FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - PREPARATION OF NOVEL CRYSTALLINE FORM OF QUINAPRIL HYDROCHLORIDE.
2. Applicant(s)
(a) NAME : ARCH PHARMALAB LIMITED
(b) NATIONALITY : INDIAN
(c) ADDRESS : "H" Wing, 4th Floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri (East), Mumbai 400 072, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

FIELD OF INVENTION
The present invention relates to a novel crystalline form of Quinapril hydrochloride of formula (I) with high purity exhibiting characteristic XRD pattern.
The present invention further relates to a process for the preparation of a novel crystalline form of Quinapril hydrochloride of formula (I), by use of solvated quinapril hydrochloride of formula (I) as an intermediate

BACKGROUND OF THE INVENTION.
The chemical species, (3S)-2[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl] amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid generically called as Quinapril. Its pharmaceutically acceptable salts, specially hydrochloride salt are represented as formula (I).
Quinapril hydrochloride (I) and its pharmaceutical acceptable salts are active as angiotensin converting enzyme (ACE) inhibitors and thus are commercial valuable antihypertensive agents.
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US patent 4,344,949 discloses the process for preparation of Quinapril hydrochloride which comprising reaction of Ethyl ester of (S, S)-a- [(1-carboxy ethyl) amino] phenyl butanoic acid with Benzyl ester or t-butyl ester of (s)-1,2,3,4-tetra hydro-3-isoquinoline carboxylic acid in the presence of 1-hydroxy benzotriazole employing standard peptide bond formation methods. The benzyl ester or t-butyl ester group of Quinapril thus formed is removed by catalytic hydrogenation or by treatment with trifluroacetic acid. Quinapril hydrochloride is isolated either by solvent precipitation with diethyl ether or by lyophilisation of the aqueous solution.
US patent 4,761,479 describes a process the preparation of Quinapril hydrochloride wherein Quinapril hydrochloride obtained from reaction mixture is crystallized by using acetonitrile or acetone to give a crystalline form of Quinapril hydrochloride possessing characteristic XRD pattern and high bulk density.
This patent mentions that quinapril hydrochloride thus obtained contains equimolar amounts of acetonitrile/acetone as a part of crystal lattice. Thus the quinapril hydrochloride obtained is in the solvated form and thus tend to contain more impurities associated with solvent. Though, the solvent present in the crystal structure can be removed under vacuum at temperature of about 50° C, however during this unit operation the crystallinity of the substance is lost due to desolvation and also diketopiperazine impurities are increased.
Even though US patent 4,761,479 discloses use of acetonitrile and acetone, the former is preferred since, unlike acetonitrile, acetone can not be removed from the crystal lattice, even on prolonged drying. Acetonitrile, which falls within the class of toxic solvents as classified by international conference of harmonization. Also, the flash point of acetonitrile is - 2° C, rendering its use on commercial scale a hazardous proposition. Thus it is necessary to replace acetonitrile by other class of solvents.
Canadian Patent application 12,293,705 describes a process of purification of impure Quinapril hydrochloride, through two step process, comprising first crystallization of the impure material from toluene followed by another crystallization using class III solvent
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as categorized by international Conference of Harmonization (ICH). The patent also mentions that initially solvate of quinapril hydrochloride with toluene is prepared, which is subsequently substituted by solvate of class III solvents used for crystallization. Among the class III solvents, ethyl formate and methyl acetate are preferred ones.
The crystalline quinapril hydrochloride thus obtained from the above mentioned method is in the solvated form and contains more impurities associated with solvents. The process for crystallization is a two step process and thus time consuming. Also the flash point methyl acetate is -16° C and that of ethyl formate is -20° C, therefore their use on commercial scale is a hazardous proposition.
WO 2004/054980 discloses the use of nitroalkanes like nitromethane, nitroethane and nitropropane to yield novel crystalline solvated forms of Quinapril hydrochloride. It also tends to contain impurities in form of associated residual solvents. None of the processes mentioned above yields non-solvated form of quinapril hydrochloride. Thus there is need for a process for the preparation of a crystalline form of quinapril hydrochloride that overcomes the shortcomings of the prior art methods.
The inventors of the present invention have developed a process for the preparation of a crystalline form of quinapril hydrochloride in non-solvated form and therefore does not contain impurities in form of residual solvent, thereby giving a novel crystalline form of quinapril hydrochloride with high purity. Also it does not employ use of hazardous solvents thereby making overall process economical and also beneficial as it contributes less towards effluent problems
OBJECT OF INVENTION
It is thus an object of the present invention to provide a novel crystalline form of quinapril hydrochloride, which is not in solvated form.
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It is further object of the present invention to provide a novel crystalline form of quinapril hydrochloride exhibiting characteristic XRD pattern.
It is further object of the present invention to provide a process for the preparation of a novel crystalline form of quinapril hydrochloride that does not employ use of hazardous solvents.
Yet another further object of the present invention to provide a novel crystalline form of quinapril hydrochloride having high purity economically.
SUMMARY OF INVENTION
Thus according to an aspect of the present invention there is provided a novel crystalline form of quinapril hydrochloride exhibiting characteristic XRD pattern, represented by Formula (I).
According to another aspect of the present invention there is provided a process for the preparation of a novel crystalline form of quinapril hydrochloride wherein demineralised water is sprinkled or sprayed on the solvated quinapril hydrochloride and the resulting residual solvents are removed by vacuum drying.
The novel crystalline form of quinapril hydrochloride exhibits the following charateristic XRD pattern:
XRD VALUES (20)
7.8600, 8.4513, 9.9000, 10.6085, 12.2800, 12.5800, 12.9019, 13.7376, 14.9800, 15.1600, 15.4367, 16.4200, 16.5400, 16.8559, 17.1200, 17.6600, 18.0291, 19.2223, 19.6233, 21.0480, 21.3000, 21.5742, 22.7743, 23.9600, 24.3353, 24.7800, 25.1702, 25.6047, 25.9600, 26.2000, 26.6635, 27.0131, 28.4600, 28.8732, 29.3200, 29.6180, 30.4560, 30.000, 31.1600, 31.7502
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DETAILED DESRIPTION
The crystalline quinapril hydrochloride represented by formula (I) is prepared by the method disclosed in the prior art as described below:
(Ill)
Benzylated Quinapril maleate represented by Formula (III) is suspended in aqueous medium and PH is adjusted to 9-10 using sodium carbonate to yield Quinapril free from maleate group as Benzylated Quinapril. Benzylated Quinapril represented by Formula (II), thus obtained is further dissolved in tetrahydrofuran and pH is adjusted to less than 1 by passing dry hydrogen chloride gas.


Hydrogenation of the Benzylated Quinapril Hydrochloride is carried out by using Pd/C as a catalyst at a pressure of 40-45 psi and temperature of 40-45°C. After complete hydrogenation catalyst is removed by filtration and filtrate is concentrated under the reduced pressure to get oil. Oil is dissolved in methanol and this mixture is poured into diethyl ether to precipitate crude quinapril hydrochloride. This crude solid is then refluxed in ethyl formate under nitrogen atmosphere followed by cooling & chilling. Solid
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obtained is slurried in n- pentane, which removes free ethyl formate. Material is dried at 40° C using a high vacuum to yield Quinapril hydrochloride of Formula (I).
Quinapril hydrochloride thus obtained is in the solvated form with ethyl formate. Solvated Quinapil hydrochloride contains 1.73% (17300ppm) impurities
Quinapril hydrochloride so obtained possesses less HPLC assay as well as titrimetric assay and is used as an intermediate for preparation of a novel crystalline form of quinapril hydrochloride of the present invention.
In the prior art methods quinapril hydrochloride is heated to remove the associated solvent impurities, which leads to degradation of quinapril hydrochloride which is a thermolabile compound.
Also, diketopiperazine impurity of Formula (IV) and diacid impurity of Formula (V) increases as temperature increases. Therefore, temperature control, while solvent removal is a critical step.
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COOC2H 5


Following chart shows effect of temperature on quinapril hydrochloride impurities.

Temperature (°C) Diketopiperazine Diacid
30 0.06 0.36
50 0.54 0.41
The novel crystalline form of quinapril hydrochloride obtained by the process of the present invention is prepared by sprinkling or spraying water / demineralised water / distilled water / deionised water on the solvated quinapril hydrochloride. Water used takes away residual ethyl formate.
About 14- 25% water / demineralised / distilled water / deionised water with respect to solvated solid (w/w) leads to complete removal of associated solvent impurities. The residual water molecules are removed by vacuum drying at the temperature of 35 to 50° C.
Pharmacopoeia does not specify the ppm level of ethyl formate. However as per ICH guideline the permissible limit of ethyl formate is 5000 ppm. Thus the novel crystalline form of quinapril hydrochloride contains residual solvent (less than) 5000ppm.
The novel crystalline form of quinapril hydrochloride of the present invention is non-solvated and thus does not contain associated impurities of solvents as residual thereby giving high purity.
Inventors of the present inventors contemplate the use of solvents like ethyl acetate, tetrahydrofuran, ethyl formate, pentane, methanol and diisopropyl ether as per ICH guidelines. Also, demineralised water is used for the preparation of a novel crystalline form of quinapril hydrochloride, which makes the overall process economical.
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The novel crystalline form of quinapril hydrochloride exhibits the following charateristic XRD pattern:
XRD VALUES (29)
7.8600, 8.4513, 9.9000, 10.6085, 12.2800, 12.5800, 12.9019, 13.7376, 14.9800, 15.1600, 15.4367, 16.4200, 16.5400, 16.8559, 17.1200, 17.6600, 18.0291, 19.2223, 19.6233, 21.0480, 21.3000, 21.5742, 22.7743, 23.9600, 24.3353, 24.7800, 25.1702, 25.6047, 25.9600, 26.2000, 26.6635, 27.0131, 28.4600, 28.8732, 29.3200, 29.6180, 30.4560, 30.000, 31.1600, 31.7502
The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to the non-limiting exemplary illustrations.
EXAMPLES:
Example 1
100 g solvated Quinapril hydrochloride is sprinkled / sprayed with 14 g of water / Distilled water / Demineralised water / Deionised water and then finally dried vacuum at 40-45° C till constant weight is obtained. Drying will remove associated ethyl formate resulting into desired novel crystalline form of Quinapril hydrochloride (94.9 g)
Example 2
100 g solvated Quinapril hydrochloride is sprinkled / sprayed with 16 g of water / Distilled water / Demineralised Water / Deionised water and then finally dried vacuum at 40-45° C till constant weight is obtained. Drying will remove associated ethyl formate resulting into desired novel crystalline form of Quinapril hydrochloride (95.2 g).
Example 3
100g solvated Quinapril hydrochloride is sprinkled / sprayed with 18 g of water/ Distilled water / Demineralised water / Deionised water and then finally dried vacuum at 40-45°
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C till constant weight is obtained. Drying will remove associated ethyl formate resulting into desired novel crystalline form of Quinapril hydrochloride (94.9 g).
Example 4
100 g solvated Quinapril hydrochloride is sprinkled / sprayed with 20 g of water / Distilled water / Demineralised water / Deionised water and then finally dried vacuum at 40-45° C till constant weight is obtained. Drying will remove associated ethyl formate resulting into desired novel crystalline form of Quinapril hydrochloride (96.3 g).
Example 5
100 g solvated Quinapril hydrochloride is sprinkled / sprayed with 22 g of water / Distilled water / Demineralised water / Deionised water and then finally dried vacuum at 40-45° C till constant weight is obtained. Drying will remove associated ethyl formate resulting into desired novel crystalline form of Quinapril hydrochloride (96.3 g).
Example 6
100 g solvated Quinapril hydrochloride is sprinkled / sprayed with 24 g of water / Distilled water / Demineralised water / Deionised water and then finally dried vacuum at 40-45° C till constant weight is obtained. Drying will remove associated ethyl formate resulting into desired novel crystalline form of Quinapril hydrochloride (96.9 g)
HPLC Purity: > 99%
Moisture content (HPLC): < 0. 3%
Diketopriperazine & Diacid: both below 0.5 %
Dated this 5th Day of May 2005.

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