School of Pharmacy, Boots Science Building, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
Pharmaceutical Development, AstraZeneca, Macclesfield, SK10 2NA, United Kingdom.
J Control Release. 2014 Aug 28;188:53-60. doi: 10.1016/j.jconrel.2014.05.061. Epub 2014 Jun 5.
We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form.
我们首次采用拉曼光谱成像结合多元曲线分辨（MCR）分析实时原位研究无定形固体分散体的溶解机制，数据直接来自剂型本身。我们还采用了新颖的旋转盘溶出速率（RDDR）方法，通过高效液相色谱（HPLC）同时跟踪多组分体系中药物和聚合物的溶解趋势。我们使用两种不同载药量（5%和 50%w/w）的聚合物基质共聚维酮 VA64 中的难溶性非洛地平作为模型，旨在研究增加活性成分数量对溶解性能的影响。结果发现，5%分散体中的非洛地平和共聚维酮以相同的溶解速率溶解，且溶解过程中没有拉曼光谱变化，表明两种成分以单一实体溶解，其行为受水溶性共聚维酮主导。对于 50%载药量的分散体，发现非洛地平和共聚维酮的部分 RDDR 值极低。MCR 拉曼图谱和经典拉曼/ X 射线粉末衍射（XRPD）表征表明，挤出物中最初失去共聚维酮后，药物重新结晶，这表明释放动力学取决于非洛地平的低水溶性和高疏水性。拉曼成像揭示了在剂型内不同位置非洛地平从无定形到结晶的不同转变速率。
