Solid state characterization of the anti-HIV drug TMC114: interconversion of amorphous TMC114, TMC114 ethanolate and hydrate.
The interconversion of the ethanolate, hydrate and amorphous form of TMC114 ((3-[(4-amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxypropyl)-carbamic acid hexahydrofuro-[2,3-b]furan-3-yl ester) in open conditions was characterized. TMC114 hydrate and ethanolate form isostructural channel solvates. The crystal structure of TMC114 was obtained from single crystal X-ray diffraction, confirming that it is a channel solvate. Ethanol and water can exchange with one another. TMC114 ethanolate converts into TMC114 hydrate at moderate or high relative humidity (RH) at 25 degrees C, and it converts back into the ethanolate in ethanol atmosphere. The hydration level of the hydrate is determined by the environmental humidity. TMC114 hydrate collapses to the amorphous product when water is removed by drying at low RH or increasing temperature. TMC114 ethanolate becomes amorphous at elevated temperature in a dry environment below the desolvation temperature. Amorphous TMC114 obtained by dehydrating the hydrate during storage at room temperature/<5% RH, by increasing the temperature, or via desolvating the ethanolate by heating, converts into the hydrate at moderate or high RH at ambient conditions, and into TMC114 ethanolate in an ethanol atmosphere. Under ambient conditions, TMC114 ethanolate may convert into the hydrate, whereas the opposite will not occur under these conditions. The amorphous form, prepared by melting-quenching shows a limited water uptake. Whereas TMC114 ethanolate is stable in the commercialized drug product, special conditions can trigger its conversion.
Laboratorium voor Farmacotechnologie en Biofarmacie, Katholieke Universiteit Leuven, Campus Gasthuisberg, O&N II, Herestraat 49 bus 921, B-3000 Leuven, Belgium.
Elke
E
Van Gyseghem
Sigrid
S
Stokbroekx
Hector Novoa
HN
de Armas
Jules
J
Dickens
Marc
M
Vanstockem
Lieven
L
Baert
Jan
J
Rosier
Laurent
L
Schueller
Guy
G
Van den Mooter
D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D000069454:Darunavir; D004355:Drug Stability; D004356:Drug Storage; D000431:Ethanol / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006813:Humidity; D013055:Spectrophotometry, Infrared / Q000379:methods; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry*; D013818:Thermogravimetry / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D000431:Ethanol; D000069454:Darunavir