Sbârcea L, Udrescu L, Drăgan L, Trandafirescu C, Szabadai Z, Bojiţă M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania.
Pharmazie. 2011 Aug;66(8):584-9.
Fosinopril is one of the most hydrophobic substances among the angiotensin-converting enzyme inhibitors, exhibiting low water solubility and poor bioavailability following oral administration. Inclusion complexes between the drug substance and cyclodextrins (CDs) were obtained in order to improve its solubility. The purpose of this study was to investigate the guest-host interaction of fosinopril sodium (FOS) with beta-cyclodextrin (beta-CD) and its derivative, randomly methylated beta-cyclodextrin (RAMEB) in solution by phase solubility diagrams (PSD) and in solid state by using thermal analysis, powder X-ray diffractometry (PXRD) and Fourier transform infrared spectroscopy (FTIR). The phase solubility analysis indicated that the solubility of FOS in simulated gastric fluid was increased in the presence of CDs and revealed for RAMEB an A(L)-type diagram, suggesting the formation of a 1:1 inclusion complex, and for beta-CD a B(s)-type phase diagram. The estimated apparent stability constant (K1:1), according to the Higuchi and Connors method, is 3209.99 M(-1) and 1770.34 M(-1) for RAMEB and beta-CD complexes respectively. The binary systems FOS/CDs were prepared using the kneading method in the molar ratio 1:1. The PXRD patterns and the thermograms indicated a drug amorphization process, higher for FOS/RAMEB binary system and the FTIR analysis suggested that the ester group of FOS is probably enclosed in the CD's cavity. The results of this study confirm the formation of inclusion complexes both in solution and in solid state and suggest that the complexes formation between FOS and CDs could improve the bioavailability of the drug due to the enhancing absorption expected from increased drug solubility.
福辛普利是血管紧张素转换酶抑制剂中疏水性最强的物质之一，口服后水溶性低且生物利用度差。为提高其溶解度，制备了药物与环糊精（CDs）的包合物。本研究旨在通过相溶解度图（PSD）在溶液中以及利用热分析、粉末X射线衍射（PXRD）和傅里叶变换红外光谱（FTIR）在固态下研究福辛普利钠（FOS）与β-环糊精（β-CD）及其衍生物随机甲基化β-环糊精（RAMEB）的客体-主体相互作用。相溶解度分析表明，在CDs存在下，FOS在模拟胃液中的溶解度增加，RAMEB呈现A(L)型图，表明形成了1:1包合物，而β-CD呈现B(s)型相图。根据Higuchi和Connors方法估算的表观稳定常数（K1:1），RAMEB和β-CD络合物分别为3209.99 M(-1)和1770.34 M(-1)。采用捏合法以1:1的摩尔比制备了二元体系FOS/CDs。PXRD图谱和热重曲线表明药物发生了非晶化过程，FOS/RAMEB二元体系更为明显，FTIR分析表明FOS的酯基可能被包封在CD的腔内。本研究结果证实了在溶液和固态中均形成了包合物，并表明FOS与CDs之间形成的络合物可能由于药物溶解度增加预期的吸收增强而提高药物的生物利用度。
