Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

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Review Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

Indumathi Sathisaran 1 and Sameer Vishvanath Dalvi 2,* ID 1 Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355, India; [email protected] 2 Department of Chemical Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355, India * Correspondence: [email protected]; Tel.: +91-792-395-2408

Received: 8 June 2018; Accepted: 25 July 2018; Published: 31 July 2018

Abstract: Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development.

Keywords: crystal engineering; cocrystals; coformers; eutectics; polymorphism; poorly water-soluble; dissolution enhancement; hydrogen bonding

1. Introduction Biopharmaceutics Classification System (BCS) of drugs classifies drugs into four major categories (Figure1) based on their solubility and permeability behavior [ 1]. BCS Class II and Class IV drugs suffer from poor aqueous solubility. Poor aqueous solubility of hydrophobic drugs can result in poor absorption, low bioavailability and poses challenges for drug development process [2]. Enhancing bioavailability of poorly water-soluble BCS class II and BCS class IV drugs therefore becomes necessary to improve drug’s efficacy.

Pharmaceutics 2018, 10, 108; doi:10.3390/pharmaceutics10030108 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2018, 10, 108 2 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 2 of 74

Figure 1. Schematic representation of Biopharmaceutics Classification System (BCS) of Drugs Figure 1. Schematic representation of Biopharmaceutics Classification System (BCS) of Drugs [Reprinted [Reprinted from [1] with permission from Elsevier]. from [1] with permission from Elsevier]. In addition to BCS of drugs, Developability Classification System (DCS) of drugs also plays a Insignificant addition role to in BCS determining of drugs, the Developability development of Classiﬁcation pharmaceutical System formulations, (DCS) especially of drugs the also oral plays a signiﬁcantformulations role in based determining on its solubility the development in biorelevant of pharmaceutical media such as formulations,FaSSIF (Fast State especially Simulated the oral Intestinal Fluid) and FeSSIF (Fed State Simulated Intestinal Fluid) rather than its solubility in buffers formulations based on its solubility in biorelevant media such as FaSSIF (Fast State Simulated Intestinal [3–5]. Very few reports are available in the literature where researchers have determined the Fluid) and FeSSIF (Fed State Simulated Intestinal Fluid) rather than its solubility in buffers [3–5]. dissolution rate of cocrystals of poorly water-soluble drugs in biorelevant media [6,7]. The studies Veryillustrate few reports that cocrystals are available exhibited in the enhanced literature dissolution where researchers rate in biorelevant have determinedmedia and buffer the as dissolution well rate ofindicating cocrystals that of the poorly DCS serves water-soluble as a highly drugs relevant in biorelevanttool in determining media developability [6,7]. The studies of cocrystals illustrate of that cocrystalspoorly exhibitedwater-soluble enhanced APIs. dissolution rate in biorelevant media and buffer as well indicating that the DCSEnhancing serves aqueous as a highly solubility relevant of poorly tool water in determining-soluble drugs developability without compromising of cocrystals on stability of poorly water-solubleis one of the APIs. major challenges faced by the pharmaceutical industries during drug discovery and Enhancingdevelopment aqueous processes solubility [8–12]. Crystal of poorly Engineering water-soluble is a drugstool which without can compromisingbe used to tailor on stabilitythe is onephysicochemical of the major challengesproperties of faced Active by Pharmaceutical the pharmaceutical Ingredients industries (APIs) [13] during such as drug melting discovery point, and dissolution rate, aqueous solubility, refractive index, surface activity, habit, density, electrostatic, development processes [8–12]. Crystal Engineering is a tool which can be used to tailor the mechanical and optical properties [14]. Cocrystallization is one of the crystal engineering approaches physicochemical properties of Active Pharmaceutical Ingredients (APIs) [13] such as melting point, adopted to prepare multicomponent pharmaceutical crystals to enhance the dissolution rates of dissolutionpoorly water rate,-soluble aqueous APIs solubility, without affecti refractiveng their index, intrinsic surface properties activity, [15]. habit, density, electrostatic, mechanicalTremendous and optical research properties is now [14 being]. Cocrystallization conducted in cocrystallization. is one of the crystalDiscovery engineering of new cocrystals approaches adoptedis now to prepareconsidered multicomponent as one of the patentable pharmaceutical invention crystals [16]. Cocrystal to enhance technology the dissolution is being considered rates of poorly water-solubleas an advanced APIs withouttechnology affecting used for their improving intrinsic the properties drug product [15]. by modifying the molecular Tremendousconformations research and intermolecular is now being interactions conducted [17]. in cocrystallization.Combination drug Discovery therapy (combining of new cocrystals two is now considereddrugs in a solid as one form of theand patentable administering invention in a single [16]. dose) Cocrystal is considered technology to be is beinganother considered important as an advancedadvant technologyage of the cocrystal used for technology improving [18,19]. the drug However, product the by number modifying of marketed the molecular cocrystal conformations products available till date is very low [20,21]. Examples of such cocrystals available in market and approved and intermolecular interactions [17]. Combination drug therapy (combining two drugs in a solid form by the Food and Drug Administration (FDA) are Entresto, Lexapro [20] and Depakote [21]. and administering in a single dose) is considered to be another important advantage of the cocrystal In this review, we provide a consolidated account of information available in the literature on technologycocrystal [18 engineering.,19]. However, We have the numberdiscussed ofdifferent marketed aspects cocrystal of cocrystallization products available technology till such date as is very low [the20, 21synthesis]. Examples techniques, of such type cocrystals of intermolecular available interactions in market involved and approved in cocrystallization, by the Food different and Drug Administrationtypes of solids (FDA) obtained are Entresto, during cocrystallization, Lexapro [20] and techniques Depakote to [21 characterize]. cocrystals, different Intypes this of review, cocrystals we and provide dissolution a consolidated of cocrystals account in aqueous of medium. information available in the literature on cocrystal engineering. We have discussed different aspects of cocrystallization technology such as the synthesis techniques, type of intermolecular interactions involved in cocrystallization, different types of solids obtained during cocrystallization, techniques to characterize cocrystals, different types of cocrystals and dissolution of cocrystals in aqueous medium. PharmaceuticsPharmaceutics 20182018,, 1010,, 108x FOR PEER REVIEW 33 of 7474 Pharmaceutics 2018, 10, x FOR PEER REVIEW 3 of 74 2. Types of Solid Forms Obtained from Cocrystallization 2.2. TypesTypes ofof SolidSolid FormsForms ObtainedObtained fromfrom CocrystallizationCocrystallization While cocrystal formation is the main desired outcome, an unsuccessful cocrystallization event mightWhileWhile result cocrystalcocrystal in formation formationformation of different isis thethe mainmain solid desireddesired forms outcome,outcome, such as an aneutectics unsuccessfulunsuccessful [22–26 cocrystallizationcocrystallization], a drug polymorph eventevent might[27,28],might resultresult coamorphous in in formation formation solids of of different [different25,28– solid33], solid physical forms forms such mixtures such as eutectics as [22,eutectics25,34], [22–26 [22],salts a– drug26 [3], 5a polymorph], drugsolvates polymorph [3[275,3,286],], coamorphoushydrates[27,28], coamorphous [35– solids37] and [25 solid ,28solids–33 solutions], [ physical25,28– [3338 mixtures],– 4physical0]. These [22 ,mixtures25solid,34 ],forms salts [22, [can3525,34],], consist solvates salts of[35 a[3 ,single365],], hydratessolvates component [[3355–,337 6or],] andmultiplehydrates solid [3components. solutions5–37] and[ 38solid –Single40 solutions]. Thesecomponent [3 solid8–40]. forms solidsThese can solidinclude consist forms amorphous ofcan a consist single forms of component a single and componentpolymorphs. or multiple or components.Multimultiplecomponent components. Single solids component canSingle be cocrystals solidscomponent include [41 ,4solids2 amorphous], salts include [41], forms coamorphous amorphous and polymorphs. solidsforms [2 and8], Multicomponent polymorphs polymorphs. of solidscocrystalsMulticomponent can be[43 cocrystals], solvates/hydrates solids can [41, 42be], cocrystals salts [36 [,3417],], [4 coamorphousand1,42 ],continuous salts [41 solids], coamorphoussolid [28 solutions], polymorphs solids or discontinuous[28], of cocrystalspolymorphs solid [43 of], solvates/hydratessolutions/eutecticscocrystals [43], solvates/hydrates [36 [34].,37], Figure and continuous 2 and [36 Table,37 solid], and1 explains solutions continuous t orhe discontinuous differences solid solutions between solid or solutions/eutectics differentdiscontinuous solid formssolid [34]. Figureofsolutions/eutectics an API.2 and Table1 explains[34]. Figure the differences2 and Table between 1 explains different the differences solid forms between of an API. different solid forms of an API.

FigureFigure 2.2. Schematic representation ofof variousvarious singlesingle andand multicomponentmulticomponent formsforms ofof anan APIAPI [Reprinted[Reprinted Figure 2. Schematic representation of various single and multicomponent forms of an API [Reprinted fromfrom [[34]34] withwith permission.permission. CopyrightCopyright 20142014 RoyalRoyal SocietySociety ofof Chemistry].Chemistry]. from [34] with permission. Copyright 2014 Royal Society of Chemistry]. As new forms of pharmaceutical solids are being produced with different type of guest As new forms of pharmaceutical solids are being produced with different type of guest molecules moleculesAs new (solvents/water/solids), forms of pharmaceutic assigningal solids an exactare being nomenclature produced for with each differentof the solid type was of a guesthotly (solvents/water/solids), assigning an exact nomenclature for each of the solid was a hotly debated debatedmolecules topic (solvents/water/solids), for many years [44–4 assigning6]. Inspired an by exact the worknomenclature of Aitipamula for each et al. of [45the], solidGrothe was et a l.hotly [46] topic for many years [44–46]. Inspired by the work of Aitipamula et al. [45], Grothe et al. [46] developed developeddebated topic a forstraightforward many years [4 4system–46]. Inspired for classification by the work ofof Aitipamula multicomponent et al. [45 solid], Grothe forms. et a l. The[46] a straightforward system for classiﬁcation of multicomponent solid forms. The classiﬁcation system classificationdeveloped a systemstraightforward proposed bysystem Grothe for et al.classification [46] is shown of in Figuremulticomponent 3. solid forms. The proposedclassification by Grothe system et proposed al. [46] is by shown Grothe in Figureet al. [436.] is shown in Figure 3.

Figure 3. Schematic representation of proposed multicomponent classification system by Grothe et Figureal.Figure [46] [Reprinted3. 3. SchematicSchematic from representation [46 representation] with permission. of proposed of proposed Copyright multicomponent multicomponent2016 American classification Chemical classiﬁcation syste Society]m by system. Grothe by et Grotheal. [46] et[Reprinted al. [46] [Reprinted from [46] fromwith [permission.46] with permission. Copyright Copyright 2016 American 2016 American Chemical ChemicalSociety]. Society]. 2.1. Cocrystals 2.1. Cocrystals Cocrystals are defined as crystalline materials with two or more different molecules (i.e., drug and coformers)Cocrystals inare the defined same crystalas crystalline lattice [4materials7]. In pharmaceutical with two or moreindustries, different cocrystals molecules have (i.e., gained drug a and coformers) in the same crystal lattice [47]. In pharmaceutical industries, cocrystals have gained a

Pharmaceutics 2018, 10, 108 4 of 74

2.1. Cocrystals Cocrystals are defined as crystalline materials with two or more different molecules (i.e., drug and coformers) in the same crystal lattice [47]. In pharmaceutical industries, cocrystals have gained a tremendous importance because of its ability to fine-tune the physicochemical properties of drugs [48]. Regulatory agencies such as United States Food and Drug Administration (USFDA) and European Medicine Agency (EMA) has provided distinct definition for these pharmaceutical cocrystals [49,50]. USFDA defines cocrystals as ‘crystalline materials composed of two or more molecules in the same crystal lattice’ [49]. According to EMA, cocrystals are ‘homogenous (single phase) crystalline structures made up of two or more components in a definite stoichiometric ratio where the arrangement in the crystal lattice is not based on ionic bonds (as with salts)’ [50]. Cocrystals are mainly stabilized by the strong intermolecular non-covalent adhesive interactions of short-range order [51] that exist between the drug and coformer molecules. The first known cocrystal called ‘quinhydrone’ was synthesized using benzoquinone and hydroquinone by Friedrich Wohler in the year 1844 [52]. It was the first cocrystal structure reported in Cambridge Structural Database [53]. Intermolecular interactions [54], structural compatibility [55] and stoichiometry of API and coformer molecules [56] determine successful formation of cocrystal during a cocrystallization event. Table2 presents the summary of a few literature reports available on representative pharmaceutical cocrystals.

Table 1. Characteristic feature of eutectics, cocrystals and solid solutions.

Property Eutectic Phase Cocrystal Solid Solution Reference(s) Structural similarity of the Similar or dissimilar Similar or dissimilar Similar [55] parent molecules Isomorphous or Isomorphous/ Isomorphous/ Isomorphous [34,55] non-isomorphous non-isomorphous non-isomorphous Mostly in between the melting points of parent Exhibits a Melting point of Lower melting than the molecules but may also be solidus-liquidus [34,55] the solid formed parent components higher or lower than the melting behavior parent molecules Binary phase Unary phase ‘V’-shaped curve ‘W’-shaped curve [34,55] diagram diagram Stronger and non-covalent Short-range and weaker adhesive interactions Stronger and Intermolecular non-covalent adhesive (hydrogen bonding, non-covalent [34,55] interactions interactions halogen bonding, Π-Π cohesive interactions interactions, etc.) Arrangement of Molecules are well Molecules are Molecules are molecules in organized and [34,55] randomly arranged well organized crystal lattice well-packed Predominant thermodynamic Entropy Enthalpy Enthalpy [34,55] force of the system Characterized by a Characterized by a new No signiﬁcant change new crystal phase Crystal structure of crystal phase formation from the parent formation and [34,55] the solid formed and hence possess a new components therefore possess a crystal structure new crystal structure Thermodynamic More stable stability of the Less stable More stable than eutectics [34] than eutectics solid formed Pharmaceutics 2018, 10, 108 5 of 74

Table 2. Summary of a few literature reports on representative pharmaceutical cocrystals.

Stoichiometric Binary/Ternary Comments on Name of the API Therapeutic Use of the API Name of the Coformer Ratio of the Preparation Method Reference(s) System Dissolution Behavior Cocrystal

Fluoxetine HCl-Succinic acid Benzoic acid, 1:1 (2:1) and Fluoxetine HCl-Fumaric acid (2:1) cocrystals exhibited enhanced intrinsic dissolution rate than Fluoxetine Hydrochloride Antidepressant drug Binary Slow evaporation raw Fluoxetine HCl while [57] Succinic acid, 2:1 Fluoxetine HCl-Benzoic acid (1:1) and Fluoxetine HCl-Fumaric acid (2:1) cocrystals showed lower Fumaric acid 2:1 powder dissolution rate than raw Fluoxetine HCl

The cocrystal phase showed 2-[4-(4-chloro-2-ﬂuorophenoxy)phenyl] 18 times increased intrinsic Sodium channel blocker Binary Glutaric acid 1:1 Solution crystallization [58] pyrimidine-4-carboxamide dissolution rate than the commercial API Benzoic acid, trans-cinnamic acid, The cocrystals showed 2,5-dihydroxybenzoic enhanced dissolution in A transient receptor potential acid, glutaric acid, Fasted Simulated Intestinal AMG 517 vanilloid 1 antagonist Binary glycolic acid, 1:1 Slow cooling [59] Fluid (FaSIF) (characterized (TRPV1) trans-2-hexanoic acid, by bell-shaped proﬁle) than 2-hydroxycaproic acid, raw AMG 517 L(+)-lactic acid, sorbic acid, L(+)-tartaric acid Solubility and permeability of Fumaric acid, 1:1.5, 1:1 Reaction crystallization method the cocrystals were higher [60] Glutaric acid A guanosine analogue than that of raw acyclovir Acyclovir Binary antiviral drug Dissolution rate of the Solution crystallization and Tartaric acid 1:1 cocrystals were faster than [61] Solvent-drop grinding anhydrous acyclovir Pharmaceutics 2018, 10, 108 6 of 74

Table 2. Cont.

Stoichiometric Binary/Ternary Comments on Name of the API Therapeutic Use of the API Name of the Coformer Ratio of the Preparation Method Reference(s) System Dissolution Behavior Cocrystal Salicylic acid 1:1 Not reported [62,63] Maleic acid or 1:1Slurry method and Not reported [64] maleinic acid, High-Throughput Screening Salicylic acid and few 1:1 methods HTS Evaporative The extruded cocrystals other carboxylic acids experiments, Sonic slurry showed faster dissolution experiments, Grinding rates than the [65] Carbamazepine Anticonvulsant drug Binary Saccharin 1:1 experiments and Reaction solvent-crystallized cocrystals crystallization Hot-Melt and raw carbamazepine Extrusion Resonant Acoustic mixing Liquid-assisted grinding, Not reported [66] 1:1, 2:1:1 cocrystal slurry conversion and solution Carbamazepine- 0 hydrate and 2:1:1 4,4 -Bipyridine crystallization methods p-aminosalicylic acid (1:1) cocrystal solvate p-aminosalicylic acid cocrystal showed enhanced [67] with methanol dissolution than raw as solvent carbamazepine Cocrystals showed Helps to lower cholesterol Solution crystallization and Fenoﬁbrate Binary Nicotinamide 1:1 enhanced dissolution [68] and fat level Solvent-drop grinding than raw nicotinamide Agomelatine-urea (1:1) and agomelatine-glycolic acid (1:1) cocrystal was prepared by Urea, glycolic solution crystallization whereas Cocrystals showed enhanced Agomelatine Antidepressant Binary acid, isonicotinamide and 1:1 agomelatine-isonicotinamide (1:1) powder dissolution rate than [69] methyl-4-hydroxybenzoate and agomelatine-methyl-4- raw agomelatine hydroxybenzoate (1:1) cocrystal was prepared by melting and recrystallizing in solvent Salicylic acid, 3,5-dinitrobenzoic acid, Neuroleptics and Solvent-assisted grinding and Benzamide Binary 3-nitrobenzoic acid and 1:1 Not reported [70] antipsychotics solvent evaporation 4-hydroxy 3-nitrobenzoic acid Adipic acid, succinic acid, terephthalic acid, Fluorocytosine Antitumor agent Binary 1:1 Solution crystallization Not reported [71] benzoic acid and malic acid Pharmaceutics 2018, 10, 108 7 of 74

Table 2. Cont.

Stoichiometric Binary/Ternary Comments on Name of the API Therapeutic Use of the API Name of the Coformer Ratio of the Preparation Method Reference(s) System Dissolution Behavior Cocrystal The cocrystals exhibited faster dissolution than raw curcumin. Solution crystallization Curcumin-pyrogallol Resorcinol, Pyrogallol 1:1 [72] and liquid- cocrystals showed enhanced dissolution than curcumin-resorcinol cocrystal and raw curcumin Curcumin-phloroglucinol cocrystal showed lower Anticancer, antimalarial and Phloroglucinol 1:1 assisted grinding [73] Curcumin Binary dissolution than raw antibacterial compound curcumin Curcumin-hydroxyquinol cocrystals showed enhanced dissolution than raw Rotary evaporation method curcumin. Hydroxyquinol 1:1 and 1:2 Solution crystallization and Curcumin-hydroxyquinol [24] Solid-state grinding (1:2) cocrystal exhibited enhanced dissolution than curcumin-hydroxyquinol (1:1) cocrystal and raw curcumin 4,40-Bipyridine-N,N0-dioxide 1:1 Solution crystallization Not reported [74] Non-Steroidal Indomethacin-saccharin Indomethacin Anti-Inﬂammatory Drug Binary Saccharin 1:1 Twin screw extrusion cocrystal showed enhanced [75] (NSAID) dissolution raw indomethacin Pharmaceutics 2018, 10, 108 8 of 74

2.2. Eutectics Eutectics are another important class of multicomponent solids that has been gaining tremendous attention in pharmaceutical research in the recent years. When attempts to obtain a cocrystal fail, one may end up with a eutectic. Eutectics are multicomponent crystalline materials which exist in the form of discontinuous solid solutions (as shown in Figure2). Cherukuvada and Nangia [ 34] defined eutectics as a conglomerate of solid solutions [34]. Unlike cocrystals, eutectic phases are stabilized by weaker adhesive interactions between the unlike molecules or stronger cohesive interactions between the molecules having similar structure [34,55]. Eutectic phases do not have a distinct or a specific crystal structure. Instead their crystalline nature resembles the combination of crystalline nature of the parent components. Eutectics possess a melting point less than the melting point of the pure components. Table1 presents characteristic features of eutectics vis- à-vis’ other solid forms. Eutectics can be as good as cocrystals in fine-tuning the physicochemical properties of an API [55]. Duarte et al. [76] reported a eutectic dispersion of fenofibrate with a low molecular weight polymer, polyethylene glycol. This eutectic dispersion is commercially being available with the trade name ‘Fenoglide’ [76,77]. These eutectic dispersions possessed lower melting point and crystalline nature similar to the parent components [76]. Furthermore, Faeges [78] formulated liquefied form of a eutectic of aspirin with 2-3 parts of glycerin or propylene glycol (w/v)[78] as an ointment for topical applications. These eutectic formulations were also reported to enhance the shelf-life of aspirin by preventing its hydrolysis [78]. Several reports are available in the literature where eutectics were used for increasing the dissolution of poorly water-soluble drugs. The summary of reports available in the literature on various drug eutectics and their dissolution behavior are presented in Table3. From Table3, it is evident that the eutectic mixtures show significantly enhanced dissolution as compared to the raw drug. This ability of eutectic mixtures to exhibit enhanced dissolution rates than the raw drug is attributed to the randomized lattice arrangement which exists in the eutectic phase [24]. Cherukuvada and Row [55] employed hydrogen-bonding principles to understand and design generalized rules involved in cocrystal/eutectic/solid solution formation by investigating cocrystallization of 4,40-bipyridine, isonicotinamide, isoniazid Fluoxetine hydrochloride drug systems as a model for their study [55]. Furthermore, Cherukuvada and Nangia [34] formulated ground rules based on the crystal engineering approach to explain the circumstances favoring cocrystal/eutectic/solid solution formation with respect to the structural similarity and intermolecular interactions existing in the binary system. While eutectic formation occurs with a pair of molecules having either similar or dissimilar structures [23,34] and sustained by weaker adhesive interactions, cocrystals are stabilized by strong adhesive interactions [34]. Table1 presents the characteristic features of cocrystals vis-à-vis eutectics and solid solutions in comparison with cocrystals.

2.3. Solid Solutions A solid solution is a homogeneous phase formed out of a solid-state reaction between the drug and coformer which are miscible into each other. When two molecules possess structural similarity (isomorphous and isostructural), then the resultant solid form is generally a solid solution [38–40]. Solid solutions are stabilized by strong cohesive interactions. Table1 presents salient features of solid solutions and explains the difference in how different a solid solution is vis-à-vis other solid forms. Table4 presents the summary of a few reports available in the literature on drug solid solutions. Pharmaceutics 2018, 10, 108 9 of 74

Table 3. Summary of few reports on pharmaceutical eutectics available in the literature.

Binary/Ternary Mole Fraction of Comments on API Therapeutic Use of API Coformers Studied Preparation Method Reference(s) System the Coformer Dissolution Behavior All the eutectics showed Nicotinamide, Binary 0.67 Solid-State Grinding enhanced dissolution than [22] raw curcumin Hydroquinone, Binary 0.5 Solid-State Grinding [22] Anticancer, antimalarial and Curcumin (Form 1) p-hydroxybenzoic acid, Binary 0.5 Solid-State Grinding [22] antibacterial compound Tartaric acid, Binary 0.5 Solid-State Grinding [22] Ferulic acid, Binary 0.5 Solid-State Grinding [22] Salicylic acid, Binary 0.67 Solid-State Grinding [24] Suberic acid Binary 0.8 Liquid-Assisted Grinding Not reported [25] Isoniazid, Binary 0.5 Solid-state grinding Showed faster dissolution Pyrazinamide Anti-tuberculosis drug Isoniazid + Fumaric acid, Ternary 0.5 Solid-state grinding [34] than raw pyrazinamide Isoniazid + Succinic acid, Ternary 0.5 Solid-state grinding Isonicotinamide, Binary 0.25, 0.5, 0.75 Solid-state grinding Not reported Nitrogen supplement in Isoniazid, Binary 0.25, 0.5, 0.75 Solid-state grinding Not reported [56] Succinamide fresh water algae cultivation Fluoxetine HCl Binary 0.25, 0.5, 0.75 Solid-state grinding Not reported Antipruritic and Isoniazid, Binary 0.25, 0.5, 0.75 Solid-state grinding Not reported Succinamic acid [55] anti-infective agent Fluoxetine HCl Binary 0.25, 0.5, 0.75 Solid-state grinding Not reported Theophylline, Binary 0.4 Hesperetin eutectics showed Antioxidant, Anticancer Adenine, Binary 0.67 Solvent-drop-assisted Hesperetin 2 to 4 times faster dissolution [79] and cardioprotective agent Gallic acid, Binary 0.6 solid-state grinding than raw hesperetin Theobromine Binary 2:1 Phenylbutazone, Binary 0.550 Not reported Not reported Phenazone Analgesic, NSAID drug Phenacetin, Binary 0.420 Not reported Not reported [80] Urea Binary 0.5 Not reported Not reported Sulfadiazine Antibiotic Trimethoprim Binary 0.737 Not reported Not reported [80] 4-aminophenazone, Binary 0.5 Not reported Not reported Analgesic, Phenacetin, Binary 0.320 Not reported Not reported Aminophenazone anti-inﬂammatory Phenylbutazone, Binary 0.5 Not reported Not reported [80] andantipyretic drug Phenazone, Binary 0.463 Not reported Not reported Etofylline, Binary 0.142 Not reported Not reported Analgesic and antipyretic Acetanilide Phenacitin Binary 0.337 Not reported Not reported [80] compound Phenacitin NSAID Phenobarbital Binary 0.340 Not reported Not reported [80] Paracetamol Treatment of pain and fever Phenobarbital Binary 0.450 Not reported Not reported [80] Pharmaceutics 2018, 10, 108 10 of 74

Table 3. Cont.

Binary/Ternary Mole Fraction of Comments on API Therapeutic Use of API Coformers Studied Preparation Method Reference(s) System the Coformer Dissolution Behavior Phenobarbital Binary 0.327 Not reported Not reported [80] Proper mixing by melting 2-3 parts glycerin or and followed by allowing Binary Not reported Not reported [78] propylene glycol (w/v) to cool to room Aspirin Treatment of pain, fever andinﬂammation temperature The eutectic mixture Simvastatin Binary 66.6% w/w Grinding exhibited enhanced [81] dissolution than raw drug Phenylbutazone, 0.867 Sulfanilamide Antibacterial agent Benzocaine,Binary 0.867 Not reported Not reported [80] 4-aminobenzoic acid 0.404 Sulfathiazole, 0.601 Caffeine CNS Stimulant Binary Not reported Not reported [80] Paracetamol 0.619 Benzocaine, 0.936 Sulfathiazole Antibiotic Binary Not reported Not reported [80] 4-aminobenzoic acid 0.574 Sulfapyridine, 0.296 Khellin Vasodilator Binary Not reported Not reported [80] Nicotinic acid 0.194 2-nitroaniline - 4-aminobenzoic acid Binary 0.052 Not reported Not reported [80] Hormonal therapeutic agent Estradiol phenyl Estradiol benzoate Binary 0.837 Not reported Not reported [80] for menopausal symptoms propionate

Pyridoxine Vitamin B6 Isoniazid, Nicotinic acid Binary 0.2, 0.25 Liquid-Assisted Grinding Not reported [82] Syringic acid Binary 50/50% w/w Solid-state grinding Irbesartan eutectic mixtures Irbesartan Antihypertensive drug Nicotinic acidv Binary 50/50% w/w Solid-state grinding exhibited 2- to 3-fold [83] enhancement in intrinsic Ascorbic acid Binary 50/50% w/w Solid-state grinding dissolution rate Pharmaceutics 2018, 10, 108 11 of 74

Table 4. Summary of a few reports available in the literature on drug solid solutions.

Binary/Ternary Name of the API Therapeutic Use of API Excipient Reference System Triiodoresorcinol (TIR) Mycoses treatment Binary Triiodophloroglucinol (TIG-O) [39] Triiodophenol (TIP) Disinfectant Binary o-Triiodoresorcinol (TIR-O) [39] Benzoic acid Antibacterial agent Binary 4-Fluorobenzoic acid [38,40] Treatment of pellagra (caused Isoicotinamide Ternary Succinic acid and fumaric acid [84] due to Niacin deﬁciency)

2.4. Coamorphous Solids Coamorphous solids are another interesting group of pharmaceutical solids. Coamorphous solids are solid forms in which the amorphous state is stabilized by weak intermolecular interactions [85,86] between the drug and coformer molecules. Coamorphous solids are used to enhance the bioavailability of hydrophobic drugs as their amorphous nature can improve aqueous solubility of an API. The term ‘coamorphous’ was ﬁrst coined by Chieng et al. [85]. A drug and the polymer combination may result into ‘Amorphous Solid Dispersions (ASDs)’ whereas a mixture of amorphous drug and low molecular weight coformers can form a ‘coamorphous solid’ [87]. Weak intermolecular interactions (such as hydrogen bonding and/or Π-Π interactions [85,86]) dominate between drug and coformer in coamorphous solids. The coamorphous solids possess glass transition temperature (Tg) in between the glass transition temperatures of individual components [86]. There are also reports where coamorphous solids with no well-deﬁned stoichiometry have been reported [30]. Table5 presents a summary of few literature reports where coamorphous solids of APIs have been reported. From the literature reports (as shown in Table5), it is evident that the coamorphous solids showed enhanced dissolution rates than the raw drug molecules [25,28–31,33,88]. This enhancement in dissolution rate mainly depends on two important factors namely: (i) capability of the drug to maintain higher supersaturation level and (ii) the strength of the API-coformer interaction to slow down the nucleation. In a study on Curcumin-artemisin coamorphous solid, Nangia and coworkers [28] have stated that coamorphization induces micronization of particles and in a way also leads to enhanced dissolution rates [28]. From the literature information available on coamorphous solids, one can conclude that coamorphous solids are one of the byproducts of a cocrystallization process which can enhance dissolution of hydrophobic drugs in aqueous medium [89], and in turn their bioavailability. Also, it was observed that the higher level of apparent solubility attained with the coamorphous solids during in vitro dissolution studies also resulted in enhanced in vivo bioavailability [89,90]. However, there is a need to investigate the long-term dissolution rates of pharmaceutical coamorphous solids. Pharmaceutics 2018, 10, 108 12 of 74

Table 5. Summary of a few reports on drug coamorphous solids available in the literature.

Therapeutic Use Coamorphous Solid API Coformer Preparation Method Comments on Dissolution Behavior Reference(s) of API Stoichiometry The coamorphous solid exhibited 2.6 times faster Artemisinin 1:1 Rotavaporization [28] dissolution than raw curcumin Curcumin-piperazine coamorphous phase showed lower dissolution than raw curcumin at Curcumin (Form 1) Anticancer compound Piperazine 1:2 Ethanol-assisted Grinding temperature above Tg of the coamorphous solid [29] and exhibited higher dissolution than raw curcumin at a temperature below Tg The coamorphous phase showed 4 times higher Folic Acid Dihydrate 1:1 Liquid-Assisted Grinding [25] dissolution than raw curcumin Non-steroidal The coamorphous solids exhibited increased 1:2, 1:1 and 2:1 (1:1 Indomethacin Anti-Inflammatory Naproxen Quench cooling intrinsic dissolution rate and 1:1 form showed a [30] was the stable form) Drug (NSAID) synchronized release Coamorphous phase showed increased intrinsic Non-steroidal Tryptophan+Proline 1:1:1 Ball milling Naproxen Anti-Inflammatory dissolution rate than the crystalline naproxen [31] Drug (NSAID) Coamorphous phase showed increased intrinsic Arginine+Proline 1:1:1 Ball milling dissolution rate than the crystalline naproxen Lipid-lowering agent Exhibited increased intrinsic dissolution rate than Atorvastatin calcium and in treatment of Nicotinamide 1:1 Solvent evaporation [88] the raw drug cardiovascular diseases Short-acting L-Tartaric acid 1:1 Co-milling Not reported Sulfathiazole [32] sulfonamide antibiotic Citric acid 1:1 Co-milling Not reported Loading of mixtures into The nanoconfined coamorphous solid showed Ibuprofen NSAID Nicotinamide 50% wt./wt. nanopores of mesoporous [33] enhanced dissolution than raw ibuprofen silica microspheres Pharmaceutics 2018, 10, 108 13 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 13 of 74

2.5. Salts 2.5.Salt Salts formation is one of the traditional methods employed to enhance the aqueous solubility of poorlySalt water-soluble formation is drugs. one of More the traditional than half methods of the medicines employed in to market enhance exist the aqueous in the form solubility of salt of [90 ]. Saltspoorly are formedwater-soluble because drugs. of intermolecular More than half hydrogenof the medicines bonding in market due to exist proton in the transfer form of between salt [90]. the moleculesSalts are withformed ionizable because functional of intermolecular groups. hydrogen Figure4 presentsbonding due the schematicto proton transfer representation between of the the differencemolecules between with ionizable a salt andfunctional cocrystal groups. [91]. Figure Hence, 4 saltpresents formation the schematic is favored representation only when of the the API containsdifference an ionizablebetween a site salt in and it [ 15cocrystal,92]. Formation [91]. Hence, of an salt API formation salt with is afavored coformer only occurs when when the API there is acontains proton an transfer ionizabl frome site an in acidit [15,92]. to a baseFormation in the of ionic an API state salt [ 91with,93 ].a coformer According occurs to Sarma when etthere al. [is44 ], APIa proton molecules transfer with from nitrogenous an acid functionalityto a base in the and ionic –COOH state [91,93]. functional According groups into theirSarma chemical et al. [44], structure API aremolecules more susceptible with nitrogenous to salt formationfunctionality [44 and] since –COOH these functional molecules group cans favor in their proton chemical transfer structure to the are more susceptible to salt formation [44] since these molecules can favor proton transfer to the coformer molecules. It has been also reported that presence of adequate number of counterions in an coformer molecules. It has been also reported that presence of adequate number of counterions in an API and coformer molecule facilitates salt formation [94]. The presence of charge-assisted hydrogen API and coformer molecule facilitates salt formation [94]. The presence of charge-assisted hydrogen bonding in salts enables coformer molecules to dissociate easily from the salt complexes resulting in bonding in salts enables coformer molecules to dissociate easily from the salt complexes resulting in peak solubility of drug in a dissolution medium within a few hours. Moreover, from thermodynamic peak solubility of drug in a dissolution medium within a few hours. Moreover, from thermodynamic point of view, salts possess higher enthalpy of hydration which also facilitates attainment of higher point of view, salts possess higher enthalpy of hydration which also facilitates attainment of higher dissolutiondissolution rate rate [95 [95].].

(A) (B)

Figure 4. Schematic representation of difference between (A) a salt and (B) a cocrystal [Reprinted Figure 4. Schematic representation of difference between (A) a salt and (B) a cocrystal [Reprinted from [91] with permission. Copyright 2007 American Chemical Society]. from [91] with permission. Copyright 2007 American Chemical Society]. 2.6. Salt-Cocrystal Continuum 2.6. Salt-Cocrystal Continuum Salt-cocrystal continuum is other interesting subset of multicomponent pharmaceutical solids whichSalt-cocrystal falls under continuum cocrystal/salt is other category. interesting When subseta multicomponent of multicomponent solid form pharmaceutical contains mixed solids whichionization falls understates (the cocrystal/salt extent of proton category. transfer When from one a multicomponent molecule to the other solid is not form predictable), contains mixedit is ionizationdifficult to states understand (the extent whether of proton the resultant transfer solid from form one is molecule a salt or tococrystal. the other This is notmainly predictable), occurs it iswhen difﬁcult the difference to understand in pKa whether value of thethe resultantdrug and solidcoformer form lies is between a salt or cocrystal.0 and 3 [93] This (Explained mainly later occurs whenin Section the difference 3.1). Childs inpKa et al. value [93] investigated of the drug the and influence coformer of liescrystal between structure 0 and on 3the [93 ionization] (Explained states later inof Section the salt 3.1-cocrystal). Childs continuum. et al. [93] investigated Jacobs and Noa the [96] inﬂuence reported of crystala hybri structured salt-cocrystal on the methanol ionization water states ofsolvate the salt-cocrystal of p-Coumaric continuum. acid-Quinine Jacobs with and unexpected Noa [96] reported stoichiometry a hybrid prepared salt-cocrystal by slow methanol evaporation water solvate[96]. of p-Coumaric acid-Quinine with unexpected stoichiometry prepared by slow evaporation [96].

3. Factors3. Factors Determining Determining Cocrystallization Cocrystallization

3.1.3.1.∆pKa ∆pKa Rule Rule ∆pKa∆pKa value value hashas beenbeen used to to assess assess cocrystal cocrystal formation formation ability ability of a ofcoformer a coformer with a with given a API given API[93,97]. [93,97 pKa]. pKa value value (negative (negative logarithm logarithm of ofdissociation dissociation constant) constant) indicates indicates the theability ability of ofan anacid acid moleculemolecule to to give give up up a a proton proton [ 93[93].]. WhenWhen the difference between between pKa pKa value value of of API API and and coformer coformer (∆pKa)(∆pKa) ranges ranges in negative in negative values, values, there there will will be no be proton no proton transfer transfer [93,98 [93,98].]. Therefore, Therefore, one can one possibly can expectpossibly cocrystal expect formation cocrystal formation in such a casein such [93 a,97 case–99 ].[93,97 On– the99]. other On the hand, other salt hand, formation salt formation is observed is whenobserved∆pKa when value ∆pKa is greater value than is greater 3 due to than completion 3 due to of completion proton transfer of proton [93, 98 transfer,99]. According [93,98,99]. to BerryAccordin and Steedg to Berry [98], and when Steed∆ pKa[98], valuewhen ∆pKa remains value close remains to that close of to a that base, of thena base, the then system the system forms a forms a salt and when it exists close to the acid, then the system forms a cocrystal [98]. da Silva et al. salt and when it exists close to the acid, then the system forms a cocrystal [98]. da Silva et al. [71] [71] designed and developed five 5-Fluorocytosine cocrystals with adipic, succinic, terephthalic, designed and developed ﬁve 5-Fluorocytosine cocrystals with adipic, succinic, terephthalic, benzoic,

Pharmaceutics 2018, 10, 108 14 of 74 and malic acid based on the ∆pKa values for API-coformer [71]. When the ∆pKa value ranges between 0 and 3 (partially ionized states), in such cases, these solid forms were referred to as Salt-cocrystal continuum [93,99,100]. Interestingly, Nangia and coworkers [100], while attempting to develop Clotrimazole (CLT) cocrystals with some carboxylic acid coformers, identiﬁed salt formation with maleic acid (MA) at a stoichiometric ratio of 1:0.5 (CLT:MA) whereas the calculated ∆pKa value for the system was 0.93 [101]. Thus, an ∆pKa value cannot always be used to predict/conﬁrm the nature of a solid phase in all the cases and an experimental analysis is required for accuracy.

3.2. Hydrogen Bond Donors and Acceptors The number of hydrogen bond donors and acceptors in a coformer and drug molecules also determines the extent of success in a cocrystallization event. Molecules that can form multiple hydrogen bonds are likely to form cocrystals with the coformer molecules [102]. Etter [103] and Donohue [104] framed HydrogenBond Rules to predict the circumstances under which hydrogen bond interactions that result into cocrystals [54,103,104]. These rules are as given below:

+ a. Mostly all good proton donors (such as –COOH, –NH4 ) and acceptors (such as –OH, –NH3) are utilized in hydrogen bonding. b. Six-membered ring intramolecular hydrogen bonds (such as C-H. . . O) are formed ﬁrst in preference to intermolecular hydrogen bonds (such as N-H. . . O and O-H. . . O) c. The best proton donors and acceptors available after intramolecular hydrogenbond formation then participate in intermolecular hydrogen bonds d. All acidic hydrogen atoms are included in hydrogen bonding in the crystal structure

3.3. Molecular Recognition Points Almarsson and Zaworotko [105] pointed out that the API molecules contain certain functional group (or molecular recognition point) in their structure which interacts with the coformer and thereby create a supramolecular unit (or molecular recognition point) called supramolecular synthons [105]. The term ‘Synthon’ was first introduced by Corey in 1967 who defined Synthons as “Structural units within supermolecules which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions”[106]. Desiraju [107] defined supramolecular synthons as spatial arrangement of intermolecular interactions which serves as a base for any supramolecular synthesis [107]. Thus, synthons are design elements in crystal engineering which are different from the term ‘intermolecular interactions’ [108]. Sometimes, a synthon can also be represented as a single interaction [107] (such as Cl. . . Cl and N. . . Br interactions) in a few supermolecular structures. Based on the complementary functional groups in the drug and coformer, these supramolecular synthons are classified as homosynthons and heterosynthons [105]. Homosynthons are formed as a result of the interaction between self-complementary functional groups such as acid. . . acid and amide. . . amide groups (Figure5) whereas the heterosynthon formation arises due to the interaction between two different functional groups (such as acid. . . amide, acid. . . pyridine and amide. . . pyridine groups (see Figure6). Heterosynthons could also be formed as a result of halogen bonding. Figure7 presents a few examples of heterosynthons formed through halogen bonding. Pharmaceutics 2018, 10, x FOR PEER REVIEW 15 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 15 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 15 of 74

Pharmaceutics 2018, 10, 108 15 of 74

(A) (B) (A) (B) (A) (B) Figure 5. Schematic representation of supramolecular homosynthons (A) acid-acid dimer and (B) Figureamide- amide5. Schematic dimer representation[34,55] [Reprinted of supramolecular from [55] with homosynthons permission. (AC)opyright acid-acid 2014 dimer American and (B) FigureFigure 5. SchematicSchematic representation representation of of supramolecular supramolecular homosynthons homosynthons (A) ( Aacid) acid-acid-acid dimer dimer and and (B) amideChemical-amide Society] dimer. [34,55] [Reprinted from [55] with permission. Copyright 2014 American (amideB) amide-amide-amide dimer dimer [34,55 [34,]55 [Reprinted] [Reprinted from from [5 [555] ]with with permission. C Copyrightopyright 2014 AmericanAmerican Chemical Society]. ChemicalChemical Society].Society].

(A) (B) (A) (B) (A) (B)

(C) (D) (C) (D) (C) (D) FigureFigure 6.6.Schematic Schematic representationrepresentation ofof supramolecularsupramolecular heterosynthonsheterosynthons ((AA)) acid-amideacid-amide dimerdimer [[29,5029,50],], Figure 6. Schematic representation of supramolecular heterosynthons (A) acid-amide dimer [29,50], (Figure(BB)) acid-pyridine acid 6.- pyridineSchematic dimer dimer representation [34 ,55[34,5], (C5],) amide-pyridine (ofC )supramolecular amide-pyridine dimer heterosynthons [dimer34,55] [Reprinted[34,55 ]( A[Reprinted) fromacid-amide [55] withfrom dimer permission. [5 5[29,50] with], (B) acid-pyridine dimer [34,55], (C) amide-pyridine dimer [34,55] [Reprinted from [55] with Copyright(permission.B) acid-pyridine 2014 Copyright American dimer 2014 Chemical[34,5 American5], ( Society]C) amide Chemical and-pyridine (D) Nitro-amineSociety] dimer and [34,5 interaction (D5)] Nitro[Reprinted [98-amine] [Reprinted frominteract [5 fromion5] w [[98]98ith] permission. Copyright 2014 American Chemical Society] and (D) Nitro-amine interaction [98] withpermission.[Reprinted permission from Copyright from[98] with Elsevier]. 2014 permission American from Chemical Elsevier] Society]. and (D) Nitro-amine interaction [98] [Reprinted from [98] with permission from Elsevier]. [Reprinted from [98] with permission from Elsevier].

(A) (B) (C) (A) (B) (C) (A) (B) (C) FigureFigure 7.7. SchematicSchematic representation representation of supramolecular heterosynthons brought about byby ((AA)) Figure 7. Schematic representation of supramolecular heterosynthons brought about by (A) Amine-halogenFigureAmine -halogen7. Schematic interaction,interaction, representation (B) Nitro Nitro-iodo- iodoof supramolecular interaction interaction and and (Cheterosynthons (C) )Halogen Halogen bonding bonding brought (X (X-Halogens-Halogens about bysuch such (A as) Amine-halogen interaction, (B) Nitro-iodo interaction and (C) Halogen bonding (X-Halogens such as asAmineCl, Cl, Br, Br, -Ihalogen and I and Y-Electron Y-Electroninteraction, pair pair ( Bdonors) Nitro donors such-iodo such as interaction N as or N O) or [9 O)and8] [[Reprinted98 (C]) [ReprintedHalogen from bonding from [98] [with 98(X]-Halogens withpermission permission such from as Cl, Br, I and Y-Electron pair donors such as N or O) [98] [Reprinted from [98] with permission from fromCl,Elsevier] Br, Elsevier]. I and. Y-Electron pair donors such as N or O) [98] [Reprinted from [98] with permission from Elsevier]. Elsevier].

Pharmaceutics 2018, 10, 108 16 of 74

3.4. Flexibility of Synthon-Forming Functional Groups In addition to molecular recognition points, the position of functional groups and the conformational flexibility of participating molecules play a significant role in determining success rate of a cocrystallization. For instance, Nangia and coworkers [22,72] identified that resorcinol can cocrystallize with curcumin whereas hydroquinone and catechol could not cocrystallize with curcumin though all the three molecules possessed same functional groups [22,72]. Such observations suggest that understanding the rationale behind formation of supramolecular synthons in the crystal lattice of the cocrystals is highly necessary for cocrystal design and development. Aakeroy et al. [108] carried out an extensive study to understand how polymorphic compounds serve as good cocrystallizing agents/coformers and emphasized the significance of flexibility of synthon-forming functional groups of coformers during any cocrystallization [108]. They experimentally studied the cocrystal forming ability of three polymorphic compounds, isonicotinamide, 2-amino 3-nitropyridine, 4-chlorobenzamide and maleic hydrazide [108]. It was observed in their study that isonicotinamide, 2-amino 3-nitropyridine and 4-chlorobenzamide participated actively in intermolecular hydrogen bonding with a variety of aliphatic and aromatic carboxylic acids and thereby favored the formation of binary/ternary cocrystals whereas maleic hydrazide was not found suitable candidate for cocrystallization with aromatic or aliphatic compounds having acid, amide and oxime functional groups. This was attributed to the flexibility of functional groups in coformers in addition to their polymorphic nature. Isonicotinamide, 2-amino 3-nitropyridine and 4-chlorobenzamide exhibit hydrogen bonding between different functional groups in each of their polymorphs whereas all the three polymorphs of maleic hydrazide always exhibited the primary hydrogen-bonding interactions between same functional groups which decreases the possibility of formation of new hydrogen bond synthons with the other molecules.

3.5. Carbon Chain Length of Dicarboxylic Acid Coformers Carboxylic acids are some of the most commonly used coformers for cocrystallization of many small molecules since they can form heterosynthons with molecules containing amide and pyridine functional groups and homosynthons with API molecules containing acid functional group. However, the cocrystal forming tendency of carboxylic acids also depends on the length of carbon chain in it. Shevchenko et al. [109] while investigating cocrystallization of itraconazole with different aliphatic dicarboxylic acids containing carbon chains of varying length observed that as the length of carbon chain in the coformer molecules increases, the packing of these molecules within the crystal lattice of drug molecules becomes increasingly difficult due to steric hindrance or incompatibility of large carbon chain to exactly fit into the crystal lattice of drug [109]. During their study, the researchers identified that itraconazole formed cocrystals with oxalic acid (C2), adipic acid (C6), malonic acid (C3), glutaric acid (C5) and pimelic acid (C7) and not with suberic acid (C8), azelaic acid (C9) and sebacic acid (C10). Based on this observation, it can be safely concluded that coformers containing longer carbon chains possibly are not suitable candidates for cocrystallization with API molecules where the probability of geometrical fitness of coformer into the API lattice is low [109].

3.6. Effect of Solvents Solubility of the API and coformer in a solvent used for cocrystallization plays a signiﬁcant role in determining the success of cocrystallization experiment. The solubility of the individual components must be determined a priori to cocrystallization experiments [110]. The Phase Solubility Diagram (PSD), also called as Ternary (API-Coformer-Solvent) Phase Diagram can be constructed using this data which then serves as a fundamental tool to identify region of cocrystal formation, understand the solution chemistry and solubility behavior of cocrystals [110]. The polarity of the solvent system, solubility of API and coformer, temperature and pH are the important parameters which determine the cocrystal forming zone in a ternary system. Robertson and his coworkers [111] observed that Pharmaceutics 2018, 10, 108 17 of 74 the polarity of the solvent determined the type of non-covalent interactions (hydrogen-bond or halogen-bond), and thereby controlling intermolecular interactions in the cocrystal phases [111]. It was summarized that the hydrogen-bonded cocrystals formation was favored by less polar solvents (such as toluene) whereas the more polar solvents (such as chloroform, dichloromethane, acetone, acetonitrile, nitromethane and 1-propanol) favored the formation of halogen-bonded cocrystals and in some cases, mixed halogen and hydrogen-bonded cocrystals [111]. This is mainly attributed to the inﬂuence of polarity of the different solvents on the strength of intermolecular interactions.

4. Screening Methods for Cocrystals As cocrystallization is inﬂuenced widely by several important parameters, selecting a suitable coformer for cocrystallization requires an effective screening process. Screening of a suitable coformer can be carried out experimentally or computationally. Experimental methods are exhaustive and time-consuming. On the other hand, computational methods can serve as a rapidscreening tool for initial assessment of coformers that are suitable for cocrystallization process. Sections 4.1 and 4.2 presents the various computational and experimental methods that can be used for coformer screening.

4.1. Computational Methods Most of the computational methods reported for coformer screening in literature till date are mainly thermodynamics-based methods. Issa et al. [112] used lattice energy calculations as an effective approach to screen coformers to form thermodynamically stable cocrystals [112]. If the lattice energy of the cocrystal is lower than the sum of lattice energies of individual components, then the cocrystal phase is said to be a thermodynamically stable phase [112]. Apart from calculation of lattice energies [112–115], several other parameters have also been employed for computational prediction of successful cocrystal formation or coformer screening. These include calculation of interaction energies [116,117], electrostatic potentials [118], molecular complementarity between API and coformers [119,120], solubility behavior [121–123], crystal energy landscapes of API-coformer pairs [124] and hydrogen bond propensities [125]. Table6 presents the summary of various computational coformer screening methods [112–132] reported so far in the literature. Despite being less labor intensive, computational screening methods suffer from the requirement of large simulation times to perform molecular dynamic simulations.

4.2. Experimental Methods Newman [133] has summarized various methods reported in the literature to obtain various solid forms such as polymorphs, salts, cocrystals and amorphous solid dispersions [133]. Though hydrogen-bonding motif structures play a signiﬁcant role in stabilizing the crystal structures of cocrystals [134–139], in some cases, evaluation of crystal structures of some cocrystals synthesized using techniques such as Solution crystallization, mechanocrystallization and hot-stage microscopy showed that these cocrystals do not possess hydrogen-bonding motifs as given by Crystal Engineering principles [124]. Therefore, a suitable coformer screening technique is highly essential for a cocrystallization process. Given below is a brief account of different experimental techniques which could be used for screening coformers for cocrystallization. Pharmaceutics 2018, 10, 108 18 of 74

Table 6. Summary or reports available in the literature on computational screening of coformers.

Computational Screening Investigated Drug-Coformer Pair Comments Reference Technique 6 cocrystals of caffeine, 8 cocrystals of succinic acid and Lattice energies of the cocrystals were compared with thesum of lattice Lattice energy prediction [112] 12 cocrystals of 4-aminobenzoic acid energies of individual crystal components

FLEXCRYST program was used to determine the relative stability of Lattice energy calculation Cocrystals of flavonoids flavonoid cocrystals stored in Cambridge Structural Database (CSD) [113] w.r.t pure crystals and a comparative analysis was made Diclofenac with 22 coformers, Piracetam with 29 coformers, Pyrazine carboxamide with 45 coformers, SSIPs (surface site interaction points) and the interaction site pairing Virtual screening tool based on gas Acetazolamide with 36 coformers, energies of different solid forms (∆E) determines the stability of the solid phase molecular electrostatic [116] Indomethacin with 57 coformers, forms and thereby enables ranking of Cocrystal Formers based on the potential surfaces (MEPS) a drug candidate with 28 coformers, calculated probability of cocrystal formation. Furosemide with 28 coformers, Nalidixic acid with 22 coformers and Paracetamol with 37 coformers Calculations were carried out for Nalidixic acid with Virtual screening tool based on This methodology utilizes surface Functional group interaction 310 coformers [117] energy calculations 44 Successful pairs were chosen for site interaction points (SSIPs) calculated from the ab initio MEPS of the experimental studies isolated molecule in the gas phase Molecular electrostatic potential surfaces enable assession of molecular Virtual screening tool based on gas Spironolactone and Griseofulvin complementarity between two cocrystal components for determining [118] phase MEPS the cocrystal forming ability Several coformers for combination with caffeine ad Interaction site pairing energies of different solid forms were calculated Virtual screening tool [126] carbamazepine (identified from literature review) w.r.t pure components and ranking is provided Miscibility affinities of liquid components under supercooledconditions Virtual cocrystal screening tool Isonicotinamide with 97 different coformers [127] were used as a key parameter to model the cocrystallization propensities Tyrosine kinase inhibitor axitinib, thiophanate-methyl Ranking is primarily based on the screening of coformers for API COSMO-RS (Conductor-like and thiophanate-ethyl benzimidazole fungicides were solubility improvement based on calculation of excess enthalpy, Hex, [122] Screening Model for Real Solvents) studied for their solubility behavior using COSMO-RS between an API-coformer mixture relative to the pure components COSMO-RS (Conductor-like COSMO-RS enables screening of coformers having good solubility with - [128] Screening Model for Real Solvents) suitable solvents for forming cocrystals Virtual coformer screening based on the API-coformer miscibility was COSMO-RS Wide range of pharmaceutical compounds performed to screen coformerto produce cocrystals with good Relative [123] Humidity (RH) stability Pharmaceutics 2018, 10, 108 19 of 74

Table 6. Cont.

Computational Screening Investigated Drug-Coformer Pair Comments Reference Technique Prediction of Hansen Indomethacin with thirty different coformers Utilization of group contribution method [121] Solubility Parameter Relative ∆∆E between heterodimers and homodimers served as a Calculation of energy difference N,N0-Diphenylureas and Triphenylphosphine Oxide int [129] good predictor of cocrystal formation in the investigated system

Pentoxifylline with coformers, aspirin, salicylic acid, FLEXCRYSTprogram was used to calculatethe free energy of experimental Free energy calculation [130] and benzoic acid and hypothetical crystal structures and then correlated with each other Computed values for the mixing enthalpies and solubility advantage In silico screening Phenylpiperazine derivatives anddicarboxylic acids [131] factors determine the cocrystallization propensities Nicotinamide, isonicotinamide, picolinamide and two Ab initio screening Lattice energy calculations [114] paracetamol cocrystals were screened for their stability Heat of formation distribution 492 pairs Calculation of Heat of formation (Hf) values [132] of components 974 cocrystal structures were investigated by Fabian Calculation ofQuantitative Structure-Activity Relationship (QSAR) Fabian approach [125] approach molecular descriptors of cocrystallizing components Carbamazepine (CBZ)-Nicotinamide (NCT), Utilization ofcomputed crystal Carbamazepine (CBZ)-Isonicotinamide (INA), Computed crystal energy landscapes of the drug-coformer pairs were [124] energy landscapes Carbamazepine (CBZ)-Benzamide (BNZ) and compared and analyzed with the binary and ternary phase diagrams Carbamazepine (CBZ)—Picolinamide (PA) Meloxicam cocrystal and Artemisinin cocrystal (pairs Molecular complementarity, hydrogen bond motifs and multicomponent Knowledge-based approach [119] reported in literature were used for the study) hydrogenbond propensities were compared and analyzed Pyrimethamine drug with carbamazepine, theophylline, Knowledge-based hydrogen Hydrogen bond propensity calculations were carried out to detect the aspirin, α-ketoglutaric acid, saccharin, p-coumaric acid, [120] bond prediction formation of new molecular adducts succinimide and L-isoleucine as coformers Involves three important steps: (1) Modelling of intermolecular Multistage lattice Cocrystal of 4-aminobenzoic acid with 2,20-bipyridine electrostatic interactions with atomic charges, (2) Interpolation of [115] energy minimization methodology and 4-nitrophenylacetic acid as coformers deformation energies and (3) Enhancement of accuracy Pharmaceutics 2018, 10, 108 20 of 74

4.2.1. Differential Scanning Calorimetric (DSC) Analysis Thermal analysis can be used for selection of a suitable coformer to form a cocrystal with a desired drug molecule. While one can detect the polymorphic transformation exhibited by the drug/coformer, a formation of a new phase (such as cocrystal), with the multicomponent reactant molecules (API and coformer) can also be easily detected. DSC has been reported to be a rapid thermal screening tool by Lu et al. [62]. Similarly, Yamashita et al. [140,141] conducted an extensive study using DSC as a coformer screening tool to identify formation of many pharmaceutical cocrystals [140,141]. Recently, Saganowska and Wesolowski [142] used DSC as a rapid screening tool and identified 15 different benzodiazepine cocrystals (at stoichiometric ratio of 1:1) [142]. DSC can be used as a tool to identify the coformers capable of forming a cocrystal with an API molecule using either of the following two approaches: (a) Nature of DSC Thermograms The nature of a DSC thermogram obtained for a binary mixture of API and coformer at a specific stoichiometric ratio can help in identifying the nature of the solid form as explained below: Physical mixture—If heating of a binary mixture at a specific heating rate yields two endotherms, each corresponding to the melting point of the individual components, in a DSC thermogram, then it suggests that the binary mixture remains as a physical mixture with no intermolecular interactions occurring between these molecules [25,34]. Eutectic—A eutectic is said to have formed when the DSC thermogram shows a single endotherm with melting temperature less than the melting points of either of the parent molecules (the drug and the coformer) [34,55,62,140,141]. Cocrystal—A binary system can be said to be capable of forming a cocrystal when the DSC thermogram exhibits a single endotherm with melting points lower or in between or greater than the melting points of the individual components [15,34,140,141]. DSC analysis along with single crystal XRD analysis can confirm the formation of a new cocrystal phase. Furthermore, if a DSC thermogram shows consecutive multiple peaks, it possibly indicates the cocrystal formation. In case of presence of two consecutive peaks, the first melting peak corresponds to the eutectic melting, followed by the cocrystal melting (represented by the second endotherm). It is also possible that two or multiple peaks are an indication of polymorphic transformation of cocrystals [62,140]. In case of presence of three consecutive endotherms in a DSC thermogram, the first represents the eutectic melt, the second represents the melting of excess component (drug or coformer), followed by the final melting of cocrystal in the third endotherm [24,62,140]. Coamorphous solid—The DSC thermogram of coamorphous solids show a glasstransition phase change implying the formation of a coamorphous solid phase [25,28,143]. Solid solution—If a DSC thermogram exhibits a simple solidus-liquidus behavior, it indicates the formation of a solid solution [34]. When two components in a binary system form a complete solution in both the solid and liquid phases, then this behavior is termed a simple solidus-liquidus behavior. If the two components in the binary system possess similar crystal structure, then the intermolecular interactions in these compounds remains similar and the difference in the size of atoms remains small. Such isomorphous compounds can result into a solid solution. (b) Binary Phase Diagrams DSC thermograms obtained for different mixtures containing drug and coformer molecules in varying stoichiometric ratios can be used to construct a binary phase diagram for any drug-coformer pair. These binary phase diagrams can be used to detect the cocrystal formation zone for a given system. Section 4.2.2 explains this in detail. Pharmaceutics 2018, 10, 108 21 of 74

4.2.2. Phase Diagrams Phase diagrams are utilized as means to identifying different solid phases that can be formed between any drug-coformer pair. These phase diagrams can be generated either for two components (API-coformer) or for three components (API-coformer-solvent) as well. (a) Binary Phase Diagrams Binary phase diagrams are generally constructed with the data points obtained from thermal analysis methods such as DSC analysis [140]. The onset temperature of the ﬁrst endotherm in a DSC thermogram is generally chosen as solidus point. The peak temperature of the second endotherm is chosen as liquidus point for constructing the phase diagram. The melting behavior of an API and coformer (congruent/incongruent melting) determines the solid solution/eutectic and cocrystal forming property for the investigated system. In general, the eutectic forming binary system adopts ‘V’-shaped curve whereas the cocrystal forming system adopts ‘W’-shaped curve indicating cocrystal formation between two eutectics. Reports are available in the literature where researchers have used binary phase diagram for determining the cocrystal formation zone for the investigated drug-coformer combination [24,25,34,50,73,140,141,144,145]. Sangster [80] has reported a set of binary phase diagrams for 60 different drug systems constructed with the help of computer-coupled phase diagram/thermodynamic analysis [80]. The commonly observed binary phase diagram for most of the drug-coformer pairs reported so Pharmaceutics far in the 2018 literature, 10, x FOR are PEER shown REVIEW in Figure 8. 22 of 74

(B)

FigureFigure 8. Schematic 8. Schematic representation representation of of Binary Binary phase phase diagramsdiagrams for for (A ()A Eutectic) Eutectic formation formation [A and[A and

B— BinaryB—Binary components; components; T TE—E—EutecticEutectic temperature]temperature] [24 [24,5,55,795,79,140,140], (B],) Formation(B) Formation of solid of solution solid [solution34], [34] , (C()C Cocrystal) Cocrystal formation formation [A and [A B—Binary and B components;—Binary component C—Cocrystals; phase;C—Cocrystal TE1 and Tphase;E2—Eutectic TE1 and TE2—temperatures]Eutectic temperatures] [24,73,140,145 [24,73,140,145] and (D) Physical] and mixture (D) [DottedPhysical line-Onset mixture of [Dotted ﬁrst component line-Onset melting of first componentand dark melting line-Melting and dark of the line second-Melting component] of the [second25]. component] [25].

(A) (B)

Figure 9. (A) Schematic representation of (A) a symmetric ternary phase diagram and (B) an asymmetric ternary phase diagram [A—API; B—Coformer, C—Solvent, E1 and E2—Eutectic points] [148].

5. Synthesis of Cocrystals Cocrystals can be synthesized using several methods which could either be the batch processes or continuous processes. Given below is a brief account of different techniques which are being used to synthesize cocrystals.

5.1. Batch Processes The batch mode cocrystallization techniques include mechanochemical methods such as Solid-State grinding [151,152], Liquid-Assisted grinding [151], Ion and Liquid-Assisted Grinding [153] and solvent-based techniques such as slow evaporation [154], ultrasound-assisted

Pharmaceutics 2018, 10, x FOR PEER REVIEW 22 of 74

(B)

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(b) Ternary Phase Diagrams Solution crystallization experiments can result in cocrystals. However, sometimes multicomponent single crystals are not formed during solution crystallization due to the incongruent solubility behavior of individual components in the solvent system. Therefore, the thermodynamic behavior of a system involving ternary components needs to be ascertained before attempting solution crystallization [146]. Ternary Phase Diagrams (Solute-solute-solvent phase diagram) help in determining the cocrystal formation region for a given system. Many researchers have employed ternary phase diagram as Figure 8. Schematic representation of Binary phase diagrams for (A) Eutectic formation [A and an optimization tool to determine suitable stoichiometric ratio of API and coformer for cocrystal B— Binary components; TE—Eutectic temperature] [24,55,79,140], (B) Formation of solid solution formation [146–150]. When the two components manifest a similar/congruent solubility, the phase [34], (C) Cocrystal formation [A and B—Binary components; C—Cocrystal phase; TE1 and diagram exhibits a more symmetrical trend [148]. On the other hand, when the two components show TE2—Eutectic temperatures] [24,73,140,145] and (D) Physical mixture [Dotted line-Onset of first dissimilar/incongruent solubility, then the phase diagram will be less symmetrical behavior [148]. componentFigure9A,B melting presents and schematics dark line of-Melting a symmetric of the andsecond an asymmetriccomponent] ternary [25]. phase diagram.

(A) (B)

FigureFigure 9. (A 9.)( ASchematic) Schematic representation of (ofA) a(A symmetric) a symmetric ternary phaseternary diagram phase and diagram (B) an asymmetric and (B) an

asymmetricternary phaseternary diagram phase [A—API;diagram B—Coformer,[A—API; B— C—Solvent,Coformer, E C1 —andSolvent, E2—Eutectic E1 and points] E2—Eutectic [148]. points] [148]. 5. Synthesis of Cocrystals 5. SynthesisCocrystals of Cocrystals can be synthesized using several methods which could either be the batch processes or Cocrystalscontinuous processes.can be synthesized Given below using is a briefseveral account methods of different which techniques could either which be arethe beingbatch used processes to or continuoussynthesize processes. cocrystals. Given below is a brief account of different techniques which are being used to synthesize5.1. Batch cocrystals. Processes

5.1. Batch TheProcesses batch mode cocrystallization techniques include mechanochemical methods such as Solid-State grinding [151,152], Liquid-Assisted grinding [151], Ion and Liquid-Assisted TheGrinding batch [153 mode] and solvent-basedcocrystallization techniques techniques such asinclude slow evaporation mechanochemical [154], ultrasound-assisted methods such as Solid-cocrystallizationState grinding [ 155[151,152,156], slurry], Liquid conversion-Assisted [140 grinding,157] or solvent-mediated [151], Ion and phase Liquid transformation-Assisted Grinding [158], [153] generationand solvent of cocrystals-based fromtechniques moisture [such159,160 as] and slow anti-solvent evaporation precipitation [154], (Liquid ultrasound Anti-Solvent-assisted precipitation) [161] and Gas Anti-Solvent precipitation [162]. Table7 presents the principle involved behind these batch cocrystallization techniques [151,153–155,159,161–163]. Mechanochemical methods, ultrasound-assisted cocrystallization, cocrystal generation using moisture are discussed in the Section 5.1 in detail. Pharmaceutics 2018, 10, 108 23 of 74

Table 7. Summary of batch processes used for cocrystal synthesis.

Cocrystallization Technique (in Batch Mode) Principle Reference(s) Low molecular weight coformer molecules diffuse into the crystal lattice of API molecules, forming Solid-State Grinding (SSG)/Neat Grinding [151] intermediate phases such as eutectic or amorphous phase which further lead to a new cocrystal phase Addition of solvent molecules during grinding of API-coformer mixture facilitates diffusion of low Liquid-Assisted Grinding (LAG) [151] molecular weight coformer molecules into the crystal lattice of an API Grinding of multiple components along with liquid phase facilitates diffusion of liquid phase into the Ion and Liquid-Assisted Grinding (ILAG) [153] solid-state thereby facilitating mobility of molecules and exposing the hidden molecules to the surface Preparing a supersaturated solution and allowing solvent to evaporate slowly at ambient conditions Slow evaporation [154] induces primary nucleation, thereby leading to slow growth of crystals The cavitation energy of ultrasonic waves induces primary nucleation of particles and leads to attainment of Ultrasound-assisted cocrystallization [155] supersaturation for cocrystal growth Keeping the binary mixture of API and coformer into a solvent/solvent mixture for a long-time enables Solvent-Mediated Phase Transformation (SMPT) phase transformation to a new phase (cocrystal) or conversion from one polymorphic form to another due [163] to the activity of solvent molecules and their nature of interaction with solute molecules over a period Uptake of moisture by a solid mixture, dissolution of reactant molecules in the mixture, attaining Cocrystal formation from moisture supersaturation leading to cocrystal nucleation and growth are the primary steps involved in cocrystal [159] generation from moisture Supersaturation of molecules (drug + coformer mixture) is attained by mixing of solvent and anti-solvent. Liquid Anti-Solvent precipitation (LAS) This results in increase in supersaturation and nucleation rate and thereby facilitates production of [161] sub-micron cocrystal particles In GAS process, gaseous phase is used as anti-solvent instead of a liquid to obtain a cocrystal from a Gas Anti-Solvent precipitation (GAS) [162] solution of API and coformer from a liquid solution Pharmaceutics 2018, 10, 108 24 of 74

(a) Mechanochemical Methods (Grinding) The API and coformer molecules can be cocrystallized by grinding together without solvent, which is termed as Solid-State Grinding (SSG) or Neat grinding or with a few drops of solvent [termed as Solvent-Drop grinding or Liquid-Assisted Grinding (LAG)]. During grinding, the low molecular weight components (solid/liquid/gas phase) diffuse easily into the API crystal lattice [152] which can result in a formation of intermediate phases such as eutectic or amorphous phase which can further result in formation of a cocrystal. According to Etter [103], conversion of individual parent molecules into hydrogen-bonded cocrystals basically occurs based on the rate and force of grinding, particle size of the components and vapor pressure of the phases [103]. Chadwick et al. [152] explained different mechanisms of cocrystal formation via grinding and the various thermodynamic parameters that influence cocrystal formation during grinding. Friscic [153] explored ion and liquid-assisted grinding (ILAG) in designing multicomponent cocrystals. It was proposed that grinding of multiple components along with liquid facilitates diffusion of liquid phase into solid-state thereby enabling mobility of molecules and exposing the hidden molecules to the surface. Numerous reports are available in the literature where grinding (solid-state or liquid-assisted) methods were used extensively to produce cocrystals [164–172]. Table8 presents a summary of a few reports available in the literature where the researchers have proposed scientific mechanisms behind solid-state or liquid-assisted grinding process [151,152,167,168,171,173,174]. (b) Ultrasound-assisted Cocrystallization Ultrasound has been widely used for inducing nucleation in solution and cocrystallizing small molecules. Ultrasound-assisted cocrystallization has several advantages over conventional solution crystallization. The mechanical energy released during passage of ultrasonic waves induces primary nucleation at lower supersaturation levels, thereby reducing the induction time and metastable zone width [175,176]. Ultrasound can therefore induce crystallization easily from solution which otherwise is difficult to attain by conventional solution crystallization experiments [155]. Reports are available in the literature where ultrasound-assisted solution cocrystallization (USSC) [60,155,156,177] has been reported as a method to crystallize caffeine-maleic acid (2:1) [155] and caffeine-oxalic acid (2:1) [155,156]. Morrison et al. [178] proposed a bench-top inexpensive method called ‘Solvent-Drop Floating Foam Rack/Sonic Bath Method’ for synthesizing cocrystals and tested the feasibility of this method for synthesis of carbamazepine-saccharin (1:1) form II, carbamazepine-nicotinamide (1:1), AMG 517-benzoic acid (1:1) and AMG 517-malic acid (1:1) cocrystals. In this technique, the moist powders were subjected to sonication in a sonic bath for an optimized period (90 min was used for carbamazepine and AMG 517 drug systems since sonication for less than 5 min yielded only partial conversion of cocrystal for many systems) using a floating foam rack for inducing cocrystallization [178]. The time duration provided for sonication and a suitable solvent selection were found to be the two critical parameters which influence cocrystal formation by this technique [178]. Pharmaceutics 2018, 10, 108 25 of 74

Table 8. Summary of various reports available in literature on using grinding to synthesize cocrystal.

Type of Grinding Mechanism of Solid Phase Formation API Therapeutic Use of the API Coformer Reference(s) Diffusion of coformer molecules into benzoquinone Antioxidant and Co-milling Benzoquinone Diols [173] crystal lattice anti-inﬂammatory compound Solid-State Antioxidant and Formation of submerged eutectic Benzophenone Diphenylamine [152] Grinding/Neat grinding anti-inﬂammatory compound Solid-State Vapor diffusion of naphthalene molecules into the Picric acid Antiseptic Naphthalene [167] Grinding/Neat grinding crystal lattice of picric acid Solid-State Vapor diffusion of naphthalene molecules into the Picric acid Antiseptic Naphthalene [168] Grinding/Neat grinding crystal lattice of picric acid Solid-State Inclusion of water (from the reactant molecules) in the Chronic Obstructive Pulmonary Disease Theophylline hydrate Anhydrous citric acid [151] Grinding/Neat grinding crystal generate a cocrystal hydrate (COPD) and Asthma Treatment Solid-State Inclusion of water (from the reactant molecules) in the Chronic Obstructive Pulmonary Disease Anhydrous Theophylline Citric acid monohydrate [151] Grinding/Neat grinding crystal lattice to generate a cocrystal hydrate (COPD) and Asthma Treatment Diffusion of anhydrous citric acid into the crystal Solid-State Chronic Obstructive Pulmonary Disease lattice of anhydrous theophylline results in Anhydrous Theophylline Anhydrous citric acid [151] Grinding/Neat grinding (COPD) and Asthma Treatment anhydrous cocrystal Solid-State No solid-state reaction Caffeine Stimulant Anhydrous Citric acid [151] Grinding/Neat grinding Solid-State No solid-state reaction Caffeine Stimulant Citric acid monohydrate [151] Grinding/Neat grinding The water molecules in the reactant molecule Solid-State facilitated formation of ‘Caffeine citrate’ cocrystal Caffeine hydrate Stimulant Anhydrous citric acid [151] Grinding/Neat grinding on grinding The water molecules in the reactant molecules Solid-State facilitated formation of ‘Caffeine citrate’ cocrystal Caffeine hydrate Stimulant Citric acid monohydrate [151] Grinding/Neat grinding on grinding Solvent vapors of acetone and methanol has catalytic Solid-State effect on Caffeine-malonic acid cocrystal ground Caffeine Stimulant Malonic acid [174] Grinding/Neat grinding mixture and generates cocrystal Solid-State Inclusion of water (from the reactant molecules) in the Theophylline Chronic Obstructive Pulmonary Disease Citric acid monohydrate [151] Grinding/Neat grinding crystal lattice to generate a cocrystal hydrate monohydrate (COPD)and Asthma Treatment An intermediate amorphous solid phase having high Neuroprotective and Liquid-assisted grinding Piracetam Tartaric acid, Citric acid [171] molecular mobility facilitates cocrystallization anticonvulsant drug Liquid-assisted grinding Inclusion of water as solvent during grinding induces Chronic Obstructive Pulmonary Disease Anhydrous Theophylline Anhydrous citric acid [151] with water cocrystal hydrate formation (COPD) and Asthma Treatment Liquid-assisted grinding Caffeine hydrate acted as an intermediate phase for Caffeine Stimulant Citric acid [151] with water cocrystal formation Liquid-assisted grinding ‘Caffeine citrate’ cocrystal formation Caffeine Stimulant Citric acid [151] Pharmaceutics 2018, 10, 108 26 of 74

PharmaceuticsPharmaceutics 2018 2018, 10, 10, x, FORx FOR PEER PEER REVIEW REVIEW 2727 of of74 74 (c) Cocrystal Generation Using Moisture (c)(c) CocrystalCocrystal G Generationeneration U Usingsing M Moistureoisture Rodriguez-Hornedo and coworkers [159] conducted a study with API molecules namely carbamazepine,RodriguezRodriguez-Hornedo theophylline-Hornedo and and andco coworkers caffeineworkers [159 to[159 understand] ]conducted conducted the a astudy mechanism study with with behindAPI API molecules molecules cocrystal namely formationnamely incarbamazepine,carbamazepine, presence of theophylline deliquescent theophylline and additiveand caffeine caffeine such to to understand understand as sucrose th the or mechanisme mechanism fructose behind [159 behind]. cocrystal Figurecocrystal 10formation formation presents a schematicinin presence presence of of of cocrystaldeliquescent deliquescent formation additive additivefrom such such as moisture as sucrose sucrose inor or fructose presence fructose [1 [1 of5959]. deliquescent ].Figure Figure 10 10 presents presents additive. a schematica schematic The study of cocrystal formation from moisture in presence of deliquescent additive. The study concluded that concludedof cocrystal that formation uptake from of moisture moisture in by presence the solid of deliquescent reactants facilitated additive. nucleationThe study concluded and growth that of uptake of moisture by the solid reactants facilitated nucleation and growth of carbamazepine-nicotinamide,uptake of moisture by carbamazepine-saccharin,the solid reactants facilitated caffeine-maleic nucleation acid, and caffeine-oxalic growth of acid, carbamazepine-nicotinamide, carbamazepine-saccharin, caffeine-maleic acid, caffeine-oxalic acid, caffeine-maloniccarbamazepine-nicotinamide, acid, caffeine-glutaric carbamazepine acid,-saccharin, theophylline-maleic caffeine-maleic acid, acid, theophylline-oxalic caffeine-oxalic acid, acid, caffeine-malonic acid, caffeine-glutaric acid, theophylline-maleic acid, theophylline-oxalic acid, theophylline-maloniccaffeine-malonic acid, acid caffeine and theophylline-glutaric-glutaric acid, theophylline acid cocrystals.-maleic acid, theophylline-oxalic acid, theophyllinetheophylline-malonic-malonic acid acid and and theophylline theophylline-glutaric-glutaric acid acid cocrystals. cocrystals. Furthermore, Good et al. [160] attempted to understand the mechanism behind carbamazepine FurthermoreFurthermore, Good, Good et et al. al. [16 [160]0 attempted] attempted to to understand understand the the mechanism mechanism behind behind carbamazepine carbamazepine (CBZ)-nicotinamide (NCT) cocrystal formation facilitated by moisture sorption by Poly Vinyl (CBZ)(CBZ)-nicotinamide-nicotinamide (NCT) (NCT) cocrystal cocrystal formation formation facilitated facilitated by by moisture moisture sorption sorption by by P olyPoly V inylVinyl Pyrollidone K12 (PVP K12). As PVP K12 decreased the ratio of cocrystal to drug solubility, increase in PyrollidonePyrollidone K12 K12 (PVP (PVP K12) K12). As. As PVP PVP K12 K12 decreased decreased the the ratio ratio of of cocrystal cocrystal to to drug drug solubility, solubility, increase increase PVP K12 concentration increased the stability of carbamazepine (CBZ)-nicotinamide (NCT) cocrystal [160]. inin PVP PVP K12 K12 concentration concentration increased increased the the stability stability of of carbamazepine carbamazepine (CBZ) (CBZ)-nicotinamide-nicotinamide (NCT) (NCT) Figurecocrystalcocrystal 11 represents [16[160].0 ]. Figure theFigure optical 1111 microscopic representsrepresents images thethe showingopticaloptical carbamazepine-nicotinamidemicroscopicmicroscopic imaimagesges showingshowing cocrystal formationcarbamazepinecarbamazepine by moisture-nicotinamide-nicotinamide sorption, cocrystal dissolution,cocrystal formation formation cocrystal by nucleationby moisture moisture and sorption, sorption, growth indissolution, presencedissolution, of cocrystal PVPcocrystal K12 as a ◦ deliquescentnucleationnucleation and polymerand growth growth at in 75%in presence presence RH and of of PVP 25 PVPC. K12 K12 as as a deliquescenta deliquescent polymer polymer at at 75% 75% RH RH and and 25 25 °C. °C.

FigureFigureFigure 10. 10. Schematic SchematicSchematic representation representation representation of of cocrystal ofcocrystal cocrystal formation formation formation by by moisture moisture by moisture uptake uptake in uptake in presence presence in presenceof of a a ofdeliquescdeliquesc a deliquescententent additive additive additive [Reprinted [Reprinted [Reprinted from from [159 [159 from] with] with [159 permission. permission.] with permission. Copyright Copyright 2007 Copyright2007 American American 2007 Chemical Chemical American ChemicalSociety]Society]. . Society].

Moisture sorption 500500μ μ Moisture sorption DissolutionDissolution

(A()A) (B()B) (C()C)

CocrystalCocrystal

(D) (E) (D) (E) Figure 11. Optical microscopic images presenting (A-C) Dissolution of CBZ and NCT and (D-E) FigureFigure 11. 11.Optical Optical microscopicmicroscopic images presenting presenting (A (A-C–)C Dissolution) Dissolution of ofCBZ CBZ and and NCT NCT and and (D- (E)D ,E) CBZ-NCT cocrystal formation by moisture sorption by PVP K12 in equimolar concentration of CBZ CBZ-NCTCBZ-NCT cocrystal cocrystal formation formation byby moisturemoisture sorption by by PVP PVP K12 K12 in in equimolar equimolar concentration concentration of ofCBZ CBZ andand NCT NCT at at75 75%% RH RH and and 25 25 °C ° C[Reprinted [Reprinted from from [16 [160] 0with] with permission. permission. Copyright Copyright 2011 2011 Royal Royal Society Society and NCT at 75% RH and 25 ◦C [Reprinted from [160] with permission. Copyright 2011 Royal Society ofof Chemistry] Chemistry]. . of Chemistry].

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5.2. Continuous Production of Cocrystals

ContinuousPharmaceutics 2018, production 10, x FOR PEER REVIEW of cocrystals has gained much attention from pharmaceutical28 of 74 sectors [179–182]. In addition to enabling large-scale production of cocrystals, continuous production methods5.2. Continuous also offer Production significant of advantagesCocrystals over batch processes [182] as mentioned below: a. BatchwiseContinuous variation production in cocrystals of cocrystals quality has can gained be rectified much attention by means from of pharmaceutical continuous production sectors by [179adopting–182]. In a Quality-basedaddition to enabling Design large (QbD)-scale approach production of cocrystals, continuous production methods also offer significant advantages over batch processes [182] as mentioned below: b. Continuous production of cocrystals is less labor intensive when compared to batch mode c. a.As Batchwise compared variation to batch in process,cocrystals the quality maintenance can be rectified of uniform by means particle of continuous distribution production throughout by theadopting entire production, a Quality-based monitoring Design (QbD) of quality approach of cocrystals by Process Analytical Technology b. Continuous production of cocrystals is less labor intensive when compared to batch mode (PAT) and maintaining consistency in the quality of products obtained is easier for c. As compared to batch process, the maintenance of uniform particle distribution throughout the continuousentire production, production monitoring of quality of cocrystals by Process Analytical Technology (PAT) Examplesand maintaining of different consistency continuous in cocrystal the quality production of products methods obtained are Twinis easier Screw for Extrusioncontinuous [183], Hot-Meltproduct Extrusionion [65,184], Co-Extrusion, Solvent-Free Continuous Cocrystallization [185], Spray Drying [186Examples], Spray of Flashdifferent evaporation continuous processcocrystal [ 187production], Solid-State methods Shear are MillingTwin Screw Technology Extrusion [ 188], melt[18 crystallization3], Hot-Melt Extrusion [48] and [65,184 melt-assisted], Co-Extrusion, grinding Solvent [179-Free]. Table Continuous9 presents Cocrystallization a summary [18 of5 a], few literatureSpray reports Drying available[186], Spray on Flash continuous evaporation cocrystallization process [187], production Solid-State techniques.Shear Milling Solid-State Technology Shear Milling[188 Technology], melt crystallization [188], melt [48 crystallization] and melt-assisted [48 ]grinding and supercritical [179]. Table fluid-based 9 presents a methodssummary [of189 a few,190 ] are discussedliterature in detail reports in available the following on continuous Section cocrystallization5.2 (a–c). production techniques. Solid-State Shear ThoughMilling Technology continuous [18 cocrystallization8], melt crystallization production [48] and methods supercritical can fluid be employed-based methods to give [189 high,190]yield are discussed in detail in the following Section 5.2 (a–c). of cocrystals, these methods have certain limitations in terms of reproducible cycling efficiency and Though continuous cocrystallization production methods can be employed to give high yield of accuratecocrystals, process these control. method Maintainings have certain stability limitations and in quality terms of reproducible products when cycling transferred efficiency fromand one unit operationaccurate process to another control. (Quality Maintaining assurance) stability to and make quality these of products products suitablewhen transferred for further from use one can be a challenge.unit operation to another (Quality assurance) to make these products suitable for further use can be a challenge. (a) Solid-State Shear Milling (S3M) Technology (a) Solid-State Shear Milling (S3M) Technology Recently, Korde et al. [188] employed ‘Solid-State Shear Milling’ technology to produce carbamazepine-salicylicRecently, Korde acid et cocrystalsal. [188] employed with 5–25 ‘Solid wt. %-State of poly(ethylene Shear Milling’ oxide) technology (PEO). Thisto produce ‘Solid-State Shearcarbamazepine Milling’ technology-salicylic was acid reported cocrystals to be with a scalable 5–25 andwt. polymer-assisted% of poly(ethylene technology oxide) (PEO). for continuous This ‘Solid-State Shear Milling’ technology was reported to be a scalable and polymer-assisted production of cocrystals [188]. Figure 12 presents the schematic of ‘Solid-State Shear Milling (S3M)’ technology for continuous production of cocrystals [188]. Figure 12 presents the schematic of technology‘Solid-State employed Shear Milling by Korde (S3M)’ et al.technology [188]. In employed this technique, by Korde well-mixed et al. [188]. API In this and technique, coformer are blendedwell along-mixed withAPI and a polymer coformer and are thenblended subjected along with to finea polymer grinding and bythen S3M. subjected The S3M to fine consists grinding of two inlaidby pans, S3M. a The rotor S3M and consists a stator of which two inlaid are made pans, up a ofrotor wear-resistant and a stator materials. which are The made applied up of shear forcewear for milling-resistant along materials. with The the applied polymeric shear aid force facilitates for milling efficient along with milling the polymeric due to generation aid facilitates of high stressefficient fields formilling grinding due to [ 188generation]. of high stress fields for grinding [188].

Figure 12. Schematic representation of ‘Solid-State Shear Milling’ technology for cocrystals Figure 12. Schematic representation of ‘Solid-State Shear Milling’ technology for cocrystals production production as proposed by Korde et al. [188] [Reprinted from [188] with permission. Copyright 2018 as proposedAmerican by Chemical Korde etSociety] al. [188. ] [Reprinted from [188] with permission. Copyright 2018 American Chemical Society].

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Table 9. Summary of reports available in literature on continuous production of pharmaceutical cocrystals.

API-Coformer Therapeutic Use Comments on the Production Method Principle API Coformer Stoichiometric Reference of the API Dissolution Behavior Ratio Non-Steroidal During powder dissolution studies, Indomethacin Anti-Inflammatory Saccharin 1:1 60–70% cocrystals dissolved in first [75] Drug (NSAID) 60 min w.r.t 30% of raw indomethacin Caffeine Stimulant Oxalic acid 2:1 Not reported [183] Raw materials were fed through Caffeine Stimulant Maleic acid 1:1 and 2:1 Not reported [185] abarrel containing one or more Carbamazepine Anticonvulsant Saccharin 1:1 Not reported [183] rotary screws towards a die Twin Screw Extrusion undercontrolled conditions. Nicotinamide Vitamin of B3 Trans-cinnamic acid 1:1 Not reported [183] (TSE)/Melt extrusion The frictional force created COPD and Theophylline Citric acid 1:1 Not reported [183] (ME) processing between thescrew and the barrel Asthma treatment /Hot-Melt at high temperatures enables Extrusion (HME) good mixing and melting of AMG-517 TRPV antagonist Sorbic acid 1:1 Not reported [180] reactants, reduction in its particle The extruded cocrystals exhibited faster size and thereby result dissolution rates than raw Carbamazepine Anticonvulsant Trans-cinnamic acid 1:1 [65] into cocrystals carbamazepine and the cocrystals produced by conventional methods TSE processed cocrystals (at temperatures of 120 ◦C, 135 ◦C, Carbamazepine Anticonvulsant Saccharin 1:1 and 140 ◦C) at different RPM (5 and [65] 10 RPM) exhibited increased dissolution rates than raw carbamazepine Hot-Melt Extruded cocrystals showed Isonicotinamide with Ibuprofen NSAID 1:1 enhanced dissolution rates than [184] Xylitol as carrier raw ibuprofen Carbamazepine-salicylic acid cocrystals prepared by continuous process The applied shear force in S3M exhibited higher dissolution than the Solid-State Shear for milling along with the cocrystals prepared by batch process. Milling (S3M) polymeric aid facilitates efficient Carbamazepine Anticonvulsant Salicylic acid 1:1 Nearly 95% of drug was dissolved in [188] Technology milling due to generation of high case of cocrystal samples treated with stress fields for grinding PolyEthylene Oxide (PEO) and nearly 90% of drug was dissolved in case of cocrystal samples without PEO treatment Pharmaceutics 2018, 10, 108 29 of 74

Table 9. Cont.

API-Coformer Therapeutic Use Comments on the Production Method Principle API Coformer Stoichiometric Reference of the API Dissolution Behavior Ratio Carbamazepine Anticonvulsant Glutaric acid 1:1 Not reported [186] COPD and Theophylline Nicotinamide 1:1 Not reported [186] Asthma treatment Urea Organic carbamide Succinic acid 1:1 Not reported [186] A technique in which dry Spray Drying cocrystal powders are obtained Caffeine Stimulant Glutaric acid 1:1 Not reported [186] from a solution or a suspension Caffeine Stimulant Oxalic acid 2:1 Not reported [186] by evaporating the solvent very rapidly in a fraction of a second Non-Steroidal by passing a hot air stream Indomethacin Anti-Inﬂammatory Nicotinamide 1:1 Not reported [186] Drug (NSAID) Subjecting the ﬂashing Caffeine Stimulant Oxalic acid 2:1 superheated liquids to a sudden Spray Flash evaporation Caffeine Stimulant Glutaric acid 1:1 pressure drop followed by process for preparation Not reported [187] atomization in atomization TNT-20 - CL20 1:1 of nanococrystals chamber yields nano-sized cocrystals HMX - CL20 1:1 Pharmaceutics 2018, 10, 108 30 of 74

(b) Melt Crystallization Melt crystallization has been adopted to produce cocrystals by several researchers [144,191,192]. This is an indirect way in which the cocrystal phase is formed from the melting of eutectic phase. Melting of API and coformer beyond the eutectic temperature creates a eutectic melt and the cocrystal phase growth appears from nucleation in the eutectic melt. For the drug-coformer pairs which form cocrystals from the eutectic melt, melt crystallization can yield cocrystal without any phase impurity [191,192]. Melt crystallization is a solvent-free, scalable and continuous method for cocrystal production [48]. Douroumis and coworkers [179] have contributed an extensive review on various solvent-free continuous cocrystal manufacturing methods [179]. Recently, Crawford [193] has contributed a review on the applications of Twin Screw Extrusion in continuous production of organic compounds [193]. Also, Shastri and coworkers [181] have recently provided a detailed review on the various challenges associated with continuous cocrystal production methods and the prospects in this technology [181].

Utilization of supercritical CO2 as solvent or an anti-solvent instead of using liquid solvents serves as an excellent mean for large-scale production of cocrystals [194]. Pando et al. [162] had presented an extensive review on preparation of pharmaceutical cocrystals using supercritical CO2 [162]. Efforts have been made by many researchers to prepare cocrystals by Gas Anti-solvent Crystallization (GAS) [189,190,194–198] and to compare its morphology, crystalline nature and dissolution rates with cocrystals prepared via Liquid Anti-Solvent (LAS) precipitation or traditional solution-based methods [194–196]. In addition to GAS, Supercritical ﬂuid Enhanced Atomization (SEA) [190], Atomization and Anti-solvent Crystallization (AAS) [191] and Supercritical Anti-solvent crystallization (SAS) [189] are a few other techniques where supercritical CO2 has been utilized as an anti-solvent for cocrystals production. Rapid Expansion of Supercritical Solutions (RESS) is an interesting technique where both micronization of particles and cocrystallization can be achieved simultaneously using supercritical CO2 as a solvent [199]. RESS involves no toxic solvents and therefore serves as an ecofriendly technique for a large-scale production of cocrystals. While supercritical CO2 methods can be used for continuous synthesis of cocrystals, requirement of high pressure and especially designed nozzles for atomization can limit the usefulness of such techniques for large-scale production.

6. Characterization of Cocrystals

6.1. Structural Analysis The crystalline nature of the cocrystals can be characterized by Powder X-Ray Diffraction (PXRD) and single crystal X-Ray Diffraction (SCXRD). While SCXRD provides detailed structural information including the lattice parameters, space group, miller indices, crystal system, unit cell volume, inter and intramolecular interactions, the PXRD provides information about the crystallinity of the solid phase. However, when the crystals produced by solution crystallization are not of good quality to conduct SCXRD analysis, one can possibly extract the structural data from PXRD data using indexing programs such as TREOR90 [200], ITO [201] and AUTOX [202], DASH [203], Rex.Cell [204] and Rietveld reﬁnement programs such as TOPAS [205] and EXPO [206]. International Union of Crystallography (IUCr) serves as a valuable resource, containing information about different crystallographic software used for determining single crystal data of cocrystals from their corresponding PXRD data [207]. Several reports are available in the literature where researchers have solved the crystal structure of cocrystals from Powder X-Ray Diffraction data [208,209]. Pharmaceutics 2018, 10, x FOR PEER REVIEW 32 of 74 Pharmaceutics 2018, 10, 108 31 of 74

6.26.2.. Thermal Thermal Analysis Analysis HotHot-Stage-Stage Microscopy Microscopy (HSM(HSM oror Koﬂer Kofler method): method): A thermal A thermal microscopic microscopic method method provides pr aovides visual a visualunderstanding understanding of phase of phase transitions transitions which which occur whileoccur heating while heating an API-coformer an API-coformer mixture tomixture a certain to a certaintemperature temperature [210–215 [21].0 It–215 is also]. It calledis also as called Mixed-fusion as Mixed method-fusion in whichmethod one in of which the components one of the components(ﬁrst component) (first component) melts initially. melts It is theninitially. followed It is bythen the followed solubilization by the of asolubilization second component of a second into componentthe molten into component. the molten This component. complete recrystallization This complete resultsrecrystallization in the formation results of in ‘Zone the formation of mixing’ of ‘Zonewhich of represents mixing’ cocrystalwhich represents formation from cocrystal eutectic formation melt or polymorphic from eutectic transformation melt or ofpolymorphic cocrystals transformation(as shown in Figure of cocrystals 13A). HSM (as was shown reported in to Figure be used 13A). as a cocrystal/cocrystal HSM was reported polymorphs to be screeningused as a cocrystal/cocrystaltechnique in several polymorphs reports [216 screening,217]. technique in several reports [216,217].

(A) (B) (C)

FigureFigure 13. 13. (A()A Schematic) Schematic representation representation of of Hot Hot-Stage-Stage Microscopy (HSM)(HSM) functioning functioning principle principle [210 [21],0], formationformation of of la lamotrigine-caffeinemotrigine-caffeine (2:1) (2:1) cocrystal usingusing HSMHSM technique. technique. ContactContact area area between between lamotriginelamotrigine and and caffeine caffeine (B (B) )At At 190 190 °C◦C [A [A—caffeine—caffeine inin solid-state;solid-state; B—lamotrigineB—lamotrigine in in solid solid state; state; D—D—MeltingMelting of ofeutectic eutectic and and C C—Formation—Formation of of cocrystal phase]phase] andand (C(C)) At At 200 200◦ C°C [A—caffeine [A—caffeine in in solidsolid-state;-state; B— B—lamotriginelamotrigine in in solid solid state; state; C C and and D observed inin FigureFigure 13 13BB disappears disappears due due to to complete complete meltingmelting of ofthe the cocrystal cocrystal phase] phase] [Reprinted [Reprinted from [[212111]] withwith permission. permission. Copyright Copyright 2012 2012 American American ChemicalChemical Society] Society]..

FigureFigure 13B 13 B,Cand showsC show an an example example of aof cocrystal a cocrystal formation formation between between lamotrigine lamotrigine and caffeineand caffeine by byusing using HSM HSM [ 211[21].1]. FigureFigure 13 13BB indicates indicates formation formation of of cocrystal cocrystal phase phase at at 130 130◦C[ °C202 [20]2 followed] followed by by meltingmelting of of eutectic phasephase at at 190 190◦C whereas°C whereas the cocrystal the cocrystal phase melt phase is observed melt is when observed the temperature when the ◦ temperatuis increasedre is toincreased 200 C (as to shown200 °C in(as Figure shown 13 inC) Figure [211]. The13C) results [211]. obtainedThe results from obtained HSM were from also HSM werecompared also compared with the DSC with thermograms the DSC thermograms obtained for lamotrigine-caffeineobtained for lamotrigine (2:1) pair.-caffeine The results (2:1) obtained pair. The resultsin HSM obtained and DSC in HSM analysis and showed DSC analysis a good correlation showed a betweengood correlation these two between techniques. these Thus, two HSM/DSC techniques. Thus,screening HSM/DSC method screening was suggested method to was be an suggested efﬁcient method to be an for efficient cocrystal method screening for whencocrystal the quantityscreening whenof sample the quantity available of forsample cocrystal available screening for cocrystal is less [211 screening]. is less [211]. In Inaddition addition to Hot-StageHot-Stage Microscopy, Microscopy, Differential Differential Scanning Scanning Calorimetry Calorimetry also serves also as serves an effective as an thermal analysis technique for characterizing the cocrystal phases (as explained in Section 4.2). effective thermal analysis technique for characterizing the cocrystal phases (as explained in Section 4.2).6.3. Spectroscopic Analysis

6.3. SpectroscopicThere are Analysis several spectroscopic techniques which are commonly used to characterize the cocrystal phases. Fourier Transform (FT-IR) Infrared Spectroscopy (a vibrational spectroscopy) is a non-destructiveThere are several analysis spectroscopic technique used techniques for identifying which hydrogen are commonly bonds and molecularused to characterize conformations the cocryin astal cocrystal phases. phase Fourier with Transform respect to its(FT pure-IR) componentsInfrared Spectroscopy based on the (a differencesvibrational in spectroscopy) the vibrational is a nonmodes-destructive exhibited analysis by the samples technique due toused absorption for ofidentifying light. hydrogen bonds and molecular conformationsFourier in Transform a cocrystal Near-Infra phase with Red respect (FTNIR) to its Spectroscopy pure components is a non-destructive based on the differences vibrational in thespectroscopic vibrational modes technique exhibited which by records the samples the vibrational due to absorption changes in of the light. near-infra red region due to absorptionFourier ofTransform light by vibrating Near-Infra molecules. Red (FTNIR) It is used Spectroscopy to detect hydrogen is a non bonds-destructive in a cocrystal vibrational phase spectroscopicbased on the technique spectral changes which seenrecords in a spectrumthe vibrational of a cocrystal changes phase in the in comparisonnear-infra red to near-infrared region due to absorptionspectrum of obtained light by for vibrating the parent molecules. molecules It [218 is ]used. to detect hydrogen bonds in a cocrystal phase based on the spectral changes seen in a spectrum of a cocrystal phase in comparison to near-infrared spectrum obtained for the parent molecules [218]. Raman spectroscopy is also a non-destructive spectroscopic technique used to detect the vibrational changes in the spectrum of a cocrystal phase which occurs due to scattering of incident

Pharmaceutics 2018, 10, 108 32 of 74

Raman spectroscopy is also a non-destructive spectroscopic technique used to detect the vibrational changes in the spectrum of a cocrystal phase which occurs due to scattering of incident light. Furthermore, through solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy, one can obtain detailed structural information of pharmaceutical solid phases such as cocrystals, eutectics and amorphous solids [219]. ssNMR spectroscopy provides information regarding molecular mobility, differences in hydrogen bonding and crystallinity of solids. The cocrystal powders which are difficult to be characterized by single crystal X-Ray diffraction analysis (due to poor crystal quality) to obtain a crystal structure can be characterized by solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy [219,220]. Proton NMR spectroscopy is a nuclear magnetic resonance spectroscopy which can be used for determining stoichiometric ratio of cocrystal phases [221]. Furthermore, Variable Temperature X-ray Diffraction (VTXRD) analysis is used to determine phase transformation events which occur at a specific temperature during heating of a cocrystal phase. Through VTXRD, in addition to identification of polymorphic phase transformations, one can also determine the crystalline nature of the solid phase at different temperatures. Reports are available in the literature were VTXRD has been used to determine phase transformation events observed for different [222,223]. Vangala et al. [222] reported that dimorphs of caffeine-glutaric acid (1:1) cocrystal are enantiotropically related with the transition temperature of 79 ◦C[222] using VTXRD studies. In addition to the characterization techniques discussed above, some of the well-advanced techniques such as pair-distribution function PXRD [224], Terahertz (THz) spectroscopic imaging [225], Probe-Type Low-Frequency Raman Spectroscopy [226], combined near IR and Raman spectroscopies [227], in situ Raman spectroscopy, in situthermomicroscopy [192], calorimetric analysis [192] and PAT [75] are being used widely by many researchers nowadays in order to understand the phase transition events that possibly occur during a cocrystallization process.

6.4. Morphological Characterization Polarized optical microscopy [228], Fluorescence microscopy [229] and Scanning Electron Microscopy (SEM) [24,147,217] are the various techniques which can be used to characterize the morphology of cocrystals.

6.5. Drug Release Testing According to United States Food and Drug Administration (US FDA), to ensure that pure drug is released from the cocrystal in vivo, evaluation of the performance of cocrystals by in vitro dissolution study or solubility testing is highly mandatory [230,231]. Determination of cocrystal solubility, determination of powder and intrinsic dissolution rates using United States Pharmacopeia apparatus [61,65,68,72,101] and evaluating cocrystal diffusivity by dialysis and Franz-diffusion cell method [232] are some of the in vitro drug release testing methods used for cocrystal formulations. Achieving in vitro-in vivo correlation (IVIVC) of a pure drug from its cocrystal form is an important criterion that must be satisﬁed by cocrystals for their use in pharmaceutical applications.

7. Influence of Intermolecular Interactions on Cocrystallization The type and strength of intermolecular interactions that occur between the drug and coformer molecules determine the nature and the stability of the multicomponent solids (cocrystals/salts/coamorphous solids/eutectics/solid solutions/physical mixture) formed during cocrystallization. There are several types of intermolecular interactions (hydrogen bonding, secondary bonding, pi-pi interactions, ionic interactions, halogen bonding, vanderwaal’s forces and dipolar interactions) which can possibly exist in multicomponent systems. However, most of the definitions for cocrystals are primarily based on considering hydrogen bonding as a predominant intermolecular interaction stabilizing the cocrystal lattice [233–235]. In 1940, Glasstone called cocrystals as ‘lattice compounds’ in his book, Textbook of Physical Chemistry and defined them as ‘substances formed between Pharmaceutics 2018, 10, x FOR PEER REVIEW 34 of 74 stability to packing in the crystal lattice, and not to ordinary valency forces’ [235]. Later, Dunitz [236] proposed that the word ‘two’ in Glasstone’s definition should be changed to ‘two or more’ [236]. However, some of the definitions given for cocrystals by many researchers were solely based on the nature of components (gas phase/ionic molecules/solid components) which constitute the crystal lattice. Later, an unambiguous definition which covers all the characteristics of cocrystal had become necessary. Attempts were made by Lara-Ochoa and Espinosa-Perez [237] to propose a universal definition for cocrystals by considering three non-ordinary valence forces (π-π interactions and vanderwaal’s forces, π-π stacking interactions and halogen bonding) stabilizing the cocrystal structure [237].Pharmaceutics 2018, 10, 108 33 of 74 The following are the different types of intermolecular interactions reported to exist in the stoichiometric amounts of “two” molecular species, which owe their stability to packing in the crystal crystal structurelattice, of anddifferent not to ordinary cocrystals: valency forces’ [235]. Later, Dunitz [236] proposed that the word ‘two’ in Glasstone’s definition should be changed to ‘two or more’ [236]. However, some of the definitions given 7.1. Hydrogen Bondingfor cocrystals by many researchers were solely based on the nature of components (gas phase/ionic molecules/solid components) which constitute the crystal lattice. Later, an unambiguous definition Hydrogenwhich bonding covers allis thea non characteristics-covalent of interaction cocrystal had becomethat occurs necessary. between Attempts a were hydrogen made by atom attached Lara-Ochoa and Espinosa-Perez [237] to propose a universal definition for cocrystals by considering to any electronegativethree non-ordinary atom valence such forces as (πoxyge-π interactionsn or andnitrogen vanderwaal’s and forces, anotherπ-π stacking electronegative interactions atom. It is commonly representedand halogen bonding)as X-H stabilizing---Y where the cocrystal X and structure Y are the [237]. electronegative atoms. Hydrogen-bonding interaction can beThe an following intermolecular are the different or types intramolecular of intermolecular interactionsinteraction. reported Hydrogen to exist in the bonding crystal is a specific structure of different cocrystals: type of dipolar interaction that serves as a key parameter in crystal engineering approach. Most of the cocrystal 7.1.structures Hydrogen Bonding reported in Cambridge Structural Database (CSD) are stabilized by hydrogen-bondingHydrogen interactions. bonding is Hydrogen a non-covalent interactionbonds are that individually occurs between a hydrogenweak bonds atom attached but collectively to they any electronegative atom such as oxygen or nitrogen and another electronegative atom. It is commonly are stronger enoughrepresented to as X-H—Yform wheresupramolecular X and Y are the electronegativesynthons in atoms. multicomponent Hydrogen-bonding interactionsystems and stabilize their structurescan [99 be an,23 intermolecular8,239]. or intramolecular interaction. Hydrogen bonding is a specific type of dipolar interaction that serves as a key parameter in crystal engineering approach. Most of the cocrystal Figure 14structures presents reported the different in Cambridge types Structural of hydrogen Database (CSD) bond are stabilized synthons by hydrogen-bonding which were reported to be observed in theophylinteractions.line Hydrogen-cinnamic bonds are acid individually (1:1) weakcocrystals bonds but [24 collectively0]. The they crystal are stronger structure enough obtained for theophylline-cinnamicto form supramolecular acid (1:1) synthons cocrystal in multicomponent (Figure 14) systems showed and stabilize that theircinnamic structures acid [99,238 forms,239]. a carboxylic Figure 14 presents the different types of hydrogen bond synthons which were reported to be acid two-pointobserved synthon in theophylline-cinnamic with carbonyl O acid of (1:1)the cocrystalspyrimidine [240]. ring The crystal and structurewith the obtained N–H forhydrogen of the imidazole ringtheophylline-cinnamic of theophylline acid to (1:1) stabilize cocrystal (Figurethe crystal 14) showed structure. that cinnamic This acid kind forms aof carboxylic stronger interaction acid two-point synthon with carbonyl O of the pyrimidine ring and with the N–H hydrogen of the prevents the forimidazolemation ring of of cocrystal theophylline hydrate to stabilize [240 the]. crystal structure. This kind of stronger interaction prevents the formation of cocrystal hydrate [240].

(A) (B)

Figure 14. (A) 1D zig-zag chain arrangement brought about by 2-point acid. . . amide synthon through Figure 14. (A) formation1D zig- ofzag O-H. chain . . O and arrangement N-H. . . O hydrogen brought bonds inabout theophylline-cinnamic by 2-point acid acid…amide (1:1) cocrystal, synthon through (B) Stacking of 2D layers by weak interactions completes the 3D arrangement [Reprinted from [240] formation of Owith-H…O permission. and CopyrightN-H…O 2014 hydrogen American Chemicalbonds Society].in theophylline-cinnamic acid (1:1) cocrystal, (B) Stacking of 2D layers by weak interactions completes the 3D arrangement [Reprinted from [240] with permission. Copyright 2014 American Chemical Society].

7.2. Halogen Bonding In recent years, halogen-bonded cocrystals have gained an extensive attention. Figure 15 presents the schematic of halogen bonding interaction between two molecules.

Pharmaceutics 2018, 10, 108 34 of 74

7.2. Halogen Bonding In recent years, halogen-bonded cocrystals have gained an extensive attention. Figure 15 presents Pharmaceuticsthe schematic 2018, 10 of, x halogenFOR PEER bonding REVIEW interaction between two molecules. 35 of 74

FigureFigure 15. 15.SchematicSchematic representation representation of of halogen halogen bondingbonding between between two two molecules molecules [241 [241]]. .

HalogenHalogen bonds bonds are are more more directional directional than than hydrogen hydrogen bondsbonds [ 242[24]2 but] but are are analogous analogous to hydrogen to hydrogen bondsbonds [243]. [243 Novick]. Novick et al. et[24 al.4] [244stated] stated that thathalogen halogen bonds bonds are are‘anti ‘anti-hydrogen-hydrogen bonds’ bonds’ [245] [245 while] Alkortawhile et Alkortaal. [245 et], al.Desiraju [245], Desirajuand Steiner and Steiner[246] called [246] calledhalogen halogen bonds bonds as ‘inverse as ‘inverse hydrogen hydrogen bonds’ [245,246bonds’] to[ emphasize245,246] to emphasize the difference the difference between between the hydrogen the hydrogen and halogen and halogen bonding. bonding. Since Since the halogen the halogen atom attached to an electronegative atom (a molecule with ‘R’ group) contains both atom attached to an electronegative atom (a molecule with ‘R’ group) contains both nucleophilic and nucleophilic and electrophilic end, it can interact with neighboring molecule to form non-covalent electrophilic end, it can interact with neighboring molecule to form non-covalent bonding, in turn bonding, in turn contributing to the building of a new supramolecular structure (as shown in Figure 15). contributingChoquesillo-Lazarte to the building of et al.a new [247 supramolecular] has investigated structure the nature (as of shown halogen in bondingFigure 15 interactions). observedChoquesillo in-Lazarte pharmaceutical et al. [247 cocrystals] has investigated of pyrazinamide, the nature lidocaineof halogen and bonding pentoxifylline interactions observedwith in perfluorinated pharmaceutical halogen-bond cocrystals donorsof pyrazinamide, namely 1,4-diiodotetrafluorobenzenelidocaine and pentoxifylline (tfib) with perfluorinatedand 1,4-dibromotetrafluorobenzene halogen-bond donors [247 ].namely The halogen1,4-diiodotetrafluorobenzene bonding interaction observed (tfib) in and 1,4-dibromotetrafluorobenzenelidocaine-1,4-diiodotetrafluorobenzene [247]. (2:1)The andhalogen lidocaine-1,4-dibromotetrafluorobenzene bonding interaction observed (2:1) in lidocainecocrystals-1,4-diiodotetrafluorobenzene are shown in Figure 16. 1,4-diiodotetrafluorobenzene (2:1) and lidocaine-1,4 and-dibromotetrafluorobenzene 1,4-dibromotetrafluorobenzene (2:1) cocrystalsare structurally are shown similarin Figure and 16. ditopic 1,4-diiodotetrafluorobenzene linear halogen-bond donors. and 1,4- Thedibromotetrafluorobenzene crystal structure of are lidocaine-1,4-diiodotetrafluorobenzenestructurally similar and ditopic linear (2:1) andhalogen lidocaine-1,4-dibromotetrafluorobenzene-bond donors. The crystal structure (2:1) of cocrystals revealed that halogen-bond donors, I/Br form intermolecular halogen bonding interaction lidocaine-1,4-diiodotetrafluorobenzene (2:1) and lidocaine-1,4-dibromotetrafluorobenzene (2:1) with carbonyl oxygen of lidocaine. Thus, the oxygen of carbonyl group in lidocaine acted as a cocrystals revealed that halogen-bond donors, I/Br form intermolecular halogen bonding halogen-bond acceptor, forming X. . . O type halogen bonding with I/Br of coformer molecules, which interactionis again with a type carbo II halogennyl oxygen bonding of interaction lidocaine. [248 Thus,] (as shown the oxygen in Figure of 16 carbonyl). group in lidocaine acted as a halogen-bond acceptor, forming X…O type halogen bonding with I/Br of coformer molecules, which is again a type II halogen bonding interaction [248] (as shown in Figure 16).

(A)

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Figure 15. Schematic representation of halogen bonding between two molecules [241].

Halogen bonds are more directional than hydrogen bonds [242] but are analogous to hydrogen bonds [243]. Novick et al. [244] stated that halogen bonds are ‘anti-hydrogen bonds’ [245] while Alkorta et al. [245], Desiraju and Steiner [246] called halogen bonds as ‘inverse hydrogen bonds’ [245,246] to emphasize the difference between the hydrogen and halogen bonding. Since the halogen atom attached to an electronegative atom (a molecule with ‘R’ group) contains both nucleophilic and electrophilic end, it can interact with neighboring molecule to form non-covalent bonding, in turn contributing to the building of a new supramolecular structure (as shown in Figure 15). Choquesillo-Lazarte et al. [247] has investigated the nature of halogen bonding interactions observed in pharmaceutical cocrystals of pyrazinamide, lidocaine and pentoxifylline with perfluorinated halogen-bond donors namely 1,4-diiodotetrafluorobenzene (tfib) and 1,4-dibromotetrafluorobenzene [247]. The halogen bonding interaction observed in lidocaine-1,4-diiodotetrafluorobenzene (2:1) and lidocaine-1,4-dibromotetrafluorobenzene (2:1) cocrystals are shown in Figure 16. 1,4-diiodotetrafluorobenzene and 1,4-dibromotetrafluorobenzene are structurally similar and ditopic linear halogen-bond donors. The crystal structure of lidocaine-1,4-diiodotetrafluorobenzene (2:1) and lidocaine-1,4-dibromotetrafluorobenzene (2:1) cocrystals revealed that halogen-bond donors, I/Br form intermolecular halogen bonding interaction with carbonyl oxygen of lidocaine. Thus, the oxygen of carbonyl group in lidocaine acted as a halogen-bond acceptor, forming X…O type halogen bonding with I/Br of coformer molecules,Pharmaceutics which2018 is ,again10, 108 a type II halogen bonding interaction [248] (as shown in Figure 16)35. of 74

Pharmaceutics 2018, 10, x FOR PEER REVIEW 36 of 74

(A)

(B)

Figure 16. Supramolecular synthons observed in crystal structures of (A) lidocaine-1,4- Figure diiodotetrafluorobenzene16. Supramolecular (2:1) cocrystal,synthons (B) lidocaine-1,4-dibromotetrafluorobenzeneobserved in crystal structures (2:1) cocrystal of (A) lidocaine[Yellow-1,4-diiodotetrafluorobenzene and orange represents halogen-bond (2:1) cocrystal, donors; (B) blue lidocaine represents-1,4- halogen-bonddibromotetrafluorobenzene acceptors] (2:1) cocrystal[Reprinted [Yellow from [ 247and] with orange permission. represents Copyright halogen 2017-bond American donors; Chemical blue Society]. represents halogen-bond acceptors] [Reprinted from [247] with permission. Copyright 2017 American Chemical Society]. 7.3. Ionic Interactions 7.3. Ionic InteractionsIonic cocrystals are another interesting class of cocrystals. These cocrystals are formed out of organic molecules and inorganic salts [248,249]. Braga and his coworkers [250] first coined the term Ionic‘ionic cocrystals cocrystals’. are Ionic another interactions interesting along with class non-covalent of cocrystals. interactions These such cocrystals as hydrogen are bonding formed and out of organic dipole-bondingmolecules and interactions inorganic stabilize salts [248,249 their crystal]. Braga structure and his [248 coworkers]. However, United[250] first States coined Food andthe term ‘ionic cocrystals’.Drug Administration Ionic interactions (US FDA) andalong EMA with has non declared-covalent that pharmaceutical interactions such cocrystals as hydrogen are crystalline bonding and dipolematerials-bonding composed interactions of two or stabilize more components their crystal interconnected structure by [24 non-ionic8]. However, interactions United in a States crystal Food and Druglattice Administration [48–50]. Hence, it(US appears FDA) that and ionic E cocrystalsMA has are declared exception that to the pharmaceutical definition given bycocrystals US FDA are and EMA on pharmaceutical cocrystals. Ionic cocrystals are also referred as ‘Salt cocrystals’ when crystalline materials composed of two or more components interconnected by non-ionic interactions the organic molecules cocrystallize with organic salts [249]. The salt entity in ionic cocrystals can be in a crystaleither lattice organic [48 [57–50] or]. inorganicHence, it [ 248appears,250,251 that]. The ionic schematic cocrystals shown are in exception Figure 17 explains to the definition a difference given by US betweenFDA and an organicEMA cocrystalon pharmaceutical and ionic cocrystal cocrystals. [252]. Ionic cocrystals are also referred as ‘Salt cocrystals’ when the organic molecules cocrystallize with organic salts [249]. The salt entity in ionic cocrystals can be either organic [57] or inorganic [248,250,251]. The schematic shown in Figure 17 explains a difference between an organic cocrystal and ionic cocrystal [252].

(A) (B)

- API - Metal cation - Organic - Metal anion conformer molecule Figure 17. Schematic representation of (A) a pharmaceutical cocrystal where the API and coformer are organic molecules and (B) an ionic cocrystal which contains an organic molecule and a metal ion.

Pharmaceutics 2018, 10, x FOR PEER REVIEW 36 of 74

(B)

Figure 16. Supramolecular synthons observed in crystal structures of (A) lidocaine-1,4-diiodotetrafluorobenzene (2:1) cocrystal, (B) lidocaine-1,4-dibromotetrafluorobenzene (2:1) cocrystal [Yellow and orange represents halogen-bond donors; blue represents halogen-bond acceptors] [Reprinted from [247] with permission. Copyright 2017 American Chemical Society].

7.3. Ionic Interactions Ionic cocrystals are another interesting class of cocrystals. These cocrystals are formed out of organic molecules and inorganic salts [248,249]. Braga and his coworkers [250] first coined the term ‘ionic cocrystals’. Ionic interactions along with non-covalent interactions such as hydrogen bonding and dipole-bonding interactions stabilize their crystal structure [248]. However, United States Food and Drug Administration (US FDA) and EMA has declared that pharmaceutical cocrystals are crystalline materials composed of two or more components interconnected by non-ionic interactions in a crystal lattice [48–50]. Hence, it appears that ionic cocrystals are exception to the definition given by US FDA and EMA on pharmaceutical cocrystals. Ionic cocrystals are also referred as ‘Salt cocrystals’ when the organic molecules cocrystallize with organic salts [249]. The salt entity in ionic Pharmaceuticscocrystals can2018 ,be10 ,either 108 organic [57] or inorganic [248,250,251]. The schematic shown in Figure36 of 17 74 explains a difference between an organic cocrystal and ionic cocrystal [252].

(A) (B)

- API - Metal cation - Organic - Metal anion conformer molecule Figure 17. SchematicSchematic representationrepresentation of of ( A(A) a) a pharmaceutical pharmaceutical cocrystal cocrystal where where the the API API and and coformer coformer are Pharmaceutics 2018, 10, x FOR PEER REVIEW 37 of 74 areorganic organic molecules molecules and and (B) an(B) ionic an ionic cocrystal cocrystal which which contains contains an organic an organic molecule molecule and and a metal a metal ion. ion. Recently, Song et al. [223] synthesized ionic cocrystal of piracetam with calcium chloride by optimizingRecently, solvent Song etparamet al. [223ers] synthesized for solution ionic crystallization cocrystal ofthrough piracetam construction with calcium of Ternary chloride Phase by optimizingDiagram. The solvent resultant parameters ionic cocrystal for solution had molecular crystallization formula through of piracetam construction2·CaCl2 of·2H Ternary2O which Phase is the Diagram.piracetam The dihydrate resultant ionic ionic cocrystal cocrystal had[223]. molecular The coordination formula of around piracetam Ca2+2· CaClcation2· 2Hin 2piraO whichcetam is CaCl the 2 2+ piracetam 2H2O ionic dihydrate cocrystal ionic and cocrystalthe 2D layer [223 of]. ThePiracetam coordination CaCl2 2H around2O ionic Ca cocrystalcation inhave piracetam been shown CaCl 2in 2HFigure2O ionic 18 [22 cocrystal3]. The andpiracetam the 2D CaCl layer2.2H of Piracetam2O crystallized CaCl in2 2H in 2aO monoclinic ionic cocrystal space have group, been P2 shown1/n. A unit in Figurecell of 18 the[ 223 ionic]. The cocrystal piracetam consisted CaCl2 .2Hof two2O crystallizedmolecules of in piracetam in a monoclinic, one CaCl space2 molecule group, P2 and1/n. two A unit H2O cellmolecules of the ionic [223 cocrystal]. Table 10 consisted presents of the two summary molecules of ionic of piracetam, cocrystals one reported CaCl2 moleculetill date in and the twoliterature. H2O molecules [223]. Table 10 presents the summary of ionic cocrystals reported till date in the literature.

(A) (B)

2+ Figure 18. (A) Coordination around Ca cation in piracetam. CaCl2 2H2O ionic cocrystal and (B). Figure 18. (A) Coordination around Ca2+ cation in piracetam. CaCl2 2H2O ionic cocrystal and (B). 2D 2D layer of Piracetam.CaCl2 2H2O ionic cocrystal [Reprinted from [223] with permission. Copyright 2018layer American of Piracetam Chemical.CaCl2 Society]. 2H2O ionic cocrystal [Reprinted from [223] with permission. Copyright 2018 American Chemical Society].

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Table 10. Summary of reports on ionic cocrystals available in the literature.

Enhancement in API Inorganic Ions Used Counterions Used Cocrystallization Process Reference(s) Dissolution Rate Exhibited lower dissolution Nicotinamide (NCT) CaCl Nil Liquid-assisted grinding and slow evaporation in Ethanol [248] 2 than raw NCT Exhibited lower dissolution Piracetam (PRT) CaCl Nil Liquid-assisted grinding and slow evaporation in Ethanol [248] 2 than raw PRT

Piracetam (PRT) CaCl2 Nil Liquid-assisted grinding using Methanol and slow evaporation Not reported [223] Barbituric acid (BBA) KBr Nil Kneading, vapor digestion and crystallization in Methanol (MeOH) Not reported [250] Barbituric acid (BBA) LiBr Nil Grinding Not reported [250] Barbituric acid (BBA) NaBr Nil Kneading, vapor digestion and crystallization in MeOH Not reported [250] Kneading, vapor digestion, crystallization in MeOH, grinding and Exhibited higher dissolution Barbituric acid (BBA) RbBr Nil [250] crystallization in Ethanol (EtOH) than raw BA Exhibited higher dissolution Barbituric acid (BBA) CsBr Nil Grinding and crystallization in EtOH [250] than raw BA Exhibited higher dissolution Barbituric acid (BBA) CsI Nil Grinding and crystallization in EtOH [250] than raw BA

Brivaracetam (BRV) MgCl2 6H2O and CaCl2 Nil Kneading and crystallization Not reported [252]

Seletracetam (SEL) MgCl2 6H2O and CaCl2 Nil Kneading and crystallization Not reported [252] L-Proline (PRO) Lithium salicylate Nil Crystallization in deionized water Not reported [253]

L-Proline (PRO) Lithium hydroxide Nicotinic acid Crystallization in deionized water Not reported [253] There was no signiﬁcant difference in the Intrinsic Piracetam (PIR) LiCl Nil Kneading at different RH conditions and crystallization [251] Dissolution Rate (IDR) of raw PIR and the ionic cocrystal There was no signiﬁcant Piracetam (PIR) LiBr Nil Kneading and crystallization difference in the IDR of raw PIR [251] and the ionic cocrystal

Trimesic acid (H3TMA) 2,6-bis(4-pyridylmethylene)cyclohexanone Nil Crystallization Not reported [254] Carbamazepine (CBZ) Sodium iodide (NaI) Acetyl chloride Crystallization in methanol Not reported [255] Sodium iodide (NaI) and Hydrobromic Acridinium I X species Crystallization in methanol Not reported [255] acid (HBr) 2 Benzoic acid (BA) Phenoxy acetic acid Nil Slow evaporation technique Not reported [249] Pharmaceutics 2018, 10, x FOR PEER REVIEW 39 of 74

Pharmaceutics 2018, 10, 108 38 of 74 7.4. Π…Π Stacking Interactions 7.4. ΠΠ…Π... Π Stacking stacking Interactions interactions are a type of attractive non-covalent interactions which occur betweenΠ... aromaticΠ stacking rings interactions (as they arecontain a type Π of bonds). attractive The non-covalent probability interactionsof occurrence which of Π…Π occur stacking between interactionsaromatic rings increases (as they when contain theΠ numberbonds). of The hydrogen probability poor of occurrencearomatic residues of Π... Πis stackingmore in interactionsa molecule [25increases6]. Several when reports the number are available of hydrogen in the poor literature aromatic where residues the role is moreof hydrogen in a molecule bonding [256 in]. altering Several physiochemicalreports are available properties in the literatureof an API where has been the rolereported of hydrogen [15,95]. bondingHowever, in very altering limited physiochemical reports are availableproperties in of the an lit APIerature has been where reported Π…Π [stacking15,95]. However, interactions very were limited utilized reports for modulatingare available the in physiochemicalthe literature where propertiesΠ... Π ofstacking pharmaceutical interactions cocrystals were utilized[17,257,258 for]. modulating the physiochemical propertiesRecently, of pharmaceutical Bora et al. [17] cocrystalsreported that [17, 257Π…Π,258 interactions]. (with T-shaped motif structures) and C−H Recently,π interactions Bora et al.can [17 ]modulate reported thattheΠ ...physiochemicalΠ interactions (withproperties T-shaped of motifcocrystals structures) such andas pH−-dependent··· π solubility, crystal packing and permeability while exploring cocrystallization of C H⋯ interactions can modulate the physiochemical properties of cocrystals such as pH-dependent acridinesolubility, with crystal isomeric packing hydroxybenzoic and permeability acids. while Since exploring acridine cocrystallization actively participates of acridine in intermolecu with isomericlar hydrogenhydroxybenzoic bonding acids. and SinceΠ-stacking acridine interactions actively participates(namely face in-to intermolecular-face π-stacking hydrogen interactions bonding and edge and toΠ -stackingface T-shaped interactions C-H…Π (namely interactions), face-to-face it π was-stacking chosen interactions for their study and edge [17]. to Itface was T-shaped concludedC-H. that . . Π packinginteractions), of the it cocrystal was chosen lattice for stabilized their study by [17 π].-stacking It was concluded interactions that and packing C-H…Π of theinteractions cocrystal affects lattice thestabilized solubility by andπ-stacking membrane interactions permeability and C-H. of cocrystals. . . Π interactions Figure 19 affects provides the solubilitya pictorial and representation membrane ofpermeability π-stacking ofand cocrystals. C-H…Π interactions Figure 19 provides observed a pictorialin these cocrystal representation structures. of π-stacking and C-H. . . Π interactionsSangtani observed et al. [257 in] these observed cocrystal concomitant structures. color polymorphism in Furosemide-4,4′-bipyridine (2:1) Sangtanicocrystals et (Forms al. [257 I] and observed II). Form concomitant I cocrystal color appeared polymorphism as pale yellow in Furosemide-4,4 needles whereas0-bipyridine form II cocrystal(2:1) cocrystals appeared (Forms as orange I and II).blocks Form [25 I7 cocrystal]. Form I appearedcocrystal was as pale observed yellow to needles crystallize whereas at faste formr rate II andcocrystal with higher appeared yield as than orange the blocks form II [257 cocrystal.]. Form The I cocrystal authors was proposed observed that to the crystallize color polymorphism at faster rate * inand furosemide with higher-4, yield4′-bipyridine than the (2:1) form cocrystals II cocrystal. can The be authorsattributed proposed to the difference that the color in Π…Π polymorphism separation in (asfurosemide-4,4 shown in Figure0-bipyridine 20) between (2:1) cocrystals the benzene can ring be attributed of furosemide to the and difference pyridine in ringΠ... ofΠ *4,separation4′-bipyridine (as inshown the sandwich in Figure 20motifs) between of form the benzeneI and form ring ofII furosemidecocrystals [25 and7]. pyridine This was ring further of 4,4 0supported-bipyridine by in Dynamicthe sandwich Functional motifs ofTheory form I(DFT) and form calculations. II cocrystals From [257 DFT]. This calculations, was further it supported was evident by Dynamicthat the HighestFunctional Occupied Theory (DFT)Molecular calculations. Orbital (HOMO) From DFT— calculations,Lowest Unoccupied it was evident Molecular that theOrbital Highest (LUMO) Occupied gap forMolecular form I pale Orbital yellow (HOMO)—Lowest needles was more Unoccupied when compared Molecular with Orbital form (LUMO) II orange gap blocks for form [257 I]. pale yellow needles was more when compared with form II orange blocks [257].

(A) (B) (C)

(D) (E) (F)

Figure 19. Pictorial representation of π-stacking interaction observed in (A) Acridine-2,3 DHBA (1:1) Figure 19. Pictorial representation of π-stacking interaction observed in (A) Acridine-2,3 DHBA (1:1) cocrystal, (B) acridine-2,4 DHBA (1:1) cocrystal, (C) acridine-2,5 DHBA (1:1) cocrystal, (D) acridine-2,6 cocrystal, (B) acridine-2,4 DHBA (1:1) cocrystal, (C) acridine-2,5 DHBA (1:1) cocrystal, (D) DHBA (1:1) cocrystal, (E) acridine-3,5 DHBA (3:1) cocrystal and (F) C-H. . . π interaction observed in acridineacridine-3,5-2,6 DHBA DHBA (1:1) (3:1) cocrystal, cocrystal [Reprinted(E) acridine from-3,5 DHBA [17] with (3:1) permission. cocrystal and Copyright (F) C-H…π 2018 interaction American observedChemical in Society]. acridine-3,5 DHBA (3:1) cocrystal [Reprinted from [17] with permission. Copyright 2018 American Chemical Society].

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(A) (B)

Figure 20. Sandwich motifs in colored furosemide-4,40-bipyridine (2:1) cocrystal polymorphs (A) form IFigure and (B )20. form Sandwich IIformed motifs viaΠ ...inΠ coloredinteractions furosemide and C-H.-4,4′ .- .bipyridineΠ interactions (2:1) [Reprinted cocrystal polymorphs from [257] with (A) permission.form I and ( CopyrightB) form IIformed 2015 American viaΠ…Π Chemical interactions Society]. and C-H…Π interactions [Reprinted from [257] with permission. Copyright 2015 American Chemical Society].

Thus, Π... Π interactions can significantly contribute to modification of physiochemical properties Thus, Π…Π interactions can significantly contribute to modification of physiochemical of an API molecule. Further research is needed to explore the role of Π... Π interactions in fine-tuning properties of an API molecule. Further research is needed to explore the role of Π…Π interactions in the solid-state properties (especially the dissolution rate, solubility, physical and chemical stability) of fine-tuning the solid-state properties (especially the dissolution rate, solubility, physical and poorly water-soluble drugs. chemical stability) of poorly water-soluble drugs. 7.5. Vanderwaal’s Interactions 7.5. Vanderwaal’s Interactions Vanderwaal’s interactions are yet other type of intermolecular interactions which contribute Vanderwaal’s interactions are yet other type of intermolecular interactions which contribute to to the packing of the cocrystal lattice [259]. It is the weakest of all intermolecular interactions. the packing of the cocrystal lattice [259]. It is the weakest of all intermolecular interactions. However, However, collectively these interactions are strong. These interactions were also observed to influence collectively these interactions are strong. These interactions were also observed to influence the the formation of coamorphous solid dispersions to a certain extent [260]. formation of coamorphous solid dispersions to a certain extent [260]. 8. Ternary and Quaternary Cocrystals 8. Ternary and Quaternary Cocrystals Ternary cocrystals and quaternary cocrystals have recently gained attention from several researchersTernary mainly cocrystals for poorlyand quaternary water-soluble cocrystals drugs have to enhance recently dissolutiongained attention rates andfrom aqueous several solubilityresearchers [261 mainly,262]. for Ternary poorly (three-component) water-soluble drugs and quaternaryto enhance (four-component)dissolution rates cocrystalsand aqueous are supramolecularsolubility [261,262 structures]. Ternary stabilized (three-component) by robust synthons and quaternary which build (four the-component) entire crystal cocrystals structure. are Synthesizingsupramolecular ternary structures cocrystals stabilized is not easyby robust when synthons compared which with thebuild synthesis the entire of binarycrystal cocrystalsstructure. asSynthesizing maintenance ternary of congruent cocrystals solubility is not easy of when drug compared and the twowith coformers the synthesis is difficultof binary and cocrystals requires as amaintenance lot of screening of congruent experiments. solubility There of drug is a needand the to two understand coformers the is basicdifficult principles and requires involved a lot inof formationscreening ofexperiments. ternary cocrystals There is and a need intermolecular to understand interactions the basic involvedprinciples in involved stabilizing in theirformation crystal of structuresternary cocrystals [263–265 ].and Several intermolecular approaches interactions have been usedinvolved by researchers in stabilizing to design their ternarycrystal cocrystalsstructures based[263–265 on]. crystal Several engineering approaches and have synthon been used engineering by researchers principles to [design265–268 ternary]. Some cocrystals of the approaches based on havecrystal been engineering explained below:and synthon engineering principles [265–268]. Some of the approaches have been explained below:

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8.1. Approaches for Designing Ternary/Quaternary Cocrystals 8.1. Approaches for Designing Ternary/Quaternary Cocrystals A. Hierarchical Fashion of Hydrogen Bond Formation A. Hierarchical Fashion of Hydrogen Bond Formation Aakeroy et al. [266] developed an approach to design ternary cocrystals based on the two Aakeroy et al. [266] developed an approach to design ternary cocrystals based on the two principle rules: principle rules: aa.. HydrogenHydrogen bond bond formation formation take take place place in in a hierarchical a hierarchical manner manner (best (best donor donor forms forms hydrogen hydrogen with with thethe best best acceptor, acceptor, the the second second-best-best donor donor with with the the second second-best-best acceptor) acceptor) [10 [1033] ] bb.. A Asmall small number number of ofspecific speciﬁc int intermolecularermolecular interactions interactions such such as as hydrogen hydrogen-bonding-bonding interactions interactions cancan contribute contribute to tolarger larger stabilization stabilization ener energygy of ofthe the molecular molecular crystals crystals [269 [269] ] BasedBased on on these these rules, rules, Aakeroy Aakeroy et et al. al. [26 [2666] ]synthesized synthesized 3,5 3,5-dinitrobenzoic-dinitrobenzoic acidacid-isonicotinamide-3-methylbenzoic-isonicotinamide-3-methylbenzoic acid (1:1:1),acid 3,5-dinitrobenzoic(1:1:1), acid-isonicotinamide-4-3,5-dinitrobenzoic acid(dimethylamino)-benzoic-isonicotinamide-4-(dimethylamino) acid (1:1:1)-benzoic and 3,5-dinitrobenzoic acid (1:1:1) acid-isonicotinamide-4-hydroxy- and 3,5-dinitrobenzoic acid3-methoxycinnamic-isonicotinamide- acid4-hydroxy (1:1:1)- ternary3-methoxycinnamic cocrystals [266 acid]. (1:1:1) ternary cocrystals [266]. BB.. Long Long-range-range Synthon Synthon Aufbau Aufbau Module Module (LSAM) (LSAM) LLSAMSAM has has its origin fromfrom thethe ‘Aufbau ‘Aufbau principle’ principle’ proposed proposed by by Kitaigorodski Kitaigorodski in the in yearthe year 1961 1961 [270 ]. [270According]. According to LSAM, to LSAM the molecules, the molecules which which are closely-packed are closely-packed in one-dimensional in one-dimensional chains, chains, arrange arrangethemselves themselves to form two-dimensionalto form two-dimensional sheets. These sheets. two-dimensional These two-dimensional sheets assemble sheets and assemb packle closely and packto form closely three-dimensional to form three-dimensional supramolecular supramolecular structural crystal structural units. Reportscrystal units. are available Reports in are the available literature inwhere the literature researchers where have researchers reported formationhave reported of binary formation (two-component) of binary (two cocrystals-component) [265 cocrystals], ternary [265(three-component)], ternary (three cocrystals-component) [265, 267cocrystals,271,272 ][26 and5,2 quaternary67,271,272 (four-component)] and quaternary cocrystals (four-component) [267] based cocrystalson LSAM. [267] based on LSAM. BinaryBinary cocrystal cocrystal of ofacetazolomide acetazolomide with with hydroxypyridine hydroxypyridine (1:2) was (1:2) synthesized was synthesized based on based LSAM on [26LSAM7]. Bolla [267 and]. Bolla Nangia and Nangia[267] had [267 synthesized] had synthesized ternary ternary cocrystals cocrystals of acetazolomide of acetazolomide by repl byacing replacing one moleculeone molecule of hydroxypyridine of hydroxypyridine with with nicotinamide nicotinamide (in (inacetazolomide acetazolomide-hydroxypyridine-hydroxypyridine (1:2) (1:2) binary binary cocrystal)cocrystal) and and attempted attempted to to understand understand the the L LSAMSAM [26 [2677].]. Cocrystallization Cocrystallization of of acetazolomide acetazolomide with with nicotinamidenicotinamide and and hydroxypyridine hydroxypyridine resulted resulted in ina ternary a ternary coc cocrystalrystal at a at stoichiometric a stoichiometric ratio ratio of 1:1:1 of1:1:1 (as shown(as shown in Figure in Figure 21). Hydrogen 21). Hydrogen bonding bonding between between sulfonamide sulfonamide N-H and N-H nicotinamide and nicotinamide –C=O resulted –C=O 2 2 inresulted R22(20) inmotifs R2 (20) whereas motifs R whereas22(8)D motifs R2 (8)D were motifs observed were in observed hydroxypyridine in hydroxypyridine dimers (as dimersshown in (as Figureshown 21). in Figure Thus, 21 –).NH Thus, functional –NH functional group groupin the inacetazolomide the acetazolomide bonds bonds with with pyridine pyridine N Natom atom of of nicotinamidenicotinamide and –NH–NH ofof nicotinamide nicotinamide is bondedis bonded to hydroxypyridine to hydroxypyridine dimers dimers to result to intoresult a cocrystal into a cocrystaladopting adopting Long-range Long Synthon-range Synthon Aufbau Aufbau principle principle (Figure (22Figure)[267 22)]. Figure[267]. Figure22 represents 22 represents the LSAM the LobservedSAM observed in acetazolomide-nicotinamide-hydroxypyridine in acetazolomide-nicotinamide-hydroxypyridine (1:1:1) (1:1:1) ternary ternary cocrystal. cocrystal.

2 2 2 2 FigureFigure 21.21. SynthonsSynthons andand R 2 (20)R2 (20) motifs motifs and R2 and(8)D motifsR2 (8)D observed motifs inobserved acetazolomide- in acetazolomidenicotinamide-hydroxypyridine-nicotinamide-hydroxypyridine (1:1:1) ternary (1:1:1) cocrystal ternary [A—Acetazolomide; cocrystal [A— B—Nicotinamide;Acetazolomide; BC—Hydroxypyridine]—Nicotinamide; C—Hydroxypyridine] [Reprinted from [Reprinted [267] with from permission [267] with ofpermission International of International Union of UnionCrystallography]. of Crystallography].

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FigureFigure 22.22. 22.Long-range LongLong-range-range Synthon SynthonSynthon Assembly AssemblyAssembly Module Module (LSAM)Module observed(LSAM)(LSAM) inobservedobserved acetazolomide- in in nicotinamide-hydroxypyridineacetazolomideacetazolomide-nicotinamide-nicotinamide-hydroxypyridine-hydroxypyridine (1:1:1) ternary (1:1:1) cocrystal(1:1:1) ternary [Reprinted cocrycocrystalstal from [Reprinted [Reprinted [267] withfrom fr om permission[267 [267] with] with of permission of International Union of Crystallography]. Internationalpermission of UnionInternational of Crystallography]. Union of Crystallography]. C. Drug-Bridge-Drug Ternary Cocrystallization Strategy C.C. Drug-Bridge-DrugDrug-Bridge-Drug TernaryTernary CocrystallizationCocrystallization Strategy Strategy Recently, Liu et al. [261] developed a ‘Drug-Bridge-Drug Ternary Cocrystallization strategy’ for Recently,cocrystallizing LiuLiu et two al. anti [[26261-1tuberculos]] developedis drugs, a ‘Drug-Bridge-Drug‘Drug isoniazid-Bridge and-Drug pyrazinamide Ternary Cocrystallization using trans-fumaric strategy’ acid as for cocrystallizinga bridge. Pyrazinamide two anti-tuberculosisanti-tuberculos has aqueousis drugs, solubility isoniazid of 15,000 and mg/L pyrazinamide [273] whereas using isoniazid trans-trans -hasfumaric aqueous acid as a bridge.solubility Pyrazinamide of 140,000 hasmg/L aqueous at 25 °C solubility[274]. Figure of 15,0002315 ,presents000 mg/Lmg/L (a) [27 [273the3 ]]chemical whereas structures isoniazid of has the aqueousAPI solubilitymolecules, of 140,000140 isoniazid,000 mg/L and at atpyrazinamide, 25 25 °◦CC[ [272744].]. trans Figure Figure and 23 23cis presentsfumaricpresents acid (a) (a) and the (b) chemical the schematic structures how fumaric of thethe API molecules,acid act isoniazid as a bridge and in pyrazinamide,interconnecting isoniazidtrans and and cis pyrazinamidefumaric acid andmolecules. (b) the schematic how fumaric Fumaric acid was chosen as a bridge to link isoniazid and pyrazinamide as the carboxylic acid acid act as a bridge in interconnecting isoniazid andand pyrazinamidepyrazinamide molecules.molecules. functional groups in fumaric acid can interact effectively with N-heterocycles of isoniazid and Fumaric acid acid was was chosen chosen as as a abridge bridge to tolink link isoniazid isoniazid and and pyrazinamide pyrazinamide as the as carboxylic the carboxylic acid pyrazinamide to form stronger heterosynthon [261]. Moreover, the amide functional group of functional groups in fumaric acid can interact effectively with N-heterocycles of isoniazid and acid functionalpyrazinamide groups and inhydrazide fumaric functional acid can interactgroup in effectively isoniazid withhas Nbeen-heterocycles reported to of isoniazidform andpyrazinamide pyrazinamidehydrogen -bondingto form to motifs formstronger with stronger dicarboxylicheterosynthon heterosynthon acids [26 and1]. tricarboxylic Moreover, [261]. Moreover,acids the inamide several the functional studies amide [27 functional5,276group]. of grouppyrazinamideThe of selection pyrazinamide and of suitablehydrazide and dicarboxylic hydrazide functional acid functional plays group an important groupin isoniazid in role isoniazid in determininghas hasbeen been thereported reportedsuccess ofto tothis form hydrogen-bondinghydrogen‘drug--bondingbridge-drug motifs ternary with cocrystallization dicarboxylic acids strategy’. and tricarboxylic acids in in several several studies studies [27 [2755,276,276].]. The selection of suitable dicarboxylic acid plays an important role in determining the success of this ‘drug-bridge-drug‘drug-bridge-drug ternaryternaryA cocrystallizationcocrystallization strategy’.strategy’.

Figure 23. (A) Chemical structures of isoniazid, pyrazinamide, trans and cis fumaric acid, (B) Schematic representation of fumaric acid acting as a bridge in interconnecting isoniazid and pyrazinamide molecules [Reprinted from [261] with permission. Copyright 2018 American Chemical Society].

Figure 23.23.( A(A) Chemical) Chemical structures structures of isoniazid, of isoniazid, pyrazinamide, pyrazinamide,trans and transcis fumaricand cis acid,fumaric (B) Schematicacid, (B) representationSchematic representation of fumaric acidof fumaric acting asacid a bridgeacting inas interconnectinga bridge in interconnecting isoniazid and pyrazinamideisoniazid and moleculespyrazinamide [Reprinted molecules from [R [eprinted261] with from permission. [261] with Copyright permission. 2018 Copyright American 2018 Chemical American Society]. Chemical Society].

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D. Ditopic Hydrogen Bond Donors and Acceptors Combination D.D. DitopicDitopic HydrogenHydrogen BondBond DonorsDonors andand AcceptorsAcceptors Combination Combination Etter’s rule of hydrogen bonding [103] suggests that design of a cocrystal mainly depends on Etter’sEtter’s rulerule ofof hydrogenhydrogen bondingbonding [[103103]] suggestssuggests thatthat designdesign ofof aa cocrystalcocrystal mainlymainly dependsdepends onon hydrogen bond acceptors and hydrogen bond donors which participate in cocrystallization hydrogenhydrogen bond bond acceptors acceptors and a hydrogennd hydrogen bond donorsbond donors which participatewhich participate in cocrystallization in cocrystallization (discussed (discussed in Section 3.2). In general, ternary cocrystals are stabilized by strong intermolecular in(discussed Section 3.2 in). Section In general, 3.2). ternaryIn general, cocrystals ternary are cocrystals stabilized are by stabilized strong intermolecular by strong intermolecular interactions interactions that exist between three components. Later, Aakeroy et al. [266] proposed that these thatinteractions exist between that exist three between components. three Later,compon Aakeroyents. Later, et al. Aakeroy [266] proposed et al. [266 that] theseproposed intermolecular that these intermolecular hydrogen-bonding interactions in ternary cocrystals can occur as per any one of the hydrogen-bondingintermolecular hydrogen interactions-bonding in ternary interactions cocrystals in ternary can occur cocrystals as per any can one occur of the as patternsper any illustratedone of the patterns illustrated in Figure 24. inpatterns Figure illustrated24. in Figure 24.

Figure 24. Schematic representation of possible structures of hydrogen-bonding interactions in FigureFigure 24.24.Schematic Schematic representation representation of possibleof possible structures structures of hydrogen-bonding of hydrogen-bonding interactions interactions in ternary in ternary cocrystals [HB # 1 and HB # 2 -Hydrogen bonds 1 and 2; A1,A2-Hydrogen bond acceptors and cocrystalsternary cocrystals [HB # 1 [H andB # HB1 and # 2HB -Hydrogen # 2 -Hydrogen bonds bonds 1 and 1 and 2; A2;1 ,AA12,A-Hydrogen2-Hydrogen bond bond acceptors acceptors andand D1,D2-Hydrogen bond donors] [Reprinted from [264] with permission. Copyright 2016 American DD11,D,D22--HydrogenHydrogen bondbond donors] [Reprinted[Reprinted fromfrom [[264264]] withwith permission.permission. CopyrightCopyright 20162016 AmericanAmerican Chemical Society]. ChemicalChemical Society].Society]. Adsmond et al. [264] adopted strategy 2 (shown in Figure 25) to design ternary cocrystals [264] Adsmond et al. [264] adopted strategy 2 (shown in Figure 25) to design ternary cocrystals [264] of acridine,Adsmond 3- ethydroxybenzoic al. [264] adopted acid strategy and 2 (shown2-amino in-4,6 Figure-dimethylpyridine 25) to design ternaryusing cocrystalscarboxyphenol [264] of acridine, 3-hydroxybenzoic acid and 2-amino-4,6-dimethylpyridine using carboxyphenol (3of-hydroxybenzoic acridine, 3-hydroxybenzoic acid) as a ditopic acid andhydrogen 2-amino-4,6-dimethylpyridine donors molecule. According using to carboxyphenolthe proposed (3-hydroxybenzoic acid) as a ditopic hydrogen donors molecule. According to the proposed strategy,(3-hydroxybenzoic a molecule acid) with as ditopic a ditopic hydrogenbond hydrogen donors donors molecule. (such as Accordingcarboxy phenols) to the proposed can be combined strategy, strategy, a molecule with ditopic hydrogenbond donors (such as carboxy phenols) can be combined witha molecule two different with ditopic molecules hydrogenbond containing donors hydrogenbond (such as carboxy acceptors phenols) in canthem be to combined generate with a new two with two different molecules containing hydrogenbond acceptors in them to generate a new threedifferent-component molecules crystal containing [264]. hydrogenbondThe schematic representation acceptors in them of the to generatestrategy used a new by three-component Adsmond et al. three-component crystal [264]. The schematic representation of the strategy used by Adsmond et al. [264crystal] in [ 264formation]. The schematic of acridine representation-3-hydroxybenzoic of the strategyacid-2-amino used by-4,6 Adsmond-dimethylpyridine et al. [264 ](1:1:1) in formation cocrystal of [264] in formation of acridine-3-hydroxybenzoic acid-2-amino-4,6-dimethylpyridine (1:1:1) cocrystal isacridine-3-hydroxybenzoic shown in Figure 25. acid-2-amino-4,6-dimethylpyridine (1:1:1) cocrystal is shown in Figure 25. is shown in Figure 25.

Figure 25. Schematic representation of ditopic hydrogen bond donors and acceptors combination FigureFigure 25.25. SchematicSchematic representationrepresentation ofof ditopicditopic hydrogenhydrogen bondbond donorsdonors andand acceptorsacceptors combinationcombination strategy proposed by Adsmond et al. (2016) in formation of acridine-3-hydroxybenzoic strategystrategy proposedproposed byby AdsmondAdsmond etet al.al. (2016) inin formationformation ofof acridine-3-hydroxybenzoicacridine-3-hydroxybenzoic acid-2-amino-4,6-dimethylpyridine (1:1:1) cocrystal [Reprinted from [264] with permission. acid-2-amino-4,6-dimethylpyridineacid-2-amino-4,6-dimethylpyridine (1:1:1) (1:1:1 cocrystal) cocrystal [Reprinted [Reprinted from [264from] with [264 permission.] with permission. Copyright Copyright 2016 American Chemical Society]. 2016Copyright American 2016 Chemical American Society]. Chemical Society].

Also, Bhogala and Nangia [277] synthesized ternary and quaternary cocrystals of 1, Also, Bhogala and Nangia [277] synthesized ternary and quaternary cocrystals of 1, 3cis,5cisAlso,-cycloh Bhogalaexanetricarboxylic and Nangia acids [277 ]with synthesized 4,4′-bipyridine ternary bases and connected quaternary by cocrystalsmethylene ofand 1, 3cis,5cis-cyclohexanetricarboxylic acids with 04,4′-bipyridine bases connected by methylene and alkene3cis,5cis-cyclohexanetricarboxylic chains [277]. It was concluded acids withfrom4,4 the-bipyridine study that bases utilization connected of triacid by methylene and differentiated and alkene alkene chains [277]. It was concluded from the study that utilization of triacid and differentiated bipyridinechains [277 ].bases It was is responsible concluded from for the the self study-assembly that utilization of the different of triacid components and differentiated through bipyridine O-H…N bipyridine bases is responsible for the self-assembly of the different components through O-H…N hydrogenbases is responsible bonds in for the the ternary self-assembly and quaternary of the different systems. components Tilborg through et al. O-H.[278 .] . Nreported hydrogen a hydrogen bonds in the ternary and quaternary systems. Tilborg et al. [278] reported a threebonds-component in the ternary cocrystal and quaternary of 1:1:1 systems.L-proline Tilborg-D-proline et al.-fumaric [278] reported acid with a three-component a racemic compound, cocrystal three-component cocrystal of 1:1:1 L-proline-D-proline-fumaric acid with a racemic compound, DL-proline and fumaric acid [278]. Interestingly, a 1:1 eutectic mixture of Pyrazinamide-Isoniazid DL-proline and fumaric acid [278]. Interestingly, a 1:1 eutectic mixture of Pyrazinamide-Isoniazid

Pharmaceutics 2018, 10, 108 43 of 74

of 1:1:1 L-proline-D-proline-fumaric acid with a racemic compound, DL-proline and fumaric acid [278]. Interestingly, a 1:1 eutectic mixture of Pyrazinamide-Isoniazid [18] yielded two different ternary cocrystals with succinic acid and fumaric acid as coformers (each with a stoichiometric ratio of 1:1:1) [23]. Also, Cheung et al. [279] reported that solid-state 13C NMR can serve as a direct method to determine the structure of ternary cocrystal of benzoquinone (BQ), racemic bis-β-Naphthol (BN) and anthracene (AN) in a stoichiometric ratio of 1:1:0.5, prepared by solid-state grinding [279]. Recently, ternary cocrystals of Bumetanide with isonicotinamide-2-picolinic acid, isonicotinamide-vanillic acid, isonicotinamide- para aminosalicylic acid and 2-hydroxypyridone-2-picolinic acid pairs were reported by Allu et al. [280]. Aitipamula et al. [262] prepared ternary cocrystals of isoniazid with enhanced dissolution rates as compared to the commercially available isoniazid [262].

8.2. Advantages of Ternary/Quaternary Cocrystals Ternary/quaternary cocrystals are highly useful in enhancing the efﬁcacy of drugs when it is not achieved by formulating binary cocrystals. Furthermore, when it is not possible to cocrystallize two different APIs (to enhance their efﬁcacy) due to their shape incompatibility; another molecule(s) can be introduced between the two drugs which can serve as a linker, propagate the growth unit and enable cocrystallization, and form a supramolecular structure [261]. Like binary cocrystals, three- or four-component cocrystals enhance dissolution rate [261,262], bioavailability and physical stability of poorly water-soluble drugs

8.3. Disadvantages of Ternary/Quaternary Cocrystals Though ternary/quaternary cocrystals possess advantages such as enhanced bioavailability, solubility, dissolution rates and physical stability, the synthesis of ternary cocrystals is difficult as the intermolecular interactions in the ternary cocrystals should be very specific and balanced. Therefore, the synthesis of ternary cocrystals involves a lot of efforts in screening and synthesis and poses difficulty in terms of understanding of the chemistry.

9. Polymorphism in Cocrystals Polymorphism can be deﬁned as the ability of a drug to exists in more than one crystalline phases with variation in arrangements or variation in the conformation of drug molecules in a crystal lattice [102,281,282]. Drugs existing in more than one crystal form can have different physicochemical properties such as dissolution rate, solubility, morphology, mechanical properties and physicochemical stability [283,284]. Polymorphism in cocrystals can inﬂuence aqueous solubility, dissolution property and bioavailability of a drug [35]. Cocrystals exhibit different types of polymorphic behaviors such as synthon polymorphism [285,286], concomitant polymorphism [257,287,288], conformational polymorphism, packing polymorphism and pseudopolymorphism [285]. Each of these types has been discussed in brief in sections below:

9.1. Synthon Polymorphism Cocrystal polymorphs exhibiting difference in their synthons are termed as Synthon polymorphs [102,215,289–299]. Synthon polymorphs occur when a molecule has several possibilities of forming hydrogen bonds with its neighboring molecule. Figure 26 presents various synthon polymorphs (forms I, II and III) observed in 4-hydroxybenzoic acid—4,40-bipyridine cocrystal [286]. Form I 4-hydroxybenzoic acid—4,40-bipyridine cocrystal is stabilized by acid-acid homosynthon (represented as synthon A) and phenol-pyridine bond (represented as synthon B) and Form II 4-hydroxybenzoic acid—4,40-bipyridine cocrystal is stabilized by phenol-acid (synthon C) and acid-pyridine bond (synthon D). Phenol-pyridine bond (synthon C) and acid-pyridine bond (synthon D) on the other hand stabilizes the cocrystal lattice of Form III 4-hydroxybenzoic acid—4,40-bipyridine cocrystal [286]. Pharmaceutics 2018, 10, 108 44 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 45 of 74

(A)

(B)

(C)

Synthon A Synthon B Synthon C Synthon D

Figure 26. SynthonSynthon polymorphs polymorphs of of ( (AA)) form form I, I, ( (BB)) form form II and (C) form IIIIII 4-hydroxybenzoic4-hydroxybenzoic acid:4,4acid:4,4′0--bipyridinebipyridine (2:1) (2:1) cocrystal (pink (pink—synthon—synthon A; A; blue blue—synthon—synthon B; orange—synthonorange—synthon C and green—synthongreen—synthon D)D) [Reprinted [Reprinted from from [286 ][286 with] permission.with permission. Copyright Copyright 2013 Royal 2013 Society Royal of Chemistry].Society of Chemistry]. 9.2. Concomitant Polymorphism 9.2. Concomitant Polymorphism Concomitant polymorphs are polymorphs which crystallize simultaneously in identical crystallizationConcomitant conditions polymorphs in the are same polymorphs batch. Reportswhich crystallize are available simultaneously in the literature in identical where researcherscrystallization have conditions reported formationin the same of batch. concomitant Reports cocrystal are available polymorphs in the literature [285,287,288 where,300– researchers302]. Color polymorphismhave reported isformation another interesting of concomitant variation ofcocrystal concomitant polymorphs polymorphism [285,287,288 in which,300 cocrystal–302]. formsColor ofpolymorphism more than one is coloranother appear interesting during variation crystallization. of concomitant A few ﬁndings polymorphism (See Section in which 7.4) on cocrystal colored polymorphismforms of more ofthan cocrystal one color have appear been reported during bycrystallization. Gonnade and A coworkers few findings [257 ,(See258]. Section 7.4) on colored polymorphism of cocrystal have been reported by Gonnade and coworkers [257,258]. 9.3. Conformational Polymorphism 9.3. Conformational Polymorphism When a molecule exists in different possible conformations which are formed as a result of a few rotationsWhen a molecule about a single exists bondin different present possible in it, then conformations they are called which as conformational are formed as polymorphs.a result of a Moleculesfew rotations which about are a conformationallysingle bond present ﬂexible in it, then possess they good are called probability as conformational to exhibit conformational polymorphs. polymorphismMolecules which because are conformationally the amounts of flexible energy possess needed good for rotation probability about to single exhibit bonds conformational are mostly equivalentpolymorphism to the because lattice energythe amounts differences of energy between needed the polymorphs for rotation [102 about]. Ethenzamide-ethyl single bonds are malonicmostly acidequivalent (1:1) cocrystal to the lattice [294], nicotinamide-pimelicenergy differences between acid (1:1) the cocrystal polymorph [214],s caffeine-glutaric[102]. Ethenzamide acid-ethyl (1:1) cocrystalmalonic acid [303 ],(1:1) trimesic cocrystal acid-1,2-bis(4-pyridylethane) [294], nicotinamide-pimelic (2:3) cocrystalacid (1:1) [ 301cocrystal] and celecoxib- [214], caffeineδ-valerolactam-glutaric (1:1)acid cocrystal(1:1) cocrystal [304] were [30 reported3], trimesic to exhibit acid conformational-1,2-bis(4-pyridylethane) polymorphic (2:3) behavior cocrystal in the [30 literature.1] and Figurecelecoxib 27- δpresents-valerolactam the packing (1:1) co thecrystal of ethenzamide-ethyl [304] were reported malonic to exhibit acid conformational (1:1) cocrystal polymorphic polymorphs, (a)behavior form 1 in and the (b) literature. form 2. The Figure Overlay 27 presents of conformers the packing of ethenzamide the of ethenzamide and ethylmalonic-ethyl malonic acid in acid (a) form(1:1) 1cocrystal and (b) formpolymorphs, 2 cocrystal (a) polymorphs form 1 and are(b) shownform 2. in The Figure Overlay 28. The of conformation conformers of of ethenzami ethenzamidede wasand observedethylmalonic to beacid identical in (a) form in both 1 and the (b) polymorphs form 2 cocrystal (Figure polymorphs 27) whereas are the shown conformation in Figure of28. ethyl The malonicconformation acid differsof ethenzamide in both (Figure was observed 28) leading to be to identical formation in ofboth conformational the polymorphs polymorphs (Figure 27) of Ethenzamide-ethylwhereas the conformation malonic of acid ethyl (1:1) malonic cocrystal acid [216 differs]. in both (Figure 28) leading to formation of conformational polymorphs of Ethenzamide-ethyl malonic acid (1:1) cocrystal [216].

Pharmaceutics 2018, 10, x FOR PEER REVIEW 46 of 74

Pharmaceutics 2018, 10, 108 45 of 74

(A)

(B)

(B) Figure 27. Packing of ethenzamide-ethyl malonic acid (1:1) cocrystal (A) form 1 and (B) form 2 Figure[Reprinted 27. Packingfrom [216 of] with ethenzamide-ethyl permission. Copyright malonic 2010 acid Royal (1:1) Society cocrystal of (Chemistry].A) form 1 and (B) form 2 [ReprintedFigure 27. fromPacking [216 ]of with ethenzamide permission.-ethyl Copyright malonic 2010 acid Royal (1:1) Society cocrystal of Chemistry].(A) form 1 and (B) form 2 [Reprinted from [216] with permission. Copyright 2010 Royal Society of Chemistry].

(A) (B)

Figure 28. Overlay of conformers of( ethenzamideA) (in left) and ethylmalonic(B acid) (in right) in (A) form 1Figure (in red) 28. and Overlay (B) form of conformers 2 (in blue) cocrystalof ethenzamide ([Reprinted (in left) from and [ 216ethylmalonic] with permission. acid (in right) Copyright in (A) 2010form 1 (in red) and (B) form 2 (in blue) cocrystal ([Reprinted from [216] with permission. Copyright 2010 RoyalFigure Society 28. Overlay of Chemistry]. of conformers of ethenzamide (in left) and ethylmalonic acid (in right) in (A) form Royal Society of Chemistry]. 1 (in red) and (B) form 2 (in blue) cocrystal ([Reprinted from [216] with permission. Copyright 2010 9.4. PackingRoyal Society Polymorphism of Chemistry]. 9.4. Packing Polymorphism Packing polymorphs possess same conformation but different intermolecular interactions, 9.4. PackingPacking Polymorphism polymorphs possess same conformation but different intermolecular interactions, therefore resulting in different packing patterns in the crystal lattice. When two cocrystal molecules therefore resulting in different packing patterns in the crystal lattice. When two cocrystal molecules havePacking same conformation polymorphs and possess different same intermolecular conformation interactions, but different then intermolecular the cocrystals are interactions, said to be have same conformation and different intermolecular interactions, then the cocrystals are said to be packedtherefore polymorphic resulting in cocrystals.different packing Packing patterns polymorphism in the crystal is one lattice. of the When rare polymorphictwo cocrystal behaviorsmolecules packed polymorphic cocrystals. Packing polymorphism is one of the rare polymorphic behaviors exhibitedhave same by conformation cocrystals and and very different limited reportsintermolecular are available interactions, in the literature then the on cocrystals packing polymorphs are said to ofbe exhibited by cocrystals and very limited reports are available in the literature on packing cocrystalspacked polymorphic [302,305–307 cocrystals.]. Skovsgaard Packing and Bond polymorphism [305] reported is one packing of the polymorphs rare polymorphic (forms I behaviors and II) in polymorphs of cocrystals [302,305–307]. Skovsgaard and Bond [305] reported packing polymorphs benzoicexhibited acid-2-aminopyrimidine by cocrystals and very (2:1) andlimited salicylic reports acid- areN,N 0available-diacetylpiperazine in the literature (2:1) cocrystals on packi [305ng]. (forms I and II) in benzoic acid-2-aminopyrimidine (2:1) and salicylic acid-N,N′-diacetylpiperazine Bispolymorphs et al. [302 ]of reported cocrystals packing [302,305 polymorphism–307]. Skovsgaard in 4-cyanopyridine-4,4 and Bond [305]0 -biphenolreported packing (2:1) cocrystals polymorphs [302]. (2:1) cocrystals [305]. Bis et al. [302] reported packing polymorphism in (formsTothadi I and [II)306 in] identifiedbenzoic acid an-2 interesting-aminopyrimidine packing (2:1) polymorphism and salicylic inacid urea-4,4-N,N′-diacetylpiperazine0-bipyridine (1:1) 4-cyanopyridine-4,4′-biphenol (2:1) cocrystals [302]. cocrystals(2:1) cocrystals [306]. Figure [3 0295]. presents Bis theet packingal. [30 polymorphs2] reported (Form Ipacking and II) of urea-4,4polymorphism0-bipyridine in Tothadi [306] identified an interesting packing polymorphism in urea-4,4′-bipyridine (1:1) (1:1)4-cyanopyridine cocrystals. Occurrence-4,4′-biphenol of urea(2:1) tapecocrystals in the [30 crystal2]. structure of urea-containing cocrystals is one cocrystals [306]. Figure 29 presents the packing polymorphs (Form I and II) of urea-4,4′-bipyridine of theTothadi rare observations [306] identified in crystallography. an interesting Till packing date, out polymorphism of 194 urea-containing in urea- cocrystal4,4′-bipyridine structures (1:1) (1:1) cocrystals. Occurrence of urea tape in the crystal structure of urea-containing cocrystals is one onlycocrystals 5 cocrystal [306]. structures Figure 29 were presents identified the packing to possess polymor urea tapephs structures(Form I and [308 II)]. of Interestingly, urea-4,4′-bipyridine both the polymorphic(1:1) cocrystals. forms Occurrence contained of urea urea tape tapes in in the their crystal crystal structure structures of urea [306-containing]. Though cocrystals the urea is tape one arrangements are common in both the polymorphs, the 3D packing significantly differed from each

Pharmaceutics 2018, 10, x FOR PEER REVIEW 47 of 74 of the rare observations in crystallography. Till date, out of 194 urea-containing cocrystal structures only 5 cocrystal structures were identified to possess urea tape structures [308]. Interestingly, both the polymorphic forms contained urea tapes in their crystal structures [306]. Though the urea tape arrangements are common in both the polymorphs, the 3D packing significantly differed from each otherPharmaceutics. In the Form 2018, 10 1, x cocrystal,FOR PEER REVIEW the consecutive planes are arranged in an ABA’B′ABA47′B ′of fashion 74 whereas in the Form 2 cocrystal, the consecutive planes are arranged in an ABAB fashion. of the rare observations in crystallography. Till date, out of 194 urea-containing cocrystal structures only 5 cocrystal structures were identified to possess urea tape structures [308]. Interestingly, both the polymorphic forms contained urea tapes in their crystal structures [306]. Though the urea tape arrangementsPharmaceutics 2018 are, 10common, 108 in both the polymorphs, the 3D packing significantly differed from46 ofeach 74 other. In the Form 1 cocrystal, the consecutive planes are arranged in an ABA’B′ABA′B′ fashion whereasother. in In the the Form Form 2 1cocrystal, cocrystal, the the consecutive consecutive planes planes are are arranged arranged in in an an ABAB ABA’B fashion.0ABA0B 0 fashion whereas in the Form 2 cocrystal, the consecutive planes are arranged in an ABAB fashion.

(A) (B)

Figure 29. Packing of (A) form I urea-4,4′-bipyridine (1:1) and (B) form IIurea-4,4′-bipyridine (1:1)

Recently,Figure Surov 29. Packing et al. of[307 (A)] formaddressed I urea-4,4 that0-bipyridine weak interactions (1:1) and (B) form can IIurea-4,4 cause 0packing-bipyridine polymorphism (1:1) in pharmaceuticalFigurecocrystals 29. Packing [Reprintedcocrystals of (A from) formwhile [306 I] urea with investigating- permission.4,4′-bipyridine Copyright (1:1)packing and 2014 ( B Royalpolymorphism) form Society IIurea of-4, Chemistry].4′- bipyridine(form I (1:1)and II) in salicylamidecocrystals-oxalic [Reprinted acid (2:1) from cocrystal [306] with permission.[307]. The Copyright crystal structures 2014 Royal Societyof form of Chemistry].I and form II cocrystal polymorphsRecently, revealed Surov that et both al. [307 the] addressed polymorphs that weak consisted interactions of conformationally can cause packing identical polymorphism molecules. inRecently, pharmaceutical Surov et cocrystals al. [307] addressed while investigating that weak interactions packing polymorphism can cause packing (form polymorphism I and II) in However, packing of the two polymorphs differed in terms of arrangement of the neighboring in salicylamide-oxalicpharmaceutical cocrystals acid (2:1) cocrystalwhile investigating [307]. The crystal packing structures polymorphism of form I and(form form I IIand cocrystal II) in ribbonssalicylamidepolymorphs [307]. In-ox form revealedalic acidI cocrystal, that(2:1) both cocrystal the the adjusted polymorphs [307]. The ribbons consistedcrystal were structures of packed conformationally of in form zig- zagI and identical fashion form molecules.II at cocrystal an angle of ~76.2°polymorphs whileHowever, it is revealed packing ~48.6° in ofthat case the both two of theform polymorphs polymorphs II cocrystal. differed consisted Crystal in terms of structure conformationally of arrangement analysis ofidentical and the Hirshfeld neighboring molecules. surface analysisHowever,ribbons revealed packing [307 ].that In formof the the Idi cocrystal,twostribution polymorphs the of adjusted weak differed ribbonsintermolecular in wereterms packed of interactionsarrangement in zig-zag fashioninof polymorphicthe atneighboring an angle forms influencedribbonsof ~76.2 [307the◦ ].whilepacking In form it is Iof ~48.6cocrystal, the◦ incocrystal casethe adjusted of formlattice IIribbons cocrystal.to a werelarger Crystal packed extent structure in [30zig7-zag]. analysis Figure fashion and30 at an Hirshfeldrepresents angle of the molecular~76.2°surface whilepacking analysis it is projections~48.6° revealed in case that of of salicylamide the form distribution II cocrystal.-oxalic of weak Crystal acid intermolecular (2:1)structure form analysis I interactionsand form and HirshfeldII in cocrys polymorphic talsurface along an axis.analysis forms revealed inﬂuenced that the the packing distribution of the cocrystal of weak latticeintermolecular to a larger interactions extent [307]. in Figure polymorphic 30 represents forms influencedthe molecular the packing packing of projections the cocrystal of salicylamide-oxalic lattice to a larger acid extent (2:1) form [307 I]. and Figure form II30 cocrystal represents along the molecularan axis. packing projections of salicylamide-oxalic acid (2:1) form I and form II cocrystal along an axis.

(A) (B)

Figure 30. Molecular(A packing) projections of salicylamide-oxalic acid (2:1)(B) (A) form I and (B) form Figure II30. cocrystal Molecular along packing crystallographic projections an axis of salicylamide [Reprinted from-oxalic [307] acid with permission.(2:1) (A) form Copyright I and ( 2017B) form II American Chemical Society]. cocrystalFigure along 30. Molecular crystallographic packing projections an axis [Reprintedof salicylamide from-oxalic [307 acid] with (2:1) permission.(A) form I and Copyright (B) form II 2017 American Chemical Society]. 9.5.cocrystal Pseudopolymorphism along crystallographic an axis [Reprinted from [307] with permission. Copyright 2017 American Chemical Society]. Hydrates/solvates of an organic compound are also referred to as ‘Pseudopolymorphs’ [44]. Cocrystal pseudopolymorphs are the cocrystals which comprise water or solvent molecules as Pharmaceutics 2018, 10, x FOR PEER REVIEW 48 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 48 of 74 9.5. Pseudopolymorphism 9.5. Pseudopolymorphism Hydrates/solvates of an organic compound are also referred to as ‘Pseudopolymorphs’ [44]. PharmaceuticsHydrates2018/solvates, 10, 108 of an organic compound are also referred to as ‘Pseudopolymorphs’ [4447]. of 74 Cocrystal pseudopolymorphs are the cocrystals which comprise water or solvent molecules as Cocrystal pseudopolymorphs are the cocrystals which comprise water or solvent molecules as inclusions in it. 4,4′-bipyridine−4-hydroxybenzoic acid (2:1) cocrystal [285], inclusions in it. 0 4,4′-bipyridine−4-hydroxybenzoic acid (2:1) cocrystal [285], Ethenzamideinclusions in-3,5 it.-dinitrobenzoic 4,4 -bipyridine −4-hydroxybenzoicacid acid(1:1) (2:1) cocrystalcocrystal [285], Ethenzamide-3,5-[294], Ethenzamide-3,5-dinitrobenzoic acid 0 (1:1) cocrystal [294], 4dinitrobenzoic-N,N′-Dimethylaminopyridine−4 acid (1:1) cocrystal- [Methyl294], 4-benzoicN,N -Dimethylaminopyridine Acid (1:1) cocrystal [309−4-Methylbenzoic], Gallic acid-succinimide Acid (1:1) 4-N,N′-Dimethylaminopyridine−4-Methylbenzoic Acid (1:1) cocrystal [309], Gallic acid-succinimide (atcocrystal different [309 ],stoichiometric Gallic acid-succinimide ratios) (atcocr differentystal stoichiometricsolvates [288 ratios)] were cocrystal reported solvates to [exist288] wereas (at different stoichiometric ratios) cocrystal solvates [288] were reported to exist as pseudopolymorphsreported to exist as pseudopolymorphsin the literature. in the literature. pseudopolymorphs in the literature. RowRow and and coworkers coworkers [28 [2888]] reported gallic acid-succinimideacid-succinimide cocrystal solvates/hydrates of of Row and coworkers [288] reported gallic acid-succinimide cocrystal solvates/hydrates of variousvarious stoichiometric stoichiometric ratios ratios formed formed with with different different types types of of solvents solvents (such (such as as 1,4 1,4-dioxane,-dioxane, water, water, various stoichiometric ratios formed with different types of solvents (such as 1,4-dioxane, water, tetrahydrofuran,tetrahydrofuran, ethyl ethyl acetate, acetate, acetone) acetone) and and water water inclusions inclusions as pseudopolymorphs as pseudopolymorphs in their in study their tetrahydrofuran, ethyl acetate, acetone) and water inclusions as pseudopolymorphs in their study [28study8]. Fig [288ures]. Figures 31 and 31 32 and present 32 present the staircase the staircase network network of ofgallic gallic acid acid-succinimide-tetrahydrofuran-succinimide-tetrahydrofuran [288]. Figures 31 and 32 present the staircase network of gallic acid-succinimide-tetrahydrofuran (2:2:1)(2:2:1) cocrystal cocrystal and and gallic gallic acid acid-succinimide-water-succinimide-water (1:1:1) (1:1:1) cocrystal cocrystal made made up of up carboxylic of carboxylic acid and acid (2:2:1) cocrystal and gallic acid-succinimide-water (1:1:1) cocrystal made up of carboxylic acid and carboxamideand carboxamide homodimers homodimers with tetrahydrofuran with tetrahydrofuran and water and molecules water moleculesas inclusions as in inclusions it. The solvent in it. carboxamide homodimers with tetrahydrofuran and water molecules as inclusions in it. The solvent moleculesThe solvent occupied molecules the occupied voids thein voidscocrystal in cocrystal lattice latticethrough through C-H…O C-H. .interactions . O interactions (in (incase case of of molecules occupied the voids in cocrystal lattice through C-H…O interactions (in case of tetrahydrofuran)tetrahydrofuran) and and through through O O-H.-H…O . . O interactions interactions (in (in case case of of water) water) [28 [2888].]. tetrahydrofuran) and through O-H…O interactions (in case of water) [288].

Figure 31. Staircase network in gallic acid-succinimide-tetrahydrofuran (2:2:1) cocrystal [Reprinted FigureFigure 31.31. StaircaseStaircase network network in ingallic gallic acid acid-succinimide-tetrahydrofuran-succinimide-tetrahydrofuran (2:2:1) (2:2:1) cocrystal cocrystal [Reprinted [Reprinted from [288] with permission. Copyright 2016 Royal Society of Chemistry]. fromfrom [28 [8288] with] with permission. permission. Copyright Copyright 2016 2016 Royal Royal Society Society of Chemistry] of Chemistry]..

Figure 32. Staircase network in gallic acid-succinimide-water (1:1:1) cocrystal [Reprinted from [288] Figure 32. Staircase network in gallic acid-succinimide-water (1:1:1) cocrystal [Reprinted from [288] withFigure permission. 32. Staircase Copyright network 2016 in gallicRoyal acid-succinimide-water Society of Chemistry]. (1:1:1) cocrystal [Reprinted from [288] withwith permission. permission. Copyright Copyright 2016 2016 Royal Royal Society Society of Chemistry]. of Chemistry]. 9.7 Impact of Cocrystal Polymorphism on Solid-State Properties of API 9.79.6. Impact Impact of C ofocrystal Cocrystal Polymorphism Polymorphism on S onolid Solid-State-State Properties Properties of API of API Similar to the single component solids, polymorphism in multicomponent solids also plays a Similar to the single component solids, polymorphism in multicomponent solids also plays a significantSimilar role to in the determining single component quality, solids, efficacy polymorphism and safety of inan multicomponent API molecule. Polymorphism solids also plays has a significant role in determining quality, efficacy and safety of an API molecule. Polymorphism has beensignificant known role to in influence determining aqueous quality, solubility efficacy and[310 safety] and of physical an API molecule.stability Polymorphism[56,230,262,310,311 has been] of been known to influence aqueous solubility [310] and physical stability [56,230,262,310,311] of cocrystals.known to influenceParadkar aqueousand coworkers solubility [310 []310 synthesized] and physical dimorphic stability forms [56,230 of carbamazepine,262,310,311] of- cocrystals.saccharin cocrystals. Paradkar and coworkers [310] synthesized dimorphic forms of carbamazepine-saccharin (1:1)Paradkar cocrystal and coworkers(Form I and [310 ]Form synthesized II) by dimorphicslow evaporative forms of carbamazepine-saccharinsolution crystallization method (1:1) cocrystal and (1:1) cocrystal (Form I and Form II) by slow evaporative solution crystallization method and characterized(Form I and Formtheir ther II) bymodynamic slow evaporative interrelationship solution crystallization[310]. During the method study, and it wa characterizeds observed from their characterized their thermodynamic interrelationship [310]. During the study, it was observed from thethermodynamic van ‘t Hoff plot interrelationship and DSC thermograms [310]. During that Form the study, I carbamazepine it was observed-saccharin from the (1:1) van remains ‘t Hoff as plot a the van ‘t Hoff plot and DSC thermograms that Form I carbamazepine-saccharin (1:1) remains as a stableand DSC form thermograms whereas the that Form Form II I carbamazepine-saccharincarbamazepine-saccharin (1:1)(1:1) remains exists asas aa stable metastable form whereas form. stablethe Formform IIwhereas carbamazepine-saccharin the Form II carbamazepine (1:1) exists as-saccharin a metastable (1:1) form. exists Moreover, as a metastable Form II polymorph form.

showed enhanced solubility than form I polymorph with respect to different temperatures in deionized water owing to its less stability than form I [310]. Pharmaceutics 2018, 10, 108 48 of 74

10. Solubility and Dissolution Enhancement by Cocrystals Bioavailability of a cocrystal is determined by its dissolution rate, aqueous solubility and permeability. Solubility is deﬁned as a maximum amount of drug that can be dissolved in a solution and is nothing but the thermodynamic equilibrium attained by a solute between a solid and liquid phase [312]. Cocrystal dissolution refers to the amount of solute which dissolves in an aqueous medium at a speciﬁc time interval. The rate at which the solute dissolves in the aqueous medium to reach its equilibrium state is called as the dissolution rate [313]. Hence, solubility is a thermodynamic process whereas dissolution is a kinetic process. Given below is a brief account of information available on solubility and dissolution of cocrystals.

10.1. Cocrystal Solubilization Many researchers have attempted to understand the mechanism behind the solubility of cocrystals [9,95,314–316]. The insight obtained from the review of such literature reports indicates that the solubility of cocrystals depends on two important parameters namely the strength of intermolecular interactions in the crystal lattice and solvation of cocrystal components [9,10,95,314–316]. Maheshwari et al. [316] reported that solubilization of a cocrystal in dissolution medium involves two main steps: (1) Release of the solute molecules from the crystal lattice of the cocrystal and (2) the solvation of the released molecules [316] (as shown in Figure 33). Therefore, free energy of cocrystal solubilization depends on the free energy associated with the release of solute molecules from the cocrystal lattice and the free energy associated with the solvation barrier of the cocrystal as given in Equation (1) [316], ∆Gsolution = ∆Glattice + ∆Gsolvation (1) where ∆Gsolution is the Gibb’s free energy associated with the solubilization process, ∆Glattice is the Gibb’s free energy associated with the cocrystal lattice and ∆Gsolvation is the Gibb’s free energy associated with the solvation barrier. When the free energy associated with the lattice interactions and the free energy associated with the solvation barrier becomes negligible, enhancement in cocrystal dissolution is achieved due to decrease in free energy change for solubilization [316]. The cocrystal formed with a highly water-soluble coformer, was found to possess high solubility [9,64]. Therefore, Maheshwari et al. [316] suggested that solvation is the most important barrier for the solubilization of cocrystals for hydrophobic drugs [316].

10.1.1. Phase Solubility Diagram (PSD) PSDs are used to identify the regions for drug and conformer stability in terms of drug and conformer concentration [9]. For a cocrystal [AαBβ], drug (A) concentration can be expressed as a function of conformer (B) concentration using following equation,

α β [drug] = Ksp/[coformer] (2) where Ksp is the solubility product for dissolution of a cocrystal. Figure 34 is a typical PSD for two different cocrystals namely stable and metastable cocrystal [9]. In this figure, the dotted line represents stoichiometric concentrations of the drug and coformer and its intersection with the cocrystal solubility curves (denoted by filled circles) gives the maximum drug concentration corresponding to the cocrystal solubility. It can be observed from Figure 34 that the stable cocrystal exhibits lower solubility than the drug solubility in a given solvent/medium. On the other hand, a metastable cocrystal exhibits solubility higher than the drug solubility [9]. The invariant points (characterized by zero degrees of freedom and represented by x marks) shown in this figure indicate the transition points or eutectic points where solid drug, cocrystal and solution containing drug and coformer are in equilibrium [9]. Furthermore, it can be noted from Figure 34 that the stoichiometric composition of the cocrystal affects the cocrystal solubility. Pharmaceutics 2018, 10, 108 49 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 50 of 74 Pharmaceutics 2018, 10, x FOR PEER REVIEW 50 of 74

DISSOLUTION MEDIUM DISSOLUTION MEDIUM 1. Release of solute molecules1. Release from of solute cocrystal latticemolecules from cocrystal lattice ∆G Hydrophobic drug ∆Glattice CocrystalHydrophobic Phase drug lattice formedCocrystal with Phase hydrophilicformed with coformerhydrophilic coformer

2. Solvation of the solute molecules2. Solvation in theof the dissolution solute molecules in the dissolution ∆Gsolubilization =∆Glattice+ ∆Gsolvation medium ∆Gsolubilization =∆Glattice+ ∆Gsolvation medium Minimal ∆Glattice and ∆Gsolvation – Minimal ∆GHighestlattice and cocrystal ∆Gsolvation solubility– Highest cocrystal solubility ∆Gsolvation ∆Gsolvation Maximum ∆Glattice and ∆Gsolvation – Lowest cocrystalMaximum solubility ∆Glattice and ∆Gsolvation – Lowest cocrystal solubility

Figure 33. Schematic representation of the steps involved in solubilization of a hydrophobic drug in FigureFigure 33. Schematic 33. Schematic representation representation of of the stepssteps involved involved in in solubilization solubilization of a hydrophobicof a hydrophobic drug in drug an in an aqueous medium. an aqueousaqueous medium medium..

Figure 34. Phase Solubility Diagram explaining the solubility behavior of a low solubility cocrystal FigureFigure 34. Phase 34. Phase Solubility Solubility Diagram Diagram explaining explaining the solubility behavior behavior of of a lowa low solubility solubility cocrystal cocrystal (stable cocrystal) and a high solubility cocrystal (metastable cocrystal) based on the Ksp value (stable(stable cocrystal) cocrystal) and and a high a high solubility solubility cocrystal cocrystal (metastable(metastable cocrystal) cocrystal) based based on on the the K Kvaluesp value (X—transition concentrations; dashed line—stoichiometric concentrations of cocrystal components;sp (X—transition(X—transition concentrations; concentrations; dashed dashed line line—stoichiometric—stoichiometric concentrationsconcentrations of of cocrystal cocrystal components; components; circles—Solubility of cocrystal in pure solvent) [Reprinted from [9] with permission.Copyright 2009 circlescircles—Solubility—Solubility of cocrystal of cocrystal in in pure pure solvent) solvent) [Reprinted from from [9 ][9] with with permission. permission.Copyright Copyright 2009 2009 American Chemical Society]. AmericanAmerican Chemical Chemical Society]. Society].

10.1.2. Factors Influencing Solubility of Cocrystals 10.1.2. Factors Influencing Solubility of Cocrystals During cocrystal dissolution in the aqueous medium, factors such as ionization of parent During cocrystal dissolution in the aqueous medium, factors such as ionization of parent components [317], pH of the aqueous medium [317], drug-solubilizing agents [317] and coformer components [317], pH of the aqueous medium [317], drug-solubilizing agents [317] and coformer concentration [317] influence the solubility of cocrystals. concentration [317] influence the solubility of cocrystals. (a) Ionization of Parent Components and pH of Aqueous Medium (a) Ionization of Parent Components and pH of Aqueous Medium Cocrystal can be synthesized by cocrystallizing a neutral drug molecule with acidic or Cocrystal can be synthesized by cocrystallizing a neutral drug molecule with acidic or amphoteric coformer molecules or a zwitterionic drug with acidic coformer or a basic drug with amphoteric coformer molecules or a zwitterionic drug with acidic coformer or a basic drug with acidic coformer molecule. As a result, the properties of a cocrystal designed for the same API but acidic coformer molecule. As a result, the properties of a cocrystal designed for the same API but with different coformers also exhibit different solubility behavior mainly due to variation in with different coformers also exhibit different solubility behavior mainly due to variation in

Pharmaceutics 2018, 10, 108 50 of 74

10.1.2. Factors Influencing Solubility of Cocrystals During cocrystal dissolution in the aqueous medium, factors such as ionization of parent components [317], pH of the aqueous medium [317], drug-solubilizing agents [317] and coformer concentration [317] influence the solubility of cocrystals. (a) Ionization of Parent Components and pH of Aqueous Medium Cocrystal can be synthesized by cocrystallizing a neutral drug molecule with acidic or amphoteric coformer molecules or a zwitterionic drug with acidic coformer or a basic drug with acidic coformer Pharmaceuticsmolecule. 2018 As, 10 a, result,x FOR PEER the REVIEW properties of a cocrystal designed for the same API but with different51 of 74 coformers also exhibit different solubility behavior mainly due to variation in ionization behavior ionizationof coformer behavior molecules. of coformer Since ionization molecules. is highly Since dependent ionization onis pH,highly pH isdependent another parameter on pH, pH which is anothersignificantly parameter affects which the cocrystal significantly solubility. affects the cocrystal solubility. MaheshwariMaheshwari et etal. al. [31 [3166] used] used Gabapentin Gabapentin-lactam-lactam (GBPL) (GBPL) as a as model a model drug drug and andsynthesized synthesized its cocrystalsits cocrystals with withcarboxylic carboxylic acids, acids, fumaric fumaric acid (FA), acid 4 (FA),-hydrobenzoic 4-hydrobenzoic acid (4HBA), acid (4HBA), genitisic genitisic acid (GA), acid 4-(GA),aminobenzoic 4-aminobenzoic acid (4AB acidA) and (4ABA) benzoic and acid benzoic (BA) acid as coformers (BA) as coformers by reaction by crystallization. reaction crystallization. The aim wasThe to aim understand was to understand the influence the influence of coformers of coformers with low with aqueous low aqueous solubility solubility on onthe the solubi solubilitylity of of cocrystalscocrystals [303 [303]. ].From From their their study, study, it itwas was identified identified that that the the so so formed formed GBPL GBPL2-2FA-FA (2:1) (2:1),, GBPL GBPL-4HBA-4HBA (1:1),(1:1), GBPL GBPL-GA-GA (1:1),(1:1), GBPL-4ABAGBPL-4ABA (1:1) (1:1) and and GBPL-BA GBPL- (1:1)BA (1:1) cocrystals cocrystals showed showed lower aqueouslower aqueous solubility solubilitythan raw GBPLthan raw [316 ]GBPL and exhibited [316] and pH-dependent exhibited solubilities.pH-dependent Figure solubilities. 35 presents Figure variation 35 in presents solubility variationof gabapentin-lactam in solubility of cocrystals gabapentin as a-lactam function cocrystals of pH. The as pHa func valuetion at of which pH. theThe solubility pH value curve at which of the thecocrystal solubility and curve drug of intersects the cocrystal is called and asdrug pH maxintersects. Figure is 35 called shows as pH themax pH. Figuremax values 35 shows exhibited the pH bymax five valuesdifferent exhibited gabapentin-lactam by five different cocrystals gabapentin [316].-lactam Below pHcocrystalsmax value, [31 the6]. Below five GBPL pHmax cocrystals value, the showed five GBPLlower cocrystals solubilitythan showed the lower drug. solubilitythan Therefore, this the pointdrug. Therefore, is called as this ‘the point Eutectic is called point’ as ‘the or ‘transition Eutectic poipoint’nt’ or [9 ,318‘transition]. The pH point’max is also[9,318 called]. The as Gibb’spHmax pHis also as it definescalled as the Gibb’s thermodynamic pH as it stabilitydefines ofthe the thermodynamiccocrystal and above stability this of pH the the cocrystal cocrystal and is unstableabove this [316 pH]. the cocrystal is unstable [316].

FigureFigure 35. 35. SolubilitySolubility-pH-pH profiles proﬁles of ofGabapentin Gabapentin-lactam-4-aminobenzoic-lactam-4-aminobenzoic acid acid (GBPL (GBPL-4ABA),-4ABA), GabapentinGabapentin-lactam-fumaric-lactam-fumaric acid acid (GBPL (GBPL2-FA),2-FA), Gabapentin Gabapentin-lactam-gentisic-lactam-gentisic acid acid (GBPL (GBPL-GA),-GA), GabapentinGabapentin-lactam-benzoic-lactam-benzoic acid acid (GBPL (GBPL-BA)-BA) and and Gabapentin Gabapentin-lactam-4-hydroxybenzoic-lactam-4-hydroxybenzoic acid acid (GBPL(GBPL-4HBA)-4HBA) cocrystals cocrystals with with respect respect to raw to rawGabapentin Gabapentin-lactam-lactam (GBPL) (GBPL) cocrystal cocrystal [Reprinted [Reprinted from [316from] with [316 permission.] with permission. Copyright Copyright 2016 Royal 2016 Society Royal Societyof Chemistry] of Chemistry]..

Thakuria et al. [314] has provided a detailed review on how the ionization of components affects the pH solubility profile of different drug pairs reported in the literature. Table 11 presents generalized observations reported in the literature about the solubility behavior of cocrystals.

Pharmaceutics 2018, 10, 108 51 of 74

Thakuria et al. [314] has provided a detailed review on how the ionization of components affects the pH solubility proﬁle of different drug pairs reported in the literature. Table 11 presents generalized observations reported in the literature about the solubility behavior of cocrystals.

Table 11. Observations made from a few literature reports on pH-solubility behavior of cocrystals different API-coformer pairs having different ionization properties.

API Coformer Ionizing Name of the Ionizing Nature of Solubility Trend w.r.t pH Reference(s) Name of the API Nature of API Coformer the Coformer Carbamazepine Non-ionizable Succinic acid Diprotic acid Increase in solubility [64] 4-aminobenzoic Carbamazepine Non-ionizable Monoprotic acid Increase in solubility [63] acid hydrate U-shaped trend in which solubility Ketoconazole Weak basic Adipic acid Diprotic acid [319] reached minimum with an increase in pH U-shaped trend in which solubility Ketoconazole Weak basic Fumaric acid Diprotic acid [319] reached minimum with an increase in pH U-shaped trend in which solubility Ketoconazole Weak basic Succinic acid Diprotic acid [319] reached minimum with an increase in pH U-shaped trend in which solubility reached minimum with an increase in pH Itraconazole Basic L-Tartaric acid Acidic (minimum solubilityoccurred in the pH [320] range which is equivalent to the differencebetween two pKa values) Gabapentin-lactam Non-ionizable Gentisic acid Acidic Increase in solubility [316] Gabapentin-lactam Non-ionizable Benzoic acid Acidic Increase in solubility [316] U-shaped trend in which solubility Gabapentin-lactam Non-ionizable 4-aminobenzoic acid Monoprotic acid [316] reached minimum with an increase in pH 4-hydroxybenzoic Gabapentin-lactam Non-ionizable Acidic Increase in solubility [316] acid Gabapentin-lactam Non-ionizable Fumaric acid Diprotic acid Increase in solubility [316] 3-hydroxybenzoic U-shaped trend leading to increase Gabapentin Zwitterionic Acidic [321] acid in solubility

(b) Effect of Solubilizing Agent Though drug-solubilizing agents such as surfactants can increase the solubility of a cocrystal in an aqueous medium [322], at a certain concentration level it also reduces the solubility of a cocrystal. The concentration of the surfactant [M] therefore determines the solubility and stability of the cocrystals in anaqueous medium. The cocrystal solubility is directly proportional to the square root of [M] whereas the drug solubility is directly proportional to [M] [314]. The concentration of surfactant at which solubility of a cocrystal and drug becomes identical is called as Critical Stabilization Concentration (CSC). The cocrystal becomes thermodynamically unstable below the CSC in the dissolution medium (See Figure 36). On the other hand, it remains in equilibrium with pure drug at CSC (this point is known as ‘the eutectic point”) and remains thermodynamically stable above CSC. Therefore, CSC serves as an important parameter in inﬂuencing the solubility of the cocrystals.

10.2. Dissolution of Cocrystals Figure 37 shows typical dissolution proﬁles of insoluble drugs [85] which can be characterized by “spring and parachute model” [323]. Babu and Nangia [85] stated that dissolution of cocrystals can also be explained using ‘Spring and parachute model’. During dissolution, cocrystals exhibit maximum peak value in the drug concentration which is attained in a shorter time (such as less than 30 min) (spring effect). This high concentration is maintained for a longer period before ultimately decreasing to the equilibrium solubility level (parachute effect) [95]. The spring and parachute effect can be explained using a mechanism proposed by Babu and Nangia [95]. As per the proposed mechanism, three main steps are involved during dissolution of cocrystals (as shown in Figure 38): Pharmaceutics 2018, 10, 108 52 of 74

(i) Dissociation of the cocrystal into amorphous or nanocrystalline drug clusters, which is represented as ‘spring’ effect (Figures 37 and 38) (ii) Transformation of the amorphous or nanocrystalline drug clusters into a stable form through PharmaceuticsPharmaceuticsformation 20182018,, of 1010, a, xx metastable FORFOR PEERPEER REVIEWREVIEW phase by adopting Ostwald’s Law of Stages 5353 ofof 7474 (iii) Attainment of higher apparent solubility and maintenance of optimal drug concentration in the (iii(iii)) aqueousAttainmentAttainment medium, ofof higherhigher which apparentapparent is represented solubilitysolubility as andand ‘parachute’ maintenancemaintenance effect ofof (Figures optimaloptimal 37 drugdrug and concentration concentration38). inin thethe aqueousaqueous medium,medium, whichwhich isis representedrepresented asas ‘parachute’‘parachute’ effecteffect (Figures(Figures 3737 andand 38).38).

FigureFigureFigure 36. 36.36.Determination DeterminationDetermination of Critical ofof CriticalCritical Stabilization StabilizationStabilization Concentration ConcentrationConcentration from the totalfromfrom surfactant thethe totatota concentrationll surfactantsurfactant [Reprintedcoconcentrationncentration from [Reprinted[Reprinted [314] with fromfrom permission [314[314]] withwith from permissionpermission Elsevier]. fromfrom Elsevier]Elsevier]..

FigureFigureFigure 37.37.37. ‘Spring‘Spring‘Spring andandand parachuteparachuteparachute model’model’model’ proposedproposedproposed tototo explainexplainexplain highhighhigh apparentapparentapparent solubilitysolubilitysolubility ofofof poorlypoorlypoorly water-solublewaterwater--solublesoluble drugs drugsdrugs [Reprinted [Reprinted[Reprinted from fromfrom [95] with[9[955]] with permission.with permission.permission. Copyright CopyrightCopyright 2011 American 20112011 AmeriAmeri Chemicalcancan ChemicalChemical Society]. Society].Society].

PharmaceuticsPharmaceutics 20182018,, 1010,, 108x FOR PEER REVIEW 5453 of 7474

FigureFigure 38.38. ProposedProposed mechanism mechanism for for dissolution dissolution of pharmaceuticalof pharmaceutica cocrystalsl cocrystals [Reprinted [Reprinted from from [95] with [95] permission.with permission. Copyright Copyright 2011 American2011 American Chemical Chemical Society]. Society].

10.2.1.10.2.1. Factors InfluencingInfluencing DissolutionDissolution ofof CocrystalsCocrystals DissolutionDissolution of cocrystalscocrystals can be influencedinfluenced byby severalseveral factorsfactors suchsuch asas aqueousaqueous solubilitysolubility ofof coformerscoformers (as(as discusseddiscussed inin SectionSection 10.2.210.2.2),), intermolecularintermolecular interactionsinteractions in cocrystalscocrystals (as(as discusseddiscussed inin SectionSection 10.2.2),10.2.2), crystal crystal habit habit of of cocrystals cocrystals (as (as discussed discussed below) below) and and pH pH of ofthe the dissolution dissolution medium medium (as (asdiscussed discussed below). below). (a)(a) CrystalCrystal HabitHabit CrystalCrystal habit of of cocrystals cocrystals can can also also influence influence its its dissolution dissolution in indissolution dissolution medium. medium. A drug A drug can cancocrystallize cocrystallize with with a coformer a coformer molecule molecule in invarious various sizes sizes and and shapes shapes depending depending on differentdifferent crystallizationcrystallization conditions.conditions. A A crystallization crystallization event event can can change change crystal crystal properties properties such as habit, polymorphismpolymorphism and sizesize [[323244].]. The The term ‘ ‘crystalcrystal habit’ is used to describe the general shape of aa crystal.crystal. ModificationModification of a drug crystal’scrystal’s habit during crystallization cancan alter its dissolution behavior duedue toto aa changechange inin thethe naturenature ofof crystalcrystal facesfaces exposedexposed toto thethe dissolutiondissolution medium.medium. However,However, studiesstudies relatedrelated toto thethe modificationmodification ofof cocrystalcocrystal habitshabits andand understandingunderstanding thethe effecteffect ofof cocrystalcocrystal habitshabits onon itsits dissolutiondissolution propertiesproperties are are limited limited [325 ].[32 Sulfadimidine5]. Sulfadimidine (SDM)-4-aminosalicylic (SDM)-4-aminosalicylic acid (4-ASA) acid cocrystal(4-ASA) (incocrystal 1:1 molar (in ratio)1:1 molar [polymorph ratio) [polymorph I and polymorph I and II]polymorph were cocrystallized II] were cocrystallized in four different in four crystal different habits. Thesecrystal habits habits. were These obtained habits bywere solvent obtained evaporation by solvent using evaporation ethanol (habit using I) andethanol acetone (hab (habitit I) and II), acetone solvent evaporation(habit II), solvent followed evaporation by grinding followed (habit by III) grinding and spray (habit drying III) and (habit spray IV) drying [See Table (habit 12 ][IV)325 [See]. It Table was observed12] [325]. thatIt was cocrystals observed prepared that cocrystals by milling prepared showed by highest milling dissolution showed highest than the dissolution cocrystal powdersthan the preparedcocrystal viapowders solvent prepared evaporation via and solv sprayent evaporation drying (as shown and inspray Table drying 12). Milling (as shown produced in Table cocrystals 12). ofMilling very fineproduced (smaller) cocrystals particle of size very thereby fine (smaller) increasing particle its surface size thereby area, increasing increasing its its flowability surface area, and enhancingincreasing its dissolution.flowability and On theenhancing other hand, its dissolution. powders prepared On the other by solvent hand, evaporationpowders prepared exhibited by comparativelysolvent evaporation lesser exhibited dissolution comparatively than the former. lesser Despite dissolution smaller than particle the former. size and Despite higher surfacesmaller area,particle cocrystals size and prepared higher bysurface spray area, drying cocrystals process showedprepared lower by spray dissolution drying which process was showed attributed lower to thedissolution agglomeration which ofwas particles attributed [325 ].to Therefore,the agglomeration Serrano andof particl coworkerses [32 [3255]. ]There suggestedfore, Serrano that crystal and habitscoworkers of cocrystals [325] suggested with poor that pharmaceutical crystal habits of characteristics cocrystals with can poor be engineered pharmaceutical to alter characteristics dissolution, flowabilitycan be engineered and compaction to alter dissolution, behavior [325 flowabil]. ity and compaction behavior [325].

Pharmaceutics 2018, 10, 108 54 of 74

Table 12. Different crystal habits of Sulfadimidine-4-aminosalicylic acid (1:1) cocrystals [305].

Cocrystal Crystal Dissolution Level S. No Preparation Method Morphology Reference Polymorph Habit in Deionized Water 1 I Liquid-assisted co-milling - - Highest Solvent evaporation Large prismatic 2 II I Higher with Ethanol crystals Solvent evaporation Large plate-like 3 II II Higher with Acetone crystals [325] Solvent evaporation with Small cube-like 4 II Ethanol followed by III Higher crystals dry milling 5 II Spray drying IV Microspheres Lower

(b) pH Cao et al. [326] showed that the dissolution behavior of cocrystals with ionizable components is highly dependent on the interfacial pH at the dissolving solid-liquid interface [326]. When a cocrystal containing non-ionizable drug and ionizable coformer is dissolved in a dissolution medium, the dissociation reaction can modify pH at the solid-liquid interface. Authors studied the dissolution behavior of carbamazepine-saccharin and carbamazepine-salicylic acid cocrystals [326] in a dissolution medium (dissolution medium was prepared by dissolving Sodium Lauryl Sulphate (SLS) in water) with varying pH such as 1.27, 2.16, 3.02, 4.03, 5.97 and 7.66. The dissolution rate of the cocrystals was found to increase with increase in pH [326]. The mechanism of cocrystal dissolution was explained by the process of interfacial mass transport. Interfacial equilibrium model and surface saturation model were used to analyze the mass transport process. The dissolution rates of these cocrystals were found to be greatly inﬂuenced by interfacial pH and the bulk pH was not found to adequately explain the dissolution behavior [326].

10.2.2. Cocrystals with Low Dissolution Rates While cocrystallization can be used to enhance solubility of drugs, it can also be used to reduce the aqueous solubility of drugs [327]. Though enhanced aqueous solubility of poorly water-soluble drugs by formulating as cocrystals has been well-documented in the literature, the number of reports on cocrystals with lower dissolution rates than the raw drug is limited. The following are the case studies of such pharmaceutical cocrystals with lower dissolution rates reported in the literature: (a) Sulfacetamide Cocrystals Sulfacetamide is a topical antibiotic used to treat conjunctivitis. Despite its therapeutic efficacy, its pharmaceutical use is limited because of physiological constraints such as tear flow, reflex blinking and drug loss. This drawback can possibly be eradicated by frequent dosing. However, frequent dosing in turn can lead to excess drug loading in patients. Therefore, reducing the aqueous solubility of sulfacetamide can help in getting rid of excess drug loading in patients without reducing the frequency of drug administration. Therefore, Nangia and coworkers [327] adopted cocrystallization approach to bring down the aqueous solubility of sulfacetamide [327]. Sulfacetamide-caffeine (1:1) and sulfacetamide-isonicotinamide (1:1) cocrystals exhibited 0.68 and 0.64 times lower dissolution rates than raw sulfacetamide whereas sulfacetamide-theophylline (1:1) cocrystal exhibited dissolution rate equivalent to that of raw sulfacetamide [327]. It was proposed that modification of intermolecular interactions (hydrogen bonding) existing in the parent drug molecule by means of cocrystallization resulted in better crystal packing, stable crystal lattice and increase in density of the cocrystals. These modifications in the crystal lattice were responsible for lower dissolution of the synthesized sulfacetamide cocrystals, which in turn can increase the residence time of sulfacetamide drug at the site of action [327]. Pharmaceutics 2018, 10, 108 55 of 74

Pharmaceutics 2018, 10, x FOR PEER REVIEW 56 of 74 (b) Fluoxetine HCl-Benzoic Acid (1:1) Cocrystal FluoxetineFluoxetine HCl is an antidepressantantidepressant drug available in the market with the trade name, Prozac. DuringDuring aa studystudy carriedcarried outout byby ChildsChilds etet al.al. [[5757]] toto prepareprepare cocrystalscocrystals ofof amineamine hydrochlorideshydrochlorides withwith organicorganic acidsacids byby meansmeans ofof crystalcrystal engineeringengineering approach,approach, itit waswas foundfound thatthat FluoxetineFluoxetine HCl-BenzoicHCl-Benzoic acidacid (1:1)(1:1) cocrystalcocrystal exhibitedexhibited lowerlower powderpowder andand intrinsicintrinsic dissolutiondissolution ratesrates thanthan thatthat ofof commercialcommercial FluoxetineFluoxetine HClHCl [ 57[57].]. However, However, ﬂuoxetine fluoxetine HCl HCl cocrystals cocrystals prepared prepared with with other other acids acids such such as fumaric as fumaric acid andacid succinicand succinic acid showed acid showed enhanced enhanced powder powder dissolution dissolution rates. Thus, rates. it Thus, is evident it is thatevident one that can increaseone can orincrease decrease or thedecrease dissolution the dissolution rates of drugs rates by appropriateof drugs by selection approp ofriate coformers selection for of cocrystallization. coformers for Thecocrystallization. reason behind The the reason inﬂuence behind of the the structural influence and of thermodynamicthe structural and parameters thermodynamic on the dissolutionparameters rateson the of dissolution these cocrystals rates of remain these unclearcocrystals [57 remain]. However, unclear it is[5 to7]. beHowever, noticed it that is to the be dissolution noticed that rates the obtaineddissolution for rates the cocrystals obtained werefor the observed cocrystals to be were in good observed correlation to be within good the aqueouscorrelation solubility with the of coformersaqueous solubility [57]. of coformers [57]. (c)(c) Curcumin Curcumin-phloroglucinol-phloroglucinol (1:1) (1:1) C Cocrystalocrystal CurcuminCurcumin is is a a natural natural phenolic phenolic ingredient ingredient with with anticancer anticancer activity. activity. Its therapeutic Its therapeutic use is limited use is limiteddue to its due poor to itsaqueous poor aqueous solubility, solubility, and hence and its hence poor itsbioavailability. poor bioavailability. Efforts have Efforts been have made been by madeseveral by researchers several researchers to enhance to its enhance aqueous its solubility aqueous by solubility forming by cocrystals forming cocrystals[24,72,328]. [ 24However,,72,328]. However,cocrystallization cocrystallization with phloroglucinol with phloroglucinol formed curcumin formed curcumin-phloroglucinol-phloroglucinol (1:1) cocrystal (1:1) cocrystal with lower with lowerdissolution dissolution rates [7 rates3] though [73] though phloroglucinol phloroglucinol has higher has higher aqueous aqueous solubility. solubility. (d)(d) Lamotrigine Lamotrigine-phenobarbital-phenobarbital (1:1) (1:1) C Cocrystalocrystal Recently,Recently, Kaur Kau etr al.et [329al.] reported[329] reported that lamotrigine—phenobarbital that lamotrigine—phenobarbital cocrystal (of cocrystal 1:1 stoichiometric (of 1:1 ratio)stoichiometri exhibitedc ratio) lower exhibited dissolution lower rate anddissolution poor aqueous rate and solubility poor aqueous than raw solubility phenobarbital than andraw lamotrigine.phenobarbital Pureand lamotrigine. lamotrigine Pure crystal lamotrigine is stabilized crystal by is N-H. stabilized . . N amide/pyridine by N-H…N amide/pyridine homodimer intermolecularhomodimer intermolecular interactions whereasinteractions the whereas crystal structure the crystal of purestructure phenobarbital of pure phenoba is stabilizedrbital byis N-H.stabilized . . O amine/carbonyl by N-H…O amine/carbonyl homodimer intermolecularhomodimer intermolecular interactions (as interactions shown in Figure(as shown 39). Inin caseFigure of lamotrigine-phenobarbital39). In case of lamotrigine (1:1)-phenobarbital cocrystal, these (1:1) lamotrigine cocrystal, and these phenobarbital lamotrigine homodimers and phenobarbital are held togetherhomodimers by stronger are held intermolecular together by interactions stronger (viaintermolecular formation of oneinteractions N-H. . . N (via bond formation and two N-H. of .one . O bondsN-H…N between bond and the moleculestwo N-H…O of lamotrigine bonds between and phenobarbital) the molecules formingof lamotrigine heterodimers and phenobarbital) (as shown in Figureforming 39 heterodimers). It was proposed (as shown by the authorsin Figure that 39). the It strongerwas proposed heterodimer by the interactions authors that in cocrystalthe stronger led toheterodimer poor dissolution interactions (as shown in cocrystal in Figure led 40 to)[ poor329]. dissolution (as shown in Figure 40) [329].

(A) (B) (C)

FigureFigure 39.39. CrystalCrystal structures structures of of(A) (Apure) pure lamotrigine, lamotrigine, (B) (Bpure) pure phenobarbital phenobarbital and and(C) (lamotrigineC) lamotrigine-phenobarbital-phenobarbital (1:1) (1:1) cocrystal cocrystal [Reprinted [Reprinted from from [329 [329] ]with with permission. permission. Copyright 20172017 AmericanAmerican ChemicalChemical Society].Society].

Pharmaceutics 2018, 10, 108x FOR PEER REVIEW 5756 of of 74

Figure 40. Comparison of Intrinsic Dissolution Rate (IDR) of lamotrigine from cocrystal (LTG CC), Figure 40. Comparison of Intrinsic Dissolution Rate (IDR) of lamotrigine from cocrystal (LTG CC), phenobarbital from cocrystal (PB CC), pure lamotrigine drug (LTG pure) and pure Phenobarbital drug phenobarbital from cocrystal (PB CC), pure lamotrigine drug (LTG pure) and pure Phenobarbital (PB pure) [Reprinted from [329] with permission. Copyright 2017 American Chemical Society]. drug (PB pure) [Reprinted from [329] with permission. Copyright 2017 American Chemical Society].

11. In Vitro and In Vivo Studies ManyManypharmaceuticalpharmaceutical cocrystals cocrystals have have been synthesized by several researchers to enhance the aqueous solubility of poorly water water-soluble-soluble drugs drugs (especially (especially the the BCS BCS Cla Classss II II and and class class IV IV drugs). drugs). However, thethe numbernumber of of cocrystals cocrystals being being used used as as a regulara regular drug drug with with the the approval approval of FDA of FDA is very is very low. Also,low. Also, the bioavailability the bioavailability studies studies for the for synthesized the synthesized cocrystals cocrystals have been have rare. been At present,rare. At Entrestopresent, (usedEntresto in the(used treatment in the oftreatment chronic heartof chronic failure), heart Lexapro failure), (used Lexapro as an antidepressant) (used as an antidepressant) and Depakote (used and Depakotein the treatment (used ofin seizure the treatment disorders of and seizure manic depression)disorders and are themanic three depression) pharmaceutical are cocrystalsthe three pharmaceuticalbeing approved cocrystals by FDA for being clinical approved use. Table by 13 FDA presents for clinical a summary use. Table of reports 13 presents available a summary in literature of reporton thes bioavailabilityavailable in literature assessment on the of bioavailability pharmaceutical assessment cocrystals. of Inpharmaceutical these reports (listedcocrystals. in Table In these 13), reportsthe pharmacokinetic (listed in Table behavior 13), the and pharmacokinetic therapeutic effect behavior of different and therapeutic solid forms effect have beenof different studied. solid It is formsevident have from been this tablestudied. that It the ispharmaceutical evident from this cocrystals table t helphat the in ﬁne-tuningpharmaceutical the dissolution cocrystals behavior help in fineand- aqueoustuning the solubility dissolution of API behavior molecules and and aqueous in turn solubility enhances of their API bioavailability. molecules and Therefore, in turn enhances there is theira need bioavailability. to conduct bioavailability Therefore, there studies is fora need the newto conduct solid phases bioavailability (cocrystals/eutectics/coamorphous studies for the new solid phasessolids) prepared(cocrystals/eutectics/coamorphous by cocrystallization and evaluatesolids) prepared their efﬁcacy by cocrystallization in terms of their and aqueous evaluate solubility their efficacyunder biological in terms pHof their conditions, aqueousin solubility vivo permeability under biological and bioavailability. pH conditions, This in would vivo permeability pave the way and for bioavailability.these cocrystals This to enter would the pave next stepthe way of clinical for these trials cocrystals for necessary to ent approvaler the next by FDA.step of clinical trials for necessary approval by FDA.

Pharmaceutics 2018, 10, 108 57 of 74

Table 13. Summary of a few literature reports on bioavailability of pharmaceutical cocrystals/eutectics/coamorphous solids.

API-Coformer Nature of the Medical Use of the Cocrystallization Pharmacokinetic/Pharmacodynamic/Bioavailability API Coformer Stoichiometric Reference(s) Solid Phase API Technique Studies Ratio Oral administration of cocrystals and raw drug to dog 2-[4-(4-chloro-2- Sodium channel indicated thatthe cocrystal increased plasma AUC fluorophenoxy)phenyl] Cocrystal Glutaric acid 1:1 Solution crystallization [58] blocker (plasma Area-Under-the-Curve) values by three times pyrimidine-4-carboxamide than the raw drug Showed improved pharmacokinetic profile than raw curcumin and did not show toxic effects even at 10 times higher concentrations (at 2000 mg/kg). Curcumin (Form I) Cocrystal Anticancer agent Pyrogallol 1:1 Liquid-assisted grinding [89] Curcumin-pyrogallol cocrystal exhibited a bioavailability of 200 mg/kg oral dose in xenograft model The coamorphous phase exhibited greater dissolution and pharmacokinetic profile than raw curcumin. It also showed higher bioavailability and therapeutic effect Curcumin (Form I) Coamorphous solid Anticancer agent Artemisinin 1:1 Rotavaporization [89] than raw curcumin. The coamorphous solid was non-toxic even at a dose of 10 times higher dose at 2000 mg/kg in xenograft model Showed 20% enhancement in antioxidant activity, 30% Liquid-assisted grinding hemolysis decrement, 72% inflammation inhibition and Hesperetin Cocrystal Antioxidant molecule Picolinic acid 1:1 [79] and solvent evaporation exhibited relative bioavailability of 1.36 w.r.t raw hesperetin Showed 30% enhancement in antioxidant activity, 40% Liquid-assisted grinding hemolysis decrement, 79% inflammation inhibition and Hesperetin Cocrystal Antioxidant molecule Nicotinamide 1:1 [79] and solvent evaporation exhibited relative bioavailability of 1.57 w.r.t raw hesperetin Showed 50% enhancement in antioxidant activity, 60% Liquid-assisted grinding hemolysis decrement, 87% inflammation inhibition and Hesperetin Cocrystal Antioxidant molecule Caffeine 1:1 [79] and solvent evaporation exhibited relative bioavailability of 1.60 w.r.t raw hesperetin Showed 30% increment in antioxidant activity w.r.t raw Liquid-assisted Hesperetin Eutectic Antioxidant molecule Theophylline 1:1.5 hesperetin and exhibited 2 times greater anti-hemolytic [79] cogrinding activity than raw hesperetin Showed decreased antioxidant activity w.r.t raw Liquid-assisted Hesperetin Eutectic Antioxidant molecule Adenine 2:1 hesperetin and exhibited 1.5 times greater [79] cogrinding anti-hemolytic activity than raw hesperetin Showed 50% increment in antioxidant activity w.r.t raw Liquid-assisted Hesperetin Eutectic Antioxidant molecule Gallic acid 1.5:1 hesperetin and exhibited 2.5 times greater [79] cogrinding anti-hemolytic activity than raw hesperetin Showed 30% increment in antioxidant activity w.r.t raw Liquid-assisted Hesperetin Eutectic Antioxidant molecule Theobromine 2:1 hesperetin and exhibited 2 times greater anti-hemolytic [79] cogrinding activity than raw hesperetin Pharmaceutics 2018, 10, 108 58 of 74

Table 13. Cont.

API-Coformer Nature of the Medical Use of the Cocrystallization Pharmacokinetic/Pharmacodynamic/Bioavailability API Coformer Stoichiometric Reference(s) Solid Phase API Technique Studies Ratio Molecular aggregates formed as a result ofthe dissolution of physical mixture reduced the integrity of intestinal cell monolayer ofNCM460 intestinal cells Carbamazepine Cocrystal Anticonvulsant Vanillic acid 1:1 Slow evaporation [330] whereas the molecular aggregates which resulted from dissolution of cocrystal phase maintained the integrity of intestinal cell monolayer of NCM460 intestinal cells Molecular aggregates formed as a result of the dissolution of physical mixtureand cocrystal phase Carbamazepine Cocrystal Anticonvulsant 4-Nitropyridine-N-oxide 1:1 Slow evaporation [330] maintained the integrity of intestinal cell monolayer ofNCM460 intestinal cells Molecular aggregates formed as a result of the dissolution of physical mixture reduced the integrity of intestinal cell monolayer ofNCM460 intestinal cells Carbamazepine Cocrystal Anticonvulsant Succinic acid 1:1 Slow evaporation [330] whereas the molecular aggregates formed from dissolution of cocrystal phase maintained the integrity of intestinal cell monolayer ofNCM460 intestinal cells Exhibited in vitro cytotoxicity on MCF-7 cancer Dichloroacetic acid Cocrystal Anticonvulsant Cu (valdien) 1:1 Controlled evaporation [331] 2 2 cell lines Diacetylmonoxime The cocrystal phase followed mitochondrial mediated and Slow cooling of cell death pathway in lung cancer cells, A549 by means Quinoxaline Cocrystal Anticancer agent 3-thiosemicarbano- 1:1:1 [332] boiled solution of activating caspase 9 and Bax. It also exhibited butan-2-oneoxime anticancer activity on breast cancer (MCF-7) cell lines (TSBO) In vivo pharmacokinetic profile of the Irbesartan Eutectic Antioxidant Syringic acid 1:1 Solid-state grinding irbesartan-syringic acid eutectic mixture showed [84] 1.5-fold improvement w.r.t raw irbesartan In vivo pharmacokinetic profile of the Irbesartan Eutectic Antioxidant Nicotinic acid 1:1 Solid-state grinding irbesartan-nicotinic acid eutectic mixture showed [84] 1.6-fold improvement w.r.t raw irbesartan In vivo pharmacokinetic profile of the Irbesartan Eutectic Antioxidant Ascorbic acid 1:1 Solid-state grinding irbesartan-ascorbic acid eutectic mixture showed 2-fold [84] improvement w.r.t raw irbesartan Lipid-lowering agent, Atorvastatin calcium-nicotinamide coamorphous phase for treatment of Atorvastatin calcium Coamorphous solid Nicotinamide 1:1 Solvent evaporation showed improved pharmacokinetic profile in rats than [88] cardiovascular raw atorvastatin calcium diseases Pharmaceutics 2018, 10, 108 59 of 74

12. Challenges and Future Perspectives Cocrystallization of poorly water-soluble drugs is one of the novel ways to improve their aqueous solubility. A lot of research efforts are now focused on synthesizing cocrystals of poorly water-soluble drugs with appropriate coformers. The physicochemical properties of cocrystals such as melting point, aqueous solubility and hence their bioavailability depends upon the type of coformer used. Also, as mentioned earlier, the cocrystallization attempts do not always lead to a successful formation of cocrystals. At times, a eutectic or even a coamorphous solid is obtained. Therefore, choosing a correct coformer is of utmost importance. However, at present, conformers are either chosen based on empirical understanding or based on cumbersome methods requiring detailed analysis and calculations. Therefore, development of a new and fast coformer screening tool is necessary to screen coformers suitable for cocrystallization. Furthermore, efforts are also needed to develop a generalized understanding of intermolecular interactions that inﬂuence the cocrystallization outcome by employing supramolecular chemistry and crystal engineering principles. While a rationale design of a cocrystal can lead to a successful outcome at the end of cocrystallization, it is equally important to develop solvent-free cocrystal production methods such as melt crystallization. At present researchers are trying to develop continuous techniques for cocrystal synthesis. Further efforts in this direction will enable a large-scale production of cocrystals. Additionally, future research also needs to focus on stability of cocrystals. At present, very little information is available on the aspects related to the cocrystal stability such as conversion of cocrystals to drug polymorphs or degradation of cocrystals upon exposure to aqueous environment, pH or temperature, etc. It is also evident from the literature reports on cocrystal/eutectic/coamorphous/solid solution formulations reviewed so far that most of the solids prepared by cocrystallization have not been studied for their bioavailability, pharmacokinetics and pharmacodynamics. Mere production of cocrystals without investigating its efﬁcacy, pharmacokinetic or pharmacodynamic behavior in biological system would end up in vain. Moreover, preclinical trials followed by clinical trials have needed to develop cocrystals into marketed product.

Author Contributions: Conceptualization was made by S.V.D. I.S. and S.V.D performed formal analysis. I.S. prepared the original draft and S.V.D. reviewed & edited the draft. Funding: I.S. gratefully acknowledges Ministry of Human Resources and Development (MHRD), India for the finanacial support. Conflicts of Interest: The authors declare no conflict of interest.

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