Functionalised calcium carbonate as a coformer to stabilize amorphous drugs by mechanochemical activation

The aim of this study was to investigate the amorphization, physical stability and drug release of a model drug, carvedilol (CAR), when loaded onto functionalised calcium carbonate (FCC) using mechanochemical activation (vibrational ball milling). The solid-state characteristics and physical stability of CAR–FCC samples, prepared at different weight ratios and for different milling times, were determined using differential scanning calorimetry and X-ray powder diffraction. Upon milling CAR–FCC samples containing 50% CAR, amorphization of CAR was observed after 10 min. For CAR–FCC samples milled for either 30 or 90 min, it was found that CAR was amorphised at all ratios (10–90% CAR), but FCC remained crystalline. The glass transition temperature (T_gα) of the various CAR–FCC samples milled for 90 min was found to be similar (38 °C) for all ratios containing 20% CAR and above. The similar T_gαs for the different drug ratios indicate deposition of amorphous CAR onto the surface of FCC. For CAR–FCC samples containing 10% CAR, a T_gα of 49 °C was found, which is 11 °C higher compared with other CAR–FCC samples. This may indicate restricted molecular mobility resulting from CAR molecules that are in close contact with the FCC surface.

The physical stability, under both stress (100 °C) and non-stress conditions (25 °C at dry conditions), showed that drug concentrations up to 30% CAR can be stabilized in the amorphous form for at least 19 weeks under non-stress conditions when deposited onto FCC, compared to less than a week physical stability of neat amorphous CAR. In vitro drug release showed that CAR–FCC samples containing 60% CAR and below can improve the drug release and generate supersaturated systems compared to neat amorphous and crystalline CAR. Samples with lower drug concentrations (40% CAR and below) can maintain supersaturation during 360 min of dissolution testing. This study indicates that the crystalline inorganic material, FCC, can facilitate amorphization of drugs, provide stabilization against drug crystallization, and improve dissolution properties of amorphous drugs upon mechanochemical activation.

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Author links open overlay panelJingwen Liu, Thomas Rades, Ingunn Tho, Eric Ofosu Kissi
European Journal of Pharmaceutics and Biopharmaceutics
Volume 155, October 2020, Pages 22-28

Keywords: Physical stability, Amorphous, Amorphization, Porous, Functionalized calcium carbonate, Drug release