FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10,and Rule 13]
Title of the Invention
"NOVEL PROCESS FOR THE PURIFICATION OF 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 particularly describes the invention and the manner in which it is to be performed.


NOVEL PROCESS FOR THE PURIFICATION OF LERCANIDIPINE HYDROCHLORIDE
This application is a Patent of Addition of Indian Patent Application No. 1164/MUM/2005.
FIELD OF THE INVENTION:
The present invention relates to the isolated N-alkylated lercanidipine hydrochloride impurity, processes for the preparation thereof and the use of N-alkylated lercanidipine impurity as a reference marker. The present invention also discloses process for preparation of substantially pure Lercanidipine hydrochloride, which comprises dissolving the lercanidipine hydrochloride in ethylacetate to obtain a solution, added with acetonitrile and heating the reaction mixture, preferably at reflux temperature and recovering substantially pure lercanidipine hydrochloride.
BACKGROUND OF THE INVENTION:
Lercanidipine hydrochloride, i.e., 3,5-Pyridinedicarboxylic acid, l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-,2-[(3,3-diphenylpropyl)methylamino]-l,l-dimethyl ester,
hydrochloride having the formula (I)

(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 can be prepared as disclosed in US4705797 (Scheme-1).

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.
Like any other 1,4-dihydropyridine compound, Lercanidipine HC1 can also contain process impurities, including unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient ("API") may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis. (See Chromatographic} 2005, 61, January (No. 1/2))
PCT application WO 2007054969 (Indian Application No: 1164/MUM/2005) discloses an alternative process for the preparation of Lercanidipine hydrochloride involves the esterification of novel halogenated compound of formula (III) with compound of formula (IV).
PCT application WO200703I865 discloses a process for the purification of Lercanidipine hydrochloride by dissolving lercanidipine hydrochloride in alcohol and added with ester containing solvent followed by recovering the pure lercanidipine hydrochloride having low content of known impurity di-ester impurity.
Impurities produced during the bulk manufacturing processes must be limited to very small amounts, and are preferably substantially absent. According to ICH guideline API manufacturers requires that process impurities be maintained below set limits. The guidance specifies the quality of raw materials, and process parameters, such as temperature, pressure, time, and stoichiometric ratios, including purification steps.

such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
Furthermore, when pharmaceutical active ingredient (API) is prepared through series of chemical reactions, it may contain side products and by-products of the reaction and adjunct reagents used in the reaction, in most cases, remain present in the final product At certain stages during processing of an API, such as Lercanidipine HC1, it must be analyzed for purity, typically by HPLC or by TLC, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
It is known in the art that side products, by-products, and adjunct reagents are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram or a spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the retention time.
Further, the retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the relative retention time ("RRT") to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.
Those skilled in the art of drug manufacturing, research and development understand that a compound in a relatively pure state can be used as a "reference standard." A

reference standard is similar to a reference marker, but can be used for quantitative analysis, rather than simply qualitative analysis, as with a reference standard.
The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined.
The reference standard can serve as an internal standard when, without the deliberate addition of the reference standard, an unknown mixture contains a detectable amount of the reference standard compound using the technique known as "standard addition."
In the "standard addition technique", at least two samples are prepared by adding known and differing amounts of the internal standard. The proportion of the detector response due to the reference standard present in the mixture without the addition can be determined by plotting the detector response against the amount of the reference standard added to each of the samples, and extrapolating the plot to zero concentration of the reference standard. The response of a detector in HPLC can be and typically is different for each compound eluting from the HPLC column. Response factors, as known, account for this difference in the response signal of the detector to different compounds eluting from the column.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Impurities in Lercanidipine hydrochloride including, but not limited to, unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.

Thus, there still exists a need in the art for a method of determining the level of impurities in Lercanidipine hydrochloride and removing the said impurities by efficient process.
SUMMARY OF THE INVENTION:
In one embodiment, the present invention provides an isolated Lercanidipine impurity, N-alkyiated Lercanidipine hydrochloride of formula (II), having the following structure.

In another embodiment, the present invention provides a process for the preparation of substantially pure Lercanidipine hydrochloride, the process comprising:
(a) dissolving lercanidipine hydrochloride in aliphatic ester containing solvent to form a solution,
(b) adding an acetonitrile solvent to the above solution,
(c) heating the reaction mixture at reflux temperature; and
(d) recovering substantially pure lercanidipine hydrochloride from the solution.

In another embodiment, the present invention provides substantially pure Lercanidipine hydrochloride having N-alkylated impurity in amount less than 1%, more preferably less than 0.8%, more preferably less than 0.5%, more preferably less than 0.3%, more preferably less than 0.1% (area as measured by HPLC).
In another embodiment, the present invention provides a pharmaceutical composition of substantially pure Lercanidipine hydrochloride having N-alkylated impurity in amount less than 1%, more preferably less than 0-8%, more preferably less than 0,5%, more preferably less than 0.3%, more preferably less than 0.1% (area as measured by HPLC).
In another embodiment, present invention provides a process for using N-alkylated impurity as a reference marker or reference standard.
In another embodiment, the present invention provides the use of N-alkylated impurity of formula (II) as a reference marker for determining the presence of N-alkylated impurity in a sample of Lercanidipine hydrochloride.
In another embodiment, the present invention provides the use of substantially pure Lercanidipine hydrochloride prepared according to the present invention for the preparation of amorphous Lercanidipine hydrochloride by method known in the art such as WO 2007054969.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure indicates typical HPLC chromatogram of Lercanidipine HCI as obtained in Example-2.
Fig. 2: This figure indicates Infrared Spectrum of N-alkylated impurity of formula
(II).

Fig. 3: This figure indicates X-ray diffraction pattern 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.
As used herein, the term "lercanidipine hydrochloride" refers to the hydrochloride salt of methyl 1,1, N-trimethyl-N-(3 ,3 -diphenylpropyl)-2-aminoethyI 1 ,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-pyridine-3,5-dicarboxylate.
As used herein, the term "crude lercanidipine hydrochloride" refers to the Lercanidipine hydrochloride containing ~l%-20% of N-alkylated impurity.
As used herein, the term "N-alkylated impurity" refers to the N-alkylated Lercanidipine hydrochloride impurity of formula (II) having the following structure.

As used herein, the term "substantially pure lercanidipine hydrochloride" means a Lercanidipine hydrochloride contains less than 1% of N-alkylated Lercanidipine impurity, more preferably less than 0.8%, more preferably less than 0.5%, more

preferably less than 0.3% , more preferably less than 0.1% (as measured by HPLC).
As used herein, the term "reference marker" is used in qualitative analysis to identify components of a mixture based upon their position, e.g., in a chtomatogram or on a Thin Layer Chromatography (TLC) plate.
As used herein, the term "reference standard" refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. For example, the HPLC retention time of the compound allows a relative retention time to be determined, thus making qualitative analysis possible. The concentration of the compound in solution before injection into an HPLC column allows the areas under the HPLC peaks to be compared, thus making quantitative analysis possible.
In one embodiment, the present invention provides a Lercanidipine impurity, Lercanidipine N-alkylated impurity of formula (II), provided (M+l) peak at 612.3 as confirmed by mass spectroscopy ("MS") analysis, and having the formula.

The N-alkylated impurity of formula (II) of the present invention may be characterized by data selected from 'H NMR spectrum having hydrogen chemical shifts at about 10.34, 8.03, 79.96, 7.17-7.20, 4.92-4.97, 3.60-3.61, 2.69, 2.29 & 1.18,

2.27 & 1.27 ppm; 13CNMR spectrum having carbon chemical shifts at about 171.97, 165.72-165.78, 65.20-65.46, 50.89, 29.49, 24.84-25.40, 18.26-18.54 ppm; and by a retention time CRT") of about 48.5-49.5 minutes in HPLC analysis or relative retention time ("RRT") of about 0.95 minute w.r.t. Lercanidipine peak.
It has been found that N-alkylated impurity of formula (II) may form during the synthesis of Lercanidipine hydrochloride, by the processes as disclosed in WO 2007054969, particularly during the esterification reaction of formula halogenated compound of (III), wherein X = CI, Br, F or I:

with 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitropheny 1)-1,4-dihydropyridine-3-carboxylic acid (IV):

in the presence of base with solvent such as acetonitrile, isopropanol, the halogenated compound of formula (III) is attached at N-atom of 1,4-dihydropyridine moiety instead of carboxylic group of 1,4-dihydropyridine derivative of formula (IV).
In another embodiment, the present invention provides an isolated N-alkylated impurity. The N-alkylated impurity of formula (II) formed during the synthesis of Lercanidipine hydrochloride may be isolated by subjecting the filtrate obtained after the purification of lercanidipine hydrochloride with ethyl acetate and acetonitrile

solvent system that contains the N-alkylated impurity to column chromatography. The column chromatography comprises using a silica gel, as a stationary phase, and a gradient of eluents that remove N-alkylated impurity from the column on which it adsorbed, starting from 100 percent n-hexane to 35 percent ethyl acetate/65 percent n-hexane over a period of 8-9 hrs.
Column chromatography is a general purification technique; it isolates desired compounds from a mixture. In the column chromatography as described herein above, the stationary phase, a solid adsorbent, is placed in a vertical glass (usually) column and the mobile phase, a liquid is added to the top and flows down through the column by either gravity or external pressure. The mixture to be analyzed by column chromatography is applied to the top of the column. The liquid solvent is passed through the column by gravity or by the application of air pressure. Equilibrium is established between the solute adsorbed on the adsorbent and the mobile phase flowing down through the column. Because the different components in the mixture have different interactions with the stationary and mobile phases, they will be carried along with the mobile phase to varying degrees and a separation will be achieved. The individual components, or eluents, are collected as the solvent drips from the bottom of the column.
Further, it has been observed that N-alkylated impurity can not be removed efficiently by repeated crystallization from different single solvent.
It has now been found when lercanidipine hydrochloride obtained according to WO 2007054969 is treated with mixed solvent system comprising aliphatic ester-containing solvent and acetonitrile in particular amount, followed by heating at reflux temperature, will efficiently remove the N-alkylated impurity of formula (II) from Lercanidipine hydrochloride.
In another embodiment, the present invention provides a process for the preparation of substantially pure Lercanidipine hydrochloride comprising:

(a) dissolving lercanidipine hydrochloride in aliphatic ester containing solvent to form a solution,
(b) adding an acetonitrile solvent to the above solution.
(c) heating the reaction mixture at reflux temperature; and
(d) recovering substantially pure Iercanidipine hydrochloride from the solution.
In step (a) of the present invention, lercanidipine hydrochloride is dissolved in aliphatic ester containing solvent. The lercanidipine hydrochloride as mentioned in step (a) is crude lercanidipine hydrochloride, which may be obtained according to the method as disclosed in WO 2007054969.
Suitable aliphatic ester containing solvents include ester groups having from about 2 to about 12 carbon atoms, e.g., ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like and mixtures thereof, more preferred is ethyl acetate.
The solution of Iercanidipine hydrochloride in aliphatic ester can be prepared by adding Iercanidipine hydrochloride in aliphatic ester containing solvent and heated the reaction mixture to a temperature ranging from about 25°C to about 45°C for a time period ranging from about 30 minutes to about 45 minutes. Then solution is preferably cooled to room temperature, a temperature ranging from about 25°C to about 35°C.
In step (b) of the process of the present invention, an acetonitrile is added to the solution obtained in step (a). An acetonitrile solvent may be present in the ratio of about 1:10 to 1:6 v/v with respect to the aliphatic ester containing solvent. The acetonitrile solvent is preferably added at room temperature, a temperature ranging from about 25°C to about 35°C to the solution obtained in step (a).
In step (c) of the process of the present invention, the obtained reaction mixture is heated at reflux temperature of the solvent system, for a time period ranging from

about 30 minutes to about 45 minutes.
In step (d) of the process of the present invention, lercanidipine hydrochloride is recovered form the solution by any method known in the art, for example, by maintaining the reaction mixture obtained at 20°C to 30°C with stirring till the precipitate comes out. Generally, the isolation of compound of formula (I) is completed in less than 3 hour. The obtained compound of formula (I) i.e. Lercanidipine is further dried in hot air oven for 2-12 hrs to obtain dry product at 25-65°C.
The above purification process i.e. step (a) to step (c) can be repeated, if Lercanidipine hydrochloride is not obtained with desired purity.
In another embodiment, the present invention provides the use of N-alkylated lercanidipine as a reference marker or reference standard.
The use of N-alkylated lercanidipine as a reference marker for determining the presence of N-alkylated lercanidipine in Lercanidipine hydrochloride by the process comprising (a) determining the retention time by a column chromatographic method, such as HPLC or TLC, corresponding to the N-alkylated impurity in a reference marker comprising N-alkylated impurity; (b) running a sample of Lercanidipine hydrochloride on a column chromatography method; and (c) using the retention time in step (a) to identify the presence of N-alkylated impurity in the sample.
In another embodiment, the present invention provides a method for determining the amount of N-alkylated impurity in Lercanidipine hydrochloride comprising (a) using a chromatographic method such as HPLC or TLC to measure the area under a peak corresponding to N-alkylated impurity in a reference standard comprising a known amount of N-alkylated impurity; and (b) determining the level of N-alkylated impurity in the sample by comparing the area of step (a) to the area under the peak in a sample comprising a Lercanidipine hydrochloride contaminated with N-alkylated

impurity.
The skilled artisan will have no difficulty performing the chromatographic method. The details for performing chromatographic separation are given in examples.
In another embodiment, the amorphous lercanidipine hydrochloride can be prepared from the pure lercanidipine hydrochloride obtained according to the present invention, by any method known in the art such as WO 2007054969 or any conventional method known to the person skilled in the art.
In another embodiment, the pharmaceutical composition of 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 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.
EXAMPLES > HPLC method for analyzing the N-alkylated Lercanidipine impurity in Lercanidipine hydrochloride sample.

No. HPLC method HPLC method for analyzing the N-alkylated impurity
1 Column & packing Waters Symmetry C-8 250×4.6 mm 5 μ
2 Eluent Mobile A: Buffer
Mobile B: Acetonitrile: Methanol (75:25)
By gradient method
3 Stop time 95 min
4 Flow 1.3 ml/min
5 Detector 220 nm
6 Injection volume 20 μl.
7 Diluent Methanol
8 Column temperature 25°C
Sample for HPLC analysis is prepared by weighing 25.0 mg in 50 ml volumetric flask, dissolving and diluting to volume with diluent and then injected into the HPLC column.

Example -1
Preparation of crude Lercanidipine base
In 2 liter round bottom flask, 2,N -Dimethyl-N-(3,3-diphenyIpropyl)-l-amino-2-propanol (150 gm), dichloromethane ( 600 ml) and triethyl amine (84.8 gm) were charged at room temperature. The solution of Methane sulphonyl chloride in dichloromethane (636.6 gm. in 150 ml) was added to the above reaction mixture at 30°C within 2-3 hours. The reaction mass was stirred for about 1 hour at 30°C. Then reaction mass was subjected to vacuum distillation to remove the solvent completely at below 35°C and stirred the reaction mass under vacuum for 15 minutes.
The obtained reaction mass was added with acetonitrile (750 ml)., 2.,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3-carboxylic acid (167.6 gm) and N,N-diisopropyIethyl amine (84.8 gm) at below 35°C. The reaction mass was heated at 60°C -65°C for 5 hrs and then cooled the reaction mixture at below 50°C and distilled out the solvent completely under vacuum.
Example-2:
Preparation of crude Lercanidipine Hydrochloride
The obtained reaction mass was added with methylene chloride (MDC) (1500 ml) at room temperature and stirred the reaction mass to dissolve the obtained reaction mass. The organic layer was washed with 10% aqueous solution of sodium carbonate (3×1500 ml). Water (1500ml) was added to the MPC layer and separated organic layer was acidified with 10% aqueous hydrochloride solution (1046 ml) at room temperature. Stirred the reaction mass at RT and settled the layers and MDC layer was washed with 20% aqueous solution of sodium chloride (1500 ml). The separated MDC layer was subjected to vacuum distillation to remove the solvent completely.
Analytical result:

No. Compound (%) area by HPLC RT
1 Lercanidipine Hydrochloride 74.18% 51.15
2 N-alkylated impurity (II) 21.12% 48.48
3 Unknown impurity 0.19% 71.03
Example-3:
Purification of crude Lercanidipine hydrochloride
The reaction mass as obtained in example-2 was added with ethyl acetate (450 ml) at below 40°C, stirred the reaction mass and distilled out the solvent completely under vacuum at below 50°C. Ethyl acetate (2.25 liter) was added to the obtained reaction mass, stirred the reaction mass to dissolve the residue in ethyl acetate at below 50°C for 30 minutes to 45 minutes. After cooled it to RT, the reaction mass was added with acetonitrile (300 ml) at the room temperature. The reaction mass was then heated at reflux temperature (~ 76°C) and maintained at reflux temperature for 30-45 minutes. The reaction mass was then cooled to RT and filtered the material followed by washing with ethyl acetate (450ml) and suck dried the material. The obtained filtrate may be subjected to column chromatographic separation for the isolation of N-alkylated impurity.
Analytical result:

No. Compound (%) area by HPLC RT
1 Lercanidipine Hydrochloride 98.09 % 51.15
2 N-alkylated impurity (II) 1.50% 48.48
3 Unknown impurity 0.17% 71.03
Example-3:
Purification of Lercanidipine hydrochloride by using methanol to remove
unknown impurity
The reaction mass as obtained in example-3 was added with ethyl acetate (750 ml) at room temperature and stirred it for 30 minutes. Then reaction mass was filtered and obtained reaction mass was added with methanol (750 ml) at 30°C-35°C and stirred it

for 30 minutes. Add activated charcoal (7.5 gm) and reaction mass was filtered through hyflow bed. The filtrated was again treated with charcoal and filtered through hyflow bed. Then solvent was completely distilled out under vacuum. Analytical result:

No. Compound (%) area by HPLC RT
1 Lercanidipine Hydrochloride 98.09 % 51.15
2 N-alkylated impurity (II) 1.50% 48.5
3 Unknown impurity 0.03 % 71.1
Example-4:
Purification of crude Lercanidipine hydrochloride
The reaction mass as obtained in example-4 was added with ethyl acetate (450 ml) at below 40°C, stirred the reaction mass and distilled out the solvent completely under vacuum at below 50°C. Ethyl acetate (1.5 liter) was added to the obtained reaction mass, stirred the reaction mass to dissolve the residue in ethyl acetate at below 50°C for 30 minutes to 45 minutes. After cooling it to RT, the reaction mass was added with acetonitrile (150 ml) at the room temperature. The reaction mass was then heated at reflux temperature (- 76°C) and maintained at reflux temperature for 30-45 minutes. The reaction mass was then cooled to RT and filtered the material followed by washing with ethyl acetate (300 ml) and suck dried the material and dried in hot air oven for 5 hrs at 55°C (weight 120 gm).
Analytical result:

No. Compound (%) area by HPLC RT
1 Lercanidipine Hydrochloride 99.9 % 51.15
2 N-alkylated impurity (II) 0.06 % 48.5
3 Unknown impurity 0.03 % 71.1
Example-6:
Preparation of Amorphous Form of Lercanidipine Hydrochloride
Prepared solution of sodium chloride (17.5 g) in water (3500 ml) at 25-30 °C and

cooled the solution at 0-5 °C. Lercanidipine hydrochloride (140 gm) was dissolved in methanol (700 ml) with stirring at 25-35°C. Filtered the solution over hyflow bed and washed the hyflow bed with methanol (140 ml) and concentrated the filtrate 1.5 to 1.8 time w.r.t. the weight of lercanidipine hydrochloride as taken initially. Then the obtained filtrate was added to the sodium chloride solution at 0-5 °C within 30 minutes. Stirred the solution at 0-5°C for 2 hour and filtered the solution and washed the wet-cake with water (280 ml), Charged water (2100 ml) to the wet-cake and keep it under stirring for 30 min. at 25-30 °C and filter the product and washed with water (280 ml) and dried the material in air tray drier at 30-35°C for 12 hrs. (Dry Wt. 128 gm).
Example 7:
Pharmaceutical composition of Lercanidipine hydrochloride
1. Microcrystalline cellulose, Maize starch, Sodium starch glycolate, Colloidal silicon dioxide and Lercanidipine hydrochloride (amorphous and micronized) were sifted and mixed thoroughly.
2. Surfactant solution in water was sprayed on dry mix prepared in step-1 without using any binder.
3. The wet granules from step 2 were dried and the dried granules were sifted.
4. Mixture of Sodium Stearyl Fumarate and Macrogol were sifted and blended with dried blend of step-3.
5. The blend from step-4 was compressed using suitable punches.
6. The compressed tablet was film coated.


We claim:
1. A compound of formula (II):
7. A Lercanidipine hydrochloride containing less than 0.1% (area as measured by HPLC) of N-alkylated impurity as claimed in claim 1.
8. A pharmaceutical composition of Lercanidipine hydrochloride containing less than 0.1% (area as measured by HPLC) of N-alkylated impurity as claimed in claim 1.
9. A process for using N-alkylated impurity as a reference marker for determining the presence of N-alkylated impurity in Lercanidipine hydrochloride comprising:
a) determining a retention time of N-alkylated impurity in reference marker comprising N-alkylated impurity by a chromatographic method;
b) running a sample of Lercanidipine hydrochloride with the chromatography
method; and
c) using the retention time in step (a) to identify the presence of N-alkylated impurity

in the sample.
5. A process for using N-alkylated impurity as a reference standard for determining
the amount of N-alkylated impurity in Lercanidipine hydrochloride comprising:
a) using a chromatographic method to measure the area under a peak corresponding to N-alkylated impurity in a reference standard comprising a known amount of said N-alkylated impurity; and
b) determining the level of N-alkylated impurity in the sample by comparing the measured area of the peak to the area under a peak measured in a sample comprising Lercanidipine hydrochloride contaminated with N-alkylated impurity.

6. The process of claim 4 or 5, wherein the chromatographic method is HPLC or TLC.
7. A process for the preparation of Lercanidipine hydrochloride having less than 0.1% of N-alkylated impurity comprising the steps of:

(e) dissolving lercanidipine hydrochloride in aliphatic ester containing solvent to form a solution,
(f) adding an acetonitrile solvent to the above solution.
(g) heating the reaction mixture at reflux temperature; and
(h) recovering substantially pure lercanidipine hydrochloride from the solution.
8. The process of claim 7, wherein aliphatic ester containing solvent of step (a) is ethyl acetate, isopropyl acetate or isobutyl acetate.
9. The process of claim 7. wherein the recovering step comprises isolating the pure lercanidipine hydrochloride from the solution of step (c).

10. A process for the preparation of substantially lercanidipine hydrochloride as herein described, particularly with reference to the foregoing examples.


Dated this 11th February, 2009