Development of a multiparticulate drug delivery system for in situ amorphisation

In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation by microwave irradiation within the final dosage form. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a fully amorphous and disintegrating system.

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Materials

Celecoxib (CCX) was purchased from Fagron (Rotterdam, Netherlands). Polyvinylpyrrolidone/vinyl acetate (PVP/VA, Kollidon® VA64, Mw = 45,000-70,000 g/mol) was kindly gifted from BASF (Ludwigshafen, Germany) and sodium dihydrogen phosphate (NaH2PO4) mono- and anhydrate were kindly gifted by Merck (Darmstadt, Germany). Microcrystalline cellulose (VivaPur 102, MCC) and mannitol (Pearlitol 200 SD, MAN) were purchased from JRS Pharma (Patterson, NY, USA) and Roquette (Lestrem, France), respectively. Crospovidone (Kollidon® CL) was purchased from BASF (Ludwigshafen, Germany), magnesium stearate (MgSt) from UNIKEM (Copenhagen, Denmark) and Vcaps Plus capsules (HPMC, size 00) were kindly gifted by Lonza (Strasbourg, France). Fasted state simulated intestinal fluid (FaSSIF) powder was purchased from Biorelevant Ltd. (London, United Kingdom). Sodium chloride and sodium hydroxide were purchased from Merck (Darmstadt, Germany). Methanol (≥99.8%, analytical HPLC grade) was purchased from VWR International Ltd. (Poole, United Kingdom). Purified water was freshly prepared using a MilliQ system from ELGA LabWater (High Wycombe, United Kingdom).

Tobias Palle Holm, Marcel Kokott, Matthias Manne Knopp, Ben J. Boyd, Ragna Berthelsen, Julian Quodbach, Korbinian Löbmann, Development of a multiparticulate drug delivery system for in situ amorphisation, European Journal of Pharmaceutics and Biopharmaceutics, 2022, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2022.09.021