Crystal Engineering of Curcumin with Salicylic Acid and Hydroxyquinol as Coformers

Abstract

Curcumin is a pharmaceutically viable ingredient derived from the rhizome of the Indian spice turmeric (Curcuma longa). However, curcumin suffers from poor water solubility, which limits its bioavailability. In this work, we report studies carried out to investigate cocrystallization of curcumin to improve its aqueous solubility. Salicylic acid and hydroxyquinol were used as coformers. Binary phase diagrams were constructed for curcumin−salicylic acid and curcumin− hydroxyquinol systems using differential scanning calorimetric (DSC) thermograms obtained for mixtures prepared by solidstate grinding. The curcumin−salicylic acid system was found to form an eutectic at a curcumin mole fraction of 0.33, whereas the curcumin−hydroxyquinol system clearly exhibited a cocrystal forming region. Out of the several curcumin to hydroxyquinol ratios studied, cocrystal formation was observed for mixtures containing curcumin mole fractions of 0.33 and 0.5. These curcumin−hydroxyquinol cocrystals were further characterized by powder X-ray diffraction analysis, DSC, scanning electron microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, and solid-state 13 C nuclear magnetic resonance spectroscopy. Intramolecular hydrogen bonding interactions in salicylic acid and weaker intermolecular interactions between hydroxyl (-OH) group present at the ortho position of salicylic acid with the keto (-CO) group of curcumin result in a generation of eutectic, whereas strong hydrogen bonding interactions between hydroxyl -OH groups present in hydroxyquinol molecule and curcumin molecule result in formation of cocrystal upon melting and recrystallization. These curcumin−salicylic acid eutectic and curcumin−hydroxyquinol cocrystals show faster powder dissolution rates than raw curcumin. In the case of curcumin−hydroxyquinol cocrystals, cocrystals containing a curcumin mole fraction of 0.33 showed enhanced dissolution than cocrystals containing a curcumin mole fraction of 0.5.

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

“…While cocrystal formation is the main desired outcome, an unsuccessful cocrystallization event might result in formation of different solid forms such as eutectics [ 22 , 23 , 24 , 25 , 26 ], a drug polymorph [ 27 , 28 ], coamorphous solids [ 25 , 28 , 29 , 30 , 31 , 32 , 33 ], physical mixtures [ 22 , 25 , 34 ], salts [ 35 ], solvates [ 35 , 36 ], hydrates [ 35 , 36 , 37 ] and solid solutions [ 38 , 39 , 40 ]. These solid forms can consist of a single component or multiple components.…”

“…From Table 3 , it is evident that the eutectic mixtures show significantly enhanced dissolution as compared to the raw drug. This ability of eutectic mixtures to exhibit enhanced dissolution rates than the raw drug is attributed to the randomized lattice arrangement which exists in the eutectic phase [ 24 ].…”

Polymorphs of Curcumin and Its Cocrystals With Cinnamic Acid

“…27 Reports of co-crystal formation of curcumin or its eutectics with polyhydroxybenzenes, aromatic acids, amides, amines and amine oxides, have been listed well in the literature, with improved solubility and enhanced rates of solubilization of curcumin along with the coformers. [28][29][30] The co-crystals of curcumin with resorcinol and pyrogallol show higher solubilization rates, 5 and 12 times, respectively, as compared to pure curcumin, in water. 28 The intermolecular hydrogen bonding with the hydroxyl group of hydroxyquinol leads to formation of two different types of cocrystals with curcumin; one in 1:2 ratio showing a better dissolution rate as compared to another cocrystal formed in 1:1 ratio.…”

“…Stronger intramolecular H-bonding interaction in salicylic acid, however, results in formation of an eutectic of the acid with curcumin. 29 Recently, Katherine et. al.…”

Characterization of donepezil prepared by cogrinding with salicylic acid and p-aminobenzoic acid

“…We attempted to form cocrystals of donepezil HCl and the solvate using a cogrinding method as two coformers (salicylic acid and p-aminobenzoic acid). Both coformers are involved as primary compounds in the synthesis of pharmaceutical compounds [32][33][34] . The approach taken aimed to understand the mechanisms involved in the process-induced cocrystal formation and to develop a solvent-free method.…”