Enhanced transdermal drug delivery of nsaids using eutectic formation and a two-phase liquid system
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The thermodynamic, eutectic and crystalline properties of binary mixtures of selected non-steroidal anti-inflammatory drugs (NSAIDs), enantiomers, eutectic and racemate of ibuprofen were investigated using differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD). DSC studies showed that melting points, enthalpy and entropy of fusion of the eutectic were significantly reduced as compared to those of the individual drugs or enantiomers. XRPD indicated that the eutectic did not form a new crystalline structure different from that of pure drugs or enantiomers. Ibuprofen and ketoprofen were selected to study the effect of eutectic formation on membrane permeation using in vitro diffusion and snake skin as the model membrane. The presence of aqueous isopropyl alcohol (IPA) was necessary to transform the solid drugs into a two-phase liquid system at ambient temperature. Due to melting point depression by eutectic formation, high drug concentration in the oily phase and maximum thermodynamic activity in the system, the preparation based on the two-phase liquid system showed significantly higher permeation rates of ibuprofen and ketoprofen as compared to other reference preparations. The stability of the two-phase system was studied and no degradation of drugs was observed. The effects of reduced melting points of the drugs on the flux of membrane permeation were also predicted by two mathematical models based on ideal solution theory and by using enthalpy, entropy, melting point and other thermodynamic parameters. The experimental data of maximum fluxes were not significantly different from the predicted values, suggesting that the changes of maximum fluxes of drugs could be estimated if their melting point depression and other relevant thermodynamic data are available. The eutectic mixture was developed into emulsion, O/W and W/O creams and gel formulations to study the effect of vehicles and formulation types on drug permeation. Drug release testing was conducted to compare the fluxes of ibuprofen and ketoprofen in different formulations and two commercial creams by using the model membrane. The stability of the cream was studied at different temperatures for six months and examined periodically for organoleptic characteristics, content of drugs, particle size and apparent viscosity. The prepared formulation was found to be stable under the condition used.