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

Abstract

Semisolids constitute a significant proportion of topical pharmaceutical dosage forms available on the market, with creams being considered profitable systems for releasing active substances into the skin. This work aimed at the development of a generic Clotrimazole topical cream, based on the assumptions that assist the development of such formulations. First, the critical parameters to obtain a final formulation as similar as possible to the reference product were defined. Then, the percentages of cetyl palmitate and octyldodecanol were identified as critical variables and chosen for optimization in further studies. A "quality by design" approach was then used to identify the effect of process variability on the structural and functional similarity (Q3) of the generic product qualitatively (Q1) and quantitatively (Q2). A two-factor central composite orthogonal design was applied and eleven different formulations were developed and subjected to physicochemical characterization and product performance studies. The results were used to estimate the influence of the two variables in the variation of the responses, and to determine the optimum point of the tested factors, using a design space approach. Finally, an optimized formulation was obtained and analysed in parallel with the reference. The obtained results agreed with the prediction of the chemometric analysis, validating the reliability of the developed multivariate models. The in vitro release and permeation results were similar for the reference and the generic formulations, supporting the importance of interplaying microstructure properties with product performance and stability. Lastly, based on quality targets and response constraints, optimal working conditions were successfully achieved.

Keywords: generic medicine; pharmaceutical development; quality by design; rheology; topical delivery system.

Figure 1

Flowchart including all experimental steps. QTPP—Quality Target Product Profile; CQAs—Critical Quality Attributes.

Figure 2

Effect of independent variables on cream viscosity: (A) F1–F6 and RF; (B) F7–F11 and RF (reference formulation). The results shown are means, n = 3.

Figure 3

Effect of independent variables on formulations’ storage modulus (G′): (A) F1–F6 and RF; (B) F7–F11 and RF; effect of independent variables on formulations’ loss modulus (G″): (C) F1–F6 and RF; (D) F7–F11 and RF; effect of independent variables on formulations’ loss factor (Tan δ): (E) F1–F6 and RF; (F) F7–F11 and RF. The results shown are means, n = 3.

Figure 4

Cumulative release drug through membranes: (A) F1–F6 and RF; (B) F7–F11 and RF. The results are mean ± SD, n = 3.

Figure 5

Drug permeation profile through newborn pig skin: (A) F1–F6 and RF; (B) F7–F11 and RF. The results are mean ± SD, n = 3.

Figure 6

Response surface plots of the fitted model for viscosity (A), storage modulus (B), loss modulus (C), in vitro release studies (D), dissolution efficiency (E), in vitro permeation studies (F) and retention studies (G).

Figure 7

Viscosity profile of the FF and RF (A) and Flow curves represented by shear stress as a function of shear rate for the FF and RF (B). Data shown are means, n = 3.

Figure 8

Release profile of drug from the FF and RF through synthetic membranes (A) and permeation profile of drug from the FF and RF through newborn pig skin (B). Data are mean ± SD, n = 6.