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

[Display omitted] •A novel co-amorphous formulation of dipyridamole (DPM) with p-hydroxybenzoic acid (HBA) was synthesized via melting method.•The molecular mechanisms of the co-amorphous were investigated via spectroscopic studies and DFT simulation.•Accelerated test and glass transition kinetics showed superior physical stability of co-amorphous compared with amorphous DPM alone.•Solubility and dissolution behavior of DPM in co-amorphous were optimized than its single crystal and amorphous forms.•The pharmacokinetic study was evaluated using SD rats, and the results showed the bioavailability of DPM is significantly improved on co-amorphizing with HBA. 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 1H nuclear magnetic resonance (1H 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.