Report No xxxx - Instytut Fizyki JÄ drowej PAN

THE MOST STABLE POLYMORPHIC FORM OF OLANZAPINE
AS STUDIED BY 13 C CP/MAS NMR AND X-RAY DIFFRACTION
Joanna Herold, 1 Łukasz Dobrzycki, 2 Edyta Pindelska, 1 Andrzej Kutner, 3 Krzysztof Woźniak, 2
Wacław Kołodziejski 1
1
Department of Inorganic and Analytical Chemistry, Medical University of Warsaw,
ul. Banacha 1, 02-097 Warszawa, Poland; 2 Chemistry Department, Warsaw University,
ul. Pasteura 1, 02-093 Warszawa, Poland; 3 Pharmaceutical Research Institute,
ul. Rydygiera 8, 01-793 Warszawa, Poland
7
8
6
5a
5
N
N
H
4
9 9a10 10a
1
N
3a
S
1
2
3
2
3
4
N
CH 3
CH 3
Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5] benzodiazepine,
belongs to a new generation of antipsychotic drugs, which modulate dopaminergic
neurotransmission by their antagonistic action on 5-HT 2A receptors. Olanzapine crystallizes in
at least five polymorphic forms. The most stable of them, form II, is used to produce a
pharmaceutical drug „Zyprexa” (Lilly). Various effects occurring during pharmaceutical
processing can lead to phase transitions, which can produce other polymorhs than that applied
to form tablets. Exposure to high pressure and temperature during compression, drying,
milling, wet granulation or presence of additional substances, required for drug formulation,
can affect polymorphic composition of a drug substunce inside a tablet. We confirmed by 13 C
CP/MAS NMR that „Zyprexa” tablets contain form II of olanzapine. The assignment of
solid-state spectra was done by comparison of chemical shifts in solid and liquid phases as
well as by analysis of CP kinetics and dipolar-dephased spectra. The 13 C CP/MAS NMR
spectrum of pure olanzapine II is in agreement with its crystal structure determined by
single-crystal X-ray diffraction.
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