FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
NOVEL PROCESS FOR THE PREPARATION OF AMORPHOUS LERCANIDIPINE HYDROCHLORIDE"
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention

NOVEL PROCESS FOR THE PREPARATION OF AMORPHOUS LERCANIDIPINE HYDROCHLORIDE
FIELD OF THE INVENTION:
The instant invention relates to novel process for the preparation of substantially pure, amorphous Lercanidipine hydrochloride directly from the lercanidipine base without having any intermediary stage of the production of crystalline lercanidipine hydrochloride, which provides better yield of production, and pharmaceutical composition containing the substantially pure amorphous lercanidipine hydrochloride.
BACKGROUND OF THE INVENTION:
Lercanidipine hydrochloride, i.e., 3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-,2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethyl ester, hydrochloride having the formula (I)

is an antagonist of type-L calcium channels, and has been found to be very active as an antihypertensive and is an useful agent for the treatment of angina and coronary diseases. Lercanidipine selectively inhibits the transmembrane influx of calcium into cardiac and vascular smooth muscle, with a greater effect on vascular smooth muscle than on cardiac smooth muscle. The antihypertensive action is due to a direct relaxant effect on vascular smooth muscle which lowers total peripheral resistance and hence


blood pressure. Lercanidipine has a prolonged antihypertensive activity because of its high membrane partition coefficient. It is devoid of negative inotropic effects and its vascular selectivity is due to its voltage-dependent calcium antagonist activity. Since the vasodilatation induced by lercanidipine hydrochloride is gradual in onset, acute hypotension with reflex tachycardia has rarely been observed in hypertensive patients.
Lercanidipine hydrochloride (I) is disclosed in US4705797.
The preparation of said compound can be obtained with different synthetic schemes. US4705797 discloses process for the preparation of Lercanidipine Hydrochloride as described according to the following scheme:


As per scheme-I crude lercanidipine is obtained as an oily residue that is purified by flash chromatography using chloroform, containing increasing amounts of acetone, as the eluant. The solvent is then evaporated to dryness and remaining residue is dissolved in methanol adding a small excess of hydrochloric acid in ethanol and solution was evaporated to dryness. The residue was redissolved in acetone and again evaporated in vacuo. The residue was crystallized from water containing little amount of hydrochloric acid and sodium chloride to give lercanidipine hydrochloride hemi-hydrate. According to EP 1423367 Bl, the obtained lercanidipine hydrochloride as disclosed in US 4705797 is in the form of amorphous, hygroscopic and unstable hemihydrate.
A major disadvantage of the process of preparing amorphous lercanidipine, as it is described in US Patent No. 4705797, is that the disclosed cyclization reaction (Hantsch synthesis) generates several by products, which results in a lower yield for the desired product. Moreover, the preparation, purification and isolation of lercanidipine hydrochloride from the lercanidipine base is quite complex as it required twice evaporation of solvents and crystallization from different type of solvents, which leads to increase in number of stages and also lowering the yield & unnecessary consumption of solvents and reagents ultimately result into the higher cost of desired product.
US Patent No. 5912351 describes an alternate process for the preparation of lercanidipine hydrochloride.
Further WO/03/014084 discloses novel crystalline form I & II of Lercanidipine Hydrochloride and mixtures of Form I & II having predetermined and reproducible content of Form I & II & optionally other forms of Lercanidipine Hydrochloride such


as amorphous. EP1600441 discloses crystalline form I of Lercanidipine Hydrochloride and a mixture of form I with amorphous and optionally form II.
WO 2006/021397 provides novel acid addition salt of lercanidipine excluding hydrochloride salt and process for the preparation thereof. The method for the preparation of novel acid addition salt of lercanidipine, preferably napadisylate, a comprises: (a) adding solution of acid counter ion dissolved in organic solvent to solution of lercanidipine base (b) removing said organic solvent under vaccum, thereby isolating resultant lercanidipine acid addition salt.
WO 2006/046830 discloses process for the preparation of amorphous lercanidipine base by several methods; started with dissolving lercanidipine base in organic solvent and amorphous lercanidipine base is formed by (a) by using antisolvent or (b) by adding water or (c) concentrating solution under reduced pressure.
Further, WO2006089787A1 discloses process for the preparation of pure amorphous lercanidipine hydrochloride having at least 95% purity from crystalline lercanidipine hydrochloride. The method comprises dissolving crystalline lercanidipine hydrochloride in an organic solvent to provide a solution and isolating amorphous lercanidipine hydrochloride by either (a) adding water to the solution to form a precipitate or (b) evaporating off the solvent. However, the process for the preparation of substantially pure amorphous lercanidipine hydrochloride disclosed in WO 2006089787 requires highly pure crystalline lercanidipine hydrochloride; hence lercanidipine hydrochloride obtained directly from lercanidipine base must require further purification or crystallization to obtain crystalline grade material. This prior-art process invariably requires to convert the lercanidipine base into crystalline lercanidipine hydrochloride, and then into amorphous lercanidipine hydrochloride,


which leads to increase in number of reaction stages, number of purification to get desired quality of amorphous lercanidipine hydrochloride.
WO 2007/031865 discloses crystalline lercanidipine hydrochloride form-V and process for the preparation substantially amorphous lercanidipine hydrochloride. A process for the preparation of amorphous lercanidipine hydrochloride includes: (a) dissolving substantially pure lercanidipine hydrochloride in organic solvent; and (b) treating solution with clarifying agent to form the clarified solution, and (c) recovering the amorphous lercanidipine hydrochloride. As disclosed in WO 2007/031865 substantially pure lercanidipine hydrochloride is either crystalline form V or it is produced by dissolving crude lercanidipine hydrochloride in alcohol and adding aliphatic ester-containing solvent to the solution and recovering pure lercanidipine hydrochloride. Furthermore the actual process for the preparation of amorphous lercanidipine hydrochloride as disclosed only in example-4 of WO 2007/031865 includes the steps of (a) dissolution, (b) treatment with a clarifying agent, (c) concentration, (d) redissolution, (e) addition, and (f) recovery of amorphous lercanidipine hydrochloride. This prior-art process is lengthy & cumbersome as it involves number of intermediary stages, number of purification & recovery stages.
As disclosed herein, above all prior art process for the preparation of amorphous lercanidipine hydrochloride demands either pure crystalline lercanidipine hydrochloride or if produced directly from base needs further purification at final stage includes evaporation, re-dissolution and recrystallization. Thus, there is a demand for a simpler, cost-effective, industrially viable process for synthesizing amorphous Lercanidipine hydrochloride, which eliminating the problems associated with prior art and results into the better yield.


The inventors of present invention have surprisingly found simpler and cost-effective process for synthesizing amorphous Lercanidipine hydrochloride directly from the lercanidipine base without having any intermediary stage of crystalline lercanidipine hydrochloride or any evaporation, re-dissolution and recrystallization at final stage leads to substantially better yield.
SUMMARY OF THE INVENTION:
The first embodiment of the instant invention is to provide a new and improved process for synthesis of substantially pure amorphous lercanidipine hydrochloride directly from the lercanidipine base, which is simple, cost effective and industrially viable.
Yet another embodiment of the instant invention is to provide pharmaceutical composition of substantially pure amorphous lercanidipine hydrochloride produced according to instant invention.
In one general embodiment, the instant invention provides a process for the preparation of amorphous lercanidipine hydrochloride of formula as described herein below:
which comprises the steps of:
(a) dissolving lercanidipine base in an organic solvent;
(b) adding solution of step (a) to aqueous hydrogen chloride solution; and
(c) isolating amorphous lercanidipine hydrochloride.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure indicates X-ray diffraction pattern of amorphous Lercanidipine hydrochloride obtained according to the instant invention.


Fig. 2: This figure indicates Infrared Spectrum of amorphous Lercanidipine hydrochloride obtained according to the instant invention.
Fig. 3: This figure indicates Differential Scaning Calorimetry of amorphous Lercanidipine hydrochloride obtained according to the instant invention.
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term "lercanidipine hydrochloride" refers to the hydrochloride salt of methyl 1 , 1 ,N-trimethyl-N-(3 ,3 -diphenylpropyl)-2-aminoethyl 1 ,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-pyridine-3,5-dicarboxylate.
The term "amorphous" refers to solid compound, which is characterized by XRPD pattern having the typical broad featureless pattern without sharp peak. Fig. 1 is one of such pattern.
As used herein, the "substantially pure" means at least 95% pure, preferably at least at least about 97% pure, more preferably at least about 99% pure and still more preferably at least about 99.5% pure.
According to one general embodiment of the present invention, there is provided a new, improved and industrially viable process for the preparation of substantially pure amorphous Lercanidipine Hydrochloride having high aqueous solubility.


In general embodiment a process for the preparation of substantially pure amorphous lercanidipine hydrochloride comprising the steps of: (a) dissolving lercanidipine base in an organic solvent; (b) adding solution of step (a) to aqueous hydrogen chloride solution; and (c) isolating amorphous lercanidipine hydrochloride.
The organic solvent of step-(a) is used to dissolve Lercanidipine base. Preferred organic solvents include, but are not limited to polar protic or aprotic solvents, and mixtures thereof. Suitable solvents include alcohols, preferably (Cl-C6)-alkanols such as methanol and ethanol; ketones, chlorinated solvents such as dichloromethane; and amides such as dimethylformamide. Particularly preferred solvent includes methanol.
In step (b) of the instant invention aqueous hydrogen chloride solution can be prepared by adding concentrated hydrochloric acid in water or by diluting HCl (g) in water. The concentration of hydrochloric acid in water can be 3-10%, preferably 4-7%, more preferably 5-6%. Furthermore, inorganic ionic salt may also be added in water before adding or passing hydrochloric acid or HCl (g) In preferred embodiment NaCI or KCI salt can be added in catalytic amount in water. Solution is stirred if required to dissolve the salt and reaction mass is cool down up to the 10 C° -15 C°, more preferably at 5 C° -10 C°, still more preferably at 0 C° -5 C°.
In step (b) of the instant invention, when solution of base is added into aqueous hydrogen chloride solution, it may optionally contain NaCI or KCI.
In step (b) of the instant invention, addition of lercanidipine base solution to the aqueous hydrogen chloride solution can be carried out at 10 C° -15 C°, more preferably at 5 C° -10 C°, still more preferably at 0 C° -5 C°. Addition time may vary from 30 minutes to 2 hours. More preferably it should be 45 to 60 minutes.

Furthermore, during the course of addition, temperature should preferably be maintained constant but not strictly required. After the complete addition of lercanidipine base solution to aqueous hydrogen chloride solution, reaction mass is maintained at the temperature about 0 C° -5 C° and then allowed to precipitate. It may require 6-8 hours.
Isolating lercanidipine hydrochloride includes filtration, washing and drying of the isolated product at appropriate condition wherein filtration should preferably be carried out after the formation of precipitates in step (b). Washing of the precipitate can be done by process known in art i.e. by using organic solvent or aqueous solvent or mixture thereof. Further, drying of the isolated product can be preferably carried out under vacuum at 20 ~ 80°C, preferably at 30 ~ 32°C, for 6 ~ 12 hours.
Lercanidipine base used in instant invention can be obtained as disclosed in WO 2007/054969 or any other method known in prior art. The obtained lercanidipine base can be optionally purified by using column chromatography or any method known in prior art if required.
Lercanidipine hydrochloride obtained according to the present invention can be formulated into pharmaceutical composition, preferably in a dosage form suitable for oral administration by methods known in the art.
Pharmaceutical composition can be prepared either alone or in combination with pharmaceutically acceptable excipients into solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules. The preferred composition according to present invention is tablet. The oral compositions may be prepared by direct blending, dry granulation, wet granulation, melt granulation or other suitable method known in the art. Compositions may be presented as uncoated,

film coated, sugar coated, powder coated, enteric coated or modified release coated.
The pharmaceutical composition of substantially pure amorphous lercanidipine hydrochloride prepared according to instant invention may comprise one or more pharmaceutically acceptable excipients selected from carrier / diluent, disintegrant, binder, film forming agent, lubricant, opacifiers, plasticizers, stabilizers, colouring agent, anti-tacking agent, organoleptic additives such as flavoring agent, sweetener or coloring agent and others known to the skilled person in the art.
Diluent / Carrier may be selected from anhydrous lactose, lactose monohydrate, dicalcium phosphate dihydrate, microcrystalline cellulose, modified lactose, starch, starch derivatives, mannitol, spray dried Mannitol, Ran Explo-C® (Microcrystalline cellulose, Colloidal silicon dioxide, Crospovidone), Ran Explo-S® (Microcrystalline cellulose, Colloidal silicon dioxide and Sodium starch glycollate) and other materials known to one of ordinary skill in the art.
Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, Low-substituted hydroxy propyl cellulose and other materials known to one of ordinary skill in the art.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, starch, pregelatinized starch, sodium alginate, gums, synthetic resins and other materials known to one of ordinary skill in the art.
Lubricant / glidant may be selected from talc, metallic stearates such as magnesium


stearate, calcium stearate, zinc stearate; sodium stearyl fumarate, colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, starch, sodium stearyl fumarate, mineral oil, magnesium trisilicate; other materials known to one of ordinary skill in the art.
The sweetener may be selected from aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, sucralose and other materials known to one of ordinary skill in the art.
The flavoring agent may be selected from cherry, black current, pineapple, orange, strawberry, banana, vanilla, mint, menthol, citric acid, fumaric acid, tartaric acid, and other materials known to one of ordinary skill in the art.
Film forming agent may be selected from hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, gelatin, hydroxypropyl cellulose, polyethylene oxide, hydroxyethyl cellulose, sodium alginate and the other materials known to one of ordinary skill in the art. The film forming agent may be used in seal coat, drug coat, separating coat, film coat and the like.
In the following section, embodiments are described by way of examples to illustrate the process of invention; however this does not limit the scope of the present invention. While the present invention has been described in term of its specific embodiments, certain modifications & equivalents will be apparent to scope of the instant invention.
Method and condition of the measurement of X-ray diffraction patterns.


(1) Method of the measurement
X-ray diffraction patterns were measured on each 400 mg of the sample of Lercanidipine hydrochloride by the following condition.
(2) Condition of measurement

Target Cu
Filter Nickel
Voltage 45 KV
Current 40 mA
Slit DS-1/2, RS0.02
Scan Speed 0.167Min
Range 2-40° 2G
Step/Sample 0.008


PREPARATORY EXAMPLES:
Example -1
Preparation of Amorphous Form of Lercanidipine Hydrochloride
In a clean RBF (round bottom flask), 245 ml of R.O. water was added and cooled up to 0C°- 5C°. Concentrated hydrochloric acid solution (48.75 gm. 32%) was added to RBF and stirred for 10 minutes at 0C°- 5C°. The prepared solution of Lercanidipine base (9.75 g) in Methanol (19.5 ml) was gradually added within 45 to 60 minutes to hydrogen chloride solution at 0C°- 5C° and stirred 8 hours. The reaction mass was filtered over Buchner funnel and washed the cake with 50 ml of water and suck dry the product for 15 minutes. The obtained amorphous lercanidipine hydrochloride was stirred with 100 ml water in RBF at room temperature for 30 minutes, filtered over Buchner funnel and washed the cake with 50 ml water and suck dry the product for 15 minutes. The obtained material was again stirred with 100 ml water in RBF at room temperature for 30 minutes, filtered over Buchner funnel and washed the cake with 50 ml water and suck dry the product for 15 minutes. Finally the material was dried under vacuum at 40°C-45°C for 8 hours or till the K.F. less than 2.5%. Dry Wt.: 9.35 gm Yield: 90.5% Purity: 99.78%
Example - 2
Preparation of Amorphous Form of Lercanidipine Hydrochloride
In a clean RBF (round bottom flask), 250 ml of R.O. water and 0.625 gm. of sodium chloride were added at room temperature. The reaction mass was stirred at room temperature until the clear solution was obtained and cooled the solution up to 0C°-5C°. Hydrochloric acid (cone. 35%) (50 gm.) was added to RBF and stirred for 10


minutes at 0C°- 5C°. The prepared solution of Lercanidipine base (10.0 g) in methanol (20.0 ml) was gradually added within 45 to 60 minutes to hydrogen chloride solution at 0C°- 5C° and stirred 8 hours. The reaction mass was filtered over Buchner funnel and washed the cake with 50 ml of water and suck dry the product for 15 minutes. The obtained amorphous lercanidipine hydrochloride was stirred with 100 ml water in RBF at room temperature for 30 minutes, filtered over Buchner funnel and washed the cake with 50 ml water and suck dry the product for 15 minutes. The obtained amorphous lercanidipine hydrochloride was again stirred with 100 ml water in RBF at room temperature for 30 minutes, filtered over Buchner funnel and washed the cake with 50 ml water and suck dry the product for 30 minutes. Finally dry the material under vacuum below. (Dry Wt. 8.9 gm; Yield: 83.9%, Purity: 99.70%)






ABSTRACT:
The invention provides a nov el process for the preparation of substantially pure amorphous Lercanidipine hydrochloride directly from the lercanidipine base without having any intermediary stage of the production of crystalline lercanidipine hydrochloride, which provides better yield of production, and pharmaceutical composition containing the substantially pure amorphous lercanidipine hydrochloride produced by the instant method.