WO2006084761A1 - Crystalline polymorphs of benazepril hydrochloride - Google Patents

Abstract

The present invention relates to a specific polymorph form of crystalline benazepril hydrochloride referred to as Form B, methods for producing this form of benazepril hydrochloride, compositions containing it, and methods for using it.

Description

CRYSTALLINE POLYMORPHS OF BENAZEPRIL HYDROCHLORIDE

The present invention relates to a specific polymorph form of crystalline benazepril hydrochloride referred to as Form B, methods for producing this form of benazepril hydrochloride, compositions containing it, and methods for using it.

Benazepril hydrochloride is an FDA-approved antihypertensive that acts by inhibition of angiotensin converting enzyme (ACE). Benazepril hydrochloride is known by the chemical name: 3S-[[(1S)-1-(ethoxy-carbonyl)-3-phenylpropyl]amino]- 2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepine-1 -acetic acid hydrochloride. It is the HCI salt of a basic amine-containing compound known as benazepril; the unprotonated or neutral (free base) form of benazepril has the following structure:

Processes for the preparation of enantiomerically pure benazepril hydrochloride are described in U.S. Patents No. 4,410,520 and 4,575,503, and European Pat. No. 072,352, and in the publications by J.W.H. Watthey, et al., in J. Med. Chem., 28, 1511-1516 (1985), and S.K. Boyer, et al., in Helvetica Chimica Acta, 71 , 337-42 (1988). While various ways to make benazepril and benazepril hydrochloride are known, each method has limitations. In U.S. Patent No. 4,410,520, for example, benazepril was converted into its hydrochloride salt by treatment with HCI in methylene chloride; concentration then provided a foamed solid rather than crystalline product. Crystallization from methyl ethyl ketone followed by recrystallization from 3-pentanone and methanol was required to produce benazepril hydrochloride (m.p. 188-190⁰C) of adequate purity.

U.S. Patent No. 4,575,503 describes scaling up this method to make a kilogram quantity of benazepril hydrochloride; in that case, dissolving the crude benazepril in dichloromethane was followed by filtration to remove undissolved material; once HCI had been added, a solution formed, and diethyl ether was added to precipitate the product. The crude material had a melting point of 175-178°C at that stage, and it was again suspended in dichloromethane, treated with hydrochloric acid (HCI), and precipitated by addition of diethyl ether to reach 96% purity and a melting point of 183-185°C. Finally, it was suspended in chloroform and heated to reflux, cooled and filtered, and then washed with chloroform and ether to provide material having a melting point of 184-186⁰C. Thus scale-up of the process rendered purification more difficult and increased the utilization of halogenated solvents for purification, which increases waste disposal costs.

Furthermore, the variability in the reported melting point of the samples suggests there may be an undesirable level of variability in the product obtained. While melting points can be affected by several factors, the variations in melting point could indicate that impurity profiles or crystal forms change depending on the method used to prepare and isolate the sample. Although data distinguishing different crystal forms of benazepril hydrochloride has not been available, the existence of multiple crystal forms has been reported. The New Drug Application (NDA) for benazepril hydrochloride states: "Benazepril exists as polymorphs which have been designated as alpha, beta, and gamma forms. The alpha and beta forms are both converted to gamma form during granulating steps." Chemistry section of NDA No. 19- 851, pg.1, (Ciba-Geigy Corp., date stamped June 1990). (Note: The NDA apparently uses the term 'benazepril' to refer to the hydrochloride salt: the Chemistry section of the NDA provides the name and structure of the hydrochloride salt as well as pKa and molecular weight data for the salt while referring to it only as 'benazepril'; furthermore, 'benazepril' is listed as another name for the drug substance, along with CGS 14824A.) The NDA, however, does not provide characterization of the different forms, nor does it describe ways to make the alpha or beta forms, or ways to make the gamma form other than "during granulating steps".

In the present application, the term 'benazepril' is used to refer to the free base or neutral form of the compound. The salts, which are protonated on the amine nitrogen, are identified as such herein, e.g., as 'benazepril hydrochloride' or 'a benazepril salt'. Benazepril in its neutral form contains both a free amine and a carboxylic acid; thus those skilled in the art will appreciate that it can be depicted as a neutral species as shown above, or as a zwitterion having a protonated, positively charged amine group and a deprotonated, negatively charged carboxylate group.

It is well known that crystalline organic compounds can exhibit polymorphism. Polymorphism is commonly defined as the ability of any substance to have two or more different crystal structures. Crystalline substances may also entrap solvent molecules when crystallized. These solvates or hydrates are referred to as pseudopolymorphs. It is also possible to produce amorphous forms, where at most a low degree of crystalline order is present. Different polymorphs, pseudopolymorphs and amorphous forms may differ in their physical properties such as melting point, solubility, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a pharmaceutical. It is therefore important to evaluate polymorphism of drugs both during initial development and in connection with improved methods of making them. Where multiple polymorphs are known, the relative amount of each present in a mixture of polymorphs can be measured with good precision by analytical methods such as infrared spectroscopy (IR) and X-ray powder diffraction (XRD). See J.W.B. Braga and R.J. Poppi, Figures of Merit for the Determination of the Polymorphic Purity of Carbamazepine by Infrared Spectroscopy and Multivariate Calibration, J. Pharm. ScL, 93(8), 2124-34 (2004). Methods to make pure benazepril hydrochloride having consistent properties and to produce it on large scale are also needed, to ensure a cost-effective and safe supply. Where a compound has multiple polymorphs like benazepril hydrochloride, methods to make each polymorph are also needed. Ideally the compound should be obtained in a form that requires no special conditions for stability during storage and that is not changed by the manipulations required for preparing pharmaceutical products.

A specific crystal form of benazepril hydrochloride was recently disclosed by Ciba Geigy in a PCT patent application, PCT EP2003/007771 , which was published as WO 2004/013105 Al The present application also describes a crystalline form of benazepril hydrochloride, herein designated as form B, which has improved stability. Although the material disclosed in the PCT application is characterized only by its X-ray powder diffraction pattern, the product of the present methods appears to be the same as the crystalline form referred to in that patent application as Form B.

The citation of documents in the Background section or elsewhere in this application is for the information of the reader; it does not constitute an admission that any document represents prior art.

The present invention relates to a specific crystalline form of benazepril hydrochloride, a polymorph referred to herein as Form B. This polymorph is produced under certain conditions, and is more stable than the form which is referred to herein as Form A, that is normally produced by methods of the prior art. Thus Form B provides advantages in handling and storage due to its increased stability. The present invention provides methods to make the Form B polymorph consistently, selectively and in high chemical purity. These methods are amenable to large scale production of benazepril hydrochloride that is of high chemical purity and is therefore well suited for use in the preparation of pharmaceutical compositions. The invention also includes compositions comprising benazepril hydrochloride having crystalline Form B, including ones where the benazepril hydrochloride present is partly or substantially in the Form B crystalline form.

One aspect of the present invention is a crystalline polymorph of 3S- [[(1S)-1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1- benzazepine-1 -acetic acid hydrochloride (benazepril hydrochloride) which exhibits a characteristic X-ray powder diffraction (XRD) pattern with characteristic peaks expressed in d-values (A) at 13.6 (vs), 10.7 (m), 8.8 (s), 6.4 (m), 6.0 (s), 5.9 (s), 5.7 (m), 5.4 (s), and 5.3 (s); this form is herein designated as Form B. The abbreviations in parentheses following each XRD peak location have the following meanings: (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity; (w) = weak intensity.

Other aspects of the invention relate to methods for preparing benazepril hydrochloride comprising Form B, pharmaceutical compositions containing Form B and one or more additional pharmaceutically acceptable components, methods of using Form B and compositions comprising it to make pharmaceutical products and to treat hypertension, and Form B crystalline benazepril hydrochloride that is prepared by the novel methods described.

Figure 1 shows the X-ray Powder Diffraction (XRD) pattern of Form B crystals of benazepril hydrochloride, which precipitated when HCI gas was added to benazepril in acetone.

Figure 2 shows the XRD spectra of benazepril hydrochloride obtained by acidification of benazepril in acetone, ethyl acetate, toluene, and isopropyl acetate, respectively (in order from the top trace down). All four spectra are aligned to simplify comparison.

Figures 3a-3d show the IR spectra of benazepril hydrochloride obtained by acidification of benazepril in acetone, ethyl acetate, toluene, and isopropyl acetate, respectively. Figure 3a corresponds to Form B as described herein; Figures b- d show IR spectra of benazepril hydrochloride in the polymorph form referred to herein as Form A.

Figure 4 charts the amount of benazeprilat (BPat) detected as an impurity in batches of benazepril hydrochloride as the process for making benazepril hydrochloride evolved. The batches are presented in chronological order, and illustrate the consistently low amount of the byproduct BPat found in batches of benazepril hydrochloride made when the process improvements of the present invention were incorporated.

Figure 5 shows the amount of an impurity referred to as Related Compound B, which is a diastereomer of benazepril, in relation to the distillation conditions used to remove the water-immiscible solvent from neutralized benazepril. The first chart shows how much of Related Compound B formed during the atmospheric distillation as a function of the duration of heating of the distillation pot, and the second chart shows how much of Related Compound B was produced during the reduced-pressure distillation over time.

The present invention provides methods that consistently produce benazepril hydrochloride in a crystal form referred to as Form B, and in very high chemical purity. A specific crystal form of benazepril hydrochloride has been disclosed by Ciba Geigy in a PCT patent application as discussed above; although the material disclosed in that PCT application is characterized only by its X-ray powder diffraction pattern (XRD), the product of the present methods has substantially the same XRD pattern as the crystalline form referred to in that PCT application as Form B. The term "Form B" as used throughout this application refers to the polymorph of benazepril hydrochloride that is produced by the methods disclosed herein and characterized by the XRD pattern and characteristic IR spectrum disclosed herein.

Form B crystals of benazepril hydrochloride are characterized by their X-ray powder diffraction pattern, which includes characteristic peaks expressed in d- values (A) at 13.6 (vs), 10.7 (m), 8.8 (s), 6.4 (m), 6.0 (s), 5.9 (s), 5.7 (m), 5.4 (s), and 5.3 (s) [(vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity; and (w) = weak intensity].

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). Small changes in the experimental details can cause small deviation in the d-values of characteristic peaks in the XRD patterns, and those of ordinary skill in the art know such variations are not indicative of different crystal forms. The term "relative vacuum" as used herein refers to the amount by which pressure in a closed system has been reduced for a particular operation, and is expressed as inches of mercury (in. Hg). Thus a distillation at atmospheric pressure would be conducted at 0 in. relative vacuum; a distillation at 20 in. Hg relative vacuum was conducted at a pressure about 20 in. Hg lower than atmospheric pressure, which corresponds to a pressure of about 10 in. Hg, i.e., about 250 mm Hg, or about 0.33 atm.

The XRD pattern from a sample of Form B benazepril hydrochloride is shown in Figure 1 ; Figure 2 shows the XRD pattern for Form B (top trace) aligned above the corresponding XRD patterns for a different crystal form of benazepril hydrochloride, which is obtained when different isolation conditions are used. Each sample of benazepril hydrochloride was obtained by adding HCI gas to a solution of the free base of benazepril in the solvent indicated at the right side of the respective XRD pattern. Form B was produced cleanly from the reaction in acetone, while a different form was produced in each of the other solvents used (toluene, ethyl acetate, and isopropyl acetate). The form obtained from solvents other than acetone corresponds to that referred to in the Ciba Geigy PCT application as Form A based on its XRD pattern, and is referred to herein as Form A.

Form B crystals (top trace in Figure 2) have a distinguishing characteristic XRD peak at approximately 2-theta = 8.0 that is absent in Form A, while Form A crystals (each of the lower three traces in Figure 2) have a distinguishing characteristic XRD peak at approximately 2-theta = 11.9 that is absent in Form B. Thus these two known crystalline forms are readily distinguished by XRD.

The Form B crystals are further characterized and distinguished from Form A crystals by their infrared (IR) spectrum: Figure 3a shows the IR spectrum of Form B crystals of benazepril hydrochloride made by the methods described above. The IR spectrum was run with crystals of Form B in Nujol oil on sodium chloride plates. Form B crystals are readily distinguished from crystals of Form A by IR, as illustrated by the IR spectra of Form A crystals shown in Figures 3b-3d, which were run under similar conditions. For example, each of the Form A IR spectra contains three distinct, sharp absorption peaks between about 1650 and 1750 cm-1 , while Form B has broader peaks at different positions in this region and has a marked shoulder peak at about 1600 cm-1 that is missing in the Form A spectra. As above, the Form A crystals for spectra 3b-3d were obtained by addition of HCI to solutions of benazepril free base in ethyl acetate, toluene and isopropyl acetate, respectively. Methods for making benazepril and its hydrochloride salt are well known. Scheme I shows one method that has been used to prepare benazepril hydrochloride, which is described for example in Boyer, et al., HeIv. Chim. Acta, 71 , 337-43 (1988). In Scheme I, the group represented by X in compound B is a leaving group: in Boyer, et. al, X was a 4-nitrophenylsulfonate group, but other leaving groups such as iodide, bromide, and other sulfonate esters can also be used.

The present methods for making benazepril hydrochloride that is partly or substantially in Form B are distinguished by the use of novel conditions for the preparation of benazepril as its hydrochloride salt, which is the chemical species that has been approved by the FDA as an antihypertensive. The present invention includes several improvements over methods known in the art for making benazepril hydrochloride. One such improvement is the formation of the hydrochloride salt in a C3-C10 ketone solvent, which produces benazepril hydrochloride with improved chemical purity and in the preferred Form B crystalline polymorph, and is thus an improvement over known conditions, which form the hydrochloride salt in solvents such as dichloromethane. "C3-C10 ketone" refers to any ketone compound having 3-10 carbon atoms; examples are acetone, methyl ethyl ketone, 3-pentanone, and methyl isopropyl ketone. The invention also provides methods to prepare the hydrochloride from salts of benazepril, which include neutralization of the benazepril salt in one solvent, and hydrochloride formation in a different solvent, a C3-C10 ketone, which may be water-miscible. The neutralization and solvent exchange followed by hydrochloride formation in a ketone solvent achieves further purification of the product with high recovery, thus it constitutes an additional process improvement. The neutralization can be performed in a water-immiscible solvent so that an aqueous base can be used if desired and can then be removed by simple separation of aqueous and organic layers, which makes the solvent exchange method valuable. The improvements of the methods of the invention include methods to wash the benazepril salt in preparation for the neutralization step to enhance the purity of the final product; methods to control the pH of the aqueous layer during the neutralization step to minimize formation of benazeprilat as an impurity; and methods to exchange the water- immiscible solvent for a C3-C10 ketone employing a distillation under conditions which avoid degradation of the benazepril. Each of these improvements enhances the purity and consistency of the benazepril hydrochloride obtained by the methods of the invention. Other methods for making benazepril and its hydrochloride salt are described in U.S. Patent No. 4,410,520 and in Watthey, et al., J. Med. Chem. 28, 1511- 16 (1985), for example though no indication of the crystal form produced by those methods is provided. The present methods include combining benazepril and nonaqueous hydrogen chloride (HCI) in the presence of a C3-C10 ketone to produce the desired Form B crystals of benazepril hydrochloride. Optionally, the benazepril may be dissolved in the C3-C10 ketone before the non-aqueous hydrogen chloride is added. The temperature of the reaction is not critical, and it may conveniently be performed without heating or cooling, depending on the rate of addition of HCI. If HCI is added rapidly, the reaction may produce heat, and it may be cooled as needed to prevent the solvent from boiling.

In some embodiments, the C3-C10 ketone is preferably a C3-C6 ketone such as acetone or methyl ethyl ketone; acetone is often used. The nonaqueous hydrogen chloride may be a solution of HCI in an organic solvent such as ether, for example, or it may be gaseous HCI. Hydrogen chloride gas is often used. For example, in one embodiment of the method, benazepril is dissolved in acetone, at least one molar equivalent of hydrogen chloride gas is added at a temperature near room temperature, and benazepril hydrochloride containing Form B crystals is obtained. The methods are amenable to large scale production of benazepril hydrochloride comprising Form B crystals and provide the material in a high chemical purity.

Scheme I

B A

Benazepril Hydrochloride The methods for making Form B benazepril hydrochloride may be applied to benazepril or a salt of benazepril obtained by any method. In the reaction sequence shown in Scheme I, for example, compound C has a t-butyl ester group that must be cleaved to a carboxylic acid to produce benazepril; that cleavage can be accomplished by treating C with a strong acid. If hydrochloric acid is used, the cleavage reaction produces benazepril hydrochloride directly as shown. However, other acids could be used instead, which would result in the formation of different salts of benazepril. The present invention provides methods by which the hydrochloride or other salts of benazepril can be converted into benazepril hydrochloride that is partly or substantially in Form B, while also providing further chemical purification of the product.

While the method for making benazepril hydrochloride shown in Scheme I results in the isolation of a salt of benazepril, other syntheses may produce benazepril in its neutral form; the methods of the present invention may readily be applied to the neutral benazepril so obtained. Thus in one aspect of the invention, the neutral form of benazepril, preferably in an organic solvent, is treated with an acid such as HCI to form a salt, as is well known in the art. The salt formation may be accomplished in any solvent that suitably dissolves benazepril; toluene, ethyl acetate, acetone, and isopropyl acetate are examples of suitable solvents for that step, but generally it can be accomplished with any organic solvent that dissolves benazepril. Generally the benazepril salt will precipitate from the solvent upon addition of the acid; if the salt does not readily precipitate, however, it may be advantageous to induce the salt to precipitate by means well known in the art, such as cooling the solution and/or adding a co-solvent that induces precipitation, i.e., one that is miscible with the first solvent but does not significantly dissolve the benazepril salt that has been formed. The salt is then recovered by conventional means and carried through the processes described herein for producing Form B crystals from a benazepril salt.

In one embodiment, the invention provides a method for producing Form B crystalline benazepril hydrochloride from the free base, referred to herein as benazepril. When the methods of the invention are applied to benazepril that is sufficiently free from interfering by-products, it is only necessary to combine this benazepril with non-aqueous HCI in the presence of a suitable solvent. Thus the free base of benazepril may be dissolved in a solvent that comprises a C3-C10 ketone such as acetone or methyl ethyl ketone, and the hydrochloride salt can be produced by adding an appropriate quantity of non-aqueous hydrogen chloride to the solution. The solvent preferably includes at least 50% by volume of one or more C3-C10 ketones. Hydrogen chloride is typically added as a gas, but optionally may be added in the form of a non-aqueous solution, such as, for example, HCI in diethyl ether. The nonaqueous hydrogen chloride solution does not need to be entirely water free: in certain embodiments, for example, the non-aqueous solution comprises less than about 20% water or other hydroxylic solvents by weight, and more typically less than about 10%. In other examples, any water or protic solvents present (excluding HCI) in the nonaqueous hydrogen chloride solution represent less than about 5% of the weight of the solution. This process directly produces benazepril hydrochloride that is partly or substantially in the Form B polymorph form. Where a salt of benazepril that requires further purification is obtained, it can advantageously be purified and converted to benazepril hydrochloride by methods of the present invention. In some embodiments of the present method, the benazepril salt is first washed at least once and preferably more than once with a suitable organic solvent having moderate polarity. Solvents suitable for this wash include C3-C10 esters such as ethyl acetate, t-butyl formate, or isopropyl acetate, C3- C10 ketones such as those mentioned above, and C6-C10 aromatics such as toluene, xylenes, or ethyl benzene; or mixtures of these solvents. Mixtures of one or more of these solvents with up to about 25% by volume of a hydrocarbon solvent such as hexane or heptane or a halogenated solvent such as dichloromethane or chloroform may also be used. A C3-C6 ester such as ethyl acetate or isopropyl acetate is sometimes advantageously used as the solvent for this wash, especially when the benazepril salt was produced using more than one molar equivalent of an acid. This step is often included to remove excess acid present from the step of forming the benazepril salt, such as when the salt is formed with excess hydrochloric acid. In one embodiment, a crude benazepril hydrochloride salt is washed at least once and preferably at least twice with ethyl acetate or isopropyl acetate.

The term 'washed' or 'washing' is sometimes used herein to describe a process of admixing a solid material with a solvent that does not significantly dissolve the desired components of the solid, then separating at least most of the solvent from the solid. This process often at least partially dissolves away one or more undesired materials from the desired components of the solid, so it increases the purity of the remaining solid. The quantity of the organic solvent can be adjusted as one of ordinary skill will appreciate; frequently, a volume of the organic solvent equal to at least about one fourth of the volume of the solid to be washed is used for this process, and often the volume of solvent will be about one to two times the volume of the solid. The entire volume of the solvent can be admixed with the solid in one batch prior to separation in some embodiments. In other embodiments, the solvent is poured over or mixed with the solid and simultaneously removal of the solvent as by vacuum filtration or centrifugation is initiated. The crude benazepril salt is then neutralized with a base in the presence of a water-immiscible solvent. Typically, the benazepril salt is admixed with an organic solvent that is immiscible with water, forming a suspension; toluene, ethyl acetate or isopropyl acetate may be used as the water-immiscible solvent, for example, and in some embodiments isopropyl acetate is used. "Immiscible" as used herein refers to a pair of solvents that do not freely mix to form a homogeneous solution; it does not require such complete incompatibility that neither solvent will dissolve at all in the other, and commonly a small amount of each solvent of an immiscible pair will dissolve in the other even though they form distinct and separable layers. Solvents commonly considered water-immiscible by those of skill in the art include ethyl acetate, diethyl ether, hexane, toluene, isopropyl acetate, dichloromethane, chloroform, and the like, while organic solvents that are water-miscible include acetone, ethanol, methanol, dioxane, tetrahydrofuran, and dimethyl sulfoxide.

Water and a neutralizing base such as sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate are typically added to the suspension of the benazepril salt, producing a mixture with two separate liquid phases referred to as the organic and aqueous layers. The benazepril hydrochloride may be partly or completely dissolved prior to addition of base, depending on the amount of water and solvent used. The organic layer is preferably in contact with the aqueous layer when the benazepril salt is neutralized with the base, so that the neutral benazepril formed can distribute into the organic layer.

The amount of base added is preferably sufficient to bring the pH of the aqueous layer to a pH between about 3.5 and 6.0. If the pH is outside this range after the base addition, it can be adjusted by adding more base to raise the pH or by adding an acid such as aqueous HCI to lower the pH, as is well known in the art. A pH between about 4 and 5 is often advantageously used for this step, which neutralizes the benazepril hydrochloride salt and generates a solution of benazepril in the water- immiscible solvent.

Careful control of the pH at this stage reduces by-product formation, and the pH is often monitored with an internal or in-line pH meter to ensure that the pH of the aqueous layer is not allowed to rise above about pH 7 while the organic and aqueous layers are in contact, and preferably the addition of base is controlled carefully enough to keep the pH below 5 continuously. In one embodiment of this method, the neutralizing base is aqueous sodium carbonate or aqueous potassium carbonate, and a sufficient amount of the neutralizing base is added to bring the pH to between 4.2 and 4.8. If the pH rises above 4.8 in this step, an acid such as aqueous HCI is added to adjust the pH until it is within the targeted range. If the pH is below the target range after adding the base, more base is added as needed to achieve a pH within the specified range.

The neutralizing base may be added as an aqueous solution, or the suspension of the benazepril salt may first be admixed with water and the base may then be added in solid form or as a solution. An aqueous solution of potassium carbonate is often used as the base, typically a solution having at least about 30% K₂CO₃. Efficient mixing is often appropriate to prevent the pH from becoming too high in localized regions as the base is added. Typically, the benazepril salt is combined with water and the water-immiscible solvent, and an aqueous base solution is added to that mixture.

Once the pH of the aqueous layer has been adjusted appropriately, the organic layer is separated from the aqueous layer, and the organic layer is concentrated to remove at least a majority of the water-immiscible organic solvent, leaving a residue in the distillation pot that contains benazepril. This concentration or solvent removal is done so that the water-immiscible solvent can be replaced by a C3- C10 ketone before hydrogen chloride is added to form the benazepril hydrochloride product: as discussed above, the desired Form B crystals are formed when the solvent for mixing benazepril and hydrogen chloride is mainly a C3-C10 ketone such as acetone. Removal of the water-immiscible solvent may be done by distillation at atmospheric pressure or at a reduced pressure. At least 40 % or at least about 50% of the water immiscible solvent is removed by this distillation, and advantageously at least about 70% is removed. In some embodiments, over 80% or over 90% of the water immiscible solvent is removed by this concentration step. The water-immiscible organic solvent used for the base-neutralization step is preferably one that forms an azeotrope with water; distillation under conditions where the solvent-water azeotrope forms may then be employed to remove residual moisture left behind by the neutralization step or by aqueous washes of the organic layer that may be used to remove residual salts, lsopropyl acetate forms an azeotrope with water under some distillation conditions and is sometimes used as the water- immiscible solvent for this step. Its removal by distillation at about atmospheric pressure acts to remove residual water from the benazepril-containing residue. Likewise, toluene forms a low-boiling azeotrope with water and may be used.

The distillation to remove this water-immiscible solvent may be performed at atmospheric pressure or at a reduced pressure, or the distillation may be conducted in part at atmospheric pressure and in part at a reduced pressure. Distillation at a reduced pressure may be advantageous to avoid heating the benazepril-containing solution in the distillation pot to a temperature that could cause degradation. Thus distillation at reduced pressure may be preferred if the boiling point of the water-immiscible solvent or of its azeotrope with water is higher than about 9O⁰C, since degradation of the benazepril begins to occur at about that temperature.

In one embodiment, the distillation temperature is maintained below about 9O⁰C; in another, which reduces by-product formation, the temperature in the distillation pot is not allowed to rise above 88°C. To minimize degradation of the benazepril, it is also preferable to minimize the duration of heating required for the distillation. Preferably, the temperature of the distillation pot does not exceed 88oC and is not kept at 88°C for more than about one hour, or at least not for more than three hours. Where the solvent used is isopropyl acetate, for example, the distillation may be performed at atmospheric pressure until the pot temperature reaches 88⁰C, which is the approximate boiling point of isopropyl acetate, and is above the boiling point of the isopropyl acetate-water azeotrope at atmospheric pressure. Then the pressure is reduced and further solvent removal may be accomplished at a temperature lower than 88°C as dictated by the reduced pressure.

The pressure for the distillation can be reduced to any extent that is practical, as long as it prevents the pot temperature from exceeding a temperature of 88oC; selection of the pressure for the distillation is within the ordinary skill in the art and depends on the boiling point of the particular solvent or solvents employed and the boiling point of any solvent-water azeotrope that may be employed to remove water from the benazepril. Thus the pressure would generally not be reduced below the point where the solvent condenses at room temperature after leaving the heated pot, for example, so that the solvent can be collected for recycling or disposal. A distillation under a relative vacuum of 20-25 in. Hg is often suitable to permit rapid removal of the solvent at a temperature that avoids degradation of the benazepril. Where the solvent used is isopropyl acetate, for example, the distillation is often conducted at atmospheric pressure until the isopropyl acetate-water azeotrope has mostly distilled out, and a relative vacuum of 22-23 in. Hg is typically used for the remainder of the distillation. By this method, isopropyl acetate can be removed without heating the benazepril- containing distillation pot above 88⁰C. In a preferred embodiment, the water-immiscible solvent is substantially removed by this two-step distillation process, beginning at atmospheric pressure until the temperature of the pot exceeds the boiling point of the solvent-water azeotrope, then continuing under 23 in. Hg of relative vacuum until the solvent has been substantially removed. Since the purpose of the removal of the water-immiscible solvent is to permit the final steps to be performed in a solvent that is predominately a C3-C10 ketone so that the desired Form B crystals will be produced, complete removal of the water-immiscible solvent is not necessary: substantial removal of the water- immiscible solvent is sufficient to achieve the objectives of the invention. Here, 'substantial' removal thus means that at least 40% or about 50% by volume of the water-immiscible solvent is removed. As indicated above, the amount of solvent removed may be70% or 80% or 90%, or even more than 90% within the scope of the invention. The extent to which the water-immiscible solvent should be removed is dictated primarily by the next step, where it is desirable to mix the benazepril and hydrochloric acid in a solvent that is at least about 50% by volume a C3-C10 ketone or mixture of such ketones.

Once the desired amount of the water-immiscible solvent has been removed, the partially purified benazepril that remains is combined with non-aqueous hydrogen chloride in a C3-C10 ketone. Typically, this is done by adding the C3-C10 ketone to the benazepril-containing residue in the distillation pot and adding the non- aqueous hydrogen chloride, but the order of mixing is not critical.

In preferred embodiments, the C3-C10 ketone is a C3-C6 ketone. Thus in one embodiment of this method, acetone is used as the C3-C10 ketone; commercially available bulk acetone is suitable. Typically, an amount of the ketone sufficient to dissolve all of the benazepril is used, and it may be added to the benazepril to form a homogeneous solution. Optionally, the resulting solution may be treated with an adsorbent solid material such as activated carbon to remove certain impurities; the adsorbent solid is then removed by conventional means such as filtration or centrifugation.

To the C3-C10 ketone solution of benazepril, non-aqueous hydrogen chloride (HCI) is then added to produce benazepril hydrochloride. Generally at least one molar equivalent of HCI (a molar quantity that is about equal to the molar quantity of benazepril present) is added to ensure complete conversion of the benazepril to benazepril hydrochloride, but less than one molar equivalent of HCI may be added since any benazepril that is not protonated will be washed away from the Form B crystalline product. The use of more than one equivalent of HCI is not deleterious to the process, either. Often at least a small excess of HCI is used, and a substantial excess can be used.

The HCI used for this step is non-aqueous hydrochloric acid, which means that HCI is not added as an aqueous solution or as a solution in a protic solvent such as methanol or ethanol; rigorous exclusion of moisture is not required for the reaction to work, however. Typically, hydrogen chloride gas is used, but a non-aqueous solution of HCI may be used as long as the solvent present when the HCI is mixed with the benazepril remains at least about 50% by volume a C3-C10 ketone or a mixture of such ketones. Optionally, the solution of benazepril may be seeded with crystals of Form B either before or during the mixing of benazepril with HCI to ensure that the desired crystal form is produced, but seeding is generally not necessary when the C3- C10 ketone used is acetone.

The addition of HCI to benazepril in a ketone solvent generally causes benazepril hydrochloride to precipitate as a crystalline solid; the solution or suspension may be cooled if desired to promote complete precipitation of the product. Typically, benazepril hydrochloride spontaneously precipitates from the C3-C10 ketone solution as crystals having Form B, as shown by the X-ray powder diffraction pattern of a sample of the product. The crystalline product may be collected using methods well known in the art. Optionally, prior to isolation, the crystalline product may be washed with a C3-C10 ketone or with any organic solvent in which benazepril hydrochloride is only sparingly soluble such as, for example, ether, dichloromethane, ethyl acetate, toluene, or isopropyl acetate. Once the product is collected, removal of residual solvent may be done using heat, suction, reduced pressure, or a combination of methods such as these, all of which are well known in the art. The foregoing method provides benazepril hydrochloride having fewer impurities than alternative known methods, and consistently produces benazepril hydrochloride at least partly in the crystal form described and referred to herein as Form B. These features make the process particularly useful for large-scale preparation of benazepril hydrochloride for pharmaceutical applications. Form B is advantageous relative to other crystal forms because it is more stable than other forms, and because it can be produced consistently; other conditions produce benazepril hydrochloride that is amorphous or has other crystal forms such as Form A, and they produce by-products such as the salt of benazeprilat, that are difficult to remove. Particularly, the current process minimizes the formation of benazeprilat (which would be found as its hydrochloride salt in the final product) and of diastereomers of benazepril hydrochloride. Benazeprilat (BPat) corresponds to benazepril in which the ethyl ester has been hydrolyzed to a carboxylic acid. It is commonly observed as an impurity in production of benazepril hydrochloride, and is also reportedly the active form of the drug in vivo.

Benazeprilat

For example, Figure 4 shows the amount of BPat present in batches of benazepril hydrochloride made using varying conditions. Samples made by the above methods are identified as batches BP4-09 to BP4-28; batches BP4-01, BP4-03, BP4-05, and BP4-07 were made under different conditions, where the crude benazepril salt was not washed with a suitable solvent prior to the neutralization and hydrochloride salt formation steps, or where the pH of the neutralization step was not kept within the ranges described above, or where the pot temperature was allowed to rise above 88oC when distilling the water-immiscible solvent away from the benazepril prior to the final acidification step. Under those conditions, the amount of BPat varies and is often significantly higher. As Figure 4 shows, the batches of benazepril hydrochloride made by the present methods consistently contain less than about 0.15% of BPat.

The foregoing method serves to remove or avoid formation of certain impurities that may be present in benazepril salts prepared by the method shown in Scheme I, while it consistently produces benazepril hydrochloride crystals of Form B. More generally, however, Form B of benazepril hydrochloride may be produced from benazepril using methods within the invention, regardless of how the benazepril was prepared. Thus in another aspect, the invention is directed to methods for making benazepril hydrochloride in crystal Form B from benazepril. Form B crystals may be obtained by combining benazepril with at least one molar equivalent of non-aqueous hydrogen chloride in a C3 to C10 ketone as solvent, preferably in a C3-C6 ketone such as acetone or methyl ethyl ketone (2-butanone). Thus when hydrogen chloride gas is added to benazepril dissolved in a C3-C10 ketone or C3-C6 ketone such as acetone, for example, benazepril hydrochloride that is partly or substantially in the Form B crystal form is produced. Adding hydrogen chloride to benazepril dissolved in organic solvents other than C3-C10 ketones generally results in the formation of Form A crystals of benazepril hydrochloride or mixtures of Forms A and B if the product precipitates in crystalline form. Figure 2 compares XRD data for benazepril hydrochloride that precipitated from ethyl acetate, toluene and isopropyl acetate (the lower three traces), which is predominantly in Form A, to data for the form that precipitated from acetone (top trace), which is substantially in Form B.

In another aspect, the invention is directed to the crystalline form of benazepril hydrochloride referred to herein as Form B. Form B is produced by the foregoing methods for isolating benazepril hydrochloride; other methods may produce Form A or other polymorphs, or they may produce an amorphous form according to the patent application identified above, VVO 2004/013105 Al The crystal form of benazepril hydrochloride is conveniently determined by XRD or by IR, since these methods allow Form A and Form B to be distinguished clearly. The invention encompasses benazepril hydrochloride crystals that are in Form B, as well as bulk material that is partly or substantially in Form B. "Partly" in form B as used herein means that at least 10% of the bulk material is in Form B, or at least 20%, or at least about 25% is in form B. "Substantially" in Form B as used herein means that at least 50% of the crystalline benazepril hydrochloride present in the bulk material is in the Form B crystalline polymorph; the balance may be of Form A or other crystalline or amorphous forms.

Benazepril hydrochloride may also exist as a mixture of Form A and Form B crystals, and the present invention encompasses benazepril hydrochloride mixtures where the benazepril hydrochloride present is partly or substantially in Form B. The amount of Form B present in a sample of benazepril hydrochloride containing a mixture of crystalline forms can be estimated by XRD or by IR. The present methods for making benazepril hydrochloride provide a product that is at least about 10% in Form B, and preferably at least 20% in Form B. The methods often provide material that is at least 50% in the Form B crystal form as judged by the XRD data, and generally at least about 70% or 80% in Form B. In some embodiments, the present methods produce at least 90% form B, or at least about 95% form B as judged by XRD. In some embodiments the benazepril hydrochloride contains less than about 20% of a polymorph having a characteristic X-ray powder diffraction peak at 2-theta = 11.9. In other embodiments, the benazepril hydrochloride produced contains less than about 10% of a polymorph having a characteristic X-ray powder diffraction peak at 2-theta = 11.9.

In another aspect, the invention is directed to crystalline benazepril hydrochloride which is produced by the foregoing method. Benazepril hydrochloride produced by methods known in the art is reported to be in Form A or in an amorphous form according to WO 2004/013105 A1. The present methods consistently provide benazepril hydrochloride that is partly or substantially in the preferred Form B crystal structure and of high purity. Thus the invention includes benazepril hydrochloride prepared by addition of hydrogen chloride to a solution of benazepril in a C3 to C10 ketone, where the product is at least 10% in the Form B crystal form, preferably at least 50% in Form B, and is at least about 98% pure 3S-[[(1 S)-1-(ethoxy-carbonyl)-3- phenylpropyl]amino]-2,3 ,4,5-tetrahydro-2-oxo-1 H-1 -benzazepine-1 -acetic acid hydrochloride. In some embodiments, the methods of the invention provide product that is at least 70% or at least 80% in Form B, and at least 98% pure. In other embodiments, these methods provide at least about 80% Form B product or at least 90% Form B product that is at least 99% pure 3S-[[(1S)-1-(ethoxy-carbonyl)-3- phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepine-1-acetic acid hydrochloride by weight. Thus materials prepared by the methods described herein and having these compositions are within the scope of the invention.

Benazepril hydrochloride having the Form B crystalline structure is useful to treat hypertension. Dosages and methods for formulating and delivering Form B benazepril hydrochloride for such treatments are readily determined by those of skill in the art. They may, for example, be determined without undue experimentation based on information contained in the FDA Label information for a pharmaceutical composition containing benazepril or benazepril hydrochloride.

The polymorph referred to as Form B may be used as single component or as mixtures with Form A or the amorphous form. Thus in another aspect, the invention is directed to pharmaceutical compositions comprising benazepril hydrochloride of Form B. In some embodiments the benazepril hydrochloride present is at least 10% in the Form B polymorph, and in some it is at least 20% in Form B. The invention includes compositions wherein the benazepril hydrochloride is substantially in the Form B crystal form. "Substantially" in Form B as used here means that at least 50% of the 3S-[[(1S)-1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2- oxo-1 H-1-benzazepine-1 -acetic acid hydrochloride present is in crystal Form B; the balance may be amorphous or Form A crystalline material, or a mixture of these two, or it may include other polymorph forms. In preferred embodiments, at least 70% or at least 80% of the benazepril hydrochloride in such compositions is in Form B crystalline form; and in some embodiments at least 90% or at least 95% of the product is crystalline 3S-[[(1 S)-1 -(ethoxy-carbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepine-1 -acetic acid hydrochloride of Form B. In other embodiments, the crystalline benazepril hydrochloride contains less than 20% or less than 10% of a polymorph having a characteristic X-ray powder diffraction peak at 2-theta = 11.9. These pharmaceutical compositions are useful to treat hypertension.

The Form B crystalline benazepril hydrochloride may be formulated or administered in combination with other drugs such as those known to treat hypertension and those known to treat conditions associated with hypertension. For example, it may be mixed with or administered with thiazide diuretics. Methods for using Form B in combination with such other drugs are readily apparent to those of ordinary skill.

Benazepril hydrochloride of Form B is also useful for the preparation or manufacture of pharmaceutical compositions and medicaments that are useful to treat hypertension. The pharmaceutical compositions of the invention include powders, granulates, aggregates and other solid compositions comprising 3S-[[(1S)-1-(ethoxy- carbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1 -benzazepine-1 -acetic acid hydrochloride comprising crystalline polymorph Form B. 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, hydroxypropylmethyl cellulose, hypromellose, carboxymethyl, cellulose salts and other substituted and unsubstituted celluloses; starch; polysorbate 80; propylene glycol; pregelatinized starch; inorganic diluents like calcium carbonate and calcium diphosphate as well as colloidal silicon dioxide, iron oxides, talc, titanium dioxide, and other excipients known to the pharmaceutical industry. Yet other suitable components include waxes, sugars including sucrose, lactose, and the like, 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 glidants such as silicon dioxide.

Preferred unit dosages of the pharmaceutical compositions of this invention typically contain from 0.5 to 100 mg of the Form B benazepril hydrochloride polymorph or mixtures thereof with other forms of benazepril hydrochloride such as Form A. 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. Thus benazepril hydrochloride comprising Form B may be used to prepare unit dosages, such as tablets, wherein each tablet contains about 5, 10, 20, or 40 mg of total benazepril hydrochloride.

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. Typically, the pharmaceutical compositions containing Form B material are provided in the form of tablets containing about 5, 10, 20 or 40 mg of total benazepril hydrochloride per tablet. In a preferred embodiment, the benazepril hydrochloride used for making such tablets is at least 10% in the Form B polymorph, or at least 20% in Form B. In more preferred embodiments, it is substantially in Form B or is at least 80% in Form B.

Dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions and elixirs. While the description is not intended to be limiting, the invention is not intended to pertain to true solutions of benazepril hydrochloride: once dissolved, the properties that distinguish the solid forms of Form B benazepril hydrochloride are lost. However, the use of Form B to prepare such solutions is within the contemplation of the invention, since the consistent properties and increased stability associated with Form B improve its usefulness for such processes. Thus benazepril hydrochloride comprising Form B may be used for the preparation of a medicament to treat hypertension within the scope of the present invention.

Capsule dosages, of course, may contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material. Tablets and powders may be coated and may include dyes or colorants. Tablets and powders may be coated with an enteric coating. The enteric coated powder forms may have coatings comprising phthalic 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 plasticizers 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.

Examples

The following Examples illustrate certain embodiments of the invention in more detail, but are not to be considered as limiting the scope of the invention. Solvents and reagents were obtained from commercial suppliers, including the following:

Acetone: Sunoco, Shell, Aristech, Union Carbide, Dow, JLM, Exxon, BTL Ethyl Acetate: Hoechst Celanese, Solutia, Eastman, Dow Hydrochloric Acid (gas): Alexander Chemical, Airgas lsopropyl Acetate: Dow, Eastman Chemical Potassium Carbonate (47% solution): Armand, Ashta

Example 1

Preparation and Washing of Crude Benazepril Hydrochloride

The following reactions were performed in a 2000 gallon reactor. Approximately 1200 pounds of the tartrate salt of compound A of Scheme I were coupled to the triflate of compound B (X = OSO₂CF₃) prepared from approximately 600 pounds of the corresponding alcohol (compound B where X = OH). This provided crude benazepril t-butyl ester.

The crude benazepril t-butyl ester (compound C, Scheme I) was dissolved in ethyl acetate (6000 Ib) and cooled to a temperature between -10⁰C and +10⁰C. Dry hydrochloric acid gas (706 Ib) was added, and the mixture was allowed to warm to room temperature. It was held at 20-25⁰C for 16 hours, by which time it had formed a slurry. The mixture was leaf filtered to remove ethyl acetate and excess hydrochloric acid. It was then washed twice with isopropyl acetate (2 x 2370 Ib) to ensure removal of excess hydrochloric acid, providing crude benazepril hydrochloride as a wet cake.

Example 2

Preparation of Benazepril To the crude benazepril hydrochloride, water (about 300 gal) and isopropyl acetate (4600 Ib) were added, forming a biphasic solution. The temperature was kept below 2O⁰C during these additions. Aqueous potassium carbonate (47% K₂CO₃, approximately 500 Ib) was then added until the pH was between 4.2 and 4.8, measured internally, producing a solution of benazepril in isopropyl acetate and an aqueous layer. The aqueous layer was then removed, and was back-extracted with a portion of isopropyl acetate, which was added to the benazepril solution. This solution was washed once with water, and then the solvent was removed by distillation. The distillation was started at atmospheric pressure, and as soon as the temperature of the distillation pot reached 88°C, heating was stopped. The pot was then placed under partial vacuum, and distillation was continued under 23 in. Hg of relative vacuum until substantially all of the isopropyl acetate had been removed, without permitting the distillation pot temperature to exceed 60⁰C.

Example 3 Preparation of Benazepril Hydrochloride Comprising Form B

The pot from the above distillation was cooled, and acetone (792 gal) was added to the benazepril residue. Activated carbon (Darco KB, 17 Ib) and Celite (17 Ib) were then added, and the mixture was heated to reflux for one hour and filtered to provide an acetone solution of the free base of benazepril. This solution was cooled to 10-20⁰C, and gaseous hydrochloric acid was added in an amount calculated to neutralize the theoretical yield of benazepril present. The batch was then warmed to 40-50⁰C for three hours, cooled to 20-25⁰C, and centrifuged to provide benazepril hydrochloride as a wet cake. The wet cake was washed with 300 gallons of acetone and then dried at 50-60⁰C to provide approximately 1150 pounds of benazepril hydrochloride containing less than 0.15% benazepril (BPat), and substantially in Form B.

The batches of benazepril hydrochloride BP4-09 to BP4-28 in Figure 4 illustrate the consistently low quantity of BPat in benazepril hydrochloride produced by this method.

Samples from three randomly chosen batches exhibited melting points of 184.8-185.4°C; 185.0-187.6⁰C; and 185.0-187.9⁰C. These melting points, which were obtained without recrystallization of the samples, are in good agreement with the melting point reported in J. Med. Chem., 28, 1511-1516 (1985), which was 188-19O⁰C (recrystallized from 3-pentanone plus methanol). However, since no IR or XRD data was provided in that reference, it is not possible to compare the crystal form obtained in this Example to that obtained in the cited reference.

Example 4 Examples 1-3 represent a 400 kg scale preparation. Using the methods exemplified in Examples 1-3 on a 100 kg scale provided benazepril hydrochloride in yields of 67-81%, with a median yield of 75% over 20 batches.

Example 5 Crude benazepril hydrochloride was prepared by the method described in Example 1 , except that the crude product was not washed with isopropyl acetate before proceeding with the process described in Example 2.

To the crude benazepril hydrochloride, water and isopropyl acetate were added, forming a biphasic solution. The temperature was kept below 20⁰C during these additions. Aqueous potassium carbonate (47% K₂CO₃, approximately 500 Ib) was then added until the pH was between about 4 and 5, producing a solution of benazepril in isopropyl acetate. The aqueous layer was then removed, and was back- extracted with a portion of isopropyl acetate, which was added to the benazepril solution. This solution was washed once with water, and then the solvent was removed by distillation. After the isopropyl acetate-water azeotrope had been distilled off, removal of isopropyl acetate was continued at 88-90⁰C for 2-4 hours. The pot was then placed under about 20 in. Hg of relative vacuum and distillation was continued until substantially all of the isopropyl acetate had been removed. Using the procedure described in Example 3, benazepril hydrochloride of Form B was isolated. Example 6

The procedure of Example 5 was repeated a number of times to evaluate its reproducibility, and it provided a median yield of 79%, with a range of 75- 80% over 15 batches. Analysis of several of these batches showed total impurities ranging from 0.36% to 0.47%. The impurities present in excess of 0.1 % by weight were acetone (0.13% in one batch), benazeprilat-HCI (BPat) ranging from 0.10% to 0.30%, and isomers of benazepril hydrochloride (including its enantiomer) ranging from 0.11% to 0.27%. By comparison, as discussed herein, the method as described in

Examples 1-3 provided benazepril hydrochloride that consistently contained less than about 0.15% BPat. Additional experiments demonstrated that benazeprilat is formed when water is added to crude benazepril hydrochloride having excess HCI present and when the neutralization step is conducted without close control of the pH. Two process changes reduced the yield and variability of BPat. First, the crude benazepril hydrochloride was washed with isopropyl acetate to remove excess HCI before adding water. Second, the pH was carefully monitored and controlled during addition of the neutralizing base: the pH was adjusted to fall between 4.2 and 4.8, and the layers were then promptly separated. Examples 1-3 illustrate these process improvements.

Example 7

One batch of product obtained by the methods discussed in Example 5 was below the quality standards established for benazepril hydrochloride, and the reasons were investigated. The distillation conditions used to remove the isopropyl acetate from the neutralized benazepril in the methods of Example 5 and 6 were found to contribute to the formation of a by-product in the sub-standard batch that was identified as a diastereomer of benazepril hydrochloride. To reduce the amount of this diastereomer, referred to as Related Compound B, the distillation conditions for subsequent batches were modified by performing the distillation at atmospheric pressure only until the distillation pot temperature reached 88°C. Heating was then stopped, and a relative vacuum of 23 in. Hg was applied to the pot. Further removal of solvent was performed at a pot temperature not exceeding 60⁰C, and the distillation was stopped within 4 hours. Under these conditions, Related Compound B was reduced to nearly undetectable levels as shown in Figure 5. Examples 1-3 incorporate this process improvement.

The foregoing examples are intended to illustrate the present invention and not to imply limitations on its scope. One of ordinary skill would recognize that many combinations of different features, details and embodiments described herein are feasible, and such combinations are within the scope of the invention. For example, applying the methods to smaller or larger scale preparations of benazepril hydrochloride is within the scope of the invention. Similarly, one of ordinary skill will appreciate that where a solvent is to be selected from a particular genus, the solvent may also be a mixture of two or more members of that genus. Furthermore, as one of ordinary skill will appreciate, minor amounts of other solvents are often tolerated in such mixtures and their inclusion, where it does not materially affect the process, does not depart from the inventive concept described herein.

Claims

1. A process for preparing benazepril hydrochloride comprising the Form B polymorph, which polymorph is characterized by X-ray powder diffraction peaks expressed in d-values (A) at 13.6 (vs), 10.7 (m), 8.8 (s), 6.4 (m), 6.0 (s),

5.9 (s), 5.7 (m), 5.4 (s), and 5.3 (s), wherein (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity; and (w) = weak intensity, said process comprising: combining benazepril and non-aqueous hydrogen chloride in a solvent comprising a C3-C6 ketone.

2. The process of claim 1 , wherein the benazepril hydrochloride produced is substantially in Form B.

3. The process of claim 1 , wherein said C3-C6 ketone is acetone or methyl ethyl ketone.

4. The process of claim 1 , wherein said solvent contains at least 50% acetone by volume.

5. The process of claim 1 , wherein said non-aqueous hydrogen chloride is hydrogen chloride gas.

6. The process of any of claims 1-5, wherein said benazepril is prepared by: neutralizing a benazepril salt with a base to form said benazepril, forming a solution of said benazepril in a water-immiscible solvent, and substantially removing said water-immiscible solvent from said benazepril.

7. The process of claim 6, wherein the water-immiscible solvent is selected from the group consisting of toluene, ethyl acetate, and isopropyl acetate.

8. The process of claim 6, wherein the water-immiscible solvent is isopropyl acetate or ethyl acetate.

9. The process of claim 6, wherein the water-immiscible solvent is isopropyl acetate.

10. The process of claim 6, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

11. The process of claim 6, wherein the base is aqueous potassium carbonate.

12. The process of claim 6, wherein an aqueous layer is present when said benazepril salt is neutralized with said base.

13. The process of claim 12, wherein the pH of the aqueous layer is adjusted to a pH between 4 and 5 while said aqueous layer is in contact with said water-immiscible solvent.

14. The process of claim 13, wherein the base is an aqueous solution of potassium carbonate.

15. The process of claim 12, wherein the base is aqueous potassium carbonate and the pH of the aqueous layer is adjusted to a pH between 4.2 and 4.8 while said aqueous layer is in contact with said water-immiscible solvent.

16. The process of claim 6, wherein the benazepril salt is washed with a C3-C6 ester before said benazepril salt is neutralized with said base.

17. The process of any of claims 6-16, wherein the water-immiscible solvent is isopropyl acetate, and the step of substantially removing said water-immiscible solvent is performed by distillation without heating the contents of the distillation pot that contains said benazepril to a temperature above 88⁰C.

18. A process for preparing benazepril hydrochloride comprising Form B, the process comprising the steps of:

(a) providing a benazepril salt,

(b) washing the benazepril salt at least once with a solvent, wherein the solvent is a C3-C6 ester, or a C3-C6 ketone, or a C6-C10 aromatic, or a mixture comprising at least one of these solvents; (c) suspending the benazepril salt in a water-immiscible solvent,

(d) neutralizing the benazepril salt with a base to Form Benazepril,

(e) substantially removing the water-immiscible solvent,

(f) dissolving the benazepril in a C3-C10 ketone, and

(g) adding non-aqueous hydrogen chloride to the solution of benazepril in the C3-C10 ketone.

19. The process of claim 18, wherein the benazepril salt is benazepril hydrochloride

20. The process of claim 18, wherein the solvent in step (b) is a C3-C6 ester.

21. The process of claim 18, wherein the water immiscible solvent in step (c) is selected from the group consisting of toluene, ethyl acetate, and isopropyl acetate.

22. The process of claim 18, wherein the base in step (d) is sodium carbonate or potassium carbonate.

23. The process of claim 18, wherein the C3-C10 ketone of step (f) and (g) is acetone or methyl ethyl ketone.

24. The process of any of claims 18-24, wherein the base of step (d) is aqueous potassium carbonate.

25. The process of any of claims 18-24, wherein the solvent of step (b) is isopropyl acetate.

26. The process of any of claims 18-24, wherein the C3-C10 ketone of step (f) and (g) is acetone.

27. The process of any of claims 18-24, wherein the water-immiscible solvent in step (c) is isopropyl acetate.

28. The process of any of claims 20-24, wherein the benazepril salt in step (a) is benazepril hydrochloride.

29. The process of any of claims 18-24, wherein the step of substantially removing the water-immiscible solvent, step (e), is performed at a temperature not exceeding 88⁰C.

30. The process of claim 26, wherein the water-immiscible solvent in step (c) is isopropyl acetate.

31. The process of claim 18, wherein the solvent in step (b) is a C3-C6 ester, and wherein in step (b), the benazepril salt is washed with said solvent at least twice.

32. The process of claim 18, wherein the water-immiscible solvent in step (c) is isopropyl acetate, and the step of substantially removing the water-immiscible solvent, step (e), is performed without heating the benazepril above a temperature of 88⁰C.

33. A crystalline polymorph of benazepril hydrochloride referred to as Form B and having characteristic X-ray powder diffraction peaks expressed in d-values (A) at 13.6 (vs), 10.7 (m), 8.8 (s), 6.4 (m), 6.0 (s), 5.9 (s), 5.7 (m), 5.4 (s), and 5.3 (s), wherein (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity; and (w) = weak intensity.

34. The crystalline polymorph of benazepril hydrochloride of claim 33, which contains less than about 20% of a polymorph having a characteristic X-ray powder diffraction peak at 2-theta = 11.9.

35. The crystalline polymorph of claim 33, which contains less than about 10% of a polymorph having a characteristic X-ray powder diffraction peak at 2-theta = 11.9.

36. The crystalline polymorph of benazepril hydrochloride of claim 33 having an X-ray powder diffraction pattern substantially as shown in Figure 1.

37. The crystalline polymorph of benazepril hydrochloride of claim 33 having an IR spectrum substantially as shown in Figure 3a.

38. Benazepril hydrochloride prepared by the process of claim 1 , wherein said benazepril hydrochloride has characteristic X-ray powder diffraction peaks expressed in d-values (A) at 13.6 (vs), 10.7 (m), 8.8 (s), 6.4 (m), 6.0 (s), 5.9 (s), 5.7 (m), 5.4 (s), and 5.3 (s), wherein (vs) = very strong intensity; (s) = strong intensity; (m) = medium intensity; and (w) = weak intensity, and which is at least 98% by weight

3S-[[(1 S)-1 -(ethoxy-carbonyl)-3-phenylpropyl]amino]- 2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepine-1 -acetic acid hydrochloride.

39. A pharmaceutical composition comprising the Form B crystalline polymorph of benazepril hydrochloride and at least one pharmaceutically acceptable excipient.

40. The pharmaceutical composition of claim 39, wherein at least 50% of the crystalline benazepril hydrochloride in the composition is of Form B.

41. The pharmaceutical composition of claim 39, wherein at least 80% of the crystalline benazepril hydrochloride in the composition is of Form B.

42. A method to treat hypertension in a subject, said method comprising administering to said subject an effective amount of benazepril hydrochloride comprising Form B.

43. A method to treat hypertension in a subject, said method comprising administering to said subject an effective amount of a pharmaceutical composition comprising benazepril hydrochloride, wherein said benazepril hydrochloride comprises Form B.

44. The method of claim 42, wherein the benazepril hydrochloride is substantially in Form B.

45. The method of claim 43, wherein the benazepril hydrochloride is substantially in Form B.