Understanding Kinetics of Drug Release from Ointments

X. Xu, M. Al-Ghabeish, Y. S. Krishnaiah, Z. Rahman, M. A. Khan U.S. Food and Drug Administration Purpose From a drug product quality perspective, in vitro release testing (IVRT) serves many different, yet crucial roles throughout the lifecycle of a drug product. Unfortunately, the maturity of IVRT methods for pharmaceutical ointments is considerably lacking and under-utilized as compared to conventional solid oral dosage forms. In parts, this may be attributed to complex physicochemical properties of the ointment formulations as well as the unique physiological constraints an IVRT method has to resemble for drug release (e.g. ophthalmic environment). It is the objective of the current study to evaluate the differences in the drug release kinetics from various ointment bases, in an attempt to understand the fundamental drug release mechanisms. Methods An in vitro release testing method (USP2 with enhancer cells) suitable for ointment formulations was developed using acyclovir as a model drug, prepared in ointments with oleaginous, absorption, and water-soluble bases. Kinetics of drug release was studied using various mathematical models, including commonly employed Higuchi model and a newly proposed Transient-Boundary model. It is hypothesized that there exists a transient-boundary at the petrolatum ointment/water interface, consisting of an initial boundary and a dynamically changing transient layer. Only drug present inside the transient layer can dissolve and further diffuse into the bulk aqueous media. The interface between transient layer and bulk aqueous media is assumed to be a perfect sink. To verify the proposed model, impact of drug solubility and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Results Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In both absorption and water-soluble bases, drug release followed Higuchi model albeit differences in the overall release profile (Figure 1); in oleaginous bases drug release followed a unique logarithmic-time dependent profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was developed (Figure 2), where the inverse-time dependency of release rate is explained by a dynamically changing “transient layer”. The key difference between the current proposed model and the Higuchi model is the direction of the boundary movement. Higuchi model describes an opposite movement for ointment depletion and drug diffusion, whereas in our current model these two are in the same direction. Conclusion A novel kinetics model was developed based on a transient-boundary hypothesis, and various factors that may influence the in vitro drug release from oleaginous ointment bases were identified. The logarithmic time drug release kinetics investigated in the current study may be further extended to other similar physical boundary condition systems to provide mechanistic understanding of the drug release phenomenon when appropriate.