The present invention relates to a novel polymorphic form of cefdinir and a process for preparation thereof. In addition the present invention also relates to pharmaceutical composition and method of treating bacterial infections using novel polymorphic form of cefdinir.
[(-)6R,7R]-7-((Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido)-3-vinyl-8-oxo -5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid commonly termed as cefdinir of Formula I is third generation semi-synthetic cephalosporin for oral use, characterized by broad antibacterial spectrum against gram-positive and gram-negative bacteria. In particular cefdinir shows excellent antibacterial activity against Streptococci and Staphylococci.
(Formula Removed)
US Patent No. 4,559,334 provides a process for preparation of cefdinir in amorphous form by lyophilization. The amorphous form produced in turn is highly hygroscopic and therefore very difficult to formulate.
US Patent No. 4,935,507 provides a crystalline Form A of cefdinir and process for preparation thereof. Form A of cefdinir is reported to be having specific X-Ray diffraction (XRD) pattern as depicted in Figure 1.
US Application No. 20030204082 provides crystalline form of cefdinir (hereinafter designated as Form R) having a specific XRD pattern as depicted in Figure 2.
PCT Application No. WO 04/46154 describes amorphous monohydrate of cefdinir and a process for preparation thereof.
US Patent No. 6,350,869 (PCT Application No. WO 98/45299) describes a process for preparation of crystalline dicyclohexylamine (DCHA) salt of cefdinir and monohydrate form of cefdinir. However, characterization data of the crystalline salt or monohydrate form of cefdinir is not provided in the '869 Patent.
Several PCT Applications detail crystalline salts of cefdinir which are either useful as intermediates in preparation of cefdinir or can be used as broad spectrum antimicrobials. WO 02/98884 (crystalline sulphate, tosylate and mesylate salt of cefdinir); WO 04/16623 (crystalline salts of acetyloximino ester of cefdinir) and WO 04/56835 (crystalline phosphate salts).
PCT Application No. WO 03/50124 describes crystalline cefdinir potassium monohydrate and process for preparation thereof. The application further details utilization of the potassium salt of cefdinir in monohydrate form as potential antimicrobial agent.
Indian Patent Application No. 1508/Del/2004 describes a crystalline Form B of cefdinir having a specific XRD (as depicted in Figure 3), DSC and FTIR spectrum.
The present inventors have now surprisingly found a new polymorphic form of cefdinir which is characteristically different from the existing crystalline forms of cefdinir.
A first aspect of the present invention provides new crystalline form of cefdinir (hereinafter referred to as Form C).
A second aspect of the present invention provides polymorphic Form C of cefdinir having characteristic XRD pattern as depicted in Figure 4 of the accompanied drawing.
A third aspect of the present invention provides polymorphic Form C of cefdinir having characteristic absorption bands at 2 values of 9.12 ± 0.2, 10.72 ±0.2, 15.04 ± 0.2, 17.96
± 6.2, 18.66 ± 0.2, 20.92 ± 0.2, 21.44 ± 0.2, 22.32 ± 0.2, 23.66 ± 0.2, 24.18 ± 0.2, 25.72 ± 0.2, 26.26 ± 0.2, 27.48 ± 0.2, 28.30 ± 0.2, 30.42 ± 0.2, 32.06 ± 0.2, 35.76 ± 0.2, 38.80 ± 0.2 and 39.22 ± 0.2.
A fourth aspect of the present invention provides polymorphic form of cefdinir having bound moisture content of about 10 to 14% w/w as measured by Thermal Gravimetric Analysis (TGA) and Karl Fischer analysis.
A fifth aspect provides polymorphic Form C of cefdinir having differential scanning calorimetric (DSC) thermogram as depicted in Figure 5 of the accompanied drawings. The characteristic exothermic peaks are obtained at 85 to 90°C and 126-131°C.
A sixth aspect of the present invention relates to a process for preparation of polymorphic Form C of cefdinir wherein the said process comprises of
a) dissolving cefdinir or salt thereof in water at pH of about 5.5 to 8,
b) optionally adding an organic solvent in the solution of step a),
c) adjusting the pH of solution obtained in step a) or b) between 1.0 and 3.5 with an acid,
d) isolating polymorphic Form C of cefdinir from the reaction mixture obtained thereof.
Cefdinir or salt thereof to be used as starting material can be prepared by conventional methods reported in the literature such as US Patent Nos. US 4,559,33; US 4,935,507; US 4,870,168; US 6,350,869 and US 6,093,814; PCT Patent Application Nos. WO 98/45299; WO 99/55710; WO 02/98884; WO 03/91261; WO 04/16623; WO 04/35800; WO 04/56835; WO 04/58695 and WO 04/46154.
Cefdinir or salt thereof is first suspended in water and the resultant mixture is cooled to about - 20 to 25°C. Preferably the temperature is adjusted in the range of -10 to 20°C. To this mixture added a suitable base in order to adjust the pH of the reaction mass in the range of 5.5 to 8. The bases are common bases known to person of ordinary skills in the art and comprise of alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate, alkali or alkaline earth metal bicarbonate, alkali or alkaline earth metal alkoxide, alkali or alkaline earth metal hydride or ammonia or an amine. The amine can be primary,
secondary or tertiary amine having alkyl, aryl, aralkyl, cycalkyl or heterocycle as substituent groups.
A clear solution thus obtained can be decolorized using charcoal and further diluted with a suitable organic solvent selected from a group comprising of alkanols, esters, ketones, acetonitrile, chlorinated hydrocarbons, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane and dimethylsulphoxide or mixtures thereof.
The pH of the clear solution is then adjusted using an acid in the range of 1.0 to 3.5. The acid can be mineral acid or an organic acid such as carboxylic or sulphonic acid.
The resultant mass is stirred at 0 to 25°C for sufficient time to precipitate Form C of cefdinir. The separated solids are filtered, washed with water. The product obtained is dried at room temperature to yield crystalline Form C of cefdinir.
A seventh aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form C of cefdinir along with pharmaceutically acceptable carrier (s) / excipient (s). The pharmaceutical compositions comprise of oral dosage forms such as tablets, capsules, liquid orals, suspensions and the like. Topical dosage forms such as creams, lotions, ointments and the like.
An eighth aspect of the present invention provides a method of treating bacterial infections comprising administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form C of cefdinir.
Figure 1 depicts XRD of Form A of cefdinir.
Figure 2 depicts XRD of crystalline cefdinir obtained as per US Application No.
20030204082.
Figure 3 depicts XRD of crystalline Form B of cefdinir.
Figure 4 depicts XRD of polymorphic Form C of cefdinir.
Figure 5 depicts DSC thermogram of polymorphic Form C of cefdinir.
Powder XRD of the samples were determined by using X-Ray Diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
PREPARATION OF CRYSTALLINE FORM C OF CEFDINIR
A stirred suspension of cefdinir (5 gm) in water was dissolved by adjusting the pH of the mixture to about 5.5 to 8.0. The clear solution was decolorized using activated charcoal (0.5 gm) and the resultant mixture was filtered. To the clear filtrate added a mixture of tetrahydrofuran and dichloromethane (10 to 40 ml). The solution is stirred at 5 to 20°C followed by addition of dilute hydrochloric acid to adjust the pH at about 2.0 to 3.0 while maintaining the temperature of the reaction mass between 5 to 20°C. The resultant mass is stirred for sufficient time to precipitate solids and the precipitated solids were filtered and washed. The product is dried at 40°C to yield crystalline Form C of cefdinir.
Yield: 4.79 gm.
Moisture content: 12.0% w/w.
XRD: As per Figure 4.

WE CLAIM:
1. A process for preparation of crystalline Form C of cefdinir wherein the said process
comprises of
a) dissolving cefdinir or salt thereof in water at pH of about 5.5 to 8,
b) optionally adding an organic solvent in the solution of step a),
c) adjusting the pH of solution obtained in step a) or b) between 1.0 and 3.5 with an acid,
d) isolating crystalline Form C of cefdinir from the reaction mixture obtained thereof.

2. A process as claimed in claim 1, wherein step a), pH is adjusted using a base.
3. A process as claimed in claim 2 wherein the base comprises of alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate, alkali or alkaline earth metal bicarbonate, alkali or alkaline earth metal alkoxide, alkali or alkaline earth metal hydride or ammonia or an amine.
4. A process as claimed in claim 3 wherein amine is selected from group comprising of be primary, secondary or tertiary amine having alkyl, aryl, aralkyl, cycalkyl or heterocycle as substituent groups.
5. A process as claimed in claim 1, wherein organic solvent is added in step b)
6. A process as claimed in claim 6 wherein organic solvent comprises of alkanols, esters, ketones, acetonitrile, chlorinated hydrocarbons, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane and dimethylsulphoxide or mixtures thereof.
7. A process as claimed in claim 6 wherein organic solvent comprises of tetrahydrofuran and dichloromethane or mixtures thereof.
8. A process as claimed in claim 1 wherein pH adjustment in step c) is carried out using an acid.
9. A process as claimed in claim 8 wherein the acid is mineral acid or organic acid.
10. A process as claimed in claim 1 wherein isolation in step d) comprises of stirring the reaction mass for 3 to 30 hours followed by filtration of precipitated solids.
11.A process as claimed in claim 1 wherein the isolated product is dried at room temperature.
12. A process as claimed in claim 1 wherein crystalline Form C of cefdinir obtained as a product has characteristic XRD pattern as depicted in Figure 4.
13. A process as claimed in claim 1 wherein crystalline Form C of cefdinir obtained as a product has characteristic XRD pattern wherein 26 values comprise of 9.12 ± 0.2, 10.72 ± 0.2, 15.04 ± 0.2, 17.96 ± 0.2, 18.66 ± 0.2, 20.92 ± 0.2, 21.44 ± 0.2, 22.32 ± 0.2, 23.66 ± 0.2, 24.18 ± 0.2, 25.72 ± 0.2, 26.26 ± 0.2, 27.48 ± 0.2, 28.30 ± 0.2, 30.42 ± 0.2, 32.06 ± 0.2, 35.76 ± 0.2, 38.80 ± 0.2 and 39.22 ± 0.2.
14. A process as claimed in claim 1 wherein crystalline Form C of cefdinir obtained as a product has characteristic DSC thermogram as depicted in Figure 5.
15. A process as claimed in claim 1 wherein crystalline Form C of cefdinir obtained as a product has characteristic DSC exothermic peaks at about 85 - 90°C and about 126-131°C.
16. A process for preparation of crystalline Form C of cefdinir as herein described and exemplified by the examples.