Purpose: Transcutol® HP (Diethylene glycol monoethyl ether) is a widely used solvent for poorly soluble actives and as a permeation enhancer for the skin. However addition of Transcutol® HP (or P) at 20% w/w or higher to creams has been challenging. The goal of this study was to formulate stable hydrous and anhydrous topical creams with high concentrations of Transcutol® HP, and to identify measurable parameters that are predictive of formulation failure prior to stability testing.
Methods: Placebo formulations were prepared by melting Phase I at 70˚C to get a homogeneous mix which was then cooled to 50˚C before Phase II was added slowly (Table 1). The contents were mixed continuously using a VMI mixer with centrifugal deflocculator attachment at 500-1000 RPM until a homogenous cream was obtained. Creams were allowed to equilibrate to room temperature for 24 hours before analyzing and storing at 40˚C/75% RH in flint glass jars with a screw top polyethylene cap.
Samples were analyzed initially and then monthly with following tests:
1) Visual inspection for homogeneity of the creams.
2) pH determination indicating moisture absorption and hydrolysis of excipients. Because many of the excipients used are esters of fatty acids, lowering of pH is indicative of fatty acid generation via excipient decomposition, leading to potential phase separation.
3) DSC was performed by heating the samples at 10˚C/min to monitor changes in melting enthalpy of the excipients. Melting point depression below 40˚C is indicative of phase separation on stability.
4) Cross polarized microscopy was performed to monitor whether the creams exhibited birefringence. Birefringence indicates that some excipients are in the solid state, which contributes to the stability of the creams.
5) Changes in viscosity profiles were also monitored using parallel plate geometry with 1mm gap at 800 RPM with linear heating ramp from 25˚C to 75˚C at 1˚C/min.
In support of the aim to identify parameters to predict cream failure, DSC analyses were employed on mixtures of Transcutol® HP and excipients to study the effect of Transcutol® HP on the melting profiles of various excipients. Centrifugation at 21,000 g for 120 minutes at room temperature was also tested as a predictive tool for stability.
Results: Transcutol® HP causes melting point depression of several excipients as shown in Figure 1. Thickeners and emulsifiers which showed lower melting point depression in the presence of Transcutol® HP were selected for cream formulation. Centrifugation had no effect on the creams, even if they phase separated in 24 hours at room temperature. Almost 30 different formulas were screened to enable formulation of three anhydrous creams and three hydrous creams that were stable for 5-6 months at 40˚C/ 75%RH with 40% Transcutol® HP loads (Table 1). The DSC profiles of the stable creams did not change over time. A melt above 40˚C is indicative of stable formulations. Thermorheological studies were also predictive of cream stability, with loss of viscosity observed above 50˚C in stable creams. Stable creams exhibited birefringence under cross polarized light at all time points (Figure 2). pH was invariant for stable formulas on storage.
Conclusion: Stable hydrous and anhydrous creams containing 40% Transcutol® HP were developed. Anhydrous creams are beneficial for formulation of moisture sensitive actives. While centrifugation was not predictive of stability in this work, DSC of premixes helped in selection of excipients which would yield stable formulations on storage. Cross polarized microscopy and thermorheology provided insight on the stability of the formulations. Future studies would include determining minimum concentration of thickeners and emulsifiers required to develop stable formulas and preforming diffusion studies for the stable creams with a model drug.
Jason Le Pree– Senior Principal Scientist, Gattefosse Corp, Paramus, New Jersey