WO2006090413A1

WO2006090413A1 - Novel crystalline form of gefitinib and a process for its preparation

Info

Publication number: WO2006090413A1
Application number: PCT/IN2006/000047
Authority: WO
Inventors: Ramanadham Jyothi Prasad; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2005-02-23
Filing date: 2006-02-10
Publication date: 2006-08-31

Abstract

The present invention relates to a novel crystalline form of Gefitinib and a process for its Preparation thereof. Gefitinib is 4-(31-chloro-41-fluoro anilino)-7-methoxy-6- (3-morpholino propoxy) quinazoline and has the structural formula (I). The present invention is to provide a stable novel crystalline form of Gefitinib designated by us as Form-6, and a process for the preparation of the same. Gefitinib is useful in the treatment of a variety of solid tumors, especially non-small cell lung cancer and hematological malignancies.

Description

A NOVEL CRYSTALLINE FORM OF GEFITINIB AND A PROCESS FOR ITS

PREPARATION

The present invention relates to a novel crystalline form of Gefϊtinib and a process for its Preparation thereof. Gefitinib is 4-(3¹-chloro-4¹-fluoro anilino)-7-methoxy-6- (3- morpholino propoxy) quinazoline and has the structural formula-I

I

Gefitinib is a well-known inhibitor of the epidermal growth factor receptor (EGFR) family of Tyrosine Kinase enzymes and possesses antiproliferative activity such as anti- cancer activity and accordingly is useful in the treatment of a variety of solid tumors, especially non-small cell lung cancer and hematological malignancies.

BACKGROUND OF INVENTION: The international Patent application WO 96/33980, in Examples (1) and (10) discloses the process for the preparation of the Gefitinib of the formula-I given above. But there is no specific disclosure about the polymorphism of Gefitinib.

But the international patent application WO 03/072108, discloses the following crystalline forms of the compound of the formula-I.

(i) Form-1 anhydrous Form

(ii) Form-2 MeOH solvate

(iii) Form-3 DMSO solvate

(iv) Form-5 trihydrate Form-1: This is an anhydrous form. It is the only single non-solvated, crystalline form of the compound of the formula-I, now known as Gefitinib and it is the most stable form. This form was prepared according to the procedure given in example (4) of the international Patent application WO 03/072108. The process comprises adding , phosphorous oxychloride to a stirred slurry of 7-methoxy-6- (3-morpholino propoxy)-3,4- dihydroquinazolin-4-one, triethylamine and Toluene, and maintaining the mixture for 5 hrs at 5O⁰C to complete the formation of the intermediate 4-chloro-7-methoxy-6- (3- morpholinopropoxy) quinazoline. This on reaction with 3-Chloro-4-fluoroaniline in Isopropyl alcohol forms Gefitinib of formula-I, which after normal work-up, finally obtained as solid at about 20⁰C. This on filtration and drying with warm nitrogen gas (60⁰C) obtained Form-I of Gefitinib. It has a melting point in the range of about 194- 198°C.

It was disclosed in International Patent application WO 96/33980 in Example (1) that the compound of the formula-I, now known as Gefitinib, which obtained after purification by column chromatography and subsequent recrystallisation from toluene is stated to have an m.p.l l9-120°C. But in the subsequent patent WO 03/072108, it is believed that the material obtained at that time may have been the metastable anhydrate polymorphic form of Gefitinib. This statement seems to be not correct due to the reasons given below.

When we conducted the experiments at our laboratory, with the same procedure and conditions as mentioned in Example (1) of WO96/33980, we isolated the product as a stable form-I with an m.ρ. Of 194 -198⁰C, but not 119-120⁰C₅ as that of Meta stable form. As such there is no Meta stable anhydrate polymorphic form. But the non-solvated anhydrous form is Form-I only.

Form-2 MeOH solvate: According to International Patent application WO 03/072108,

Example (2), it was prepared by dissolving Gefitinib in Methanol at reflux temperature and then cooled to O⁰C, the resultant crystalline solid was collected by suction filtration and pulled dry on the filter. The form-2 methanol solvate, so obtained had about 2- equivalents of the compound to about 1 equivalent of methanol i.e., the material was approximately a hemi-solvate. So the methanol content in the material is about 3.45%

Form-3 DMSO solvate: According to International Patent application WO 03/072108, example (1), it was prepared by dissolving Gefitinib in a mixture of ethyl acetate and dimethyl sulfoxide at 75⁰C and subsequent filtration and cooling of the filtrate to 10⁰C, then again heated to 4O⁰C for 1 hour and then cooled to 0⁰C. The resultant solid so obtained after filtration is Form-3 DMSO solvate. In this the molar ratio of compound of the formula-I to DMSO solvent is in the range of 1 equivalent of compound of Formula-I to about 1 equivalent of DMSO. So the DMSO content in the material is about 14.88%.

The International Conference on Harmonization (ICH) adopted guidelines, (Ref: European Pharmacopoeia Supplement 1999, Sec.5.4) for residual solvent level in active substances, excipients and medicinal products indicates the limit for DMSO and MeOH as 0.5% and 0.3% respectively. Whereas the actual content of DMSO is 30 times and MeOH is 11.5 times more than the stipulated limit in the above mentioned solvated forms. As such both these solvated forms are not suitable for pharmaceutical preparations.

Moreover both these solvate forms may readily be converted back into Form-I upon removal of the solvent in it. Therefore Forms -2 and 3 can be considered as the Pseudo forms of stable form-I of Gefitinib.

Form-5 Trihydrate: During our attempt to make Form-5 Trihydrate, by using the procedure given in Example (7) of patent WO 03/072108, accordingly isopropyl alcohol and water are added to the compound Gefitinib and the mixture was stirred and heated to reflux to achieve complete dissolution of the solid, the solution was maintained at reflux for 2 hrs and then cooled to room temperature in about six hours time, the resulting product was isolated by filtration and found that it is not trihydrate by measuring water content by Karl Fisher titration. The water content is about 23%w/w instead of 10.78% w/w (theoretical value for trihydrate). Then the material is air dried at room temperature and observed that after 24 hrs, water content is 10.60% w/w, which is nearly equal to trihydrate. This trihydrate is not stable for longer time. The water content after 48 hrs is 4.30% w/w and after 7 days 2.4%w/w, after 15 days 1.10% w/w and after 30 days it almost lost water and became anhydrous.

Our further studies revealed that, there exists an another novel form of Gefitinib, which is monohydrate and it is characterized by XRPD, DSC and water content by Karl Fisher Titration. This is a more stable form than trihydrate and we have named it as Form-6.

Stability Data (25-35⁰O

Therefore the main objective of the present invention is to provide a stable novel crystalline form of Gefitinib designated by us as Form-6.

Another objective of the present invention is to provide a process for the preparation of stable novel crystalline form of Gefitinib designated by us as Form-6.

Accordingly the present invention provides a novel stable crystalline Gefitinib Form-6 having the characteristics given below: XRPD: having typical characteristic peaks at about 7.05, 9.36, 12.3, 14.8, 16.8, 18.60,20.68, 24.72 on the 2Θ scale as shown in Fig 1 of the drawing accompanying this specification

DSC: having a typical first endotherm with a peak at approximately 66.4 to 82.4⁰C and a second endotherm with a peak at approximately 193.3 to 195.3⁰C. as shown in Fig 2

K.F. Value of 3.70%-3.95% w/w, preferably 3.75-3.85% w/w equivalent to monohydrate.

According to another feature of the invention there is provided a process for the preparation of a novel crystalline form of Gefitinib, designated as Form-6 having the above-mentioned characteristics, which comprises mixing anhydrous Gefitinib of the formula-I,

With water and stirring the resulting slurry at ambient temperature for a period ranging fcom 18 to about 20 hrs, filtering and air-drying the resultant Form-6 of Gefitinib formed.

The following Example given for the purpose of illustrating the process of the present invention and therefore should not be considered to limit the scope or spirit of the invention. Example-l

Into a one litre three-necked flask equipped with a mechanical stirrer, condenser, thermometer socket etc. is charged with dematerialized water (700 ml), followed by anhydrous Gefitinib (10 g) and stirred the resultant slurry at 25⁰C for 18 hrs and filtering the slurry using Buchner runnel and air dried the resultant Form-6 of Gefitinib

M.C (KF) = 3.70% w/w D.S.C = 66.4 to 82.4⁰C & 193.3 to 195.3⁰C

Advantages of the present invention:

(1) Novel form of Gefitinib, designated by us, as form-6 is fine crystalline in nature and stable.

(2) The novel Form-6, monohydrate can be readily converted into Form-I, under heating conditions at 75-85⁰C for 6 hrs

(3) DSC data indicates that monohydrate form has lower melting point than anhydrous form, this indicates that form-6 may have better bioavailability.

Claims

We Claim:

1. A novel stable crystalline Gefitinib Form-6 having the characteristics given below: XRPD: having typical characteristic peaks at about 7.05, 9.36, 12.3, 14.8, 16.8, 18.60,20.68, 24.72 on the 2Θ scale as shown in Fig 1 of the drawing accompanying this specification

DSC: having a typical first endotherm with a peak at approximately 66.4 to 82.4⁰C and a second endotherm with a peak at approximately 193.3 tol95.3°C as shown in Fig 2

2. A process for the preparation of a novel crystalline form of Gefitinib, designated as Form-6 having the above mentioned characteristics, which comprises mixing anhydrous Gefitinib of the formula-I,

I

with water, stirring the resulting slurry at ambient temperature for a period ranging from 18 to about 20 hrs, filtering and air-drying the resultant Form-6 of Gefitinib formed.

3. A process as claimed in claim 2 where in the stirring of anhydrous Gefitinib and the water is effected for a period in the range of 15-25 hours, preferably between 18-20 hours.

4. A pharmaceutical composition useful for anti-cancer activity comprising the novel stable crystalline Form-6 of Gefitinib as claimed in claim 1 and a pharmaceutically acceptable carrier.

5. A process for the preparation of a novel crystalline form of Gefitinib, designated as Form-6 having the above mentioned characteristics, as claimed in claim 1 of Gefitinib of the forrnula-I substantially as herein described with reference to Example 1.