Spontaneous carbonate formation in an amorphous, amine-rich, polymeric drug substance: sevelamer HCl product quality.
Spectral differences among multiple manufacturers/lots of sevelamer HCl were observed by Fourier transform infrared spectroscopy, and further characterization was performed to identify the cause for these differences. The drug substance is a polymer that possesses a large molecular weight, is amorphous, and is practically insoluble in both water and organic solvents. Thus, solid-state characterization methods (spectroscopic and thermal) were required to identify and characterize differences among the samples to assess possible differences in product quality. ¹³C cross-polarization-magic-angle-spinning nuclear magnetic resonance spectroscopy of sevelamer HCl substances demonstrated the presence of a carbonyl-containing species, which was attributed to a carbonate impurity among samples. Stability studies demonstrated that this carbonate impurity formed spontaneously upon exposure of the drug substance to atmospheric water vapor and carbon dioxide, even under ambient conditions. Mechanistically, this behavior likely arises from the large number of primary and secondary amine groups, the hygroscopicity of the HCl salt, and a high degree of molecular mobility due to the amorphous nature of the drug substance.
Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Science, Food and Drug Administration, Silver Spring, Maryland 20993, USA.
Robert T
RT
Berendt
Raghu
R
Samy
Alan S
AS
Carlin
Anil
A
Pendse
Paul
P
Schwartz
Mansoor A
MA
Khan
Patrick J
PJ
Faustino
D002152:Calorimetry, Differential Scanning; D002245:Carbon Dioxide / Q000737:chemistry; D002254:Carbonates / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry*; D003460:Crystallization; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy; D011073:Polyamines / Q000737:chemistry*; D000069603:Sevelamer; D013818:Thermogravimetry; D014867:Water / Q000737:chemistry
D002254:Carbonates; D002614:Chelating Agents; D011073:Polyamines; D014867:Water; D002245:Carbon Dioxide; D000069603:Sevelamer