Rheology by Design: A Regulatory Tutorial for Analytical Method Validation.

Ana Simões,Carla Vitorino,Catarina Cardoso,Francisco Veiga,Margarida Miranda

doi:10.3390/pharmaceutics12090820

Ana Simões, Carla Vitorino + Show 3 more

Open Access

https://doi.org/10.3390/pharmaceutics12090820

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Abstract

The increasing demand for product and process understanding as an active pursuit in the quality guideline Q8 and, more recently, on the draft guideline on quality and equivalence of topical products, has unveiled the tremendous potential of rheology methods as a tool for microstructure characterization of topical semisolid dosage forms. Accordingly, procedure standardization is a dire need. This work aimed at developing and validating a methodology tutorial for rheology analysis. A 1% hydrocortisone cream was used as model cream formulation. Through a risk assessment analysis, the impact of selected critical method variables (geometry, temperature and application mode) was estimated in a broad range of rheological critical analytical attributes—zero-shear viscosity, upper-shear thinning viscosity, lower-shear thinning viscosity, infinite-shear viscosity, rotational yield point, thixotropic relative area, linear viscoelastic region, oscillatory yield point, storage modulus, loss modulus, and loss tangent. The proposed validation of the approach included the rheometer qualification, followed by the validation of numerous operational critical parameters regarding a rheology profile acquisition. The thixotropic relative area, oscillatory yield point, flow point and viscosity related endpoints proved to be highly sensitive and discriminatory parameters. This rationale provided a standard framework for the development of a reliable and robust rheology profile acquisition.

Highlights

Topical semisolid dosage forms include complex multiphase systems demanding a detailed rheological characterization, since these properties may meaningfully affect quality and performance [1,2]
The acquired rheograms clearly show three distinct regions: (A) 1st Newtonian range with a plateau value corresponding to the zero-shear viscosity (η0); (B) shear-thinning range with shear stress-dependent viscosity function η = f(τ) and (C) 2nd Newtonian range with the plateau value corresponding to the infinite shear viscosity (η∞)
The results suggest that cone-plate configuration is preferred to perform rotational measurements, since the shear rate is the same throughout the sample, in opposite to plate-plate configuration, where the shear rate varies along the plate radius, increasing from the center to the edge

Summary

Introduction

Topical semisolid dosage forms include complex multiphase systems demanding a detailed rheological characterization, since these properties may meaningfully affect quality and performance [1,2]. Allied to formulation viscosity, elasticity and plasticity, rheological behaviour may impact product manufacturing, appearance, packaging, long-term stability, dispensing, sensory properties and the in vivo performance [4,5]. Topical semisolid dosage forms predominantly exhibit a non-newtonian behaviour, since a higher shear rate induces a viscosity decrease, which enables an easier skin application [9]. A given critical stress value (yield stress) is required for the formulation to start to flow. This point, the products majorly present elastic properties; on the contrary, above this endpoint, the material predominantly displays a plastic flow [10]

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