Mechanistic Investigation into Crystallization of Hydrated Co-Amorphous Systems of Flurbiprofen and Lidocaine.

It is generally accepted that water as a plasticizer can decrease the glass transition temperatures (Ts) of amorphous drugs and drug delivery systems, resulting in physical instabilities. However, a recent study has reported an anti-plasticizing effect of water on amorphous lidocaine (LID). In co-amorphous systems, LID might be used as a co-former to impair the plasticizing effect of water. Flurbiprofen (FLB) was used to form a co-amorphous system with a mole fraction of LID of 0.8. The effect of water on the stability of co-amorphous FLB-LID upon hydration was investigated. The crystallization behaviors of anhydrous and hydrated co-amorphous FLB-LID systems were measured by an isothermal modulated differential scanning calorimetric (iMDSC) method. The relaxation times of the co-amorphous FLB-LID system upon hydration were measured by a broadband dielectric spectroscopy (BDS), and the differences in Gibbs free energy (ΔG) and entropy (ΔS) between the amorphous and crystalline phases were determined by differential scanning calorimetry (DSC). It was found that the crystallization tendency of co-amorphous FLB-LID decreased with the addition of water. Molecular mobility and thermodynamic factors were both investigated to explain the difference in crystallization tendencies of co-amorphous FLB-LID upon hydration. The results of the study showed that LID could be used as an effective co-former to decrease the crystallization tendency of co-amorphous FLB-LID upon hydration by enhancing the entropic (ΔS) and thermodynamic activation barriers (TΔS)/ΔG) to crystallization.