Curcumin Eutectics with Enhanced Dissolution Rates: Binary Phase

Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Curcumin Eutectics with Enhanced Dissolution Rates: Binary Phase Diagrams, Characterization, and Dissolution Studies Indumathi Sathisaran,† Jenna Marie Skieneh,‡ Sohrab Rohani,‡ and Sameer Vishvanath Dalvi*,§ †

Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382 355, India Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, N6A 5B9, Canada § Department of Chemical Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382 355, India ‡

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S Supporting Information *

ABSTRACT: Curcumin is a potentially viable pharmaceutical ingredient obtained from the rhizome of a turmeric plant, Curcuma longa. It is a polyphenolic compound which is known to possess antibacterial, anti-inflammatory, antitumor, and anticancer properties. Its use in pharmaceutical applications has been limited because of its poor aqueous solubility and hence poor bioavailability. In this work, attempts were made to formulate new solid forms of Curcumin with several coformers, mainly to enhance the dissolution rate of curcumin in aqueous medium. Ibuprofen, succinic acid, paracetamol, carbamazepine, ethyl paraben, glycine, tyrosine, N-acetyl D,Ltryptophan and biotin are the coformers investigated in this study. Binary phase diagrams were constructed for each binary system which helped in identifying the nature and the composition of the solid phase. All binary systems except curcumin−ibuprofen exhibited eutectic formation. The curcumin−ibuprofen system resulted in a physical mixture. These solid phases were further characterized through powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and Raman spectroscopy. Dissolution studies conducted for eutectics showed enhanced dissolution rates as compared to raw curcumin. The results obtained were compared with the literature reports to present a consolidated account of research being conducted to enhance aqueous solubility of curcumin by developing new solid forms of curcumin such as eutectics, coamorphous solids, and cocrystals. Further, attempts have been made to understand how molecular geometry and intermolecular interactions influence the formation of a specific solid form.

1. INTRODUCTION Cocrystallization has received tremendous attention as one of the promising methods to enhance the solubility of BCS Class II and Class IV drugs.1−4 Cocrystallization is a crystal engineering approach where a multicomponent pharmaceutical solid phase can be engineered using water-soluble coformers to enhance dissolution rates and improve the bioavailability of drugs.5 The aqueous solubility of active pharmaceutical ingredient (API) molecules can be enhanced by synthesizing multicomponent solid phases such as cocrystals, eutectics, and coamorphous solids. Cocrystals are synthesized either by using a mechanochemical approach or by crystallization. Noncovalent intermolecular interactions such as strong hydrogen bonding,6−9 halogen bonding,7−10 and Π−Π interactions11,12 between drug and coformer molecules mainly result in supramolecular structures such as homosynthons or heterosynthons which facilitate crystallization of drug and coformer molecule in a single lattice as cocrystals. However, at times, one may end up with an eutectic or coamorphous solid formation instead of the expected cocrystal mainly due to poor interaction between drug and coformer molecules.13 Eutectic and coamorphous solids are thus the byproducts of a cocrystallization event.14 In recent years, extensive research has been carried out related to the © XXXX American Chemical Society

synthesis of eutectic phases to improve physicochemical properties of pharmaceutical drugs such as stability, dissolution rate, and solubility, etc.15−21 In this work, we report the synthesis of eutectics of curcumin which is a natural polyphenolic ingredient present in an herbal spice, turmeric (Curcuma longa). Curcumin is reported to have antibacterial,22 anti-inflammatory,23 antitumor,24 and anticancer25 properties. Despite its medicinal properties, its use in pharmaceutical applications has been restricted due to its limited aqueous solubility (and poor bioavailability).26,27 Sharma et al.28 reported that the level of curcumin and its in vivo metabolites in serum falls to a very low value within a short period of time after administration.28 Therefore, it is a necessity to enhance the aqueous solubility of curcumin. Numerous attempts have been made by researchers to improve the aqueous solubility of curcumin by techniques such as forming solid dispersions,29 precipitation as nanoparticles,30 solubilization using surfactants,31 and crystal engineering approaches.32−39 Several attempts have also been made by many researchers to design Received: December 23, 2017 Accepted: September 7, 2018

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DOI: 10.1021/acs.jced.7b01105 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

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Table 1. Summary of Reports Available in the Literature on Curcumin Eutectics and Coamorphous Solids

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Table 1. continued

and develop curcumin cocrystals.18,32−35 While some researchers have been successful in synthesizing cocrystals of curcumin, in some cases, cocrystallization attempts yielded eutectics15,18,36 or coamorphous solid forms, 13,37,38 or even curcumin polymorphs39 instead of a cocrystal. These byproducts have been observed to result in enhanced dissolution rates as compared to the commercially available curcumin.13,15,18,37−39 Table 1 presents the summary of reports available in the literature where curcumin solid forms (other than cocrystals) were synthesized and reported to enhance aqueous solubility of curcumin. Among the various curcumin eutectic mixtures reported, curcumin eutectics formed with coformers such as ferulic acid, tartaric acid, and salicylic acid exhibited nearly more than two times higher dissolution when compared to the raw curcumin.15,18 Curcumin coamorphous solid phase formed with folic acid dihydrate37 showed 4 times higher intrinsic dissolution rate than raw curcumin in 40% ethanol (EtOH)−water medium, whereas curcumin−artemisinin coamorphous solid13 exhibited 2.6 times faster intrinsic dissolution rate compared to the raw curcumin in 60% EtOH−water medium. Recently, Mannava and co-workers40 had investigated the application of curcumin− pyrogallol cocrystal32 and curcumin−artemisinin coamorphous solid13 on a xenograft model in a preclinical study and observed that curcumin−artemisinin coamorphous solid showed two times higher bioavailability than the curcumin−pyrogallol cocrystal.40 Also, a study carried out by Pang et al.38 revealed that curcumin−piperazine coamorphous solid phase showed lower dissolution than raw curcumin at 37 °C, whereas an enhanced dissolution than that of raw curcumin was observed at a lower temperature of 20 °C (which is its glass transition temperature) in 30% EtOH−water medium.38 In this work, we report observations from our study where efforts were made to enhance the aqueous solubility of curcumin by formulating new solid forms with coformers such as ibuprofen, succinic acid, paracetamol, carbamazepine, ethyl paraben, glycine, tyrosine, N-acetyl D,L-tryptophan and biotin.

During the selection of coformers, molecules with different hydrogen bond donors such as −COOH, −NH2, and −OH, which are capable of forming intermolecular hydrogen bonds with curcumin were initially chosen. Later, this list was further screened for their generally regarded as safe (GRAS) status and pharmaceutical/nutraceutical significance (such as amino acids, vitamins, drugs, few dicarboxylic acids). Liquid-assisted grinding was performed followed by DSC heating for each curcumin− coformer pair (a total of nine pairs) and binary phase diagrams were constructed for each of these pairs. The binary phase diagram for curcumin−ibuprofen pair showed that it formed a physical mixture, whereas the remaining eight pairs formed eutectic phases instead of a cocrystal phase. The so-formed solid phases were further characterized by powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR), and Raman spectroscopic analyses in order to confirm the nature of solid forms deduced through binary phase diagrams. Powder dissolution (PD) studies were conducted. Further, efforts have been made to compare the results obtained in this work with the literature reports in order to understand the effect of intermolecular interactions between curcumin and coformers on determining formation of new solid phases and its dissolution behavior.

2. MATERIALS AND METHODS 2.1. Materials. Curcumin (CUR), ibuprofen (IBU), carbamazepine (CBZ), glycine (GLY), N-acetyl D,L-tryptophan (N-ATP), biotin (BIO), and ethyl paraben (ETP) were procured from Sigma-Aldrich Ltd., India. Succinic acid (SUC), Paracetamol (PAR) and L-tyrosine (TYR) were purchased from Thermo Fisher Scientific Pvt. Ltd., SD FineChem Ltd., and Alfa Aesar chemicals, India. Table 2 presents the details of chemicals used in this work. All the chemicals were used as is without any further purification. EtOH (99.8% pure) was purchased from Jiangyin Tenghua Import & Export Co. Ltd. Deionized Millipore water was used in all the experiments. C



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Table 2. Detailed Information on the Materials Used in This Work

2.2. Construction of Binary Phase Diagrams. Curcumin and coformer mixtures containing various curcumin mole fractions were properly ground in a mortar and pestle with five drops of ethanol at ambient temperature for about 30 min. Approximately 5 mg of curcumin/coformers/liquid-assisted ground (LAG) mixtures were taken into a platinum crucible and subjected to thermal analysis using DSC (NETZSCH STA 449 F3 Jupiter, Germany) and simultaneous thermogravimetric analysis (TGA) at a heating rate of 10 °C/min. The equipment was calibrated against barium carbonate (BaCO3, 99.98%),

benzoic acid (C6H5COOH, 99.5%), cesium chloride (CsCl, 99.99%), and potassium perchlorate (KClO4, ≥ 99%) for its sensitivity and temperature range. Dry nitrogen gas was purged through the DSC chamber at a flow rate of 40 mL min−1 as a protective gas during the analysis. The binary phase diagrams were constructed for each pair using DSC thermograms obtained from DSC heating experiments. 2.3. Characterization of Ground Mixtures. The ground mixtures were further analyzed using powder X-ray diffraction (PXRD) analysis (D8 Discover, Bruker AXS GmbH, Germany) D



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Figure 1. (A) Binary phase diagram of the CUR−IBU system;45 (B) overlay of PXRD patterns of raw IBU (red), raw CUR (green), and CUR−IBULAG-XCUR-0.5 (black).

Figure 2. (A) Binary phase diagram of CUR−SUC system; (B) overlay of PXRD patterns of raw SUC (red), raw CUR (green), and CUR−SUC-LAGXCUR-0.5 (black).

Figure 3. (A) Binary phase diagram of CUR−PAR system; (B) overlay of PXRD patterns of Raw PAR (red), raw CUR (green), and CUR−PAR-LAGXCUR-0.25 (black).

at a 2θ range of 5 to 50 degrees at a scanning rate of 0.02 s per minute, PerkinElmer Spectrum version 10.5.2 Fourier transform infrared spectrometer from 4500 to 500 cm−1, and Raman spectroscopic (iRaman series portable Raman spectrometer, B&W Tek) analyses. All liquid-assisted grinding experiments were performed at room temperature and 101.325 kPa (1 atm). 2.4. Equilibrium Solubility Determination. Approximately 15 mg of raw curcumin and 8 mg of the curcumin eutectic compositions synthesized in this work were added to 10 mL of EtOH−water mixture (XEtOH = 0.0697), and the mixture was stirred gently at 250 rpm for 24 h at 37 °C and 101.325 kPa. After 24 h, the solution was centrifuged at 14000 rpm for 15 min at 25 °C. The resultant supernatant was then diluted with EtOH−water mixture (XEtOH = 0.0697), and its optical density was recorded at 430 nm. The equilibrium concentration of raw curcumin and the apparent concentration of curcumin eutectics

were determined from the calibration curve generated for raw curcumin and curcumin eutectic mixtures at 430 nm. 2.5. Powder Dissolution (PD) Studies. Powder dissolution (PD) studies were performed in EtOH−water mixture (XEtOH = 0.0697) at 37 °C. The 35 mg of the solid mixture (raw curcumin/curcumin eutectics) sieved using 212 μm pore size mesh, was dissolved in 70 mL of EtOH−water (XEtOH = 0.0697) and gently stirred at 120 rpm continuously in a glass vessel for a total period of 3 h. About 1 mL of dissolution medium was withdrawn from the glass vessel without media replacement at a constant interval of 15 min. The amount of curcumin released (mg/L) from the eutectic phases was estimated using separate calibration curves constructed for each eutectic composition in EtOH−water mixture containing XEtOH of 0.0697 using UV1800 SHIMADZU UV spectrophotometer at 430 nm. The molar extinction coefficients at 430 nm were calculated from E



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Figure 4. (A) Binary phase diagram of CUR−CBZ system; (B) overlay of PXRD patterns of Raw CBZ (red), raw CUR (green) and CUR−CBZ-LAGXCUR-0.4 (black).

Figure 5. (A) Binary phase diagram of CUR−GLY system; (B) overlay of PXRD patterns of raw GLY (red), raw CUR (green), and CUR−GLY-LAGXCUR-0.67 (black).

Figure 6. (A) Binary phase diagram of CUR−TYR system; (B) overlay of PXRD patterns of raw TYR (red), raw CUR (green) and CUR−TYR-LAGXCUR-0.67 (black).

Figure 7. (A) Binary phase diagram of CUR−N-ATP− system; (B) overlay of PXRD patterns of raw N-ATP (red), raw CUR (green), and CUR−NATP−-LAG-XCUR-0.75 (black).

each of these calibration curves. Table S1 presents the calculated values of molar extinction coefficients.

The pH of the dissolution medium was measured at the beginning and at the end of the dissolution experiment using a F



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Figure 8. (A) Binary phase diagram of CUR−BIO system; (B) overlay of PXRD patterns of raw BIO (red), raw CUR (green), and CUR−BIO-LAGXCUR-0.7 (black).

Figure 9. (A) Binary phase diagram of CUR−ETP system;45 (B) overlay of PXRD patterns of raw ETP (red), raw CUR (green) and CUR−ETP-LAGXCUR-0.1 (black).

molecule. To do so, results obtained in this work have been compared vis-à-vis the principle rules proposed by Cherukuvada and Nangia17 (summarized in Table 3) to identify a possible correlation between molecular geometry as well as intermolecular interaction and the cocrystallization outcome.

Cole-Parmer (P100 model) pH meter. The residual powders obtained after completion of dissolution studies were dried and were subjected to PXRD analysis in order to understand the nature of the residual powders left behind in the slurry medium.

3. RESULTS AND DISCUSSIONS 3.1. Binary Phase Diagrams. Binary phase diagrams were constructed for each pair using DSC endotherms obtained during DSC heating of LAG mixtures. The onset of the first endotherm was chosen as the solidus point and the peak temperature of the second endotherm was chosen as the liquidus point in order to construct the melting point-composition diagram. Figures 1−9 present the melting point−composition diagrams along with PXRD patterns for the nine binary systems investigated in this study. It can be seen from these figures that curcumin forms a physical mixture with ibuprofen (Figure 1A), whereas it forms eutectics with succinic acid (Figure 2A), paracetamol (Figure 3A), carbamazepine (Figure 4A), glycine (Figure 5A), tyrosine (Figure 6A), N-acetyl D,L-tryptophan (Figure 7A), biotin (Figure 8A) and ethylparaben (Figure 9A). Curcumin (also known as diferuloylmethane) is a linear diarylheptanoid. It exists in enol as well as keto form as it exhibits tautomerism.41−44 The phenolic −OH, and keto (CO) functional groups of curcumin actively participate in intermolecular hydrogen bonding.32,34 In addition, the methoxy (−OCH3) group also participates in weaker intermolecular interactions.32 Though the coformers used in this work possessed possible hydrogen-bond acceptors (−NH2) or hydrogen bond donors such as −COOH or −OH, all of these molecules resulted either into eutectic phases or a physical mixture instead of forming a cocrystal with curcumin. Therefore, efforts have been made to understand why curcumin forms an eutectic, a cocrystal or a physical mixture with a particular

Table 3. Principal Rules Proposed by Cherukuvada and Nangia17 To Explain Eutectic/Solid Solution/Cocrystal Formation during a Cocrystallization Event structural similarity between drug and coformer nature of solid form molecules eutectic

similar or dissimilar

solid solution/ continuous solid solution cocrystal/ discontinuous solid solution

isomorphous and isostructural similar or dissimilar

type of intermolecular interactions stronger cohesive and weaker adhesive interactions strong cohesive interactions strong adhesive and weak cohesive interactions

3.1.1. Physical Mixtures of Curcumin. Among all the curcumin−coformer pairs studied in this work, curcumin and ibuprofen remained as a physical mixture at all curcumin mole fractions. This is clearly evident from Figure 1A which shows the binary phase diagram for the curcumin−ibuprofen pair.45 It can be observed that there is no eutectic point or a cocrystal forming region in the phase diagram indicating no interaction between curcumin and ibuprofen. The DSC thermograms corresponding to points plotted in Figure 1A have been shown in Figure S1. Each of these DSC thermograms show individual peaks corresponding to the separate melting events for ibuprofen and curcumin implying that there is no interaction between G



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curcumin and ibuprofen. This is further evident from Figure 1B which shows a PXRD pattern for liquid-assisted ground mixture of curcumin−ibuprofen in a stiochiometric ratio of 1:1. It can be easily observed that the PXRD pattern of the ground mixture simply appears to be the combination of PXRD patterns of curcumin and ibuprofen. To understand this behavior, molecules which have been reported to form cocrystals with ibuprofen were examined to understand interactions between these coformer molecules and ibuprofen. A list of these coformer molecules has been presented in Table S2. The chemical structure of ibuprofen is shown in Figure S2. It is clear from Table S2 and Figure S2 that ibuprofen forms strong hydrogen bonding with N-heterocyclic atoms (as observed in 2-aminopyrimidine and 4,4′-bipyridine in Table S2) and strong heterosynthons with molecules containing amide (−CONH2) functional groups. However, curcumin lacks functional groups with N-heterocycles which can form strong intermolecular hydrogen bonding interactions as well as amide functional groups which can form a strong heterosynthon with ibuprofen and hence curcumin does not form a cocrystal with ibuprofen. Also, it does not form an eutectic with ibuprofen as can be observed from Figure 1A and Figure S1. A eutectic is characterized by the single and sharp low-melting endotherm, whereas a physical mixture is characterized by more than one endotherm corresponding to the melting of individual components) which can be verified for the curcumin−iburpofen pair from Figure S1). A similar observation was made for solid-state ground mixtures of the curcumin−L-malic acid pair15 for which curcumin−L-malic acid resulted in a physical mixture. It was explained that when two components are not entropically favored to fit within a crystal lattice, a physical mixture is formed despite the facilitation of molecular diffusion of individual components via solid-state grinding.15 Also, liquid-assisted ground mixtures of curcumin−dextrose were found to result in a physical mixture instead of a cocrystal.37 Since the dextrose molecule contains several −OH groups, it can be speculated that a large number of −OH groups might offer steric hindrance to the interaction between curcumin and coformer molecules and hence result in a physical mixture. 3.1.2. Curcumin Eutectics. As mentioned earlier, curcumin was found to form a eutectic with succinic acid, paracetamol, carbamazepine, glycine, L-tyrosine, N-acetyl D,L-tryptophan, biotin, and ethyl-paraben. Tables 4−11 report the eutectic composition and corresponding eutectic temperatures (determined in triplicate) for these pairs. Curcumin−Succinic Acid. Figure 2A shows the binary phase diagram for the curcumin−succinic acid pair. It can be observed that curcumin forms a eutectic with succinic acid at a curcumin mole fraction of 0.5. Table 4 presents the experimental solidus and liquidus temperatures of the curcumin−succinic acid pair as a function of curcumin mole fraction at 0.10 MPa. Figure 2B shows the PXRD pattern for this eutectic phase. To understand this behavior, molecules which have been reported to form cocrystals with succinic acid were examined to understand interactions between these coformer molecules and succinic acid. A list of these coformer molecules is presented in Table S3.47−60 It is evident from Table S3 that all the molecules which have been reported to form a cocrystal with succinic acid possess either heterocyclic N atoms or amide groups or both. It is clear that the carboxylic acid functional group (−COOH) of succinic acid forms heterosynthons with either −CONH2 functional group of amide coformers or strong hydrogen bonding

Table 4. Experimental Solidus Temperatures (TS) and Liquidus Temperatures (TL) of CUR−SUC Binary System as a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with SUC at a Mole Fraction of 0.5a mole fraction of curcumin (XCUR) 0 0.1 0.25 0.33 0.5 0.67 0.75 0.9 1

solidus temperature (TS) (in °C)

liquidus temperature (TL) (in °C) 196.8 183.9 180.6 177.3

155 153.9 154 159.7 153.2

168.3 170.5 176.87

151.7

Standard uncertainties u are u(XCUR) = 0.000932, u(T) = 2.735 °C, and u(P) = 1 kPa.

a

interaction with N-heterocycles present in coformer molecules in order to form a new cocrystal phase. Curcumin does not possess-heterocyclic ring or amide (−CONH2) functional group to form stronger intermolecular adhesive interaction with succinic acid. Thus, as per the principle rules proposed by Cherukuvada and Nangia,17 the existence of stronger cohesive interaction among succinic acid molecules and weaker adhesive interaction between curcumin and succinic acid molecules could be a possible reason for formation of an eutectic between curcumin and succinic acid. Curcumin−Paracetamol. Paracetamol, also known as acetaminophen or N-(4-hydroxyphenyl) acetamide61,62 was observed to form an eutectic with curcumin at a curcumin mole fraction of 0.25 (Figure 3A). The experimental solidus and liquidus temperatures determined for different curcumin mole fractions of curcumin−paracetamol system at 0.10 MPa are presented in Table 5. Figure 3B shows PXRD pattern for this eutectic mixture. To understand this behavior, molecules which have been reported to form cocrystals with paracetamol were examined to understand interactions between these coformer molecules and paracetamol. A list of these coformer molecules has been presented in Table S4.63−73 It can be observed from Table S4 that phenolic O−H and the −NH functional group of Table 5. Experimental Solidus Temperatures (TS) and Liquidus Temperatures (TL) of CUR−PAR Binary System As a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with PAR at a Mole Fraction of 0.25a mole fraction of curcumin (XCUR) 0 0.1 0.2 0.25 0.33 0.42 0.5 0.67 0.8 0.9 1

solidus temp (TS) (in °C) 147.9 147.2 146.9 140.6 149.5 141.7 133.9 142

liquidus temp (TL) (in °C) 173.3 163.1 156.2

160 162.4 172 170 176.3


a

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the paracetamol molecule participate in strong hydrogen bonding with functional groups such as amine, pyridyl nitrogen, amide, or carboxylic acid functional groups (in coformer molecules such as 5-nitroisopthalic acid, citric acid) and form a cocrystal. As curcumin does not possess the acid/amine/ amide/pyridyl nitrogen to form stronger hydrogen bonds with paracetamol, it is quite feasible that weaker adhesive interactions between curcumin and paracetamol (adhesive interactions) result into an eutectic, according to the ground rules postulated by Cherukuvada and Nangia.17 Curcumin−Carbamazepine. In this work, carbamazepine was found to form a eutectic with curcumin at a mole fraction of 0.4 (as shown in Figure 4A). Table 6 presents the experimental

Table 7. Experimental Solidus Temperatures (TS) and Liquidus Temperatures (TL) of CUR−GLY Binary System as a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with GLY at a Mole Fraction of 0.67a

Table 6. Experimental Solidus Temperatures (TS) and Liquidus Temperatures (TL) of CUR−CBZ Binary System as a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with CBZ at a Mole Fraction of 0.4a mole fraction of curcumin (XCUR) 0 0.1 0.25 0.33 0.4 0.5 0.67 0.75 0.9 1

solidus temp (TS) (in °C) 132.5 129.4 120.4 132.2 117.2 128.1 137.3

mole fraction of curcumin (XCUR)

solidus temp (TS) (in °C)

0 0.1 0.2 0.25 0.33 0.5 0.67 0.8 0.9 1

169.6 169.7 163.8 161.5 162 169.03 170.6 169.5

liquidus temp (TL) (in °C) 233 232.3 228.6 223.5 214.4

176.3


a

liquidus temp (TL) (in °C)

stabilizes the cocrystal structure. Since curcumin does not have a carboxylic acid (−COOH) functional group, curcumin could not form strong acid−acid homosynthon with glycine. Also, glycine has been found to form a dimer with itself.89 Thus, as per the ground rules stated by Cherukuvada and Nangia,17 curcumin−glycine binary system is influenced by dominant cohesive interactions (and weak adhesive interactions), thereby resulting in a eutectic mixture. Curcumin−Tyrosine. In the case of tyrosine, a eutectic formation was observed at a curcumin mole fraction of 0.67 (Figure 6A). The experimental solidus and liquidus temperatures obtained for different curcumin mole fractions of the curcumin−tyrosine system at 0.10 MPa are presented in Table 8. The phenolic −OH of tyrosine has the tendency to behave as both hydrogen bond donor as well as acceptor.90 Reports are available in the literature where tyrosine has been reported to exist as a dimer91,92 indicating strong cohesive interactions. It therefore seems that the phenolic −OH or carboxyl group of tyrosine might be involved in weaker adhesive interactions with keto or the enolic −OH group of curcumin and hence curcumin

192.8 183.6 152.4 142.6 144.4 159.4 167.5 175.4 176.3

a Standard uncertainties u are u(XCUR) = 0.000384, u(T) = 7.081 °C, and u(P) = 1 kPa.

solidus and liquidus temperatures determined for curcumin− carbamazepine pairs of different curcumin mole fractions at 0.10 MPa. Carbamazepine is an anticonvulsive drug and has been reported to form cocrystals with several coformers especially with molecules with amide, acid, aldehyde, ketone, and pyridine rings as functional groups (as reported in Table S5). From the reports available until date74−82 (summarized in Table S5), it is evident that carbamazepine mainly forms homosynthons or heterosynthons in order to form a cocrystal. However, the absence of acid or amide groups to form strong heterosynthons or homosynthons in curcumin might result in a weaker noncovalent interaction between the keto group of curcumin (−CO) and one of the amide hydrogen (−NH2) in carbamazepine. Further, it is quite likely that carbamazepine forms a dimer with itself83 indicating a strong cohesive interaction among carbamazepine molecules. Therefore, it can be surmised that the dominance of strong cohesive interactions over weak adhesive interactions17 possibly results in a formation of a eutectic phase for the curcumin and carbamazepine pair. Curcumin−Glycine. Curcumin formed an eutectic with glycine at a mole fraction of 0.67 (Figure 5A). The experimental solidus and liquidus temperatures determined for the curcumin−glycine system as a function of curcumin mole fraction at 0.10 MPa are shown in Table 7. Glycine has been observed to form cocrystals with carboxylic acids and hydroxybenzoic acids (Table S6). From the literature reports84−88 (summarized in Table S6), it is clear that glycine mainly forms homosynthons with the carboxylic acid (−COOH) functional group in the coformer molecules and

Table 8. Experimental Solidus Temperatures (TS) and Liquidus Temperatures (TL) of CUR−TYR Binary System as a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with TYR at a Mole Fraction of 0.67a mole fraction of curcumin (XCUR) 0 0.05 0.1 0.15 0.25 0.33 0.4 0.5 0.6 0.67 0.8 0.9 1


170 169.4 164.5 172.4 162.4 171.6 171.65 172.03 161.5 172.5

liquidus temp (TL) (in °C) 319.1 297.5 267.1 256.8 254.3 246.3 244.5 246.5 247.4

176.3


a

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forms a eutectic with tyrosine as cohesive interaction outgains the adhesive interaction. Curcumin−N-Acetyl D,L-tryptophan. Curcumin was observed to form an eutectic with N-acetyl D,L-tryptophan at a mole fraction of 0.75 (Figure 7A). Table 9 presents the

Table 10. Experimental Solidus Temperatures (TS) and Liquidus Temperatures (TL) of CUR−BIO Binary System as a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with BIO at a Mole Fraction of 0.7a

Table 9. Experimental Solidus Temperatures (TS) and Liquidus Temperatures (TL) of CUR−N-ATP− Binary System as a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with N-ATP− at a Mole Fraction of 0.75a mole fraction of curcumin (XCUR)


0 0.1 0.25 0.33 0.5 0.67 0.75 0.8 0.9 1

165.4 161.2 157.7 164.7 157.5 165.57 163.4 158.4

liquidus temp (TL) (in °C) 211 204.2 195.7 190.5 185.1



0 0.1 0.25 0.33 0.4 0.5 0.6 0.65 0.7 0.75 0.8 0.9 1

168.9 167.4 164.3 168.6 158.7 167.5 168.1 169.17 175.3 168.8 167.9

liquidus temp (TL) (in °C) 235.1 227.3 222.2 218.1 210 208.1 205.3 201.8

176.3


a

Table 11. Experimental Solidus (TS) and Liquidus Temperatures (TL) of CUR−ETP Binary System as a Function of Curcumin Mole Fraction at 0.10 MPa. CUR Forms a Eutectic with ETP at a Mole Fraction of 0.1a

176.3

Standard uncertainties u are u(XCUR) = 0.000384, u(T) = 3.491 °C, and u(P) = 1 kPa. a

experimental solidus and liquidus temperatures obtained for various curcumin mole fractions of the curcumin−N-acetyl D,Ltryptophan system at 0.10 MPa. Curcumin requires −COOH or −NH2 functional groups to form homosynthon or heterosynthon in order to form a cocrystal with N-acetyl D,Ltryptophan. As curcumin does not possess −COOH or −NH2 functional groups, it is likely that the −COOH functional group of N-acetyl D,L-tryptophan might be involved only in a weaker interaction with the −CO (keto) group of curcumin resulting in a eutectic phase.17 Curcumin−Biotin. From the binary phase diagram for curcumin−biotin pair, it can be observed that curcumin forms an eutectic with biotin at a mole fraction of 0.7 (Figure 8A). The experimental solidus and liquidus temperatures determined for curcumin−biotin system as a function of curcumin mole fraction at 0.10 MPa are shown in Table 10. It could be possible that the carboxylic acid (−COOH) functional group in biotin might be involved in weaker noncovalent interactions with the keto (−CO) group of curcumin, as observed in the case of coformers such as succinic acid, glycine, tyrosine, and N-acetyl D,L-tryptophan (as discussed above) thereby ending up in a eutectic phase during cocrystallization. Curcumin−Ethyl Paraben. Curcumin also formed a eutectic with ethyl paraben at a mole fraction of 0.1 (as shown in Figure 9A).45 Table 11 presents the experimental solidus and liquidus temperatures determined for various curcumin mole fractions of curcumin−ethyl paraben system at 0.10 MPa. Table S7 presents a list of coformer molecules that have been reported to form cocrystal with ethyl paraben.93,94 It is clear from Table S7 that ethyl paraben forms stronger hydrogen bonds with coformers having amide (−CONH2) and acid (−COOH) functional groups. As curcumin does not possess amide or acid functional groups to form stronger hydrogen bonding with ethyl paraben, the strength of adhesive interaction between curcumin and ethyl paraben is weaker than the cohesive interaction. Therefore, in accordance to the ground rules framed by Cherukuvada and



0 0.1 0.25 0.33 0.5 0.67 0.75 1

109.53 108.7 107.6 103.9 96 96.9

liquidus temp (TL) (in °C) 118 130 138.1 149.3 159.7 164.4 176.3


a

Nangia,17 curcumin and ethyl paraben results into an eutectic phase owing to the dominant cohesive and weaker adhesive interactions. 3.1.3. Fourier Transform Infrared (FT-IR) and Raman Spectroscopic (RS) Analyses. Fourier transform-infrared (FTIR) spectroscopy and Raman spectroscopy (RS) provide detailed information regarding intermolecular interactions between API and coformers. Figure 10 and Figures S11−S18 present the overlay of FT-IR spectra for each of the curcumin− coformer pairs investigated in this work. It is very clear from these figures that liquid-assisted ground (LAG) mixtures did not show any unique peaks which are different from that of the parent components confirming formation of eutectics or a physical mixture and no formation of a cocrystal phase. Similarly, Figure 11 and Figures S19−S26 present the overlay of Raman spectra for each of the curcumin−coformer pairs investigated in this work. It is evident that the liquid-assisted ground (LAG) mixtures did not show significant chemical shifts in comparison to that of the parent components, thereby confirming formation of eutectics or physical mixtures and no cocrystal phases. 3.1.4. Curcumin Cocrystals. Even though all the coformers studied in this work resulted in eutectics or a physical mixture J



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Figure 10. Overlay of FT-IR spectra of (A) raw SUC, (B) raw CUR, and (C) CUR−SUC−LAG−XCUR-0.5.

Figure 11. Overlay of Raman spectra of (A) raw SUC, (B) raw CUR, and (C) CUR−SUC−LAG−XCUR-0.5.

−OH group in the third carbon position of the benzene ring and that the position of the −OH functional group in the benzene ring had an influence on cocrystal forming pathway (direct pathway, cocrystal formation without intermediate phase; and indirect pathway, cocrystal formation facilitated via eutectic melt). Two more cocrystals of curcumin with 4,4′-bipyridine-N,N′dioxide, namely JUC-C14 and JUC-C15, were reported by Su et al.34 These were cocrystallized using EtOH and methanol (MeOH) as solvents. The crystal structure of JUC-C14 was found to be in the triclinic space group (P1), and JUC-C15 was found to be in the orthorhombic space group (Pccn) (explained in Table 4). On the basis of the review of all the curcumin−coformer pairs which resulted in cocrystals (reported in Table 12) and the pairs which did not form cocrystals (reported in Tables 1 and 3 and Table S8), it can be clearly stated that small coformer molecules containing (1 or 2) aromatic rings such as N-heterocycle or aromatic rings with hydroxyl functional groups (but no carboxylic acid groups) generally form cocrystals with curcumin. Also, it is clear from Table S8 that all dihydroxybenzoic acid molecules and most of the amino acids are not suitable for cocrystallization with curcumin.15 This is mainly because molecules which are structurally smaller than curcumin are geometrically compatible to fit into the crystal lattice of curcumin. 3.2. Equilibrium Solubilities and Powder Dissolution Studies. The experimentally determined equilibrium solubilities of raw curcumin and the apparent solubilities of curcumin

with curcumin, a literature review was conducted to compile a list of coformers which have been reported in the literature to form cocrystals with curcumin. This was done mainly to identify the molecular interactions that result in formation of the cocrystal with curcumin. Table 12 represents the summary of such reports available in the literature on curcumin cocrystals. Curcumin−resorcinol and curcumin−pyrogallol pairs were found to form cocrystals in a stiochiometric ratio of 1:1 through solution crystallization, by Sanphui et al.32 Both of these cocrystals were found to have crystal structures in the monoclinic (P21/c) space group.32 From the cocrystal structures, it was observed that the phenolic −OH of resorcinol as well as pyrogallol forms intermolecular hydrogen bonding with the keto group (−CO) of curcumin (This has been elaborated in Table 12). Chow et al.33 cocrystallized curcumin with phloroglucinol as coformer by a rapid solvent removal technique.33 It was hypothesized that the presence of −OH functional group in the third carbon position of the benzene ring is possibly necessary for cocrystal formation as observed in the case of molecules such as resorcinol and pyrogallol as well as phloroglucinol (all these molecules have an −OH group in the third carbon position of the benzene ring). Sathisaran and Dalvi18 reported formation of cocrystals of curcumin with hydroxyquinol (which is an isomer of the three benzene triols). It was identified that curcumin forms cocrystals from a eutectic melt with hydroxyquinol at two different stoichiometric ratios of 1:2 and 1:118 This elucidated the fact that curcumin cocrystal formation can occur even if there is no K



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Table 12. Summary of Reports Available in the Literature on Curcumin Cocrystals

L



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Table 12. continued

eutectics in EtOH−water mixture (of XEtOH, 0.0697) at 37 °C and 101.325 kPa have been presented in Table 13. The solubilities for eutectics have been termed as “apparent solubilities” since in all the cases (except curcumin−ethyl paraben eutectic mixture), the eutectic powders transformed to curcumin Form 1 (as verified by the PXRD studies and explained in the following paragraph). Powder dissolution studies were conducted for eutectic mixtures containing drug particles of approximately 200 μm size using UV-spectrophotometer, and an EtOH−water mixture

containing XEtOH of 0.0697 was used as a dissolution medium. The amount of curcumin released during powder dissolution (PD) experiments was determined using the Molar extinction coefficients (ε) obtained for curcumin and each of the eutectic phases at 37 °C and 101.325 kPa. Since curcumin is unstable in an alkaline environment and has good stability as well as solubility in ethanol, an EtOH−water solution (XEtOH = 0.0697) was used as dissolution medium for conducting powder dissolution experiments. Figure 12 shows the variation in the amount of curcumin released with time for different eutectic M



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Table 13. Equilibrium Solubility of Raw Curcumin and the Apparent Solubilities of Curcumin Eutectics Synthesized in This Work in EtOH−Water Mixture (XEtOH = 0.0697) at 37 °C and 0.10 MPa

sample raw curcumin CUR−SUC−LAG−XCUR-0.5 eutectic CUR−PAR−LAG−XCUR-0.25 eutectic CUR−CBZ−LAG−XCUR-0.4 eutectic CUR−GLY−LAG−XCUR-0.67 eutectic CUR−TYR−LAG−XCUR-0.67 eutectic CUR−N-ATP−LAG−XCUR-0.75 eutectic CUR−BIO−LAG−XCUR-0.7 eutectic CUR−ETP−LAG−XCUR-0.1 eutectic

equilibrium/apparent solubility of curcumin solid phases (M)

standard uncertainty for equilibrium/ apparent solubility (M)

cumulative curcumin released from curcumin solid phases during 3 h of powder dissolution experiments (×10−5 M)

average standard uncertainty for curcumin released from the solid phases (×10−6 M)

2.2368 × 10−5 1.43 × 10−4

1.99034 × 10−6 6.7454 × 10−6

1.1265 8.2605

1.2114 1.0854

1.1× 10−4

1.11502 × 10−5

5.6857

6.7612

4.3097 × 10−5

6.012 × 10−6

3.0287

2.7638

7.81331 × 10−5

4.51138× 10−6

5.7274

3.2235

1.05× 10−4

1.446 × 10−5

4.53

3.4214

5.8014 × 10−5

5.6471× 10−6

2.9849

2.4287

4.1530 × 10−5

5.889 × 10−6

1.8278

3.7269

7.7633 × 10−5

4.4386 × 10−6

6.6738

8.1345

Figure 12. Dissolution profiles for various solid forms in in EtOH−water mixture (XEtOH = 0.0697) at 37 °C and 101.325 kPa: (A) CUR (yellow), (B) CUR−BIO−LAG−XCUR-0.7 eutectic (light green), (C) CUR−CBZ−LAG−XCUR-0.4 eutectic (orange), (D) CUR−N-ATP−−LAG−XCUR-0.75 eutectic (red), (E) CUR−PAR−LAG−XCUR-0.25 eutectic (black), (F) CUR−ETP−LAG−XCUR-0.1 eutectic (purple), (G) CUR−TYR−LAG− XCUR-0.67 eutectic (brown), (H) CUR−GLY−LAG−XCUR-0.67 eutectic (sky blue), and (I) CUR−SUC−LAG−XCUR-0.5 eutectic (dark green).

Table 14. pKa Values of the Coformers, pH of Dissolution Medium before and after Powder Dissolution Experiments in EtOH− water Mixture with EtOH Mole Fraction (XEtOH) of 0.0697) at 37 °C and 0.10 MPa pH of dissolution medium sample

name of the coformer

reported pKa value

before dissolution studies

after dissolution studies

Raw CUR CUR−SUC−LAG−XCUR-0.5 CUR−PAR−LAG−XCUR-0.25 CUR−CBZ−LAG−XCUR-0.4 CUR−GLY−LAG−XCUR-0.67 CUR−TYR−LAG−XCUR-0.67 CUR−N-ATP−LAG−XCUR-0.75 CUR−BIO−LAG−XCUR-0.7 CUR−ETP−LAG−XCUR-0.1

curcumin succinic acid paracetamol carbamazepine glycine tyrosine N-acetyl D,L-tryptophan biotin ethyl paraben

7.8, 8.5, and 9128 4.16129 9.38130 13.9131 2.34 and 9.60132 2.20 and 9.11132 3.65133 4.4 and −1.9134 8.34135

5.17 ± 0.15 5.17 ± 0.15 5.17 ± 0.15 5.17 ± 0.15 5.17 ± 0.15 5.17 ± 0.15 5.17 ± 0.15 5.17 ± 0.15 5.17 ± 0.15

5.8 ± 0.2 3.57 ± 0.15 5.67 ± 0.29 5.5 ± 0.3 6.3 ± 0.26 5.3 ± 0.3 4.17 ± 0.25 4.5 ± 0.1 5.7 ± 0.1

mixtures. The PXRD patterns of powders obtained after the dissolution experiments have been given in Figure 13A−I.

It can be observed from Figure 12 that the curcumin−succinic acid eutectic with a curcumin mole fraction of 0.5 (CUR− N



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Figure 13. PXRD patterns of eutectic powders before and after dissolution studies. All powder dissolution experiments were carried out for 3 h in EtOH−water mixture (XEtOH = 0.0697) at 37 °C and 101.325 kPa: (A) raw curcumin, (B) CUR−SUC−LAG−XCUR-0.5, (C) CUR−PAR−LAG− XCUR-0.25, (D) CUR−CBZ−LAG−XCUR-0.4, (E) CUR−GLY−LAG−XCUR-0.67, (F) CUR−TYR−LAG−XCUR-0.67, (G) CUR−N-ATP−−LAG− XCUR-0.75, (H) CUR−BIO−LAG−XCUR-0.7, and (I) CUR−ETP−LAG−XCUR-0.1.

SUC−LAG−XCUR-0.5) exhibited nearly five times higher dissolution rate than raw curcumin. Further, it is clear from Table 2 and Figure 12 that, in almost all the cases, the dissolution

rate of the eutectic mixture is directly proportional to the aqueous solubility of the excipients. Amino acid excipients such as glycine and tyrosine improved dissolution of curcumin four O



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bond donors or acceptors in the molecule. Cocrystallization is favored only when the molecules of curcumin and coformers are geometrically compatible so that the resultant supramolecular synthon can fit well into a crystal lattice. In the absence of geometrical compatibility, a probability of eutectic formation (driven through entropic gain in the system) or a physical mixture increases. Powder dissolution studies revealed that the curcumin−succinic acid eutectic (1:1) exhibits 5 times higher dissolution as compared to raw curcumin, whereas the curcumin−biotin eutectic (2.5:1) did not show any significant improvement in the dissolution when compared to that of raw curcumin.

times when compared with raw curcumin. Though glycine has the highest aqueous solubility among the nine excipients investigated in this study, the curcumin−glycine eutectic mixture (CUR−GLY−LAG−XCUR-0.67) showed lesser dissolution of curcumin when compared with the curcumin− succinic acid eutectic mixture (CUR−SUC−LAG−XCUR-0.5). This might be attributed to the reduction in the solubility behavior of glycine in the EtOH−water mixture when compared with its solubility in water.95 Excipients, namely, N-acetyl D,Ltryptophan and paracetamol improved curcumin dissolution by 3.5 times, whereas biotin, carbamazepine, and ethyl paraben showed 1.5, 3, and 3.67 times dissolution enhancement in curcumin dissolution, respectively. To understand the influence of ionizing components (of excipients) on curcumin dissolution, the pH of the dissolution medium was measured before the commencement and after the completion of powder dissolution studies. Table 14 presents the values of pH of the dissolution medium at the start of the experiment and after the completion of dissolution experiments along with the pKa value of the excipients. It can be observed from the table that the pH of dissolution medium did not vary significantly for excipients such as paracetamol, carbamazepine, tyrosine, and ethyl paraben, whereas pH varied slightly for excipients namely succinic acid, glycine, N-acetyl D,L-tryptophan and biotin. The residues left behind after completion of dissolution studies were dried well and subjected to PXRD analysis (Figure 13A−13I) in order to understand the nature of the resultant powders (left behind). In the case of raw curcumin (Figure 13A), it can be observed that the crystalline nature of raw curcumin (Form 1 polymorph) enhances after 3 h of dissolution experiment. Further, all eutectics excluding CUR−ETP−LAG− XCUR-0.1 (Figure 13I) were transformed to the stable curcumin polymorph, Form 1. In the case of CUR−ETP−LAG−XCUR-0.1, the powder left behind mainly consisted of ethyl paraben (Figure 13I) primarily due to a higher starting mole fraction of ethyl paraben in this eutectic mixture.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.7b01105. Tables containing list of coformer molecules which have been reported to form cocrystals with ibuprofen, succinic acid, paracetamol, carbamazepine, glycine and ethyl paraben; table listing the coformers which were reported to form neither eutectics nor cocrystal with curcumin and tables presenting molar extinction coefficients obtained for curcumin and different curcumin eutectic mixtures; DSC thermograms of each curcumin−coformer pair investigated in this study, PXRD patterns for 0.5 curcumin mole fraction of curcumin−ibuprofen physical mixtures and the eight curcumin eutectic compositions, FTIR and Raman spectra of the eight eutectic curcumin compositions (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: 079-23-952408. ORCID

Sohrab Rohani: 0000-0002-1667-1736 Sameer Vishvanath Dalvi: 0000-0001-5262-8711

4. CONCLUSIONS Liquid-assisted grinding was performed for nine curcumin− coformer pairs. Out of nine molecules used in this study, eight molecules (i.e., succinic acid, paracetamol, carbamazepine, glycine, tyrosine, N-acetyl D,L-tryptophan, biotin, and ethyl paraben) were found to form eutectics with curcumin. The eutectic compositions were determined through DSC studies. From the experimental observations recorded in this work and a thorough review of research papers published until date on curcumin cocrystallization, it was observed that almost all straight chain coformers with a carboxylic acid functional group were not able to cocrystallize with curcumin. Interestingly, coformers with a carboxylic acid (−COOH) functional group tend to result into eutectics instead of cocrystals with curcumin. Results obtained in this work were further assessed vis-a-vis the ground rules framed by Cherukuvada and Nangia in order to understand the rationale behind the formation of different solid forms (such as eutectic/solid solution/cocrystal/physical mixture). It was observed that dominance of cohesive interactions over adhesive interactions in the binary system results in the formation of a eutectic phase or a physical mixture. Out of several coformers attempted until date for cocrystallization with curcumin (including eight coformers studied in this work), cocrystal formation was observed only with the coformers containing 1 or 2 aromatic rings with hydrogen

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge MITACS-MHRD Globalink research grant and Indian Institute of Technology Gandhinagar (IITGN) for funding this work. We acknowledge Mr. Mayuresh for helping in the liquid-assisted grinding experiments. The authors are grateful to B&W Tek for providing access to Raman spectroscopy and Mr. Prahlada for recording the Raman spectra. The authors are very thankful to Ms. Komal Pandey, Mr. Bhanu Pratap Singh and Ms. Sophia Varghese of Central Instrumentation Facility, IIT Gandhinagar, for conducting PXRD experiments. The authors are thankful to Mr. Sanat Chandra Maiti and Mr. Nakrani Dharmit Ashwin for their assistance in a few DSC experiments.

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ABBREVIATIONS CUR = curcumin SUC = succinic acid PAR = paracetamol CBZ = carbamazepine IBU = Ibuprofen GLY = glycine

P



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TYR = tyrosine N-ATP− = N-acetyl D,L-tryptophan BIO = biotin ETP = ethyl paraben LAG = liquid-assisted grinding EtOH = ethanol EtAc = ethyl acetate DSC = differential scanning calorimetry PXRD = powder X-ray diffraction RES = resorcinol PYR = pyrogallol JUC-C14 = Jilin University, china-cocrystal 14 JUC-C15 = Jilin University, china-cocrystal 15 MeOH = methanol HXQ = hydroxyquinol IDR = intrinsic dissolution rate PD = powder dissolution BPNO = 4,4′-bipyridine-N,N′-dioxide PXRD = powder X-ray diffraction DSC = differential scanning calorimetry FT-IR = Fourier transform-infrared spectroscopic analysis RS = raman spectroscopic analysis NMR = nuclear magnetic resonance TE = eutectic temperature TS = solidus temperature TL = liquidus temperature XCUR = curcumin mole fraction XEtOH = ethanol mole fraction u(TE) = standard uncertainty in eutectic temperature u(XCUR) = standard uncertainty in mole fraction of curcumin Symbols

°C/min = celsius per minute mg/L = milligram per liter v/v = volume/volume nm = nanometer atm = atmosphere kPa = kilopascal

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