The purpose of this study was to identify a degradation product formed in the clinical parenteral formulation of BMS-204352, investigate the role of excipients in its formation, and develop a strategy to minimize/control its formation. The degradant was identified as the hydroxy methyl derivative (formaldehyde adduct, BMS-215842) of the drug substance based upon liquid chromatography/mass spectroscopy (LC/MS), liquid chromatography/mass spectroscopy/mass spectroscopy (LC/MS/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to an authentic sample of hydroxymethyl degradation product, BMS-215842. An assay method for the detection of formaldehyde based on HPLC quantitation of formaldehyde dinitrophenylhydrazone was developed to quantitate its levels in various Polysorbate 80 and PEG 300 excipient lots. A direct relationship between the levels of formaldehyde in the excipients and the formation of the hydroxymethyl degradant was found. To confirm the hypothesis that the formaldehyde impurity in these two excipients contributed to the formation of the hydroxymethyl degradant, several clinical formulation lots were spiked with formaldehyde equivalent to 1, 10, and 100 mg/g of BMS-204352. A correlation was found between the formaldehyde level and the quantity of the hydroxymethyl degradant formed upon storage at 5 and 25 degrees C. From these experiments, a limit test on the formaldehyde content in polysorbate 80 and PEG 300 can be set as part of a strategy to limit the formation of the degradation product.
The purpose of this study was to investigate the effects of cations and anions of various electrolytes on the glass transition temperature (Tg') of frozen solutions of excipients commonly used in freeze-drying. The effect of electrolyte concentration on freezable water content was also investigated by measuring the enthalpy of melting (DeltaH) using Differential Scanning Calorimetry (DSC). Cations and anions induce changes in Tg' of frozen solutions of commonly used parenteral excipients. These changes are dependent on the properties of the excipients used. Tg' values of 5% w/v solutions of maltose, trehalose, sucrose, dextran 40, and polyvinylpyrrolidone (PVP, 17K) were determined as a function of sodium chloride (NaCl) or potassium chloride (KCl) concentrations. In general, a significant decrease in Tg' was observed as a function of increasing the electrolyte concentration. For the disaccharide solutions, the decrease in Tg' due to the addition of NaCl or KCl was similar in magnitude, indicating that changing the cation from K+ to Na+ had no effect on Tg'. However, the decrease in Tg' for the PVP solution due to the addition of KCl was greater than that observed by the addition of NaCl . The differences in the electrolyte-induced changes on Tg' between the disaccharides and PVP may be potentially attributed to the formation of complexes between the cations and the properly oriented hydroxyl groups in the sugars leaving the anions (Cl- ions) to exert their effect on Tg'. While zero cation effect would be consistent with these results for the disaccharides, these results do not mean that the cation effects are zero; they only mean that the cation effects are the same. For the PVP solution, K+ and Na+ ions are not engaged in complex formation with PVP due to the lack of hydroxyl groups. We hypothesize that the structure-breaking K+ ions increase the fluidity of water and exert a greater plasticizing effect on Tg', leading to a more significant decrease in Tg' than the structure-making Na+ ions, which increase the viscosity of water. The decrease in Tg' of frozen solutions of pharmaceutical excipients caused by the addition of electrolytes may be primarily attributed to an increase in the unfrozen plasticizing water surrounding the excipient molecules. Formulation scientists should evaluate the use of electrolytes in the formulation development of lyophilized products containing commonly used excipients. Electrolytes are often needed as stabilizers for protein formulations; however, their selection and use should be properly evaluated. Because electrolytes cause a decrease in Tg' as a function of electrolyte concentration, it is recommended that the minimum electrolyte concentration needed to maintain product stability should be used to minimize the effect of the electrolyte on lowering the Tg'.
The purpose of this study was to identify two degradation products formed in the parenteral lyophilized formulation of BMS-204352, investigate the possible role of elastomeric closures in their formation, and develop a strategy to minimize/control their formation. The first degradant was identified as the hydroxymethyl derivative (formaldehyde adduct, BMS-215842) of the drug substance formed by the reaction of BMS-204352 with formaldehyde. Structure confirmation was based on liquid chromatography/mass spectroscopy (LC/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to an authentic sample of the hydroxymethyl degradation product, BMS-215842. To confirm the hypothesis that formaldehyde originated from the rubber closure, migrated into the product, and reacted with BMS-204352 drug substance to form the hydroxymethyl degradant, lyophilized drug product was manufactured, the vials were stoppered with two different rubber closure formulations, and its stability was monitored. The formaldehyde adduct degradant was observed only in the drug product vials stoppered with one of the rubber closures that was evaluated. Although formaldehyde has not been detected historically as leachable and is not an added ingredient in the rubber formulation, information obtained from the stopper manufacturer indicated that the reinforcing agent used in the stopper formulation may be a potential source of formaldehyde. The second degradant was identified as the desfluoro hydroxy analog (BMS-188929) based on LC/MS, NMR, and chromatographic comparison to an authentic sample of the desfluoro hydroxy degradation product.
A two-step s y n t h e s i s of t h r e e carbonate and f o u r carbamate esters l a b e l e d a t t h e carbonyl with c a r n-14 i s described. The method u t i l i z e s t h e r e a d i l y a v a i l a b l e [' %I -phosgene which i s f i r s t converted t o an i s o l a b l e [14C] -labeled a l k y l o r a r y l chloroformate and subsequently r e a c t e d with t h e a p p r o p r i a t e a l c o h o l o r amine t o give t h e corresponding ester.Synthesis of [Carbonyl-"C] Labeled Carbonate and Carbamate 675 with carbon-14. procedures (9) is not limited by the availability of the [l4C1labeled isocyanates. formate intermediate is isolable, asymmetric carbonates can be easily prepared. This method unlike previously reported Furthermore since the [ l4C1 -labeled chloro-
The objectives of the present study were to investigate the formation and rate of hydrolysis of ethyl methanesulphonate (EMS) in BMS-214662 mesylate drug substance and parenteral formulation by a gas chromatographic/mass spectrometric (GC/MS) method. EMS levels in the drug substance ranged between 0.3 microg/g and 0.8 microg/g. The parenteral formulation contains ethanol and the reaction between residual free methane sulphonic acid and ethanol may lead to the formation of EMS. Given that EMS is a potent mutagen, it is therefore of vital importance to eliminate or reduce the risk of human exposure. Data indicate no significant increase in the levels of EMS following storage of the drug product for 18 weeks at 25 degrees C or six weeks at 60 degrees C indicating that the potential reaction between ethanol and free methane sulphonic acid may not occur in the BMS-214662 formulation under the storage conditions evaluated and therefore causes no plausible safety concerns of EMS exposure in humans. Kinetic studies were conducted by spiking 200 ppb of EMS into water and the diluted and undiluted parenteral formulation. The rates of hydrolysis of EMS at 25 degrees C followed pseudo-first order kinetics and were determined to be 2.35 x 10(-4)min(-1), 67.4 x 10(-4)min(-1), and 1.32 x 10(-4)min(-1) in water, undiluted, and diluted drug product, respectively.
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