Supersaturated amorphous solid dispersions of celecoxib prepared in situ by microwave irradiation. 2022

Tobias Palle Holm, and Matthias Manne Knopp, and Ragna Berthelsen, and Korbinian Löbmann
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

This study investigated the ability of in situ amorphisation using microwave irradiation in order to prepare highly supersaturated ASDs, i.e. ASDs with drug loads higher than the saturation solubility in the polymer at ambient temperature. For this purpose, compacts containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA), or polyvinyl acetate (PVAc), were prepared at drug loads between 30 and 90 % w/w. Sodium dihydrogen phosphate (NaH2PO4) monohydrate was included in all compacts, as a source of water, to facilitate the dielectric heating of the compacts upon dehydration during microwave irradiation. After processing, the samples were analysed towards their solid state using X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC). Complete amorphisation of CCX was achieved across all the investigated polymers and with a maximal drug load of 90, 80, and 50 % w/w in PVP, PVP/VA, and PVAc, respectively. These drug loads corresponded to a 2.3-, 2.4-, and 10.0-fold supersaturation in the investigated polymers at ambient temperature. However, dissolution experiments with the in situ prepared ASDs in fasted state simulated intestinal fluid (FaSSIF), showed a lower initial drug release (0-2 h) compared to equivalent physical mixtures of crystalline CCX and polymers or crystalline CCX alone. The lower drug release rate was explained by the fusion of individual drug and polymer particles during microwave irradiation and, subsequently, a lack of disintegration of the monolithic ASDs. Nevertheless, supersaturation of CCX in FaSSIF was achieved with the in situ amorphised ASDs with PVP and PVP/VA, albeit only after 3-24 h. Overall, the present study confirmed that it is feasible to prepare supersaturated ASDs in situ. However, in the current experimental setup, the monolithic nature of the resulting ASDs is considered a limiting factor in the practical applicability of this preparation method, due to limited disintegration and the associated negative effect on the drug release.

UI MeSH Term Description Entries
D008872 Microwaves That portion of the electromagnetic spectrum from the UHF (ultrahigh frequency) radio waves and extending into the INFRARED RAYS frequencies. EHF Waves,Extremely High Frequency Radio Waves,Micro Wave,Micro Waves,Ultrahigh Frequency Waves,Microwave Radiation,EHF Wave,Micro Waves,Microwave,Microwave Radiations,Radiation, Microwave,Ultrahigh Frequency Wave,Wave, EHF,Wave, Micro,Wave, Ultrahigh Frequency,Waves, Micro
D011108 Polymers Compounds formed by the joining of smaller, usually repeating, units linked by covalent bonds. These compounds often form large macromolecules (e.g., BIOPOLYMERS; PLASTICS). Polymer
D011145 Polyvinyls POLYMERS derived from the monomer VINYL COMPOUNDS. Polyvinyl
D011205 Povidone A polyvinyl polymer of variable molecular weight; used as suspending and dispersing agent and vehicle for pharmaceuticals; also used as blood volume expander. Polvidone,Polyvidon,Polyvinylpyrrolidone,Arufil,Bolinan,Bolinan 40,Crospovidone,Dulcilarmes,Duratears Free,Enterodes,Enterodez,Hypotears,Kollidon,Lacophtal,Lacri-Stulln,Lagrifilm,Liquifilm Lagrimas,Nutrivisc,Oculotect,PVP 40,Periston,Plasdone,Polyplasdone XL,Povidone, Unspecified,Protagens,Protagent,Unifluid,Vidirakt S mit PVP,Vidisic PVP Ophtiole,Wet-Comod,Dulcilarme,Enterode,Hypotear,Polyvidons,Protagen,Unspecified Povidone
D000068579 Celecoxib A pyrazole derivative and selective CYCLOOXYGENASE 2 INHIBITOR that is used to treat symptoms associated with RHEUMATOID ARTHRITIS; OSTEOARTHRITIS and JUVENILE ARTHRITIS, as well as the management of ACUTE PAIN. 4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide,Celebrex,SC 58635,SC-58635,SC58635
D012995 Solubility The ability of a substance to be dissolved, i.e. to form a solution with another substance. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Solubilities
D014867 Water A clear, odorless, tasteless liquid that is essential for most animal and plant life and is an excellent solvent for many substances. The chemical formula is hydrogen oxide (H2O). (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) Hydrogen Oxide

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