# US 2017/0253597 A9 · Crystalline forms of pemetrexed diacid and manufacturing processes therefor

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- Number: US 2017/0253597 A9
- Document ID: US20170253597A9
- Status: Published application
- Kind: A9
- Application number: 15/150,720
- Filed: 2016-05-10
- Published: 2017-09-07
- Earliest claimed: 2014-10-30
- Assignees: ScinoPharm Taiwan, Ltd.
- Applicants: Scinopharm Taiwan, Ltd.
- Inventors: Ying-Tzu Lin; Kuan-Hsun Wang; Wei-Shuo Lo; Wen-Wei Lin; Wan-Yin Cheng
- Web page: https://patentgrep.com/patent/US20170253597A9

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Crystalline forms of pemetrexed diacid are provided (Forms 1 and 2) which are readily produced for either laboratory-scale or industrial scale. Processes for the preparation of Forms 1 and 2 are also provided.

## Claims

### Claim 1

A crystalline Form 1 of pemetrexed diacid, characterized by a powder X-ray diffraction pattern with peaks at about 13.3, 15.8, 21.2, 26.2 and 26.7±0.2 degrees two-theta.

### Claim 2 (depends on 1)

The crystalline Form 1 of pemetrexed diacid of claim 1, further characterized by a powder X-ray diffraction pattern with peaks at about 7.7, 14.4, 16.6, 17.0 and 18.7±0.2 degrees two-theta.

### Claim 3 (depends on 2)

The crystalline Form 1 of pemetrexed diacid of claim 2, further characterized by a powder X-ray diffraction pattern with peaks at about 11.5, 16.1, 17.5, 20.0 and 24.4±0.2 degrees two-theta.

### Claim 4 (depends on 1)

The crystalline Form 1 of pemetrexed diacid of claim 1, characterized by a powder X-ray diffraction pattern as substantially depicted in FIG. 1.

### Claim 5 (depends on 1)

The crystalline Form 1 of pemetrexed diacid of claim 1, further characterized by a weight loss of about 8% to about 11% at a temperature up to 120° C., as measured by thermal gravimetric analysis.

### Claim 6 (depends on 1)

The crystalline Form 1 of pemetrexed diacid of claim 1, wherein the crystalline Form 1 of pemetrexed diacid is a hydrated form.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

The crystalline Form 1 of pemetrexed diacid of claim any of claim 1, 2, 3, 4, 5 or 6, which is substantially free of other crystalline forms of pemetrexed diacid.

### Claim at position 8

-14. (canceled)

### Claim 15 (depends on 1)

A process for preparing the crystalline Form 1 of pemetrexed diacid of claim 1, wherein the process comprises:
a) dissolving pemetrexed disodium in a mixture of water and methanol at a temperature of about 15-30° C. to form a solution;
b) adjusting the pH of the solution to a range of 2.5 to 3.5 with an acid;
c) isolating the precipitate; and
d) drying the precipitate at a temperature of 15-30° C. to provide the crystalline Form 1 of pemetrexed diacid.

### Claim 16

(canceled)

### Claim 17 (depends on 15)

The process of claim 15, wherein the mixture of water and methanol has a volume ratio of 3:1 to 1:1 (water:methanol).

### Claim 18 (depends on 15)

The process of claim 15, wherein the acid is an inorganic acid selected from the group consisting of: HCl, HBr, H2SO4, and mixtures thereof.

### Claim 19 (depends on 15)

The process of claim 15, wherein the acid is an organic acid selected from the group consisting of: acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, and mixtures thereof.

### Claim 20 (depends on 15)

The process of claim 15, wherein the crystalline Form 1 of pemetrexed diacid is isolated substantially free of other crystalline forms of pemetrexed diacid.

### Claim 21

(canceled)