PROCESS FOR PREPARING PURE AMORPHOUS QUINAPRIL

HYDROCHLORIDE

FIELD OF THE INVENTION

This invention, in general, relates to an improved process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

Quinapril hydrochloride hydrochloride is an ethyl ester of a nonsulfhydryl Angiotension-Converting Enzyme (ACE) inhibitor. Quinapril hydrochloride is chemically described as (3S- (2(R*)),3R*)) -2- (2- ((l-(ethoxycarbonyl)- 3 - phenylpropyl) amino) -1-oxopropyl) -l,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride. Its pharmaceutically acceptable salts, especially the hydrochloride salt is active as Angiotensin Converting Enzyme (ACE) inhibitors and is commercially important anti-hypertensive agent. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces the decapeptide angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs. The ACE inhibitors intervene in the rennin > angiotensin I > angiotensin II sequence by inhibiting angiotensin I converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II, and therefore are useful in reducing or relieving hypertension. Thus by the administration of a composition containing one or a combination of amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts, hypertension in the species of mammal suffering therefrom is alleviated.

Quinapril hydrochloride was first disclosed in US 4,344,949 which describes a process for preparation of quinapril hydrochloride comprising deprotection of benzyl or t-butyl ester of quinapril by catalytic hydrogenolysis in the presence of the catalyst, 20% Pd/C at low pressure followed by isolation of quinapril hydrochloride by adding ether. Alternatively, the benzyl or t-butyl ester of quinapril is unprotected

by treatment with trifluoroacetic acid followed by treatment with dry hydrogen chloride in dry ether and quinapril hydrochloride thus obtained by lyophilization of an aqueous solution. The reaction scheme is illustrated herein below:

Quinapril obtained by this process is invariably contaminated with diketopiperazine derivative formed either during removal of the carboxylic acid protective group i.e. deprotection by catalytic hydrogenolysis or treatment with trifluoroacetic acid or during isolation of quinapril, as quinapril degrades easily due to intramolecular cyclization to yield a diketopiperazine both in aqueous or organic solution as well as in the solid state.

Quinapril hydrochloride is generally available in two forms namely crystalline and amorphous.

US 4,761,479 describes a process for preparing quinapril hydrochloride, which comprises unprotecting t-butyl ester of quinapril with hydrogen chloride gas in acetic acid followed by isolating the precipitated quinapril hydrochloride after diluting the reaction mixture with xylene and stripping xylene under vacuum. The product is purified by crystallization with acetonitrile including seeding and drying the crystalline product at 25 to 50 °C for 1 to 24 hrs to yield a crystalline quinapril hydrochloride solvate of acetonitrile which was subsequently dried to remove

acetonitrile at 50 to 60 °C for 1 to 16 hours. The solvent of acetonitrile solvate can be removed, without degradation of quinapril hydrochloride, by drying in vacuum oven. However, acetonitrile is a class 2 solvent, defined by ICH as a Non-mutagenic carcinogen in animals or possible cause of other irreversible toxicity such as neurotoxicity, teratogenesis and therefore proportion has to be limited, hi the case of acetonitrile, the ICH recommends a limit not above 250 ppm (0.025 %). This limit is difficult to achieve at the industrial scale due to the less stability of the product.

The abovementioned patent also discloses that the crystalline material thus obtained contains equimolar amounts of acetonitrile/acetone as part of the crystal lattice. The patent further reveals that the solvent(s) present in the crystal structure can be removed under vacuum at a temperature of about 50°C. However during this unit operation the crystallinity of the substance is lost due to desolvation during drying, and an amorphous material is obtained which is claimed to be free of impurities, specially the diketopiperazine.

US 6,617,457 describes a process for preparing quinapril hydrochloride which comprises catalytic hydrogenolysis of benzyl ester of quinapril in alcoholic solvent, with concentrated hydrochloric acid or with a solution of hydrogen chloride - in isopropanol at a pressure of 2 bar (29 psi) and a temperature in the range of 10- 40°C using a catalyst like Pd/C followed by precipitating the quinapril hydrochloride as a toluene solvate. The solvate is further treated with a solvent selected from ethyl or methyl formate and the solvate of ethyl or methyl formate is dried to yield crystalline quinapril hydrochloride. Solvents like methyl acetate and ethyl formate have low flash point (i.e. methyl formate- 16° C and ethyl formate -20° C) because of which they are unsafe and have to be carefully handled. Therefore, the process is not commercially viable.

WO 2004/054980 provides a process for the preparation of a pure crystalline quinapril hydrochloride associated with the solvate of nitroalkane. On de-solvation of the nitroalkane solvate, amorphous quinapril hydrochloride is obtained. Desolvation is cumbersome to carry out as it involves drying at 40°C/0.5 mm Hg for 60 hrs.

US 6.858,735 describes a process for the preparation of quinapril hydrochloride in amorphous and crystalline forms. The tert.butyl ester of quinapril hydrochloride is deprotected by treatment with aqueous or anhydrous hydrogen chloride in the presence of aprotic or protic solvents to yield quinapril hydrochloride in solution, which is converted into acetone solvate and subsequently re-crystallized with acetonitrile. The solvate, is dried to obtain amorphous quinapril hydrochloride. The process is complicated and time consuming as two solvates are involved in order to get pure compound.

WO 2007/054966 unveils the process for the preparation of quinapril hydrochloride. This process offers reduced quantity of diketopiperazine impurity and prevention of degradation of the product. Wherein the solution of benzyl ester of quinapril hydrochloride is prepared with an alkyl nitrile and is subjected to catalytic hydrogenolysis, after pH adjustment of the solution to 0.8 to 1 by adding 3 to 17% solution of hydrogen chloride in dry ether or dry alkyl nitrile. The solvent is distilled out to 50-70% of its volume to obtain crystalline quinapril hydrochloride, which is washed with n-pentane and dried.

J.Pharm.Sci. VoI 89, 128-143 (2000) describes physical characteristics and chemical degradation of amorphous quinapril hydrochloride. This paper investigates the relationship between the solid-state chemical instability and physical characteristics quinapril in amorphous state. This paper describes the preparation of amorphous quinapril hydrochloride samples were prepared by rapid evaporation from dichloromethane solution and by grinding and subsequent heating of the crystalline form.

The prior-art processes for the preparation of quinapril hydrochloride are generally associated with lengthy and cumbersome procedures and are time consuming, costly and difficult to be carried out. The crude product formed is converted into solvates and purified by crystallization and then dried. Some of the solvents used are also unsafe and difficult to handle.

Most of the prior-art methods for the preparation of amorphous form of quinapril are from crystalline material. Thus after drying up still few peaks remains in the PXRD and the compound is not complete pure amorphous.

Keeping in view of the above disclosed limitations, there still exists a need for developing a process to prepare pure amorphous quinapril hydrochloride which addresses the shortcomings associated with the prior-art processes.

SUMMARY OF THE INVENTION

It is a principal aspect of the present invention, there is provided a process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts, wherein the obtained amorphous quinapril hydrochloride is devoid of diketopiperazine and other related impurities and are characterized by using PXRD.

In accordance with another aspect of the present invention, there is provided a simple and commercially viable process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts, wherein the process involves minimum steps and less time.

In accordance with one other aspect of the present invention, there is provided a simple and commercially viable process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts, wherein the process employs the solvents, which are environment friendly, safe and is easy to handle.

In accordance with another aspect of the present invention, there is provided a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts having absolutely no crystallinity in its wet condition.

In accordance with preferred embodiment of the present invention, there is provided a simple and commercially viable process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts, wherein the

process comprises of dissolving or suspending crystalline or solvate form of quinapril hydrochloride in a suitable solvent, adding a second solvent, which is immiscible with the solvent, followed by gradual cooling and isolating the pure amorphous quinapril hydrochloride.

In accordance with another preferred embodiment of the present invention, there is provided a simple and commercially viable process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts, wherein the solvent is lower alcohol having carbon chain length of 1-4.

In accordance with yet another preferred embodiment of the present invention, there is provided a simple and commercially viable process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts, wherein the second solvent is selected from lower chain aliphatic hydrocarbons.

In accordance with yet another preferred embodiment of the present invention, there is provided a method of packing quinapril hydrochloride, wherein the method comprises of placing quinapril hydrochloride in a sealed container under an inert atmosphere, placing the sealed container, a desiccant, and an oxygen adsorbent in a second sealed container, placing the second sealed container in a triple laminated bag and sealing and enclosing the triple laminated bag in a closed high density polyethylene container.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:

Figure 1 is the X-ray powder diffraction pattern of wet cake of quinapril hydrochloride.

Figure 2 is the X-ray powder diffraction pattern of dry product of quinapril hydrochloride.

Figure 3 is the X-ray powder diffraction pattern of commercially available quinapril hydrochloride. Figure 4 is the X-ray powder diffraction pattern of pure amorphous quinapril hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included example.

The present invention provides a process for essentially pure amorphous quinapril hydrochloride. Normally amorphous materials are prepared by precipitation, spray drying, freeze drying (lyophilisation), melt precipitation, vapor condensation, crash cooling, from supercritical fluids e.g using Solution Enhanced Dispersion by Supercritical fluids (SEDS), Rapid Expansion of Supercritical Solution (RESS) processes etc. from among the methods mentioned above, precipitation using an anti-solvent is advantageous industrially. Thus this invention details the preparation of amorphous quinapril, wherein any form of quinapril hydrochloride is dissolved in a suitable solvent such as alcohol and subsequently adding the anti-solvent selected form aliphatic hydrocarbons such as pentane, hexanes, heptane, etc.

It is known' that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties. The amorphous form of a drug may exhibit different dissolution characteristics and in some case different bioavailability patterns compared to crystalline forms. Further, amorphous and crystalline forms of a drug may have different handling properties, dissolution rates, solubility, and stability, access to a choice between the amorphous or crystalline forms of a drug is desirable for different applications. Furthermore,

different physical forms may have different particle size, hardness and glass transition temperatures. Amorphous materials do not exhibit the three-dimensional long-range orders found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random. Amorphous solids do not give a definitive X-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a melting point and tend to liquefy at some point beyond the glass transition temperature. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide enhanced bioavailability characteristics such as a higher rate and extent of absorption of the compound from the gastrointestinal tract. Also, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in solid dosage form manufacture process such as compressibility, economically or environmentally suitable solvents or process, or higher purity or yield of the desired product.

The term 'any form' includes solvated and desolvated forms, crystalline forms and other non-crystalline forms.

In a typical procedure solvated crystalline quinapril hydrochloride is dissolved in C ₁ -C ₄ alcohol. After dissolution, the alcohol was reduced to 1/3 of its volume and aliphatic hydrocarbon solvent is added and stirred for 10-30 minutes.

Then the obtained wet cake is washed with n-pentane. The material was cooled and subsequently the obtained product was milled and dried.

The Ci-C ₄ alcoholic solvents employed for dissolution of quinapril hydrochloride are selected form methanol, ethanol, isopropanol and n-butanol. The aliphatic hydrocarbons employed as anti-solvent are selected form n-pentane, hexanes etc. The preferred solvent is methanol and anti-solvent is n-pentane.

The crystalline quinapril used in the process of the present invention is prepared by prior-art methods.

The advantage realized in the present process of the invention is that there is absolutely no crystallinity observed even in the wet product. As the wet product is

also amorphous then in drying there is obtained a pure amorphous compound and no sharp peaks are observed in PXRD. The inventors have observed that commercially available amorphous quinapril hydrochloride contains some amount of crystallinity, whereas the present process of the invention yields essentially pure amorphous quinapril hydrochloride. The commercially available amorphous quinapril hydrochloride when analysed contains detectable amounts of both crystalline and amorphous having both characteristic sharp peaks and the diffuse halo(s) on XRPD.

The present invention provides pure amorphous quinapril hydrochloride characterized by PXRD containing one or more broad diffuse halo, and lack of discernible acute peaks which are characteristics of crystalline compounds.

The essentially pure amorphous quinapril hydrochloride is prepared by converting the crystalline quinapril hydrochloride which is depicted in Fig 1. This crystalline material after drying gives amorphous quinapril hydrochloride contaminated with some crystalline peaks which is depicted in Fig 2.

Powder X-ray Diffraction (PXRD)

The polymorphs form of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu- anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

According to the present invention, the packaging conditions have been modified for the quinapril hydrochloride to provide consistent purity, resistant to moisture and formation of diketopiperazine impurity. The susceptibility of quinapril hydrochloride to moisture leads to deviating drug regulatory requirements. Therefore, to provide consistent purity of quinapril hydrochloride, a packaging and storage method for stabilizing hygroscopic quinapril hydrochloride is disclosed, wherein the method comprises of placing quinapril

hydrochloride in a sealed container under an inert atmosphere, placing the sealed container, a desiccant, and an oxygen adsorbent in a second sealed container, placing the second sealed container in a triple laminated bag and sealing and enclosing the triple laminated bag in a closed high density polyethylene container.

The inert atmosphere disclosed in the method can be provided to the compound, which is kept in a polythene bag, or has been stored in a more rigid container. The bag or container, which is used to provide the inert atmosphere to quinapril hydrochloride, is sealed airtight after providing the inert atmosphere. In case the container employed to provide the inert atmosphere to quinapril hydrochloride is transparent and exposes the product to light, then it can be covered using a non-transparent material.

The disclosed steps to place the sealed container, a desiccant, and an oxygen adsorbent in a second sealed container, the desiccant and the oxygen adsorbent are included in order to adsorb any moisture and oxygen which penetrates the package. Suitable moisture adsorbents is used in the present invention include, but are not limited to molecular sieve zeolites, high silica zeolites, having a high silica/alumina ratio of 25 or more, such as ZSM-5 (made by Mobil Oil Co., silica/alumina ratio of 400), silicalite, USY (Ultra Stable Y type zeolite, by PQ Corp., silica/alumina ratio of 78), mordenite and the like, a low silica system zeolite such as Ca-X type zeolite, Na-X type zeolite, silica super fine granulated particle (for example, particles having an average particle size of 1.5 mm which has been obtained by granulating the silica super fine particle having a size of 0.1 μm or less), silica gel, alumina and the like.

Suitable oxygen adsorbents is used herein include, but are not limited to CuO (activated by reduction with hydrogen) on an inorganic oxide, sachet of Ageless Z

200 which reduces the oxygen concentration in a sealed container less than 0.01% creating a very low-oxygen environment. Ageless Z sachets contain fine iron powder covered with sea salt and a natural zeolite impregnated with a NaCl solution.

One sachet of Ageless Z 200 adsorbs 2000 ml of oxygen (the oxygen from 10 L of air) and other similar oxygen absorbents can be used.

In the step where a second bag or container is placed in a triple laminated bag followed by sealing, the package containing the compound and the oxygen and moisture adsorbents are kept in a triple laminated bag, having layers of polyethylene terephthalate film, aluminum foil, and linear low-density polyethylene film. The triple laminated bag provides protection to the contents from oxygen, moisture, light, and other contaminants.

Optionally, an additional desiccant (moisture adsorbent) is put into the triple laminated bag as an additional precaution to adsorb any moisture.

The triple laminated bag is heat sealed to prevent the entry of any contaminants. The heat sealing can be done using a vacuum nitrogen sealer (VNS) for effective sealing and thereafter storing the triple laminated bag in a High-density polyethylene (HDPE) container.

According to the present invention, it is found that the packaging and storage process disclosed herein provides substantially pure quinapril hydrochloride, which is stable during storage and does not undergo agglomeration, and also results in minimizing diketopiperazine impurity.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

Example 1

Quinapril hydrochloride (100 gms) was dissolved in methanol at 25-35 ⁰ C and stirred for 15 minutes. The reaction mixture is cooled to 2O ⁰ C. After dissolution methanol was distilled off to get a residue. To this residue pentane (500 ml) was added at 25-35 ⁰ C and stirred for 10-30 minutes. Precipitation occurs and the obtained cake is filtered over hyflo. The cake obtained was dried at 40-50 ⁰ C for 5 hrs.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description and drawings given above are intended to illustrate and not to limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof that do not depart from the spirit and scope of the invention.