Title of Invention

PROCESS FOR THE PREPARATION OF A NOVEL CRYSTALLINE FORM OF A CEPHALOSPORIN ANTIBIOTIC

Abstract The present invention relates to novel crystalline form of a cephalosporin antibiotic. More particularly, the present invention relates to novel crystalline form (Crystal B) of cefdinir of the formula (I).
Full Text

Field of the Invention
The present invention relates to novel crystalline form of a cephalosporin antibiotic. More particularly, the present invention relates to novel crystalline form (Crystal B) of cefdinir of the formula (I).

The present invention also provides a process for the preparation of novel crystalline form (Crystal B) of cefdinir of formula (I).
Background of tlie Invention
Cefdinir is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria, especially against Streptococci, than other antibiotics for oral administration.
US patent number 4,935,507 claims the novel crystalline form (Crystal A) of the cefdinir and a process for preparing the same. The X-ray crystallography data given in this patent is as given in the following table:

The crystalline form (Crystal A) of cefdinir disclosed in US 4,935,507 is prepared by dissolving 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-

vinyl-3-cephem.-4-carboxylic acid (syn isomer)(an amorphous product) in a solvent and adjusting the pH at room temperature.
The dosage form that is approved for crystalline form (Crystal A) of cefdinir is capsule. The major disadvantage with the crystalline form (Crystal A) of cefdinir is that it cannot be made into any other dosage form and it has low solubility. Crystalline form (Crystal A) of cefdinir is slightly soluble in dilute hydrochloric acid and sparingly soluble in 0.1 M pH 7.0 phosphate buffer. Because of its poor solubility the crystalline form (Crystal A) is not highly bioavailable.
In view of the vital antibiotic activities of cefdinir of the formula (I), the inventors of the present invention succeeded in obtaining the compound (I) in different crystal form, i.e. Crystal B, by adjusting the pH to 2.5 to 4.5 at low temperatures, which form has high solubility and more bioavailability.
Objectives of the Invention
The main objective of the present invention is to provide novel crystalline form (Crystal B) of cefdinir.
Another objective of the present invention is to provide novel crystalline form (Crystal B) of cefdinir which has very good bioavailability and useful in developing different dosage forms.
Summary of the Invention
Accordingly, the present invention provides novel crystalline form (Crystal B) of cefdinir of the formula (I)
1

IR : 3841, 3753, 3300, 980, 1782, 1666, 1611, 1544, 146, 1349, 1190, 1134, 1049, 1017, 866, 813, 793, 691, 562, 475.
X-ray powder diffraction (29) : 5.90, 7.10, 7.90, 8.10, 10.70, 11.80, 15.70, 16.20, 18.60, 19.40, 22.40, 22.60, 23.70, 24.50, 25.70, 26.30, 28.60, 30.20, 31.80.
The present invention also provides a process for the preparation of novel crystalline form (Crystal B) of cefdinir of the formula (I), which comprises the steps of:
i) hydrolyzing the compound of the formula (II) using a mixture of water and water miscible solvent at a temperature in the range of 30 to 40 °C, ii) adding EDTA to the resulting solution, iii) cooling to 0 to 15 °C and
iv) adjusting the pH to 2.0 to 4.5 to obtain novel crystalline form (Crystal B) of cefdinir of formula (I).

Description of Figures
Figure 1 : Powder XRD pattern of crystalline form (Crystal A) and novel crystalHne form (Crystal B) of cefdinir of formula (I).
Figure 2 : Infrared Spectrum of crystalline form (Crystal A) and novel crystalline form (Crystal B) of cefdinir of formula (I).

Detailed description of the invention
In an embodiment of the present invention, the counter ion represented by M is selected from sodium, potassium, lithium, magnesium, ammonium, dicyclohexylamine, N,N'-dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine and the like.
In yet another embodiment of the present invention, the water miscible solvent used is selected from acetone, DMF, THF, dioxane, 2-butanone, methanol, isopropanol, ethanol, acetonitrile, DMAc, and the like or mixtures thereof
In yet another embodiment of the present invention, the ratio of water and water miscible solvent may be in the range of 1:1 to 100:1, preferably in the range oflO:l.
In yet another embodiment of the present invention, the pH is adjusted using acid selected from HCl, H2SO4, phosphoric acid and the like.
In yet another embodiment of the present invention, the crystalline form (Crystal B) of cefdinir is a monohydrate.
In yet another embodiment of the present invention, the compound of formula (I) obtained is a syn isomer.
The present invention is also based on our observation that if the pH of the solution is adjusted above 20 °C, the crystalline form (Crystal A) of cefdinir is obtained.
The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing viewpoint and affords good quality of amorphous cefdinir of the formula (I).
Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.

The present invention is provided by the examples given below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
The compound of formula (II) is prepared according to the procedure described in our copending application No. 152/MAS/2003.
Example 1
Preparation of crystalline (Z)-7p-[2-(2-amino-4-thiazolyl)-2-
(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid
Ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (50 gm) was added to a mixture of water (720 ml) and acetone (80 ml) and stirred at 33-35 ^C for 20 min. The resulting turbid aqueous solution was filtered and washed with water (400 ml). To the aqueous filtrate EDTA (0.5 g) was added and treated twice with activated charcoal (5.0 g) at 35 °C for about 30 min. The carbon was filtered and the carbon bed was washed with water (200 ml) each time. The filtrate was cooled to 5°C and pH was adjusted to 3.8-3.9 by 1:1 HCl and stirred for 5-10 min. The solid thus obtained was filtered and washed with chilled water (400 ml). Then the pH of the filtrate was adjusted to 2.5 at 12 °C with 1:1 HCl. The solid obtained was stirred at 10-12 'C for about 12 min. The slurry was filtered and washed with chilled water (50 ml) and dried under vacuum at 45°C for 5-6 hrs to give crystalline (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula (I) (8.8 gm, HPLC quality 99.5%, water content 4,5 to 5.5%).
Example 2
Preparation of crystalline (Z)-7P-[2-(2-amino-4-thiazolyl)-2-
(hydroxyimino)acetamido]-3-vinyl-3-cepliem-4-carboxylic acid

Ammonium (Z)-7P-[2"(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (75 gm) was added to a mixture of water (1080 ml) and acetone (120 ml) and stirred at 33-35 °C for 20 min. The resulting turbid aqueous solution was filtered and washed with water (600 ml). To the aqueous filtrate EDTA (0.75 g) was added and treated twice with activated charcoal (7.5 g) at 35 °C for about 30 min. The carbon was filtered and the carbon bed was washed with water (300 ml) each time. The filtrate was cooled to 5 °C and the pH was adjusted to 3.6-3.7 by 1:1 HCl and stirred for 5-10 min. The solid obtained was filtered and washed with chilled water (600 ml). The pH of the filtrate was adjusted to 2.5 at 10-12 °C in about 12 min. with 1:1 HCl and stirred at 10-12 °C. The solid precipitated slowly in 30 min, was filtered and washed with chilled water (50 ml). The product obtained is dried under vacuum at 45 °C to give crystalline (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula (I) (9.4 gm, HPLC quality 99.37% %, water content 4.5 to 5.5%).
Example 3
Preparation of crystalline (Z)-7p-[2-(2-amino-4-thiazolyl)-2-
(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid
Ammonium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (75 gm) was added to a mixture of water (1080 ml) and acetone (120 ml) and stirred at 35-38 °C for 20 min. The resulting turbid aqueous solution was filtered and washed with water (600 ml). To the aqueous filtrate EDTA (0.75 g) was added and treated twice with activated charcoal (7.5 g) at 35 "^C for about 30 min. The carbon was filtered and the carbon bed was washed with water (300 ml) each time. The filtrate was cooled to 5 °C and pH was adjusted to 3.55 by 1:1 HCl and stirred at 4-5 °C for 5-10 minute. The solid obtained was filtered and washed with chilled water (600 ml). The pH of the filtrate was adjusted to 2.55 at

10-12 °C in about 12 min with 1:1 HCl and stirred at 10-12 °C for 30 min. The precipitate obtained was filtered and washed with water (50 ml). The resulting solution was further stirred at 10-12 °C for about 2-3 hrs. The solid formed was filtered and washed with chilled water (50 ml) to give crystalline (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]"3-vinyl-3-cephem-4-carboxylic acid of formula (I) (10.6 gm, HPLC quality 99.45%, water content 5 to 6.5%).
Example 4
Preparation of crystalline (Z)-7p-[2-(2-amino-4-thiazolyl)-2-
(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid
Ammonium (Z)-7p-[2-(2"amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (25 gm) was added to a mixture of water (360 ml) and acetone (40 ml) and stirred at 35-40 °C for 20 min. The resulting turbid aqueous solution was filtered and washed with water (150 ml). To the aqueous filtrate EDTA (0.5 g) was added and treated twice with activated charcoal (5,0 g) at 35 °C for about 30 min. The carbon was filtered and the carbon bed was washed with water (200 ml) each time. The filtrate was cooled to 10 °C and pH was adjusted to 2.6 with 1:1 HCl and stirred at 5-10 °C for 5-10 min. The solid obtained was filtered and washed with chilled water (200 ml). To the filtrate seeding was added and stirred at 19-21 °C. The solid precipitated was filtered and washed with of chilled water (50 ml) and dried under vacuum at 45 °C to give (crystalline (Z)"7p-[2-(2-amino-4"thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid of formula (I) (4.3 gm, HPLC quality 99.5%, water content 6.0 to 6.5%).




We claim :
1. Novel crystalline form (Crystal B) of cefdinir of the formula (I)

which is characterized by the following data:
IR : 3841, 3753, 3300, 980, 1782, 1666, 1611, 1544, 146, 1349, 1190, 1134, 1049,
1017, 866, 813, 793, 691, 562, 475.
X-ray powder diffraction (29) : 5.90, 7.10, 7.90, 8.10, 10.70, 11.80, 15.70, 16.20,
18.60, 19.40, 22.40, 22.60, 23.70, 24.50, 25.70, 26.30, 28.60, 30.20, 31.80.
2. A process for the preparation of novel crystalline form (Crystal B) of cefdinir
of the formula (I),

which comprises the steps of:
i) hydrolyzing the compound of the formula (II)

using a mixture of water and water miscible solvent at a temperature in the range of
30 to 40 ^C,
ii) adding EDTA to the resulting solution,
iii) cooling to 0 to 15 °C and
iv) adjusting the pH to 2.0 to 4.5 to obtain novel crystalline form (Crystal B) of
cefdinir of formula (I).

3. The process as claimed in claim 1, wherein the counter ion represented by M
is selected from sodium, potassium, lithium, magnesium, ammonium,
dicyclohexylamine, N,N'-dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-
7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine,
l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine and N,N-
diisopropylamine.
4. The process as claimed in claim 1, wherein the water miscible solvent used
in step (i) is selected from acetone, DMF, THF, dioxane, 2-butanone, methanol,
isopropanol, ethanol, acetonitrile, DMAc or mixtures thereof.
5. The process as claimed claim 1, wherein the ratio of water and water
miscible solvent may be in the range of 1:1 to 100:1, preferably in the range of 10:1.
6. The process as claimed in claim 1, wherein the crystalline form (Crystal B)
of cefdinir is a monohydrate.
7. The process as claimed in claim 1, wherein the compound of formula (I)
obtained is a syn isomer.


Documents:

456-che-2003 abstract granted.pdf

456-che-2003 claims granted.pdf

456-che-2003 description (complete) granted.pdf

456-che-2003 drawings granted.pdf

456-che-2003-abstract.pdf

456-che-2003-claims.pdf

456-che-2003-correspondnece-others.pdf

456-che-2003-correspondnece-po.pdf

456-che-2003-description(complete).pdf

456-che-2003-form 1.pdf

456-che-2003-form 13.pdf


Patent Number 225589
Indian Patent Application Number 456/CHE/2003
PG Journal Number 52/2008
Publication Date 26-Dec-2008
Grant Date 19-Nov-2008
Date of Filing 05-Jun-2003
Name of Patentee ORCHID CHEMICALS & PHARMACEUTICALS LTD.
Applicant Address ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI 600 034
Inventors:
# Inventor's Name Inventor's Address
1 PANDURANG BALWANT DESHPANDE F-3, SAND STONE APARTMENT, FIRST AVENUE, INDIRA NAGAR, CHENNAI 600 020
2 BHAUSAHEB PANDHARINATH KHADANGALE SANTHI AVENUE NO.7, Dr. RADHAKRISHNAN ROAD, TIIRUVANMIYUR, CHENNAI 600 041,
3 CHANDRESEKARAN RAMASUBBU NO 3, (NEW NO.7), B1, RAMMIYAM FOUNDATION, 7 TH MAIN ROAD DHANDEESWARNAGAR, VELACHERY, CHENNAI 600 042,
PCT International Classification Number C07D 501/124
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA