Rheological temperature sweeping in a quality by design approach for formulation development and optimization

Many topical drug products are multi-phase systems which are prone to phase separation exhibiting a high risk for not meeting the critical quality attributes (CQAs) of a pharmaceutical product such as uniform active pharmaceutical ingredient (API) distribution and physical homogeneity. In order to investigate and control these CQAs a rheological temperature sweeping (RTS) method was implemented and refined to enable quantification of these characteristics within a quality by design (QbD) approach. For method implementation, emulsion and ointment compositions were prepared within a design of experiments (DoE) and critical responses from RTS were extracted via principal component analysis (PCA) in a multivariate data analysis (MVA) approach. The span after 3 cycles of RTS on emulsions and a combination of 5 principal components (PCs) for ointments were selected as responses from PCA. The span correlates with the droplet size of selected emulsions followed during stability whereas the combination of the PCs for ointments enables a differentiation of the compositions. Identified critical material attributes (CMAs) are the emulsifier concentration of the emulsion and the liquid paraffin (LP) content of the ointments. In conclusion, RTS enables a rapid screening of liquid and semi-solid products in a quantitative manner for pharmaceutical development and formulation optimization.