Preparation of a crystalline salt of indomethacin and tromethamine by hot melt extrusion technology

Abstract

Although salt formation is the most ubiquitous and effective method of increasing the solubility and dissolution rates of acidic and basic drugs, it consumes large quantities of organic solvents and is a batch process. Herein, we show that the dissolution rate of indomethacin (a poorly water-soluble drug) can be increased by using hot melt extrusion of a 1:1 (mol/mol) indomethacin:tromethamine mixture to form a highly crystalline salt, the physicochemical properties of which are investigated in detail. Specifically, pH-solubility studies demonstrated that this salt exhibited a maximal solubility of 19.34 mg/mL (>1000 times that of pure indomethacin) at pH 8.19. A solvent evaporation technique was also used for salt formation. Spectroscopic analyses (infrared, nuclear magnetic resonance) of both; demonstrated, in situ salt formation with proton transfer. Powder X-ray diffraction and differential scanning calorimetry confirmed the crystalline nature of salts formed by both methods. Even though a number of amorphous salts of acidic drugs have been reported, the formation of a crystalline salt of an acidic drug by hot melt extrusion is completely unprecedented, which makes this study an important benchmark for the pharmaceutical production industry.

Multicomponent crystals of mefenamic acid-tromethamine with improved dissolution rate

“…Whereas, if the pKa difference >3, then it can form a salt-type multicomponent crystal [31,32]. The pKas of MA and TM are reported as 4.2 and 8.07, respectively [11,33]. In the present study, the difference in pKa between these two solid phases is 3.87 (>3).…”

“…The lower the melting point of the solid phase, the weaker the lattice energy of the crystalline phase. Hence, the dissolution rate is faster [18,24,33,36]. Figure 6.…”

Studies on Ocimum basilicum mucilage based solid dispersions of indomethacin for enhancement of dissolution rate

“…The FTIR pattern revealed that breakdown of the intermolecular hydrogen bond of crystalline drug had taken place with the formation of hydrogen bond between the drug and the polymer. This could be confirmed by slight shift of IR bands related to hydroxyl group to lower side indicates the hydrogen bonding [5,9].…”

“…It is a poorly water soluble antirheumatic agent. In literature attempts has been mase to improve the dissolution rate of indomethacin by various techniques like supersaturable delivery systems such as amorphous self-micellizing solid dispersions (SmSDs) [5] amorphous indomethacin coating with chitosan [6] mesoporous silica nanorods [7], spray drying with silica, polyvinylpyrrolidone (PVP) or 2-hydroxypropyl-β-cyclodextrin (HPβCD) [8] Indomethacin:tromethamine a highly crystalline salt by hot melt extrusion technology [9] melt-electrospun fibers (MSFs) [10], Solid dispersions by modified melt and quench-cooling (QC) method with graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol) [11], microwave assisted in situ amorphization of indomethacin with PVP [12], coamorphous salts of indomethacin-lysine [13] .…”

Effect of Polymer Type on the Dissolution Profile of a Solid Dispersion of Cilostazol

“…[12][13][14] Typically, amorphous solid dispersions result in a supersaturated solution of the poorly watersoluble drugs during the dissolution process both in vitro and in vivo, which enhances oral bioavailability. [18][19][20][21] To date, however, selection of an appropriate polymer for the preparation of an amorphous solid dispersion on the basis of structure-activity relationships remains challenging, and the optimal polymer-to-drug ratio continues to be determined using empirical data. [18][19][20][21] To date, however, selection of an appropriate polymer for the preparation of an amorphous solid dispersion on the basis of structure-activity relationships remains challenging, and the optimal polymer-to-drug ratio continues to be determined using empirical data.…”