NMR and thermal studies for the characterization of mass transport and phase separation in paracetamol/copovidone hot-melt extrusion formulations.
NMR and thermal studies for the characterization of mass transport and phase separation in paracetamol/copovidone hot-melt extrusion formulations.
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DOI：
10.1021/acs.molpharmaceut.0c00188
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发表时间：
2020-04
影响因子：
4.9
通讯作者：
E. Pisa;L. Hughes;S. Wren;J. Booth;J. McCabe;David T. E. Whittaker;M. Mantle
中科院分区：
文献类型：
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作者：
E. Pisa;L. Hughes;S. Wren;J. Booth;J. McCabe;David T. E. Whittaker;M. Mantle
药物/聚合物非晶态固体分散体（ASDs）是提高难溶性活性药物成分（api）口服生物利用度的最成功策略之一。热熔挤压（HME）是制备asd的一种方法，在制药工业中越来越重要，但我们对药物在粘性聚合物中的溶解和分散动力学以及最终配方的物理稳定性的理解仍然存在很大差距。此外，为了预测最佳加工条件，已经建立了计算模型，但由于缺乏关键的质量传递参数（如扩散系数）的实验数据，它们受到限制。本文介绍的工作报告使用高温脉冲场梯度核磁共振直接测量API在药用聚合物熔体中的扩散。在与HME过程相关的温度下，测定了模型药物/聚合物体系（扑热息痛/copovidone）在不同载药量下的扩散系数。扩散过程的机制也探索与斯托克斯-爱因斯坦和阿伦尼乌斯模型。结果表明，扩散系数与温度呈指数关系。此外，本研究还包括流变学表征、DSC和1H ssNMR T1和T1ρ测量，以进一步了解扑热息痛/copovidone ASD配方中的物理状态、相分离和API/聚合物相互作用。
The formulation of drug/polymer amorphous solid dispersions (ASDs) is one of the most successful strategies for improving the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Hot melt extrusion (HME) is one method for preparing ASDs that is growing in importance in the pharmaceutical industry, but there are still substantial gaps in our understanding regarding the dynamics of drug dissolution and dispersion in viscous polymers and the physical stability of the final formulations. Furthermore, computational models have been built in order to predict optimal processing conditions, but they are limited by the lack of experimental data for key mass transport parameters, such as the diffusion coefficient. The work presented here reports direct measurements of API diffusion in pharmaceutical polymer melts, using high-temperature pulsed-field gradient NMR. The diffusion coefficient of a model drug/polymer system (paracetamol/copovidone) was determined for different drug loadings and at temperatures relevant to the HME process. The mechanisms of the diffusion process are also explored with the Stokes-Einstein and Arrhenius models. The results show that diffusivity is linked exponentially to temperature. Furthermore, this study includes rheological characterization, DSC and 1H ssNMR T1 and T1ρ measurements to give additional insights into the physical state, phase separation, and API/polymer interactions in paracetamol/copovidone ASD formulations.