Drug Solubilization using N-Methyl Pyrrolidone: Efficiency and Mechanism

Abstract

The solubilization efficiency of N-methyl pyrrolidone (NMP) has been determined and compared to that of ethanol and propylene glycol for 13 poorly soluble drugs. NMP is a more efficient solubilizer for all these drugs. The solubility enhancement as high as about 800-fold is obtained in 20% v/v NMP solution as compared to water. The mechanism of drug solubilization by NMP has also been investigated. It is proposed that NMP enhances drug solubility by simultaneously acting as a cosolvent and a complexing agent. A mathematical model to estimate drug solubility in NMP-water mixture is proposed, according to which the total solubility enhancement is a sum of these two effects. This model describes the experimental data well and is more accurate than the existing models. The cosolvent effect of NMP is demonstrated by a large and uniform reduction in the surface tension of water as a function of its concentration. Complexation is supported by the fact that it's strength is reduced upon increasing the temperature or lowering the polarity of the medium. Increasing the medium polarity on the other hand strengthens complexation. A strong correlation exists between log Kow of the drugs and the respective cosolvency coefficients. The correlation between log Kow and the respective complexation coefficients is weak suggesting that factors like molecular shape and aromaticity are significant in determining the complexation strength. This is confirmed by the absence of a significant complexation with linear molecules. It is also noticed that besides NMP, two other pyrrolidone derivatives enhance drug solubility following the same mechanism.