Signature of interfacial water structure at the air–drug–polymer aqueous interface studied by sum frequency generation vibrational spectroscopy

The selection of polymers suitable for the formulation of supersaturating drug-delivery systems is imperative to improve the solubility, thermodynamic stability, precipitation inhibition ability, and bioavailability of drugs in vivo. However, a detailed molecular-level understanding of finding the right drug-polymer combination in the aqueous medium is still ambiguous and often selected based on the trial procedure. Here, we have employed sum frequency generation vibrational spectroscopy (SFG-VS) to probe the impact of drug-polymer interactions on the interfacial water structure at the model biorelevant medium (BM) interface to extract better insights into the molecular system. We investigated two different polymers, Eudragit EPO (E-EPO) and polyvinylpyrrolidone K30 (P-K30), resulting in a considerable difference in the supersaturation limits of the atorvastatin calcium (ATC), the model drug molecule in the BM solution. The solubility study suggests an ∼42 times enhancement in the solubility of ATC drug with the presence of E-EPO polymer and merely an ∼2.6 times enhancement for polymer P-K30. Interestingly, SFG spectroscopic studies showed that E-EPO supports a substantial orientational ordering of the interfacial water molecules with the signature of strongly hydrogen (H)-bonded water molecules. An opposite trend is witnessed for the P-K30 polymer with less preferential ordering and weakly H-bonded water molecules at the air-BM interface. The microscopic insights from the SFG spectroscopy, in correlation with the observations on drug solubility, present a new potential approach for probing drug-polymer interactions. The implementation of SFG vibrational spectroscopy can be beneficial in selecting suitable polymers to adopt better strategies for bioavailability enhancement in drug formulation development.