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Title: Solid state characterization of the anti-HIV drug TMC114: interconversion of amorphous TMC114, TMC114 ethanolate and hydrate
Authors: Van Gyseghem, Elke
Stokbroekx, Sigrid
Novoa de Armas, Hector
Dickens, Jules
Vanstockem, Marc
Baert, Lieven
Rosier, Jan
Schueller, Laurent
Van den Mooter, Guy #
Issue Date: 14-May-2009
Conference: BGFW edition:14 location:Floreal Club, Blankenberge date:14-15 May 2009
Abstract: TMC114 (PrezistaTM, Darunavir), a next-generation, synthetic nonpeptidic protease inhibitor, is a key component of many salvage therapies in multiexperienced HIV-patients. TMC114 shows pseudopolymorphic behaviour as it exists as TMC114 ethanolate and hydrate crystals; the non-solvated form is amorphous.
Amorphous TMC114 was produced to compare its bioavailability to the marketed product TMC114 ethanolate-hydrate, which is stable. The desolvation/solvation mechanism and kinetics were characterized in open conditions using Fourier transform infrared and Raman spectroscopy, thermogravimetric analysis, (modulated) differential scanning calorimetry, X-ray powder diffraction, dynamic vapour sorption and head space gas chromatography to explain the interconversion processes and conditions. In addition, contact angle measurement, intrinsic dissolution and helium pycnometry were executed.
TMC114 hydrate and ethanolate form isostructural channel solvates, confirmed by single crystal X-ray diffraction. Ethanol and water can exchange with one another, ethanol being more tightly bound. TMC114 ethanolate converts into TMC114 hydrate at moderate or high relative humidity (RH) at 25°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 by storage at RT/<5%RH or by increasing the temperature, or obtained by 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 has no channels any more and therefore shows a limited water uptake. Whereas the commercialised TMC114 ethanolate-hydrate is stable, special conditions can trigger conversion of amorphous TMC114, TMC114 ethanolate or hydrate.
Publication status: accepted
KU Leuven publication type: AMa
Appears in Collections:Drug Delivery and Disposition
# (joint) last author

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