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The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures.
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-03-30 , DOI: 10.1021/acs.molpharmaceut.8b00173
Andrew J Clulow 1 , Malinda Salim 1 , Adrian Hawley 2 , Elliot P Gilbert 3 , Ben J Boyd 1, 4
Affiliation  

Efforts to develop orally administered drugs tend to place an exceptional focus on aqueous solubility as this is an essential criterion for their absorption in the gastrointestinal tract. In this work we examine the solid state behavior and solubility of OZ439, a promising single-dose cure for malaria being developed as the highly water-soluble mesylate salt. The aqueous phase behavior of the OZ439 mesylate salt was determined using a combination of small angle neutron and X-ray scattering (SANS and SAXS, respectively). It was found that this salt has low solubility at low concentrations with the drug largely precipitated in free base aggregates. However, with increasing concentration these crystalline aggregates were observed to dissociate into cationic micelles and lamellar phases, effectively increasing the dissolved drug concentration. It was also found that the dissolved OZ439 spontaneously precipitated in the presence of biologically relevant anions, which we attribute to the high lattice energies of most of the salt forms of the drug. These findings show that aqueous solubility is not always what it seems in the context of amphiphilic drug molecules and highlights that its use as the principal metric in selecting drug candidates for development can be perilous.

中文翻译:

OZ439甲磺酸盐的奇特案例:具有不同溶液和固态结构的两亲抗疟药。

研发口服药物的努力往往将重点放在水溶性上,因为这是其在胃肠道吸收的必要标准。在这项工作中,我们研究了OZ439的固态行为和溶解度,OZ439是一种有前途的单剂量疟疾治疗药,已开发为高度水溶性的甲磺酸盐。OZ439甲磺酸盐的水相行为是使用小角度中子和X射线散射(分别为SANS和SAXS)的组合确定的。发现该盐在低浓度下具有低溶解度,并且药物大量沉淀在游离碱聚集体中。然而,随着浓度的增加,观察到这些结晶聚集体解离成阳离子胶束和层状相,有效地增加了溶解的药物浓度。还发现溶解的OZ439在生物相关阴离子的存在下自发沉淀,这归因于该药物大多数盐形式的高晶格能。这些发现表明,在两亲性药物分子的情况下,水溶性并非总是如此,并突显了其在选择待开发药物候选者时作为主要指标的危险性。
更新日期:2018-03-20
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