Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Department of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
J Pharm Sci. 2018 Sep;107(9):2420-2427. doi: 10.1016/j.xphs.2018.04.030. Epub 2018 May 31.
It has been previously shown that the interaction of some weakly basic drugs with oppositely charged fatty acids during digestion can influence the solid-state form of the drug if it precipitates. The present study hypothesized the opposite effect for weakly acidic drugs. Tolfenamic acid (TA) and an oppositely charged cationic surfactant, didodecyldimethylammonium bromide (DDAB) were combined in a model medium chain lipid formulation. The phase distribution upon in vitro lipolysis was determined using HPLC and the solid-state form of precipitated TA was determined using X-ray diffraction and crossed polarized light microscopy. TA precipitated in a different polymorphic crystalline form to the starting reference material in the absence of DDAB but precipitated in an amorphous form when DDAB was included in the same formulation. The solubility of TA upon dispersion and digestion of the formulation was considerably higher in the presence of DDAB. The findings point to ionic interactions between TA and DDAB as the reason for the improved drug solubility throughout digestion, and precipitation of drug in an amorphous salt form, analogous to what has been observed in the past for some poorly water-soluble weakly basic drugs with anionic co-formers.
先前已经表明，一些弱碱性药物在消化过程中与带相反电荷的脂肪酸相互作用，如果药物发生沉淀，则会影响药物的固态形式。本研究假设弱酸性药物会产生相反的效果。托芬那酸（TA）和带相反电荷的阳离子表面活性剂双十二烷基二甲基溴化铵（DDAB）在模型中链脂质制剂中组合。使用 HPLC 测定体外脂肪分解时的相分布，并使用 X 射线衍射和交叉偏振光显微镜确定沉淀的 TA 的固态形式。在不存在 DDAB 的情况下，TA 以与起始参考物质不同的多晶型晶体形式沉淀，但当将 DDAB 包含在相同制剂中时，TA 以无定形形式沉淀。在存在 DDAB 的情况下，配方分散和消化时 TA 的溶解度大大提高。研究结果表明，TA 和 DDAB 之间的离子相互作用是整个消化过程中提高药物溶解度的原因，并且药物以无定形盐的形式沉淀，类似于过去观察到的一些水溶性差的弱碱性药物与阴离子共晶形成物。
