Co-amorphous formulation of dipyridamole with p-hydroxybenzoic acid: Underlying molecular mechanisms, physical stability, dissolution behavior and pharmacokinetic study

Author：Wei Guo 1 , Xueqing Dong 1 , Yuanchun Li, Congwei Li, Yawen Tian, Huibing Gao, Tiantian Li, Hanruo Zhu, Jing Wang * , Caiqin Yang

ABSTRACT：Coamorphization has been proven to be an effective approach to improve bioavailability of poorly soluble active pharmaceutical ingredients (APIs) by virtue of solubilization, and also contributes to overcome limitation of physical stability associated with amorphous drug alone. In current work, a co-amorphous formulation of dipyridamole (DPM), a poor solubility drug, with p-hydroxybenzoic acid (HBA) was prepared and investigated. At a molar ratio of 1:2, DPM and HBA were melted result in the formation of a binary co-amorphous system. The DPM-HBA co-amorphous was structurally characterized by powder X-ray diffraction (PXRD), temperature modulated differential scanning calorimetry (mDSC), high performance liquid chromatography (HPLC) and solution state 1 H nuclear magnetic resonance ( 1 H NMR). The molecular mechanisms in the co-amorphous were further analysed via Fourier-transform infrared (FTIR) and Raman spectroscopies, as well as density functional theory (DFT) calculation. All the results consistently revealed the presence of hydrogen bonding interactions between –OH of DPM and − COOH on HBA. Accelerated test and glass transition kinetics showed excellent physical stability of DPM-HBA co-amorphous compared with amorphous DPM along with glass transition temperatures (Tg). The phase-solubility study indicated that complexation occurred between DPM and HBA in solution, which contributed to the solubility and dissolution enhancement of DPM in co-amorphous system. Pharmacokinetic study of co-amorphous DPM-HBA in mouse plasma revealed that the DPM exhibited 1.78-fold and 2.64-fold improvement in AUC0‑∞ value compared with crystalline and amorphous DPM, respectively. This current study revealed coamorphization is an effective approach for DPM to improve the solubility and biopharmaceutical performance.

Keywords:Dipyridamole Co-amorphous system Physicochemical properties Intermolecular interactions Glass transition kinetics Pharmacokinetic study

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