Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907; Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064.
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064.
J Pharm Sci. 2011 Aug;100(8):3316-3331. doi: 10.1002/jps.22579. Epub 2011 May 23.
Amorphous solid dispersions (ASDs) are widely utilized in the pharmaceutical industry for bioavailability enhancement of low solubility drugs. The important factors governing the dissolution behavior of these systems are still far from adequately understood. As a consequence, it is of interest to investigate the behavior of these systems during the dissolution process. The purpose of this research was twofold. First, the degree of supersaturation generated upon dissolution as a function of drug-polymer composition was investigated. Second, an investigation was conducted to correlate physical behavior upon dissolution with polymer loading. Felodipine and indomethacin were selected as model drugs and hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were used to form the dispersions. Diffusion and nuclear magnetic resonance spectroscopy experiments revealed that the extent of bulk supersaturation generated on dissolution of the ASD did not depend on the drug-polymer ratio. Interestingly, the maximum supersaturation generated was similar to the predicted amorphous solubility advantage. However, dynamic light scattering measurements revealed that particles on the submicron scale were generated during dissolution of the solid dispersions containing 90% polymer, whereas solid dispersions at a 50% polymer loading did not yield these nanoparticles. The nanoparticles were found to result in anomalous concentration measurements when using in situ ultraviolet spectroscopy. The supersaturation generated upon dissolution of the solid dispersions was maintained for biologically relevant timeframes for the HPMC dispersions, whereas PVP appeared to be a less effective crystallization inhibitor.
无定形固体分散体（ASD）广泛应用于制药行业，以提高低溶解度药物的生物利用度。尽管这些系统的溶解行为的重要因素仍远未得到充分理解，但仍需要进行研究。本研究旨在探讨这些系统在溶解过程中的行为。本研究有两个目的。首先，研究了药物-聚合物组成对溶解时产生的过饱和度的影响。其次，研究了物理行为与聚合物负载之间的相关性。选择非洛地平（felodipine）和吲哚美辛（indomethacin）作为模型药物，羟丙基甲基纤维素（HPMC）和聚乙烯吡咯烷酮（PVP）用于形成分散体。扩散和核磁共振波谱实验表明，溶解 ASD 时产生的体相过饱和度的程度与药物-聚合物的比例无关。有趣的是，生成的最大过饱和度与预测的无定形溶解度优势相似。然而，动态光散射测量表明，在含有 90%聚合物的固体分散体溶解过程中会生成亚微米级的颗粒，而在 50%聚合物负载的固体分散体中则不会生成这些纳米颗粒。当使用原位紫外光谱法进行浓度测量时，发现这些纳米颗粒会导致异常的浓度测量。在 HPMC 分散体中，溶解时生成的过饱和度可以维持在生物学相关的时间范围内，而 PVP 似乎是一种不太有效的结晶抑制剂。
