Purpose: In the development of topical formulations, Hot-Melt Extrusion (HME) techniques have already been established to be a cost efficient process and considered as a suitable alternative over the conventional methods of manufacturing. The objective of this work was to manufacture topical creams through HME technology using a Quality by Design (QbD) approach to study the effects of the processing parameters of the HME technology on the characteristic properties of the final product.
Methods: The idea of QbD as a strategy to acquire an in depth understanding of the pharmaceutical manufacturing process has been encouraged by global regulatory agencies. Hydrocortisone acetate was chosen as a model drug for this work. Stearic acid, stearyl alcohol and cetyl alcohol comprised the oil phase (14%) whereas propyl paraben, glycerin, drug, potassium hydroxoxide and water comprised the water phase (86%). The preliminary studies were conducted to identify the process variables that would have a significant impact on the characteristic properties of the cream formulations. Based on preliminary extrusion studies conducted on an 11mm twin screw extruder (Process 11, Thermo Fisher Scientific), three critical process parameters (CPP) were identified: temperature of zone 2 (40℃ and 50℃), screw speed (50 and 70 rpm) and two screw configurations. Each of these factors were studied at two levels (a lower and a higher level). Both of the screw configurations comprised two mixing zones to provide a homogenous product. Critical quality attributes (CQA) were identified based on literature and preliminary studies, which were yield stress, work of adhesion and globule size distribution. Based on the CPP and CQA, a 23 design was selected and resulted in 8 formulations. Formulations were analyzed for texture analysis (Model TA. XT2i, Texture Technologies Corp. / Stable Micro Systems), rheological characterization (DHR 2 rheometer), in-vitro release studies, ex-vivo permeation studies, pH, and globule size measurements. Through the full factorial design, the main factor effects and the interaction effects on the characteristic properties of the cream formulations were determined. The membranes used for the release study and the permeation study were silicone membranes and porcine skin membranes respectively.
Results: As the process parameters of screw speed and zone 2 temperature were steadily increased, creams of less viscous nature were formed and clumps of the oil phase components were obtained upon extrusion. Based on results of the texture analysis studies, microscopic study and rheology, work of adhesion obtained was in the range of 37.64 – 57.09 g.sec., a globule size in the range of 0.550 – 2.667 µm and yield stress in the range of 26 – 52 Pa was obtained. The DOE study performed revealed that effect of the temperature of zone 2 on the work of adhesion of the formulations were significant. The amount of Hydrocortisone released was in the range of 25- 107 µg/cm2 with the amount of drug permeating the range of 3.3 - 5 µg/cm2. The 8 formulations had a pH of 6.0 to 6.8 which would be considered safe for application on the skin.
Conclusion: Based on the results of the DOE study, only the temperature of zone 2 had a significant effect (p<0.05) on the work of adhesion of the formulations. Through the QbD approach, one would acquire a good understanding of the product, its process design and further improvement, the scale-up parameters and optimize and control these steps, therefore improving the efficiency of the process and the quality of the product. Operational flexibility is possible provided the product variables and the process parameters remained within the approved design space.
This study was supported by Grant Number P20GM104932 from the National Institute of General Medical Sciences and the Biopharmaceutics-Clinical and Translational Core E of the COBRE, a component of the National Institutes of Health