Tuning Mechanical Properties of Pharmaceutical Crystals with Multicomponent Crystals: Voriconazole as a Case Study
Tuning Mechanical Properties of Pharmaceutical Crystals with Multicomponent Crystals: Voriconazole as a Case Study
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DOI：
10.1021/mp500719t
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发表时间：
2015-03-01
影响因子：
4.9
通讯作者：
Desiraju, Gautam R.
中科院分区：
文献类型：
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作者：
Sanphui, Palash;Mishra, Manish Kumar;Desiraju, Gautam R.
伏立康唑是一种抗真菌药物，其晶体本质上是软的，这在对固体施加压力的压实研究中是不利的。晶体工程是用来制造具有改进的机械性能(例如，硬度)的共晶和盐。采用溶剂辅助研磨法制备了富马酸、对羟基苯甲酸、对氨基苯甲酸等生物安全构型的共晶及其与盐酸、草酸形成的盐类。单晶X射线衍射明确证实了这些多组分晶体中质子转移的存在(盐)或不存在(共晶体)。所有的共晶都具有1：1的化学计量比，而盐类具有不同的化学计量比，如盐酸盐(1：2)和草酸盐(1：1.5和1：1)。将纳米压痕技术应用于盐和共晶的单晶。在盐类药物共晶体中，盐表现出比药物和共晶体更好的硬度。根据晶体结构中的滑移面和分子相对于纳米压痕方向的相对取向，解释了这种机械调制的分子起源。盐酸盐是这个家庭中最硬的固体。这对于制剂和药物开发过程中的药物压片可能是有用的。
Crystals of voriconazole, an antifungal drug, are soft in nature, and this is disadvantageous during compaction studies where pressure is applied on the solid. Crystal engineering is used to make cocrystals and salts with modified mechanical properties (e.g., hardness). Cocrystals with biologically safe coformers such as fumaric acid, 4-hydroxybenzoic acid, and 4-aminobenzoic acid and salts with hydrochloric acid and oxalic acid are prepared through solvent assisted grinding. The presence (salt) or absence (cocrystal) of proton transfer in these multicomponent crystals is unambiguously confirmed with single crystal X-ray diffraction. All the cocrystals have 1:1 stoichiometry, whereas salts exhibit variable stoichiometries such as HCl salt (1:2) and oxalate salts (1:1.5 and 1:1). The nanoindentation technique was applied on single crystals of the salts and cocrystals. The salts exhibit better hardness than the drug and cocrystals in the order salts drug cocrystals. The molecular origin of this mechanical modulation is explained on the basis of slip planes in the crystal structure and relative orientations of the molecules with respect to the nanoindentation direction. The hydrochloride salt is the hardest solid in this family. This may be useful for tableting of the drug during formulation and in drug development.