GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA.
Int J Pharm. 2021 Feb 15;595:120228. doi: 10.1016/j.ijpharm.2021.120228. Epub 2021 Jan 21.
Salt formation can enable the development of poorly water-soluble drugs containing at least one ionizable moiety. Not only can salts offer a solubility enhancement that can sometimes far exceed that of other commonly used solubilization strategies applied across the pharmaceutical industry, they can simultaneously bestow additional benefits such as providing low-cost formulation options. The goal of this work is to put forth a simple methodology to enable one to accurately predict the maximal solubility advantage of acidic and basic drugs whose unionized conjugate (neutral parent molecule) is poorly soluble. While published equations leveraging the Henderson-Hasselbalch/H-H relationship reasonably estimate the thermodynamic solubility limit (in systems where there is no supersaturation), under physiologically relevant conditions the maximal/kinetic solubility can play an important role in determining oral bioavailability, as in the case of amorphous drugs. Under these circumstances, a higher solubility can be maintained for short durations through drug supersaturation provided that the precipitation is slow, thereby causing deviations from H-H predictions. It is possible also that, in some instances, supersaturation could coincide with behavior previously attributed to drug aggregation in solution. The proposed methodology utilizes speciation across the pH range to allow one to determine the maximal amount of ionized and unionized drug in solution at each pH. The calculation is easily extended to cases where the counterion serves as a competing weak acid, weak base, or as a common ion. Additionally, a more thorough assessment of the Gibbs free energy change associated with the solubilization of salts is also presented, as this energy describes the key driving force for the recrystallization of the neutral parent by triggering its nucleation. Lastly, to demonstrate applicability to real-world compounds containing multiple ionizable moieties, the complex pH-solubility profile of a drug maleate salt taken from the literature is simulated.
盐形成可以使含有至少一个可离子化部分的难溶性药物得以开发。盐不仅可以提供溶解度的提高，有时甚至超过制药行业中常用的其他增溶策略，而且还可以同时提供额外的益处，例如提供低成本的配方选择。这项工作的目的是提出一种简单的方法，使人们能够准确预测其非电离共轭（中性母体分子）难溶性的酸性和碱性药物的最大溶解度优势。虽然利用亨德森-哈塞尔巴尔赫（Henderson-Hasselbalch）/H-H 关系的已发表方程可以合理地估计热力学溶解度极限（在没有过饱和度的系统中），但在生理相关条件下，最大/动力学溶解度在确定口服生物利用度方面可能发挥重要作用，例如在无定形药物的情况下。在这些情况下，通过药物过饱和可以在短时间内维持更高的溶解度，只要沉淀缓慢，从而导致与 H-H 预测的偏差。在某些情况下，过饱和度也可能与先前归因于溶液中药物聚集的行为相吻合。所提出的方法利用 pH 范围内的形态分布，使人们能够确定在每个 pH 值下溶液中电离和非电离药物的最大量。该计算很容易扩展到抗衡离子作为竞争弱酸、弱碱或同离子的情况。此外，还提出了对与盐溶解相关的吉布斯自由能变化的更全面评估，因为这种能量描述了通过引发其成核来使中性母体再结晶的关键驱动力。最后，为了证明适用于含有多个可离子化部分的实际化合物，模拟了文献中马来酸盐药物的复杂 pH-溶解度曲线。
