Solubility Improvement of Drugs using N-Methyl Pyrrolidone

Abstract

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 found to be a more efficient solubilizer for all the drugs studied. 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 is used to estimate the drug solubility in NMP-water mixture, according to which the total solubility enhancement is a sum of the two effects. This model describes the experimental data well and is more accurate than other models. A large and uniform reduction in the surface tension of water as a function of NMP concentration demonstrates its cosolvent effect. The complexation is supported by the fact that it's strength is affected by the temperature and the polarity of the medium. A strong correlation exists between log K ow of the drugs and the cosolvency coefficients. The correlation between log K ow and the complexation coefficients is weak suggesting that factors such as molecular shape and aromaticity of the drug molecule are significant in determining the complexation strength. This has been confirmed by the absence of a significant complexation between NMP and linear drug-like solutes.

A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules

“…We chose NMP for exploring this potential application due to its thermal stability and low toxicity. Furthermore, it had been demonstrated that NMP had a greater solubilizing power than ethanol and propylene glycol, 11 and NMP was previously used for solubility enhancements both in bioassays 31 and commercial pharmaceutical applications such as the Eligard Ò formulation for delivery of leuprolide to prostate cancer patients. We stored the compound test set (Fig.…”

Supramolecular aggregates of oligosaccharides with co-solvents in ternary systems for the solubilizing approach of triamcinolone

“…For example, in a previous study, it was demonstrated that the solubilizing effect of NMP for estrone and griseofulvine drugs showed a positive deviation of linearity from the log-linear model, as a consequence of the dual mechanism whereby NMP modified drug solubility (co-solvency and complexing) (Sanghvi et al, 2008). In this present study, deviations of linearity were not identified, corroborating the idea that the solubilizing effect of the TEA and NMP for the TRI drug occurred through the co-solvency mechanism.…”

“…Thus, deviations from linearity could be noticed when the solubilizing compounds modify these interactions, for example, when the solubilization ionizes the drug or forms a complex, modifying its initial structure and interaction mechanisms with the aqueous medium (Sanghvi et al, 2008).…”

“…The N-methyl pyrrolidinone (NMP) is also a cosolvent and has been investigated in the solubilization of several compounds. In a recent study, the solubility of a similar corticosteroid drug, testosterone, was enhanced about 14-fold by using NMP (Sanghvi, Narazaki, Machatha, & Yalkowsky, 2008). Triethanolamine was used as an antichagasic benznidazole solubilizer (de Melo et al, 2013) and the authors also identified the co-solvent mechanism, showing the potential co-solvent activity for further studies with nonpolar drugs.…”

Formulation of meloxicam gel for topical application: In vitro and in vivo evaluation

“…Solubility of MLX in Solutol HS 15, Transcutol P and Tween 80 was 9.5, 5.4 and 5.0 mg mL -1 , respectively. NMP was selected as the vehicle of choice to formulate MLX gel, based on its solubilization capacity and penetration enhancing effect on hydrophilic and hydrophobic actives as well as dermal acceptability (17,18).…”