F Benaouda1, M B Brown, G P Martin, S A Jones. 1. King's College London, Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
Abstract
PURPOSE: To understand in situ drug thermodynamic activity when embedded in a supramolecular structured hydrophilic matrix that simultaneously self-assembled during drug supersaturation. METHODS: A propylene glycol (PG)/water, hydroxypropyl methyl cellulose matrix containing ethanol was used to support diclofenac supersaturation. Phase behaviour, thermodynamics and drug transport were assessed through the determination of evaporation kinetics, supersaturation kinetics and transmembrane penetration. RESULTS: Initial ethanol evaporation from the drug loaded matrix (2.9 ± 0.4 mg.min(-1).cm(-2)) was comparable to that of the pure solvent (ca. 3 mg.min(-1).cm(-2)). When 25% w/w of the total ethanol from the applied phase was lost (ethanol/water/PG molar ratio of 7:5:1.2), an inflection point in the evaporation profile and a sudden decrease in drug solubility demonstrated that a defined supramolecular structure was formed. The 55-fold decrease in drug solubility observed over the subsequent 8 h drove in situ supersaturation, the rate of which was a function of the drug load in the matrix (y = 0.0078x, R(2) < 0.99). CONCLUSION: The self-assembling supramolecular matrix prevented drug re-crystallisation for >24 h, but did not hinder mobility and this allowed the thermodynamic activity of the drug to be directly translated into highly efficient transmembrane penetration.
PURPOSE: To understand in situ drug thermodynamic activity when embedded in a supramolecular structured hydrophilic matrix that simultaneously self-assembled during drug supersaturation. METHODS: A propylene glycol (PG)/water, hydroxypropyl methyl cellulose matrix containing ethanol was used to support diclofenac supersaturation. Phase behaviour, thermodynamics and drug transport were assessed through the determination of evaporation kinetics, supersaturation kinetics and transmembrane penetration. RESULTS: Initial ethanol evaporation from the drug loaded matrix (2.9 ± 0.4 mg.min(-1).cm(-2)) was comparable to that of the pure solvent (ca. 3 mg.min(-1).cm(-2)). When 25% w/w of the total ethanol from the applied phase was lost (ethanol/water/PG molar ratio of 7:5:1.2), an inflection point in the evaporation profile and a sudden decrease in drug solubility demonstrated that a defined supramolecular structure was formed. The 55-fold decrease in drug solubility observed over the subsequent 8 h drove in situ supersaturation, the rate of which was a function of the drug load in the matrix (y = 0.0078x, R(2) < 0.99). CONCLUSION: The self-assembling supramolecular matrix prevented drug re-crystallisation for >24 h, but did not hinder mobility and this allowed the thermodynamic activity of the drug to be directly translated into highly efficient transmembrane penetration.