Cryomilling-induced solid dispersion of poor glass forming/poorly water-soluble mefenamic acid with polyvinylpyrrolidone K12

Abstract

The effect of mechanical impact on the polymorphic transformation of mefenamic acid (MFA) and the formation of a solid dispersion of mefenamic acid, a poor glass forming/poorly-water soluble compound, with polyvinylpyrrolidone (PVP) K12 was investigated. The implication of solid dispersion formation on solubility enhancement of MFA, prepared by cryomilling, was investigated. Solid state characterization was conducted using powder X-ray diffraction (PXRD) and Fourier-transform infrared (FTIR) spectroscopy combined with crystal structure analysis. Apparent solubility of the mixtures in pH 7.4 buffer was measured. A calculation to compare the powder patterns and FTIR spectra of solid dispersions with the corresponding physical mixtures was conducted. Solid state characterization showed that (1) MFA I transformed to MFA II when pure MFA I was cryogenically milled (CM); and (2) MFA forms a solid dispersion when MFA was cryogenically milled with PVP K12. FTIR spectral analysis showed that hydrogen bonding facilitated by mechanical impact played a major role in forming solid dispersions. The apparent solubility of MFA was significantly improved by making a solid dispersion with PVP K12 via cryomilling. This study highlights the importance of cryomilling with a good hydrogen bond forming excipient as a technique to prepare solid dispersion, especially when a compound shows a poor glass forming ability and therefore, is not easy to form amorphous forms by conventional method.

The Need for Restructuring the Disordered Science of Amorphous Drug Formulations

“…Ninety-two of the 101 studies reported solubility and dissolution studies (71–74,77–79,81–92,95,97–107,109–111,113–119,121,123,124,126–133,135–139,141–154,156,157,160,161,166,168–176). The USP in vitro dissolution type II apparatus was the most commonly used instrument (67%), followed by the USP type I apparatus (6%), while the remaining 27% used various other apparatuses, including modified versions of the USP type I only (148) or paired with confocal Raman microscopy (98), USP types I and II apparatus (72), USP type IV (152), closed loop of USP types II and IV (152), a perspex flow cell (73,142), a rotary mixer (131), a Chinese pharmacopoeia type III apparatus (118), an in-house miniaturized USP type II apparatus (175), Sirius T3 apparatus (146), μFLUX dissolution-permeation apparatus (141), Raman UV-Vis flow cell system (99), a centrifuge (88), high throughput screening using a 96-well plate (82,115,157), Wood’s apparatus (99,137), an orbital shaking incubator (156), and another shake-flask method (171) (Fig. 6).…”

Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepared by different techniques

“…Various techniques have been used in the investigation of solid dispersions (SDs) of various weakly soluble drugs and other organic compounds (Moneghini et al, 2008, Aso et al, 2009, Moneghini et al, 2009, Menéndez et al, 2010, Maurya et al, 2010, Van Eardenbrugh and Taylor, 2010, Issa et al, 2013, Paudel et al, 2013, Li et al, 2014, Xiqiang et al, 2014, Fulop et al, 2015, Kang et al, 2015, Wang et al, 2015, Altamimi and Neau, 2016). Microwave technology has been investigated rarely in literature in order to enhance solubility, in vitro dissolution, therapeutic efficacy and in vivo bioavailability of such drugs.…”

Formation and Characterization of Mefenamic acid-Nicotinamide Cocrystal during Co-milling Based on X-ray Powder Diffraction Analysis

“…The MFA form I was used as received without recrystalized. The MFA form II were recrystalized from DMF as described by Kang et al (2015). The IR absorption bands (Fig.…”

“…Many approaches have been studied to enhance solubility and dissolution profile of MFA. The techniques such as solid dispersion with polyvinylpyrrolidone (Kang et al, 2015) or modified starch (Vikram, 2012), a complex with cyclodextrin (Hladon et al, 1999), and also a cocrystal formation (Fabian et al, 2011) have been tried. The progress of solid stage of MFA in various pharmaceutical dosage form was also hindered by polymorphic transformation of MFA along of the formulation process.…”

“…The MFA form II has also been investigated widely due to its advantage than MFA form I in solubility and dissolution rate (Dixit et al, 2012;Romero et al, 1999). The polymorphic transformation of MFA I to MFA II to be formed by co-milling (Kato et al, 2014), cryomilling process (Kang et al, 2015), heating crystals of MFA I above the transition temperature (165-175°C) and by rapid cooling of a supersaturated of MFA I in DMF (Romero et al, 1999 ;Surov et al, 2009) Fabian et al (2011) has been studied cocrystal formation of five fenamic acid drugs, including MFA with NIC based on supramolecular heterosynthon of both. The cocrystal of MFA be formed by comilling and liquid assisted co-milling.…”