FORM2THE PATENTS ACT, 1970(39 of 1970)& The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10; rule 13)
1. Title of the invention. - NOVEL METHOD FOR PREPARATION OF CRYSTALLINE PERINDOPWL ERBUMINE
2. Applicant(a) NAME :(b) NATIONALITY(c) ADDRESS : LUPIN LIMITEDAn Indian Company159, C.S.T. Road, Kalina, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a novel process for preparation of crystalline perindopril erbumine of formula (II)

BACKGROUND OF THE INVENTION
The chemical entity (2S)-2-[(lS)-l-carbethoxybutylamino]-l-oxopropyl-(2S,3aS,7aS)-perhydroindole-2-carboxylic acid of formula (I), known generically as perindopril

and its pharmaceutically acceptable salts, specially salt of perindopril with tertiary butyl amine i. e. perindopril erbumine of formula (II)

are therapeutically valuable ACE Inhibitors, useful for the treatment of hypertension.
The drug is commercially sold as the erbumine salt and was approved in the USA on December 30, 1993 for the treatment of hypertension. The final printed label of the approved drug, ACEON® Tablets states that perindopril erbumine is a white, crystalline
2

powder with a molecular weight of 368.47 (free acid) or 441.61 (salt form) and freely soluble in water (60% w/w), alcohol and chloroform.
Several methods are known for preparation of perindopril and perindopril erbumine as well as methods for preparation of compounds useful as intermediates for preparation of perindopril and perindopril erbumine. A brief summary of such methods are given hereinbelow:
US 4 508 729, which is the product patent of perindopril, discloses a method for preparation of perindopril monoammonium salt, as a mixture of two diastereomers, involving reductive animation of (2S)-l-[(S)-alanyl]-2-carboxyperhydroindole with pyruvic acid in the presence of sodium cyanoborohydride. The (2S)-l-[(S)-alanyl]-2-carboxyperhydroindole, in turn is prepared by reaction of (2S)-2-ethoxycarbonylperhydroindole with L-BOC.-alanine to give (2S)-N-[(S)-BOC.-alanyl]-2-ethoxycarbonylperhydroindole, which on step-wise removal of the carboxyl and amino protecting groups gives (2S)-l-[(S)-alanyl]-2-carboxyperhydroindole. The synthesis is schematically represented hereinbelow.
3


However, this method gives perindopril as a mixture of two diastereomers, of which only one is a therapeutic. Further, there is neither any enabling disclosure in the patent as to how the diastereomers are separated to give perindopril, having the desired (S) configuration for all the five chiral centers in the molecule nor any method is disclosed as to how the tert-butylamine salt i. e. perindopril erbumine can be prepared.
Moreover, the method involves protection-of the amino group of the alanine moiety as the t-BOC group, which necessitates use of corrosive trifluoroacetic acid for its subsequent removal, thereby rendering the method industrially unattractive.
US 4 902 817 discloses a stereoselective process for the industrial synthesis of N-[(S)-1-carbethoxybutyl]-(S)-alanine comprising reaction of ethyl-L-norvalinate hydrochloride with pyruvic acid under catalytic hydrogenation conditions. The N-[(S)-1-carbethoxybutyl]-(S)-alanine thus obtained is a key intermediate for perindopril. The synthesis is schematically represented hereinbelow.
4


However, this patent does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-l-carbethoxybutyl]-(S)-alanine thus obtained.
EP 0 309 324 discloses another method for synthesis of (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reaction of L-alanine benzyl ester p-toluenesulfonate with ammonia to form the free base, which is condensed with ethyl cc-bromo valerate to give a racemic mixture of N-[(S)-1-carbethoxybutyl]-(S)-alanine and N-[(R)-l-carbethoxybutyl]-(S)-alanine. The (S) isomer is separated by resolution with maleic acid and subsequent removal of the benzyl ester group provides the (S,S) diastereoisomer of N-[(S)-l-carbethoxybutyl]-(S)-alanine, which can be further elaborated to perindopril and perindopril erbumine.


However, this patent, also does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-l-carbethoxybutyl]-(S)-alanine thus obtained.
WO 01/56353 discloses yet another method for preparation of the (S,S) diastereoisomer of N-[(S)-l-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting sodium pyruvate with L-norvaline ester under reducing conditions using palladium carbon as catalyst.

However, this patent, also does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-l-carbethoxybutyl]-(S)-alanine thus obtained.
WO 01/56972 discloses a further method for preparation of the (S,S) diastereoisomer of N-[(S)-l-carbethoxybutyl]-(S)-alanine, a key intermediate for perindopril comprising reacting 1-alanine and ethyl 2-oxo-pentanoic acid under catalytic hydrogenation conditions and isolating the product at a pH between 3to 3.5, followed by crystallization.

However, this patent, also does not provide any enabling method for preparation of perindopril or perindopril erbumine from N-[(S)-l-carbethoxybutyl]-(S)-alanine thus obtained.
6

EP 1 256 590 discloses a process for preparation of (2S, 3aS, 7aS)-l-(S)-alanyl-octahydro-lH-indole-2-carboxylic acid, an intermediate for perindopril comprising reaction of (2S)-2,3-dihydroindole-2-carboxylic acid with t-BOC-L-alanine to form the amide compound followed by hydrogenation to give (2S, 3aS, 7aS)-l-(S)-alanyl-octahydro-lH-indole-2-carboxylic acid, which can be further elaborated to perindopril.

However, this patent does not provide any enabling method for preparation of perindopril or perindopril erbumine from (2S, 3aS, 7aS)-l-(S)-alanyl-octahydro-lH-indole-2-carboxylic acid thus obtained.
WO 96/33984 discloses N-sulfoxy anhydrides of N-[l-(S)-ethoxycarbonyl-3-phenylpropyl/butyl-S-alanine, and a process for preparation of several ACE inhibitors including perindopril using the said N-sulfoxy anhydride compounds. The N-sulfoxy anhydride is in turn prepared by reacting the corresponding carboxylic acid compound with N-(chlorosulfinyl)-heterocyclic compound, wherein the heterocycle is an alkyl imidazole, benzimidazole, tetrazole or other similar heterocyclic compounds.
7

H5C2Ov^O o H5C20\C^°CH3
C 3 II | I
^^M^Ay™ + ^st2j CH2C'2 > H3C—^N^C^°
^s—o
H
+0p,,cooR
H Perindopril (I)
However, this patent application specifically discloses detailed methods for synthesis of trandolapril, but not perindopril.
GB 2 095 252 claims certain N-(substituted aminoalkanoyl) heterocyclic compounds having antihypertensive and ACE Inhibition activity and a process for preparation thereof, which comprises an amide forming reaction of a suitable amine compound and the reactive derivatives of the suitable carboxylic acid compound. The reactive carboxylic derivatives mentioned therein include acyl halides, anhydrides, mixed anhydrides, lower alkyl esters, carbodiimides, carbonyl diimidazoles and the like.

However, this patent disclosure does not include perindopril as the antihypertensive and ACE inhibitory compounds mentioned therein.
8

DE. 197 21 290 describes a method for preparation of several ACE Inhibitors of formula (D), including perindopril, wherein Z is alkyl or phenyl and R\ is an amino acid as found in commercially valuable ACE inhibitors. The process comprises the steps of first silylating the compound of formula (A) to give the (bis)silyl derivative of formula (B), followed by reaction of compound (B) with thionyl chloride to give the silylated acid chloride derivative of formula (C). Compound (C) is then reacted with the respective amino acid, R1H to give compound of formula (D).

This method is however, lengthy and not cost-effective since there is a step of silylation using expensive silylating agents and subsequent step of desilylation involved.
The first enabling industrial method for preparation of perindopril erbumine was disclosed. In US 4 914 214 comprising reaction of (2S, 3aS,7aS)-2-carboxyperhydroindole, wherein the carboxylic acid at 2-position of the octahydroindole ring is protected as the benzyl group or is esterified with a linear or branched alkyl group, with (S,S) diastereoisomer of N-[(S)-l-carbethoxybutyl]-(S)-alanine in an alkaline medium in the presence of a catalyst, such as dicyclohexylcarbodiimide and in the presence of 1-hydroxybenzotriazole to give perindopril benzyl or alkyl ester. Subsequent deprotection of the carboxylic acid protective group gives perindopril in the form of a base.
9

The perindopril free base is dissolved in a solvent chosen from lower aliphatic alcohol, acetonitrile, ethyl acetate or dioxane or mixtures thereof and the solution reacted with tert-butylamine to form perindopril erbumine, which is crystallized by heating the reaction mixture, filtering hot, cooling and finally filtering of the crystallized perindopril erbumine.
This patent gives a detailed description of synthesis of perindopril erbumine divided in three stages - one related to synthesis of (2S,3aS,7aS)-2-Carboxyoctahydroindole; second describing synthesis of N-[(S)-l-Carbethoxybutyl]-(S)-alanine and the third stage comprising reaction of the compounds obtained by stages one and two to give perindopril and perindopril erbumine thereof. The chemistry practiced therein is summarized in Scheme-I.
10

Stage -I: Synthesis of(2S.3aS. 7aS)-2-Carboxvoctahvdroindole ester (A)


However, apart from the description of synthesis given therein the US 4 914 214 does not provide any detail of the crystal nature of perindopril erbumine obtained.
In addition, the method utilizes solvents such as acetonitrile and 1,4-dioxane for crystallization/purification of the erbumine salt, which come under the category of Class II solvents as categorized by International Conference of Harmonisation (ICH). The guidelines recommend that such solvents i. e. belonging to Class II category should not be used or their use should be limited in a method for manufacture of a drug substance.
WO 01/58868 discloses a method for preparation of perindopril erbumine comprising reacting benzyl ester of (2S, 3aS,7aS)-2-carboxyperhydroindole, p-toluenesulfonate salt with (S,S) diastereoisomer of N-[(S)-l-carbethoxybutyl]-(S)-alanine in the presence of 0.4 to 0.6 moles of 1-hydroxybenzotriazole; 1 to 1.2 moles of dicyclohexylcarbodiimide and 1 mole of triethylamine at 77° C to give the dipeptide compound, which on debenzylation gives perindopril.

Example-3 of this patent application, describes a method for preparation of perindopril erbumine consisting refluxing a suspension of perindopril and tert-butylamine in ethyl acetate, followed by cooling the solution to 15-20° C and isolating the crystallized product by filtration.
However, this application also does not provide any detail of the crystal nature of perindopril erbumine thus obtained.
EP 1 279 665 discloses N-carboxy anhydride of N-[l-(S)-ethoxycarbonyl-3- butyl-S-
alanine (B), and a process for its preparation by reaction of N-[l-(S)-ethoxycarbonyl-3-
butyl-S-alanine (A) with phosgene. The application further relates to a method for
12

preparation of perindopril and perindopril erbumine using the said N-carboxy anhydride compound (B).
Claim 9 of this application recites a process for preparation of N-[l-(S)-ethoxycarbonyl-3-butyl-S-alanine (A), comprising reaction of a suitably protected alanine of formula (C) with a suitably functionalised pentanoic acid ester, in particular wherein the leaving group is a trifluroromethanesulfonyloxy (-OSO2CF3) group of formula (D) as summarized in Scheme-II.
It might be mentioned herein that the chemistry embodied in claim 9 of EP 1 279 665 is obvious and anticipated from similar chemistry reported by D. W. Payling et. al. in J. Med. Chem., 1991, 34,430-447
Example-2 of this patent application, describes a method for preparation of perindopril erbumine consisting heating a mixture of perindopril and tert-butylamine in acetonitrile at 40° C, followed by cooling the solution to 5° C and isolating the crystallized product by filtration. However, for reasons mentioned hereinearlier use of acetonitrile poses hazards in operability on a commercial scale.
Further, this application also does not provide any detail of the crystal nature of perindopril erbumine obtained.
Moreover, this method utilizes toxic and hazardous phosgene for preparation of the N-carboxy anhydride compound, thereby rendering it commercially unattractive.
13


Scheme - II: Synthesis of Perindopril Erbumine as disclosed in EP Patent No. 1 279 665
WO 01/87835, WO 01/87836 and WO 01/83439, all having an international filing date of July 06, 2001 and drawing priority from three French Applications, all in turn having a filing date of July 06, 2000 claim three different crystalline forms of perindopril erbumine and a process for preparation thereof.
WO 01/87835 teaches a crystalline form, designated as the a crystalline form of perindopril erbumine, which is obtained by bringing to reflux a solution of the erbumine salt of perindopril in ethyl acetate and cooling the solution progressively or gradually till complete crystallization.
WO 01/87836 teaches a crystalline form, designated as the P crystalline form of perindopril erbumine, which is obtained by bringing to reflux a solution of the erbumine salt of perindopril in dichloromethane and cooling the solution rapidly to 0° C and isolation of the solid obtained by filtration. Alternatively, the p crystalline form is prepared by bringing to reflux a solution of the erbumine salt of perindopril in ethyl acetate and cooling the solution rapidly to 5° C and isolation of the solid obtained by filtration.
14

This method suffers from a serious limitation in that use of dichloromethane for preparation of a finished drug is not recommended by regulatory and environment bodies by virtue of it being included in the list of Class II solvents categorized by International Conference on Harmonization (ICH).
WO 01/83439 teaches a crystalline form, designated as the y crystalline form of perindopril erbumine, which is obtained by bringing to reflux a solution of the erbumine salt of perindopril in chloroform and cooling the solution rapidly to 0° C and isolation of the solid obtained by filtration. Alternatively, the y crystalline form is prepared by bringing to reflux a solution of the erbumine salt of perindopril in ethyl acetate and cooling the solution rapidly to 5° C and isolation of the solid obtained by filtration, followed by suspending the solid in chloroform and agitating at room temperature for 5 to 10 days, and collecting the solid by filtration.
This method also suffers from a serious limitation in that use of chloroform for preparation of a finished drug is not recommended by regulatory and environment bodies by virtue of it being included in the list of Class II solvents categorized by International Conference on Harmonization (ICH).
All the three abovementioned applications i. e. WO 01/87835, WO 01/87836 and WO 01/83439 state that taking into account the pharmaceutical and therapeutic importance of perindopril erbumine it was primordial to obtain the drug not only in excellent purity but also to synthesize the compound easily and efficiently on an industrial scale, notably in a (crystalline) form allowing filtration and drying of the product quickly. Moreover, the applicants further state that the (crystalline) form thus obtained must be highly reproducible, should be easily amenable for formulation into a dosage form and should possess sufficient stability on storage under special conditions of temperature, light, humidity or oxygen.
Against this backdrop, the applicants contend that they have invented a method, whereby perindopril erbumine could be obtained in three distinct well-defined crystalline forms,
15

viz. the a crystalline form disclosed in WO 01/87835, the (3 crystalline form disclosed in WO 01/87836 and the y crystalline form disclosed in WO 01/83439 in a highly reproducible manner and which, moreover, exhibit the desired characteristics like, ease of filtration, drying and suitability for formulation into a dosage form etc. This forms the basis of the invention embodied in WO 01/87835, WO 01/87836 and WO 01/83439.
Further, the method disclosed in EP. 0 308 341 (the equivalent of US 4 914 214) for synthesis of perindopril erbumine, as summarized in Scheme-I does neither state clearly and precisely the conditions for obtaining perindopril erbumine in a (crystalline) form exhibiting the abovementioned desired characteristics nor contains any mention on the crystalline nature of the product thus obtained.
However, as mentioned herein earlier, perindopril erbumine was approved by the US FDA on December 30, 1993 and has been available in the market since 1994 as ACEON® Tablets, useful for the treatment of hypertension. Apparently, the product has been obtained on crystallization from any one of the solvents i. e. ethyl acetate, acetonitrile, 1,4-dioxane or a lower aliphatic alcohol disclosed in US4914214 and is reportedly stable. Moreover, the crystal nature of the product thus obtained ought not to conform with any one of the a, p, or y forms disclosed in WO 01/87835, WO 01/87836 and WO 01/83439, which as mentioned hereinearlier have a filing date of July 06, 2001. The said filing date of WO 01/87835, WO 01/87836 and WO 01/83439 are much later than the filing date of the product patent of perindopril i. e. US 4 508 729, first filed on Dec 03, 1980 and the first process patent providing an enabling disclosure for preparation and crystallization of perindopril erbumine i. e. US 4 914 214, first filed on Sepl6, 1988, which, in turn are earlier than the approval date of the product i. e. December 30, 1993 by the US FDA. On the contrary, if the crystalline nature of perindopril erbumine in the market conforms with any one of the a, p, or y forms disclosed in WO 01/87835, WO 01/87836 and WO 01/83439, then it would suggest a case of double patenting of the said a, P, or y forms over that already existing, albeit not characterized and known to the public in large.
16

From the foregoing, it would be apparent that:
i) Neither the product patent of perindopril i. e. US. 4 508 729 nor the majority of the
large number of subsisting process patents, contain any enabling disclosure for preparation of perindopril and/or perindopril erbumine,
ii) Those patents, in particular US. 4 914 214, . WO 01/58868 and EP. 1 279 665 that do disclose a method for preparation of perindopril and perindopril erbumine, however, do not specify the crystal nature of the product thus obtained,
iii) The only report wherein the crystalline nature of perindopril erbumine has been specified are contained in. WO 01/87835, WO 01/87836 and WO 01/83439, covering three distinct crystalline forms, designated as a, B, or y forms respectively and a process for preparation thereof,
iv) The crystal nature of perindopril erbumine as contained in the marketed dosage form of ACEON® Tablets ought not to conform with any one of the a, p, or y forms disclosed in. WO 01/87835, WO 01/87836 and WO 01/83439, since these applications have a filing date of July 06, 2001, which are much later than the filing date of the product patent of perindopril i. e. US. 4 508 729, first filed on Dec 03, 1980 and the first process patent providing an enabling disclosure for preparation and crystallization of perindopril erbumine i. e. US. 4 914 214, first filed on Sep 16, 1988, which, in turn are earlier than the approval date of the product i. e. December 30,1993 by the US FDA,
v) If the crystalline nature of perindopril erbumine as contained in the marketed dosage form of ACEON® Tablets conforms with any one of the a, P, or y forms disclosed in. WO 01/87835, WO 01/87836 and WO 01/83439, then it would suggest a case of double patenting of the said cc, p, or y forms over that already existing, albeit not characterized and known to the public in large, and
17

vi) The known methods for crystallization of perindopril erbumine use solvents such as acetonitrile, chloroform, dichloromethane and 1,4-dioxane, all belonging to Class II as categorized by International Conference on Harmonization (ICH), thereby limiting their use on industrial scale for manufacture of the finished drug.
Thus, a need exists for a method of obtaining perindopril erbumine in a crystalline form conforming to that presumably existing in the marketed dosage form of ACEON® Tablets in a reproducible manner, which moreover, is obtained through utilization of solvents that are not frowned upon by regulatory authorities all over the world.
OBJECT OF THE INVENTION
It is thus the basic object of the present invention to provide a method for production of a crystalline form of perindopril erbumine conforming to that presumably existing in the marketed dosage form of ACEON® Tablets in a highly reproducible manner on an industrial scale, which moreover is easily amenable for formulation into a dosage form and possesses sufficient stability on storage and better physical characteristics like particle size, flowability or Compressibility Index which results in improved bioavailability.
In accordance with the abovementioned objective, the present inventors first carried out the following studies, primarily to determine the crystal nature of perindopril erbumine prepared as per the methods disclosed in the prior art documents cited hereinbefore. This consisted synthesis and crystallization of perindopril erbumine from various sets of solvents exactly as per the methods disclosed in the prior art documents. The experiments carried out were :
a) Preparation of perindopril (I) exactly as per the method described in the Example Stage la to 3C, columns 6-9 of US. 4 914 214; converting the perindopril thus obtained to perindopril erbumine (II) and its crystallization from ethyl acetate exactly as per the method described in the Example Stage 3D, column 9 of US. 4 914 214, the chemistry of which is summarized in Scheme-I and recording the DSC thermogram, IR spectrum, and X-ray (powder) diffraction pattern of the
18

product thus obtained, the latter two being reproduced in Table-I and Fig-6, given in a later part of this application,
b) Reproduction of the method given in section (a) hereinabove, but with substitution of ethyl acetate with 1,4-dioxane - a solvent claimed in US . 4 914 214 and recording the X-ray (powder) diffraction pattern of the product thus obtained, which in turn is reproduced in Table-II, given in a later part of this application,
c) Reproduction of the method given in section (a) hereinabove, but with substitution of ethyl acetate with acetonitrile - a solvent claimed in US . 4 914 214 and recording the X-ray (powder) diffraction pattern of the product thus obtained, which in turn is reproduced in Table-Ill, given in a later part of this application,
d) Reproduction of the method given in section, (a) hereinabove, but with substitution of ethyl acetate with a lower aliphatic alcohol, viz. methanol, ethanol, n-propanol etc. i. e. the solvents claimed in US. 4 914 214. In this case, however, no product crystallized out from any of these solvents even after standing in solution for several days.
e) Preparation of the a crystalline form of perindopril erbumine by bringing to reflux a solution of the erbumine salt of perindopril in ethyl acetate and cooling the solution progressively or gradually till complete crystallization, exactly as per the method described in. WO 01/87835 and recording the X-ray (powder) diffraction pattern of the product thus obtained,
f) Preparation of the P crystalline form of perindopril erbumine by bringing to reflux a solution of the erbumine salt of perindopril in dichloromethane and cooling the solution rapidly to 0° C and isolation of the solid obtained by filtration, exactly as per the method described in. WO 01/87836 and recording the X-ray (powder) diffraction pattern of the product thus obtained, and
19

g) Preparation of the y crystalline form of perindopril erbumine by bringing to reflux a solution of the erbumine salt of perindopril in chloroform and cooling the solution rapidly to 0° C and isolation of the solid obtained by filtration, exactly as per the method described in. WO 01/83439 and recording the X-ray (powder) diffraction pattern of the product thus obtained.
The X-ray (powder) diffraction patterns of perindopril erbumine prepared and crystallized by the six different methods mentioned hereinabove revealed that the powder pattern of:
i) those prepared as per methods (e), (f) and (g) conformed with/were identical to that of the a, P, and y crystalline forms respectively disclosed in. WO 01/87835, WO 01/87836 and WO 01/83439,
ii) that prepared as per method (a) i.e. crystallization from ethyl acetate as per the method described in US. 4 914 214 was different from any of the a, P, and y crystalline forms reported in. WO 01/87835, WO 01/87836 and WO 01/83439.
iii) that prepared as per method (b) i.e. crystallization from 1,4-dioxane as per the method described in US. 4 914 214 was also different from any of the a, P, and y crystalline forms reported in. WO 01/87835, WO 01/87836 and WO 01/83439, and also different from the crystalline form obtained through method (a), but identical with that obtained through method (c), and
iv) that prepared as per method (c) i.e. crystallization from acetonitrile as per the method described in US. 4 914 214 was different from any of the a, p, and y crystalline forms reported in. WO 01/87835, WO 01/87836 and WO 01/83439, and also different from the crystalline form obtained through method (a), but identical with that obtained through method (b).
The above results clearly indicate that perindopril erbumine as crystallized from ethyl acetate as per the method described in Example Stage 3D, column 9 of US. 4 914 214 has
20

the X-ray (powder) diffraction pattern summarized in Table-I and Fig-1, whereas the nature of the crystals obtained on crystallization from acetonitrile and/or 1,4-dioxane are different from that obtained through use of ethyl acetate. Moreover, no product crystallized from a lower aliphatic alcohol, contrary to the claims of US. 4 914 214.
The applicants have now found that a crystalline form of perindopril erbumine having identical and/or superimposable IR spectrum, DSC thermogram and X-ray (powder) diffraction pattern to that obtained on crystallization of perindopril erbumine from ethyl acetate as per the method described in Example Stage 3D, column 9 of US. 4 914 214 -which presumably is the form found in the marketed samples of ACEON® Tablets of the drug - could be further obtained through a selection of solvents in a highly reproducible manner.
Various solvents, a list of which is given hereinbelow were tried for crystallization of perindopril erbumine, manufactured by any of the prior art methods or through methods invented by the inventors. These solvents are :
a) Ethers, both cyclic and acyclic, such as tetrahydrofuran, diethyl ether, diisopropyl ether etc.;
b) Ketonic solvents, both cyclic and acyclic, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone, cyclopentanone, cyclopentanone etc.;
c) Hydrocarbons, both aliphatic and aromatic, such as n-hexane, n-heptane, toluene, chlorobenzene etc;
d) Nitroalkanes, such as nitromethane, nitroethane, nitropropane etc.
However, all the solvents were found to give either the α- or β-crystalline forms exclusively.
Against this backdrop, the applicants have found that solvents selected from N,N-dimethylformamide or dimethyl acetals of lower aliphatic aldehydes and ketones give exclusively the crystalline form of perindopril erbumine having identical and/or
21

superimposable IR spectrum, DSC thermogram and X-ray (powder) diffraction pattern to that obtained on crystallization of perindopril erbumine from ethyl acetate as per the method described in Example Stage 3D, column 9 of US. 4 914 214.
These solvents, unlike those used in the prior art, such as acetonitrile, 1,4-dioxane, dichloromethane, chloroform etc. are tolerated better by International Conference on Harmonization (ICH), and thereby rendering the process more amenable for commercial manufacture from a safety, environmental and regulatory point of view.
Further, the crystalline material obtained from crystallization of perindopril erbumine from these solvents was found to possess better physical characteristics like particle size, flowability or Compressability Index etc. compared to the material obtained by crystallization from ethyl acetate. These characteristics result in improved dissolution profile, which in turn, results in improved bioavailability, thereby rendering the crystalline perindopril erbumine obtained by the process of the present invention more amenable for formulation into a suitable dosage form.
SUMMARY OF THE INVENTION
22
Thus, in accordance with an aspect of the present invention there is provided a selective method for production of crystalline perindopril erbumine of formula (II), possessing the X-ray (powder) diffraction pattern, which moreover, is easily amenable for formulation into a dosage form and possesses sufficient stability on storage,


d-spacing (A) Angle