Investigation of the Capacity of Low Glass Transition Temperature Excipients to Minimize Amorphization of Sulfadimidine on Comilling

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• 作者：Vincent Curtin ; Youness Amharar ; Yun Hu ; Andrea Erxleben ; Patrick McArdle ; Vincent Caron ; Lidia Tajber ; Owen I. Corrigan ; Anne Marie Healy
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：January 7, 2013
• 年：2013
• 卷：10
• 期：1
• 页码：386-396
• 全文大小：588K
• 年卷期：v.10,no.1(January 7, 2013)
• ISSN：1543-8392

文摘

The coprocessing of active pharmaceutical ingredient (API) with an excipient which has a high glass transition temperature (T_g) is a recognized strategy to stabilize the amorphous form of a drug. This work investigates whether coprocessing a model API, sulfadimidine (SDM) with a series of low T_g excipients, prevents or reduces amorphization of the crystalline drug. It was hypothesized that these excipients could exert a T_g lowering effect, resulting in composite T_g values lower than that of the API alone and promote crystallization of the drug. Milled SDM and comilled SDM with glutaric acid (GA), adipic acid (AA), succinic acid (SA), and malic acid (MA) were characterized with respect to their thermal, X-ray diffraction, spectroscopic, and vapor sorption properties. SDM was predominantly amorphous when milled alone, with an amorphous content of 82%. No amorphous content was detected by dynamic vapor sorption (DVS) on comilling SDM with 50% w/w GA, and amorphous content of the API was reduced by almost 30%, relative to the API milled alone, on comilling with 50% w/w AA. In contrast, amorphization of SDM was promoted on comilling with 50% w/w SA and MA, as indicated by near-infrared (NIR) spectroscopy. Results indicated that the API was completely amorphized in the SDM:MA comilled composite. The saturated solubility of GA and AA in the amorphous API was estimated by thermal methods. It was observed that the T_g of the comelt quenched composites reached a minimum and leveled out at this solubility concentration. Maximum crystallinity of API on comilling was reached at excipient concentrations comparable to the saturated concentration solubility of excipient in the API. Moreover, the closer the Hildebrand solubility parameter of the excipient to the API, the greater the inhibition of API amorphization on comilling. The results reported here indicate that an excipient with a low T_g coupled with high solubility in the API can prevent or reduce the generation of an amorphous phase on comilling.

Keywords:

glass transition; amorphous; comilling; solubility; excipient; thermal methods; vapor sorption; X-ray diffraction