Abstract
This work aims at providing the assumptions to assist the sustainable development of cream formulations. Specifically, it envisions to rationalize and predict the effect of formulation and process variability on a 1% hydrocortisone cream quality profile, interplaying microstructure properties with product performance and stability. This tripartite analysis was supported by a Quality by Design approach, considering a three-factor, three-level Box-Behnken design. Critical material attributes and process parameters were identified from a failure mode, effects, and criticality analysis. The impact of glycerol monostearate amount, isopropyl myristate amount, and homogenization rate on relevant quality attributes was estimated crosswise. The significant variability in product droplet size, viscosity, thixotropic behavior, and viscoelastic properties demonstrated a noteworthy influence on hydrocortisone release profile (112 ± 2–196 ± 7 μg/cm2/√h) and permeation behavior (0.16 ± 0.03–0.97 ± 0.08 μg/cm2/h), and on the assay, instability index and creaming rate, with values ranging from 81.9 to 120.5%, 0.031 ± 0.012 to 0.28 ± 0.13 and from 0.009 ± 0.000 to 0.38 ± 0.07 μm/s, respectively. The release patterns were not straightforwardly correlated with the permeation behavior. Monitoring the microstructural parameters, through the balanced adjustment of formulation and process variables, is herein highlighted as the key enabler to predict cream performance and stability. Finally, based on quality targets and response constraints, optimal working conditions were successfully attained through the establishment of a design space.
Highlights
In dermatological therapy, semisolid dosage forms, including cream formulations, remain the gold-standard vehicles for topical drug delivery [1]
Besides stratum corneum (SC) barrier function, structural changes of diseased skin, active substance solubility, lipophilicity, molecular weight, concentration and physical state, the understanding and selection of a suitable vehicle microstructure is of crucial importance, since it plays a fundamental role on skin application/sensory properties, formulation appearance, product performance, physical stability and patient compliance
The cumulative % of HC released after 6 h (R6h) and 24 h (R24h) were used for comparison among formulations
Summary
Semisolid dosage forms, including cream formulations, remain the gold-standard vehicles for topical drug delivery [1]. Topical therapeutic efficacy is highly dependent on skin conditions, physicochemical properties of the active substance and vehicle/formulation characteristics because of their significant impact on drug release and permeation. Besides stratum corneum (SC) barrier function, structural changes of diseased skin, active substance solubility, lipophilicity, molecular weight, concentration and physical state (solubilized or dispersed), the understanding and selection of a suitable vehicle microstructure is of crucial importance, since it plays a fundamental role on skin application/sensory properties, formulation appearance, product performance, physical stability and patient compliance. What is the interdependency among variables and how can we systematically measure and control it?
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