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'.
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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-
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