Field of the invention:

The present invention provides a novel polymorph of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride represented by the following structural formula-la and process for its preparation.

Background of the invention:
Isobutyric acid 2-((R)-3-diisopropylamino-l -phenylpropyl)-4-(hydroxymethyl)phenyl ester is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.

U.S. Patent No. 6,713,464 Bl discloses a variety of 3,3-diphenylpropylamine derivatives, processes for their preparation, pharmaceutical compositions comprising their derivatives and methods of use thereof. These compounds are anti-muscarimc agents with superior pharmacokinetic properties compared to existing drugs such as oxybutynin and tolterodine which are useful in the treatment of urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions. Among them, isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.

Pharmaceutically acceptable salts of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester and processes for their preparation is specifically disclosed in US 6,858,650 Bl.

The said patent discloses the hydrochloride salt of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester in hydrated form and process for its preparation. The said process involves the treatment of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester with isobutyryl chloride in dichloromethane results in amorphous solid foam of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride which on further crystallization from a mixture of acetone/water/diethyl ether by treatment with ultrasound provides crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride hydrate having melting point 97.1°C and 97.0% of purity by HPLC. The said patent has not characterized the solid state characteristics of the obtained solid.

In the said process the product is initially obtained as an amorphous solid, which is further crystallized from the above said solvent mixture by treatment with ultrasound. Ultrasound technique is not advisable on industrial scale. Further the disclosed process is a lengthy process and involves the usage of many solvents. Further in this process, isobutyryl chloride is used as HC1 source, which is not simple when compared to the conventional HC1 sources such as dry HC1 or other commercial HC1 sources like isopropyl alcohol-HCl, ethyl acetate-HCl etc.,

Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) which have been used to distinguish polymorphic forms.

The discovery of new polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.

The present inventors surprisingly found the novel anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, which is showing advantageous properties.

Brief description of the invention:
The first aspect of the present invention is to provide anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, herein after designated as crystalline form-M.

The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

The third aspect of the present invention is to provide another process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

The fourth aspect of the present invention is to provide a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound offormula-la.

Figure-2: Illustrates the DSC thermogram of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula-la.

Advantages of the present invention:
• The present invention involves the usage of simple and commercially available HC1 sources for the preparation of HC1 salt instead of isobutyryl chloride.

• Direct formation of crystalline Fesoterodine HC1 without involving the formation of amorphous compound.

• The present invention provides anhydrous Fesoterodine HC1, which is highly stable.
• The present invention provides anhydrous Fesoterodine HC1 in highly pure form.
• The anhydrous Fesoterodine HC1 of the present invention is non-hygroscopic in nature which is highly advantageous for formulators.
• The present invention involves lesser number of steps.

• Avoids the usage of ultrasound technique (not suggestible on industrial scale) for crystallization.

• Anhydrous Fesoterodine HC1 of the present invention is more suitable for pharmaceutical compositions.

Detailed description of the invention:
As used herein the present invention the term "suitable solvent" refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methyl pyrrolidone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; or mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention provides crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride salt compound of formula-la. The crystalline form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 9.3, 10.6, 11.7, 16.7, 16.9, 17.5, 18.7, 19.9, 23.2, 24.6, 24.9, 25.6, 25.8, 28.0, 28.7, 30.4, 32.1 ± 0.2 degrees of 2-theta. The crystalline form-M of the present invention is further characterized by its X-Ray powder diffraction pattern having additional peaks at about 12.3, 14.2, 14.8, 18.1, 21.7, 26.9, 28.3, 29.6 ±.0.2 degrees of 2-theta. The crystalline form-M is further characterized by the PXRD pattern as illustrated in figure-1 and its differential scanning calorimetric (DSC) thermogram having an endotherm at 147.03°C as illustrated in figure-2.

The crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula-la is further characterized by its IR absorption spectrum having absorption bands at 3327, 2975, 2938, 2610, 1751, 1601, 1497, 1226, 1174, 866 and 701 cm"1.

It is known in the art that X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure.

Generally, a measurement error of a diffraction angle in an X-ray powder diffraction pattern is typically ± 0.2° of 2-theta.

A person skilled in the art will also appreciate that slight variations in the melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting the DSC data. As a skilled person will realize, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point. Therefore, the melting points disclosed herein may vary by ± 5°C from the values quoted herein.

The second aspect of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula-la, which comprises of:

a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester acetyl mandelate salt with a suitable aqueous base in a suitable solvent or mixture of solvents at a suitable temperature,

b) separating the aqueous and organic layers,

c) distilling off the solvent completely from organic layer,

d) adding suitable solvent to the obtained compound,

e) cooling the reaction mixture,

f) treating the reaction mixture with a suitable HC1 source,

g) stirring the reaction mixture,

h) filtering the precipitated solid and washing with a suitable solvent to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride.
The suitable solvent used in step-a) is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents or mixtures thereof; the suitable base used is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates; and step-a) is carried out at a temperature of 0-5°C to room temperature (25-30°C), preferably at 0-5°C;

The suitable solvent used in step-d) & step-h) is selected from ester solvents, ketone solvents, ether solvents, alcoholic solvents, nitrile solvents or mixtures thereof;

In step-f) the suitable HC1 source is selected from dry HC1 gas, ethyl acetate-HCl, ethanolic HC1, IPA-HC1, ethereal HC1, acetyl chloride, tri(C1-C6 alkyl)silyl chloride, NH4CI and the like, wherein acetyl chloride and tri(C1-C6 alkyl)silyl chloride are used preferably in combination with alcoholic solvents.

A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula-la, comprising of:

a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester acetyl mandelate salt with aqueous sodium carbonate solution in a mixture of dichloromethane and water at 0-5 °C,
b) separating the aqueous and organic layers,

c) distilling off the solvent completely from organic layer,

d) adding ethyl acetate to the obtained compound,

e) cooling the reaction mixture to 0-5°C,

f) passing the dry HC1 gas into the reaction mixture,

g) stirring the reaction mixture,

h) filtering the precipitated solid and washing with ethyl acetate to get crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

The isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester acetyl mandelate salt or isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester used in the present invention can be prepared by using any prior known methods or they can be prepared by the processes disclosed in our earlier PCT application WO2012098560A2.

The third aspect of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula-la, comprising of:
a) Dissolving the isobutyric acid 2-((R)-3-diiso
b) propylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester in a suitable solvent, cooling the reaction mixture,
c) treating the reaction mixture with a suitable HC1 source,
d) stirring the reaction mixture,
e) filtering the precipitated solid and washing with a suitable solvent to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride.

Wherein, the suitable solvent used in step-a) & step-e) is selected from ester solvents, ketone solvents, ether solvents, alcoholic solvents, nitrile solvents or mixtures thereof; In step-c) the suitable HC1 source is same as defined for step-f) of the second aspect of the present invention;

A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula-la, comprising of:

a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester in ethyl acetate,

b) cooling the reaction mixture to 0-5°C,

c) passing the dry HC1 gas into the reaction mixture,

d) stirring the reaction mixture,

e) filtering the precipitated solid and washing with ethyl acetate to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

The fourth aspect of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula-la, comprising of;

a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride in a suitable solvent or mixture of solvents at a suitable temperature,

b) stirring the reaction mixture,

c) cooling the reaction mixture to a suitable temperature and stirring the reaction mixture,

d) filtering the precipitated solid to get pure isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

Wherein, in step-a) the suitable solvent is selected from ketone solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, alcoholic solvents, nitrile solvents or mixtures thereof; and the suitable temperature ranges between 40°C to reflux temperature of the solvent; and in step-c) the reaction mixture is cooled to a temperature ranges between 0-30°C.

A preferred embodiment of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of;

a) Dissolving the isobutyric acid 2-((R)-3-diisopropyIamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride in acetone by heating to reflux temperature,

b) stirring the reaction mixture,

c) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,

d) filtering the precipitated solid to get pure isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

The isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride utilized in step-a) of the fourth aspect can be synthesized by the processes disclosed in the second and third aspects of the present invention.

The anhydrous crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride obtained in the present invention is stable and non-hygroscopic in nature. The non-hygroscopic nature of the compound is determined by the method described in European pharmacopeia.

The non-hygroscopic nature of crystalline form-M obtained by the process of the present invention is confirmed by the fact that there is no substantial change in the water content even after the compound is placed in a desiccator containing aqueous ammonium chloride solution for a period of 24 hours at 80±2% relative humidity (RH). The water content of crystalline form-M produced according to the present invention is increased by 0.02% in 24 hours, which confirms the non-hygroscopic nature of the compound. The said characteristic nature is always an advantageous property for formulations.

The crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride salt of the present invention can be utilized in the preparation of pharmaceutical compositions useful for the treatment of overactive bladder syndrome.

The PXRD analysis of the crystalline compound of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C/min.

The isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride compound of formula-la of the present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Column: Inert sustain C18, 250x4.6 mm, 5μm or equivalent; Flow rate: 1.2 mL/min; Wavelength: 220 nm; Column temperature: 45°C; Auto sampler temperature: 5°C; Injection volume: 20 uL; Run time: 55 min; Elution: gradient; Buffer: 3 mL of H3P04 (85%) and 1.0 gm of 1-octane sulfonic acid sodium salt anhydrous in 1000 mL of milli Q water and adjust its pH to 7.2 with dil.KOH and filtered the solution through 0.22μm Nylon membrane paper and sonicate to degas it; Mobile phase-A: Buffer: acetonitrile (60:40 v/v); Mobile phase-B: Acetonitrile: water (90:10, v/v); Diluent: Mobile phase-A. Isobutyric acid 2-((R)-3-diisopropylamino-1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la) Dichloromethane (500 ml) and water (100 ml) were added to isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester acetyl mandelate (100 gm) at 25-30°C and cooled the reaction mixture to 0-5°C. Basifying the reaction mixture using 10% sodium carbonate solution (70 gm of sodium carbonate in 700 ml of water). Both the organic and aqueous were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (600 ml) was added to the obtained compound and cooled the reaction mixture to 0-5°C. Dry HC1 gas was passed into the reaction mixture until the pH of the reaction mixture reached to 2.0. Stirred the reaction mixture for 2 hrs at 0-5°C. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 68.0 gm; Purity by HPLC: 99.46%; Water content: 0.07% w/w.

Example-2: Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la) Ethyl acetate (1000 ml) was added to isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester (100 gm) at 25-30°C and cooled the reaction mixture to 0-5°C. Dry HC1 gas was passed into the reaction mixture until the pH of the reaction mixture reached to 2.0. Stirred the reaction mixture for 2 hrs at 0-5°C. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 92.0 gm. Purity by HPLC: 99.48%; Water content: 0.09% w/w.

Example-3: Purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la) To 50 gm of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride obtained in example-1 or example-2 added 250 ml of acetone at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the pure title compound; The PXRD of the obtained compound is shown in figure-1. Yield: 42.0 gm. Purity by HPLC: 99.88%; M.R: 139-143°C; Water content: 0.09% w/w.

We Claim:
1. Anhydrous crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.

2. Crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, characterized by;

a) Its powder X-Ray diffraction pattern having characteristic peaks at 9.3, 10.6, 11.7, 16.7, 16.9, 17.5, 18.7, 19.9, 23.2, 24.6, 24.9, 25.6, 25.8, 28.0, 28.7, 30.4, 32.1 ± 0.2 degrees of 2-theta, and the powder X-Ray diffraction pattern substantially as illustrated in figure-1,

b) its differential scanning calorimetric (DSC) thermogram having an endotherm at 147.03°C substantially in accordance with figure-2.

3. Crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride according to claim 1 & 2, which is non-hygroscopic in nature.

4. A process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of;

a) Adding a suitable solvent or mixture of solvents to isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester acetyl mandelate,

b) cooling the reaction mixture,

c) treating the reaction mixture with a suitable base,

d) separating the organic and aqueous layers,

e) distilling off the solvent completely from the organic layer,

f) adding a suitable solvent to the obtained compound,

g) cooling the reaction mixture,

h) adding suitable HC1 source to the reaction mixture,
i) stirring the reaction mixture,
j) filtering the precipitated solid and washing with a suitable solvent to get crystalline
form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-
(hydroxymethyl)phenyl ester hydrochloride.

5. The process according to claim 4, wherein in step-a) the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents or mixtures thereof;

in step-c) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates; in step-f) and step-j) the suitable solvent is selected from ester solvents, ketone solvents, ether solvents, alcoholic solvents, nitrile solvents or mixtures thereof; in step-h) the suitable HC1 source is selected from dry HC1 gas, ethyl acetate-HCl, ethanolic HC1, IPA-HC1, ethereal HC1, acetyl chloride and tri(C1-C6 alkyl)silyl chloride and the like, wherein acetyl chloride and tri(C1-C6 alkyl)silyl chloride are used in combination with alcohol.

6. A process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of;

a) Adding dichloromethane and water to isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester acetyl mandelate,

b) cooling the reaction mixture to 0-5°C,

c) treating the reaction mixture with aqueous sodium carbonate solution,

d) separating the organic and aqueous layers,

e) distilling off dichloromethane completely from the organic layer,

f) adding ethyl acetate to the obtained compound,

g) cooling the reaction mixture to 0-5°C,

h) passing dry HC1 gas into the reaction mixture,

i) stirring the reaction mixture,

j) filtering the precipitated solid, and washing with ethyl acetate to get crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride salt.