FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"SUBTANTIALLY PURE LERCANIDIPINE HYDROCHLORIDE AND PROCESS FOR THE PREPARATION THEREOF"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION


BACKGROUND OF THE INVVENTION
1. Technical Field
[0002] The present invention provides substantially pure lercanadipine hydrochloride
having HPLC purity equal to or greater than 99.5%
[0003] Preferably, the substantially pure lercanadipine hydrochloride has an HPLC
purity equal to or greater than 99.5% and less than 0.15% oxidized impurity i.e. 2,6-dimethyl-
4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-l,l-
dimethyl ethyl methyl ester is represented by the following formula.

[0004] The present invention further provides a process for the preparation of
substantially pure lercanadipine hydrochloride.
DESCRIPTION OF RELATED ART
[0005] Lercanidipine hydrochloride, also known as l,4-dihydro-2,6-dimethyl-4-(3-
2
nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[(3,3-diphenylpropyl)methylamino]-l,l-dimethylethylmethyl ester hydrochloride, is represented by the structure of Formula I.


Lercanidipine hydrochloride is a synthetic antihypertensive calcium channel blocker sold under the brand names Lercadip, Lerdip, Lerzam, Zanedip, and Zanidip®. Lercanidipine hydrochloride is a dihydropyridine calcium channel blocker used for the treatment of hypertension. It can reduce systemic arterial blood pressure with a long duration of action and is believed to slow the progression of atherosclerosis. See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 973, monograph 5465.
[0006] European Patent No. 0153016 ("the '016 patent") and U.S. Patent No.
4,968,832 ("the '832 patent"), herein incorporated by reference, disclose lercanidipine hydrochloride. The '016 and '832 patents further disclose processes for the preparation of lercanidipine hydrochloride.
SUMMARY OF THE INVENTION
[0007] The present invention provides substantially pure lercanadipine hydrochloride
having HPLC purity equal to or greater than 99.5%.
Preferably, the substantially pure lercanadipine hydrochloride has an HPLC purity equal to or greater than 99.5% and less than 0.15% oxidized impurity i.e. 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-l,l-dimethyl ethyl methyl ester.
The present invention also provides process for the preparation of substantially pure lercanadipine hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
[0008] In accordance with a first embodiment of the present invention, provides
substantially pure lercanadipine hydrochloride having HPLC purity equal to or greater than
99.5%.
[0009] Preferably, the substantially pure lercanadipine hydrochloride has an HPLC
purity equal to or greater than 99.5% and less than 0.15% oxidized impurity i.e. 2,6-dimethyI-
3

4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-1,1-dimethyl ethyl methyl ester is represented by the following formula.

In accordance with a second embodiment of the present invention, a process for preparing lercanidipine hydrochloride substantially free of 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-1,1 -dimethyl ethyl methyl ester is provided, the process comprising:
(a) dissolving lercanadipine hydrochloride in an alcoholic solvent to obtain solution;
(b) additing an aliphatic ester solvent to the solution of step (a);
(c) recovering lercanidipine hydrochloride substantially free of 2,6-dimethyl-4-(3-
nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-1,1-
dimethyl ethyl methyl ester.
In accordance with a third embodiment of the present invention provides a pharmaceutical composition comprising lercanidipine hydrochloride substantially free of 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylicacid 2-[(3,3-diphenylpropyl)methylamino]-1,1 -dimethyl ethyl methyl ester.
(0010] Efforts are made to prepare pharmaceutical products of a high grade and with a
minimum amount of impurities present. The control of impurities requires a study of various options to decide upon the reaction conditions and testing protocols necessary to insure that drugs which are administered to the public are substantially pure. Accordingly, there remains a need for an improved process for preparing lercanidipine hydrochloride that eliminates or substantially reduces the impurities in a convenient and cost efficient manner to provide substantially pure of lercanidipine hydrochloride.
4

[0011] In step (a) of the process of the present invention, lercnadipine hydrochloride
in any form is dissolved in an alcoholic solvent. Suitable alcoholic solvents include, but are not limited to, methanol, ethanol and the like mixtures thereof.
[0012] In step (b) of the purification process of the present invention, the dilution
further includes adding to the solution an aliphatic ester having from about 2 to about 12
carbon atoms, e.g., isopropyl acetate. The aliphatic ester may be present in a ratio of about
10:1 v/w with respect to the lercanidipine hydrochloride. The aliphatic ester can be added at
room temperature, a temperature in the range of from about 25°C to about 30°C.
[0013] In step (c) of the present invention, the solution may be stirred at a temperature
ranging from about 25°C to about 30°C. The solution may be stirred at about 60 rpm to about 100 rpm for a time period ranging from about 12 hours to about 20 hours. The resulting solid can be isolated by conventional techniques, e.g., filtration, and optionally washed with, for example, isopropyl acetate.
[0014] The term "lercanidipine hydrochloride substantially free of 2,6-dimethyl-4-(3-
nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[(3,3-diphenyIpropyl)methylamino]-1,1 -dimethyl ethyl methyl ester" as used herein shall be understood to mean lercanidipine hydrochloride formed with little to no content of 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-1,1 -dimethyl ethyl methyl ester. In this manner, the amount of 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-l,l-dimethyl ethyl methyl ester, if present, resulting from the process for preparing lercanidipine hydrochloride present will be in relatively minor amounts, e.g., less than about 0.15 weight percent, preferably less than about 0.1 weight percent and most preferably 0 weight percent.
[0015] Another aspect of the present invention is directed to a pharmaceutical
composition containing at least lercanidipine hydrochloride substantially free of 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-[(3,3-diphenylpropyl) methylamino]-1,1-dimethyl ethyl methyl ester, wherein the D50 and D90 particle size of the unformulated lercanidipine or pharmaceutically acceptable salt thereof used as starting material is less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than
5

about 15 microns. Any milling, grinding micronizing or other particle size reduction method
known in the art can be used to achieve desired particle size range set forth above.
(0053] The substantially pure lercanidipine or pharmaceutical^ acceptable salts
thereof thus obtained may then be formulated into a pharmaceutical composition or dosage form. Such compositions and dosage forms include, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals either orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), intracistemally, intravaginally, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray. For example, the active ingredient of the invention, or salts or solvates thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or un-coated form as desired.
[0054] Actual dosage levels of the substantially pure lercanidipine lercanadipine in the
compositions of the invention may be varied to obtain an amount of that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. The total daily dose of the compounds of this invention administered to a host in single or divided dose and can vary widely depending upon a variety of factors including, for example, the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc. The pharmaceutical compositions herein can formulate in any release form, e.g., immediate release, sustained release, controlled release, etc.
6

[0055] The following examples are provided to enable one skilled in the art to practice
the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLE 1
[0056] Into a 2L 4-necked round bottom flask, lercanidipine hydrochloride (1 l0g) and
methanol (110 ml) were added at a temperature ranging from about 25°C to about 30°C under stirring. The reaction mixture was then heated to a temperature ranging from about 50°C to about 55°C and maintained for about 30 minutes. Cold water was circulated to the condenser. Next, the clear reaction mass was brought to room temperature. This was followed by addition of isopropyl acetate (1100 ml) at room temperature and maintained for about 16 hours at about 60 to about 100 RPM. The precipitated solid was filtered and washed with isopropyl acetate (110 ml). The wet cake weighed about 132.0 g.
[0057] The product was dried in an oven at a temperature in the range of from about
50°C to about 55°C for 8 hours wherein the LOD was less than about 10.0%. The dried product was lercanidipine hydrochloride weighing about 86.9 g, with a yield of about 79% and purity greater than about 99.7%; oxidized impurity 0.02%
[0058] It will be understood that various modifications may be made to the
embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the features and advantages appended hereto.
Dated this Twenty-Fourth (24Th) day of March, 2006

7