title: Optimization and development of stable w/o/w cosmetic multiple emulsions by means of the Quality by Design approach.
abstract: OBJECTIVE
  The aim of our present work was to develop stable water-in-oil-in-water (w/o/w) cosmetic multiple emulsions that are proper for cosmetic use and can also be applied on the skin as pharmaceutical vehicles by means of Quality by Design (QbD) concept. This product design concept consists of a risk assessment step and also the 'predetermination' of the critical material attributes and process parameters of a stable multiple emulsion system. We have set up the hypothesis that the stability of multiple emulsions can be improved by the development based on such systematic planning - making a map of critical product parameters - so their industrial usage can be increased.
  
  
  METHODS
  The risk assessment and the determination of critical physical-chemical stability parameters of w/o/w multiple emulsions to define critical control points were performed by means of quality tools and the leanqbd(™) (QbD Works LLC, Fremont, CA, U.S.A.) software.
  
  
  RESULTS
  Critical materials and process parameters: Based on the results of preformulation experiments, three factors, namely entrapped active agent, preparation methodology and shear rate, were found to be highly critical factors for critical quality attributes (CQAs) and for stability, whereas the nature of oil was found a medium level risk factor. The results of the risk assessment are the following: (i) droplet structure and size distribution should be evaluated together to be able to predict the stability issues, (ii) the presence of entrapped active agents had a great impact on droplet structure, (iii) the viscosity curves represent the structural changes during storage, if the decrease in relative viscosity is >15% the emulsion disintegrates, and (iv) it is enough to use the shear rate between 34g and 116g relative centrifugal force (RCF). CQAs: By risk assessment, we discovered that four factors should be considered to be high-risk variables as compared to others: droplet size, droplet structure, viscosity and multiple character were found to be highly critical attributes.
  
  
  CONCLUSIONS
  The preformulation experiment is the part of a development plan. On the basis of these results, the control strategy can be defined and a stable multiple emulsion can be ensured that meets the relevant stakeholders' quality expectations.
authors.affiliation: Institute of Drug Regulatory Affairs, University of Szeged, Eötvös str. 6., 6720, Szeged, Hungary.
authors.forename: A
authors.initials: A
authors.lastname: Kovács
authors.affiliation: Institute of Pharmaceutical Technology, University of Szeged, Eötvös str. 6, 6720, Szeged, Hungary.
authors.forename: I
authors.initials: I
authors.lastname: Erős
authors.affiliation: Institute of Drug Regulatory Affairs, University of Szeged, Eötvös str. 6., 6720, Szeged, Hungary.
authors.forename: I
authors.initials: I
authors.lastname: Csóka
mesh_terms: D003358:Cosmetics; D004655:Emulsions; D018570:Risk Assessment
chemical_list: D003358:Cosmetics; D004655:Emulsions
keywords: Quality by Design concept; droplet size; multiple emulsion; risk assessment; stability; viscosity