title: Absolute molecular weight determination of hypromellose acetate succinate by size exclusion chromatography: use of a multi angle laser light scattering detector and a mixed solvent.
abstract: Molecular weight distribution is an important quality attribute for hypromellose acetate succinate (HPMCAS), a pharmaceutical excipient used in spray-dried dispersions. Our previous study showed that neither relative nor universal calibration method of size exclusion chromatography (SEC) works for HPMCAS polymers. We here report our effort to develop a SEC method using a mass sensitive multi angle laser light scattering detector (MALLS) to determine molecular weight distributions of HPMCAS polymers. A solvent screen study reveals that a mixed solvent (60:40%, v/v 50mM NaH(2)PO(4) with 0.1M NaNO(3) buffer: acetonitrile, pH* 8.0) is the best for HPMCAS-LF and MF sub-classes. Use of a mixed solvent creates a challenging condition for the method that uses refractive index detector. Therefore, we thoroughly evaluated the method performance and robustness. The mean weight average molecular weight of a polyethylene oxide standard has a 95% confidence interval of (28,443-28,793) g/mol vs. 28,700g/mol from the Certificate of Analysis. The relative standard deviations of average molecular weights for all polymers are 3-6%. These results and the Design of Experiments study demonstrate that the method is accurate and robust.
authors.affiliation: Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340, USA. raymond.chen@pfizer.com
authors.forename: Raymond
authors.initials: R
authors.lastname: Chen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ilasi
authors.forename: Sonja S
authors.initials: SS
authors.lastname: Sekulic
mesh_terms: D000085:Acetates / Q000032:analysis* / Q000737:chemistry; D002138:Calibration; D002850:Chromatography, Gel / Q000379:methods*; D005079:Excipients / Q000032:analysis* / Q000737:chemistry; D006801:Humans; D065347:Hypromellose Derivatives; D007834:Lasers; D008027:Light; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000032:analysis; D008970:Molecular Weight; D011108:Polymers / Q000032:analysis / Q000737:chemistry; D012015:Reference Standards; D012542:Scattering, Radiation; D012997:Solvents; D013386:Succinates / Q000032:analysis* / Q000737:chemistry
chemical_list: D000085:Acetates; D005079:Excipients; D011108:Polymers; D012997:Solvents; D013386:Succinates; D065347:Hypromellose Derivatives; D008747:Methylcellulose