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首页> 美国卫生研究院文献>ACS AuthorChoice >Use of Terahertz-Raman Spectroscopy to Determine Solubilityof the Crystalline Active Pharmaceutical Ingredient in Polymeric Matricesduring Hot Melt Extrusion
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Use of Terahertz-Raman Spectroscopy to Determine Solubilityof the Crystalline Active Pharmaceutical Ingredient in Polymeric Matricesduring Hot Melt Extrusion

机译：使用太赫兹拉曼光谱法测定溶解度基质中结晶活性药物成分的制备热熔挤出过程中

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Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoringthe API structural phase transitions from crystalline to amorphousas an excess of crystalline drug dissolved in the polymeric matrix.THz-Raman results enabled construction of solubility phase diagramsand highlighted significant differences in the solubilization capacityof the two polymer systems. The maximum stable API-load was 20 wt% for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanningcalorimetry and XRPD studies corroborated these results. This approachhas demonstrated a novel capability to provide real-time API–polymerphase equilibria data in a manufacturing relevant environment andpromising potential to predict solid-state solubility and physicalstability of ASDs.
机译：基于聚合物的无定形固体分散体（ASD）包含最有前途的配制策略之一，该策略旨在改善水溶性差的药物的口服生物利用度。由于对物理稳定性的了解不足，因此在市场上销售此类系统受到了限制。内部无序结构和增加的自由能为相分离和重结晶提供了热力学驱动力，这会损害治疗效果并限制产品的保质期。稳定ASD的开发中主要关注的是药物在聚合物载体中的溶解性，但是缺乏可靠的分析技术来测定其。在这项工作中，引入了太赫兹（THz）拉曼光谱作为一种新颖的经验方法，可直接在热熔挤出过程中确定结晶活性药物成分（API）在聚合物基质中的饱和溶解度。通过监测，确定模型化合物扑热息痛在两种聚合物体系（Affinisol 15LV（HPMC）和Plasdone S630（copovidone））中的溶解度API结构相从结晶转变为非晶作为溶解在聚合物基质中的过量结晶药物。太赫兹-拉曼结果可构建溶解度相图并强调了溶解能力的显着差异两种聚合物体系中的一种。最大稳定API负载为20 wtAffinisol 15LV为40％，Plasdone S630为40 wt％。差异扫描量热法和XRPD研究证实了这些结果。这种方法已展示出提供实时API聚合物的新颖功能与制造相关的环境中的相平衡数据；以及预测固态溶解性和物理性的潜力ASD的稳定性。

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