Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

中文翻译：

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解决发现和开发中药物溶解度低的策略。

水溶性低的药物易引起口服生物利用度低和可变，因此，临床反应易变。尽管在铅优化过程中付出了巨大的努力来“设计”可接受的可显影性（包括水溶性），但大约40％的目前市场上销售的化合物和大多数最新的药物开发候选产品仍难溶于水。如此大量的这类候选药物已进入开发和临床评估这一事实，证明了人们对可以采取的促进胃肠道表观溶解度和支持口服给药后药物暴露的方法的认识日益复杂。在这里，我们提供了对水溶性差的先导或开发候选物的发展所面临的主要挑战的详细评论，并回顾了可促进化合物发展的方法和策略。特别是，我们解决了使用策略的基本原理，包括pH调节和盐形式选择，多晶型物，共晶体，助溶剂，表面活性剂，环糊精，粒径减小，无定形固体分散体和基于脂质的制剂。在每种情况下，都将描述效用的理论基础，并详细回顾该领域的最新进展。