WO2007092758A2

WO2007092758A2 - Crystalline forms of perindopril erbumine

Info

Publication number: WO2007092758A2
Application number: PCT/US2007/061524
Authority: WO
Inventors: Surya Narayana Devarakonda; Minakshi Asnani; Sivakumarr Reddy Bonnareddy; Pratap Reddy Padi; Udhaya Kumar Chandramohan; Saurabh Shashikant Chitre; Venu Nalivella; Satish Kumar Vasamsetti
Original assignee: Dr. Reddy's Laboratories Ltd.
Priority date: 2006-02-03
Filing date: 2007-02-02
Publication date: 2007-08-16
Also published as: WO2007092758A3

Abstract

Crystalline Forms zeta and eta of perindopril erbumine.

Description

CRYSTALLINE FORMS OF PERINDOPRIL ERBUMINE

INTRODUCTION TO THE INVENTION

The present invention relates to crystalline forms of perindopril erbumine. More specifically it relates to crystalline Form ζ ("zeta") and Form η ("eta") of perindopril erbumine, their combination with pharmaceutically acceptable carriers and processes for their preparation.

Perindopril erbumine is the adopted name for a drug compound having the chemical name (2S₁SaS₁ZaS)-I -[(S )-N-[(S)-1-carboxy-butyl]alanyl]hexahydro-2- indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine, and being structurally represented by Formula I.

Formula I

Perindopril erbumine is the ethyl ester of a non-sulfhydryl angiotensin- converting enzyme (ACE) inhibitor useful for the treatment of hypertension and is commercially available under the brand name ACEON ™ as tablets in 2 mg, 4 mg and 8 mg strengths for oral administration.

U.S. Patent No. 4, 508,729 discloses perindopril and its derivatives and their pharmaceutically acceptable salts, pharmaceutical compositions containing them, processes for their preparation, and their use in the treatment of hypertension.

U.S. Patent No. 4,914,214 describes a process for the preparation of perindopril, and perindopril erbumine.

International Application Publication Nos. WO 01/87835, WO 01/87836, and WO 01/58868 describe crystalline Forms α, ε, and γ of perindopril erbumine, processes for preparing them and pharmaceutical formulations containing the same. International Application Publication No. WO 06/0063941 describes perindopril erbumine monohydrate and a process for its preparation.

Processes for the preparation of perindopril and its pharmaceutically acceptable salts have also been described in U.S. Patent Nos. 4,914,214 and 6,835,843, International Application Publication Nos. WO 05/037788, WO 04/113293, WO 04/046172, and WO 05/068425, and U.S. Patent Application Publication No. 2003/0186896.

Regulatory authorities throughout the world require that all possible crystalline forms of the same active drug compound be synthesized and characterized as completely as possible. There is thus a continuing need to prepare new polymorphic forms of pharmacologically active compounds of commercial interest such as perindopril or its salts, which provide the pharmaceutical formulation scientist with a broader spectrum of crystalline forms of an active ingredient to choose from, based on their differing physiochemical properties.

It is also important that the processes for the preparation of the polymorphic forms be robust and reproducible, so that the processes are easily scaled up in the plant.

The present invention provides crystalline forms of perindopril erbumine, their combinations with a pharmaceutically acceptable carrier, and processes for their preparation, which are robust and reproducible.

SUMMARY OF THE INVENTION

The present invention relates to crystalline Form ζ and Form η of perindopril erbumine, their combinations with pharmaceutically acceptable carriers, and processes for their preparation.

One aspect of the present invention provides crystalline Form ζ and Form η of perindopril erbumine, and their combination with pharmaceutically acceptable carriers characterized by their X-ray powder diffraction ("XRPD") patterns, differential scanning calorimetry ("DSC") curves, and infrared ("IR") absorption spectra.

Another aspect of the present invention provides processes for the preparation of Form ζ and Form η of perindopril erbumine and their combinations with a pharmaceutically acceptable carrier. In an embodiment, a process for the preparation of Form ζ and Form η of perindopril erbumine and their combination with a pharmaceutically acceptable carrier comprises: a) providing a solution of perindopril erbumine either alone or in combination with a pharmaceutically acceptable carrier in a suitable solvent; b) adding an anti-solvent to the solution obtained in step a); and c) recovering the solid;

Another aspect of the present invention provides an alternative process for the preparation of crystalline Form ζ of perindopril erbumine. In an embodiment, an alternative process for preparation of crystalline Form ζ of perindopril erbumine comprises: a) providing a solution of perindopril erbumine in an alcohol solvent; and b) removing the solvent from the solution obtained in step a). Yet another aspect of the present invention provides an alternate process for the preparation of Form η of perindopril erbumine starting from Form ζ with or without a pharmaceutically acceptable carrier by subjecting it to pressure.

In a still further aspect, the present invention provides a pharmaceutical composition comprising crystalline Form ζ or Form η of perindopril erbumine with or without a pharmaceutically acceptable carrier and their combinations with one or more pharmaceutically acceptable carriers, excipients or diluents.

In an embodiment, the invention provides perindopril erbumine having crystalline Form zeta.

In another embodiment, the invention provides perindopril erbumine having crystalline Form eta.

An embodiment of the invention provides a process for preparing perindopril erbumine having crystalline form zeta, comprising removing solvent from a solution comprising perindopril erbumine and ethanol.

A further emodiment of the invention provides a process for preparing perindopril erbumine having crystalline Form zeta, comprising adding an antisolvent to a solution comprising perindopril erbumine and ethanol. In a further embodiment, the invention provides a process for preparing perindopril erbumine having crystalline Form eta, comprising adding an antisolvent to a solution comprising perindopril erbumine and isopropanol.

A still further embodiment of the invention provides perindopril erbumine having crystalline Form eta, in a molecular dispersion with a pharmaceutically acceptable hydrophobic carrier.

A yet further embodiment of the invention provides a process for preparing perindopril erbumine in a molecular dispersion with a pharmaceutically acceptable hydrophobic carrier, comprising removing solvent from a solution comprising perindopril erbumine and a pharmaceutically acceptable hydrophobic carrier.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an X-ray powder diffraction pattern of crystalline Form ζ of perindopril erbumine prepared in Example 2. Fig. 2 is a differential scanning calorimetric curve of crystalline Form ζ of perindopril erbumine prepared in Example 2.

Fig. 3 is an infrared absorption spectrum of crystalline Form ζ of perindopril erbumine prepared in Example 2.

Fig. 4 is an X-ray powder diffraction pattern of crystalline Form η of perindopril erbumine prepared in Example 6.

Fig. 5 is a differential scanning calorimetric curve of crystalline Form η of perindopril erbumine prepared in Example 6.

Fig. 6 is an infrared absorption spectrum of crystalline Form η of perindopril erbumine prepared in Example 6.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to crystalline Form ζ and Form η of perindopril erbumine, their combinations with pharmaceutically acceptable carriers, and processes for their preparation. One aspect of the present invention provides crystalline Form ζ and Form η of perindopril and their combinations with pharmaceutically acceptable carriers characterized by their X-ray powder diffraction ("XRPD") patterns, differential scanning calorimetry ("DSC") curves, and infrared ("IR") absorption spectra. The XRPD data reported herein were obtained using Cu Kα-1 radiation, having the wavelength 1.541 A, and were generated using a Bruker Axe, D8 Advance Powder X-ray Diffractometer.

Crystalline Form ζ of perindopril erbumine and its combination with a pharmaceutically acceptable carrier are characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 1. Crystalline Form ζ of perindopril erbumine and its combination with a pharmaceutically acceptable carrier are also characterized by an XRPD pattern having significant peaks at about 9.3, 10.4, 13.5, 14.1 , 15.2, 15.9, 19.9, 20.6, 21.3, 23.1 , and 26.4, ± 0.2 degrees 2Θ. The pattern is also characterized by the additional XRPD peaks at about 21.0 and 21.5, ± 0.2 degrees 2Θ.

Crystalline Form η of perindopril erbumine and its combination with a pharmaceutically acceptable carrier are characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 4. Crystalline Form η of perindopril erbumine and its combination with a pharmaceutically acceptable carrier are also characterized by an XRPD pattern having significant peaks at about 9.4, 10.6, 15.5, 15.7, 15.9, 16.6, 19.3, 21.6, 22.9, 24.1 , 25.7, and 26.8, ± 0.2 degrees 2Θ. The pattern is also characterized by the additional XRPD peaks at about 27.1 and 15.4, ± 0.2 degrees 2Θ. The infrared (IR) spectra of crystalline Form ζ, and η of perindopril erbumine and combinations with a pharmaceutically acceptable carrier have been recorded on a Perkin Elmer System Spectrum 1 model spectrophotometer, between 450 cm^"1 and 4000 cm^"1, with a resolution of 4 cm^"1 in Nujol.

Crystalline Form ζ, of perindopril erbumine and its combination with a pharmaceutically acceptable carrier are characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 708, 1070, 1292, 1376, 1388, 1463, 1573, 1726, 1744, 2642, and 2749, ± 5 cm^"1. Crystalline Form ζ of perindopril erbumine and its combination with a pharmaceutically acceptable carrier is also characterized by its infrared absorption spectrum in potassium bromide substantially in accordance with the spectrum of Fig. 2.

Crystalline Form η of perindopril erbumine and its combination with a pharmaceutically acceptable carrier are characterized by their infrared absorption spectrum in potassium bromide comprising peaks at about 708, 738, 812, 893, 1070, 1292, 1315, 1389, 1573, 1644, 1726, 1745, 2229, 2556, 2642, and 2749 + 5 cm^'1. Crystalline Form η of perindopril erbumine and its combination with a pharmaceutically acceptable carrier are characterized by their infrared absorption spectrum in potassium bromide substantially in accordance with the spectrum of Fig. 5.

Differential scanning calorimetric analysis was carried out in a Perkin Elmer pyres 6 DSC model from Perkin Elmer Instruments with a ramp of 10 °C/minute. The starting temperature was 40 ⁰C and ending temperature was 200 ⁰C.

Crystalline Form ζ of perindopril erbumine and its combination with a pharmaceutically acceptable carrier have a characteristic differential scanning calorimetry curve substantially in accordance with Fig. 3, having an endotherm at about 130 ⁰C.

Crystalline Form η of perindopril erbumine and its combination with a pharmaceutically acceptable carrier have a characteristic differential scanning calorimetry curve substantially in accordance with Fig. 6, having an endotherm at about 133 ⁰C.

Another aspect of the present invention provides a process for the preparation of crystalline Form ζ and Form η of perindopril erbumine and their combination with a pharmaceutically acceptable carrier. In an embodiment, a process for the preparation of Form ζ and Form η of perindopril and their combinations with a pharmaceutically acceptable carrier comprises: a) providing a solution of perindopril erbumine either alone or in combination with a pharmaceutically acceptable carrier in a suitable solvent; b) adding an anti-solvent to the solution obtained in step a); and c) recovering the solid.

Step a) involves providing a solution of perindopril erbumine either alone or in combination with a pharmaceutically acceptable carrier in a suitable solvent.

The solution of perindopril erbumine may be obtained by dissolving perindopril erbumine in the solvent, or such a solution may be obtained directly from a reaction in which perindopril erbumine is formed.

When the solution is prepared by dissolving perindopril erbumine in a suitable solvent, any form of perindopril erbumine such as any crystalline form of perindopril erbumine including any solvates and hydrates may be utilized for preparing the solution.

When the solution of perindopril erbumine is prepared along with a pharmaceutically acceptable carrier, the order of charging the different materials is not critical for the product obtained. A specific order may be preferred with respect to the equipment actually used and will be easily determined by a person skilled in the art. In any case, the perindopril erbumine must be completely soluble in the solvent of the invention and should provide a clear solution.

Suitable solvents which can be used for dissolving perindopril erbumine either alone or along with a pharmaceutically acceptable carrier include but are not limited to alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, ethylene glycol, and the like; chlorinated solvent like dichloromethane, chloroform, carbon tetrachloride and the like.

Suitably, the mixture can be heated to higher temperatures of the range of above 30 °C to get a clear dissolution.

The pharmaceutically acceptable carriers that can be used for the preparation of crystalline Form ζ and Form η of perindopril erbumine include but are not limited to pharmaceutical hydrophilic carriers such as polyvinylpyrrolidone (homopolymers or copolymers of N-vinyl pyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose and others), cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohol, propylene glycol derivatives and the like. The use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation.

The ratio of perindopril erbumine to the pharmaceutically acceptable carrier can range from about 0.1 :99.9 to about 1 :1 w/w. These lists of solvents and pharmaceutically acceptable carriers are merely representative of those that can be used, and the lists are not intended to be exhaustive. The quantity of solvent used for dissolution depends on the alcohol used and the dissolution temperature adopted. The concentration of perindopril erbumine in the solution generally ranges from about 0.1 to about 10 g/ml in the solvent. Perindopril erbumine and the pharmaceutically acceptable carrier used can be dissolved either in the same solvent or they may be dissolved in different solvents of the same class and then combined to form a mixture.

The solution may optionally be treated with materials such as carbon or sodium sulfate for clarification. Optionally, the solution obtained above can be filtered to remove any undissolved particles followed by further processing. The undissolved particles can be removed suitably by filtration, centrifugation, decantation, and other techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step b) involves adding an anti-solvent to the solution of step a). Suitably, the solution obtained in step a) can be further cooled to temperatures lower than the dissolution temperatures and maintained under stirring before addition of the anti-solvent.

Suitable solvents which can be used as anti-solvents include, but are not limited to acetone, propanone, butanone, methyl isobutyl ketone, ethyl methyl ketone, isobutyl ketone and the like; hydrocarbon solvents such as toluene, xylene, N-heptane, N-hexane and the like, and mixtures thereof.

Suitably, the anti-solvent is cooled to lower temperatures of the range of below 5 ⁰C and added at temperatures below the temperatures used for dissolution. The reaction mass can be maintained for further periods at the same temperature or at lower temperatures for isolation of the product. Isolation may be performed with stirring until the desired crystal yield has been obtained, such as for about one hour to about 10 hours, or longer. The crystallization step may further include facilitative measures known to one skilled in the art. For example, a crystallization step may further include cooling the solution, heating the solution, or adding an agent to induce precipitation.

The temperature of the solution may be brought down for crystallization to occur either rapidly using external cooling, or it may be allowed to cool by radiation without external cooling.

Optionally, small amounts of seeding crystals of the desired compound may be added to the reaction mixture. Small amounts are about 1 to 20 weight %, more preferably about 5-weight %. Seeding crystals may be added before or, where appropriate, after the step initiating the precipitation Step c) involves recovering the solid.

The method by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as filtration by gravity or by suction, decantation, centrifugation, and the like. The crystals so isolated will usually carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals can be washed with a solvent to wash out the mother liquor.

The obtained product is further dried and the duration of drying is a factor, which determines the nature of the crystalline form obtained.

Suitably the wet solid is dried at about 20-40 ⁰C for duration of about less than 2 hours to obtain perindopril erbumine crystalline Form ζ.

When the duration of drying ranges from about 2 hours to about 15 hours, perindopril erbumine crystalline Form η is obtained.

Drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35 ⁰C to about 70 ⁰C. Drying may be carried out for shorter or longer periods of time depending on the desired product to be obtained.

Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like.

Another aspect of the present invention provides another alternative process for the preparation of crystalline Form ζ of perindopril erbumine. In an embodiment, an alternative process for the preparation of perindopril erbumine crystalline Form ζ comprises: a) providing a solution of perindopril erbumine in an alcohol solvent; and b) removing the solvent from the solution obtained in step a).

Step a) involves providing a solution of perindopril erbumine.

The solution of perindopril erbumine may be obtained by dissolving perindopril erbumine in an alcohol solvent, or such a solution may be obtained directly from a reaction in which perindopril erbumine is formed in an alcohol medium.

When the solution is prepared by dissolving perindopril erbumine in an alcohol solvent, any form of perindopril erbumine such as any crystalline form of perindopril erbumine including any solvates and hydrates may be utilized for preparing the solution.

Suitable alcohol solvents which can be used for dissolving perindopril erbumine include but are not limited to methanol, ethanol, isopropanol, n- propanol, tertiary-butyl alcohol, and the like, and mixtures thereof.

The quantity of solvent used for dissolution depends on the alcohol and the dissolution temperature adopted. The concentration of perindopril erbumine in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.

Step b) involves removing the solvent from the solution obtained from step a), using a suitable technique.

Removal of the solvent may be carried out suitably using evaporation under atmospheric conditions, atmospheric distillation, or distillation under vacuum.

Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20° C to about 70° C. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product. Suitable techniques which can be used for the distillation include, distillation using a rotational evaporator device such as a Buchi Rotovapor, spray drying, agitated thin film drying ("ATFD"), and the like.

Techniques such as atmospheric evaporation, Buchi Rotovapor drying and dry distillation under vacuum, may be suitable for laboratory-scale processes such as for quantities less than about 100 g. Other techniques such as spray drying and ATFD are more suitable for industrial scale production with a batch size of at least about 100 g or about 1 kg, or greater.

The crystalline material obtained from step b) can be collected from the equipment using techniques such as by scraping, or by shaking the container. Optionally the solid obtained after removing the solvent can be dried further. Drying can be carried out at temperatures such as about 20 °C to about 40 °C. The drying can be carried out for about less than 2 hours.

Still another aspect of the present invention provides an alternate process for the preparation of Form η of perindopril from Form ζ with or without a pharmaceutically acceptable carrier by subjecting it to pressure.

Crystalline Form ζ of perindopril can be converted to Form η by applying pressure to the crystalline Form ζ with or without a pharmaceutically acceptable carrier. Suitable techniques for subjecting it to pressure include, but are not limited to techniques such as grinding with a mortar and pestle, grinding, milling, and the like.

Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.

The process of the present invention provides a stable crystalline Form η and Form ζ of perindopril erbumine and their combinations with a pharmaceutically acceptable carrier.

The term "stable crystalline form" refers to stability of the crystalline form under the standard temperature and humidity conditions of testing of pharmaceutical products, wherein the stability is evaluated by preservation of the original polymorphic form.

Crystalline Form ζ and Form η of perindopril erbumine and their combination with a pharmaceutically acceptable carrier obtained in this invention contain less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of methanol, and less than about 200 ppm, or less than about 100 ppm of other individual residual organic solvents.

A still further aspect of the present invention provides pharmaceutical compositions comprising crystalline Form ζ and Form η of perindopril erbumine with or without a pharmaceutically acceptable carrier, together with one or more pharmaceutically acceptable excipient.

The pharmaceutical composition comprising crystalline Form ζ and Form η of perindopril erbumine and their combination with a pharmaceutically acceptable carrier of this invention may further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like. In the compositions of present invention perindopril erbumine is a useful active ingredient in the range of 2 mg to 5 mg, or 8 mg to 15 mg, per dosage unit.

Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are provided only for the purpose of illustration and are not intended to limit the scope of the appended claims in any manner.

EXAMPLE 1

PREPARATION OF CRYSTALLINE FORM η and Form C USING SQLVENT- ANTISOLVENT TECHNIQUE

40 g of perindopril erbumine and 400 ml of isopropyl alcohol were taken into a round bottom flask and stirred for 20 minutes. The solution was filtered and the filter bed was washed with 40 ml of isopropyl alcohol. The filtrate was taken into another round bottom flask and cooled to -10 ⁰C. The mass was maintained at -15 to -10 ⁰C for 4 hours. 440 ml of chilled acetone was added to the mass and stirred for 30 minutes. The mass was filtered and a wet sample was analyzed by XRPD, giving the pattern of Fig. 1 , which indicates Form Q .

The remaining material was dried at 26 ⁰C under vacuum over phosphorus pentoxide for 3 hours and the sample was analyzed by XRPD, giving the pattern of Fig. 4, which indicates the Form η.

EXAMPLE 2

PREPARATION OF CRYSTALLINE FORM C USING SQLVENT-ANTISOLVENT TECHNIQUE 300 mg of perindopril erbumine and 1.5 ml of ethanol were taken into a round bottom flask and stirred for 5 minutes. 25 ml of methyl isobutyl ketone was added to the above mass with stirring. The mixture was stirred for 15 minutes, and the mass was filtered. The wet solid gave the XRPD pattern of Fig. 4. EXAMPLE 3

PREPARATION OF CRYSTALLINE FORM C USING EVAPORATION TECHNIQUE

250 mg of perindopril erbumine was taken into a round bottom flask and 1.5 ml of methanol was added to it and stirred for 10 minutes. The solution was put in a Petri dish and covered with Parafilm. The solution was allowed to evaporate slowly under atmospheric conditions. The dry sample was recovered by scraping to get the title compound.

EXAMPLE 4

PREPARATION QF CRYSTALLINE FORM C WITH ETHYL CELLULOSE USING DICHLOROMETHANE AND N-HEPTANE

50 g of perindopril erbumine, 3.75 g of ethyl cellulose and 750 ml of dichloromethane were taken into a round bottom flask and stirred for 10 minutes. The mixture was heated to 50 ⁰C and stirred for 30 minutes. Then the mixture was gradually cooled to 0⁰C, and the solvent was distilled off under a vacuum of 42 mm Hg and a temperature below 0 ⁰C to remove 470 ml of the solvent. To the remaining residue, 400 ml of chilled n-heptane was added and stirred for 30 minutes. The separated solid was filtered and washed with 100 ml chilled of n- heptane. The wet solid was dried at 42 ⁰C under a vacuum of 700 mm Hg to yield 49 g of the title compound.

EXAMPLE 5 PREPARATION OF CRYSTALLINE FORM C USING DICHLOROMETHANE AND N-HEPTANE

100 g of perindopril erbumine and 1500 ml of dichloromethane were taken into a round bottom flask and stirred for 10 minutes. The mixture was heated to 40 ⁰C and stirred for 30 minutes to get clear dissolution. Then the solution was gradually cooled to 0⁰C, and the solvent was distilled under a vacuum of 40 to 90 mm Hg to remove 480 ml of the solvent. To the remaining residue, 800 ml of chilled n-heptane was added and stirred for 30 minutes. The separated solid was filtered and washed with 200 ml of chilled n-heptane. The wet solid was dried at 43 ⁰C under a vacuum of 0.1 mm Hg to yield 49 g of the title compound. EXAMPLE 6

PREPARATION OF CRYSTALLINE FORM n USING ISOPROPYL ALCOHOL AND ACETONE 30 g of perindopril erbumine was taken into a round bottom flask and 330 ml of isopropyl alcohol was added to it. The mixture was heated to 49 °C and filtered in the hot condition. The filtrate was taken into another round bottom flask and cooled gradually to -16 ⁰C. The mass was maintained at -16 ⁰C for 4 hours. 1200 ml of chilled acetone was added to the mass and maintained at -16 ⁰C for one hour. The separated solid was filtered and the solid was washed with 30 ml of chilled acetone. The wet solid was dried at 35 ⁰C under a vacuum of 700 mm Hg for 3 hours to yield 20 g of the title compound.

EXAMPLE 7 CONVERSION QF CRYSTALLINE FORM C TQ FORM τi BY GRINDING IN A MORTAR AND PESTLE

15 g of crystalline perindopril Form ζ with ethylcellulose prepared in Example 4 was taken into a mortar and pestle and ground under a nitrogen atmosphere for 30 minutes to get 14.5 g of the title compound. The XRPD pattern of the resultant product revealed a conversion of the crystalline Form ζ to crystalline Form η.

EXAMPLE 8

CONVERSION OF CRYSTALLINE FORM C TO FORM rt BY GRINDING IN A MORTAR AND PESTLE

15 g of crystalline perindopril Form ζ prepared in Example 5 was taken into a mortar and pestle and grinded under nitrogen atmosphere for 30 minutes to get 14.5 g of the title compound. XRD of the resultant product revealed a conversion of the crystalline Form ζ to crystalline Form η. EXAMPLE 9

PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM η OF PERINDOPRIL ERBUMINE WITH 0.5% ETHYLCELLULOSE

10 g of perindopril erbumine, 50 mg of ethylcellulose (7CPS) and 110 ml of isopropyl alcohol were taken into a round bottom flask and stirred for 30 minutes. The resultant solution was filtered through Whatman No.1 filter paper to make it particle free followed by washing the filter paper with 10 ml of isopropyl alcohol. The filtrate was taken into another round bottom flask and stirred for 10 minutes. The filtrate was then cooled to -20 °C and maintained for 5 hours. 110 ml of pre- cooled acetone was added to the above filtrate and stirred for 2 hours. The separated solid was filtered and washed with 10 ml of pre-cooled acetone. The solid obtained was dried over phosphorous pentoxide (P2O5) under a vacuum of 300 mm Hg at 35 ⁰C for 4 hours to afford 5.2 g of the title composition.

EXAMPLE 10

PREPARATION OF STABLE CRYSTALLINE FORM τi OF PERINDOPRIL ERBUMINE WITH 0.5% POLYETHYLENE GLYCOL

5 g of perindopril erbumine, 0.025 g of polyethylene glycol (PEG 6000) and 55 ml of isopropyl alcohol were taken into a clean and dry round bottom flask and stirred for 30 minutes. The resultant solution was filtered through Whatman No.1 filter paper to make it particle free, and the filter paper was washed with 5 ml of isopropyl alcohol. The combined filtrate was stirred for 10 minutes followed by cooling to about -15 ⁰C and maintained for 5 hours. 55 ml of pre-cooled acetone was added to the above reaction mass followed by stirring for 2 hours. The separated solid was filtered and the solid was washed with 5 ml of pre-cooled acetone. The solid obtained was dried over phosphorous pentoxide (P2O5) under a vacuum of 300 mm Hg at 30 ⁰C for 3 hours to afford 3.5 g of the title composition. EXAMPLE 11

PREPARATION QF STABLE CRYSTALLINE FORM n OF PERINDOPRIL ERBUMINE WITH 0.5% HYDROXYPROPYL CELLULOSE

5 g of perindopril erbumine, 0.025 g of hydroxypropyl cellulose (HPC-LF) and 55 ml of isopropyl alcohol were taken into a clean and dry round bottom flask and stirred for 30 minutes. The resultant solution was filtered through Whatman No. 1 filter paper to make it particle free, and the filter paper was washed with 5 ml of isopropyl alcohol. The combined filtrate was stirred for 10 minutes followed by cooling to -20 ⁰C for 5 hours. 55 ml of precooled acetone was charged followed by stirring for 2 hours. Separated solid was filtered and washed with 5 ml of precooled acetone. The solid obtained was dried over phosphorous pentoxide (P₂O₅) under a vacuum of 300 mm Hg at 30 ⁰C for 2.5 hours to afford 1.4 g of the title composition.

EXAMPLE 12

PREPARATION OF STABLE CRYSTALLINE FORM τi OF PERINDOPRIL ERBUMINE WITH 0.5% POLYVINYLPOVIDONE (PVP)

40 g of perindopril erbumine, 0.2 g of povidone (PVP K-30) and 440 ml of isopropyl alcohol were taken into a clean and dry round bottom flask followed by stirring for 30 minutes. The resultant reaction solution was filtered through Whatman No.1 filter paper to make it particle free, and the filter paper was washed with 40 ml of isopropyl alcohol. The filtrate was stirred for 10 minutes followed by cooling to -15 ⁰C for 5 hours. 440 ml of precooled acetone was charged followed by stirring for 2 hours. Separated solid was filtered and the solid was washed with 40 ml of precooled acetone. The solid obtained was dried over phosphorous pentoxide (P2O5) under a vacuum of about 300 mm Hg at 26 ⁰C for 3 hours to afford 24 g of the title compound.

EXAMPLE 13 COMPARISON OF SOLUBILITY FOR FORM n WITH AND WITHOUT A PHARMACEUTICALLY ACCEPTABLE CARRIER

The solubility of Form η with ethyl cellulose prepared in Example 4 and without ethylcellulose was compared by determining the quantity of sample that dissolved in 1 ml of each of the solvents water, isopropyl alcohol, toluene, and dichloromethane. The results are given below in Table 1.

Table 1

It is evident from the results that the solubility of Form η in organic solvents can be increased by combining it with a pharmaceutically acceptable carrier.

EXAMPLE 14 STABILITY QF PERINDOPRIL CRYSTALLINE FORM τi

Crystalline Form η of perindopril was prepared according to the process given in Example 7 and was packed in a self-sealing polythene bag. The material was stored for 3 weeks under normal indoor atmospheric conditions and checked for polymorphic stability. The material was found to retain its polymorphic form after three months of holding as indicated by maintenance of the original XRPD pattern.

Claims

CLAIMS:

1. Perindopril erbumine having crystalline Form zeta.

2. A process for preparing perindopril erbumine of claim 1 , comprising removing solvent from a solution comprising perindopril erbumine and ethanol.

3. A process for preparing perindopril erbumine of claim 1 , comprising adding an antisolvent to a solution comprising perindopril erbumine and ethanol.

4. The process of claim 3, wherein an antisolvent comprises a hydrocarbon, a ketone, a nitrile, or an ether.

5. The process of claim 3, wherein an antisolvent comprises a ketone.

6. Perindopril erbumine having crystalline Form eta.

7. A process for preparing perindopril erbumine of claim 6, comprising adding an antisolvent to a solution comprising perindopril erbumine and isopropanol.

8. The process of claim 7, wherein an antisolvent comprises a hydrocarbon, a ketone, a nitrile, or an ether.

9. The process of claim 7, wherein an antisolvent comprises a ketone.

10. Perindopril erbumine having crystalline Form eta, in a molecular dispersion with a pharmaceutically acceptable hydrophobic carrier.

11. A process for preparing perindopril erbumine of claim 10, comprising removing solvent from a solution comprising perindopril erbumine and a pharmaceutically acceptable hydrophobic carrier.

12. A pharmaceutical composition comprising perindopril erbumine of claim 1 and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising perindopril erbumine of claim 6 and at least one pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising perindopril erbumine of claim 10 and at least one pharmaceutically acceptable excipient.