The present application is a patent of addition for our co-pending Indian Patent Application 1646/DEL/2004 dated August 31, 2004.
The present invention relates to a method for identification of crystalline cefdinir dihydrate by determining the free and bound moisture content.
[(-)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.
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.
US Application No 20040210049 provides crystalline acid addition salts of cefdinir specifically sulphate and mesylate salt.
PCT Application No WO 04/104010 provides crystalline form R of cefdinir having a specific XRD pattern.
US Application No 20040242556 provides a process for preparation of crystalline form of cefdinir designated as Form B having a specific XRD pattern. Said form B is prepared from crystalline form A by first forming the trifluoroacetic acid salt followed by basification with
ammonia. However the said morph closely resembles morph "R" of cefdinir disclosed in WO 04/104010.
PCT Application No WO 04/46154 describes process for preparation of amorphous monohydrate of cefdinir.
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, DSC and FTIR spectrum which is different from that disclosed in the US' '556 application.
Our pending Indian patent application 1646/DEL/2004 relates to crystalline Form C of cefdinir. The total moisture content in crystalline Form C of cefdinir is about 12-13%.
Herein after the term "crystalline Form C of cefdinir" refers to the crystalline Form C of cefdinir reported in the Indian patent application No 1646/DEL/2004.
Polymorphism is the occurrence of different crystalline forms of a substance. The different hydrates of a substance are known as pseudopolymorphs. The different crystal arrangements in polymorphs and hydrates lead to different melting points and solubility profiles. In order to prepare pharmaceutical formulations with predictable dissolution, which
would enable high bioavailability of the drug, the exact form of the drug must be known. The nature of the drug or the active ingredient determines the ratio and proportion of the other constituents in the formulation.
In case of hydrated forms of drugs it is essential to determine the amount of free and bound moisture because the total moisture content for different hydrates may be the same but the ratio of free and bound moisture may vary significantly. The total moisture content of about 12-13% in crystalline Form C of cefdinir does not suggest whether the said form is monohydrate or dihydrate or trihydrate etc. Theoretically the moisture content of about 4% in cefdinir should correspond to the monohydrate, that of about 8-9% should correspond to the dihydrate while that of about 12-13% should correspond to the trihydrate. In order to prepare pharmaceutical formulations requiring a definite dose of a drug it is necessary to know the free and bound moisture as this would ensure content uniformity in the formulation.
The present inventors have found after extensive analytical studies that the crystalline Form C of cefdinir has about 8% bound moisture and about 4% free moisture content. The bound moisture content of about 8% corresponds to the dihydrate of cedinir (theoretical value of moisture content for dihydrate is 8-9%). Contrary to the surprising result obtained by the present inventors the total moisture content of about 12-13% in crystalline Form C of cefdinir indicates a possibility of trihydrate.
Figure 1 depicts X-ray diffraction pattern (XRD) of crystalline Form C of cefdinir.
Figure 2 depicts Differential Scanning Calorimetric (DSC) thermogram of crystalline Form C
of cefdinir.
Figure 3 depicts Thermogravimeric Analysis (TGA) profile of crystalline Form C of cefdinir.
Figure 4 depicts an overlay of X-ray diffraction pattern (XRD) of crystalline Form C of cefdinir
at 30°C, 50°C, 60°C and 70°C.
Figure 5 depicts an overlay of X-ray diffraction pattern (XRD) of crystalline Form C of cefdinir
at70°Cand80°C.
Figure 6 and 7 depict an overlay of Differential Scanning Calorimetric (DSC) thermogram of
crystalline Form C of cefdinir at 30°C, 50°C and 80°C.
Table 1 represents the moisture content of crystalline Form C of cefdinir at different
temperature.
A first aspect of the present invention provides crystalline dihydrate of cefdinir. The crystalline dihydrate of cefdinir has about 8% bound moisture and about 4% free moisture. The crystalline dihydrate of cefdinir has X-ray diffraction pattern as depicted in Figure 1, Differential Scanning Calorimetric thermogram as depicted in Figure 2 and Thermogravimetric Analysis profile as depicted in Figure 3.
The total moisture content of crystalline Form C of cefdinir as determined by Karl Fisher auto titrator was about 12-13%. The TGA profile exhibited two weight losses of about 4% around 40°C and of about 7.5% around 100°C. The first weight loss in the TGA of crystalline Form C of cefdinir occurred at ambient temperature and the second weight loss was a sharp one starting at about 60°C and going upto 120°C with a peak temperature of about 100°C. The TGA profile indicated a possibility that the initial weight loss at around 40°C could be due to surface moisture while the second weight loss at around 100°C could be due to bound moisture. The present inventors carried out further experiments to substantiate the TGA data.
Samples of crystalline Form C of cefdinir were kept at elevated temperature ranging from 30°C to 80°C for atleast 1 hour. The XRD, DSC and moisture content of the samples kept at different temperatures were recorded. The DSC thermogram as depicted in Figure 2 exhibited two endotherms at around 65°C (broad) and 120°C (sharp) and an exotherm at about 190°C (broad).
The overlay of the DSC thermograms at different temperatures as depicted in Figure 6 exhibit disappearance of the first endotherm observed at about 60° whereas the sharp endothermic peak at about 120°C remained unaffected (Figure 7). The peak area was found to be around 150 joule/g upto 50°C but reduced to 128 joule/g at 80°C. The disappearance of the first endotherm with increasing temperature of the cefdinir sample confirms that the first endotherm must due to surface or free moisture whereas the second unaffected endotherm must be due to bound moisture.
The overlay of the XRD patterns at 30°C to 70°C as depicted in Figure 4 exhibited no change in terms of the peak pattern or 29 values indicating no change in the crystal arrangement between 30°C to 70°C. The overlay of XRD patterns at 70°C and 80°C as depicted in Figure 5 showed significant shift in the peaks and changes in the peak pattern. It
was evident at this stage that crystalline Form C of cefdinir begins to lose its crystal habit between 70°C and 80°C:
The effect of temperature on moisture content of crystalline Form C of cefdinir can be understood from Table 1. The moisture content of initial sample was 12.6%. There was a substantial decrease in the moisture content from 12.6% to 9.9% at 50°C as compared to the initial sample. Subsequently the decrease in moisture content was slow from 9.9% to 8.4% between 50°C to 70°C and from 8.4% to 7.6% between 70°C and 80°C.
The moisture content at 70°C was 8.4% with no change in the XRD pattern at this temperature with respect to that of the initial sample. The moisture content at 80°C was 7.6% but at this temperature the crystalline Form C of cefdinir showed significant changes in the XRD pattern with respect to the initial sample. The changes in XRD pattern can be correlated with the loss of bound moisture because the loss of bound moisture will affect the XRD pattern whereas the loss of free or surface moisture will not. Thus it could be concluded from the combined study of TGA, DSC, XRD and Karl Fisher that crystalline Form C of cefdinir contains about 8% bound moisture and about 4% free moisture.
Powder XRD of the samples were determined by using X-Ray Diffractometer, Rigaku Corporation, RU-H3R, Goniometer, X-Ray tube with Cu K alpha target anode, Divergence slits 1°, 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.
The thermal profiles were recorded using Differential Scanning Calorimeter DSC821 e, Mettler Toledo, Sample weight: 3.1 mg, Temperature range: 20-350° C, Heating rate: 10° C/min, Nitrogen 50.0 mL/min, Number of holes in the crucible: 1.
The percentage weight loss was recorded using a thermogravimetric analyzer (TGA) Perkin Elmer, Model Pyris 1, Temperature range: 20-350°C, Heating rate: 10° C/min, purged with Nitrogen.
The moisture content was determined using Karl Fischer auto titrator, Mettler Toledo, model DL 38.
EXAMPLE
Crystalline Form C of cefdinir was kept at ambient temperature (about 25°C) and at elevated
temperatures- 30°C, 50°C, 60°C, 70°C and 80°C for 1 hour each. The XRD, DSC and
moisture content of the samples kept at the above mentioned temperatures were recorded.
XRD as per Figures 1, 4 and 5
DSC as per Figure 2, 6 and 7
TGAas per Figure 3
Moisture content as per Table 1

WE CLAIM:
1 . Crystalline cefdinir dihydrate.
2. Crystalline cefdinir having about 8% bound moisture and about 4% free moisture.
3. Crystalline cefdinir dihydrate having XRD pattern with characteristic absorption bands at
29 values 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.
4. Crystalline cefdinir dihydrate having characteristic exothermic peaks in DSC thermogram
at85to90°Cand126-131°C.
5. Crystalline cefdinir dihydrate having Thermogravimetric Analysis (TGA) profile as
depicted in Figure 3.
6. Crystalline cefdinir dihydrate as claimed in claim 5 exhibiting weight loss of about 4% at
40°C and about 8% at 100°C in the TGA profile.
7. A process for identification of crystalline cefdinir dihydrate wherein the said process
comprised of,

a) keeping crystalline cefdinir at elevated temperature
b) determining the moisture content of the sample.

8. A process according to claim 7 wherein in step a) crystalline cefdinir is kept at elevated
temperature for atleast 1 hour.
9. A process for identification of crystalline cefdinir dihydrate as described herein and
exemplified in the example.