Probing fluconazole deposition inside mesoporous silica using solid-state NMR spectroscopy: Crystallization of a confined metastable form and phase transformations under storage conditions.

Encapsulation of molecules into mesoporous silica carriers continues to attract considerable interest in the area of drug delivery and crystal engineering. Here, MCM-41, SBA-15 and MCF silica matrices were used to encapsulate fluconazole (FLU), a pharmaceutically relevant molecule with known conformational flexibility, using the melting method. The composites have been characterized using 1H, 13C and 19F NMR spectroscopy, nitrogen adsorption, PXRD and thermal analysis (DSC, TGA). Drug loading up to 50 wt% allowed us to probe the crystallization process and to detect different local environments of confined FLU molecules. 19F NMR spectroscopy enabled us to detect the gradual pore filling of silica with FLU and differentiate the amorphous domains and surface species. The use of the complementary structural and thermal techniques enabled us to monitor crystallization of the metastable FLU form II in MCF. Using 1H and 19F NMR spectroscopy we observed pore-size dependent reversible dehydration/hydration behaviour in the MCM and SBA composites. As water content has considerable importance in understanding of physicochemical stability and shelf-life of pharmaceutical formulations, experimental evidence of the effect of API-water-carrier interactions on the API adsorption mechanism on silica surface is highlighted.

The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome.

INTRODUCTION: Antiphospholipid syndrome (APS) is a common acquired thrombophilia associated with a high thrombotic risk, in which vitamin K antagonists (VKA) represent the mainstay of therapy. Case series involving up to 35 patients with APS suggested limited efficacy and safety of direct oral anticoagulants (DOACs). MATERIAL AND METHODS: In the prospective case series we followed 56 consecutive patients with APS (44 women and 12 men, aged from 22 to 64years), including 33 (60%) associated with systemic lupus erythematosus (SLE) and 16 (28.6%) with triple APS who were treated with DOACs due to their preferences or unstable anticoagulation with VKA. DOACs were started at least 3months since the thromboembolic event in patients with D-dimer below 500ng/ml. RESULTS: Forty-nine (87.5%) patients were treated with rivaroxaban, 4 (7.3%) with dabigatran and 3 (5.4%) with apixaban. During follow-up of 2 to 43 (mean 22) months, 6 (10.7%, 5.8 per 100 patient-years) patients (4 women and 2 men, 4 with triple positive APS) experienced recurrent thrombosis, including deep vein thrombosis (n=4, including 2 episodes preceded by nonadherence), superficial vein thrombosis (n=1) and non-ST elevation myocardial infarction (n=1). The recurrence rate of VTE on DOACs was 5.8 per 100 patient-years. Two patients (3.6%) experienced severe bleeding. CONCLUSIONS: This case-series suggests that DOACs are safe in patients with APS. These findings need to be confirmed in larger studies.