Solubility enhancement has become a common requirement for formulation development to deliver poorly water soluble drugs. Amorphous solid dispersions (ASDs) and salt formation have been two successful strategies, yet there are opportunities for further development. For ASDs, drug–polymer phase separation may occur at high drug loadings during dissolution, limiting the increase of drug loadings in ASD formulations. For salt formation, a salt form with high crystallinity and sufficient solid-state stability is required for solid dosage form development. This work studied the effect of counterions on the dissolution performance of ASDs. Surface area normalized dissolution or intrinsic dissolution methodology was employed to eliminate the effect of particle size and provide a quantitative comparison of the counterion effect on the intrinsic dissolution rate. Using indomethacin (IMC)–poly(vinylpyrrolidone-co-vinyl acetate) ASD as a model system, the effect of different bases incorporated into the ASD during preparation, the molar ratios between the base and IMC, and the drug loadings in the ASD were systematically studied. Strong bases capable of ionizing IMC significantly enhanced drug dissolution, while a weak base did not. A physical mixture of a strong base and the ASD also enhanced the dissolution rate, but the effect was less pronounced. At different base to IMC molar ratios, dissolution enhancement increased with the base to IMC ratio. At different drug loadings, without a base, the IMC dissolution rate decreased with the increase of drug loading. After incorporating a strong base, it increased with the increase of drug loading. The observations from this study were thought to be related to both the ionization of IMC in ASDs and the increase of microenvironment pH by the incorporated bases. With the significant enhancement of the drug dissolution rate, our work provides a promising approach of overcoming the dissolution limitation of ASD formulations at high drug loadings.

中文翻译：

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用表面积归一化溶解研究抗衡离子对非晶态固体分散体溶解的影响

提高溶解度已成为配方开发以提供水溶性差的药物的常见要求。无定形固体分散体 (ASD) 和成盐是两种成功的策略，但仍有进一步发展的机会。对于 ASD，药物-聚合物相分离可能会在溶解过程中的高载药量下发生，从而限制了 ASD 制剂中载药量的增加。对于盐的形成，固体剂型开发需要具有高结晶度和足够固态稳定性的盐形式。这项工作研究了抗衡离子对 ASD 溶解性能的影响。采用表面积归一化溶出或固有溶出方法来消除粒径的影响，并提供抗衡离子对固有溶出速率的影响的定量比较。以吲哚美辛（IMC）-聚（乙烯基吡咯烷酮-共-醋酸乙烯酯）ASD为模型体系，在制备过程中掺入ASD的不同碱基的影响、碱基与IMC的摩尔比以及ASD中的载药量为系统地研究。能够电离 IMC 的强碱显着增强药物溶出，而弱碱则没有。强碱和 ASD 的物理混合物也提高了溶解速率，但效果不太明显。在不同的碱与 IMC 摩尔比下，溶出增强随着碱与 IMC 的比例而增加。在不同的载药量下，在没有碱的情况下，IMC溶出度随着载药量的增加而降低。加入强碱后，随着载药量的增加而增加。这项研究的观察结果被认为与 ASD 中 IMC 的电离和掺入的碱基对微环境 pH 值的增加有关。随着药物溶出率的显着提高，我们的工作提供了一种有前途的方法来克服 ASD 制剂在高载药量下的溶出限制。