Progressing Towards the Sustainable Development of Cream Formulations

Abstract

<jats:p>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.</jats:p>

Complying with the Guideline for Quality and Equivalence for Topical Semisolid Products: The Case of Clotrimazole Cream

“…In addition, the pH of the skin is normally acidic, ranging between 4 and 6 [ 25 ]. The acquired results are slightly above the skin pH range but are stated that topical formulations pH between 5 and 7 do not seem to cause skin irritation, suggesting a safe application of the DoE formulations [ 26 ].…”

“…According to the Stokes law, the diffusion coefficient of the drug is inversely proportional to viscosity, since more viscous formulations will retain the active substance, hindering its release from the vehicle for longer [ 26 ]. Bearing in mind that the viscosity results are quite similar for FF and RF, the drug release results are also similar.…”

Rheology by Design: A Regulatory Tutorial for Analytical Method Validation

“…HC o/w cream formulations were conventionally prepared resorting to an Ultra-Turrax X 10/25 (Ystral GmbH, Dottingen, Germany) equipment. Both continuous and dispersed phases were separately prepared and heated to 70 °C [ 11 , 28 ]. Afterward, the active pharmaceutical ingredient was solubilized in the dispersed phase.…”

“…In order to document the discriminatory power of the proposed rheological analysis, three formulations were prepared considering different concentration of glycerol monostearate: 5% (F 5 ), 10% (F 10 ) and 20% (F 20 ). This excipient bears a significant impact on product microstructure due to its thickening properties [ 11 , 28 ]. Please note that F 10 was considered as the reference formulation.…”

“…Generally, these measurements, due to the decreased shear stress applied, can be considered as non-destructive, nevertheless, it should be pointed out that minor system perturbations can still occur during amplitude sweep tests. Oscillatory measurements aim to assess the material viscoelastic properties, while exposed to small-amplitude deformation forces [ 28 ]. The following sections detail the main outputs of both methodologies.…”