Dicarboxylic acid as a linker to improve the content of amorphous drug in drug-in-polymer film: Effects of molecular mobility, electrical conductivity and intermolecular interactions

Amorphous solid dispersion (ASD) is a well-established approach to improve the dissolution rate of the drugs with low water solubility. However, the application of the ASD was hindered by the low drug content and high risk of re-crystallization of drugs. The purpose of this research was to develop an ASD film with high content of amorphous olanzapine (OLN) for oral delivery. To overcome the high crystallization tendency of OLN in polyvinyl alcohol (PVA) films, three dicarboxylic acids (succinic acid (Suc), fumaric acid (Fum) and malic acid (Mal)) were introduced in the drug-in-polymer system as linkers between the drug and the polymer. The influence of the linkers on the re-crystallization of OLN in PVA films was evaluated by polarized light microscopy (PLM) and x-ray diffraction (XRD). Then, the possible mechanisms of crystallization inhibition were discussed based on the results of dielectric spectroscopy (DES), differential scanning calorimetry (DSC), attenuated total reflectance Fourier transform infrared (ATR-FTIR), Raman spectroscopy and molecular modeling. Finally, the effect of the linkers on the in vitro dissolution of the OLN-in-PVA films was studied in simulant saliva, and the in vivo performance of the optimal formulation was evaluated in rats. The results showed that OLN-in-PVA film have lower molecular mobility, lower electrical conductivity and stronger intermolecular interactions with the existence of Mal, which led to a better crystallization inhibition of OLN in PVA films. The re-crystallization of OLN in PVA films decreased the dissolution rate of OLN in simulant saliva. The in vivo performance of the optimal formulation was similar with that of OLN solution in rats. This study introduced a novel strategy to reduce the risk of drug re-crystallization in ASD, and also provided a deeper insight into the mechanisms of crystallization inhibition in ASD. The results will improve the judicious selection of excipients in pharmaceutical formulations.