title: Imaging dehydration kinetics of a channel hydrate form of the HIV-1 attachment inhibitor prodrug BMS-663068.
abstract: An analysis of the free acid form of the HIV-1 attachment inhibitor prodrug BMS-663068-01 revealed a reversible moisture sorption event in the 42%-46% relative humidity (RH) range. An existing single-crystal analysis indicated that these observations were due to the formation of a nonstoichiometric channel hydrate. This effect was reproducible on repeated cycles, suggesting that the material's structural integrity was not compromised because of the interconversion process. Small, reversible, and predictable changes in the atomic structure were observed by solid-state nuclear magnetic resonance (ssNMR). Atomic force microscopy (AFM) and environmental scanning electron microscopy (ESEM) could discern changes in surface topography as a function of RH. Surface cracks were visible at 25% RH, most of which disappeared at 60% RH. This change was reversible on reducing the RH, with cracks reappearing in the same locations. A reduction in surface roughness was seen at high humidity, which was consistent with the uptake of moisture causing surface swelling. The observations by AFM/ESEM were consistent with the atomic alterations seen with ssNMR. Changes in unit cell dimensions are not uncommon with channel hydrates as the crystal lattice expands or contracts when the crystal structure absorbs/desorbs water, but concomitant, reversible surface morphology property changes have not been widely reported.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral, CH46 1QW, UK.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Leane
authors.forename: John F
authors.initials: JF
authors.lastname: Gamble
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brown
authors.forename: Helen
authors.initials: H
authors.lastname: Hughes
authors.forename: George
authors.initials: G
authors.lastname: Crull
authors.forename: Josh
authors.initials: J
authors.lastname: Engstrom
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Matt
authors.initials: M
authors.lastname: Bunker
authors.forename: Sandra
authors.initials: S
authors.lastname: Rutherford
authors.forename: Andrew
authors.initials: A
authors.lastname: Parker
authors.forename: Clive J
authors.initials: CJ
authors.lastname: Roberts
authors.forename: Mike
authors.initials: M
authors.lastname: Tobyn
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D006813:Humidity; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D010755:Organophosphates / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D013499:Surface Properties; D014867:Water / Q000737:chemistry*
chemical_list: D019380:Anti-HIV Agents; D010755:Organophosphates; D010879:Piperazines; D011355:Prodrugs; D014867:Water; C576364:fostemsavir
keywords: ESEM; atomic force microscopy; dynamic vapor sorption; hydrates; solid-state NMR; surface roughness