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Molecules 2015, 20(8), 13814-13829; doi:10.3390/molecules200813814

New Polymorphic Forms of Pemetrexed Diacid and Their Use for the Preparation of Pharmaceutically Pure Amorphous and Hemipentahydrate Forms of Pemetrexed Disodium

Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland
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Academic Editor: Derek J. McPhee
Received: 21 May 2015 / Revised: 22 July 2015 / Accepted: 24 July 2015 / Published: 30 July 2015
(This article belongs to the Section Medicinal Chemistry)
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Abstract

The preparation of stable amorphous pemetrexed disodium of pharmaceutical purity as well as the process optimization for the preparation of the hemipentahydrate form of pemetrexed disodium are described. Analytical methods for the polymorphic and chemical purity studies of pemetrexed disodium and pemetrexed diacid forms were developed. The physicochemical properties of the amorphous and hydrate forms of pemetrexed disodium, as well as new forms of pemetrexed diacid (a key synthetic intermediate) were studied by thermal analysis and powder X-ray diffraction. High-performance liquid chromatography and gas chromatography methods were used for the chemical purity and residual solvents determination. In order to study the polymorphic and chemical stability of the amorphous and hemipentahydrate forms, a hygroscopicity test (25 °C, 80% RH) was performed. Powder diffraction and high-performance liquid chromatography analyses revealed that the amorphous character and high chemical purity were preserved after the hygroscopicity test. The hemipentahydrate form transformed completely to the heptahydrate form of pemetrexed disodium. Both pemetrexed disodium forms were produced with high efficiency and pharmaceutical purity in a small commercial scale. Amorphous pemetrexed disodium was selected for further pharmaceutical development. Two new polymorphs (forms 1 and 2) of pemetrexed diacid were used for the preparation of high purity amorphous pemetrexed disodium. View Full-Text
Keywords: pemetrexed diacid; pemetrexed disodium; powder X-ray diffraction; thermal analysis; phase transition pemetrexed diacid; pemetrexed disodium; powder X-ray diffraction; thermal analysis; phase transition
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Michalak, O.; Łaszcz, M.; Jatczak, K.; Witkowska, A.; Bujak, I.; Groman, A.; Cybulski, M. New Polymorphic Forms of Pemetrexed Diacid and Their Use for the Preparation of Pharmaceutically Pure Amorphous and Hemipentahydrate Forms of Pemetrexed Disodium. Molecules 2015, 20, 13814-13829.

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