2-C10 ether, or mixtures thereof 3. A process for the preparation of a crystalline polymorph B of 3-[[(lS)-l-(ethoxy-carbonyl)-3-phenylpropyl]amino]-2,3,4,5- tetrahydro-2-oxo-1 H-1 -benzazepine-1 -acetic acid monohydrochloride which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d values (A) at 13.2 (vs), 10.7 (s), 8.8 (m), 6.4 (m), 5.87 (s), 5.75 (m), 5.35 (m), 5.26 (m), 4.87 (m), 4.66 (s), 4.40 (m), 3.86 (m), 3.79 (m), 3.66 (m), 3.60 (m), 3.57 (m), 3.52 (m),3.45 (m), 3.40 (m), 3.36 (m), 3.27 (m), 3.18 (m), 2.95 (m), 2.72 (m), 2.65 (m); wherein (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity, wherein a suspension of Form A or the amorphous form 3[[(lS)-l-(ethoxy-carbonyl)-3-phenyl-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid monohydrochloride is stirred in an organic solvent. 4. The process as claimed in claim 3, wherein the organic solvent is a C3-C10 ketone, C3-C10 acetate, C2-C10 nitrile, C1-C10 alcohol or C2-C10 ether, or mixtures thereof. 5. The process as claimed in claim 3 or 4, wherein the organic solvent is selected from acetone, 1-butanol, 2-butanol, butyl actetate, tert- butylmethyl ether, cumene, dimetylsulfoxide, ethanol, ethylether, ethylformiate, heptane isobutylacetate, isopropyl acetate, methylacetate 3-methyl-1-butanol, methylethyl ketone. 6. The process as claimed in claim 3 or 4, wherein the organic solvent is selected from acetone, methyl ethyl ketone; ethylacetate, isopropylacetate, acetonitrile, isopropylalcohol, methyl-tert.butyl ether and THF. 7. The process as claimed in any of claims 3 to 6, wherein the organic solvent contains small amounts of water. 8. The process as claimed in claim 7, wherein the amount of water is 0.1 to 15% by volume of the suspension of 3[[(IS)-1-(ethoxy-carbonyl)-3-phenyl-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid monohydrochloride. 9. The process as claimed in claim 8, wherein the amount of water is 0.5 to 10% by volume of the suspension of 3[[(lS)-l-(ethoxy-carbonyl)-3-phenyl-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1 -benzazepine-1 -acetic acid monohydrochloride. 10. A process for the preparation of a crystalline polymorph B of 3-[[(1S)-l-(ethoxy-carbonyl)-3-phenylpropyl]amino]-2,3,4,5- tetrahydro-2-oxo-l H-l-benzazepine-1 -acetic acid monohydrochloride which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d values (A) at 13.2 (vs), 10.7 (s), 8.8 (m), 6.4 (m), 5.87 (s), 5.75 (m), 5.35 (m), 5.26 (m), 4.87 (m), 4.66 (s), 4.40 (m), 3.86 (m), 3.79 (m), 3.66 (m), 3.60 (m), 3.57 (m), 3.52 (m),3.45 (m), 3.40 (m), 3.36 (m), 3.27 (m), 3.18 (m), 2.95 (m), 2.72 (m), 2.65 (m); wherein (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity, wherein a suspension of Form A or the amorphous form of 3[[(lS)-l-(ethoxy-carbonyl)-3-phenyl-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1 -benzazepine-1 -acetic acid monohydrochloride is stirred in water. 11. The process as claimed in any one of claims 1 to 10, wherein 3-[[(lS)-l-(ethoxy-carbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid monohydrochloride is isolated by filtration and dried in air or vacuum. 12. The process as claimed in any one of claims 1 to 11, wherein seeding is carried out with crystals of the crystalline polymorph as claimed in claim 1.

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