Solid state characterization of the anti-HIV drug TMC114: interconversion of amorphous TMC114, TMC114 ethanolate and hydrate

• Published in: European journal of pharmaceutical sciences Vol. 38; no. 5; pp. 489 - 497
• Main Authors: Van Gyseghem, Elke, Stokbroekx, Sigrid, de Armas, Hector Novoa, Dickens, Jules, Vanstockem, Marc, Baert, Lieven, Rosier, Jan, Schueller, Laurent, Van den Mooter, Guy
• Format: Journal Article
• Language: English
• Published: Netherlands 08.12.2009
• Subjects: Calorimetry, Differential Scanning - methods; Chemistry, Pharmaceutical - methods; Crystallization; Darunavir; Drug Stability; Drug Storage; Ethanol - chemistry; HIV Protease Inhibitors - chemistry; Humidity; Spectrophotometry, Infrared - methods; Stereoisomerism; Sulfonamides - chemistry; Thermogravimetry - methods; X-Ray Diffraction - methods
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2009.09.013

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.