Modelling of Active Ingredient Release from an Emulsion and its Dependence Upon Formulation
Chemical Product Design and Engineering (CPD&E)
Chemical Product Design & Engineering - Poster (CPD&E - P)
Keywords: active ingredient release, partition/diffusion models, emulsions, structured products
The rate at which an ingredient is released from a product formulation is a relevant issue in different applications, such as drug release from pharmaceutical formulations, pesticide release from agrochemical products and fragrance release from cosmetic, personal care and food products. The design of such products for controlled release of the active ingredient (AI) may be supported by physico-chemical models describing the release process, as a result of the intrinsic structure of the product and also its interaction with the environment/user.
In order to be applicable for design purposes, such models must establish a relationship between product design variables (composition and structure) and AI release rate. Therefore, they need to incorporate constitutive models relating physico-chemical properties (e.g. AI equilibrium and transport parameters) with product composition.
Since the pioneering work of Higuchi [1], who proposed the first mechanistic model of drug release from a solid matrix, a great number of related and further detailed models have been developed [2,3], but in general they do not incorporate constitutive relationships.
Recently, Muro-Suñé et al.[4] overcame this limitation for the case of pesticide release from polymeric microcapsules, combining the basic mass transfer model with constitutive predictions for pesticide solubility and diffusivity in the polymeric matrix. In this paper, we pursue the same goal for the case of AI release from an emulsion formulation, with the effect of emulsion composition being incorporated in the modelled phenomena.
In particular, the system under analysis that we will consider here is an emulsion layer applied over a flat surface that absorbs the AI. The emulsion consists of an internal phase homogeneously dispersed as droplets in an external continuous phase, with the droplets being surrounded by a stabilizing layer of surfactant. The AI release is described as the result of two main phenomena: interfacial transfer (from each droplet to the continuous phase) and diffusion in the continuous phase, with interfacial transfer comprising permeation through the surfactant layer followed by dissolution in the continuous phase. The resulting mathematical model is a system of two partial differential equations with the constitutive parameters being Ps (surfactant layer permeability), Kcd (partition coefficient between continuous and dispersed phases) and Dc (diffusion coefficient in the continuous phase), and with geometrical parameters L (emulsion layer thickness), (dispersed phase volume fraction) and Ld (droplet mean diameter). The adimensional number N3=6×Ps×Kcd×L^2/(Ld×Dc) may be interpreted as the interfacial transfer rate relative to diffusion rate in the continuous phase, and thus the importance of interfacial resistance decreases as N3 increases. A simplified model for high N3 is then derived, for which there is an analytical solution.
Our generic release model is then applied to a pharmaceutical ointment for cutaneous use, which consists of an emulsion of a solution S (drug + solvent) dispersed in a highly viscous lipid phase L, comprising four excipients (surfactant included).
For this particular application, the constitutive parameters are estimated as follows: (i) the drug partition coefficient Kcd is calculated based on regular solution theory with activity coefficients estimated making only use of pure components solubility parameters; (ii) the drug diffusivity Dc is predicted based on free-volume theory as applied to the mixture of excipients which comprise the continuous phase and with parameters estimated from pure excipients data (density and viscosity); (iii) the surfactant layer permeability Ps is derived from a very simplified free interfacial area model, that takes into account the surfactant surface density.
Our global model (release model altogether with constitutive models) is then used to study the effect of emulsion formulation over the drug release process, for two different situations: release to a perfect sink (strictly a theoretical scenario, but that may also resemble the conditions of release tests obtained with a permeable membrane) and transfer into skin. In the latter case, the mass transfer model is expanded to include the several skin layers, with the drug partition coefficient between the continuous phase and the outermost skin layer (K2c) being estimated as a function of emulsion composition.
The results obtained so far indicate that the excipients formulation has an important impact over the dynamics of AI release, affecting all the four constitutive parameters (Kcd, K2c, Dc and Ps). The release rate is also affected by droplet size, with a higher interfacial resistance found for coarser emulsions. Under low values of Kcd and Ps, a lower droplet size is required in order to reduce interfacial resistance (N3 increase). The impact of the formulation over the release process is naturally weakened when the emulsion is applied on skin, given that drug diffusivity through skin is very low and considered independent of emulsion composition. However, the effects of the most hydrophilic excipient are still significant, since this component influences the partition coefficient, K2c. In this respect, our model predicts a more controlled drug release (lower K2c) for more hydrophilic formulations.
As a conclusion, we believe that the developed models can be extremely useful to support the design of emulsion products that must release a certain AI. The general framework supporting such models (mass transfer + prediction of equilibrium and transport parameters) can also be applied to other product structures, under the general scope of a multiphasic system with multiple dispersed and continuous phases.
References
1. Higuchi T. Rate of Release of Medicaments from Ointment Bases Containing Drugs in Suspension. J. Pharm. Sci. 1961;50:874-875.
2. Frenning G, Strømme M. Drug release modeled by dissolution, diffusion, and immobilization. Int. J. Pharm. 2003;250:137-145.
3. Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv. Drug. Deliv. Rev. 2001;48:139-157.
4. Muro-Suñé N, Gani R, Bell G, Shirley I. Model-based computer-aided design for controlled release of pesticides. Comput. Chem. Eng. 2005;30:28-41.
Presented Wednesday 19, 13:30 to 15:00, in session Chemical Product Design & Engineering - Poster (CPD&E - P).
