# US 7,612,077 B2 · Crystalline forms of the anti-cancer compound ZD1839

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- Number: US 7,612,077 B2
- Document ID: US7612077B2
- Status: Granted
- Kind: B2
- Application number: 10/505,690
- Filed: 2003-02-24
- Published: 2005-09-22
- Granted: 2009-11-03
- Earliest claimed: 2002-02-26
- Assignees: AstraZeneca AB
- Inventors: John Peter Gilday
- Web page: https://patentgrep.com/patent/US7612077B2

## CPC

- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/94: Nitrogen atoms
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention concerns certain crystalline solvates and hydrates of the compound of the Formula (I) which is known inter alia by way of the code number ZD1839. In particular, the invention concerns a first solvate that occurs in the presence of methanol which is designated as Form 2 ZD1839 MeOH solvate, a second solvate that occurs in the presence of dimethyl sulphoxide which is designated as Form 3 ZD1839 DMSO solvate and a trihydrate that occurs in the presence of water which is designated Form 5 ZD1839 trihydrate. The invention further concerns processes for the preparation of these solvates and the trihydrate and for their conversion back to the compound ZD1839, pharmaceutical compositions containing them and their use in the manufacture of medicaments for use the production of an anti-proliferative effect in a warm-blooded animal such as man.

## Claims

### Claim 1

Crystalline DMSO solvate of Form 3 ZD1839, according to the following formula I:

### Claim 2 (depends on 1)

The solvate according to claim 1 characterised by an X-ray diffraction pattern having characterising peaks at about 8.9, 17.8, 22.6 and 23.2° on the 2θscale.

### Claim 3 (depends on 1)

The solvate according to claim 1 characterised by an X-ray diffraction pattern substantially as shown in FIG. 7.

### Claim 4 (depends on 1)

The solvate according to claim 1 characterised by a desolvation point in the range of about 127° C. to 132° C.

### Claim 5 (depends on 1)

The solvate according to claim 1 characterised by one or both of the Differential Scanning Calorimetry thermogram and Thermal Gravimetric Analysis trace substantially as shown in FIG. 8.

### Claim 6 (depends on 1)

The solvate according to claim 1 characterised by a Diffuse Reflectance Infrared Fourier Transform spectrum with distinguishing peaks at about 1640, 1520, 1450, 880 and 560cm−1.

### Claim 7 (depends on 1)

The solvate according to claim 1 characterised by a Diffuse Reflectance Infrared Fourier Transform spectrum substantially as shown in FIG. 9.

### Claim 8 (depends on 1)

The crystalline DMSP solvate of Form 3 ZD1839 according to claim 1, which is substantially free of any other ZD1839 solvate of any Form 1 ZD1839 polymorph.

### Claim 9 (depends on 1)

A process for preparing a crystalline DMSO solvate of Form 3 ZD1839 according to claim 1 which comprises:—
(a) heating a mixture of the compound 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline in dimethyl sulphoxide or a solvent mixture containing dimethyl sulphoxide and a co-solvent until dissolution has occurred;
(b) reducing the temperature of the solvent system to induce nucleation;
(c) maintaining the mixture at a temperature below that at which nucleation has commenced; and
(d) isolating the crystalline solid so deposited.

### Claim 10 (depends on 1)

A process for the conversion of the compound of crystalline DMSO solvate of Form 3 ZD1839 according to the Formula of claim 1, to a compound of Form I ZD1839 polymorph which comprises:—
(a) washing Form 3 ZD1839 DMSO solvate according to claim 1 with a washing solvent or solvent mixture substantially to remove dimethyl sulphoxide; and
(b) isolating the Form 1 ZD1839 polymorph so formed.

### Claim 11 (depends on 1)

The crystalline form of the compound of the Formula I according to claim 1 wherein at least 90% of the compound of Formula I is in the form of Form 3 ZD1839 DMSO solvate.

### Claim 12 (depends on 1)

The crystalline form of the compound of the Formula I according to claim 1 wherein at least 95% of the compound of Formula I is in the form of Form 3 ZD1839 DMSO solvate.

### Claim 13 (depends on 1)

The crystalline form of the compound of the Formula I according to claim 1 wherein at least 98% of the compound of Formula I is in the form of Form 3 ZD1839 DMSO solvate.