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Solid-state transformation of different gabapentin polymorphs upon milling and co-milling
Shan-Yang Lin1, Cheng-Hung Hsu, Wen-Ting Ke
1Lab. Pharm. Biopharm., Department of Biotechnology, Yuanpei University, No. 306, Yuanpei Street, Hsin Chu, Taiwan, ROC. sylin@mail.ypu.edu.tw
International Journal of Pharmaceutics
|June 22, 2010
Summary
Milling gabapentin (GBP) without additives causes polymorphic transformations, with Form II converting to Forms III and IV. Adding excipients largely prevents these changes, though some additives induce Form IV or GBP-lactam formation.
Area of Science:
- Pharmaceutical Sciences
- Solid-State Chemistry
Background:
- Gabapentin (GBP) exists in four polymorphic forms (I-IV), with Form II being the most stable and commercially prevalent anhydrate.
- Understanding the solid-state behavior of GBP polymorphs is crucial for drug formulation and stability.
Purpose of the Study:
- To investigate the impact of milling on the polymorphic transformation of four gabapentin (GBP) forms (I-IV) without additives.
- To examine the effect of co-milling GBP Form II with various excipients on its polymorphic stability.
Main Methods:
- Fourier transform infrared (FTIR) microspectroscopy was used to analyze samples withdrawn at intervals during 120-minute milling or co-milling processes.
- Four GBP polymorphs (Forms I-IV) were subjected to milling individually and co-milled with different pharmaceutical additives.
Main Results:
- In the absence of additives, all GBP polymorphs underwent transformations: Form I dehydrated to Form II, Form II transformed to Forms III and IV, Form III converted to Form II then IV, and Form IV transformed to II, then III, and finally IV.
- Co-milling GBP Form II with certain excipients (Emcompress, beta-cyclodextrin, mannitol, corn starch, magnesium stearate) prevented polymorphic transitions.
- Co-milling GBP Form II with other additives (Avicel, dextrin, hydroxypropyl beta-cyclodextrin, hydroxypropyl methylcellulose, Kollidon K-30, gelatin) resulted solely in transformation to Form IV.
- Co-milling with Aerosil or talc led to the formation of GBP Form IV and GBP-lactam, indicating additive-dependent solid-state transformations.
Conclusions:
- Milling induces significant polymorphic transformations in gabapentin (GBP) forms, influenced by the presence and type of additives.
- The choice of excipient is critical in co-milling processes to maintain the polymorphic stability of GBP Form II.
- The formation of GBP-lactam is associated with the presence of GBP Forms III and IV in milled mixtures.
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