title: Investigating the feasibility of temperature-controlled accelerated drug release testing for an intravaginal ring.
abstract: The objective of the present study was to investigate if temperature can be utilized to accelerate drug release from Nuvaring®, a reservoir type intravaginal ring based on polyethylene vinyl acetate copolymer that releases a constant dose of contraceptive steroids over a duration of 3 weeks. The reciprocating holder apparatus (USP 7) was utilized to determine real-time and accelerated etonogestrel release from ring segments. It was demonstrated that drug release increased with increasing temperature which can be attributed to enhanced drug diffusion. An Arrhenius relationship of the zero-order release constants was established, indicating that temperature is a valid parameter to accelerate drug release from this dosage form and that the release mechanism is maintained under these accelerated test conditions. Accelerated release tests are particularly useful for routine quality control to assist during batch release of extended release formulations that typically release the active over several weeks, months or even years, since they can increase the product shelf life. The accelerated method should therefore be able to discriminate between formulations with different release characteristics that can result from normal manufacturing variance. In the case of Nuvaring®, it is well known that the process parameters during the extrusion process strongly influence the polymeric structure. These changes in the polymeric structure can affect the permeability which, in turn, is reflected in the release properties. Results from this study indicate that changes in the polymeric structure can lead to a different temperature dependence of the release rate, and as a consequence, the accelerated method can become less sensitive to detect changes in the release properties. When the accelerated method is utilized during batch release, it is therefore important to take this possible restriction into account and to evaluate the accelerated method with samples from non-conforming batches that are explicitly "out of specification" under real-time test conditions.
authors.affiliation: Department of Pharmacy, University of Greifswald, Greifswald, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Externbrink
authors.forename: Meredith R
authors.initials: MR
authors.lastname: Clark
authors.forename: David R
authors.initials: DR
authors.lastname: Friend
authors.forename: Sandra
authors.initials: S
authors.lastname: Klein
mesh_terms: D000282:Administration, Intravaginal; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003692:Delayed-Action Preparations; D017135:Desogestrel / Q000031:analogs & derivatives* / Q000737:chemistry; D004058:Diffusion; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004997:Ethinyl Estradiol / Q000737:chemistry*; D005260:Female; D006801:Humans; D007700:Kinetics; D010539:Permeability; D011108:Polymers / Q000737:chemistry; D011786:Quality Control; D012995:Solubility; D013696:Temperature; D014621:Vagina / Q000187:drug effects
chemical_list: D003692:Delayed-Action Preparations; D004338:Drug Combinations; C516519:NuvaRing; D011108:Polymers; D004997:Ethinyl Estradiol; D017135:Desogestrel
keywords: Diffusion-controlled drug release; Extended release delivery systems; Nuvaring®; Quality control; Reciprocating holder; USP apparatus 7; Vaginal delivery