Co-crystallization and small molecule crystal form diversity: from pharmaceutical to materials applications

Suryanarayan Cherukuvada , Ramanpreet Kaur and Tayur N. Guru Row *
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560012, India. E-mail: ssctng@sscu.iisc.ernet.in

Received 22nd August 2016 , Accepted 19th September 2016

First published on 19th September 2016


Co-crystallization is the supramolecular phenomenon of aggregation of two or more different chemical entities in a crystalline lattice through non-covalent interactions. It encompasses the study of the manifestation of multi-component crystalline solids as well as their design. The chemistry community and the literature suggest cocrystals with reference to co-crystallization products and multi-component crystalline solids. Over the last decade cocrystals have become very popular as a potential new/alternate solid form of pharmaceuticals. However, there is no consensus on what exactly a cocrystal means and what it constitutes across academia, industry and regulatory bodies. On the other hand, cocrystals have been endorsed to the extent that the following facts have been obscured: (1) cocrystals are only one of the putative outcomes of co-crystallization, if at all, and (2) their application goes way beyond pharmaceuticals. Solvates, solid solutions, eutectics, salts, ionic liquids, solid dispersions, supramolecular gelators etc. are among the multifarious products of co-crystallization. The manifestation of these supramolecular/non-covalent crystalline adducts is controlled by the inherent nature of the system (the components involved) besides the surroundings (temperature, solvent, pH etc.); in effect it is a thermodynamic outcome. Each of these adducts, including cocrystals, are unique, exhibit varied physicochemical properties and are amenable to design and therefore have, and potentially find, manifold applications in diverse fields such as organic synthesis & separation, green chemistry, energy storage, solar cells, electronics, luminescent and smart materials, apart from pharmaceuticals. This article highlights the diversity of crystal forms and the utility of small molecule supramolecular combinations.


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Suryanarayan Cherukuvada

Suryanarayan Cherukuvada was born at Kakinada, Andhra Pradesh, India, in 1980. He received his Masters (Biochemistry) from Acharya Nagarjuna University in 2003 and obtained Bachelors (Education) from Andhra University in 2006. He completed PhD (Chemistry) in 2013 at Prof. Ashwini Nangia's Research Group, University of Hyderabad, as an ICMR Research Fellow. He worked as a Dr. D. S. Kothari Post Doctoral Fellow in Prof. T. N. Guru Row's Research Group, Indian Institute of Science, and currently is an independent researcher holding a Start-Up Research Grant from SERB, India. His research activities are in organic and pharmaceutical solid state chemistry.

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Ramanpreet Kaur

Ramanpreet Kaur was born in Patiala, Punjab, India, in 1988. She received her Bachelors (Chemistry Honors) from Panjab University, Chandigarh, India, in 2009. She completed her Masters (Chemistry) in 2011 and PhD (Chemistry) in 2015 from Prof. T. N. Guru Row's Research Group, Indian Institute of Science, Bengaluru, India, as an Integrated PhD student. Currently, she is working as a Post-doctoral Fellow in Prof. Adam Matzger's Research Group, University of Michigan, USA. Her research activities are in pharmaceutical solid state chemistry and material applications of organic multi-component systems.

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Tayur N. Guru Row

Guru Row is Dean (Sciences) and Professor at the Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru, India. He completed Masters from Bangalore University (1971) and PhD from the Indian Institute of Science (1976). After a post doctoral stint at Buffalo, USA, he worked as a Scientist in NCL-Pune, India, and later joined Indian Institute of Science and became a full Professor in 1998. His research interests are charge density analysis of organic and inorganic compounds, halogen bonding and other exotic interactions, polymorphism, in situ cryo-crystallography and photo-catalytic and proton conduction applications. He has authored about 450 research publications and is a recipient of J. C. Bose National Fellowship. He is serving as the Editor of Publications, Indian Academy of Sciences, and Regional Co-Chair, ICDD, USA.


Introduction

Chemistry plays a pivotal role in serving the day-to-day needs of food production, clean water, healthcare, power generation, transport etc., apart from its multitude of applications in terms of new materials and appliances that enhance human comfort.1 In the current age of dwindling resources and the pressing global need for sustainable development,2 the value of chemistry and chemistry research in the conservation/judicial use of resources3,4 perhaps has higher significance than ever before. This context necessitates the development of methodologies that tap the full potential of existing materials to generate improved/new materials and thus create new opportunities to address diverse challenges. In pharmaceutical chemistry, the multi-target approach of developing a single drug that can bind to multiple targets is being increasingly appreciated/pursued5–7 rather than developing multiple drugs that bind different targets in treating a particular disease.8 Developing a salt9 or an amorphous solid dispersion10,11 is a conventional and alternate chemical approach to enhance the solubility of a low-soluble drug compared to the laborious synthetic approach of making a more soluble drug candidate.12 Co-crystallization is another such chemical approach that targets the design and development of a variety of new multi-component crystalline solids, viz. cocrystals, salts (molecular), salt cocrystals, solvates, solid solutions, eutectics etc., from existing materials to cater for diverse/multiple applications in different fields.13–37 A given molecular (organic) material can be combined with other suitable materials to manifest different co-crystalline solids for various purposes. For instance, co-crystallization studies on the anti-tuberculosis drug molecule isoniazid resulted in (i) its cocrystals having higher solubility and stability than the pure drug,38–41 (ii) its eutectics showing a greater dissolution rate38 and (iii) a hydrated mixed-ionization complex which exhibits proton conduction28 and dielectric properties.42 This shows that one can utilize co-crystallization methodology to produce multifarious crystalline solids not only for different materials but also for a given material and provide manifold applications in areas such as pharmaceuticals and materials (as is the case with isoniazid) among others.

Significance of co-crystallization

The advantages of co-crystallization and its products are many fold: (i) Novelty/diversity: each of the solid forms that can be obtained from co-crystallization are unique in terms of both structure and property.43 (ii) Non-obviousness: The understanding of the manifestation of these diverse solid forms is in itself a fundamental problem that needs to be addressed in order to achieve a desired solid form with desired properties in a desired way.43,44 (iii) Utility: All these solid forms exhibit varied physicochemical properties, by virtue of their uniqueness, which in essence can be exploited for specific as well as wide-ranging applications.43,45 (iv) Multiplicity: As for an estimate of the number of ionic liquids, one of the products of co-crystallization (in a limited scope as discussed later), as many as 106 possible ionic liquids can be made if all currently known cations and anions are paired, and the number goes to 1018 if all ternary combinations were to be considered.46,47 If one takes into account the hundreds of thousands of organic compounds along with their ever-increasing library in multinary combinations, the exponent shoots even more geometrically to result in a myriad of co-crystallization products; such a multiplicity cannot possibly be achieved with combinations involving inorganic materials or metals. (v) Greenness: The availability of hundreds of bio-organic compounds and natural products as raw/starting materials for co-crystallization and relatively less demanding synthetic procedures allows for the saving of energy, effort, money and time and thus provides a greener43,45–51 and more sustainable approach compared to organic synthesis. Altogether, the most significant and attractive aspect of co-crystallization is the promise of generating a multitude of functional materials from the available simple organic compounds.

Is co-crystallization limited to cocrystals?

Until recently, many of the studies on co-crystallization have been devoted to cocrystals and their the applications to pharmaceuticals. This situation can be attributed to the advent of ‘High Throughput Combinatorial Medicinal Chemistry’,52 in the 1990s in the drug discovery arena, which led to non-ionic and hydrophobic candidate molecules53 and therefore the need to develop technologies that can enhance the solubility of the candidates in lieu of salts.54,55 Coincidentally, this paralleled the budding interest in design concepts that bring together two different molecules into a crystalline lattice using non-covalent interactions, particularly hydrogen bonds.13,14,56,57 This concept has been popularized as ‘co-crystallization’ and the crystalline entity designed to contain two or more different molecules has been termed a ‘cocrystal’.58 Being easy to comprehend, both these terms found rapid and widespread assimilation into the chemistry community with respect to supramolecular solid state synthesis.15–28,59 Consequently, the majority of the investigations, articles, reviews and books focussed on co-crystallization aspects related to cocrystals.15–28,38–41,44,45,48–51,54,60–83 Their appreciation has been such that (i) it overshadowed the usage of the term ‘co-crystallization’ in multi-component crystallization of macromolecules (proteins, polymers etc.)58,84–86 and inorganic materials,58,87 respectively and (ii) the term ‘cocrystal’, as derived from ‘co-crystallization’, has been considered to be the sole purpose and the putative outcome of a co-crystallization experiment.33 Thus, there is a clear need to emphasize the broad horizons of ‘co-crystallization’ in terms of form (crystal form diversity beyond cocrystals) and function (a wide array of applications beyond pharmaceuticals). We deal with these in this article. See Scheme 1 for a depiction of the matters discussed. Since the scope of the terms ‘co-crystallization’ and ‘cocrystal’ is too exhaustive to comprehend,58 herein we restrict the discussion to the diversity of solid forms exhibited by binary combinations involving small molecules. The intent of this article is to provide in a nutshell the current status of research activity and progress in this area. Thus, what we cover will be the tip of the iceberg and in-depth details can be found in the references cited. We represent the terms ‘co-crystallization’ and ‘cocrystal’ with and without a hyphen respectively as per the semantics interpreted independently by Patrick Stahly88 and Babu et al.89
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Scheme 1 (a) Various outcomes from co-crystallization of molecular materials. (b) An array of applications made possible through the co-crystallization approach.

What prompts co-crystallization and its varied outcomes?

Co-crystallization is such a phenomenon that even compounds that are not polymorphic (to date) tend to co-crystallize, as observed in the cases of benzoic acid and urea.90 Patrick Stahly observed that the propensity for the formation of multi-component crystals is almost double that of polymorphs among organic compounds.88 Hydration/hydrate formation is a very common type of co-crystallization wherein the water of crystallization associates with a different chemical entity through non-covalent interactions in the crystal lattice. It is observed in all kinds of chemical substances: viz. inorganic, organic, coordination, organometallic, clathrate, bio- and synthetic polymers etc. The prevalence of solvation (solvent incorporation in a crystal) is as much as 43% among the reported binary organic crystals in the Cambridge Structural Database (CSD),90 according to the latest survey by Grothe et al.91 The hydration issue of the popular psychoactive drug ‘caffeine’ was one of the first case studies investigated for the application of co-crystallization92 to address, interestingly, co-crystallization with water. Caffeine is found to be disordered in its crystalline state (in both polymorphs)93 but upon hydration (formation of a hydrate crystal)94 the molecule becomes fully ordered (Fig. 1). Remarkably, the molecule oxalic acid, which is again prone to exist as a dihydrate,90,95 resolves the disorder of caffeine in their cocrystal92 (Fig. 1d). The caffeine–oxalic acid cocrystal is anhydrous and further resistant to hydration. Thus, the formation of hydrate respectively for caffeine and oxalic acid and also the caffeine–oxalic acid cocrystal can be considered to be some kind of free energy minimum, if not the global minimum, on the corresponding crystal energy landscapes of caffeine and oxalic acid. The crystal landscape is a profile of the structural and energetic changes that take place during crystallization and represents the different local minima possible (ranging from polymorphs to multi-component adducts) in arriving at the most stable solid state assembly (the global minimum, which may never be reached) of a system.96–106 Thus, essentially, it is the manifestation of thermodynamics, the outcome being dependent both on the inherent nature of the system involved and on its interaction with the surroundings. In the case of caffeine, both its dimorphs are manifested with disordered caffeine molecules and weak intermolecular (C–H⋯O and C–H⋯N) interactions.93 Exposure of caffeine to an aqueous environment/oxalic acid results in its facile transformation to hydrate/cocrystal form, since the weak cohesive interactions are replaced by strong adhesive ones (O–H⋯O and O–H⋯N) with further disorder of caffeine molecules being resolved92,94 (see Fig. 1). Here, the nature of the system (to resolve disorder and become more stable) has driven it to hydrate/co-crystallize. On the other hand, for caffeine or any material having the tendency to hydrate, one can resist this by insulating the material. Here, the surroundings exercise control on the reactivity of the system. Thus, the system is made to react differently to different conditions (external) to arrive at a particular minimum (here the crystal form) in the landscape. With an increase in the diversity of the surroundings (external elements), the landscape of the system becomes more rugged (activation barriers) thereby manifesting more pits (energy minima). This means that by manipulating or designing the external components, it is possible to obtain diverse crystal forms such as salts, solid solutions, eutectics, ionic liquids, solid dispersions, supramolecular gelators etc., apart from cocrystals and solvates, for a given system (as will be discussed later). All these varied multi-component systems are supramolecular/non-covalent crystalline adducts and can be deliberately obtained by co-crystallization. Further, there is a possibility of formation of mixed adducts such as salt cocrystals, cocrystal solvates, salt solvates and salt cocrystal solvates, apart from polymorphs and multiple stoichiometries of these adducts, mixed-ionization complexes and, intriguingly, polymorphs of individual components or a concomitant mixture of any these during co-crystallization.21,22,28,40,48,78,98–103,107–115 Caffeine has been shown to form, both deliberately and indeliberately, several other cocrystals including polymorphic cocrystals,48,92,116–118 salts,119 eutectics120 and a solid solution,117 all of which represent different free energy minima on caffeine's crystal landscape. Altogether, co-crystallization takes place both naturally and by design.
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Fig. 1 Asymmetric unit of caffeine dimorphs (a and b) (CSD (ref. 90) refcodes: NIWFEE05 and NIWFEE04), (c) 0.8 hydrate (CAFINE) and (d) cocrystal with oxalic acid (GANXUP). Disorder of caffeine in its polymorphs is resolved upon hydration/co-crystallization. Capped stick style is used for dimorphs and ball and stick for hydrate/cocrystal. CPK colors are used for all atoms except hydrogen for which sky blue is used.

An understanding of the supramolecular solid state is the crux to design concepts in co-crystallization, especially for cocrystals and of late for solvates, ionic liquids, supramolecular gelators and eutectics (discussed next). In the case of caffeine, it is of particular interest to note that the higher symmetry trigonal polymorph of caffeine is a metastable one with the monoclinic form being the stable one at ambient temperature (both are enantiotropically related).93,94 Additionally, all the cocrystals of caffeine belong to either the monoclinic or the triclinic space group.92,116–118 This brings in the role of close packing and directional intermolecular forces and their interplay in the outcome of co-crystallization. In general, awkward molecular shapes (typical of organic molecules) and strong intermolecular interaction geometries do not allow molecular packing in higher crystal symmetries.15 The enthalpic loss facilitated by non-covalent interactions such as strong hydrogen bonds, between the components, compensates for close packing in salts and in a good number of cocrystals and solvates (the thermodynamic aspects are discussed in the penultimate section). As such, these adducts exhibit different crystal packing compared to their parent materials owing to the structure-directing supramolecular (heteromolecular) interactions:33,121e.g. a caffeine–oxalic acid cocrystal and caffeine hydrate are distinct in their crystal structures. Entropy gain is the factor that drives the manifestation of solid solutions, eutectics etc.,15 which retain the crystal packing of their parent components: e.g. the caffeine–theophylline solid solution is isostructural with the caffeine trigonal polymorph.117 The comprehension of why certain combinations result, say, in cocrystals, some in solvates and others in eutectics etc. and the underlying design principles in their manifestation lies in understanding the supramolecular solid state assembly.

Supramolecular solid state and co-crystallization by design

The theme of supramolecular solid state has its roots in the correlation between ‘supermolecules and molecules’ observed by Jean-Marie Lehn as “supermolecules are to molecules and the intermolecular bond what molecules are to atoms and the covalent bond”.122 Jack D. Dunitz has extended this concept to the crystalline state by appreciating a “crystal as a supramolecular entity” and a “crystal as the supramolecule par excellence”.123 These concepts signify that if molecules are built by connecting atoms with covalent bonds, supermolecules/crystals are built by connecting molecules with intermolecular interactions. Thus, the identification of a crystal as a supermolecule can be considered as a ‘paradigm shift124 in supramolecular solid state chemistry since it showed that some fundamental properties, as simple as the melting point, of a compound are not controlled by the molecular structure but by the crystal structure.15 For instance, crystal polymorphs exhibit different physicochemical properties—viz. melting point, compressibility, solubility, stability, bioavailability etc.—owing to differences in supramolecular organization.125 An understanding of how molecules recognize/interact with each other and the factors determining differential molecular arrangements in the crystal lattice leading to different properties is thus crucial for desired applications and this forms modern crystal engineering.126 Gautam R. Desiraju's ‘supramolecular synthon57 concept in crystal engineering is a reductionist approach which dissects the crystal network to a molecular level so as to appreciate molecular recognition and binding phenomena with the ultimate goal of designing novel and functional solid materials. Functional groups of a compound play a major role in the supramolecular aggregation and depending on the type of functional groups involved in the interaction/assembly, supramolecular synthons are categorized into two kinds:127 (i) a homosynthon, wherein the same functional groups interact (e.g. carboxylic acid/carboxamide dimers), and (ii) a heterosynthon, in which two different groups (e.g. acid–amide and acid–pyridine dimers) associate (Scheme 2).
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Scheme 2 Some supramolecular synthons with their frequency of occurrence in the CSD.128–131

A cocrystal, as mentioned before, is a distinct supramolecular adduct formed by heteromolecular interactions. Thus, for a cocrystal to form, the homomeric (cohesive) interactions of the materials combined should be replaced by heteromeric (adhesive) interactions.33,34 For instance, if one has to design a cocrystal for a molecule having a carboxylic acid group, a different molecule containing a carboxamide or pyridyl group should be combined with the molecule of interest. As a carboxylic acid–carboxamide or carboxylic acid–pyridine heterodimer synthon is dominant over a carboxylic acid homodimer synthon (Scheme 2), the combination can result in a cocrystal. In contrast, if one has to design a eutectic, materials that can form strong heteromolecular synthons should be avoided so that the homomeric interactions are largely sustained with the feasibility of only finite/discrete heteromers in the crystal lattice.33,34 For example, the combination of succinamide–isonicotinamide forms a eutectic (discussed later) since the system has a weak carboxamide–pyridine heterosynthon that cannot outcompete the stronger carboxamide homomeric interactions. Thus, the differences in the manifestation of supramolecular synthons result in the formation of different crystal forms, each of which, being unique, exhibits distinct physicochemical properties. Accordingly, all these solid forms facilitate diverse/customized applications, rendering them useful in different settings. Hence, understanding their nature and manifestation and attaining design control over them paves the way to exploit their full potential for a variety of tasks. Herein, we illustrate the issues related to the design and formation of various multi-component supramolecular adducts and their applications, beyond the pharmaceutical field, as depicted in Scheme 1.

Multi-component supramolecular family and their applications

I. Cocrystal

The popularity of co-crystallization can undoubtedly be attributed to cocrystals and their pharmaceutical applications in terms of modulating the solubility, stability, melting point, compressibility, bioavailability etc. of drugs.15,20,21,45,54,60–83 Owing to their fundamental and practical significance, no other member of the supramolecular family (see Scheme 1a) has attracted such a wide interest in as little time from crystallographers, chemists, theoreticians and pharmaceutical scientists, around the globe. Within a decade of active research,20,82 the importance of cocrystals has been appreciated by the United States Food and Drug Administration (US-FDA)132 and the European Medicines Agency (EMA)133 for pharmaceutical purposes. This can be viewed as ‘the end of the beginning134 since the implications of cocrystal research have gone way beyond. It paves the way towards a superior understanding of intermolecular interactions and the crystallization phenomenon itself and thus augments efforts in the ultimate goal of making desired solid forms with desirable properties.34 To quote a lead, attempts to make cocrystals have resulted in (i) new polymorphs of many compounds,110–113 (ii) solvates,68 (iii) eutectics38,120 and (iv) solid dispersions135,136 respectively, in various systems, each of which have their own importance. On the other hand, cocrystals have been shown to be new materials with potential applications in organic separation, energy storage, optoelectronics, and luminescent and smart materials.23–28,137–151 Thus, both fundamentally and utility wise, understanding the phenomena that lead to cocrystals is beneficial. Many excellent reviews dealing with the design & synthesis and pharmaceutical applications of cocrystals are available in the literature.45,54,62,64,67,71,77,81–83 Herein, we will discuss the energetics of cocrystal formation followed by material applications of cocrystals. Since the term ‘cocrystal’ is too broad, as stated earlier, the discussion is reserved for the more popular crystalline complexes of small molecules. Before going into these matters, we first briefly discuss the important phenomenon of the salt-cocrystal continuum108 which is also a lead into the electron/proton conduction and ferroelectric/dielectric applications of cocrystals.
Salt-cocrystal continuum. A salt is well-known as an ionic compound and a cocrystal had been well-accepted as a neutral (un-ionized) molecular crystalline complex.71,108 It is often encountered that co-crystallization of an acid with several bases (a homologous series or structurally related ones) or vice versa results in various acid–base crystalline complexes: viz. salts (molecular), cocrystals, mixed-ionization complexes (a partial proton transfer case) and salt cocrystals (having both ionized and unionized species).108,109,152–154 Thus, salt and cocrystal are considered to be the two extremes of a continuum with intermediate structures such as mixed-ionization complexes and salt cocrystals being possible. These varied products arise due to relative ΔpKa (pKa of base − pKa of acid) differences among the combinations subjected to co-crystallization. Since pKa is related to equilibrium behavior in aqueous solution, the manifestation of a particular adduct depends on the solvent used, supersaturation, temperature, etc. According to the ΔpKa rule,9,108,109,153–159 a rule of thumb is that a salt can form when ΔpKa > 3 and a cocrystal when ΔpKa < 0. When ΔpKa lies between 0 and 3, limits recently extended from −1 to 4 by Cruz-Cabeza,158 the formation of a particular adduct is unpredictable and is quoted as a ‘grey area’.156 Since the ratio of concentrations of ionized and unionized species decreases from 1000 fold and attains equilibrium as the ΔpKa comes down from 3 to 0, there is equal probability for all four kinds of adducts mentioned above crystallizing out. Consequently, one can see different adducts even for the same combination e.g. 1[thin space (1/6-em)]:[thin space (1/6-em)]1 salt and 1[thin space (1/6-em)]:[thin space (1/6-em)]2 salt cocrystal of maleic acid–cytosine160,161 (Fig. 2), 1[thin space (1/6-em)]:[thin space (1/6-em)]1 salt and 1[thin space (1/6-em)]:[thin space (1/6-em)]2 salt cocrystal of pyridoxine–p-nitrobenzoic acid,162 dimorphic mixed-ionization complex of pyrazinoic acid–isonicotinamide.163 The formation of a cocrystal for formic acid–pyridine at 1[thin space (1/6-em)]:[thin space (1/6-em)]1 combination and a salt at 4[thin space (1/6-em)]:[thin space (1/6-em)]1 combination was analyzed very recently by Pratik and Datta, on the basis of periodic DFT calculations.164 The first example to illustrate that the same 1[thin space (1/6-em)]:[thin space (1/6-em)]1 combination can manifest both as a molecular salt and as a cocrystal was reported by Xue Fu et al.,165 very recently, for ‘sulfamethazine–saccharin’ (Fig. 3). This excellent case, especially as an indisputable pharmaceutical combination, effectively counters any criticism/opinion that a cocrystal is not equivalent to a salt both fundamentally and practically. The drug prescribed for the treatment of apnea of prematurity in infants is ‘caffeine citrate’118 which is administered as an injection or an oral liquid.166 Although the name of the medication sounds like a salt and one may think that it may exist in ionic form in the liquid state, the drug actually exists as a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 dimorphic cocrystal118 in the solid state (Fig. 4). Further, the negative ΔpKa value of −2.61 between caffeine (pKa = 0.52) and citric acid (pKa1 = 3.13)167 supports cocrystal formation and not a salt for the combination. However, caffeine citrate is generally treated as a salt in the literature.168 The salt cocrystals ‘valproic acid sodium valproate’169–171 and ‘escitalopram oxalic acid oxalate’172 (Fig. 5) are the marketed solid forms of the drugs ‘valproic acid’ and ‘escitalopram’, respectively.77,82 Altogether, the inter-relationship and overlap of salt and cocrystal has been well-established so that an evolved definition for cocrystals, which can even encompass salts, salt cocrystals, solvates etc., emerged from an Indo-US group173 in 2012 as follows: “cocrystals are solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio”.
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Fig. 2 (a) 1[thin space (1/6-em)]:[thin space (1/6-em)]1 salt and (b) 1[thin space (1/6-em)]:[thin space (1/6-em)]2 salt cocrystal of maleic acid–cytosine combination (CSD refcodes: ROFLAZ and DUJCAN) with the latter manifesting both ionized and unionized cytosine molecules.

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Fig. 3 Sulfamethazine–saccharin (a) cocrystal (with intact saccharin) and (b) salt (with deprotonated saccharin). Salt was reported earlier by Enxian Lu et al.174 (CSD refcode: XOBCOH) and Xue Fu et al.165 reported both salt and cocrystal (CCDC no. 1416185 and 1437001) recently.

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Fig. 4 (a) Two-point and (b) single-point carboxylic acid–imidazole interaction in caffeine–citric acid cocrystal dimorphs (CSD refcodes: KIGKER and KIGKER01), respectively.

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Fig. 5 (a) Valproic acid sodium valproate and (b) escitalopram oxalic acid oxalate salt cocrystal hydrates (CSD refcodes: SITXID and SETVUJ) manifest both unionized and ionized moieties (carboxylic acid and carboxylate), respectively. The former is a coordination polymer with symmetry-independent sodium ions (violet) in penta- and tetracoordination.
Energetics of cocrystal formation. The identification of a suitable partner molecule, popularly called a cocrystal former or coformer,62,71 is the key to successfully making a cocrystal, or for that matter any supramolecular adduct, with the molecule of interest. The manifestation and design of cocrystals look simple but is a complex problem in crystal engineering, although a certain degree of success has been achieved on various fronts, including making five-component crystals.17,34,40,82,92,155,175–179 This can be exemplified by three cases in the literature: (i) the simple benzoic acid–benzamide combination, which could be thought to result in a cocrystal through a carboxylic acid–carboxamide heterosynthon, actually makes a eutectic.33,180–182 (ii) In terms of energetics, the lattice energy values of the majority of the cocrystals were calculated to be lower, albeit marginally, than the sum of their component lattice energies, meaning that cocrystals are more stable than their components and thus thermodynamically facile to form.97,183,184 However, the manifestation of a salicylic acid–benzamide cocrystal happens via a positive enthalpy of formation.182 (iii) Although thermodynamically favored, it has taken a mammoth effort by four research groups to obtain the cocrystal of the caffeine–benzoic acid combination.185 In the case of the benzoic acid–benzamide system, due to the lack of additional acceptor groups for auxiliary interactions, hetero-supramolecular growth beyond carboxylic acid–carboxamide heterodimers cannot take place, with the result that the combination forms a eutectic and not a cocrystal33,182 (Fig. 6a). In the salicylic acid–benzamide case, the presence of a hydroxyl group facilitates the propagation of acid–amide heterodimers through auxiliary C–H⋯O interactions, so that the combination makes a cocrystal (Fig. 6b). It is interesting to note that both benzoic acid–benzamide and salicylic acid–benzamide systems were calculated to have positive values of enthalpy of formation, by Colin Seaton et al.,182 indicating that the systems do not have the energetic drive to form respective cocrystals. However, the latter system forms a cocrystal and was opined to be entropically favored. This was reflected in the positive enthalpy of fusion (24.71 kJ mol−1) and lower melting point for the cocrystal compared to its parent components (m.p. cocrystal 118 °C, salicylic acid 160 °C, benzamide 128 °C).182 This example shows that although it may be reasonable to think that cocrystal formation happens via enthalpic loss (or free energy minimization) owing to the replacement of homomeric by heteromeric interactions,184,186 it is not always the case that the crystal lattice energy should be minimal for a cocrystal to form. The same was also observed in several systems by Sarah Price and others.97,183,187 Thus, cocrystal formation may be enthalpically or entropically driven and a cocrystal may accordingly be stable or metastable in comparison to its parent materials. On the other hand, the four research groups led by Dejan-Krešimir Bučar185 found from their lattice energy calculations that the formation of a cocrystal for the caffeine–benzoic acid combination is thermodynamically favorable (by >10 kJ mol−1 as compared to the pure constituents). However, the system failed to form a cocrystal even after the components were subjected to numerous co-crystallization experiments employing neat grinding, liquid-assisted grinding, sonic slurry and solution-mediated phase transformation techniques. The first but unsuccessful attempt to make its cocrystal can be traced back to 1961, where Keiji Sekiguchi120 reported eutectic formation for the combination (Fig. 7a). Finally, after a lot of time and effort, Bučar et al. were successful in making a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 cocrystal by ingeniously employing a heteronuclear seeding technique.185 They hypothesised that the manifestation of a caffeine–benzoic acid cocrystal might be hindered by a high activation barrier which could be overcome by using a heteronuclear seed that matches the cocrystal either structurally or epitaxially. As such, 1[thin space (1/6-em)]:[thin space (1/6-em)]1 caffeine–fluorobenzoic acid cocrystals as heteroseeds facilitated the formation of a caffeine–benzoic acid cocrystal. The intriguing behavior of the caffeine–benzoic acid combination, forming a eutectic as well as a cocrystal in independent experiments, was very recently appraised by Cherukuvada188 (through phase diagram analyses, Fig. 7b and c) and points towards the necessity for a greater understanding of the energetics of co-crystallization which exercise control over the outcome of co-crystallization.
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Fig. 6 (a) The lack of acceptors for CH donors in the benzoic acid–benzamide system restricts the extension of acid–amide heterodimers such that the system cannot grow as a cocrystal and instead forms a eutectic. Reproduced from ref. 33 with permission from the Royal Society of Chemistry. (b) The phenolic group of salicylic acid is involved in C–H⋯O interactions in both b and c directions and thus propagates the acid–amide heterodimers to result in a cocrystal for the salicylic acid–benzamide system (CSD refcode: URISAQ).

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Fig. 7 Temperature-composition phase diagrams of the caffeine–benzoic acid system as reported by (a) Sekiguchi (reproduced in part with permission from Yakugaku Zasshi, vol. 81 (ref. 120). Copyright 1961 The Pharmaceutical Society of Japan) and (b & c) by Cherukuvada (“J. Chem. Sci., 2016, 128, 487 (ref. 188), copyright 2016, with permission of Springer”). The former two depicting the characteristic ‘V’-type pattern represent the eutectic phase obtained from straightforward (unseeded) co-crystallization experiments. The latter one with ‘W’-type pattern is the characteristic of cocrystal phase obtained from heteronuclear seeding experiments of the combination.
Material applications of cocrystals. The potential of cocrystals for material applications was successfully investigated before pharmaceutical applications took centre stage. The earliest examples studied were donor–acceptor (DA) or charge transfer complexes towards producing highly conducting organic materials.137–139 John Ferraris et al.,137 in 1973, reported a complex between the strong electron donor molecule tetrathiafulvalene (TTF) and the strong electron acceptor molecule tetracyanoquinodimethane (TCNQ), showing electrical conductivity of the order of a metal (106 S m−1), making it the first organic metal (TTF-TCNQ).139 Further chemical modifications on TTF led to tetraselenafulvalene (TSF, an analogue of TTF) and its derivative tetramethyl-TSF (TMTSF), using which Klaus Bechgaard et al.138 made the first organic superconductor ‘di-tetramethyltetraselenafulvalenium hexafluorophosphate’ ([TMTSF]2PF6) and other superconducting salts (Curie temperature, Tc = 1–2 K) in 1980, since when they have been regarded as Bechgaard's salts.139 Both the organic conductors manifest segregated stacks/sheets of cations (TTF/TMTSF radical cation) and anions (TCNQ/PF6) which lead to high conductivity along the sheets when intermolecular electron transfer takes place. Such intermolecular electron transfer also causes molecular displacement, resulting in ‘displacive-type’ ferroelectric behavior, as found in TTF complexes of p-bromanil and p-chloranil, respectively.140–142 These complexes show a mixed stack arrangement (unlike the discrete stacking of cations and anions in previous organic conductors) wherein the component molecules follow a non-polar DA DA… pattern. The neutral-ionic (NI) phase transition at low temperature means that the ionized molecules form dipolar DA dimers (DA DA… and AD AD…), breaking the symmetry and facilitating ferroelectric ordering by the transformation of a centric to an acentric space group.142 During the late 1980s, Margaret C. Etter's group, using hydrogen bonds, pioneered the design of acentric organic solids, in both single-component and multi-component (the first cocrystals by design) forms, towards making non-linear optical materials.13,14,58,143 Her group made an ample number of acentric cocrystals based on the feasibility of formation of one-dimensional (1D) polar hydrogen bonded chains involving nitro-amino groups, among other functional group combinations. In 2005, Sachio Horiuchi et al.144 showed that strongly hydrogen bonded cocrystals can show room temperature ferroelectricity and facilitate the making of all-organic electronic devices. They exploited the strong hydrogen bonding possible between phenolic hydrogen and pyridyl nitrogen (O–H⋯N interactions) in chloranilic/bromanilic acid–phenazine (acid–base) combinations to form cocrystals. The infinite DA alternating chains and aromatic π-stacks along the b-axis (Fig. 8a) in the cocrystals allows them to exhibit high anisotropy and consequent high dielectric constant (κ exceeding 100) at room temperature. This ferroelectric polarization follows the Curie–Weiss law and increases more than 20 fold (κ = 2000 to 3000) at the Curie temperature, where the cocrystals convert from a centric (paraelectric phase) to an acentric (ferroelectric phase) space group at low temperature.142,144 Recently, our group has uncovered proton conduction28 and dielectric/ferroelectric behavior42 in a hydrated mixed-ionization complex, between gallic acid and isoniazid, which exhibits a noncentrosymmetric structure. The proton conduction and ferroelectric properties were explained based on the proton dynamics between acid and base molecules and a long-range proton transfer mechanism (Grotthus mechanism) involving lattice water (Fig. 8b). In the area of organic separation, co-crystallization was found to be a reliable technique, as shown by chiral resolution and product purification applications. Minor R. Caira et al.145 have resolved the racemic compound 4-amino-p-chlorobutyric acid into its enantiomers by combining the racemate with (2R,3R)-(+)-tartaric acid and effecting cocrystal formation of the latter with R-isomer. The utility of co-crystallization in the separation of desired products from a process such as fermentation was successfully demonstrated through a cinnamic acid-3-nitrobenzamide cocrystal by Johan Urbanus et al.26 Of late, interest in organic materials as optoelectronic, luminescent, sensor, smart materials etc., has gathered momentum. Dongpeng Yan et al.27 tuned the luminescent properties of 1,4-bis-p-cyanostyrylbenzene in terms of multiple colors, fluorescence emission, enhanced lifetime and quantum yield by the formation of several hydrogen- and halogen-bonded cocrystals. Ming Dong et al.146 have shown that the detection of explosives such as 2,4,6-trinitrophenol (picric acid) is possible based on the colorimetric and fluorescence response when the compound co-crystallizes with suitable partners. A new set of cocrystals termed ‘energetic cocrystals’ has emerged from Adam J. Matzger's group24,147,148 with respect to modulating the sensitivity, stability and detonation power of explosive chemicals such as TNT, HMX, and CL-20. An illustrious example of a cocrystal that can be designated as a smart material was identified by Morimoto and Irie.23 The cocrystal of a diarylethene derivative and perfluoronaphthalene exhibits remarkable photomechanical behavior of rapid and reversible bending in a wide temperature range and a capacity to lift metal balls (Fig. 9) 600 times heavier than itself. For solar cell applications, the significance of cocrystals as efficient components of luminescent solar concentrators (LSCs) was exemplified by Griffini et al.25 through an anthracene–tetracene cocrystal. All in all, cocrystals exhibit ubiquitous applications149–151,189–193 and show promise to become reliable organic solids for materials applications, as evidenced by their success in the pharmaceutical field.
image file: c6ce01835a-f8.tif
Fig. 8 (a) In phenazine–chloranilic/bromanilic acid cocrystals, the infinite DA alternating chains and aromatic π-stacks along the b-axis results in high anisotropy/dielectric constant in both room temperature (paraelectric/centric) and low temperature (ferroelectric/acentric) phases with the latter having a very high value. Reprinted by permission from Macmillan Publishers Ltd: Nat. Mater., 2005, 4, 163 (ref. 144), copyright 2005. (b) Grotthus mechanism of proton conduction in hydrated mixed-ionization complex of gallic acid and isoniazid. Reprinted with permission from R. Kaur et al., Cryst. Growth Des., 2014, 14, 423 (ref. 28). Copyright 2014 American Chemical Society.

image file: c6ce01835a-f9.tif
Fig. 9 Photomechanical work of crystal cantilever made of 1,2-bis(2-methyl-5-(1-naphthyl)-3-thienyl)perfluorocyclopentene-perfluoronaphthalene cocrystal. Bending of crystal cantilever (weighing 0.17 mg) and its subsequent lifting of a 2 mm lead ball (weighing 46.77 mg) upon UV irradiation. Reprinted with permission from M. Morimoto and M. Irie, J. Am. Chem. Soc., 2010, 132, 14172 (ref. 23). Copyright 2010 American Chemical Society.

II. Solid solution

A solid solution is one of the crystalline phases that comprise a range of stoichiometries of a particular combination wherein a component is incorporated substitutionally in the host lattice of another component.15,31–33,194–196 As the name indicates, it is a solution in a solid/crystalline state formed between materials having compatibility in terms of similar size, shape or crystal structure such that they can exhibit unlimited solubility/miscibility to result in a series of homogeneous crystalline phases. The relative composition of constituents in a solid solution is established by X-ray crystallography and phase diagram analysis.32,33,194,195,197 Since the constituents randomly occupy equivalent crystallographic sites, there will be a substitutional or positional disorder that is fixed by site occupancy refinement which in turn gives the composition of a solid solution (Fig. 10a). Continuous solid solutions exhibit intermediate melting points, in general, with outliers not uncommon, which are graded according to their compositions between the parent materials in the phase diagram32,194,195,198–200 (Fig. 10b). A solid solution usually adopts the crystal structure of the major component with the constituents being called major (solvent) and minor (solute) components. The manifestation of solid solutions in organic materials is well-known likewise to their inorganic counterparts. That similarity between the molecular structures in the combination results in solid solutions among molecular crystals was identified by Kitaigorodsky's group for the anthracene–acridine combination.194,201 The notion of continuous solubility was also reviewed by Kitaigorodsky,194 including a notable example of naphthalene-2-R-substituted naphthalene (R = F, Cl, Br, OH, SH, NH2, CH3) combinations originally investigated by Chanh and Haget-Bouillaud.202 It was observed that complete miscibility is a rare phenomenon and further isolating the entire series of solid solutions or a desired composition is difficult. However, based on the Hume-Rothery rules (similar size, valence, electronegativity and crystal structure)194,195 for making solid solution alloys of metals, an isomorphous (same space group and unit cell dimensions and/or almost the same type and position of atoms or functional groups)203 and/or isostructural (having the same structure but not necessarily the same unit cell dimensions)204,205 relationship between molecules has been established in the design of organic solid solutions. Using these attributes, various kinds of solid solutions have been designed: from binary to quaternary solid solutions31,32,194,206–209 and solid solutions between cocrystals32,198,199,210 and salts200,211,212 independently (Table 1). Recently, the first examples of solid solutions between the organic liquids thiophenol and selenophenol (Fig. 11) were reported by our group.213 In terms of applications, organic solid solutions can enable a continuum of physicochemical properties,82 but they have not been much explored, with only few examples being investigated to modulate thermal behavior (melting point32,198,199 and phase transition212). A very recent example of a solid solution, formed from cocrystals, enhancing the pharmacokinetic profile of a drug molecule210 demonstrates the potential utility of solid solutions.
image file: c6ce01835a-f10.tif
Fig. 10 (a) A solid solution, in general, features a single entity (disordered) in the asymmetric unit since the components occupy same crystallographic sites, as exemplified by benzoic acid-p-fluorobenzoic acid solid solution.31 The composition of the solid solution is resolved by site occupancy refinement of the disordered position. The occupancies of hydrogen (blue) and fluorine (yellow), shown in the red circle, were found to be 0.268 and 0.732, meaning the manifestation of 1[thin space (1/6-em)]:[thin space (1/6-em)]3 solid solution for benzoic acid-p-fluorobenzoic acid combination (CSD refcode: SATHOK). (b) A phase diagram schematic of a combination forming continuous solid solutions. ‘L’ and ‘α’ represent liquid and solid solution phases, respectively.194,195
Table 1 Examples of solid solutions
Binary Ternary Quaternary Between cocrystals Between salts
1. Anthracene–acridine194 (1,4-Diazabicyclo-[2.2.2]octane)–(4-chlorophenol)–(4-methylphenol)32 (1,4-Diazabicyclo-[2.2.2]octane)–(4-chlorophenol)–(4-methylphenol)–(4-bromophenol)32 1. (1,4-Diazabicyclo-[2.2.2]octane–4-chlorophenol)–(1,4-diazabicyclo-[2.2.2]octane–4-methylphenol)32 (±)-4′-Methylmethcathione hydrochloride–(±)-4′-methylmethcathione hydrobromide212
2. Benzoic acid–p-fluorobenzoic acid31 2. (Isonicotinamide–succinic acid)–(isonicotinamide–fumaric acid)198
3. Tritylnitrile–tritylisonitrile208 3. (Ornidazole–p-aminobenzoic acid)–(ornidazole–p-hydroxybenzoic acid)199



image file: c6ce01835a-f11.tif
Fig. 11 Asymmetric unit of organic liquids thiophenol and selenophenol and their solid solutions (CSD refcodes: JUJPEL, JUJNEJ01, JUJNEJ02, JUJNEJ03, JUJNEJ and JUJPAH). Sulfur is represented in yellow and selenium in magenta.

III. Eutectic

Eutectics are well-known both in inorganic and organic materials as the lowest melting composition of a combination.33–37,162,163,188,194,195,199,214 Despite their long history and everyday applications,33,35–37,195,215 their structural integrity and organization are not well-understood because of their heterogeneity/multi-phase nature. Recently, Cherukuvada and Nangia33 gave a structural definition for eutectics and conceptualized the design aspects for organic eutectics. They elucidated the structural inter-relationships among eutectics, solid solutions and cocrystals and observed them to be alternate outcomes of co-crystallization. They opined that the unsuccessful cocrystal hits could be latent eutectics and proposed eutectics to be novel organic materials, particularly as novel pharmaceutical solids on similar lines to cocrystals. Our group has broadened the design principles of eutectics in conjunction with cocrystals towards making a win-win situation in terms of targeted screening of both eutectics and cocrystals for a given set of materials.34,162,163,199,216 We found several attributes that dictate cocrystal/eutectic formation in binary combinations: (i) a cocrystal results when the primary hetero-supramolecular motif in the order of dimer to tetramer can propagate in a continuous manner, either through interactions with other such motifs or through auxiliary interactions: e.g. the isonicotinamide–succinamic acid cocrystal (Fig. 12a); a eutectic manifests when such heteromeric motifs remain restricted due to the lack of viable interactions that can propagate them in the lattice: e.g. the isonicotinamide–succinamide eutectic34 (Fig. 12b). (ii) The higher the supramolecular affinity or propensity between interacting functional groups of a combination, the more likely that the combination forms a cocrystal (e.g. combinations containing the 91% frequent carboxylic acid–pyridine synthon); the converse case gives rise to a eutectic (e.g. combinations containing the 5% frequent carboxamide–pyridine synthon).34 (iii) When the inductive strength complementarity between interacting functional groups of a combination is greater, it leads to cocrystal formation and to eutectic for the opposite situation: e.g. interaction of a high −I group with a high +I group resulted in cocrystals and that with a weak +I group resulted in eutectics199 (Fig. 13). (iv) Geometric or steric fit/comfort between interacting functional groups and/or in the packing of components results in cocrystals of the combination and steric misfit/hindrance gives rise to eutectics: e.g. pyrazinoic acid–isomeric pyridine carboxamide combinations.163 Altogether, eutectics can be designed based on the selection of components that have functionalities which cannot make continuous heteromeric motifs, with less inductive strength complementarity or lacking steric compatibility.
image file: c6ce01835a-f12.tif
Fig. 12 (a) The strong carboxylic acid–pyridine and carboxamide heterodimer synthons propagate continuously to give rise to a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 cocrystal for the isonicotinamide–succinamic acid combination (CSD refcode: ROQYIH). (b) For the isonicotinamide–succinamide combination, the weak carboxamide–pyridine heterosynthon cannot facilitate the continuity of carboxamide heteromers so that the combination forms a eutectic. Adapted with permission from S. Cherukuvada and T. N. G. Row, Cryst. Growth Des., 2014, 14, 4187 (ref. 34). Copyright 2014 American Chemical Society.

image file: c6ce01835a-f13.tif
Fig. 13 (a) The ornidazole-p-aminobenzoic acid combination forms a cocrystal (CSD refcode: DOMHAQ) because of the strong inductive force complementarity between a high −I nitro group and a high +I amine group so that it facilitates continuous growth of carboxylic acid–imidazole heteromers. (b) A eutectic manifests for the ornidazole–benzoic acid combination, as evaluated by a characteristic ‘V’-type phase diagram, due to the weak complementarity between a high −I nitro group and a low +I –CH group making the carboxylic acid–imidazole heteromers remain discrete. Reproduced from ref. 199 with permission from the Royal Society of Chemistry.

Eutectics are well-recognized as phase-change materials for anti-freeze, heat storage and solar energy applications much of which are based on inorganic eutectics.33,36,195,215,217 The trend has been changing, of late, with organic eutectics being successfully investigated for the above applications.36,37,218,219 Apart from being established for pharmaceutical applications,33,35,214,220 organic eutectics are expanding their horizons into organic synthesis and separation,221–224 heat storage,225,226 solar cells,227,228 ferroelectric materials229etc. Liang-sun Lee et al.221 have undertaken an ingenious approach based on eutectic crystallization to separate mixtures containing chemicals that exhibit close boiling points. The petroleum distillate contains m-cresol and 2,6-xylenol whose boiling points are too close (475 K and 474 K, respectively) to be separated by conventional distillation. They have taken tert-butyl alcohol (b.p. 355 K) as an adductive agent that can make two different complexes (a cocrystal, termed a congruent complex by them, and a eutectic) with m-cresol and 2,6-xylenol, respectively, in the mixture, as analyzed by binary and ternary phase diagrams. As the complexes exhibit different crystallization temperatures, they were separated from the mother liquor sequentially by manipulating the temperature and then later distilled to obtain the pure components. In the field of organic synthesis, using mild conditions and green methods is gaining significance in handling sensitive and hazardous reactions.46 Sangram Gore et al.224 have shown the utility of non-toxic and non-volatile L-(+)-tartaric acid–dimethylurea eutectic melt (m.p. 70 °C) as a solvent as well as a catalyst for Fischer indole synthesis (Fig. 14). For heating applications in buildings and greenhouses, eutectic mixtures of fatty acids have been developed as phase-change materials, as was demonstrated by Ahmet Sari et al.225 through a lauric acid–stearic acid eutectic. An efficient way of tapping solar energy as an alternate and renewable source of energy has become one of the global challenges to be addressed for a sustainable future.3,4 Several approaches are in vogue and recently dye-sensitized solar cells (DSCs)230 have shown promise for the purpose. However, the existing DSC electrolytes using organic solvents and room temperature ionic liquids have volatility and viscosity problems. Yu Bai et al.227 showed the reliability and efficiency of organic eutectic melts as solvent-free liquid redox electrolytes. Further, the utility of organic eutectics as better ferroelectric materials was disclosed by Yueqing Zheng et al.229 All in all, organic eutectics hold prospective applications akin to their inorganic counterparts.


image file: c6ce01835a-f14.tif
Fig. 14 Synthesis of functionalized indoles using the medium of L-(+)-tartaric acid–dimethylurea eutectic melt. Reprinted with permission from S. Gore et al., Org. Lett., 2012, 14, 4568 (ref. 224). Copyright 2012 American Chemical Society.

IV. Salt cocrystal

The term ‘salt cocrystal’ indicates that a salt, be it inorganic or organic, can co-crystallize with an organic molecule. As a quick example, one can easily think of a ‘salt-sugar’ crystalline adduct. Indeed, the sodium chloride–sucrose salt cocrystal is known and dates back to the early 19th century.231 Similarly, a cocrystal between sodium chloride and glucose was known from the same time.232 The existence of the former as a dihydrate (NaCl–sucrose–2H2O) has been established beyond doubt in the literature; however, its crystal structure is still elusive.233 On the other hand, the latter exists both as a dimorphic hydrate (NaCl–(glucose)2–H2O) and as an anhydrate (NaCl–(glucose)2) whose crystal structures (Fig. 15) were determined at the end of 20th century.234–236 Very recently, Heiko Oertling233 has reviewed the halide salts of mono- and disaccharides, including the above salt cocrystals, and found that most of them are coordination polymers and exist as hydrates. Of late, salt cocrystals have become more popular as ‘ionic cocrystals’22,82 in the context of pharmaceutical applications.237–240 Although the term ‘salt cocrystal’ is somewhat restricted,241 both the terms essentially represent the same basic composition A+BN, where the ionic species (either A+ or B) and non-ionic species (N, an organic molecule) are either chemically related or unrelated.239 For instance, apart from the sodium chloride–glucose adduct,233 the ionic and non-ionic entities are not related in alkali bromide–barbituric acid22 and in the well-known fluoxetine hydrochloride–carboxylic acid21 (discussed next) adducts. However, there is another category of ionic cocrystal where they are closely related: e.g. valproic acid sodium valproate,169–171 escitalopram oxalic acid oxalate172 (see Fig. 5), nicotinamide nicotinamidium hydrochloride,242 and para-nitrobenzoic acid pyridoxine–p-nitrobenzoate162 (Fig. 16). Herein the ionic and non-ionic species are conjugate acid–base pairs (of an organic molecule) and hence this class of ionic cocrystals is termed conjugate acid–base (CAB) cocrystals.242–244 The formation of CAB cocrystals looks serendipitous, although the possibility of their occurrence is not totally unpredictable. The phenomenon of a salt-cocrystal continuum in acid–base crystalline complexes and the associated ΔpKa rule lend support to their manifestation, as discussed earlier. CAB cocrystals were shown to be obtainable for combinations having ΔpKa values between 0 and 1, the region where the concentrations of ionized and unionized species is close, so that both species can crystallize out: e.g. carboxylic acid–carboxylate and pyridine–pyridinium molecular complexes.162,242,244–247
image file: c6ce01835a-f15.tif
Fig. 15 Sodium chloride–glucose (a) hydrate and (b) anhydrate ionic cocrystals (CSD refcodes: VEGLOI01 and XOZVOY) show distorted octahedral coordination of sodium ion (violet) to hydroxyl oxygens of glucose molecules. The chloride ion (green) has no direct interaction with the sodium ion and is involved in hydrogen bonding with glucose and/or water molecules.

image file: c6ce01835a-f16.tif
Fig. 16 (a) Asymmetric unit of nicotinamide nicotinamidium hydrochloride salt cocrystal hydrate and (b) para-nitrobenzoic acid pyridoxine–p-nitrobenzoate salt cocrystal (CSD refcodes: PARPUV and VUKPAU).

On the other hand, the manifestation of cocrystals for, believably highly stable, alkali salts is a matter of interest to begin with. An analysis of their crystal structures reveals the underlying design principles for this class of supramolecular adducts. Cook and Bugg,248 in 1973, based on their studies of calcium halide–carbohydrate complexes, observed that the interactions between calcium ions and hydroxyl groups successfully outcompete the cation–anion attractions so that calcium is coordinated to hydroxyl groups with no direct contacts to halide anions. Crystal structure analysis of either hydrated or anhydrous sodium chloride–glucose adduct shows that no direct interaction exists between sodium and chloride ions which are separated by glucose molecules coordinating with sodium through hydroxyl oxygen atoms (see Fig. 15). Chloride ions are involved in hydrogen bonding with hydroxyl groups and/or water molecules. This behavior is akin to solvation with the organic partner acting like a solvent/water presenting a lone pair (oxygen) to the cation and hydrogen(s) to the anion. Dario Braga et al.22 opined that the interactions between inorganic ions and organic molecule (enthalpic contribution), besides the entropic contribution from the multi-component nature, compensates for the loss of crystal lattice energy of pure ionic salts. Thus, the selection of molecules with functionalities that can replace cation–anion interactions of the parent salt is the key to forming/designing ionic cocrystals. Braga et al.237,238 and Michael J. Zaworotko's group239,240 were recently successful in making ionic cocrystals involving metal salts based on alkali–amido and lithium–carboxylate/hydroxyl coordination bonds, respectively. On the other hand, an elegant design of ionic cocrystals of organic salts was put forward by Scott L. Childs et al.21 at the dawn of active cocrystal research (in 2003). They have successfully co-crystallized the anti-depressant drug fluoxetine hydrochloride with several organic acids based on the ability of the chloride ion to form charge-assisted hydrogen bonds with carboxylic acids. The weak C–H⋯Cl homomeric interactions of fluoxetine hydrochloride are replaced by strong O–Hacid⋯Cl heteromeric interactions so that it manifests ionic cocrystals with organic acids (Fig. 17). These ionic cocrystals demonstrated that physicochemical properties such as solubility can be modulated, from one extreme to the other, to cater for the fast dissolving and slow dissolving requirements of a particular drug, with coformers having control over the final property.


image file: c6ce01835a-f17.tif
Fig. 17 The strong O–H(acid)⋯Cl and N+–H⋯O(acid) heteromeric interactions replace the weak homomeric C–H⋯Cl (fluoxetine hydrochloride) and O–H⋯O (fumaric acid) interactions to result in a salt cocrystal for fluoxetine hydrochloride–fumaric acid combination (CSD refcode: RAJFIS). Reproduced from ref. 33 with permission from the Royal Society of Chemistry.

V. Ionic liquid

Ionic liquids (ILs) are broadly defined as organic salts that melt below 100 °C and if they are liquids at room temperature (m.p. ≤ 25 °C) then they are designated as ‘room temperature ionic liquids’ (RTILs).46,47,249,250 The term ‘ionic liquids’ is somewhat misleading as it sounds as if these materials are all invariably liquids at NTP. However, following the definition, some ionic liquids exist in the solid state in the temperature range 20–100 °C (Scheme 3) by virtue of which they can exhibit polymorphism251–254 (e.g. ethambutol dibenzoate,251 just as high melting salts/compounds) and are amenable to design by co-crystallization (just as molecular salts and cocrystals). The design and development of ILs, begun in 1990s, had been primarily to generate a liquid medium (hence the name) having the attributes of low/non-volatility, low viscosity, molten ionicity, conductivity etc. for applications in organic synthesis and separation (as solvents and catalysts), electrochemistry (as electrolytes), pharmaceuticals (as liquid salt forms of drugs in lieu of solid forms) etc.46,47,249,250,255–258 The basic concept in the design of a liquid salt phase is the identification of features that circumvent crystallization: the selection of combinations with asymmetry in size and shape between components, enhancing charge delocalization between the components, reducing adhesive interactions by avoiding potential heterosynthons etc.:47,250 in effect, an anti-crystal engineering approach.259 Such an approach is also the basis for the design of deep eutectic solvents, amorphous materials and some supramolecular gels.260–263 The process of making such liquid salts can also facilitate the manifestation of ILs with melting points between ambient temperature and 100 °C: i.e. low melting solid salts.
image file: c6ce01835a-s3.tif
Scheme 3 Classification of ionic liquids.

Although inorganic ILs are known, the majority of the vast number of ILs are based on organic cations pairing with organic or inorganic anions. ILs can be protic (involving proton transfer) or aprotic (with a charge balance between counter-ions) formed either by direct reaction of acids and bases or by salt metathesis reactions.264,265 The popular organic ions are of awkward shape, with bulky substituents, long alkyl chains, non-planar, charge delocalized, e.g. imidazolium, pyrrolidinium, pyridinium, tetraalkylammonium cations and hexafluorophosphate, triflate, imidazolate, dicyanamide anions (Fig. 18) etc. All these moieties in combination thus feature asymmetric ions and delocalized charge, leading to non-specific interactions and inefficient packing so that the product, i.e. IL, exhibits low crystal lattice energy and low melting or no apparent melting at all.47,249,250 Nevertheless, the ionic and low melting nature can be exploited for solubility enhancement of drugs. For pharmaceutical purposes, the choline cation and saccharinate, acesulfamate, mesylate, tosylate anions etc. (Fig. 18) are available.259 Several pharmaceutical ILs, which are crystalline solids at ambient temperature, such as 2-pyrrolidinoethanol salicylate (m.p. 49 °C), 2-pyrrolidinoethanol gentisate (97 °C)264 (Fig. 19), ethambutol dibenzoate (90 °C),251 tuaminoheptane benzoate (91 °C),264 and pyridostigmine saccharinate (94 °C)259 were reported in the literature. Low melting salts, apart from other applications that can be tapped, can be used as solvents in organic synthesis for moderately high temperature reactions, at about 100 °C, similar to the eutectic melt used for Fischer indole synthesis described before. All in all, as mentioned earlier, the theoretical possibility of 1018 ILs provides unimaginable opportunities for achieving desired applications in various fields.


image file: c6ce01835a-f18.tif
Fig. 18 Some examples of ionic liquid cations and anions.46,47,249,250,259

image file: c6ce01835a-f19.tif
Fig. 19 Asymmetric unit of 2-pyrrolidinoethanol (a) salicylate and (b) gentisate ionic liquids (CSD refcodes: KASXIN and KASWEI).

VI. Solvate

As stated previously, solvate formation is a very common type of co-crystallization. Solvates are well-established solid forms for pharmaceutical applications20,62,166,266,267 and have been studied as part of host–guest/inclusion/clathrate compounds.15 However, they are not without problems with regard to nomenclature issues.15,29,173,267,268 At a trivial level, the solvent which is included as a guest in a host material is a solute. As per the understanding that solvent or solute can be a solid, liquid or gas, in addition to the knowledge of clathrate hydrates15 and acetylene cocrystals,269 a solvate is generally considered to be a multi-component crystalline solid containing water or any organic solvent (a compound which is a liquid at NTP). They were classified as ‘cocrystals’ by Ann L. Bingham et al.29 at the dawn of active cocrystal research. In the pharmaceutical sector, solvates are more popularly called ‘pseudopolymorphs’, defined as “crystals formed by the same substance crystallized with different amounts or types of solvent molecules”.15,270 Thus, a given material can incorporate different ratios of the same solvent (e.g. the antibiotic drug norfloxacin forms a dihydrate, trihydrate, pentahydrate, 1.25 hydrate and 1.125 hydrate)271–273 or different solvents in its crystal lattice (e.g. the antibacterial drug nitrofurantoin forms solvates with water, DMSO,274 methanol78etc.) or even form polymorphs of solvates (e.g. the nitrofurantoin monohydrate forms I and II,274Fig. 20). Understandably, for pharmaceutical usage, solvents with low toxicity need to be used and hence are classified based on decreasing toxicity, from class I (should be avoided: e.g. benzene, carbon tetrachloride etc.) to class II (should be limited: e.g. acetonitrile, methanol etc.) to class 3 (can be preferred because of their low toxicity: e.g. ethanol, acetic acid etc.) solvents.275 Solvates have various implications in the pharmaceutical field: (i) some solvates upon controlled desolvation can produce new polymorphs of the parent substance (e.g. the caffeine monoclinic polymorph from its hydrate) and hence purposive solvation and desolvation experiments are routine during drug polymorph screening and have further importance for the crystallization of a desired polymorph.29,94,267,276–279 (ii) Hydrates, in general, have low aqueous solubility compared to their anhydrates. This is because they have less free energy available to bond with the aqueous medium, since the parent material uses some free energy for making hydrogen bonds with water to manifest as the hydrate.77,280 Nevertheless, for special requirements like slow/low dissolving solid drug formulations, pharmaceutical hydrates come to the rescue (e.g. nitrofurantoin monohydrate form II, brand name ‘Macrobid’).281 (iii) Solvates/hydrates are also important in issues concerning intellectual property protection, illustrated by the case of the anti-depressant drug paroxetine hydrochloride (brand name ‘Paxil’).266
image file: c6ce01835a-f20.tif
Fig. 20 Dimorphs of nitrofurantoin monohydrate (CSD refcodes: HAXBUD01 and HAXBUD).

The majority of the solvates in the CSD contain polar solvents, with water representing the bulk of them followed by methanol occurring 10 times less frequently than water.15 The predominance of hydrates is for enthalpic reasons280 based on the excellent hydrogen bonding capability of water. Water exceptionally presents two hydrogen bond donors and an acceptor for a stable supramolecular assembly and therefore plays a critical role in crystallization. Hydrogen bonding and charged groups such as COOH, COO, OH, Ca2+, and Na+ understandably have high water affinity and hence facilitate the formation of hydrates.280,282,283 Many crystal forms of amino acids and mono/oligosaccharides exist in a hydrated form as water balances their polar functionalities, such as COO, NH3+ and OH groups.90 Non-polar solvents are important in situations requiring hydrophobic interactions and for their space-filling role.15,284 Although solvates/hydrates are considered a nemesis15,285 to crystal engineering and often manifest as unintended co-crystallization products, careful studies of molecular recognition and aggregation via solvent functional groups render them predictable and designable:270e.g. a record of a century plus of solvates of sulfathiazole,29 a half-century plus of axitinib solvates,277 twenty plus of gallic acid solvates274etc. William Jones's group286 have successfully made several caffeine–succinic acid host framework-based isomorphous solvates on the basis of shape/size mimicry between aromatic and alicyclic solvents (Fig. 21a). Vânia André et al.30 and Christina Tauoss et al.287 made 1,4-dioxane and morpholine solvates of the anti-tubercular drug 4-aminosalicylic acid (PAS) and urea/thiourea, respectively, utilizing the complementary hydrogen bonding possible between ether ‘O’/amine ‘NH’ (of solvent) and amine/carboxyl (of PAS/urea) groups (Fig. 21b–g). Krystle Chavez et al.288 utilized the potential interaction between the hydroxyl group and the carboxylate/ether group to make a homologous series of alcoholic solvates of the anti-inflammatory drug sodium naproxen. Further efforts from various groups specifically targeting solvate formation have also proven successful.289–291 Our group has recently designed solvates of the gallic acid–succinimide cocrystal and further demonstrated solvent exchange among them.103 Altogether, solvates can be designed and find applications in purification, solvent removal/recovery292 and also proton conduction, as discussed before, apart from their use in pharmaceuticals.


image file: c6ce01835a-f21.tif
Fig. 21 (a) A caffeine–succinic acid combination forms a host framework for the formation of isomorphous solvates, respectively involving dioxane, thioxane, tetrahydrofuran, tetrahydropyran, thiophene, benzene, cyclohexane etc. solvents (solvent indicated as a yellow circle). Reproduced with permission from T. Friščić et al., Angew. Chem., Int. Ed., 2006, 45, 7546 (ref. 286), Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. 1,4-Dioxane and morpholine solvates of (b and c) 4-aminosalicylic acid, (d and e) urea and (f and g) thiourea (CSD refcodes: CUKVEK, CUKVAG, SIDJEW, SIDJIA, SIDHUK and SIDJAS), respectively.

VII. Solid dispersion

A solid dispersion is a solid phase composite formed by random incorporation of a substance in the lattice (called a matrix) of another substance, classically called a carrier.214,293 They are very popular as ‘amorphous solid dispersions’, chiefly in the pharmaceutical industry, typically comprising an amorphous polymer matrix in which the active substance is dispersed.10,11,214,293 Many drugs are administered as these solid forms to achieve higher solubility, yet with uncompromised stability, and consequent bioavailability, conferred by a hydrophilic but stable polymer (having a high glass transition temperature) and overall amorphous nature: e.g. the antifungal itraconazole–hydroxypropyl methylcellulose solid dispersion (brand name ‘Sporanox’).10,294 However, not all solid dispersions are amorphous with crystalline ones and those with carriers other than polymers have been known. Indeed, the first-generation solid dispersions (1960s) were of crystalline nature, having the integrity of eutectics and solid solutions, respectively.11,293,295–297 Highly water soluble crystalline carriers such as urea, mannitol, and sorbitol, had been used to make soluble crystalline solid dispersions of insoluble/low soluble drugs: e.g. sulfathiazole–urea295 and sulfanilamide–mannitol296 (Fig. 22). Chiou and Riegelman,293 in 1971, classified solid dispersions as (i) simple eutectic mixtures, (ii) solid solutions, (iii) glass solutions, (iv) amorphous precipitations in a crystalline carrier and (v) compound or complex formations. Strictly speaking, the last category does not come under solid dispersions, as was also maintained by the same authors. Apart from that, glass solutions are nothing but amorphous solid dispersions and the category amorphous precipitations in a crystalline carrier comes under solid solutions, since the overall integrity is of the carrier itself with the other/minor component being molecularly dispersed. For clarity on the nature and classification of solid dispersions in the literature, we have illustrated the different kinds of solid dispersions in Scheme 4.
image file: c6ce01835a-f22.tif
Fig. 22 Phase diagrams of (a) sulfathiazole–urea (reproduced with permission from Chem. Pharm. Bull., vol. 9 (ref. 295). Copyright 1961 The Pharmaceutical Society of Japan) and (b) sulfanilamide–mannitol (reprinted from J. L. Kanig, J. Pharm. Sci., 1964, 53, 188 (ref. 296), copyright 1964, with permission from Elsevier) crystalline solid dispersions showing their eutectic integrity.

image file: c6ce01835a-s4.tif
Scheme 4 Classification of solid dispersions.

Numerous studies on polymer-based amorphous as well as crystalline dispersions (e.g. fenofibrate–polyethylene glycol,10,298 itraconazole–polyethylene glycol299) in terms of suitable carrier selection for a drug and drug-carrier compatibility issues11,214,293,294,300 are available in the literature. However, small molecule-based amorphous dispersions have been less explored (e.g. Chiou and Riegelman's griseofulvin–citric acid glass solution)293 and have garnered attention in recent times due to the drawbacks with drug-polymer dispersions. Norman Chieng et al., in 2009, found that co-milling of the two drugs ‘indomethacin’ and ‘ranitidine hydrochloride’ resulted in a stable amorphous binary mixture.301 Such amorphous mixtures, termed ‘coamorphous solids’,302 were also shown to be formed between a drug and a small molecule, as in ‘repaglinide–saccharin’, by Yuan Gao et al.,303 which also exhibited high solubility and stability. Later, Yun Hu et al.135 studied the formation of a cocrystal, a salt and coamorphous solids in sulfathiazole–carboxylic acid combinations. The high ΔpKa of 6 between sulfathiazole (pKa = 7.2)167 and oxalic acid (pKa1 = 1.2) resulted in their salt and the grey zone ΔpKa value of 2.9 resulted in a cocrystal of sulfathiazole with glutaric acid (pKa1 = 4.3). Hydrogen bond donor–acceptor mismatch gave rise to L-tartaric acid and citric acid coamorphous solids of sulfathiazole, although the corresponding ΔpKa values (4.2 and 4.1) of the combinations are favourable for salt formation. Recently, Kuthuru Suresh et al.136 demonstrated improved pharmacokinetics for the bioactive molecule curcumin through its coamorphous solid with anti-malarial artemisinin. Among other things, they opined that the coamorphous solid drug formulations based on small molecules can be advantageous because of the hundreds of safe additives available and plausible synergism with them (the coformer effect).38,71,77,107,304 However, as was also observed by them, the design aspect is semi-empirical, although traits like the mismatch of the hydrogen bond donor–acceptor ratio, geometric incompatibility between the components and short-range heteromolecular interactions have been ascribed to their manifestation. Thus, the bottom line in the design of solid dispersions (both amorphous and crystalline) is similar to that of eutectics and ionic liquids in that one has to exploit the features of molecular asymmetry, non-specific interactions and inefficient packing and in this regard the negative cocrystal hits can potentially give rise to these solid forms. Since research on small molecule based solid dispersions is still rudimentary, full-fledged applications are yet to follow.

VIII. Supramolecular gelator

A gel is a well-known colloidal system, composed of a liquid dispersed phase in a solid dispersion medium, having a wide range of applications in foodstuffs, cosmetics, pharmaceuticals, materials, molecular biology etc.305–307 A gelling agent or gelator is a solid substance that can make fibrillar networks and holds the liquid substance. Gelators range from small molecules (e.g. silica) to polymers (e.g. polyacrylamide) which form porous structures by intertwined or cross-linked fibres wherein the liquid is accommodated. Gelation is considered to be an aborted crystallization process wherein the gelator molecules (in the solvent medium), instead of showing three-dimensional (3D) growth, aggregate to form one-dimensional (1D) fibres resulting in what are known as ‘self-assembled fibrillar networks (SAFINs)’, which in turn entangle to form 3D networks within which solvent molecules are immobilized.307 The formation of network or porous structures by gelators is what makes them interesting and amenable to design, particularly from a supramolecular viewpoint, towards catering for various applications. From the late 1980s, gels based on low molecular weight gelators (LMWGs of molecular mass <3000) gained attention and by the end of 20th century supramolecular gels based on hydrogen bonds and metal–ligand interactions could be routinely designed using single-component gelators and organometallic compounds.305–308 That 1D hydrogen bonding networks promote gelation, as revealed by microscopic observations on SAFINs featuring 1D fibres, was elegantly utilized by Dastidar's group307,309–311 in the design of supramolecular multi-component based gelators. They selected acid–base combinations devoid of functionalities that promote 3D growth, just allowing the constituents to form ion-pairing 1D synthons.312 These pioneering studies resulted in organic salt based gelators that are formed by the manifestation of secondary ammonium monocarboxylate (SAM), secondary ammonium dicarboxylate (SAD), primary ammonium monocarboxylate (PAM) and primary ammonium dicarboxylate (PAD) supramolecular synthons between different combinations of amines and carboxylic acids (Fig. 23). Some of these gelators were shown to exhibit attractive properties, such as instantaneous formation of gels with oil (petrol, kerosene and diesel, respectively) from oil–water mixtures (Fig. 24) thus finding applications in oil spill problems,309 as supramolecular containers,310 drug delivery vehicles311etc. Several other groups also reported multi-component supramolecular gelators with interesting applications.313–315 In all, supramolecular gelators can be designed and utilized for a variety of applications.
image file: c6ce01835a-f23.tif
Fig. 23 Supramolecular synthons in organic salt based gelators. Reproduced from ref. 307 with permission from the Royal Society of Chemistry.

image file: c6ce01835a-f24.tif
Fig. 24 Selective gelation of petrol, kerosene and diesel, respectively, from an oil–water mixture by hexadecylammonium 4-bromocinnamate. Reprinted with permission from a. Ballabh et al., Chem. Mater., 2006, 18, 3795 (ref. 309). Copyright 2006 American Chemical Society.

Free energy profile of supramolecular adducts

The manifestation of not only numerous but also various supramolecular adducts for a given material shows that its energy landscape is more wide-ranging than one can presume. Even for a particular binary combination, as mentioned earlier, multiple crystallization possibilities exist: viz. a cocrystal, a salt, a salt cocrystal and their respective stoichiometric variants and polymorphs; a cocrystal solvate & a salt cocrystal solvate and their polymorphs (of course, here a third component, the solvent, is involved) etc.316 Thus, the free energy landscape for a given system can be imagined as a mountain range with a vast number of diverse ridges and plateaus denoting activation barriers and free energy minima, respectively. As different life forms (different kinds of plants and animals) exist at different levels in the mountain ranges, different crystal forms can be sustained in the crystal energy landscape of a system. The fact that different supramolecular adducts are manifest does not necessarily mean that they are more stable than their respective parent materials: i.e. the products can have more or less or intermediate stability compared to the reactants by virtue of either an exergonic or an endergonic process. Further, as is indicated by different levels in the landscape, a hierarchy in terms of free energy/stability exists among the supramolecular adducts. Based on an understanding of the formation of various supramolecular adducts from the literature, we present a putative free energy profile of the adducts317 along with some of their physical attributes (stability and melting point) in Scheme 5. The spontaneity or propensity of occurrence of certain crystal forms is due to a net loss of free energy for the system (combination) with respect to its surroundings: i.e. a negative ΔG thermodynamic process driven by enthalpic loss of the system (−ΔH) or by entropic gain in the system and/or its surroundings (+ΔS) or by the compromise between enthalpy and entropy changes.318–321 The formation of a salt for an acid–base pair is purely enthalpy driven because of the strong tendency of the combination to manifest ionic bonds and become stable: i.e. enthalpic loss due to bond formation leading to energy minimization for the system.322,323 Similarly, the formation of many cocrystals and solvates, especially strongly hydrogen bonded ones such as hydrates, is again enthalpy driven.300,324–326 However, their free energy is not as low as that of salts, since the non-covalent forces in them (such as hydrogen bonds) are not as energetic/strong as those in salts (electrostatic),326 and therefore they lie at a higher level in the free energy profile. Some cocrystals show positive enthalpy of formation182,187 and therefore are entropically driven and the overall cocrystals can have higher, lower or intermediate free energies, depending on the strength of interactions and packing efficiency between the constituents, in comparison to their parent materials. On the other hand, solid solutions are entropically stabilized15 since they are substitutional in nature and therefore have more or less the same free energy as that of the parent components. Typically, they exhibit a continuum of free energies, graded according to their compositions, between their parent materials. In the case of eutectics and ionic liquids, they are characterized by non-specific interactions, unfulfilled bonds and imperfect packing,33,47,249 which are the manifestation of both enthalpy and entropy gain effects.180,214,250 Hence, they possess high free energies and appear at higher levels on the free energy diagram in comparison to their parent substances as well as to other supramolecular adducts, as discussed above.
image file: c6ce01835a-s5.tif
Scheme 5 A hypothetical free energy profile of supramolecular adducts that can manifest for combinations of a pyridine-containing compound with a homologous series of aliphatic carboxylic acids. Strong inter-component interactions invoked by pKa differences and supramolecular compatibility between the components for heteromolecular growth result in salts/cocrystals. With an increase in the chain length of carboxylic acids, steric issues arise and the combinations can manifest as supramolecular gelators/ionic liquids/eutectics based on how the heteromeric units grow/propagate in the lattice. Solid solutions and solvates do not come under these acid–pyridine combinations but, in general, are considered to exhibit intermediate free energies compared to their parent materials. Crystalline solid dispersions have the integrity of either eutectics or solid solutions.

Conclusions

A first-of-its-kind effort on consolidating co-crystallization in terms of crystal form diversity and wide-ranging applications was presented. Co-crystallization is essentially a supramolecular phenomenon wherein a combination of materials condenses into a crystalline phase via the interplay of directional non-covalent (homomeric vs. heteromeric) interactions and close packing (lattice organization) aspects between the components. A given material can form various adducts: namely cocrystals, salts, solvates, solid solutions, eutectics, ionic liquids, solid dispersions, supramolecular gelators, mixed adducts etc., respectively, in combination with different materials. Even for the same combination, crystallization of a particular adduct does not necessarily mean that it is the only feasible one, or the most stable, in the energy landscape, with several other variants (polymorphs, multiple stoichiometry ones etc.) possible. Overall, the thermodynamic principles, in terms of the factors related to both system and surroundings, dictate the outcome of co-crystallization. The non-occurrence of some adducts is subject to conditions such that one can manipulate/design the conditions to arrive at the same place in the landscape. Thus, all the varied co-crystallization products can be rationally designed towards accomplishing desired applications in diverse fields. On the other hand, although the synthetic effort from a chemist's viewpoint is minimal, obtaining a desired product is still challenging and gives way for extensive theory and experiment. While some of the topics are emerging and some are still in their infancy, co-crystallization of small molecules has immense potential to generate reliable technologies, as demonstrated by the success of cocrystals. We hope that this treatise stimulates efforts to this effect.

Software programs

X-Seed

Crystal packing diagrams were made using X-Seed free software.327

ChemDraw

Molecular and supramolecular schematics were made using ChemBioDraw Ultra (version 14) software.328

Acknowledgements

SC thanks the SERB for Start-Up Research Grant and RK thanks the Institute for Senior Research Fellowship. TNGR thanks the DST for J. C. Bose Fellowship. We thank the Institute for infrastructural facilities.

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