Crystal Engineering of Curcumin with Salicylic Acid and

Article

Crystal Engineering of Curcumin with Salicylic acid and Hydroxyquinol as Coformers Indumathi Sathisaran, and Sameer Vishvanath Dalvi Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 31 May 2017 Downloaded from http://pubs.acs.org on June 1, 2017

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Crystal Growth & Design

Crystal Engineering of Curcumin with Salicylic acid and Hydroxyquinol as Coformers Indumathi Sathisarana and Sameer Vishvanath Dalvib,* a

Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355,

India. b

Chemical Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355,

India. KEYWORDS: Curcumin, Cocrystals, Salicylic acid, Hydroxyquinol, Eutectic, Phase diagram

ABSTRACT: Curcumin is a pharmaceutically viable ingredient derived from the rhizome of 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 solid-state grinding. The curcumin-salicylic acid system was found to form an eutectic at curcumin mole fraction of 0.33 whereas curcumin-hydroxyquinol system clearly exhibited a cocrystal forming region. Out of the several curcumin to

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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 (PXRD) analysis, Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), Raman Spectroscopy (RS), Fourier Transform Infrared (FT-IR) Spectroscopy and Solid-state

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C Nuclear Magnetic Resonance spectroscopy

(ssNMR). 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 results in a generation of eutectic whereas strong hydrogen bonding interactions between hydroxyl –OH groups present in hydroxyquinol molecule and curcumin molecule results 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 case of curcumin-hydroxyquinol cocrystals, cocrystal containing curcumin mole fraction of 0.33 showed enhanced dissolution than cocrystal containing curcumin mole fraction of 0.5.

1. INTRODUCTION Curcumin is a polyphenolic compound obtained from the rhizome of turmeric, Curcuma longa. It exists in a keto-enol tautomeric form. Curcumin has been shown to possess antibacterial1, antimalarial2 and antitumor properties3,4. Even at high dosage levels, it exhibits non-toxicity5 but its efficacy is reduced due to its low aqueous solubility and low bioavailability. Salt formation is the traditional approach for enhancing the solubility and bioavailability of poorly water soluble APIs. However, for drug molecules like curcumin which lack ionizable groups, salt formation fails. When the possibility of salt formation is ruled out, one can look forward to increasing the


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drug’s solubility by forming various solid forms like polymorphs, pseudo-polymorphs (stoichiometric solvates), solid solutions, co-amorphous solids, eutectics and cocrystals. Curcumin is highly sensitive to the pH conditions. It exists in keto form in acidic as well as in neutral solutions and in enol form in alkaline environment. The keto-enol tautomers of curcumin offer higher affordability for new hydrogen bonds formation by modifying the intermolecular interactions between curcumin and coformers. Summary of reports available in the literature on formation of curcumin cocrystals and coamorphous solid is presented in Table 1. It can be observed from Table 1 that curcumin has been reported to form cocrystals with resorcinol6, pyrogallol6, phloroglucinol7 and 4,4’-bipyridine-N, N’ dioxide8. Several other coformers such as nicotinamide, ferulic acid, hydroxyquinone, p-hydroxybenzoic acid and L-tartaric acid were found to form only eutectic crystalline solids with curcumin9. Similarly, Suresh et al10 showed that it is possible to form co-amorphous solid of curcumin along with antimalarial drug, artemisinin. In this work, attempts have been made to produce cocrystals of curcumin with salicylic acid (Monohydroxybenzoic acid, also known as o-hydroxybenzoic acid) and hydroxyquinol (1, 2, 4Benzene triol or 1, 2, 4-Trihydroxybenzene) as coformers in order to enhance bioavailability of curcumin by increasing its aqueous solubility. Salicylic acid, a primary metabolite of aspirin has been shown to possess anti-cancer properties12 and hydroxyquinol (Hydroxyl hydroquinone) is an organic compound reported to possess anti-breast cancer (in vitro) properties13. Curcumin itself have been shown to possess anticancer properties14,15,16. Salicylic acid has aqueous solubility of 2240 mg/L (at 25 °C)17 and hydroxyquinol has an aqueous solubility of 44.1 mg/mL18 which are higher than the solubility of curcumin. Therefore, we attempted cocrystallization of curcumin with salicylic acid and hydroxyquinol as these molecules possess


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anticancer properties as well as higher aqueous solubility than curcumin. The chemical structures of curcumin and the coformers, salicylic acid and hydroxyquinol are shown in Fig. 1. Efforts have been made to investigate cocrystal forming ability of salicylic acid and hydroxyquinol with curcumin. Binary phase diagrams have been prepared for curcumin-salicylic acid as well as curcumin-hydroxyquinol pairs in order to determine the cocrystal forming zone. The cocrystals formed have been characterized using PXRD, DSC, FE-SEM, FT-Raman, FT-IR and Solid-state 13

C NMR spectroscopy.

2. EXPERIMENTAL 2.1 Materials Curcumin (CUR), salicylic acid (SAA) and hydroxyquinol (HXQ) were purchased from SigmaAldrich Inc. India and were used without any further purification. Ethanol (EtOH, 99.8 % pure) was purchased from Jiangyin Tenghua Import & Export Co. Ltd. Other solvents were obtained from Merck Chemicals Pvt. Ltd. Deionized Millipore water was used throughout the experiments. 2.2 Construction of binary phase diagrams Curcumin-salicylic acid and curcumin-hydroxyquinol mixtures with curcumin mole fractions ranging from 0 to 1 were ground well in mortar and pestle, for ten minutes at ambient temperature in order to produce microcrystalline powder. The resultant ground products were analyzed by Differential Scanning Calorimetry (NETZSCH STA 449 F3 Jupiter ®) simultaneous TGA-DSC (Germany) from temperature range of 30 °C to 250 °C at the heating rate of 10 K/min to generate Binary Phase Diagram. The ground products were further analyzed by Powder X-Ray Diffraction system (D8 Discover, Bruker AXS GmbH, Germany).


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2.3 Curcumin-hydroxyquinol cocrystals Formation of CUR-HXQ cocrystal phase following the eutectic melt corresponding to curcumin mole fractions of 0.33 and 0.5 was evident from the binary phase diagram. The ground mixture with curcumin mole fraction of 0.5 was heated till 130 °C and then dissolved completely in organic solvent. Around 29 different solvent systems [ethanol, methanol, acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, ethanol + benzene (1:1, 1:2 and 9:1), methanol + benzene (1:1, 1:2 and 9:1), acetone + benzene (1:1), ethanol + toluene (1:1), methanol + toluene (1:1), acetone + toluene (1:1), acetone + water (1:1), acetone + DCM (1:1), DCM + petroleum ether (1:1), ethyl acetate + tetrahydrofuran (1:1), ethyl acetate + water (1:1 and 1:2), ethyl acetate + benzene (1:1 and 1:2), acetonitrile + DCM (1:1 and1:2) and ethanol + methanol + benzene (1:1:3) and ethanol + methanol + toluene (1:1:3)] were used to dissolve the heated ground mixture and the organic solvent was allowed to evaporate slowly at 25 °C until a complete drying is achieved. Probe sonication at 35 % amplitude for ten minutes was used to dissolve the heated mixture completely. Out of all the solvent systems studied, crystallization carried out in acetone-toluene and ethyl acetate-toluene solvent systems (1:1) resulted in curcuminhydroxyquinol cocrystals. However, the crystals suitable for single crystal X-ray Diffraction studies could not be obtained. Similarly, the CUR-HXQ ground mixture of curcumin mole fraction, 0.33 was heated till 135 °C and dissolved in 10 mL of acetone-toluene (1:1) system and ethyl acetate-toluene (1:1) system in presence of sonication. However, attempts to perform crystallization without ultrasound also resulted in microcrystalline powder particles. The microcrystalline powder was then used for further characterization by DSC and PXRD analysis.


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The morphology of the curcumin-hydroxyquinol cocrystals crystallized in acetone-toluene (1:1 volume ratio) and ethyl acetate-toluene (1:1 volume ratio) solvent systems were determined using Field Emission-Scanning Electron Microscope (FE-SEM) [JSM 7600F, JEOL Japan]. The Raman spectra of the CUR-HXQ cocrystals were acquired on BRUKER RFS 27: Stand alone FT-Raman Spectrometer using Nd: YAG laser power of 1064 nm excitation wavelength from 50 cm-1 to 4000 cm-1 at a resolution of 2 cm-1 available with IIT Madras. The FT-IR spectra of the CUR-HXQ cocrystals were recorded in Micro ATR mode from 4000 cm-1 to 500 cm-1 using 3000 Hyperion Microscope with Vertex 80 FTIR System (Bruker, Germany) available with IIT Bombay. The number of scans per sample was 65 with a spectral resolution of 0.2 cm-1. The cocrystals were structurally characterized by Solid-state 13C NMR spectroscopy. The Solidstate

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C NMR spectra of cocrystals were recorded with ECXII 400-Jeol 400 MHz High

Resolution FT-NMR Spectrometer available with IISc Bangalore. Approximately 150 – 200 mg of samples was taken in 4 mm rotor made of ZrO2 with a vespel cap. A Cross Polarization-Magic Angle Spinning (CP-MAS) with a pulse frequency of 10 kHz (magnetic field strength of 9.39 T) was used for obtaining the spectra. The storage stability of the prepared cocrystals was investigated by storing the cocrystal samples at 75 % Relative Humidity (RH) and 40 °C in a stability chamber (Thermo Lab equipment Pvt. Ltd., Model No: TS0000400G). 2.4 Powder Dissolution studies The powder dissolution rates of curcumin-salicylic acid eutectic mixture with curcumin mole fraction of 0.33 as well as curcumin-hydroxyquinol cocrystals obtained from the melt of solidstate ground (SSG) mixtures containing curcumin mole fractions, 0.33 and 0.5 were determined at 37 °C in 40% Ethanol-water medium ((vol/vol ratio) using UV-1800 SHIMADZU UV


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Spectrophotometer at 430 nm. To determine the dissolution rates of raw curcumin, curcuminsalicylic acid eutectic mixture, curcumin-hydroxyquinol cocrystals crystallized from acetonetoluene (1:1 volume ratio) and ethyl acetate-toluene (1:1 volume ratio), a known quantity of solid particles (35 mg of raw drug/eutectic mixture/cocrystals) sieved using 212 µm pore size mesh were dissolved in 30 mL of 40% Ethanol-water medium at 37 ºC and stirred continuously. At fixed time interval of 15 minutes, a known volume of the dissolution medium (1.5 mL) was withdrawn without replacement. The collected sample was centrifuged at 14000 rpm for 5 minutes in order to separate undissolved drug particles. The supernatant was then analyzed spectrophotometrically at 430 nm. The concentration of drug released was estimated from the calibration curve. The pH of the dissolution medium was measured before the commencement and after the completion of dissolution experiments using Cole-Parmer (P100 Model) pH meter. After 3 hours, the dissolution medium was centrifuged and the residues were dried well in a dessicator. The PXRD patterns of the solid residues were recorded. 2.5 Stability of curcumin solid forms in water To estimate the stability of CUR-SAA-SSG-XCUR-0.33 eutectic and CUR-HXQ-XCUR-0.33 and 0.5 cocrystals prepared by melting and recrystallization in acetone-toluene (1:1) system in deionized water, approximately 10 mg of solid forms (raw drug/eutectic mixture/cocrystals) were dissolved in 10 mL of water and stirred continuously for 3 hours at a temperature of 37 ͦC. After 3 hours, the solution was centrifuged and residues were dried in dessicator. The PXRD patterns of the solid residues were recorded.


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3. RESULTS AND DISCUSSIONS 3.1 Binary phase diagram (BPD) for curcumin-salicylic acid system Solid-state ground mixture containing curcumin mole fractions ranging from 0 to 1 were prepared and DSC analysis was carried out. The DSC thermograms obtained for various curcumin-salicylic acid ground mixtures heated are shown in Fig. S1. The melting point-phase composition diagram was then constructed for curcumin-salicylic acid system. The onset temperature of the first endotherm of DSC thermogram was used as the solidus point and the peak temperature of the second endotherm was used as the liquidus point. Fig. 2 shows the binary phase diagram constructed for curcumin (CUR) - salicylic acid (SAA) system. The phase diagram of curcumin-salicylic acid system (Fig. 2) confirms the formation of an eutectic at a temperature of 128.1 °C corresponding to curcumin mole fraction of 0.33 (equivalent to molar ratio of 1:2 of curcumin and salicylic acid). No cocrystal forming regions were observed in this phase diagram indicating that curcumin and salicylic acid do not form a cocrystal. The eutectic nature of the system was also reflected in the powder X-ray diffraction patterns (shown in Fig. 3), since none of the PXRD patterns show any new peaks as compared to PXRD patterns of curcumin and salicylic acid. All the PXRD patterns for solid-state ground (SSG) mixtures appear to be the combinations of PXRD patterns of raw curcumin (Form 1) and salicylic acid. It can therefore be safely concluded that curcumin-salicylic acid system do not form a cocrystal. Till date, the synthon formation between acid-acid, amide-amide, amide-pyridine, amidePyridine N- oxide19, acid-imide20 and acid-amide has been explored extensively during cocrystallization studies. Kaur et al20 explored the hypothesis that geometrical fitness of the coformer with the API stabilizes the homosynthons or heterosynthons formation in a cocrystal while investigating carboximide-carboxylic acid combinations. Salicylic acid cocrystals21-31


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reported till date were formed through strong intermolecular interactions between salicylic acid and coformer molecules with N-heterocyclic hydrogen bond acceptors21-28 or amide C=O functional group29-31. Moreover, salicylic acid has been reported to form eutectics with molecules such as benzoic acid32, borneol33 and acetanilide34. These three molecules do not contain Nheterocyclic hydrogen bond acceptors or –CONH2 groups which can form a stable heterosynthon with salicylic acid to result into a cocrystal. Further, salicylic acid has been reported to form acid-acid dimer with itself21,22 which is a strong homosynthon. As reported by Cherukuvada and Row35, an eutectic formation takes place when the cohesive interactions are stronger than the adhesive interactions. Therefore, it is clear that salicylic acid is not capable of forming cocrystal with any other molecules except the ones with N-heterocyclic hydrogen bond acceptors or – CONH2 group, due to its tendency to form a strong dimer through formation of acid-acid homosynthon. Further, Goud et al9 reported that attempts to form curcumin cocrystals with Ferulic acid9, L-Tartaric acid9and p-hydroxybenzoic acid9 resulted into an eutectic rather than a cocrystal. It seems that the enol (C-OH) group of curcumin is unlikely to involve as a hydrogen bond acceptor for –C=O group of the carboxylic acids which might result into a eutectic. Thus it can be surmised that the inability of salicylic acid to form strong heterosynthons with molecules containing groups other than –CONH2 or N-heterocyclic hydrogen bond acceptors, its tendency to form a strong acid dimer with itself and inability of C-OH group of curcumin to involve in hydrogen bonding with –C=O group of carboxylic acids are the factors responsible for weaker interaction between curcumin and salicylic acid and hence the formation of an eutectic phase instead of a cocrystal phase.


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3.2 Curcumin-hydroxyquinol system 3.2.1 Binary phase diagram Fig. S2 presents DSC thermograms for several SSG mixtures of curcumin-hydroxyquinol containing curcumin mole fractions ranging from 0 to 1. Fig. 4 presents the binary phase diagram constructed based on DSC thermograms of all SSG mixtures shown in Fig. S2. The binary phase diagram shows a cocrystal forming region between two eutectics corresponding to curcumin mole fractions of 0.17 and 0.62. Interestingly, the DSC thermogram for SSG mixture containing curcumin mole fraction of 0.33 (CUR-HXQ-XCUR-0.33, equivalent to a molar ratio of 1:2 of curcumin and hydroxyquinol), shows three endothermic peaks (Fig. S2D). The first endothermic peak corresponds to the eutectic melting of a coformer and API which then interact to form a cocrystal. This event generally appears as an exothermic peak in DSC thermograms36. However, the appearance of exothermic event is dependent on the heating rate and such events have generally been observed to appear distinctly at lower heating rates such as 1K/min30. In this work, we have used heating rate of 10K/min which generally does not enable appearance of exothermic events due to faster heating30. The second endothermic peak corresponds to the melting of a cocrystal with an excess of coformer36 to form supersaturated liquid melt which then crystallizes to form a cocrystal. This cocrystal melts upon further heating indicated by the third endothermic peak36. In case of SSG mixture of curcumin and hydroxyquinol containing curcumin mole fraction of 0.5 (CUR-HXQ-XCUR-0.5, equivalent to a molar ratio of 1:1 of curcumin and hydroxyquinol), the first endothermic peak corresponds to eutectic melting which is followed by cocrystal melting represented by the second endothermic peak (as shown in Fig. S2E).


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In order to confirm formation of a new phase upon heating of SSG mixtures as indicated by DSC thermograms, SSG mixtures CUR-HXQ-XCUR-0.33 and CUR-HXQ-XCUR-0.5, were heated till the temperatures at the end of the first and second endothermic peaks (based on DSC thermograms) and their PXRD patterns were recorded. The SSG mixture containing curcumin mole fraction of 0.33 (CUR-HXQ- XCUR-0.33) was heated upto 135 °C (upto the end of the first endothermic peak of DSC thermogram D shown in Fig. S2) and then upto 145 °C (upto the end of the second endothermic peak of DSC thermogram D shown in Fig. S2). Similarly, SSG mixture containing curcumin mole fraction of 0.5 (CUR-HXQ- XCUR-0.5) was heated upto 150 °C (upto the end of the first endothermic peak of DSC thermogram E shown in Fig. S2). Fig. 5 presents the overlay of PXRD patterns of these heated SSG mixtures. CUR-HXQ-XCUR0.33 mixture heated till 135 °C and 145 °C showed prominent peaks (at 2Ɵ positions of 18.620, 21.030, 25.160 and 27.460) which are different from that of curcumin and hydroxyquinol (Fig. 5D and 5E). Similarly, the SSG mixture of CUR-HXQ-XCUR-0.5 mixture melted at 150 ºC exhibited similar characteristic peaks (Fig. 5G). As the heated SSG mixtures of XCUR-0.33 and 0.5 exhibited new diffraction peaks different from that of curcumin and hydroxyquinol, generation of a new crystalline phase from the eutectic melt representing cocrystal formation was clearly evident. In order to check if solid-state grinding (SSG) and liquid-assisted grinding (LAG) yield different results, liquid-assisted grinding of two mixtures of curcumin and hydroxyquinol with curcumin mole fractions, 0.33 and 0.5 (which are susceptible for cocrystal formation) was carried out using 2 drops of ethanol as solvent. Grinding was performed for 10 minutes. DSC thermograms and PXRD patterns were recorded for these ground mixtures. The DSC thermograms (shown in Fig. S3) and PXRD patterns (shown in Fig. S4) of the liquid-assisted ground mixtures exhibited no


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significant differences from that of the solid-state ground mixtures (Fig. S2(D and E) for DSC thermograms and Fig. 5(C and F) for PXRD patterns). Therefore, solid-state ground mixtures were used throughout the further experiments. 3.2.2 Solvent crystallization of eutectic melts Further, efforts were made to crystallize melted SSG mixtures containing curcumin mole fractions of 0.33 and 0.5 (CUR-HXQ-XCUR-0.33 and CUR-HXQ-XCUR-0.5) from acetonetoluene (1:1 volume ratio) and ethyl acetate-toluene (1:1 volume ratio) mixtures by slow solvent evaporation technique. However, these experiments did not yield single crystals and instead a microcrystalline powder was obtained. The cocrystal powders obtained could not be tested by single crystal X-ray diffraction studies7 as no crystals of quality good enough for single crystal XRD analysis could be grown despite of several attempts of varying concentration, temperature and solvent system (a total of 29 solvent systems were studied as mentioned in Section 2.3). Formation of large single crystals is facilitated by slower generation of supersaturation which results in a lower number of nuclei and promotes growth over nucleation. However, as can be seen from Fig. 6 which shows the SEM images of these recrystallized samples, it was not possible to produce large crystals despite of several attempts. It can be observed from Fig. 6(AF) that the recrystallization of SSG mixture CUR-HXQ-0.33 heated till 135 °C yields cauliflower-like aggregates containing individual acicular particles. On the other hand, the SSG mixture CUR-HXQ-0.5 heated till 130 °C yielded ball-like structures with no clearly visible primary particles [Fig. 6(G-L)]. Since single crystal XRD analysis could not be carried out for these recrystallized samples no crystal structure data could be obtained. However, PXRD, DSC, FT-Raman, FT-IR analysis and Solid-state 13C NMR spectroscopic analysis were carried out for these recrystallized particles.


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The powder X-RD patterns for these recrystallized samples of melted CUR-HXQ-XCUR-0.33 and CUR-HXQ-XCUR-0.5 showed prominent peaks which are different from the PXRD patterns of curcumin and hydroxyquinol, which confirm the formation of a cocrystal (Fig. 7). Similarly, DSC thermogram for CUR-HXQ-XCUR-0.33 eutectic melt recrystallized in acetone-toluene (1:1 volume ratio) system and ethyl acetate-toluene (1:1 volume ratio) system showed an endothermic peak at 160.2 °C and 159.8 °C confirming the generation of cocrystal from eutectic melt (Fig. 8C and 8D). Thermal analysis of CUR-HXQ-XCUR-0.5 eutectic melt recrystallized in acetonetoluene (1:1volume ratio) and ethyl acetate toluene (1:1 volume ratio) system showed a single endotherm with peak temperature of 163.2 °C (Fig. 8E) and 161.8 °C (Fig. 8F) respectively, which lies between the melting points of curcumin and hydroxyquinol confirming the formation of a cocrystal phase. Fig. 9 and 10 represent the FT-Raman spectra for heated SSG mixtures and solvent-crystallized CUR-HXQ-XCUR-0.33 and 0.5 cocrystal powders. The ground mixtures did not show any unique characteristic peaks. The stretching modes of C=C bonds in the heated samples of SSG mixtures and solvent recrystallized melts were found to significantly differ from the solid-state ground mixtures with appearance of a new peak at the wave numbers greater than 1525 cm-1 (between 1525 cm-1 and 1531 cm-1) [Fig. 9 (D-G) and 10 (D-F)]. Similar observation was made in case of curcumin - pyrogallol cocrystals by Sanphui et al6. This new peak indicates stretching corresponding to the formation of supramolecular structure between curcumin and coformer from the eutectic melt. Moreover, the enolic C-O, phenolic C-O and C=O bonds also exhibited appreciable difference in their stretching behavior (Table 2 and 3). The variations in stretching frequencies of various functional groups of the eutectic melts and solvent crystallized powders


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symbolize the prevelance of a new chemical environment in these powders which is different from that of CUR and HXQ. Similar to the observations made from FT-Raman spectra, FTIR spectra of the heated SSG mixtures and solvent-recrystallized melts of CUR-HXQ-XCUR-0.33 and CUR-HXQ-XCUR-0.5, showed significant differences in the phenolic O-H stretching frequencies (shown in Figure S5 and S6). A large shift of the peaks from the frequencies of 3277.75 cm-1 (in case of HXQ) and 3510.26 cm-1 (in case of CUR) to a new wavenumber of around 3400 cm-1indicates the change in the chemical environment of phenolic O-H groups.6,7 This confirms the interaction between CUR and HXQ resulting into cocrystals from eutectic melts. In addition to the difference in the stretching behavior of phenolic O-H groups, appreciable difference was also observed in the stretching frequencies of C=C stretching, enol C-O stretching, phenolic C-O stretching and C=O stretching (as shown in Table S1 and S2). In addition to FT-Raman and FTIR spectroscopic analysis, Solid-state

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C NMR spectroscopic

analysis was carried out to structurally characterize the newly formed solid phases (cocrystals). Fig. 11(A-B) and Fig. S7(A-B) present the overlay of Solid-state 13C NMR spectra of CUR-HXQ cocrystals along with Solid-state

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C NMR spectra of curcumin and hydroxyquinol. It can be

observed that the phenolic carbon (C-OH) of curcumin has been shifted upfield to ̴ 152 ppm in CUR-HXQ-XCUR-0.33 and CUR-HXQ-XCUR-0.5 cocrystals from 159.904 ppm in curcumin (as shown in Table 4). In addition to this, the methoxy carbons of curcumin has shifted upfield to ̴ 56 ppm and ̴ 55 ppm in the cocrystals from 58.041 ppm and 56.161 ppm in curcumin confirming the formation of new crystalline phases. The enolic –OH of curcumin exhibited an upfield shift of ̴ 179 ppm from 183 ppm indicating variation in molecular arrangements. However, the keto carbon (-C=O) of curcumin did not show significant chemical shifts.


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Thus, it can be concluded that curcumin and hydroxyquinol form two cocrystals corresponding to curcumin to hydroxyquinol ratios of 1:2 and 1:1 (equivalent to curcumin mole fractions of 0.33 and 0.5). There are several studies reported in the literature where researchers have observed stoichiometrically diverse cocrystals for the same pair of drug and coformer. Table 5 summarizes some pair of such reports. 3.3 Stability of curcumin-hydroxyquinol cocrystals The cocrystal powders prepared by recrystallizing eutectic melts of CUR-HXQ mixtures (with curcumin mole fractions of 0.33 and 0.5) in acetone-toluene (1:1 volume ratio) system and ethyl acetate-toluene (1:1 volume ratio) system were stored at 40 °C and 75 % RH for a period of 3 weeks. The PXRD patterns of the stored samples were recorded after 3 weeks (Fig. 12). The CUR-HXQ cocrystals showed good stability at the controlled accelerated conditions as no changes in PXRD patterns were observed. 3.4 Powder Dissolution studies The powder dissolution rates of raw curcumin, curcumin-salicylic acid eutectic (with XCUR-0.33) and curcumin-hydroxyquinol cocrystals (with XCUR-0.33 and 0.5) in 40 % Ethanol-water system were estimated using UV-Vis spectrophotometer. Readings were recorded in triplicates for a period of 3 hours at an interval of 15 minutes. The CUR-SAA-XCUR-0.33 eutectic and CURHXQ-XCUR-0.33 cocrystals showed higher dissolution than CUR-HXQ-XCUR-0.5 cocrystals and raw curcumin (Fig. 13). The powder and intrinsic dissolution studies conducted by Sanphui et al6 showed that curcumin-pyrogallol cocrystals6 exhibited higher dissolution than commercial curcumin. It is interesting to note curcumin-salicylic acid eutectic exhibits higher dissolution rates than curcumin-hydroxyquinol cocrystals. This could be attributed to factors such as aqueous solubility


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of coformer and free energy requirements for solubilization. Curcumin has Log P value of 3.241 whereas for salicylic acid and hydroxyquinol, the log P values are reported as 2.342 and 1.543 respectively. Since log P value and aqueous solubility are inversely proportional, salicylic acid has lower aqueous solubility than hydroxyquinol. In addition to coformer solubility, lattice energies also influence dissolution of solid phases. Free energy of a cocrystal solubilization (∆Gsolubilization) is the sum of free energy associated with crystal lattice interactions (∆Glattice) and free energy associated with solute-solvent interactions (∆Gsolvation)44. To dissolve a cocrystal, solute molecules need to release from the crystal lattice followed by the solvation of the released solute molecules45. In case of curcumin-salicylic acid eutectic, the crystal lattice is not wellpacked (due to random arrangement of molecules) and hence there exists negligible/lower barrier corresponding to crystal lattice interactions. Also, the solvation barrier is negligible as salicylic acid is more soluble than curcumin. However, in case of curcumin-hydroxyquinol cocrystals, a well-organized lattice structure (cocrystal formation) is formed after eutectic melt during cocrystallization. Therefore, free energy change associated with solubility of curcuminhydroxyquinol cocrystals due to crystal lattice interactions is much higher than the free energy change associated to the dissolution of curcumin-salicylic acid eutectic. This possibly explains why CUR-SAA eutectic exhibits higher dissolution rates than CUR-HXQ cocrystals. Further, it can be observed from Fig. 13 that the dissolution profiles show a decrease in dissolution rates after exhibiting maximum. This could be attributed to the consumption of dissolved curcumin by nucleation occurring due to the supersaturation generated during the course of dissolution46,47. In order to understand the exact nature of the precipitating phase, the solid residues left behind after dissolution experiments were collected, dried well and the PXRD patterns were recorded for these dry powders (Fig. S8). It is evident from the PXRD patterns


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(shown in Fig. S8) that eutectics and cocrystals transformed to a stable monoclinic curcumin polymorph, Form 1 during the dissolution process which resulted in a decline in the dissolution rates. It is also possible that the pH of the dissolution medium or a change in pH during dissolution might affect dissolution rates. Therefore, pH of 40 % EtOH-water (vol/vol ratio) medium was measured before and after dissolution experiment. In case of curcumin-salicylic acid eutectic, pH of dissolution medium changed from 5.29 ± 0.19 to 3.41 ± 0.02 at the end of dissolution. In case of CUR-HXQ cocrystals, the pH of dissolution medium before conducting experiments was found to be 5.29 ± 0.19 and pH of dissolution medium after dissolution experiments were 4.54 ± 0.26 (for CUR-HXQ-XCUR-0.33 cocrystals prepared by recrystallization in acetone-toluene (1:1) system) and 4.50 ± 0.06 (for CUR-HXQ-XCUR-0.5 cocrystals prepared by recrystallization in acetone-toluene (1:1) system). Thus, it can be observed that pH of the dissolution medium does not change significantly during the process of dissolution. Further, pKa value of salicylic acid is ̴ 2.9748, pKa values of hydroxyquinol are 9.39 and -5.649. Curcumin has pKa values of 7.5, 8.5 and 9 at which one, two or all three -OH groups (curcumin has one enolic –OH and two phenolic –OH groups) dissociate respectively50,51. Since the pH of the dissolution medium at the end of dissolution in case of curcumin-salicylic acid eutectic is still below pKa value of curcumin and above pKa value of salicylic acid, and in case of curcumin-hydroxyquinol cocrystals, it is much far away from the pKa values of hydroxyquinol and curcumin, the dissolution process is possibly unaffected by pH of the dissolution medium. 3.5 Stability of curcumin solid forms in water Stability of CUR-SAA eutectic and CUR-HXQ-XCUR-0.33 and 0.5 cocrystals prepared by recrystallization in acetone-toluene (1:1) system in water was estimated at 37 °C. PXRD patterns


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for powders obtained at the end of 3 hours are shown in Figure S10 (A-C). It was observed that CUR-SAA eutectic mixture converted to form 1 curcumin after stirring for 3 hours at 37 °C in water. On the other hand, CUR-HXQ cocrystals (XCUR-0.33 and 0.5) remained intact in water at 37 °C.

4. CONCLUSION The use of curcumin in pharmaceutical applications is restricted, despite of its diverse pharmacological activities, due to its poor water solubility and hence low bioavailability. Therefore, enhancement in curcumin dissolution by formulating cocrystals with highly soluble coformers has been attempted in this work. Binary phase diagrams were constructed in order to determine the nature of the solid form (eutectic vs cocrystal) and the cocrystal forming zones. An eutectic of curcumin with salicylic acid with curcumin mole fraction of 0.33 (CUR-SAA-XCUR0.33) and two new curcumin cocrystals with hydroxyquinol containing curcumin mole fraction of 0.33 and 0.5 (CUR-HXQ-XCUR-0.33 and CUR-HXQ-XCUR-0.5) were prepared. Several attempts were made to form single crystals of these cocrystals. However, no good quality single crystals could be obtained. Instead, a microcrystalline cocrystal powders were obtained through solvent evaporation technique. These cocrystal powders were characterized by FE-SEM, DSC, PXRD, FTIR, Raman and Solid-state 13C NMR spectroscopy. Inability of salicylic acid to form a strong heterosynthon with C-OH group of curcumin and its tendency to form a strong acid dimer with itself could possibly be responsible for formation of a eutectic between curcumin and salicylic acid. In case of curcumin-hydroxyquinol system, the significance of appearance of three (for SSG mixture containing curcumin mole fraction, 0.33) and two endotherms (for SSG


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mixture containing curcumin mole fraction, 0.5) in DSC thermograms indicated the curcuminhydroxyquinol cocrystal formation from the eutectic melt induced by thermal energy. Curcuminsalicylic acid eutectic (CUR-SAA-SSG-XCUR-0.33) showed faster dissolution rate than curcumin-hydroxyquinol cocrystals (CUR-HXQ-XCUR-0.33 and 0.5) and raw curcumin.

ASSOCIATED CONTENT Supporting Information DSC thermograms of various curcumin mole fractions of CUR-SAA and CUR-HXQ systems are shown in the Electronic Supplementary Information (ESI). DSC thermograms and PXRD patterns of CUR-HXQ liquid-assisted ground mixtures of curcumin mole fractions, 0.33 and 0.5 (CUR-HXQ-LAG-XCUR-0.33 and 0.5) are enclosed in ESI. Tables and figures presenting the FTIR spectral peak assignments for CUR-HXQ eutectic melts, cocrystals prepared heating and recrystallization in acetone-toluene (1:1 volume ratio), ethyl acetate-toluene (1:1 volume ratio) solvent systems are provided, Solid-state

13

C NMR spectra of CUR-HXQ-XCUR-0.33 and 0.5

cocrystals prepared by recrystallization in Ethyl acetate-Toluene (1:1) system, PXRD patterns of drug particles (raw curcumin / curcumin-salicylic acid eutectics / curcumin-hydroxyquinol cocrystals) after the completion of dissolution experiments, DSC thermograms of raw curcumin particles recorded before and after the dissolution experiment and PXRD patterns illustrating the solution stability of CUR-SAA eutectic and CUR-HXQ cocrystals in water are given in the ESI.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; Phone: 091-70-69021623; Fax: 091-79-2397 2324.


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Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We gratefully acknowledge Indian Institute of Technology Gandhinagar (IITGN) for funding this work. We are very thankful to Ms. Komal Pandey for her assistance in carrying out powder X-RD analysis. The authors would also like to acknowledge Dr. Palash Sanphui (Research Scientist, Lupin Ltd.) for suggestions on preparation of single crystals. The authors also thank Ms. Praseetha. E. K. for helping in the interpretation of Solid-state 13C NMR data. The authors are very grateful to IIT Bombay, IIT Madras, IISc Bangalore and Oasis Testing House, Ahmedabad for providing access to FTIR spectroscopy, Raman spectroscopy, Solid-state

13

C

NMR spectroscopy and Stability chambers respectively.

ABBREVIATIONS API: Active Pharmaceutical Ingredient CUR: Curcumin SAA: Salicylic acid HXQ: Hydroxyquinol SSG: Solid-State Grinding LAG: Liquid-Assisted Grinding XCUR: Curcumin mole fraction K: Kelvin TE1: First Eutectic temperature TE2: Second Eutectic temperature PXRD: Powder X-Ray Diffraction


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FE-SEM: Field Emission Scanning Electron Microscope RS: Raman Spectroscopy RH: Relative Humidity Ace: Acetone Tol: Toluene EtAc: Ethyl acetate EtOH: Ethanol DCM: Dichloromethane DSC: Differential Scanning Calorimetry FTIR: Fourier Transform - Infra Red Spectroscopy ssNMR: Solid-state Nuclear Magnetic Resonance Spectroscopy 13

C: Carbon-13

ppm: parts per million T: tesla nm: nanometre cm-1: centimetre-1 mL: millilitre rpm: revolution per minute pH: Hydrogen ion concentration pKa: Dissociation constant vol: volume Symbols 2Ɵ: 2 Theta °C: Degree Celsius


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FIGURES

(A)

(B)

(C)

Figure 1. Chemical structure of (A) Curcumin (B) Salicylic acid and (C) Hydroxyquinol.

Figure 2. Binary Phase Diagram of CUR-SAA system (The solidus temperatures are shown in open circles and the liquidus temperatures are shown in filled circles).


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CUR-SAA-SSG-XCUR-0.33

(C)

(B)

Raw CUR

(A)

Raw SAA

Figure 3. Overlay of powder X-RD patterns of (A) Raw SAA, (B) Raw CUR and (C) SSG mixture of CUR-SAA-XCUR-0.33.


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Figure 4. Binary Phase Diagram of CUR-HXQ system (The solidus temperatures are shown in open circles and the liquidus temperatures are shown in filled circles. The second endotherm of CUR-HXQ-SSG-XCUR-0.33 is denoted by open square).


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CUR-HXQ-SSG-XCUR-0.5 heated till 150 ° C

(G)

CUR-HXQ-SSG-XCUR-0.5

(F)


(E)


(D)


(C)

(B)

Raw CUR

(A)

Raw HXQ

Figure 5. Powder X-RD patterns of (A) Raw HXQ, (B) Raw CUR, (C) SSG mixture of CURHXQ-XCUR-0.33, (D) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 135 °C, (E) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 145 °C, (F) SSG mixture of CUR-HXQ-XCUR-0.5, and (G) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 150 °C.


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(A)

(B)

(D)

(E)

(G)

(H)

(I)

(J)

(K)

(L)

(C)

(F)

Figure 6. SEM micrographs of (A) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system at 100 X magnification, (B) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system at 1000 X magnification, (C) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio)

system at 5000 X

magnification, (D) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system at 100 X magnification, (E) SSG mixture of


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CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) at 1000 X magnification, (F) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system at 5000 X magnification, (G) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system at 100 X magnification, (H) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system at 1000 X magnification, (I) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system at 5000 X magnification, (J) SSG mixture of CURHXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system at 100 X magnification, (K) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) at 1000 X magnification and (L) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system at 5000 X magnification.


33


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Page 34 of 48

(F)

CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in EtAc-Tol (1:1)

(E)

CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in Ace-Tol (1:1)

(D)


(C)


(B)

Raw CUR

(A)

Raw HXQ

Figure 7. Overlay of powder X-RD patterns of (A) Raw HXQ, (B) Raw CUR, (C) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system, (D) SSG mixture of CUR-HXQ-SC-XCUR-0.33 heated till 135 ͦC and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system, (E) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system, and (F) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system.


34

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(F)

(E)

(D)

(C)



CUR-HXQ-SSG-XCUR-0.33 heated till 135 °C and recrystallized in EtAc-Tol (1:1) CUR-HXQ-SSG-XCUR-0.33 heated till 135 °C and recrystallized in Ace-Tol (1:1)

(B)

Raw CUR

(A)

Raw HXQ

Figure 8. Overlay of DSC thermograms of (A) Raw HXQ, (B) Raw CUR, (C) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system, (D) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system, (E) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system, and (F) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system.


35


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Page 36 of 48


(G)

CUR-HXQ-SSG-XCUR-0.33 heated recrystallized in Ace-Tol (1:1)

(F)

till

135

(E)

CUR-HXQ-SSG-XCUR-0.33 heated till 145 °C

(D)


°C


(C)

(B)

Raw CUR

(A)

Raw HXQ

Figure 9. Raman spectra of (A) Raw HXQ (B) Raw CUR (C) SSG mixture of CUR-HXQ-XCUR0.33, and (D) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C, (E) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 145°C, (F) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system, and (G) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system.


36

and

Page 37 of 48

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(F)

CUR-HXQ-SC-XCUR-0.5 heated till 130 °C and recrystallized in EtAc-Tol (1:1)

(E)

CUR-HXQ-SC-XCUR-0.5 heated till 130 °C and recrystallized in Ace-Tol (1:1)


(D)

(C)


(B)

Raw CUR

(A)

Raw HXQ

Figure 10. Raman spectra of (A) Raw HXQ (B) Raw CUR (C) SSG mixture of CUR-HXQXCUR-0.5, and (D) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 150 °C, (E) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system, and (F) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system.


37


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Page 38 of 48

(B)

(A)

Figure 11. Overlay of Solid-state

13

C NMR spectra of (A) SSG mixture of CUR-HXQ-XCUR-

0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system and (B) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system [Black – Raw hydroxyquinol; Green – Raw curcumin and Red Cocrystal]


38

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(J)

CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in EtAc-Tol (1:1) – After 3 weeks

(I)

CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in EtAc-Tol (1:1) - Freshly prepared

(H)

CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in Ace-Tol (1:1) – After 3 weeks

(G)

CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in Ace-Tol (1:1) - Freshly prepared

(F)

CUR-HXQ-SSG-XCUR-0.33 heated till 135 recrystallized in EtAc-Tol (1:1) – After 3 weeks

°C

and

(E)

CUR-HXQ-SSG-XCUR-0.33 heated till 135 recrystallized in EtAc-Tol (1:1) - Freshly prepared

°C

and

(D)

CUR-HXQ-SSG-XCUR-0.33 heated till 135 recrystallized in Ace-Tol (1:1) – After 3 weeks

°C

and

(C)

CUR-HXQ-SSG-XCUR-0.33 heated till 135 recrystallized in Ace-Tol (1:1) - Freshly prepared

°C

and

(B)

Raw CUR

(A)

Raw HXQ

Figure 12. Overlay of powder X-RD patterns of (A) Raw HXQ (B) Raw CUR (C) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system - Freshly prepared, (D) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system – After 3 weeks, (E) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system – Freshly prepared, (F) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system – After 3 weeks, (G) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system - Freshly prepared, (H) SSG mixture of CUR-HXQ-XCUR-0.5 heated


39


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Page 40 of 48

till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system – After 3 weeks, (I) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetatetoluene (1:1 volume ratio) system - Freshly prepared and (J) SSG mixture of CUR-HXQ-XCUR0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system – After 3 weeks.


40

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(C) (B) (D) (E) (F) (A)

Figure 13. Dissolution profiles of (A) Raw CUR [filled circle], (B) CUR-SAA-SSG-XCUR-0.33 eutectic [open circle], (C) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1 volume ratio) system - [filled square], (D) ) SSG mixture of CUR-HXQ-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system [open square], (E) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1 volume ratio) system [filled triangle] and (F) SSG mixture of CUR-HXQ-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetate-toluene (1:1 volume ratio) system [open triangle].


41


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Page 42 of 48

Table 1. Summary of literature reports available on cocrystallization of curcumin

S. No

01.

Form of Curcumin used Form 1

Name of the coformer Resorcinol

Nature of the solid formed Cocrystal

Crystal structure reported Yes

Cocrystallization method Liquid Assisted Grinding

Effect of cocrystallization on Dissolution

Reference

Enhanced dissolution than commercial form

6

Enhanced dissolution than Curcumin-Resorcinol cocrystal and commercial form 1

6

No significant improvement in dissolution -

7

02.

Form 1

Pyrogallol

Cocrystal

Yes

Solution crystallization Liquid Assisted Grinding

03.

Form 1

Phloroglucinol

Cocrystal

Not reported

Solution crystallization Rapid Solvent Removal

04.

Form 1

Cocrystal

Yes

Solution crystallization

05.

Form 1

4,4’-bipyridineN, N’-dioxide Nicotinamide

Eutectic

Not reported

Solid-State Grinding


9

06.

Form 1

Hydroquinone

Eutectic

Not reported


9

07.

Form 1

Eutectic

Not reported


08.

Form 1

phydroxybenzoic acid Tartaric acid

Enhanced dissolution than commercial form Enhanced dissolution than commercial form

Eutectic

Not reported


09.

Form 1

Ferulic Acid

Eutectic

Not reported


10.

Form 1

Artemisinin

Coamorphous solid

Not reported

Grinding (LiquidAssisted & Neat) and Solution crystallization


Enhanced dissolution than commercial form Enhanced dissolution than commercial form Exhibited higher dissolution rate than CUR-NAM, CUR-HQ, CURPHBA and CUR-TA eutectics Enhanced dissolution than commercial form

8

9

9 9

10

42

Page 43 of 48

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48


11.

Form 3

L-lysine

Cocrystal

Not reported

12.

Form 3

Nicotinamide

Cocrystal

Not reported

Not reported

Not reported

11


11

Showed 2 times greater dissolution than Curcumin-2aminobenzimidazole cocrystal


43


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Page 44 of 48

Table 2. FT-Raman spectral peak assignments for various functional groups of CUR-HXQXCUR-0.33 Cocrystal system

Aromatic C=C stretching

Wave numbers (cm-1) Enol C-O Phenolic Stretching C-O Stretching

C=O Stretching

Raw HXQ

1632.69

-

1112.35

-

Raw CUR

1599.99

1428.75

1249.62

1627.60


1600.13

1429.15

1249.75

1627.45

CUR-HXQ-SSG-XCUR-0.33 heated till 135

1599.93

1428.49

1248.99

1628.30

1599.76

1426.09

1215.15

1637.31

1597.26

1431.06

1232.92

1638.51

1597.28

1428.67

1271.50

1638.62

Sample Code

°C CUR-HXQ-SSG-XCUR-0.33 heated till 145 °C CUR-HXQ-SSG-XCUR-0.33 heated till 135 °C and recrystallized in acetone-toluene (1:1) system

CUR-HXQ-SSG-XCUR-0.33 heated till 135 °C and recrystallized in ethyl acetatetoluene (1:1) system


44

Page 45 of 48

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Table 3. FT-Raman spectral peak assignments for various functional groups of CUR-HXQXCUR-0.5 Cocrystal system

Aromatic C=C stretching

Wave numbers (cm-1) Enol C-O Phenolic Stretching C-O Stretching

C=O Stretching

Raw HXQ

1632.69

-

1112.35

-

Raw CUR

1599.99

1428.75

1249.62

1627.60


1600.32

1429.29

1248.02

1626.87


1602.53 &

1425.08

1216.60

1637.57

1600.30

1425.79

1229.17

1638.84

1593.13

1424.64

1232.99

1638.82

Sample Code

1526.41 CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in acetone-toluene (1:1) system

CUR-HXQ-SSG-XCUR-0.5 heated till 130 °C and recrystallized in ethyl acetateToluene (1:1) system


45


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Page 46 of 48

Table 4. 13C peak shifts observed in Solid-state NMR spectra of CUR-HXQ-XCUR-0.33 & CURHXQ-XCUR-0.5 cocrystals crystallized in Acetone-Toluene (1:1 volume ratio) and Ethyl acetateToluene (1:1 volume ratio)

13

CUR-HXQXCUR-0.33 crystallized in Ace-Tol (1:1 vol ratio)

CUR-HXQXCUR-0.33 crystallized in EtAc-Tol (1:1 vol ratio)

CUR-HXQXCUR-0.5 crystallized in Ace-Tol (1:1 vol ratio)

CUR-HXQXCUR-0.5 crystallized in EtAc-Tol (1:1 vol ratio)

Form 1 CUR

1, 17

152.384

152.897

152.641

152.127

159.904

2, 18

147.940

148.026

148.026

147.684

149.308

3, 19

106.386

105.896

108.375

108.204

109.400

4, 14

129.738, 128.456

129.824, 128.628

129.995, 127.089

129.824, 128.542

130.849, 130.080

5, 15

111.622

111.707

111.195

111.024

111.024

6, 16

116.236, 114.954

116.151, 115.125

115.040

115.126

115.980, 115.467

7, 13

139.737

139.993

141.788

139.737

141.446

8, 12

119.911

120.765

123.243, 121.192

123.585, 119.825

125.979, 123.928

9

188.019

188.105

187.848

187.934

188.104

10

102.734

103.161

100.457

100

99.829

11

179.986

179.645

179.559

179.644

183.746

20, 21

56.674, 55.392

56.759, 55.563

56.589, 55.563

56.503

58.041, 56.161

C Peaks


46

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Table 5. Summary of a few reports available in the literature on stoichiometrically diverse cocrystals of a pair of drug and coformer

S. No

01.

API

Salicylic acid

Coformer

Benzamide

API-Coformer

Melting point of

stoichiometry

the cocrystal (°C)

1:1 and 1:2

117.1 °C and 109.3

Reference

30

°C 02.

Salicylic acid

Isonicotinamide

1:1 and 2:1

132.1 °C and 135.6

30

°C 03.

Carbamazepine

4-Aminobenzoic acid

1:1, 2:1 and 4:1

148 °C, 157 °C and ̰

37

120 °C 04.

Nicotinamide

R-Mandelic acid

1:2, 1:1 (2 forms) and

66.8 °C, 89.1 °C

4:1

(form 1), 85.2 °C

38

(form 1) and 98.3 °C 05.

Urea

Succinic acid

1:1 and 2:1

̰ 140 °C and ̰ 150 °C

39

06.

Indomethacin

Saccharin

1:0.2, 1:0.3, 1:0.5,

179 °C, 181 °C, 184

40

1:0.8,

°C, 184 °C, 184 °C,

1:1,

1:1.2,

1:1.5, 1:2 and 1:3

184 °C, 184 °C, 184 °C and 184 °C


47


For Table of Contents Use only Crystal Engineering of Curcumin with Salicylic acid and Hydroxyquinol as Coformers Indumathi Sathisarana and Sameer Vishvanath Dalvib,* a

Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355,

India. b

Chemical Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355,

India.

Cocrystals

Eutectic (1:1 and 1:2) Melts

TOC Graphic

Eutectic (1:2)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 48 of 48

Synopsis Cocrystallization of curcumin has been attempted to improve its aqueous solubility. Curcumin was found to form two cocrystals via eutectic melting with hydroxyquinol at drug to coformer stoichiometric ratios of 1:2 and 1:1 and an eutectic with salicylic acid at stoichiometric ratio of 1:2. The eutectic as well as two cocrystal phases exhibit higher aqueous solubility than raw curcumin.


48

Crystal Engineering of Curcumin with Salicylic Acid and

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