Haskins Molly M, Lusi Matteo, Zaworotko Michael J
Department of Chemical Sciences and Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland.
Cryst Growth Des. 2022 May 4;22(5):3333-3342. doi: 10.1021/acs.cgd.2c00150. Epub 2022 Apr 19.
Approximately 80% of active pharmaceutical ingredients (APIs) studied as lead candidates in drug development exhibit low aqueous solubility, which typically results in such APIs being poorly absorbed and exhibiting low bioavailability. Salts of ionizable APIs and, more recently, pharmaceutical cocrystals can address low solubility and other relevant physicochemical properties. Pharmaceutical cocrystals are amenable to design through crystal engineering because supramolecular synthons, especially those sustained by hydrogen bonds, can be anticipated through computational modeling or Cambridge Structural Database (CSD) mining. In this contribution, we report a combined experimental and CSD study on a class of cocrystals that, although present in approved drug substances, remains understudied from a crystal engineering perspective: ionic cocrystals composed of dihydrogen phosphate (DHP) salts and phosphoric acid (PA). Ten novel DHP:PA ionic cocrystals were prepared from nine organic bases (4,4'-bipyridine, 5-aminoquinoline, 4,4'-azopyridine, 1,4-diazabicyclo[2.2.2]octane, piperazine, 1,2-bis(4-pyridyl)ethane, 1,2-bis(4-pyridyl)xylene, 1,2-di(4-pyridyl)-1,2-ethanediol, and isoquinoline-5-carboxylic acid) and one anticonvulsant API, lamotrigine. From the resulting crystal structures and a CSD search of previously reported DHP:PA ionic cocrystals, 46 distinct hydrogen bonding motifs (HBMs) have been identified between DHP anions, PA molecules, and, in some cases, water molecules. Our results indicate that although DHP:PA ionic cocrystals are a challenge from a crystal engineering perspective, they are formed reliably and, given that phosphoric acid is a pharmaceutically acceptable coformer, this makes them relevant to pharmaceutical science.
在药物研发中作为先导候选物进行研究的活性药物成分（API）中，约80%表现出低水溶性，这通常导致此类API吸收不佳且生物利用度低。可电离API的盐以及最近的药物共晶体可以解决低溶解度和其他相关物理化学性质的问题。药物共晶体适合通过晶体工程进行设计，因为超分子合成子，尤其是那些由氢键维持的合成子，可以通过计算建模或剑桥结构数据库（CSD）挖掘来预测。在本论文中，我们报告了一项关于一类共晶体的实验与CSD相结合的研究，这类共晶体尽管存在于已批准的药物中，但从晶体工程角度来看仍未得到充分研究：由磷酸二氢盐（DHP）和磷酸（PA）组成的离子共晶体。从九种有机碱（4,4'-联吡啶、5-氨基喹啉、4,4'-偶氮吡啶、1,4-二氮杂双环[2.2.2]辛烷、哌嗪、1,2-双（4-吡啶基）乙烷、1,2-双（4-吡啶基）二甲苯、1,2-二（4-吡啶基）-1,2-乙二醇和异喹啉-5-羧酸）和一种抗惊厥API拉莫三嗪制备了十种新型的DHP:PA离子共晶体。从所得晶体结构以及对先前报道的DHP:PA离子共晶体的CSD搜索中，在DHP阴离子、PA分子以及某些情况下的水分子之间鉴定出了46种不同的氢键模式（HBMs）。我们的结果表明，尽管从晶体工程角度来看DHP:PA离子共晶体具有挑战性，但它们能够可靠地形成，并且鉴于磷酸是一种药学上可接受的共形成剂，这使得它们与药物科学相关。
