Agatonovic-Kustrin S, Markovic N, Ginic-Markovic M, Mangan M, Glass B D
School of Pharmacy and Molecular Sciences, James Cook University, Townsville, QLD 4811, Australia.
J Pharm Biomed Anal. 2008 Sep 29;48(2):356-60. doi: 10.1016/j.jpba.2008.02.009. Epub 2008 Feb 17.
Omeprazole, commonly used in the treatment of various gastrointestinal disorders degrades rapidly in acidic pHs and results in inter-individual variability due to different rates of metabolism amongst patients. Since S-omeprazole shows more predictable bioavailability and excipients have been known to interact with active pharmaceutical ingredients to produce altered bioavailability, it was decided to investigate the compatibility of omeprazole sodium isomers with mannitol, the major excipient in omeprazole formulations using differential scanning calorimetry (DSC) for bulk drug, attenuated total reflectance (ATR) infrared (IR) spectroscopy in a powder mixture and localized thermal analysis (LTA) from a drug disk. DSC results clearly indicate an interaction between mannitol and R-omeprazole sodium due to decreased melting temperatures and broadening peaks. The DSC of S-omeprazole sodium does not show melting temperature although the drug was crystalline. Because of the accelerated temperature conditions during DSC experiments applied in this work, ATR-IR was undertaken to determine whether these results occurred at room temperature for the solid dosage form. The ATR-IR results show a difference between R- and S-omeprazole sodium with mannitol by the appearance of both the amino (N-H) and imino (N-H) stretching frequencies for R-omeprazole and only the N-H for the S-omeprazole sodium. It may thus be concluded that different ratios for the tautomeric forms for S- and R-omeprazole sodium result in changes in the degree of crystallinity and are responsible for the interaction with mannitol, common excipient in formulation. These interactions may be directly related to the difference in terms of bioavailability.
奥美拉唑常用于治疗各种胃肠道疾病,在酸性pH值下会迅速降解,且由于患者之间代谢速率不同,会导致个体差异。由于S-奥美拉唑显示出更可预测的生物利用度,并且已知辅料会与活性药物成分相互作用以产生改变的生物利用度,因此决定使用差示扫描量热法(DSC)对原料药进行研究,对粉末混合物进行衰减全反射(ATR)红外(IR)光谱分析,并对药物盘进行局部热分析(LTA),以研究奥美拉唑钠异构体与甘露醇(奥美拉唑制剂中的主要辅料)的相容性。DSC结果清楚地表明,由于熔点降低和峰变宽,甘露醇与R-奥美拉唑钠之间存在相互作用。尽管S-奥美拉唑钠为晶体,但DSC未显示其熔点。由于本研究中DSC实验采用了加速温度条件,因此进行了ATR-IR分析,以确定这些结果在室温下是否适用于固体剂型。ATR-IR结果显示,R-奥美拉唑钠和S-奥美拉唑钠与甘露醇之间存在差异,R-奥美拉唑出现了氨基(N-H)和亚氨基(N-H)伸缩频率,而S-奥美拉唑钠仅出现了N-H伸缩频率。因此可以得出结论,S-和R-奥美拉唑钠互变异构体的不同比例导致结晶度的变化,并导致与制剂中常用辅料甘露醇发生相互作用。这些相互作用可能与生物利用度的差异直接相关。