Journal of Drug Delivery Science and Technology xxx (xxxx) xxx Please cite this article as: Jidnyasa Pantwalawalkar, Journal of Drug Delivery Science and Technology, https://doi.org/10.1016/j.jddst.2020.102233 Available online 23 November 2020 1773-2247/© 2020 Elsevier B.V. All rights reserved. Research paper Novel curcumin ascorbic acid cocrystal for improved solubility Jidnyasa Pantwalawalkar a , Harinath More a , Deu Bhange b , Udaykumar Patil a , Namdeo Jadhav a, * a Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Kolhapur, 416013, Maharashtra state, India b Department of Chemistry, Shivaji University, Kolhapur, 416004, Maharashtra state, India A R T I C L E INFO Keywords: Curcumin Ascorbic acid In silico screening Cocrystal Solubility and dissolution improvement ABSTRACT The present investigation aims to develop novel curcumin-ascorbic acid cocrystal for enhancing the solubility, stability, and complementary biological activities for curcumin. Based on in silico approach to screen ascorbic acid as a coformer for curcumin, cocrystals were prepared by the solvent evaporation method, and further evaluated for saturation solubility, cocrystal propensity, physicochemical interactions (FTIR and DSC), XRD, drug dissolution, etc. In silico fndings confrmed the suitability (H_ex, G_mix) of ascorbic acid for the cocrys- tallization of curcumin. The DSC and XRD data of the solvent evaporated curcumin-ascorbic acid mixture confrmed the formation of cocrystal, eutectic, and binary mixture with an excess of coformer. The binary phase diagram implied 0.5 to the 0.65-mole fraction of curcumin, essential for cocrystallization with ascorbic acid. The novel curcumin ascorbic acid cocrystals revealed extraordinary improvement in aqueous solubility of curcumin, especially, 576 fold in distilled water, 10 fold in the buffer pH 1.2, and 9 fold in the buffer pH 6.8. The curcumin- ascorbic acid cocrystal system exhibited a superior dissolution profle compared to neat curcumin. Thus, ascorbic acid has enunciated its role as a coformer for curcumin in cocrystal formation, which has been complemented by predicted complementary biological activities, and stability (acidic milieu). 1. Introduction Curcumin (diferuloylmethane); a polyfunctional phytochemical, has been extensively used as an antioxidant, anti-infammatory, anticancer, antiulcer, anti-Alzheimer, antibacterial [1,2], etc. Due to a multitude of pharmacological actions, it has been widely investigated physicochem- ically and physico-technically, to enable effcient and effcacious phar- maceutical formulation design. The vital aspect of formulation design and biological activities is its polymorphic and crystal form and physi- cochemical properties. Reportedly, it exhibits three polymorphs [3,4]. Amongst them, form 1 (monoclinic) is relatively stable compared to form 2 and form 3. From the dissolution viewpoint, form 2 (ortho- rhombic) dissolves rapidly, whereas form 3 (orthorhombic) has been reported to be unstable and hence its reproducibility is a key concern [3, 4]. Despite appreciable safety, even at high doses in humans (12 g/day); its therapeutic effectiveness is limited due to poor aqueous solubility and pH-dependent instability [5–7]. Precisely, rapid decomposition at neutral and alkaline pH (>90% in 30 min) is a drawback [6,7]. The problem stems from the hydrophobic polyphenol ring in its structure [8]. Poor absorption, rapid metabolism, fast systemic elimination, poor bioavailability, are its consequences [8–10]. To improve the solubility and stability of curcumin, numerous novel approaches have been adopted by workers viz: liposomes, nanoparticles, bioemulsion, micelles, flms, micro/nanoencapsulation [11–23], etc. Concomitant administration of curcumin with lecithin, quercetin, gen- istein, eugenol, terpinol has also been attempted [24]. Complexation of curcumin with robusoside and phosphatidylcholine in equimolar quantities has been successfully demonstrated [25]. In furtherance to it, lucrative strategies like the formation of nanofbers, metal complexes, cocrystals, eutectic mixtures, co-amorphous mixtures [26–41], etc. have been tried and seem appreciable. Certainly, aforesaid strategies imply improved solubility, dissolution, and bioavailability to curcumin. Recently, cocrystallization has been marked as a novel promising approach, to improve the solubility of curcumin. It offers a simple, feasible, and cost-effective method, sometimes green as well. Various coformers like resorcinol, pyrogallol, isonicotinamide, gallic acid, cin- namic acid, hydroxyquinol, dextrose have reported for cocrystallization of curcumin hitherto [30–35]. Eutectic mixtures running alongside, have been formulated for curcumin using coformers like salicylic acid, * Corresponding author. E-mail address: nrjadhav18@rediffmail.com (N. Jadhav). Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst https://doi.org/10.1016/j.jddst.2020.102233 Received 19 August 2020; Received in revised form 12 October 2020; Accepted 15 November 2020