Department of Chemistry, Koç University, Istanbul, Turkey.
Department of Chemistry, Koç University, Istanbul, Turkey.
Int J Pharm. 2020 May 15;581:119284. doi: 10.1016/j.ijpharm.2020.119284. Epub 2020 Mar 31.
Co-amorphous systems have been increasingly investigated to improve the solubility and dissolution rate of poorly soluble drugs. Considering the ability of tannic acid (TA), a polyphenolic compound, to form hydrogen bonds with compounds that contain carbonyl groups, we hypothesized that tannic acid will also be effective in stabilizing amorphous form of drugs in co-amorphous systems. Co-amorphization by TA of two poorly soluble model drugs, carbamazepine (CBZ) and indomethacin (IND) was investigated. Tannic acid facilitated the amorphization of studied drugs and successful co-amorphous systems were obtained as proved by powder X-Ray diffraction (PXRD). Differential scanning calorimetry (DSC) confirmed the homogeneous structure as indicated by the existence of a single T for each co-amorphous product. The expected molecular interactions between phenolic groups in TA and carbonyl groups in the studied drugs (CBZ and IND) were confirmed by analyzing their infrared spectra. Drug-TA co-amorphous formulations showed an enhanced equilibrium solubility over the individual drugs. Powder dissolution test under sink conditions showed improved dissolution profiles of drug-TA co-amorphous formulations compared to the corresponding crystalline drugs and physical mixtures. Tannic acid also showed a superior stabilizing effect. CBZ-TA co-amorphous system was physically stable at dry conditions (up to 6 months at 40 °C), under 60% relative humidity (up to one month at 20 °C), and in solution (after 48 h of solubility measurements), as revealed by PXRD examination of the remaining solid after solubility measurement. However, IND-TA co-amorphous formulation remained stable at dry conditions up to 6 months at 4 °C and up to one month at 60% relative humidity at 20 °C. These findings demonstrate the potential of tannic acid as a promising co-former in co-amorphous systems of poorly soluble drugs.
共无定形系统已被越来越多地研究用于提高难溶性药物的溶解度和溶解速率。考虑到单宁酸（TA）作为一种多酚化合物与含有羰基的化合物形成氢键的能力，我们假设单宁酸也将有效地稳定药物在共无定形系统中的无定形形式。研究了单宁酸（TA）对两种难溶性模型药物卡马西平（CBZ）和吲哚美辛（IND）的共无定形作用。单宁酸促进了研究药物的无定形化，并通过粉末 X 射线衍射（PXRD）证实获得了成功的共无定形系统。差示扫描量热法（DSC）证实了每个共无定形产物中存在单一 T 表明其具有均匀的结构。通过分析它们的红外光谱证实了 TA 中的酚基团和研究药物（CBZ 和 IND）中的羰基之间存在预期的分子相互作用。药物-TA 共无定形制剂的平衡溶解度高于单个药物。在溶出条件下的粉末溶解试验表明，与相应的晶型药物和物理混合物相比，药物-TA 共无定形制剂的溶解曲线得到了改善。单宁酸还表现出优越的稳定作用。CBZ-TA 共无定形系统在干燥条件下（在 40°C 下长达 6 个月）、在 60%相对湿度下（在 20°C 下长达一个月）以及在溶液中（在溶解度测量 48 小时后）具有物理稳定性，如通过剩余固体的 PXRD 检查在溶解度测量后揭示。然而，IND-TA 共无定形制剂在干燥条件下在 4°C 下长达 6 个月和在 20°C 下 60%相对湿度下长达一个月保持稳定。这些发现表明单宁酸作为难溶性药物共无定形系统中一种有前途的共晶形成剂的潜力。
