title: Analysis of amorphous solid dispersions using 2D solid-state NMR and (1)H T(1) relaxation measurements.
abstract: Solid-state NMR (SSNMR) can provide detailed structural information about amorphous solid dispersions of pharmaceutical small molecules. In this study, the ability of SSNMR experiments based on dipolar correlation, spin diffusion, and relaxation measurements to characterize the structure of solid dispersions is explored. Observation of spin diffusion effects using the 2D (1)H-(13)C cross-polarization heteronuclear correlation (CP-HETCOR) experiment is shown to be a useful probe of association between the amorphous drug and polymer that is capable of directly proving glass solution formation. Dispersions of acetaminophen and indomethacin in different polymers are examined using this approach, as well as (1)H double-quantum correlation experiments to probe additional structural features. (1)H-(19)F CP-HETCOR serves a similar role for fluorinated drug molecules such as diflunisal in dispersions, providing a rapid means to prove the formation of a glass solution. Phase separation is detected using (13)C, (19)F, and (23)Na-detected (1)H T(1) experiments in crystalline and amorphous solid dispersions that contain small domains. (1)H T(1) measurements of amorphous nanosuspensions of trehalose and dextran illustrate the ability of SSNMR to detect domain size effects in dispersions that are not glass solutions via spin diffusion effects. Two previously unreported amorphous solid dispersions involving up to three components and containing voriconazole and telithromycin are analyzed using these experiments to demonstrate the general applicability of the approach.
authors.affiliation: Chemical Development, GlaxoSmithKline plc, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Tran.N.Pham@gsk.com
authors.forename: Tran N
authors.initials: TN
authors.lastname: Pham
authors.forename: Simon A
authors.initials: SA
authors.lastname: Watson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Edwards
authors.forename: Manisha
authors.initials: M
authors.lastname: Chavda
authors.forename: Jacalyn S
authors.initials: JS
authors.lastname: Clawson
authors.forename: Mark
authors.initials: M
authors.lastname: Strohmeier
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Vogt
mesh_terms: D000082:Acetaminophen / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D003911:Dextrans / Q000737:chemistry; D004304:Dosage Forms; D007213:Indomethacin / Q000737:chemistry; D048628:Ketolides / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011743:Pyrimidines / Q000737:chemistry; D012995:Solubility; D013535:Suspensions; D014199:Trehalose / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry; D065819:Voriconazole
chemical_list: D003911:Dextrans; D004304:Dosage Forms; D048628:Ketolides; D011743:Pyrimidines; D013535:Suspensions; D014230:Triazoles; D000082:Acetaminophen; D014199:Trehalose; D065819:Voriconazole; C106791:telithromycin; D007213:Indomethacin