Abstract
Drug substance degradation kinetics in solid dosage forms is rarely mechanistically modeled due to several potential micro-environmental and manufacturing related effects that need to be integrated into rate laws. The aim of our work was to construct a model capable of predicting individual degradation product concentrations, taking into account also formulation composition parameters. A comprehensive study was done on active film-coated tablets, manufactured by layering of the drug substance, a primary amine compound saxagliptin, onto inert tablet cores. Formulation variables like polyethylene glycol (PEG) 6000 amount and film-coat polymer composition are incorporated into the model, and are connected to saxagliptin degradation, via formation of reactive impurities. Derived reaction equations are based on mechanisms supported by ab initio calculations of individual reaction activation energies. Alongside temperature, relative humidity, and reactant concentration, the drug substance impurity profile is dependent on micro-environmental pH, altered by formation of acidic PEG degradation products. A consequence of pH lowering, due to formation of formic acid, is lower formation of main saxagliptin degradation product epi-cyclic amidine, a better resistance of formulation to high relative humidity conditions, and satisfactory tablet appearance. Discovered insights enhance the understanding of degradational behavior of similarly composed solid dosage forms on overall drug product quality and may be adopted by pharmaceutical scientists for the design of a stable formulation.
Highlights
Drug substance degradation kinetics in solid-state pharmaceutical systems is rarely studied and modeled based on actual degradation mechanisms
It is worth noting that no impurity originating from drug substance or film-coated tablet manufacture is above the quantitation limit of the analytical method and no SAXA degradation occurred prior to stability study initiation
This paper presents the development of a model, describing degradation kinetics of drug substance SAXA in active film-coat of a tablet
Summary
Drug substance degradation kinetics in solid-state pharmaceutical systems is rarely studied and modeled based on actual degradation mechanisms. Published studies that take into account formulation composition variables are; limited [1,2,3,4]. Polyethylene glycols (PEGs), as one of the most commonly used excipients in pharmaceutical formulations, as film-coat plasticizers, have been largely investigated over recent decades in relation to their susceptibility to degradation [5,6,7,8]. Can changes to their chemical structure affect functional characteristics of pharmaceutical dosage forms and their performance, they can decrease drug’s potency through formation of reactive impurities. Reactive impurities control in excipients is a challenge, since they can originate from synthetic processes, typically with high batch-to-batch variability, or from final dosage form manufacture and storage. Formation of the last two is a consequence of radical-initiated oxidation reactions, propagated by peroxides/oxygen, and are reported [5,6,7,8] to be catalyzed by different material properties, as for instance PEG chain length, moisture content, presence of residual metals, and other
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