New Polymorphic Forms of Pemetrexed Diacid and Their Use for the Preparation of Pharmaceutically Pure Amorphous and Hemipentahydrate Forms of Pemetrexed Disodium.
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.
Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland. o.michalak@ifarm.eu.
Olga
O
Michalak
Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland. m.laszcz@ifarm.eu.
Marta
M
Łaszcz
Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland. k.jatczak@ifarm.eu.
Kamil
K
Jatczak
Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland. a.witkowska@ifarm.eu.
Anna
A
Witkowska
Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland. i.bujak@ifarm.eu.
Iwona
I
Bujak
Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland. a.groman@ifarm.eu.
Aleksandra
A
Groman
Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warszawa, Poland. m.cybulski@ifarm.eu.
Marcin
M
Cybulski
D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D008968:Molecular Conformation; D000068437:Pemetrexed / Q000138:chemical synthesis* / Q000737:chemistry*; D033362:Powder Diffraction; D013678:Technology, Pharmaceutical / Q000379:methods*; D013696:Temperature; D013818:Thermogravimetry; D017155:Wettability; D014961:X-Ray Diffraction
D000068437:Pemetrexed
pemetrexed diacid; pemetrexed disodium; phase transition; powder X-ray diffraction; thermal analysis