Hsieh Yi-Ling, Taylor Lynne S
Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Dr., 47907, West Lafayette, Indiana, USA.
Pharm Res. 2015 Feb;32(2):549-61. doi: 10.1007/s11095-014-1484-2. Epub 2014 Aug 22.
The aim of this study was to investigate how factors such as temperature, relative humidity and particle size impact the extent of disproportionation (salt to free base conversion) in powder blends of miconazole, benzocaine or sertraline mesylate salts mixed with a basic additive.
Raman spectroscopy was used to quantitate the extent of disproportionation. The data was further analyzed by multivariate analysis with partial least squares (PLS) modeling.
It was found that salt disproportionation was significantly influenced by % weight gain due to moisture sorption both in terms of the kinetics and the conversion extent, suggesting a solution-mediated reaction. Temperature plays an important role in impacting the value of pHmax which in turn has a significant correlation to the amount of free base formed. The particle size and drug: additive ratio were also found to influence the extent of disproportionation.
This study shows that the extent of salt disproportionation is influenced by multiple factors and the application of PLS modeling demonstrated the feasibility of utilizing multivariate analysis to generate a predictive model for estimating the extent of conversion and thus may serve as a tool for risk assessment.
本研究旨在探究温度、相对湿度和粒径等因素如何影响咪康唑、苯佐卡因或甲磺酸舍曲林盐与碱性添加剂混合的粉末混合物中的歧化程度（盐到游离碱的转化）。
采用拉曼光谱法定量歧化程度。通过偏最小二乘法（PLS）建模的多变量分析对数据进行进一步分析。
研究发现，无论是在动力学还是转化程度方面，盐歧化均受到因吸湿导致的重量增加百分比的显著影响，这表明存在溶液介导的反应。温度在影响pHmax值方面起着重要作用，而pHmax值又与游离碱的形成量显著相关。还发现粒径和药物与添加剂的比例会影响歧化程度。
本研究表明盐歧化程度受多种因素影响，PLS建模的应用证明了利用多变量分析生成预测模型以估计转化程度的可行性，因此可作为风险评估的工具。
