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Multiple Linear Regression Modeling To Predict the Stability of Polymer–Drug Solid Dispersions: Comparison of the Effects of Polymers and Manufacturing Methods on Solid Dispersion Stability
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-03-13 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00021
Gudrun A. Fridgeirsdottir 1 , Robert J. Harris 2 , Ian L. Dryden 3 , Peter M. Fischer 1 , Clive J. Roberts 1
Affiliation  

Solid dispersions can be a successful way to enhance the bioavailability of poorly soluble drugs. Here 60 solid dispersion formulations were produced using ten chemically diverse, neutral, poorly soluble drugs, three commonly used polymers, and two manufacturing techniques, spray-drying and melt extrusion. Each formulation underwent a six-month stability study at accelerated conditions, 40 °C and 75% relative humidity (RH). Significant differences in times to crystallization (onset of crystallization) were observed between both the different polymers and the two processing methods. Stability from zero days to over one year was observed. The extensive experimental data set obtained from this stability study was used to build multiple linear regression models to correlate physicochemical properties of the active pharmaceutical ingredients (API) with the stability data. The purpose of these models is to indicate which combination of processing method and polymer carrier is most likely to give a stable solid dispersion. Six quantitative mathematical multiple linear regression-based models were produced based on selection of the most influential independent physical and chemical parameters from a set of 33 possible factors, one model for each combination of polymer and processing method, with good predictability of stability. Three general rules are proposed from these models for the formulation development of suitably stable solid dispersions. Namely, increased stability is correlated with increased glass transition temperature (Tg) of solid dispersions, as well as decreased number of H-bond donors and increased molecular flexibility (such as rotatable bonds and ring count) of the drug molecule.

中文翻译:

多元线性回归模型可预测聚合物-药物固体分散体的稳定性:聚合物和制造方法对固体分散体稳定性的影响比较

固体分散体可能是提高难溶性药物生物利用度的成功方法。在这里,使用十种化学上多样化,中性,难溶性药物,三种常用聚合物以及两种制造技术(喷雾干燥和熔体挤出)生产了60种固体分散体配方。每种配方均在40°C和75%相对湿度(RH)的加速条件下进行了六个月的稳定性研究。在两种不同的聚合物和两种加工方法之间都观察到了明显的结晶时间差异(结晶开始)。观察到从零天到一年以上的稳定性。从该稳定性研究中获得的广泛实验数据集用于建立多个线性回归模型,以将活性药物成分(API)的理化特性与稳定性数据相关联。这些模型的目的是指出加工方法和聚合物载体的哪种组合最有可能产生稳定的固体分散体。基于从33种可能的因素中选择最有影响力的独立物理和化学参数,生成了六种基于数学多元线性回归的模型,该模型对聚合物和加工方法的每种组合均具有一个模型,并且具有良好的稳定性可预测性。从这些模型中提出了三个通用规则,以开发适当稳定的固体分散体。即T g)以及药物分子的H键供体数量减少和分子柔性(例如可旋转键和环数)的增加。
更新日期:2018-03-13
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