Claims:1. A process for the preparation of methylprednisolone hemisuccinate comprising reaction of methylprednisolone with succinic anhydride in the presence of base and N-methyl pyrolidone solvent.
2. The process according to claim 1, wherein the base is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium carbonate decahydrate, methylamine, triethylamine, N,N dimethylethylamine, N,N-dimethylamine, 4-dimethyl aminopyridine, aniline, morpholine, N-methyl morpholine, di-isopropyl ethyl amine and pyridine.

3. An improved method for the crystallization of methylprednisolone hemisuccinate, which comprises:
i) dissolving methylprednisolone hemisuccinate in a first solvent;
ii) optionally filtering the obtained solution;
iii) adding antisolvent, to the reaction mixture of Step (ii);
iv) isolating crystalline methylprednisolone hemisuccinate.

4. The process according to claim 3, wherein the first solvent is tetrahydrofuran.

5. The process according to claim 3, wherein the antisolvent is cyclohexane.

6. A process for the preparation of methylprednisolone sodium succinate comprising reaction of methylprednisolone hemisuccinate with sodium source in the presence of tetrahydrofuran/water as a solvent.
7. The process according to claim 6, wherein the sodium source is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide and sodium carbonate decahydrate.

8. An improved process for purification of methylprednisolone sodium succinate, which comprises:
i) adding first anti-solvent to a solution of methylprednisolone sodium succinate;
ii) adding second antisolvent to the reaction mixture of step (i);
iii) isolating of pure methylprednisolone sodium succinate;
iv) washing of pure methylprednisolone sodium succinate with first anti-solvent; and
v) drying of pure methylprednisolone sodium succinate.

9. The process according to claim 8, wherein the first anti-solvent used in step (i) and (iv) is acetone.
10. The process according to claim 8, wherein the second anti-solvent used in step (ii) is 2 methyl tetrahydrofuran.
11. A novel crystalline form of methylprednisolone hemisuccinate, having a XRPD pattern comprising characteristic peaks in terms of 2? at 6.11, 10.61, 12.24, 15.03, 17.63, 18.42, 19.70 and 24.62 ± 0.2 degrees.
, Description:Field of the Invention:
The present invention relates to an improved process for the preparation of methylprednisolone sodium succinate in pure form.
Background of the Invention:
Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is approved by US FDA in 1958.
Methylprednisolone sodium succinate, USP, is the sodium succinate ester of methylprednisolone, approved in Jul 24, 1984 and it occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. The chemical name for methylprednisolone sodium succinate is pregna-1,4-diene-3,20-dione, 21-(3-carboxy-1-oxopropoxy)-11, 17-dihydroxy-6-methyl-monosodium salt, (6a, 11ß). Methylprednisolone Sodium Succinate – Injection is used to treat conditions such as arthritis, blood disorders, severe allergic reactions, certain cancers, eye conditions, skin/kidney/intestinal/lung diseases, and immune system disorders. It decreases immune system's response to various diseases to reduce symptoms such as swelling, pain, and allergic-type reactions.
US 2897218 discloses preparation of methylprednisolone sodium succinate by using sodium hydroxide followed by lyophilization. The lyophilization process has disadvantages like high capital cost of equipment, high energy cost, long process time and production efficiency is low.
PL161016 discloses preparation of methylprednisolone sodium succinate by using sodium-2-ethylhexanoate followed by crystallization. The product obtained by this process is hygroscopic, required costly reagents and production efficiency is low.
Hence there is need of effective purification process which would be industrially feasible and cost effective.
The manufacture of pharmaceutical products is a highly regulated area with many guidelines and rules concerning quality/purity of active pharmaceutical ingredients (API). It is therefore a requirement that manufacturing routes ensure a high purity of final products, one approach towards this aim is to develop specific purification steps by using crystallization as one of the tool.
Summary of the Invention:
In one aspect, present invention provides process for the preparation of methylprednisolone hemisuccinate by using N-methyl pyrolidone as a solvent.
In another aspect, the present invention provides an improved method for crystallization of methylprednisolone hemisuccinate.
In another aspect, the present invention provides novel crystalline form of methylprednisolone hemisuccinate.
In another aspect, present invention provides process for the preparation of methylprednisolone sodium succinate by using tetrahydrofuran/water as a solvent.
In another aspect, the present invention provides an improved method for crystallization of methylprednisolone sodium succinate.

Description of drawings:
Figure 1: illustrates X-ray powder diffraction pattern of crystalline methylprednisolone hemisuccinate.

Detail Description of the Invention:
Pure form of methylprednisolone sodium succinate comprises controlling the limit of any unspecified impurities below 0.05%.
In one aspect, present invention provides process for the preparation of methylprednisolone hemisuccinate, which comprises:
i) reacting methylprednisolone,

with succinic anhydride in the presence of base and N-methyl pyrolidone as a solvent to give methylprednisolone hemisuccinate.

The reaction of step (i) is carried out at -10 to 30°C.
Base used for the reaction is selected from sodium carbonate, sodium bicarbonate, sodium carbonate decahydrate, methylamine, triethylamine, N,N dimethylethylamine, N,N-dimethylamine, 4-dimethyl aminopyridine, aniline, morpholine, N-methyl morpholine, di-isopropyl ethyl amine and pyridine, preferably base used is 4-dimethyl aminopyridine.
In another aspect, the present invention provides an improved method for the crystallization of methylprednisolone hemisuccinate, which comprises:
i) dissolving methylprednisolone hemisuccinate in a solvent;
ii) optionally filtering the obtained solution;
iii) adding antisolvent, to the reaction mixture of step (ii); and
iv) isolating crystalline methylprednisolone hemisuccinate.
Solvent used in step (i) is selected from the group which includes but not limited to 1, 4- dioxane, pyridine, tetrahydrofuran, tert. Butanol, dimethyl sulfoxide, isopropyl alcohol, xylene, diethyl ether, tert. butyl ether, methyl isobutyl ketone, N, N dimethylformamide, dichloromethane, toluene, acetonitrile, acetone or mixtures thereof. More preferably, the solvent used is tetrahydrofuran.
Antisolvent used in step (iii) is selected from the group which includes but not limited to chloroform, carbon tetrachloride, methylene chloride, ethylene dichloride, tetrahydrofuran, isopropyl alcohol, cyclohexane, acetone, methyl ethyl ketone, diethyl ketone, tert. butyl methyl ether, diethyl ether, tert. butyl ether, methyl isobutyl ketone, toluene, xylene, hexane, pantane and heptane or mixtures thereof. More preferably, the solvent used is cyclohexane.
The isolation of crystalline methylprednisolone hemisuccinate of step (iv) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.
In another aspect, the present invention provides novel polymorph of crystalline methylprednisolone hemisuccinate, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 6.11, 10.61, 12.24, 15.03, 17.63, 18.42, 19.70 and 24.62 ± 0.2 degrees. The XRPD of crystalline methylprednisolone hemisuccinate is depicted in figure I.
In yet another aspect, the present invention provides method for the preparation of methylprednisolone sodium succinate which comprises:
i) reacting methylprednisolone hemisuccinate with sodium source in the presence of tetrahydrofuran/water solvent mixture to give methylprednisolone sodium succinate.

The reaction is carried out at 10 to 50°C.
Sodium source used for the reaction is selected from sodium carbonate, sodium bicarbonate, Sodium hydroxide and sodium carbonate decahydrate. More preferably, sodium source used is sodium carbonate.
In another aspect, the present invention provides an improved method for crystallization of methylprednisolone sodium succinate, which comprises;
i) addition of first anti-solvent to a solution of methylprednisolone sodium succinate;
ii) addition of second antisolvent to the reaction mixture of step (i);
iii) isolation of pure methylprednisolone sodium succinate;
iv) washing of pure methylprednisolone sodium succinate by first anti-solvent; and
v) drying of pure methylprednisolone sodium succinate.
Solution of step (i) can be mother liquor of methylprednisolone sodium succinate obtained from previous reaction step.
First anti-solvent used in step (i) and (iv) is selected from but not limited to chloroform, carbon tetrachloride, methylene chloride, ethylene dichloride, isopropyl alcohol, cyclohexane, acetone, methyl ethyl ketone, diethyl ketone, tert. butyl methyl ether, diethyl ether, tert. butyl ether, methyl isobutyl ketone, hexane, pantane and diethyl ketone. More preferably, solvent used is acetone.
Second anti-solvent used in step (ii) is selected from 2-methyl tetrahydrofuran, tert. butyl methyl ether, diethyl ether, tert. butyl ether, acetone, methyl isobutyl ketone, cyclohexane, hexane, cyclopentyl methyl ether, tert. butyl acetate, ethyl acetate and heptane. More preferably, solvent used is 2-methyl tetrahydrofuran.
The isolation of methylprednisolone sodium succinate of step (iii) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.
Examples:
Preparation of methylprednisolone hemisuccinate
Methylprednisolone (100 gm, 0.267 mmol) and succinic anhydride (80.1 gm, 0.801 mmol was added to the N methyl pyrrolidone (300 ml). Then reaction mixture was allowed to cool at -50C and added 4-dimethyl amino pyridine (12.9 gm, 0.12 mmol) dissolved in acetone (200 ml). Reaction mixture was stirred at same temperature for 7-8 hrs. After completion of reaction on TLC plate, water was added to the reaction mass and stirred for 10 min. The solid formed was filtered to get crude product which was further crystallized by using cyclohexane/THF to get the desired product (110 gms) as white solid.
Example 2.
Preparation of methylprednisolone sodium succinate
Product obtained in step I (100 gm, 0.21 mmol) was added to RBF containing tetrahydrofuran (500 ml) and water (50 ml). Reaction mature was stired at room temperature for 5 min. and then added sodium carbonate (11.8 gm, 0.11 mmol). Reaction mixture was allowed to stir for 20-30 hrs. at room temperature. After completion of reaction reaction mass was filtered to remove the inorganic material. Acetone was added to the filtrate obtained and stirred at room temperature. Methylprednisolone sodium succinate seeds were added to get the slurry. 2-Methyl tetrahydrofuran (2 lit) was added to the slurry and filtered to get the solid cake which was washed with acetone to remove traces of 2-Methyl tetrahydrofuran and dried to get the pure product (90 gm) as white solid.