Abstract by Xiaoyue Xu

It is commonly believed that water is a universal plasticizer, that will lower the glass transition temperatures (T_gs) of amorphous drugs and pharmaceutical systems, leading to physical instability. This thesis aims to offer insights into the anti-plasticizing effect of water on amorphous drugs and systems, and to explore practical applications for impairing the plasticizing effect of water on amorphous pharmaceutical systems.

Recent reports indicate that water increases the T_g of the amorphous form of prilocaine (PRL), thus indicating an anti-plasticizing effect. This was previously attributed to the formation of a dimeric structure in the drugs, bridged by a single water molecule. Lidocaine (LID), which is structurally similar to PRL, might also exhibit an anti-plasticizing effect of water in its amorphous form. Understanding the effect of water on amorphous LID could prove beneficial in elucidating the general nature of this effect of water on amorphous drugs. Furthermore, exploring the effect of water on co-amorphous systems containing PRL and LID as co-formers could offer insights into whether the anti-plasticizing effect of water on co-formers enhances the stability of amorphous pharmaceutical systems upon hydration.

In the first part of this thesis, the effect of water on the T_g of amorphous LID was investigated to determine if water is an anti-plasticizer for amorphous LID. The influence of water on the T_g of LID cannot be measured directly, due to fast crystallization of amorphous LID. The T_gs of anhydrous and hydrated LID were extrapolated from those of co-amorphous PRL-LID systems. The molecular interactions in anhydrous and hydrated co-amorphous PRL-LID were investigated using Fourier transform infrared spectroscopy (FTIR) and principal component analysis (PCA). The T_g of amorphous LID was predicted using the modified Gordon-Taylor approach, by treating the optimal co-amorphous system as one component and the excess drug as the other component. The optimal co-amorphous PRL-LID system was found to be consistent with maximally enhanced molecular interactions according to spectroscopic investigations. Overall, upon maximal hydration at a water-to-drug molar ratio of X_H2O=50%, the T_g of hydrated LID increased by a maximum of 0.9±0.7 K, compared to the T_g of anhydrous LID, indicating an anti-plasticizing effect of water on amorphous LID.

The second part of this thesis explored the mechanism of water’s anti-plasticizing effect on amorphous PRL and LID. FTIR and quantum chemical simulations were conducted to compare the interactions and resulting structural properties of amorphous PRL and LID with different solvents. Heavy water (deuterium oxides) was chosen as a solvent due to the electronic equivalence between deuterium and hydrogen atoms. The solvents ethanol and ethylene glycol were chosen due to their differing capacities to interact with the C=O group of the amide moieties in PRL and LID. Comparison of the various T_gs showed a similar anti-plasticizing effect of heavy water on PRL to that of water, and an anti-plasticizing potential of ethanol and ethylene glycol on PRL and LID. The frequency shifts of the amide C=O groups of PRL and LID observed in the FTIR spectra, due to interactions with water, heavy water, ethanol, ethylene glycol, correlated with the simulated binding energies. Overall, the results indicated that a combination of weak hydrogen bonding and strong electrostatic contributions could be favourable to induce anti-plasticization of water on the drugs PRL and LID.

In the last part of the thesis, PRL and LID were used as co-formers, while nicotinamide (NIC) and flurbiprofen (FLB) were chosen as model drugs. The effect of water on the T_gs, molecular mobility and thermodynamic properties of these co-amorphous systems was investigated, focusing on their physical stability upon hydration. The influence of water on the T_gs, molecular mobility, and thermodynamics of co-amorphous systems of NIC-PRL and FLB-LID was determined using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). The crystallization behaviours of co-amorphous FLB-LID systems upon hydration were investigated in DSC. At high mole fractions of PRL of 0.8 and above, an anti-plasticizing effect of water on co-amorphous NIC-PRL systems was observed, with increased T_gs and restricted molecular mobility. Furthermore, at a high mole fraction of LID of 0.8, water decreased the crystallization tendency of co-amorphous FLB-LID system, which was associated with increased entropic (ΔS) and thermodynamic activation barriers (((TΔS)³/ΔG²). Overall, water influenced the T_gs, molecular mobility, and thermodynamic factors of co-amorphous systems of NIC-PRL and FLB-LID, potentially enhancing the physical stability of these systems.

In summary, this thesis enhances the understanding of water’s anti-plasticizing effect on amorphous drugs and systems and opens up the feasibility of using co-formers that are susceptible to anti-plasticization by water to impair the plasticizing effect of water on amorphous pharmaceutical systems.