FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
TITLE OF THE INVENTION:
MITIGLINIDE CALCIUM HAVING A SPECIFIC PARTICLE SIZE AND A
PROCESS FOR PREPARATION THEREOF
APPLICANT(S):
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.

FIELD OF THE INVENTION
The present invention relates to particulate mitiglinide calcium wherein at least 90% of the particles, by volume, having particle size in the range of about 50 microns to about 300 microns and a process for the preparation thereof. The present invention also relates to a process for the preparation of crystalline mitiglinide calcium. The present invention further relates to a pharmaceutical composition comprising the mitiglinide calcium wherein at least 90% of the particles, by volume, having particle size of about 50 microns to about 300 microns and one or more pharmaceutically acceptable excipients.
BACKGROUND OF THE INVENTION
Mitiglinide is chemically known as (2S)-2-benzyl-3-(cis-hexahydro-2-iso-indolinyl carbonyl)propionic acid has the following formula (I).

Formula (I)
Mitiglinide is the third agent in the class of meglitinides that targets postprandial hyperglycemia. Meglitinides bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic beta cells in a similar manner to sulfonylureas but at a separate binding site. Mitiglinide is known as insulin secretagogues, which have been

widely used alone or in combination with other oral hypoglycemic drugs to improve postprandial hyperglycemia in early type II diabetes.
Mitiglinide calcium is marketed as Glufast® in the form of (2S)-2-benzyl-3-(cis-hexahydro-2-iso-indolinylcarbonyl)propionic acid calcium dihydrate (mitiglinide calcium dihydrate).
Mitiglinide and its salt were first disclosed in EP 507534 Al. This patent discloses preparation of mitiglinide by the reaction of (5)-3-benzyloxycarbonyl-4-phenylbutyric acid with cis-hexahydroisoindoline in presence of N-methylmorpholine and isobutyl chloroformate followed by debenzylation with palladium on carbon in ethyl acetate to yield mitiglinide as viscous oil. Mitiglinide is converted into its hemi calcium salt by dissolving mitiglinide in water by addition of 25% of ammonia solution followed by addition of calcium chloride in water and the obtained solid is further recrystallized with diisopropyl ether.
EP 0994854 A1 discloses a process for the preparation of mitiglinide by reacting dimethyl succinate with benzaldehyde in methanolic medium, to yield a diacid which is converted to corresponding anhydride and is further reacted with the perhydroisoindole to yield 2-[(cis- perhydroisondol-2-yl)carbonylmethyl]-3-phenylacrylic acid which is then subjected to catalytic hydrogenation using ruthenium (Rh) complex as asymmetric hydrogenation catalyst, followed by conversion to pharmaceutically acceptable salt of mitiglinide.
EP 0967204 Al discloses the preparation of mitiglinide by deprotecting benzyl-(S)-2-benzyl-3-(cis-hexahydro-2-isoindolinyl-carbonyl) propionate and converting the same to calcium dihydrate salt in crystalline form using calcium chloride, water and ethanol. The crystals of calcium salt are further recrystallized using ethanol and water.

WO 2009047797 discloses the use of novel amide intermediate for the preparation of mitiglinide and its pharmaceutically acceptable salts. The said publication also discloses the crystalline and amorphous form of mitiglinide and its pharmaceutically acceptable salt and process for the preparation thereof
Mitiglinide calcium is a white to off-white crystalline powder. The solubility of the drug substance mitiglinide calcium is very low. Poor solubility poses a significant problem in formulating the drug into suitable dosage form with desired dissolution and bioavailability. Because of this problem, it is very difficult to get desired dissolution of the compound.
To overcome the said problems many attempts have been made like US 7166301 suggests the formulation of mitiglinide and its salt with disintegrating agents like silicon dioxide and partly pregelatinized starch along with diluents to get desired dissolution profile.
WO 2003061650 discloses orodispersible formulation of mitiglinide which contains co-spray dried lactose and starch to form granules.
The solid state physical properties of an active pharmaceutical ingredient (API), such as mitiglinide calcium, can be very important in formulating a drug substance and can have profound effects on the dissolution as well as ease and reproducibility of formulation. Particle size, for example, may affect the dissolution of a drug substance. Therefore, it is highly essential to achieve an optimum particle size of the API to get desired dissolution profile.
Thus, there is a need in the art to prepare particulate of mitiglinide calcium having an optimum particle size, which has good flow properties and can give predictable dissolution profile. Generally it is not possible to predict the exact particle size distribution required for any particular drug substance to achieve a specific

dissolution profile or a specific in vivo behavior, as different drugs show differing dissolution characteristics with a different particle size. The inventors of the present invention have surprisingly found that mitiglinide calcium having specific range of particle size provides good flow properties, better solubility and predictable dissolution profile.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 300 microns.
In another embodiment, the present invention provides particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 200 microns.
In yet another embodiment, the present invention provides particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 150 microns.
In yet another embodiment, the present invention provides particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 70 to about 120 microns;
In yet another embodiment, the present invention provides a process for the preparation of particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 300 microns comprising the steps of:
(a) combining mitiglinide calcium with a solvent selected from the group consisting of aromatic hydrocarbons, aliphatic ethers, C5-C8 aliphatic alkanes, (C3-C8)ketones, esters, halogenated hydrocarbons and mixtures thereof, to obtain a slurry;

(b) heating the slurry of step (a) to a temperature of about to reflux to obtain a clear solution;
(c) recovering particulate mitiglinide calcium wherein at least 90 % of the particles, by volume, have particle size of about 50 to about 300 microns; and
(d) optionally further controlling the particle size of mitiglinide calcium obtained in step (c) by mechanical process.
In yet another embodiment, the present invention provides a process for the preparation of crystalline mitiglinide calcium comprising the steps of:
(a) combining mitiglinide calcium with a solvent selected from the group consisting of aromatic hydrocarbons, aliphatic ethers, C5-C8 aliphatic alkanes, (C3-C8)ketones, esters, halogenated hydrocarbons and mixtures thereof, to obtain a slurry;
(b) heating the slurry of step (a) to a temperature of about to reflux to obtain a clear solution; and
(c) recovering crystalline mitiglinide calcium.
In yet another embodiment, the present invention provides pharmaceutical compositions including mitiglinide calcium prepared according to the present invention in any of its embodiments and one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWING
Figure-1 shows a powdered X-ray diffraction pattern of crystalline form of Mitiglinide calcium.

DETAILED DESCRIPTION OF THE INVENTION
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.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The invention provides a process for preparing particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 300 microns. It is surprisingly found that this particle size as obtained by process of the present invention allows the dissolution rate of the mitiglinide calcium to be controlled. Mitiglinide calcium obtained by the present invention is thus well suited for formulations which can be used for the treatment of diabetes. Further, it has been observed that the pharmaceutical composition prepared by using mitiglinide calcium having particle size out of the optimum range didn't provide composition having desired dissolution profile.
"Mitiglinide calcium" refers to "(2S)-2-benzyl-3-(cis-hexahydro-2-iso-indolinylcarbonyl)propionic acid calcium" is intended to include its hydrates, solvates, polymorphs or a mixture thereof.
"Particulate mitiglinide calcium" refers to mitiglinide calcium in powder or granular form comprised of a plurality of discrete particles, or individual units of mass.

"Crystalline mitiglinide calcium" refers to any crystalline mitiglinide calcium known in prior art or crystalline form of mitiglinide calcium having XRPD as shown in figure (1).
The individual particles of a sample or aliquot of the solid particulate mitiglinide calcium of the present invention are not of uniform size. Rather, a sample or aliquot of solid particulate mitiglinide calcium of the present invention is comprised of particles of different sizes that can be size-classified or distributed in an array of discrete, adjacent intervals of particle size. If the size of the intervals is small enough, the array of particle sized approaches a continuum of particle sizes. This collection of discrete particle size intervals together with their population is referred to as the particle size distribution (PSD).
Measurement and characterization of particle size distributions is known in the art. It is possible to compare samples of particulate mitiglinide calcium on the basis of individual points on a cumulative particle size distribution curve.
The term "D90 value" means at least 90% of the particles have volume diameter in the specified range when measured by a suitable method for example Malvern Mastersizer,
The skilled artisan knows that the results of PSD determination by one technique can be correlated with that from another technique on an empirical basis by routine experimentation.
In general, the present invention provides a process for the preparation of particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 300 microns including the steps of:

(a) combining mitiglinide calcium with a solvent selected from the group consisting of aromatic hydrocarbons, aliphatic ethers, C5-C8 aliphatic alkanes, (C3-C8)ketones, esters, halogenated hydrocarbons and mixtures thereof, to obtain a slurry;
(b) heating the slurry of step (a) to a temperature of about to reflux to obtain a clear solution;
(c) recovering particulate mitiglinide calcium wherein at least 90 % of the particles, by volume, have particle size of about 50 to about 300 microns; and
(d) optionally further controlling the particle size of mitiglinide calcium obtained in step (c) by mechanical process.
In step (a), mitiglinide calcium is combined with a solvent selected from the group consisting of aromatic hydrocarbons like benzene, toluene and xylenes; aliphatic ethers like diethyl ether, diisopropyl ether and methyl tertiary butyl ether; C5-C8 aliphatic alkanes like pentane, hexane, heptane, octane including cyclic aliphatic alkanes like cyclopentane, cyclohexane, cycloheptane and cyclooctane; (C3-C8)ketones like acetone, ethyl methyl ketone and diethyl ketone; esters like ethyl acetate, ethyl acetoacetate and ethyl butyrate; halogenated hydrocarbons like methylene chloride, dichlorobenzene and chlorobenzene and mixtures thereof to form a reaction mixture.
Preferred solvents in step (a) include aromatic hydrocarbon, aliphatic alkanes and halogenated hydrocarbon and more preferred solvent includes toluene, benzene, xylene and methylene chloride; most preferable solvent is toluene.
Preferably, the slurry of step (a) is prepared by combining about 2 % to about 25% of mitiglinide calcium in above mentioned solvent by volume.

In step (b) of the process of the present invention, the obtained reaction mixture is heated at reflux temperature to obtain clear solution and maintained the temperature of reaction mixture for a time period ranging from about 15 minutes to about 45 minutes.
In step (c) of the process of the present invention, particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 300 microns can be recovered form the solution by any method known in the art, such as cooling, filtering, washing, preferably washing with the solvent used and drying. For example, the suspension can be cooled to room temperature and stirred the reaction mixture till the precipitate comes out. Generally, the isolation of compound of formula (I) is completed within 2-5 hour. Drying is carried out at a temperature of from about 40°C to about 60°C in hot air oven or under vacuum.
It has been observed that heating the slurry obtained in step (a) to a temperature of about reflux leads to dissolution of mitiglinide calcium having a small particle size and subsequent cooling of the suspension induces crystallization of the new larger particle size mitiglinide calcium on the existing mitiglinide calcium precipitate.
Particulate of mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size about 50 microns to about 300 microns can be further controlled by mechanical process like milling or sieving to obtain mitiglinide calcium having optimum particle size. Thus, the mechanical process provides control over the obtained particle size of mitiglinide calcium. For example, milling can be performed by a cone mill, which operates by breaking particles with an impeller that revolves within a conical perforated screen. The material to be milled is fed to the mill by either manual feeding, a mechanical feeder or by pneumatic conveying. The milled particles exit the mill through the perforated holes and are either collected in a closed container attached to the mill discharge or conveyed by vacuum to a collector. The

particle size of the product can be controlled by either changing the rotating speed of the impeller, selection of screens with different hole sizes, or using different types of impellers.
The optimum particle size, as obtained in step (c) or (d) is D90 about 50 to 200 microns. Preferably, the optimum particle size, as obtained in step (b) is D90 about 50 to 150 microns. Most preferably, the optimum particle size is D90 about 70 to 120 microns.
The present invention also provides a process for the preparation of crystalline mitiglinide calcium including the steps of:
(a) combining mitiglinide calcium with a solvent selected from the group consisting of aromatic hydrocarbons, aliphatic ethers, C5-C8 aliphatic alkanes, (C3-C8)ketones, esters, halogenated hydrocarbons and mixtures thereof, to obtain a slurry;
(b) heating the slurry of step (a) to a temperature of about to reflux to obtain a clear solution; and
(c) recovering crystalline mitiglinide calcium.
In step (a), mitiglinide calcium is combined with a solvent selected from the group consisting of aromatic hydrocarbons like benzene, toluene and xylenes; aliphatic ethers like diethyl ether, diisopropyl ether and methyl tertiary butyl ether; C5-C8 aliphatic alkanes like pentane, hexane, heptane, octane including cyclic aliphatic alkanes like cyclopentane, cyclohexane, cycloheptane and cyclooctane; (C3-C8)ketones like acetone, ethyl methyl ketone and diethyl ketone; esters like ethyl acetate, ethyl acetoacetate and ethyl butyrate; halogenated hydrocarbons like methylene chloride, dichlorobenzene and chlorobenzene and mixtures thereof to form a reaction mixture.

Preferred solvents in step (a) include aromatic hydrocarbon, aliphatic alkanes and halogenated hydrocarbon and more preferred solvent includes toluene, benzene, xylene and methylene chloride; most preferable solvent is toluene.
Preferably, the slurry of step (a) is prepared by combining about 2 % to about 25% of mitiglinide calcium in above mentioned solvent by volume.
In step (b) of the process of the present invention, the reaction mixture obtained in step (a) is heated at reflux temperature to obtain clear solution and maintained the temperature of reaction mixture for a time period ranging from about 15 minutes to about 45 minutes.
In step (c) of the process of the present invention, crystalline mitiglinide calcium can be recovered form the solution by any method known in the art, such as cooling, filtering, washing, preferably washing with the solvent used and drying. For example, the suspension can be cooled to a temperature room temperature and with stirred the reaction mixture till the precipitate comes out. Generally, the isolation of compound of formula (I) is completed within 2-5 hour. Drying is carried out at a temperature of from about 40°C to about 60°C in hot air oven or under vacuum.
The pharmaceutical composition according to present invention comprises the mitiglinide calcium prepared according to the present invention and one or more pharmaceutically acceptable excipients. The said pharmaceutical composition can be in solid or liquid form suitable for oral, parenteral or intravenous administration. Preferably said pharmaceutical composition is in solid form suitable for oral delivery. Said composition can be formulated as tablet, capsule, granules or powders.
Suitable pharmaceutical excipients comprise one or more of diluents, binders, disintegrants, lubricants, glidants, solubilizers, alkalinizers, surfactant and the like.

Suitable diluents may include one or more cellulose or cellulose derivatives such as macrocrystalline cellulose and the like, sugar or sugar alcohols such as lactose, mannitol, sorbitol and the like, pregelatinized starch or inorganic diluents such as calcium carbonate and the like.
Suitable binders include one or more hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose or mixtures thereof, acrylates, methacrylates, povidone, starch, stearic acid, gums, and other materials known to have cohesive and desirable binding properties.
Lubricants may include, those well known to a person skilled in the art, for example, stearic acid, calcium stearate, magnesium stearate, talc, hydrogenated vegetable oils, hydrogenated castor oil, sodium stearyl fumarate and sodium benzoate, palmitic acid, carnauba wax, glyceryl monostearate, and the like.
Disintegrants may include, those well known to a person skilled in the art, as exemplified starch, pregelatinized starch, L-HPC, sodium carboxymethyl starch, crospovidone, sodium starch glycolate, polacrilin potassium and the like.
Suitable glidants may include colloidal anhydrous silica, talc, cornstarch, dried aluminium hydroxide gel, magnesium silicate and the like.
Suitable alkalinizers may include meglumine, Glycine, N-methyl glucamine, L-lysine and the like.
Suitable solubilizers may include poloxamer 188 and the like and suitable surfactant includes sodium lauryl sulfate and the like.
The invention is described in the following examples by way of illustration only and should not be construed to limit the scope of the invention.

Example-1:
Mitiglinide calcium (10gm) and toluene (120 ml) was charged in to 250ml 3-necked RB flask and stirred for 5 minute. Temperature was raised to reflux (106 to 110 °C) and maintained till solution becomes clear. Reaction mixture was then cooled to room temperature and stirred for 2 hours. After filtering the obtained mixture, it was washed twice with 5ml of toluene. The obtained wet mass was dried under vacuum at 43 to 47 °C to get mitiglinide calcium (8.4 gm) with particle size of D90 = about 300 microns.
Example-2:
Mitiglinide calcium obtained in Example-l having particle size of D90 = about 300 microns was air jet milled. The resulting mitiglinide calcium has particle size of D90 - about 100 microns.
Example-3:
Mitiglinide calcium prepared according to Example 2 is used for the preparation of tablet.
No. Ingredients Quantity (mg/tablet)
1 Mitiglinide Calcium 10.00
2 Microcrystalline cellulose (Avicel PH 102) 30.99
3 Lactose 85.36
4 Crospovidone XL 10 8.40
5 Hydroxypropyl methyl cellulose (HPMC) 2.80
6 Calcium stearate 1.05
7 Aerosil 1.40
Procedure:

Mitiglinide Calcium 10 mg, 30.99 mg microcrystalline cellulose (Avicel PH 102) and lactose (85.36 mg) was sieved through mesh # 40, and sifted materials were blended together with crospovidone XL 10 (4.20 mg) and HPMC 3cps by dry mixing in rapid mixer granulator. Obtained mass was subjected to granulation after addition of purified water, followed by drying under fluidized bed dryer and sizing. Obtained granules were lubricated with crospovidone XL 10 (4.20 mg) and aerosil (1.40 mg), previously sieved through mesh #40 and lubricated with calcium stearate (1.05 mg) which was sieved through mesh #60. Total mass was subjected to Rotary Compression Machine to give compressed tablet of mitiglinide Calcium.

We claim
1. Particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 300 microns.
2. Particulate mitiglinide calcium according to claim 1, wherein at least 90% of the particles, by volume, have particle size of about 50 to about 150 microns.
3. Particulate mitiglinide calcium according to claim 1, wherein at least 90% of the particles, by volume, have particle size of about 70 to about 120 microns.
4. A process for the preparation of particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have particle size of about 50 to about 300 microns comprising the steps of:

(a) combining mitiglinide calcium with a solvent selected from the group consisting of aromatic hydrocarbons, aliphatic ethers, C5-C8 aliphatic alkanes, (C3-C8)ketones, esters, halogenated hydrocarbons and mixtures thereof, to obtain a slurry;
(b) heating the slurry of step (a) to a temperature of about to reflux to obtain a clear solution;
(c) recovering particulate mitiglinide calcium wherein at least 90 % of the particles, by volume, have particle size of about 50 to about 300 microns; and
(d) optionally further controlling the particle size of mitiglinide calcium obtained in step (c) by mechanical process.
5. A process for the preparation of particulate mitiglinide calcium according to
claim 4, wherein solvent is selected from benzene, toluene, xylene, diethyl
ether, diisopropyl ether, methyl tertiary butyl ether, pentane, hexane, heptane,

octane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, acetone, ethyl methyl ketone, diethyl ketone, ethyl acetate, ethyl acetoacetate, ethyl butyrate, methylene chloride, dichlorobenzene and chlorobenzene.
6. A process for the preparation of particulate mitiglinide calcium according to claim 4, wherein solvent is toluene.
7. A process for the preparation of crystalline mitiglinide calcium comprising the steps of:

(a) combining mitiglinide calcium with a solvent selected from the group consisting of aromatic hydrocarbons, aliphatic ethers, C5-C8 aliphatic alkanes, (C3-C8)ketones, esters, halogenated hydrocarbons and mixtures thereof, to obtain a slurry;
(b) heating the slurry of step (a) to a temperature of about to reflux to obtain a clear solution; and
(c) recovering crystalline mitiglinide calcium.

8. A process for the preparation of crystalline mitiglinide calcium according to claim 7, wherein solvent is toluene.
9. A pharmaceutical composition comprising of particulate mitiglinide calcium wherein at least 90% of the particles, by volume, have a particle size of about 50 to about 300 microns and at least one pharmaceutically acceptable excepient.