Curcuminâa biological wonder molecule: A crystal engineering point

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Review

Curcumin—a biological wonder molecule: A crystal engineering point of review Palash Sanphui, and Geetha Bolla Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00646 • Publication Date (Web): 25 Jul 2018 Downloaded from http://pubs.acs.org on July 26, 2018

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Crystal Growth & Design

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Curcumin—a biological wonder molecule: A crystal engineering point of review Palash Sanphui*† and Geetha Bolla*‡ † Department of Chemistry, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu-603203, India. ‡ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Abstract Curcumin is a principal active ingredient of turmeric, extracted from the Curcuma longa plant. The

presence

of

several

curcuminoids

(e.g.,

curcumin,

demethoxycurcumin,

bisdemethoxycurcumin and cyclocurcumin) with extended π-π conjugation makes the Indian spice, turmeric bright yellow color. Curcumin can modulate various cellular targets and exhibits preventive and clinical efficacy against a wide variety of diseases like inflammatory, alzheimer, proliferative, angiogenic, malaria, cancer, HIV etc. Curcumin has been widely exploited by the several branches of research scientists to study the chemistry behind its biological and chemical significance. However, application of curcumin is limited as medicine due to poor aqueous solubility

and

bioavailability.

While

there

are

recent

reports

on

curcumin

on

solubility/bioavailability improvement using excipients/additives, there was a little discussion on the point of crystal engineering. There is a need for understanding of the solid phases of curcumin to tailor physicochemical properties as they are alternative preformulations with prominent applications in pharma. Hence, in this review, we will focus on several crystalline solid forms such as polymorphs, cocrystals, eutectics and noncrystalline solid forms like amorphous phases, coamorphous solid forms of curcumin reported in the literature/patent till date. In addition, we will briefly discuss metal complexes of curcumin and their application on drug development in combating modern lifestyle related disease like cancer, alzheimer etc. Keywords: curcumin, crystal engineering, polymorphs, cocrystals, eutectics, coamorphous, medicinal properties.

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1. Introduction Pharmaceutical industry prefers active pharmaceutical ingredients (APIs) as the solid oral dosage forms, which are developed in a systematic manner during research and development and finally delivered orally to the patients. Generally medicines are formulated as tablets (>80%) among all the suitable solid/liquid formulation like capsules, gels, injectable forms etc. The crystalline form is absolutely the preferred one because of its utmost purity and ease of handle by patients.1 Crystalline forms may exist as polymorphs, cocrystals, salts, eutectics, solid solutions; which are generally obtained during high throughput solid form screening.2-4 Crystalline solids offer different

physicochemical

properties

like

solubility,

dissolution

rate,

bioavailability,

permeability, tabletability etc. depending upon the structural aspects within their crystal lattice and several other factors.4-8 Along with the well-established solid forms e.g., polymorphs, cocrystals; eutectics, solid solutions and amorphous phases of the active pharmaceutical ingredients (API) are the current area of research interest due to their certain favorable physicochemical properties. Among the crew, the pioneer preliminary classification is polymorphs, which are defined as the different crystalline packing arrangements of a compound in a periodic manner. Out of the several classifications of polymorphs based on packing, synthons and conformations; conformational polymorphism9,10 in flexible organic molecules is an interesting phenomenon to study due to their tuning in certain physical properties e.g., molecular shape, color, solubility etc. For e.g., 5-methyl-2-[(2-nitrophenyl)amino]-3thiophenecarbonitrile is commonly known as ROY, that has been extensively studied due to their coloristic polymorphic appearances as red, orange and yellow.11 The colors of these polymorphs are strongly correlated with their molecular conformation and packing arrangement. The next important classification of solid form, cocrystal which is a multi-component system of two or more number of different solid components interact in a definite stoichiometric ratio via non-covalent interactions such as hydrogen bonds, halogen bonds, charge transfer etc.1213

Pharmaceutical cocrystal consists of an active ingredient and generally regarded as safe

(GRAS) molecule or biological acceptable component and they can offer towards the tuning of physicochemical properties during formulation of a drug molecule.14,15 Along with the pharmaceutical cocrystals, other types of cocrystals are nutraceutical cocrystals,16 ionic 2



cocrystals/ zwitterionic cocrystals,17 drug-drug cocrystals,18 drug-(coformer) bridge-drug ternary cocrystals19 are also remarkable in the recent years. Other multi-component solid forms are hydrate and solvates (including water/solvents)20 also play important role during drug development. Another valuable addition of multi-component solid form is eutectic.4,21 The eutectic is a multi-component heterogeneous crystalline solid, which generally exhibits lower melting point compared to the individual components. Eutectics are close to the solid solution from the structural point of view, but vary in structural integrity. Solid solution is a mixture of two components, in which minor components uniformly distributed in the crystal lattice of major components and coexist as a new crystalline solid form.22 The crystal structure of eutectic is like discontinuous or conglomerate solid solutions. The 3D coordinates of a cocrystal should be different from its initial components, whereas unit cells of a solid solution may be identical with one of the components because of shape/size mimicry. In the recent past, amorphous forms have gained diverse research interest among the scientific community as well as generic pharmaceutical industry because of their modified dissolution impact and bioavailability.5 The major drawback of amorphous solid is their physical/chemical instability in the solid state. Amorphous premix and coamorphous solid forms are generally developed for pharmaceuticals with the idea of dual advantage of solubility and stability. For e.g., antifungal drug Itraconazole is marketed as an amorphous form coated on sugar sphere (Sporanox capsule) and exhibits improved solubility compared to its crystalline form, while not compromising with stability.23 Scheme 1 represents various flavors of solid forms. Recently regulatory authorities like United States Foods and Drugs Administration (USFDA)24 and European Medical Agency (EMA)25 delivered a few guidelines to approve pharmaceutical cocrystals as novel solid form, similar to polymorphs and salts. According to USFDA guidelines, cocrystals need to be characterized by crystal structure and spectroscopy techniques and applicant needs to prove that the cocrystals must dissociate before reaching the site of pharmacological activity. The guidelines suggest that the applicant needs to distinguish cocrystals from salts using IR/Raman/ssNMR spectroscopy/single crystal X-ray diffraction and confirm the dissociation of the cocrystal into active drug component, which only should reach 3


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the target site of action. Recently, Novartis availed US-FDA approval of ENTRESTO to commercialize an ionic cocrystal of saccubitril valsartan trisodium hemipentahydrate.26 A few more cocrystals e.g., ertugliflozin–L-pyroglutamic acid27 and metaxalone–fumaric acid28 are in the clinical trials and expected to be in the market soon. Regarding eutectic solid forms, we may need to understand the supramolecular interactions between the two heterogeneous compounds via several characterization techniques like pair distribution function29 or any other advanced analytical tools before regulator authority approve eutectic as novel solid form.

Scheme 1. Different aspects of solid forms. (a) and (b) polymorphs; (c) amorphous phase; (d) molecular or ionic cocrystal/salt/solvate/hydrate/metal complexes; (e) coamorphous phase; (f) & (g) solid solutions with (7:3) & (3:7) stoichiometry; (h) & (i) eutectic phases as discontinuous solid solutions.

4



2. Curcumin Curcumin is extracted traditionally from rhizome of the herb Curcuma longa and accounts almost 60-70% in Indian spice turmeric.30,31 Other curcuminoids are its analogues like demethoxycurcumin (20-27%), bisdemethoxycurcumin (10-15%) and cyclocurcumin (1-2%), see Figure 1. Turmeric is generally ground into a powder and used in Asian cookery, medicine, cosmetics, and fabric dying since ancient times. Last 3-4 decades of thorough scientific research on curcumin confirmed its diverse pharmacological activities starting from anti-inflammatory, anti-malaria to anti-HIV, anti-cancer etc. Vogel and Pierre Joseph Pelletier was the pioneer to isolate curcumin from rhizomes of turmeric in 1815,32 and further Lampe and Milobedeska characterized it by several analytical techniques in 1910.33 Curcumin was first synthesized in a laboratory and confirmed its chemical structure in 1913. During the years 1914-1994, there were a few publications on curcumin based on its synthesis, and antioxidant activity. Singh and Aggarwal34 are the pioneer, who demonstrated potential anti-cancer activity of curcumin in 1995. Thereafter, research on biological activity of curcumin has been increased by many fold till date. Scopus database35 suggests 2381 and 1267 numbers of articles are published on curcumin in 2017 and current year till date, which indicates the importance of curcumin among the scientists. Extensive research on curcumin is going on to know the Chemistry behind its diverse pharmaceutical applications. Synthetic experts are involved in the extraction and preparation of curcumin and its derivatives. The chelating abilities of curcumin with several metal ions and their biochemical activities have been demonstrated. Time dependent UV spectroscopy is deployed to study the interactions of curcumin with polymer micelles, which are able to suppress degradation rate significantly in micellar nanocavity.36 Moreover, curcumin is exploited to appraise the trace elements for e.g., boron, lead etc. both qualitatively and quantitatively.37 Structural chemists are busy in exploring novel solid forms like polymorphs, cocrystals, salts, eutectics, amorphous and coamorphous phases etc. using crystal engineering principles38 and their structural aspects at the supramolecular level.

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Figure 1. Chemical structures of (a) curcumin (b) bisdemethoxycurcumin, (d) cyclocurcumin as a part of turmeric.

demethoxycurcumin,

(c)

2.1 Bioavailability problem of curcumin Curcumin (chemical name: diferuloylmethane) has two 2-methoxy phenols attached symmetrically through seven carbon unsaturated diketone linker, which induces keto–enol tautomerism, see Scheme 2. In solution, there is equilibrium between two tautomers of curcumin; acidic and neutral solutions favor the β-diketo form and the alkaline medium opt for keto-enol tautomer. Among two tautomers of curcumin, the keto-enol form is more stable by 6.7 kcal/mol in the gas phase,39 and is present in the solid state in most of the reported crystal structures. Curcumin is extremely safe even at high doses of 8-12

g/day, but its clinical efficacy is limited by poor aqueous solubility (7.8 mg/L) and bioavailability (typically short half-life =30-45 minutes).40 The poor bioavailability of curcumin is due to its minimal absorption, rapid metabolism in the liver and intestinal wall and fast systemic elimination through urine and feces.41 Curcumin is highly insoluble in acidic or neutral medium and comparatively better soluble in alkaline medium. Downside, curcumin has also stability related issues in basic medium as it decomposes rapidly in neutral and alkaline medium more than 90% decomposition occurs within half an hour in 0.1 M phosphate buffer (pH 7.2) medium.42 Stability of curcumin is improved in cell culture medium containing 10% fetal calf serum and in human blood, which prevents its degradation upto 20% within an hour and 50% after incubation for 8 hour. Trans-6-(4'-hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal (a) is the major degraded product, while vanillin (b), ferulic acid (c) and feruloyl methane (d) are the minor products, see Scheme 3. Hence, despite its clinical efficacy and safety, yet curcumin is not approved as a medicine. Salt formation is the first-choice to enhance the aqueous solubility and bioavailability of active pharmaceutical ingredients (APIs) and bioactive molecules.43,44 Curcumin [(1E,6E)-1,76



bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] consists of 3 ionizable hydroxyl groups having pKa 7.8 (enolic), 8.5 and 9.0 (phenolic). Absence of any electron withdrawing groups in curcumin makes difficulty for salt formation, provided it degrades in alkaline medium. The stability and bioavailability of curcumin was improved by several methods, e.g., (1) addition of adjuvants such as piperine to suppress metabolism of curcumin, (2) novel drug delivery platforms such as nanoparticles, liposomes, micelles, phospholipid complexes, (3) concomitant administration of lecithin, quercetin, genistein, eugenol, terpinol etc. and (4) complexation with cyclodextrin and phosphatidyl choline.41 The aqueous solubility of curcumin was increased by 38 fold in the presence of a natural sweetener, rubusoside.45 Remarkably, molecular complex of curcumin with cationic copolymer eudragit (1:2) enhances the aqueous solubility (2000 fold), stability, peak plasma concentration (6 fold) and bioavailability (20 fold) of curcumin.46

Scheme 2: Tautomers of curcumin exists as (1:1) mixture in solution.

7


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Scheme 3. Possible mechanistic pathways of curcumin degradation products like (a) Trans-6-(4'hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal as major and (b) vanillin, (c) ferulic acid, (d) feruloyl methane as minor in the alkaline (pH 7.2) medium. 2.1.1 Curcumin nanoparticles and improved dissolution Crystallization of poor water soluble drugs as nanoparticles is one of the promising techniques to enhance their aqueous solubility, bioavailability and drug exposure for oral dosage forms.47 Liquid antisolvent (LAS) precipitation is one of the emerging techniques to produce nanoparticles of the APIs, which will improve dissolution rate due to increase in surface to volume ratio. Liquid (EtOH) antisolvent (water) precipitation of curcumin with ultrasound effect and polymeric additive such as sodium dodecyl sulfate (SDS), Tween 80, hydroxyl propyl methylcellulose (HPMC), polyvinyl pyrrolidone (PVP), and bovine serum albumin (BSA) resulted in the precipitation of nanoparticles (50-200 nm), which loosely assembled to particles of 1-5 μm in size.48 Curcumin nanoparticles (nanocurcumin) were synthesized using wet-milling technique resulted a narrow particle size distribution in the range of 2−40 nm. Unlike raw 8



curcumin, nanocurcumin was found to disintegrate in water without any surfactants.49 Donsì et al. employed high-pressure homogenization (HPH) technique to enhance the water dispersity (10 fold) of curcumin due to formation of reduced particle sizes (~600 nm) and crystallinity caused by mechanical stresses.50 Simultaneous HPH treatment and spray drying with maltodextrin exhibited rapid dissolution of curcumin, while maintaining its higher water dispersity. In addition to the liquid antisolvent precipitation and high-pressure homogenization methods, one more innovative way to prepare curcumin nanoparticles is supercritical carbon dioxide (CO2) (scCO2) technology. In this process, scCO2 was employed as an anti-solvent for the precipitation of curcumin dissolved in acetone. The resulted curcumin nanoparticles (~325 nm) with a spherical shape improved dissolution rate by 7 times within 3h.51 Dalvi and coworkers utilized scCO2 to precipitate ultra-fine particles (~0.4-34 μm) of curcumin at a pressure of 40 bar by producing superfast and uniform supersaturation in the solution at 40-70 K.52 Last one decade, several research groups worldwide revisited curcumin and carried out high throughput screening for novel solid forms. As an outcome, they published novel polymorphs, solvates, cocrystals, eutectics, amorphous phases and even coamorphous phases of curcumin with the motif of improving solubility, stability and bioavailability via crystal engineering principle.38 A summary of different solid forms of curcumin (reported) is displayed in Scheme 4.

9


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Scheme 4. Several solid forms of curcumin (from literature/patents). 2.2. Curcumin polymorphs Curcumin is known for over two centuries after the first laboratory extraction.32 However, no structural reports of curcumin were available in the public domain till 1980. The crystal structure of curcumin was reported in 1982 in the monoclinic crystal lattice (P21/n).53 No polymorphs were known for this biologically active ingredient after 30 years of its reported crystal structure, despite urgent need to improve its solubility and bioavailability. High throughput solid form screening of curcumin was carried out by solution crystallization, solvent-anti-solvent crystallizations, layering technique, capillary crystallization, heat and pressure induced crystallizations, addition of coformers or additive, melting, sublimation etc.54,55 Commercial curcumin is identical with the known stable Form 1, confirmed by powder X-ray diffraction pattern (PXRD) comparison. Solvent evaporation crystallizations of curcumin from several common laboratory solvents at ambient conditions often harvested the stable form. Single crystals of a new polymorph 2 were harvested upon attempted during cocrystallization of curcumin with 4-hydroxypyridine, caffeine, amodiaquine dihydrochloride and further with 10



dextrose in EtOH at ambient conditions.56,57 The same Form 2 was obtained from saturated DMSO solution at room temperature and also in EtOH at 10 °C. Another new polymorph, Form 3 was harvested in presence of coformers like chrysine and 4, 6-dihydroxy, 5-nitro pyrimidine during attempting cocrystallization experiments in an equimolar ratio (Figure 2).55 Form 3 was also crystallized in presence of additives like hydroxypropylmethyl cellulose (HPMC) and bovine serum albumin (BSA) using ultrasound effect.48,58,59 Both the novel polymorphs were crystallized in orthorhombic lattice. Different colors (dark red) of the polymorphs may be due to conformational differences like more planarity in the structure of metastable Forms 2 and 3 compared to twisted stable Form 1 (yellow). An amorphous phase of curcumin was obtained on melting of the compound, followed by cooling to room temperature or freeze cooling.56 The amorphous phase was unusually stable at ambient conditions of temperature (20-35 °C) and humidity (40-70%) in a closed sample vial till 6 months.

Figure 2: Three crystalline polymorphs and an amorphous phase of Curcumin obtained during attempted cocrystallizations.56 The refined single crystal structure of Curcumin Form 1 contains one molecule (keto-enol tautomer) in the asymmetric unit and contains a curved, slightly twisted conformation. Phenyl rings at both the terminals of curcumin are a little twisted from each other. Four curcumin molecules form a macrocyclic ring of R45(42) graph set60 via O–H···O hydrogen bonds. Form 2 has two symmetry independent molecules in the asymmetric unit. Both the curcumin molecules (Z′=2) have intramolecular O−H···O hydrogen bonds in the enol tautomer and form zigzag 11


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patterns. Similar to Form 2, Form 3 (Z′=1) also has planar conformation. The curcumin molecules in Form 2 and Form 3 possess linear structure when compared with the twisted structure of Form 1. Both polymorphs exhibit packing similarity due to identical crystal lattice parameters,56 despite a few differences of auxiliary C−H···O hydrogen bonds and molecular orientations in their crystal structures, see Figure 3.

(a) (b)

(c)

(d)

Figure 3. (a) Tetramer assembly of curcumin molecules form macrocylic ring motif of R54(42) in Form 1. Hydrogen bonding and packing differences between 3 polymorphs of curcumin (b) Form 1 (c) Form 2 and (d) Form 3.56 2.2.1 Curcumin pseudo polymorphs Possibility of hydrate/solvate may play an important role for tuning solid state properties during research and development.20 Silva et al. communicated a dichloromethane solvate of curcumin (2:2), of which the crystal structure was solved in triclinic crystal lattice (P-1) with two molecules of curcumin and dichloromethane each in the asymmetric unit.61 Curcumin exists as usual in keto-enol tautomer in both the symmetry independent molecules. Similar to Form 2 and 3, curcumin molecules in DCM solvate have planar structures, but interestingly, orientation of hydroxy and methoxy functional groups are similar as Form 1. Three molecules of curcumin form hydrogen bonded trimer assembly via O–H···O hydrogen bonds between phenolic –OH 12



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and keto-enol group, which result small ring motifs of R32(7) and macrocyclic ring of R32(37) to a 2D layer structure (Figure 4a). These layer structures are stacked by auxiliary π–π interactions between olefinic bonds (one layer), aromatic ring of curcumin (next layer) with centroid to centroid distance of 3.3Å (Figure 4b). Dichloromethane molecules are involved only in auxiliary C–H···Cl and C–H···O hydrogen bonds.

(b)

(a)

Figure 4. (a) 2D sheet like structure of curcumin-DCM solvate. (b)Two symmetry independent curcumin molecules (green and blue traces) in successive layers form π–π stacking interactions. DCM molecules are omitted for picture clarity.61 2.2.2 Possibility of novel curcumin polymorph The keto-enol tautomer exists in all the crystalline polymorphs and DCM solvate of curcumin, and still no polymorph having only β-diketo form (centrosymmetric) in the literature till date. The dihedral angle between two phenyl rings in the metastable polymorphs and solvate vary from 3.9° (DCM solvate) to 20.6° (Form 1) and there is a large dihedral angle gap between Form 2 (12.6°) and Form 1 (20.6°), in which novel polymorphs may crystallize depending upon crystallization conditions. Gately and coworkers reported a novel anhydrous polymorph, Form III and two solvates with 1, 4-dioxane (Form V) and methyl acetate (Form VI) of curcumin in a patent no. PCT/US2012/032396.62 Form III was characterized by XRD, DSC and TGA with an endothermic transition at 162 °C. The novel polymorph was a highly metastable form and transformed to stable Form 1 at 40 °C even. Crystallization condition and crystal structure of Form III was not reported in the above mentioned patent. Presence of two phenolic moieties, along with enolic –OH group in curcumin ensure possibility of a hydrate via O–H···O hydrogen 13


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bonds of curcumin, although curcumin molecule is perfectly balanced between 3 donors and 3 acceptors. The possibility of curcumin monohydrate (Form X) was reported by Chava and coworkers in a patent no. PCT/IB2014/002034.63 The crystallization of Form X involves dissolving curcumin in (16V) acetone, followed by addition to (1V) water and allowed for slow evaporation at 5 °C. Crystalline orange thin needle crystals were obtained after a day and the novel Form X was confirmed by PXRD data. Moisture content (4.6%) indicated possibility of a monohydrate, which was supported by DSC and TGA. However, there was no single crystal Xray data of Form X mentioned in the patent reported yet. Hence there is a need for conformation of Form X by its crystal structure and see whether curcumin can exist as rare β-diketo form or as usual keto-enol tautomer.

2.2.3 Importance of polymorphism and additive induced crystallization Extensive research activity on solid form screening of APIs is going on across academics and pharmaceutical industry because of their enormous significance on physicochemical properties of a compound.55 Polymorphism presents both opportunities and challenges for innovator and generic pharma industry because stability and bioequivalence are equally important to introduce new polymorph against the commercialized one.64,65 High throughput screening of a commercial drug

may

lead

to

novel

solid

forms

with

improved

half-life

period,

higher

solubility/bioavailability, extended release profiles etc. In general, polymorphs can increase solubility/bioavailability by 2-4 fold66 and that is sufficient for the alteration of formulation in the drug product, clinical efficacy or decrease the dosage form to reduce toxicity. Novel polymorphs may decrease the manufacturing costs of the API and increase purity via crystallization techniques. Polymorphs with improved pharmaceutically relevant properties are patentable and can provide a healthy competition between innovator and generic companies. At the same time, innovator can increase their API life time in the market by producing novel polymorphs of the same drug. Hence investigation of possible solid forms of a new chemical entity should be carried out as early as possible during drug development processes. For example Form I of anti-HIV drug, ritonavir dissolved 5 time faster than Form II in aqueous ethanol, but reproducing Form I was challenging task.65 The relative bioavailability of Form I of antiepileptic drug, carbamazepine is more than 2 fold compared to Form III or dihydrate and this is 14



attributed due to the rapid phase transformation of Form III to dihydrate formation.67 Superior compressibility/tabletability of anti-bacterial drug sulfamerazine polymorph I compared to polymorph II was explained with respective to the active slip planes in the former and absence in the later.68 Despite its potential implications, the phenomenon of polymorphism is still not properly understood, and even after many decades of extensive research, there is no clear answer to what type of molecules will exhibit polymorphism, in which crystallization conditions to follow and how many polymorphs are possible of a compound?69 Polymorph prediction is even more difficult for flexible organic molecules specially active pharmaceutical ingridients.70 Advancement of computational techniques and software programs may help to predict correct polymorph in the near future. Sometimes it is difficult to reproduce certain polymorphs, which have appeared initially, defined as disappearing polymorphs;71 for e.g., Ritonavir Form 1. Among the several crystallization methods, the induced nucleation or pseudo-seeding with the adequate seed crystals of the desired form is the most straightforward and promising to obtain the desired polymorph.72 Generally, drug molecules have more tendencies to crystallize as polymorphs when compared with the organic compounds because of their molecular flexibility and competition between the functional groups involved.73 Often, changing the crystallization conditions such as solvents, temperature, pressure, addition of impurities, seeds, additives or polymer, gel induction etc. yielded novel polymorphs, which was difficult under usual crystallization conditions. For example, a new polymorph II of maleic acid was discovered during cocrystallization experiments with caffeine, 124 years after the first crystal structure was reported.74 There were difficulties in reproducing Form II crystal of maleic acid without the coformer. Similarly, a second polymorph of the aspirin was obtained in the presence of an epileptic drug, levetiracetam and aspirin anhydride. Caira and coworkers reported new polymorphs of nicotinamide and isonicotinamide during cocrystallization experiments with an anti-tuberculosis drug, isoxyl.75 These experiments suggest that additives/coformers can induce the appearance of new polymorphic forms. There are three possibilities during additive induced nucleation of new polymorphs.76,77 (i) Addition of various concentrations of additives may change the supersaturation of a system, which in turn changes the crystallization pattern in situ to produce novel polymorphs. (ii) Additives may block 15


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the crystallization process of the most stable form via adsorption in the fast grown crystal faces and inhibit regular deposition of incoming layers of the substrate and thus favor metastable phases by lowering the activation energy barrier during crystallization process. (iii) Weak auxiliary interactions between the API and coformer/additive in the solution stage and later during supersaturation stage, they separate and end up with higher energy metastable polymorph. In general, Form 1 is the thermodynamically most stable polymorph of curcumin and appeared during most of the crystallization experiments. Further in a direction of finding new polymorphs, addition of a few coformers such as 4-hydroxypyridine, caffeine, amodiaquine dihydrochloride, 4, 6-dihydroxy-5-nitropyrimidine, chrysin and dextrose during cocrystallization of curcumin produced novel polymorphs either Form 2 or 3.56,58 Dalvi and coworkers exploited liquid (EtOH) anti-solvent (water) precipitation of metastable curcumin polymorphs with ultrasound effect and polymeric additives such as sodium dodecyl sulfate (SDS), Tween 80, hydroxyl propyl methylcellulose (HPMC), polyvinyl pyrrolidone (PVP), and bovine serum albumin (BSA) to precipitate curcumin super particles in orthorhombic forms (Form 2 or Form 3), whereas raw curcumin as dendritic particles precipitated without ultrasound effect and additives exist in monoclinic form only, see the possible mechanism (Figure 5).48 The absence of ultrasound effect during precipitation of curcumin results in dendritic particles (Form 1) due to a diffusion-limited growth in the absence of uniform mixing (path A). Precipitation of curcumin particles (Form 2/3) with ultrasound effect and (with or without) stabilizers may follow a nonclassical crystallization pathway (path B). The use of ultrasound and stabilizers lead to large nucleation rates and hence to a greater population of stabilized nanoparticles. These stabilized nanoparticles assemble under the influence of ultrasound to form superstructures. Ultrasound effect prevents hydrogen bonding among curcumin molecules and promotes polymorphic crystallizations (Form 2/3). All these coformers either have pyridine ring nitrogen heteroatom or aliphatic/aromatic hydroxyl group, which may form initially weak hydrogen bonded complexes with curcumin in solution and then at supersaturation stage, they may follow the third possibility of nucleation and end up with the novel polymorphs 2 or 3.

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Figure 5. Probable mechanism of the formation of curcumin superparticles with and without ultrasound effect.48 2.3 Curcumin cocrystals After successful polymorph screening, cocrystals were explored to enhance solubility and stability of curcumin. The β-diketone linker in the seven carbon chain of curcumin may be responsible for the poor stability of curcumin at physiological pH. The reactivity of the keto-enol group can be modulated by cocrystallization through intermolecular hydrogen bonds with suitable coformers, which in succession may enhance physiochemical properties of curcumin. Cocrystal screening was carried out with biologically safe coformers having carboxylic acids, phenols, pyridine, amides, keto functionalities etc. However, only two cocrystals were confirmed with resorcinol and pyrogallol, which indicated that there is a possibility of hydrogen bonding between keto functional groups (curcumin) and hydroxyl group of phenols via O–H···O hydrogen bonds.78 A broad range of cocrystals with other dihydroxy/trihydroxybenzene compounds such as catechol, orcinol, quinol, phloroglucinol etc. were unsuccessful. A few research groups reported cocrystals with phloroglucinol80 and hydroxyquinol81 among the phenol functional groups, but their crystal structure determination were not successful till date. Chart 1 summarizes successful coformers of curcumin published in the literature/patents till date.

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Chart 1: Chemical structures of (a) curcumin and binary cocrystal coformers e.g., (b) resorcinol, (c) pyrogallol, (d) phloroglucinol, (e) hydroxyquinol, (f) methylparaben, (g) 4,4'-bipyridine N, N'-dioxide, (h) 2-aminobenzimidazole, (i) lysine, (j) nicotinamide, (k) isonicotinamide, (l) piperazine, (m) piperidine, (n) naproxen sodium and (o) ibuprofen sodium reported in the research articles and patents.62-63,78-82 2.3.1 Cocrystals with phenols Curcumin–resorcinol (1:1) and curcumin–pyrogallol (1:1) cocrystals were obtained via solvent (EtOH) assisted grinding of the equimolar individual components.78 The crystal structure of curcumin–resorcinol was solved in the monoclinic space group P21/c. The curcumin molecule is almost planar, similar to the metastable polymorphs. The dihedral angle between the least squares planes passing through C4−C7−C8−C9−C10−C11 and C12−C13−C14 atoms of curcumin is 4.9° in the cocrystal. One resorcinol molecule donates O−H···O hydrogen bonds to the carbonyl group of curcumin and form a ladder motif along the a-axis (Figure 6a).

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Curcumin–pyrogallol (1:1) cocrystal was refined in the monoclinic crystal lattice (P21/n). The curcumin molecule with keto-enol tautomer is almost planar: the dihedral angle between the least squares planes in curcumin is 6.7°. Two pyrogallol molecules form hydrogen bonds to the carbonyl oxygen of the β-keto group of curcumin via O−H···O hydrogen bonds. An O−H···O hydrogen-bonded trimer is established between the phenol OH of two curcumin molecules with pyrogallol oxygen acceptor (Figure 6b). The cocrystal of curcumin with resorcinol is a pharmaceutical cocrystal as resorcinol is a GRAS molecule, and further curcumin–pyrogallol can also classified as a drug-drug cocrystal, provided pyrogallol which can inhibit potentially lung cancer and tumor growth.79

(a)

(b) Figure 6. Hydrogen bonding in (a) curcumin–resorcinol and curcumin–pyrogallol cocrystals.78 Chow et al.80 reported a phase-pure curcumin–phloroglucinol (CUR−PHL) cocrystal obtained from acetone via rapid solvent (acetone) removal and (1:1) stoichiometry was confirmed by DSC, ss-NMR (Figure 7a) and PXRD techniques (Figure 7b). PXRD indicated, cocrystal prepared by EtOH may have trace of curcumin, whereas acetone solvent produced pure 19


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cocrystals. The cocrystal was a kinetically stable form, which was prepared by fast solvent removal crystallization process only.

13

C ss-NMR and PXRD data suggest that the cocrystals

have slight amorphous content in the solid form, which is generally observed in case of rapid solvent removal under vacuum. SS-NMR data supports keto-enol form of curcumin and the possibility of O‒HˑˑˑO hydrogen bonds between phloroglucinol and curcumin.

(a)

(b) 20



Figure 7. (a) 13C CP/MAS ss-NMR spectra comparison of CUR, PHL, and CUR−PHL cocrystal. (b) PXRD patterns of CUR, PHL, and CUR−PHL cocrystals using acetone and EtOH indicates that the acetone is better choice to produce cocrystal.80 Curcumin–hydroxyquinol (CUR−HXQ, 1:2 & 1:1) cocrystals were reported by melting using their eutectic compositions.81 The microcrystalline cocrystals (1:2, 1:1) were characterized by PXRD (Figure 8), DSC, Scanning Electron Microscopy (SEM), FT-IR, FT-Raman and 13C ssNMR spectroscopy. The crystal structure of CUR−HXQ was not reported yet, as the suitable single crystals for X-ray diffraction were not able to harvest during crystallization experiments. There is a possibility of O−H···O hydrogen bonding interactions between hydroxyl groups in hydroxyquinol and β-diketo group of curcumin results in formation of cocrystal.

Figure 8. PXRD patterns of (A) Raw HXQ, (B) Raw CUR, (C) ground mixture of CUR−HXQ (1:2), (D) ground mixture of CUR-HXQ (1:1) heated till 135 °C, (E) ground mixture of CUR−HXQ−XCUR-0.33 heated till 145 °C, (F) ground mixture of CUR−HXQ (1:1), and (G)ground mixture of CUR−HXQ (1:1) heated till 150 °C.81 A cocrystal of curcumin with methyl paraben (1:1) was reported by wet granulation with ethanol.82 The cocrystal was confirmed by several analytical techniques like FT-IR, DSC, PXRD and SEM analysis. Curcumin exhibited hexagonal prism like morphology with smooth surface (Figure 9). The cocrystals showed some irregular shapes mostly parabola type (reduced particle size), which was easily distinguishable from curcumin and the coformer methyl paraben. There 21


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is a possibility of intermolecular hydrogen bonding between hydroxyl group of methyl paraben and β-diketo of curcumin.

Figure 9. SEM images of curcumin, methyl paraben and curcumin−methyl paraben cocrystal (left to right), which indicated the smaller irregular crystal sizes for cocrystals.82 2.3.2 Curcumin cocrystals with non-phenol coformers Except phenolic coformers, recent reports on curcumin cocrystal formation with basic coformers like bipyridine N, N′-dioxide, lysine, 2-aminobenzimidazole, nicotinamide, isonicotinamide, piperazine, piperidine and drug molecules such as naproxen sodium and ibuprofen sodium,62,63,83 see Scheme 6. Curcumin is reported to be more soluble in alkaline medium, but degrade faster than acidic pH medium. Hence coformers need to be selected based on theirs low basicity. Su et al.81 reported two cocrystals of curcumin with 4,4-bipyridine N, N′-dioxide (BPNO) based on hydrogen bond formation between phenolic –OH (CUR) and N-oxides (BPNO). Controlled crystallization of equimolar mixture of curcumin and BPNO from EtOH resulted (1:1) cocrystals with yellow block morphology. The crystal structure was solved in triclinic system (P-1 space group) and there is one curcumin molecule (keto-enol tautomer) and one BPNO molecule in the asymmetric unit. The curcumin molecule is very close to planar as the dihedral angle between the least squares planes is 10.2°. Curcumin molecule forms two intermolecular hydrogen bonds with two neighboring BPNO molecules through O–H···O– intermolecular hydrogen bonds (Figure 10a). When the equimolar mixture was cocrystallized from MeOH, red color crystals appeared via slow evaporation. The crystal structure was solved in the orthorhombic space group Pccn with half equivalent of curcumin (centrosymmetric), half equivalent of BPNO and one methanol in the asymmetric unit. The curcumin molecule is exact planar: the dihedral angle between the least squares planes is only 1.2°. Strong intermolecular O–H···O– intermolecular heterosynthons of curcumin and BPNO molecules were observed as the anhydrous cocrystal, see Figure 10b. In 22



addition, the solvent methanol interacts with the C=O of the curcumin via O–H···O hydrogen bonds, which resulted in the β-diketo structure of curcumin. For the first time, the rare β-diketo tautomer of curcumin was observed in this cocrystal; which is generally employed to construct curcumin-metal complexes. These crystal structure data suggest that the metastable β-diketo form (MeOH solvate) transform to stable (enol) form via desolvation process.

(a)

(b) Figure 10. (a) Hydrogen bond between curcumin and BPNO molecules forming 1D chain. (b) O–H···O– hydrogen bonds between curcumin (β-diketo) and BPNO molecules, when MeOH solvents are hydrogen bonded with diketo functional groups of curcumin.83 Gately and coworkers filed a patent no. PCT/US2012/032396 on curcumin cocrystals with 2-aminobenzimidazole and nicotinamide.62 Equimolar mixture of curcumin and 2aminobenzimidazole were ground together with dropwise addition of methylisobutylketone in a ball mill grinder resulted the cocrystal. For curcumin and nicotinamide equimolar mixture, ethylacetate was used as lubricants during ball mill grinding. The stoichiometry (1:1) was confirmed by 1H NMR, XRD, DSC etc. No crystal structures were reported in the patent. 23


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Chava and coworkers explored several cocrystals of curcumin with piperazine (1:1 & 2:1), piperidine (1:1), nicotinamide (1:1), isonicotinamide (1:1 and 1:2), naproxen sodium (1:1) and ibuprofen sodium (1:1) in a patent no. PCT/IB2014/002034.63 Curcumin also forms cocrystal dimorphs with piperazine (1:1). Curcumin–piperazine (2:1) cocrystal was prepared by slurry grinding in MeOH for 4h. Curcumin–piperazine (1:1) cocrystal polymorphs I and II were obtained by slurry grinding the equimolar mixture in acetonitrile for 6h and 24h respectively. The slurry experiments indicated that the Form II was thermodynamically stable cocrystal. Depending upon the time period of the slurry experiments in the same solvents, one can control the expected polymorph outcome. Piperidine cocrystal (1:1) was obtained by slurry grinding in acetonitrile solvent. Curcumin cocrystals with nicotinamide and isonicotinamide were synthesized by dissolving equimolar mixture in n-propyl acetate or ethyl acetate, followed by slow evaporation. Cocrystal with naproxen sodium was obtained from acetone using slurry grinding technique. Sonicating the physical mixture of curcumin and ibuprofen sodium in acetone for 15 minutes resulted the corresponding cocrystal. These cocrystallization experiments indicate that slurry grinding of physical mixture for long time resulted cocrystal formation instead of neat grinding or wet granulation. All these novel cocrystals were confirmed by XRD and DSC and no structural reports on these curcumin cocrystals were published in the patent.

2.4 Eutectic solid forms of curcumin Cohesive interactions may play an important role to form novel eutectic solid forms.4 Similar to cocrystals, the same design principle is extended to eutectics in a broad manner.84 Cocrystals are formed due to adhesive interactions and eutectics are formed when the cohesive interactions are dominant over size/shape mismatched components. Eutectics generally exhibits lower melting endotherm compared to the individual molecules. Hence from the PXRD or FT-IR or ss-NMR patterns, final solid may appear as a physical mixture of individual components; one should look out at eutectic solid forms by determining its melting point. From the binary phase diagram of two components using thermal methods like DSC, one can get the solid evidence of eutectic in a certain stoichiometric ratio of physical mixture. During cocrystals screening with several biologically safe coformers like nicotinamide (NAM), ferulic acid (FA), hydroquinone (HQ), p-hydroxybenzoic acid (PHBA), and L-tartaric 24



acid (TA); novel eutectic solid forms of curcumin were obtained85 (Chart 2). Curcumin and the coformers were taken in an equimolar ratio and ground in a mortar-pestle for 15 min. The resultant solid was characterized by DSC and all the eutectics exhibited lower melting points compared to the individual curcumin and coformers. The stoichiometry of curcumin–coformer eutectics were confirmed by proton integration of each components in 1H NMR spectra. Except thermal studies, other characterization techniques like XRD, ss-NMR, IR, Raman spectroscopy indicated the novel forms as the physical mixture.

Chart 2. Chemical structures of (a) curcumin and eutectic coformers (b) nicotinamide, (c) ferulic acid, (d) hydroquinone, (e) p-hydroxybenzoic acid, (f) L-tartaric acid, (g) salicylic acid and (h) suberic acid.81,85-86 Recently, Sathisaran and Dalvi81 published curcumin–salicylic acid (1:2) as novel eutectic composition, prepared by solid-state grinding. The corresponding eutectic was confirmed from the binary phase diagram (Figure 11) of curcumin–salicylic acid systems using DSC thermograms for different stoichiometric mixtures. The intramolecular hydrogen bonding 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 resulted the eutectic solid form. Curcumin also forms a eutectic (5:1) with suberic acid using EtOH assisted grinding.86

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Figure 11. Binary Phase Diagram of curcumin–salicylic acid (1:2) eutectic. The solidus and liquidus temperatures are shown in open and filled circles.81 2.5 Coamorphous solids of curcumin Coamorphous is a multi-component amorphous phase, which lacks 3D packing arrangement of molecules in the lattice and generally associated by weak and discrete intermolecular interactions between the components.87 Like single component amorphous system, one may think of cocrystal without periodic arrangement as a coamorphous solid phase. Application of coamorphous systems in active pharmaceutical ingredients is a relatively new approach, in which the dual advantage of the drug combination (synergistic effect) and high energy of the amorphous phase (dissolution advantage) are combined to provide an improved pharmaceutical solid dosage form. Here we will discuss a few coamorphous phases of curcumin and their enhanced dissolution rate and pharmacokinetics. To improve solubility and bioavailability of curcumin and combined effect of curcumin (CUR) and artemisnin (ART) in killing plasmodium falciparum in cell culture; Nangia and coworkers attempted CUR–ART cocrystal (Figure 12a). Instead they end up with a novel coamorphous system, which was characterized by XRD (Figure 12b), DSC, ss-NMR and IR.88 The coamorphous solid was synthesized by dissolving (1:1) mixture of CUR and ART in ethanol, followed by fast distillation using a rotavapor. It is surprising that both curcumin and artemisnin are crystalline in nature, but their combination under vacuum resulted high energy coamorphous solid.88 Of course, one cannot exclude the possibility of cocrystals based on 26



variable stoichiometry. Similarly, coamorphous phases of curcumin–lysine62 and curcumin–folic acid86 are reported recently.

(a) (b) Figure 12. (a) Probable intermolecular O–H···O (=C) H-bonds between CUR and ART. (b) XRD comparison of CUR–ART coamorphous solid with the crystalline CUR and ART.88 A coamorphous phase of curcumin–piperazine (CUR–PP, 1:2) was reported by Panga et al. via EtOH-assisted grinding.90 The new solid form was characterized by PXRD (Figure 13), DSC, TGA, FT-IR and

13

C ss-NMR. Depending upon the initial stoichiometry of individual

mixture of CUR and PP taken, one may get CUR–PP (1:1 & 1:2) cocrystals and CUR–PP (1:2) coamorphous system by solvent assisted grinding. The glass transition temperature (Tg) of CUR– PP coamorphous is only 306 K, which makes it challenging to develop as an acceptable pharmaceutical composition. It is expected that N–H···O hydrogen bonds may form between the N–H group of piperazine and the carbonyl group of CUR, which stabilizes the β-di-keto structure of CUR in the amorphous solid.

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Figure 13. PXRD patterns of the CUR–PP system prepared using EtOH-assisted grinding method: (a) CUR, (b) PP, (c) CUR–PP (1:1); (d) CUR–PP (1:2) grinding for 15 min; (e) CUR– PP (2:1) and (f) CUR–PP (1:2) grinding for 30 min.90 2.6 Molecular conformations of curcumin Conformational optimization always occurs for any flexible organic molecule during crystallization process.91,92 The organic molecule with several rotational bonds adjusts in the supramolecular level by slightly twisting its molecular conformations resulted the minimization of lattice energy with the negotiation of a small conformational energy penalty. Curcumin is a good example of conformational polymorph based on flexible seven carbon linkers between two terminal phenyl rings and also flexible hydroxyl and methoxy groups.56 Phenyl rings are slightly twisted from each other in Form 1, compared to Form 2 and 3. The dihedral angle between the least-square planes passing through C4/C7/C8/C9/C10/C11 and C12/C13/C14 in Form 1 is 20.6°, see Figure 14a. In Form 2, among the two symmetry independent molecules, one is almost planar (dihedral angle between two phenyl rings, 9.42°), but another one is little twisted (dihedral angle, 12.6°). The dihedral angle between these planes is 11.8° in Form 3. In DCM solvate,60 the corresponding dihedral angles are 3.9 and 10.3° (Z'=2), which is similar to the metastable forms. Interestingly, curcumin molecules in DCM solvate are planar, but their functional groups orientation is similar as Form 1. Torsional flexibility between two phenyl rings 28



in three polymorphs suggests that curcumin exist as conformational polymorphs. Molecular overlay of several conformers of curcumin are displayed in Figure 14b, which indicates that there is more possibility of curcumin conformations based on orientation of –OH and –OMe groups with respect to the central keto-enol group, which may adjust between angular Form 1 and close to planar Forms 2, 3 and DCM solvate. Except, the six conformers of curcumin polymorphs and DCM solvates, other four conformers of curcumin in cocrystals also exhibit variable torsions along the C5–C14 chains connecting two phenyl rings. Based on the fixed central keto-enol group and the orientation of hydroxyl group, these ten conformers (including β-diketo form) can be divided into four groups such as syn-anti, syn-syn, anti-syn and anti-anti, see Figure 15. For example, hydroxyl groups orientations compared to central keto-enol group are syn-anti position in Form 1. This syn-anti conformer is also observed in DCM solvate and both functional groups (OH and OMe) are in the same direction as Form 1. Form 2 has two different conformations: syn-syn and anti-syn based on the –OH groups orientation only. Except that, there is one more difference: one pair of –OH and –OMe groups orientation are in the opposite direction in one symmetry independent molecule and another pair are in the same direction in another symmetry independent molecule. The anti-syn conformer is also present in Form 3, which supports the similar packing in Form 2 and 3. In CUR–RES cocrystals, curcumin conformation follows the Form 2 orientation (syn-syn) considering –OH groups only, although there is opposite directionality of one pair of OH and OMe groups. Curcumin conformation follows the Form 3 (anti-syn) orientation in CUR–PYR cocrystals. In BPNO cocrystals, curcumin conformation follows syn-syn conformation and again one pair of OH and OMe groups are in opposite direction. Surprisingly, in CUR–BPNO-MeOH cocrystals solvate, curcumin conformations follow anti-anti conformation compared to central βdiketo group. Based on the orientation of both –OH and –OMe groups, these 10 conformations can be divided into two parts: in one part, both –OH and –OMe groups are in the same direction (6/10) and in rest, –OH and –OMe groups are oriented in opposite direction (4/10). Even these 3 curcumin conformations (Form 3/Form 2, CUR–RES, CUR–BPNO) are also different from each other on the basis of both –OH and –OMe groups orientations with respect to the central part of curcumin. Now if we consider the planarity of curcumin molecule, except Form 1, almost all other conformers are close to planarity. Both Form 1 and DCM solvate showed similar 29


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conformation of curcumin, not straight chain moiety. Two symmetry independent molecules in DCM solvate are planar compared to the angular Form 1. To conclude, there are minimum seven conformations of curcumin possible in the literature and many more yet to appear in near future.

(b) (a) Figure 14. (a) Torsional flexibility in curcumin. (b) Molecular overlay of curcumin polymorphs, solvate and cocrystals, which indicates highly flexible curcumin molecule, may offer more numbers of crystalline solid forms.

Form 2a-BINMEQ08—syn-syn

Form 1-BINMEQ02—syn-anti DCM solvate -OJIWOV— syn-anti

Form 3-BINMEQ07—anti-syn Form 2b-BINMEQ08— anti-syn CUR–PYR cocrystal - AXOGOK—anti-syn

CUR–RES cocrystal- AXOGIE—syn-syn CUR–BPNO cocrystal- QUMDEJ —synsyn

CUR–BPNO-MeOH cocrystal - QUMDIN—anti-anti β-diketo form Figure 15. Several conformations of curcumin based on functional groups orientation.

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2.7 Physicochemical properties of curcumin solid forms Generally, polymorphs can improve solubility/dissolution rate of a compound by 2-4 fold and in exception case, solubility ratio may go up to 20-25 fold with respect to the most stable solid phase.66 Sometimes, anhydrous polymorphs have much better solubility/dissolution rate compared to the most stable hydrated forms e.g., anhydrous niclosamide and its monohydrate.93 Curcumin exhibits very poor aqueous solubility (~1 μg/ml) and can’t be detected by HPLC analysis. The equilibrium solubility of curcumin (Form 1) in 40% aqueous EtOH medium is 1.2 g/L. The corresponding solubility of Form 2, Form 3 and amorphous phases are 2.3, 2.6 and 2.1 g/L and partial phase transformation was observed to Form 1 in each case. The intrinsic dissolution rate experiment indicated that the metastable form dissolved 3 times faster than the commercial Form 1 and amorphous phase enabled intermediate dissolution rate.56 Compared to polymorphs, cocrystals with resorcinol and pyrogallol exhibited 5-12 times higher dissolution rate than curcumin alone (Figure 16a).78 Curcumin–hydroxyquinol (CUR–HXQ) cocrystals also showed faster powder dissolution rates than the raw curcumin. CUR–HXQ cocrystals (1:2) exhibited enhanced dissolution rate than corresponding (1:1) cocrystal and it is expected as 2 equivalent soluble coformer (here HXQ) is present in the former.81 Among the eutectics, curcumin–nicotinamide (1:2) eutectic exhibited 10 fold faster dissolution rate compared to curcumin alone possibly due to presence of 2 equivalent nicotinamide as high soluble coformer (Figure 16b).85 All the multi-component eutectic compositions were exceptionally stable at ambient conditions of 30-35 °C and 40±5% RH for over 6 months. The curcumin–artemisnin coamorphous solid dissolved 2.6 times faster than curcumin alone in the aqueous ethanol solution.88 The higher curcumin concentration with AUC0-12h = 3.7 μg.h/ml, which was 2 fold compared to CUR–PYR cocrystal, indicates encouraging strategy to modulate the physicochemical properties of nutraceuticals through coamorphous solid phases.94 Surprisingly, the CUR–LYS coamorphous solid did not improve aqueous solubility in various pH media.62 Among the four coamorphous systems discussed, CUR–PP enhanced dissolution rate compared to curcumin (at 20 °C). However, amorphous form as we expect to follow spring or parachute model5 of dissolution with high solubility ratio (4-14), not observed for these four coamorphous systems. Rather all the coamorphous systems exhibited dissolution behavior similar to amorphous curcumin. Most of the novel solid phases of curcumin transformed to Form 1 during 31


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solubility experiments, which indicated Form 1 is the thermodynamically most stable solid form. In summary, curcumin–nicotinamide eutectic showed the highest aqueous solubility, and would be a promising candidate for further development of curcumin as medicine, provided nicotinamide is a vitamin used as dietary supplements.

(a)

(b)

Figure 16: Intrinsic dissolution profiles of curcumin (a) cocrystals78 and (b) eutectics85 in aqueous ethanol medium, which indicate cocrystal and eutectics can enhance dissolution rate upto 12 fold. 2.7.1 In vivo clinical studies: Along with the solubility/dissolution rate advantage, pharmacokinetics study of curcumin solid forms was carried out by several research groups. Nangia and coworkers demonstrated that CUR–ART coamorphous enabled improved bioavailability than pure CUR at 200 mg/kg oral dosage administration in Sprague Dwaley (SD) rats.94 Remarkably the coamorphous solid exhibited maximum plasma concentration (Cmax = 0.90 μg/mL) within half an hour and very long half-life for curcumin (T1/2 = 7.0 h) compared to curcumin alone (T1/2

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