Tailoring supersaturation from amorphous solid dispersions.
Tailoring supersaturation from amorphous solid dispersions.
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DOI：
10.1016/j.jconrel.2018.04.014
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发表时间：
2018-06-10
期刊：
影响因子：
--
通讯作者：
Taylor LS
中科院分区：
文献类型：
--
作者：
Li N;Taylor LS
溶液中药物可达到的最大浓度是由固体形式的化学势决定的。由于非晶固体比相应的晶体形式具有更高的化学势，在没有相变的情况下，期望具有更高的瞬态溶解度。然而，无定形药物的化学势可以通过与另一种成分混合而降低。因此，当与聚合物混合形成非晶固体分散体（ASD）时，达到的最大溶液浓度可能会发生改变，特别是当聚合物在溶解介质中难溶时。药物化学势的这种变化可能是决定可达到的最大溶液浓度的关键因素，并可能改变药物的结晶驱动力。因此，本研究的目的是深入了解难溶性聚合物对作为非晶态固体分散体配制的药物的“非晶态溶解度”的影响。洛匹那韦被选为低结晶倾向的模型药物，可以测定其非晶态溶解度与ASD组成的关系。模型聚合物包括醋酸纤维素（CA），邻苯二甲酸钙（CAP），乙基纤维素（EC）， Eudragit®RL PO (EUD)，羟丙基甲基纤维素（HPMC）， HPMC乙酸琥珀酸酯（HPMCAS）和HPMC邻苯二甲酸酯（HPMCP）。测定了药物单独的“无定形溶解度”，然后测量了最大可达到浓度的变化作为药物负载的函数。采用红外光谱（IR）、差示扫描量热法（DSC）和吸湿分析对药物-聚合物相互作用进行了表征。结果表明，洛匹那韦的最大可达浓度（“无定形溶解度”）随药物-聚合物相互作用的程度以及ASD中药物重量分数的变化而变化。这一信息在评估pH响应聚合物配制的非晶态体系的最大可实现浓度时具有重要价值，并有助于更广泛地了解asd背景下的药物相行为。
The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the solid form. Because an amorphous solid has a higher chemical potential than the corresponding crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an amorphous solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the “amorphous solubility” of drugs formulated as amorphous solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The “amorphous solubility” of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration (“amorphous solubility”) of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.
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