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Solubility advantage of amorphous drugs and pharmaceutical cocrystals

机译：无定形药物和药物共晶体的溶解度优势

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The current phase of drug development is witnessing an oncoming crisis due to the combined effects of increasing R&D costs, decreasing number of new drug molecules being launched, several blockbuster drugs falling off the patent cliff, and a high proportion of advanced drug candidates exhibiting poor aqueous solubility. The traditional approach of salt formulation to improve drug solubility is unsuccessful with molecules that lack ionizable functional groups, have sensitive moieties that are prone to decomposition/racemization, and/or are not sufficiently acidic/basic to enable salt formation. Several novel examples of pharmaceutical cocrystals from the past decade are reviewed, and the enhanced solubility profiles of cocrystals are analyzed. The peak dissolution for pharmaceutical cocrystals occurs in a short time (<30 min), and high solubility is maintained over a sufficiently long period (4-6 h) for the best cases. The enhanced solubility of drug cocrystals is similar to the supersaturation phenomenon characteristic of amorphous drugs. However, in contrast to the metastable nature of amorphous phases, cocrystals are stable owing to their crystalline nature. Yet, cocrystals can exhibit dramatic solubility advantage over the stable crystalline drug form, often comparable to amorphous pharmaceuticals. The "spring and parachute" concept for amorphous drug dissolution is adapted to explain the solubility advantage of pharmaceutical cocrystals. Thus (1) the cocrystal dissociates to amorphous or nanocrystalline drug clusters (the spring), which (2) transform via fast dissolving metastable polymorphs to the insoluble crystalline modification following the Ostwalds Law of Stages, to give (3) high apparent solubility for cocrystals and optimal drug concentration (the parachute) in the aqueous medium.
机译：由于研发成本增加，新药分子的投放数量减少，几种重磅炸药从专利悬崖上掉下来，以及高比例的候选药物表现出以下综合作用，药物开发的当前阶段正面临即将到来的危机：溶解度。盐配制物改善药物溶解性的传统方法对于缺少可离子化的官能团，具有易于分解/外消旋的敏感部分和/或不足以使盐形成的酸性/碱性的分子而言，是不成功的。回顾了过去十年中药物共晶体的几个新实例，并分析了共晶体溶解度的提高。药物共晶体的峰值溶解发生在短时间内（<30分钟），对于最佳情况，在足够长的时间内（4-6小时）可以保持高溶解度。药物共晶体的增加的溶解度类似于无定形药物的过饱和现象特征。但是，与非晶相的亚稳态性质相反，共晶由于其结晶性质而稳定。然而，与稳定的结晶药物形式（通常可与无定形药物媲美）相比，共晶体可表现出显着的溶解性优势。用于无定形药物溶解的“弹簧和降落伞”概念适用于解释药物共晶的溶解性优势。因此（1）共晶体解离为无定形或纳米晶体药物簇（弹簧），其（2）通过快速溶解的亚稳态多晶型物转变，遵循奥斯特瓦尔德斯分阶段定律，从而产生（3）高的表观溶解度以及水性介质中的最佳药物浓度（降落伞）。

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