Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin

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.

LC and NMR Studies for Identification and Characterization of Degradation Byproducts of Olmesartan Acid, Elucidation of Their Degradation Pathway and Ecotoxicity Assessment

“…Olmesartan acid could undergo the oxidation of the side-chain at carbon C23 to obtain intermediate I1, whose subsequent decarboxylation at carbon C22 generates intermediate I2 . The reaction of this with HClO could generate intermediate I3 from which intermediate I4 can be obtained via nucleophilic attack of the CH 3 O − ion [ 40 , 41 , 42 ]. The oxidation at carbon C23 (intermediate I5 ) and C24 (intermediate I6 ) and the chlorination at carbon C22 could provide DP5.…”

A Novel Testing Approach for Oxidative Degradation Dependent Incompatibility of Amine Moiety Containing Drugs with PEGs in Solid-State

“…The following is reflected in a very high N-formyl to N-methyl impurity ratio ( Table 7). The N-formylation reaction has been shown to have high activation energy (activation energy of 151.6 kJ per mole was determined for saxagliptin N-formylation in our previous study [15]). Free base forms of secondary amines, as the most reactive of tested compounds, are capable of overcoming this barrier, and readily react with formic acid (ratio N-FOR vs. N-MET above 1).…”

“…Stock solutions of standards and samples were prepared in a concentration of about 1 mg/mL in methanol (paroxetine, desloratadine, vortioxetine) or in 60% methanol (varenicline and saxagliptin). Drug substance standards were further diluted with the corresponding solvent to obtain seven working solutions for plotting a calibration curve with the following concentrations (35,30,25,20,15,10, and 5 µg/mL). Standards of N-methyl and N-formyl impurities were first diluted to 25 and 10 µg/mL and, subsequently, to ten additional working solutions for plotting the calibration curves with the following concentrations (3000, 1500, 750, 375, 187.5, 93.7, 46.9, 23.4, 11.7, 5.8 ng/mL).…”

“…The low molecular weight organic impurities formaldehyde and formic acid were determined by an adopted liquid chromatography method [15].…”

On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

“…The observation of this degradation pathway is of paramount importance for design of solid dosage forms containing venetoclax. It implies that excipients based on polyether compounds such as polyethylene glycol (PEG), polyethylene oxide (PEO) and poloxamer should be avoided in excipient selection, since polyether compounds are susceptible to degradation by molecular oxygen and form small molecular weight organic impurities such as formaldehyde to a high extent [44][45][46]. Therefore, the use of polyether compounds together with venetoclax in the final dosage form could lead to the formation of dimeric degradation products.…”