Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion
Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion
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DOI：
10.1021/acs.molpharmaceut.9b00703
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发表时间：
2019-10-01
影响因子：
4.9
通讯作者：
Robertson, John
中科院分区：
文献类型：
--
作者：
Bordos, Ecaterina;Islam, Muhammad T.;Robertson, John
基于聚合物的无定形固体分散体（ASD）是设计用于改善水溶性差的药物的口服生物利用度的最有前途的制剂策略之一。由于对物理稳定性的理解不足，在市售产品中开发此类系统受到限制。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，这可能损害治疗功效并限制产品保质期。在开发稳定的ASD中，主要关注的是药物在聚合物载体中的溶解度，但缺乏可靠的分析技术来测定。在这项工作中，太赫兹（THz）拉曼光谱作为一种新的经验方法，以确定在聚合物基质中的结晶活性药物成分（API）的饱和溶解度直接在热熔挤出。通过监测API从结晶到无定形的结构相变，测定模型化合物对乙酰氨基酚在两种聚合物系统Affinisol 15 LV（HPMC）和Plasdone S630（共聚维酮）中的溶解度，因为过量的结晶药物溶解在聚合物基质中。太赫兹-拉曼光谱的结果，使建设的溶解度相图，并突出了显着差异的两种聚合物系统的增溶能力。对于Affinisol 15 LV，最大稳定API负载为20重量%，对于Plasdone S630，最大稳定API负载为40重量%。差示扫描量热法和XRPD研究证实了这些结果。这种方法已经证明了一种新的能力，提供实时API-聚合物相平衡数据，在制造相关的环境和有前途的潜力，预测固态溶解度和物理稳定性的ASD。
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 monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API-polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.