Two-Component Pharmaceutical Cocrystals Regulated by

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Perspective

Two–Component Pharmaceutical Cocrystals Regulated by Supramolecular Synthons Comprising Primary N•••H•••O Interactions Hai-Lei Cao, Jun-Ru Zhou, Feng-Ying Cai, Jian Lü, and Rong Cao Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01663 • Publication Date (Web): 19 Nov 2018 Downloaded from http://pubs.acs.org on November 20, 2018

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Crystal Growth & Design

Dedicate to Prof. Xin–Tao Wu (Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences) on the occasion of his 80th birthday.

Two–Component Pharmaceutical Cocrystals Regulated by Supramolecular Synthons Comprising Primary N•••H•••O Interactions Hai–Lei Caoa, Jun–Ru Zhoua, Feng–Ying Caia, Jian Lü*a,c and Rong Cao*b aFujian

Provincial Key Laboratory of Soil Environmental Health and Regulation, College of Resources

and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, P.R. China; bState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P.R. China; cSamara Center for Theoretical Materials Science (SCTMS), Samara State Technical University, Molodogvardeyskaya St. 244, Samara 443100, Russia.

ACS Paragon Plus Environment

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Abstract The fundamental research focusing on structural characterizations of drug substances has been developed greatly over the past decade, which has aroused extensive interest in manipulation on enhanced physical property of drug substances. In this context, the cocrystallization technique has been effectively applied to optimize solid forms of active pharmaceutical ingredients (APIs), which decide the physicochemical properties i.e. stability and solubility of so–called medicinal ‘cocktails’ on the molecular level. This Perspective focuses on two–component pharmaceutical cocrystals of APIs regulated by supramolecular synthons comprising primary N•••H•••O interactions, in terms of the synthetic methodology, supramolecular cocrystallization, polymorphism and solvatomorphism, cocrystal growth kinetics etc. Special attention is paid to supramolecular assembly of APIs based on stoichiometric ratio, functional group effect, and competing reactions of coformers that are well–defined thanks to the increasing knowledge of crystal engineering concepts.

Keywords: cocrystal; supramolecular assembly; active pharmaceutical ingredient; intrinsic dissolution rate; stability; tablet formulation.


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1. INTRODUCTION The physicochemical property and bioavailability of drugs are the key factors that determine their successful application in clinical trials that have aroused wide attention from pharmaceutical scientists1,2. Crystalline drugs, as preferable pharmaceutical candidates, possess exceptional stability and processability derived from their solid dosage forms3, which include polycrystalline forms, hydrates, solvates, and salts. The discovery of crystalline drugs has been undergone unprecedented development in recent years, taking advantage of the supramolecular chemistry and crystal engineering concepts, which drastically leads to the formation of new research areas such as the pharmaceutical cocrystals (PCCs)4–8. PCCs are complex crystals comprised by active pharmaceutical ingredients (APIs) and cocrystal formers (CCFs) in certain stoichiometric ratios9–12, which has been extensively investigated with the aim of improving physicochemical property of drug substances13,14. The APIs, either molecular or ionic, and CCFs in PCCs shall be normally in the solid state at room temperature. CCFs are typically bio–compatible acids and bases, or vitamins, minerals, amino acids, as well as food additives. Meanwhile, APIs can also be used as CCFs to realize synergistic effect, by which PCCs provide a new platform to prepare compound medicines. Indeed, PCCs, unlike pharmaceutical salts and solvates, have shown great advantages in drug discovery. For example, the degree of proton transfer in pharmaceutical cocrystals and salts is differentiable: PCCs are composed of neutral molecules via intermolecular forces, whereas salts are only applicable to drugs that are ionizable. Pharmaceutical solvates is defined by the forms of guest molecules (liquid at ambient conditions). At present, there are only a few pharmaceutically acceptable solvents. Besides, the solvent molecules are easy to migrate due to high vapor pressure, which causes the loss of solvents and turns into amorphous solids. The APIs with polymorphic forms and various conformations are much easier to form PCCs with appropriate CCFs, largely due to their flexible molecular arrangement and packing in a crystal lattice15. Supramolecular interactions that underpin the solid state structures of APIs and CCFs, such as hydrogen



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bonding (HB), halogen bonding (XB), π–π interaction, Van der Waals’ force, and other non–covalent interactions, are found to be crucial for controlled molecular assembly and property modulation of PCCs16. Of special notice, HBs might be involved in various supramolecular synthons i.e. C–H•••O, O–H•••O, O–H•••N, N–H•••N etc. Among these, the O•••H•••N interactions seem to be one of the most viable supramolecular synthons for PCCs formation. Moreover, polymorphism in multicomponent crystals is frequently accompanied by the change in primary H–bonded moieties, resulting in synthon polymorphism17. Therefore, PCCs are promising candidates as novel pharmaceutical materials in terms of their wide applicability and superior stability. This Perspective introduces the recent research progress in two–component pharmaceutical cocrystals regulated by supramolecular synthons comprising primary N•••H•••O interactions, with actual case study to analyze the innovation and concerns related to PCCs by: ● classifying types of drug substances successfully employed in PCCs preparation; ● identifying viable supramolecular interactions and synthons that underpin PCCs solid state structures; ● exploring structure–function relationships in controlled PCCs assembly; ● discovering new PCCs with optimized physiochemical property, i.e. melting point (MP), stability, mechanism, solubility, and intrinsic dissolution rate (IDR) etc. 2. DESIGN STRATEGY Despite the various supramolecular interactions available for pharmaceutical cocrystals (PCCs), hydrogen bonds (HBs) become somehow dominant in the formation of PCCs. The design of PCCs has thus been greatly advanced by following the supramolecular assembly principles: the analysis of structural information related to API conformation, functionality, as well as the number and location of the hydrogen bond donors and acceptors of APIs; the search of supramolecular synthons; and the selection of


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appropriate CCFs based on the property of drug substances, taking also the complementary features of hydrogen bonding and structural prediction into consideration. 3. METHODOLOGY 3.1. Synthesis A wide variety of synthetic methods for the crystallization of pharmaceutical cocrystals (PCCs) has been advanced with the rapid development of crystal engineering in the past decades18–20. One of the most popular and efficient methods has been the conventional solution crystallization which allows growth of crystalline materials and structural determination of PCCs by means of the single crystal X–ray diffraction technique. The solution crystallization method typically involves cooling, evaporation, melting, as well as the anti–solvent method, sometimes at elevated temperature and pressure. It is noteworthy that interactions between APIs and CCFs must be dominant over APIs/CCFs and solvent molecule interactions, which requires the rational selection of solvents, reaction temperature, stoichiometric ratio etc. for a delicate control on crystallization. Thus solution crystallization method can somehow be inefficient for PCCs formation in cases that solubility of APIs and CCFs is significantly different, or interactions amongst APIs, CCFs, and solvent molecules become imbalanced. Solid state synthesis includes mainly sublimation, dry and solvent–assisted grinding, the so–called mechanochemical methods21. Different from the solution crystallization methods, mechanochemical methods avoid harsh reaction conditions in the use of mechanical energy originated from shear, friction, impact, extrusion etc. Moreover, this method has advantages over solution crystallization due to the absence or minimized use of solvents. However, grinding turns to be laborious and time–consuming when cocrystallization of APIs and CCFs is neither straightforward nor well–defined. In addition, supercritical fluid extraction, ultrasonic–assisted cocrystallization, and high–throughput crystallization technique are complementary and alternative choices for PCCs synthesis. Particularly interesting is that high–throughput crystallization method features an efficient and convenient ACS Paragon Plus Environment


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trial–and–error mode for batch experiments, crystallization methods and conditions, which facilitate greatly the screening and preparation of PCCs22–24. 3.2. Characterization With the advances of modern analytical and testing techniques, the characterization of pharmaceutical cocrystals (PCCs) renovates progressively. At present, single crystal and power X–ray diffractions (SCXRD and PXRD), spectroscopy and thermal analysis are the main characterization methods for PCCs. For example, the clear shifts of characteristics observed in PXRD, in comparison with the individual APIs and CCFs, are the evidence of PCCs formation. Furthermore, SCXRD is widely used to determine the spatial arrangement of atoms in PCCs, as well as the exact ratio of APIs and CCFs. In addition, the ratio of APIs and FCCs molecules can be determined by elemental analysis, NMR, and thermogravimetric analysis (TGA). 4.

TWO–COMPONENT

PHARMACEUTICAL

COCRYSTALS

(PCCS)

WITH

SUPRAMOLECULAR SYNTHONS COMPRISING PRIMARY N•••H•••O INTERACTIONS 4.1. PCCs of carboxyl–functionalized APIs

Scheme 1 Various forms of Norfloxacin at different degree of (de)protonation. Norfloxacin Carboxyl–functionalized APIs are known to form PCCs via intermolecular hydrogen bonds with various CCFs with functional carboxyl, amide, pyridyl groups. Norfloxacin (NOR), as a common antibacterial drug, exhibits poor solubility due to the acid/base interaction between the carboxylic group


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and nitrogen of piperazine ring, presenting in the zwitterionic form as shown in Scheme 1. Meanwhile, the structural information for crystals of NOR is oddly rare, although it is generally accepted that two polymorphic forms and hydrates exist25,26. Therefore, the improvement on aqueous solubility of NOR favors the formulation of conventional dosage forms, and, at the same time, can be extremely challenging. In this context, the pharmaceutical property of NOR has been studied based on cocrystals and salt forms. NOR can crystallize with succinic acid (SUC), malonic acid (MAL), or maleic acid (MAE) into a salt, and with isonicotinamide (i–NIC) into a cocrystal.

Figure 1. View of the molecular synthon (a) and crystal structure (b) of Norfloxacin–Saccharin cocrystal. Color code: C, grey; H, light gray; N, blue; O, red; S, yellow.


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

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Table 1 List of major APIs and CCFs with full names, abbreviation, and chemical structures. Name

Abbreviatio n

Chemical Structure

Name

Abbreviatio n

APIs Norfloxacin

NOR

Ciprofloxacin

CIP

Indomethacin

IND

Furosemide

FUR

Caffeine

CAF

Sulfamethazine

SUL

Nitrofurantoin

NIT

Carbamazepine

CAR

AMG 517

AMG

Agomelatine

AGO

Curcumin

CUR

Quercetin

QUE

Silibinin

SIL

Artemisinin

ART


Chemical Structure

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Spironolactone

SPI

Aspirin

ASP

Meloxicam

MEL

CCFs Malonic acid

MAL

Isonicotinamide

i–NIC

Saccharin

SAC

Nicotinamide

NIC

4−Hydroxybenzoic acid

HYD

p−Aminobenzoic acid

AMI

Resorcinol

RES

Pyrogallol

PYR

Phloroglucinol

PHL

Orcinol

ORC

Terephthalic acid

TP



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It has been found that quinolone units in these structures are involved in π–π interactions and form channels containing solvent molecules (CHCl3 or H2O), by which aqueous solubility of NOR are greatly improved (3–45 times of increase in the solubility). In the salt structures, deprotonated dicarboxylates of SUC, MAL, or MAE interact typically with the piperazinyl groups in NOR, whereas amide groups in i−NIC form dimer synthons and additional hydrogen bonds with the carboxyl groups in NOR molecules. One common feature of the salt and cocrystal structures is the formation of π–stacked layers along crystallographic a axis and channels with guest solvent molecules. In the system of NOR and saccharin (SAC), pharmaceutical cocrystals have been prepared by the formation of a salt of NOR and saccharinate ion and the subsequent formation of a cocrystal comprising this salt and saccharin27. The NOR molecules interact with saccharinate ions via N−H•••O hydrogen bonds between the piperazine ring and carbonyl groups, while with saccharin molecules through N−H•••O of carboxyl to N−H groups (Figure 1). This demonstrates a solid state salt of API is capable of crystallizing further with a CCF into a cocrystal, which offers a new insight into the cocrystal concepts. Cocrystallization of NOR and its structural analog, ciprofloxacin (CIP), leads to the heteroassociation of both APIs in the solid state28. The resultant multicomponent molecular complex comprises three crystallographically independent zwitterions with an overall ratio 1:1 of ionized NOR and CIP statistically distributed at those sites29. N−H•••O hydrogen bonds between piperazinyl and carboxylate groups and π–stacking between fluorophenyl rings uphold the crystal structure in a cooperative binding model30. These results open new prospects for the exploration of synergistic antibacterial activity of NOR and CIP, as well as the adverse effects, pharmacokinetic and


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pharmaceutical property in related systems. Indomethacin Indomethacin (IND) is an anti−inflammatory, antipyretic and analgesic drug with high permeability and poor water solubility. In order to improve the physical property of IND, especially the solubility and dissolution rate, cocrystals of IND have been designed based on crystal engineering approaches. A series of IND−SAC cocrystals with various structures and properties were successfully isolated by using conventional and advanced synthetic methodology. IND–SAC cocrystal is constructed through the interconnection of two types of dimer synthons via N−H•••O (between SACs) and O−H•••O (between INDs) hydrogen bonds, which is interestingly unique by contrast to the cocrystals of NOR and SAC. The IND–SAC cocrystal is nonhygroscopic and shows significantly faster dissolution rate, as well as dynamic vapor sorption property. Moreover, it has been demonstrated that the formation of cocrystal does not induce any effect on the integrity, being able to increase the permeation of indomethacin31,32. Cocrystals of IND and SAC have also been successfully isolated with high purity by means of a combinational anti−solvent and cooling method33,34. Furthermore, cocrystal form of IND and SAC has been detected via the real−time screening technique using DSC–FTIR microspectroscopy35,36. IND can also crystallize with nicotinamide (NIC) into cocrystals, in which solubility of IND and NIC is improved and significantly leveled by solvent mixture at appropriate temperature37. The specific intermolecular O−H•••O, O−H•••N and C−H•••O hydrogen–bonding interactions in IND−NIC cocrystal has been identified through advanced multinuclear solid–state NMR, although the crystal structure has not been determined to date by X−ray diffraction methods38. Moreover, the impact of thermal stress, generated by different solvent evaporation rates, on IND−NIC cocrystal 11



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formation with neat cogrinding has been studied using differential scanning calorimetry (DSC) and simultaneous DSC–FTIR microspectroscopy in the solid or liquid state. The results indicate thermal stress influences more significantly the cocrystal formation in liquid phase39. Moreover, IND is also capable of cocrystallizing with 2−hydroxy−4−methyl−pyridine, 2−methoxyl−5−nitroanilline, or 4,4'−bipyridine (BIP)32.

Figure 2. View of the molecular synthon (a) and hydrogen–bonded structure (b) of Indomethacin–Carbamazepine cocrystal. Color code: Cl, green. Of special note is that IND crystallizes with carbamazepine (CAR), a common psychotropic drug (see below for more details), into 1:1 cocrystal via the amorphous state by means of 12


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co−grinding/ball milling method40. Geometry of the API molecules is satisfactorily preserved in the cocrystal structure which features acid−amide and amide−amide supramolecular synthons (Figure 2). In most cases of indomethacin cocrystals, grinding/milling techniques advance greatly the exploration of new cocrystal forms, by which powder X−ray diffraction has played a crucial role in terms of supramolecular synthon determination, although detailed information of crystal structures and structural packing modes is still an impediment, counting on the high−quality single crystals. Furosemid Another well−investigated carboxyl–functionalized API is the furosemid (FUR), a loop diuretic drug commonly used for the treatment of hypertension and edema, which suffers from low solubility and permeability. FUR is able to react with coformer BIP in the same stoichiometry (2:1) to form cocrystal polymorphisms (form I, yellow thin needles; form II, orange blocks), albeit both forms crystallize at different velocity of crystallization41. Crystallography has revealed that sandwich motifs are constructed by FUR and BIP molecules mostly through O−H•••N, C−H•••π, and π−π stacking interactions (Figure 3). The conformational flexibility of FUR in both polymorphs contributes greatly to the polymorphism, as evidenced by the different configuration of furyl group in the cocrystals (Figure 3). More interestingly, a series of ternary cocrystals has been synthesized with predictable structural features of robust asymmetric two−dimensional (2D) network structures based on the geometrical features of the functional groups in FUR, BIP, and a ternary component hydroquinone (Figure 4)42. The pseudo−tetrahedral geometry of the sulphonamide group and the planarity of the carboxylic acid groups are central to all of the ternary cocrystals that also provide insights into the process of crystallization.

13



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Figure 3. View of the sandwich motifs (a) and hydrogen–bonded structure (b) of Furosemide−4,4'−bipyridine cocrystal. In the case of FUR−piperazine (PIP) cocrystallization, two salts with different stoichiometry have been isolated43. The FUR and PIP molecules form individual chain units via O–•••H+•••N and N−H•••N interactions, respectively into a FUR−PIP (1:1) salt. Moreover, the FUR−PIP salt is able to convert into the thermodynamically more stable form of FUR−PIP (2:1) within an hour, which also leads to the decrease of solubility due to the increased ionic interaction in their structures. The apparent solubility of FUR−PIP (1:1) salt is approximately three times higher than the equilibrium solubility of the thermodynamically stable FUR−PIP (2:1) salt.

Figure 4. A view of the hydrogen–bonded network structure of ternary Furosemide cocrystal. FUR can also form versatile cocrystals with NIC (1:1), of which five anhydrous polymorphs (Forms I−V) and one hydrate of FUR−NIC cocrystal have been discovered44. The anhydrous polymorphs exhibit diverse thermodynamic stability, as well as structural similarity i.e. lattice parameters, molecular configuration of FUR, supramolecular interactions between the FUR and 14


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NIC (N−H•••O and O−H•••N hydrogen bonds), and synthons, whereas the hydrated cocrystal shows contraction along the a−axis, coupled with the twist of pyridyl rings in NIC. The higher number of polymorphs existed in FUR−NIC cocrystals suggests the importance of polymorph screening and characterization of cocrystals, as well as other solid forms of APIs. However, only one 2:1 cocrystal of FUR and the i−NIC isomer has been identified45, in which the sulphonamide groups in FUR are massively disordered. Furthermore, no evidence for dynamic proton transfers in the short O−H•••N hydrogen bond is observed. The IDR of FUR−i−NIC remains the same as that of commercial FUR, yet the apparent equilibrium solubility is much higher (ca. 5.6 times in this case), which is in accordance with the observation for all reported FUR cocrystals. Also, FUR−i−NIC undergoes a partial conversion into the initial components over the solubility measurement, like most of the other FUR cocrystals. The crystallization of FUR and caffeine (CAF) as a ground mixture from methanol–acetonitrile solvents has afforded a binary complex that has been characterized as a neutral cocrystal46,47. The most acidic carboxyl group in FUR is hydrogen bonded to the most basic nitrogen acceptor of CAF via O−H•••N hydrogen bonds. The primary sulfonamide NH donor interacts with a different CAF by carbonyl acceptor groups, and the secondary NH is bonded to one of the sulfonyl O acceptors. Thus a novel cocrystal of FUR is obtained by liquid–assisted grinding48. The solubility of FUR−CAF cocrystal is approximately 6−fold higher than FUR and the dissolution rate is about two times faster than the pure drug. In view of the individual components that are polymorphic, the probable mechanism of cocrystal formation in this system has been tentatively studied. The binary phase diagram (composition–temperature plots) of FUR−CAF cocrystal system has been determined by means of differential scanning calorimetry (DSC) measurements. It has been demonstrated that a

15



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transition of the stable polymorph of FUR at the lower temperature (137 ºC) triggers FUR−CAF cocrystal formation, in other words, cocrystal formation may initiate when suitable mass transfer occurs. 4.2. PCCs of amine/amide–functionalized APIs Sulfadimidine Sulfadimidine (SUL), as a broad−spectrum antibacterial drug with poor water solubility, is used in a variety of treatments, such as those of rheumatoid fever and malaria49. From a structural point of view, SUL possesses amine and amide groups as potential hydrogen bond donors and sulfo groups as acceptors, which endow SUL with predominant ability to build cocrystals with CCFs and APIs via supramolecular hydrogen bonding interactions. It has been demonstrated that SUL is capable of forming cocrystals with various carboxylic acids and amides by forming robust hydrogen bonding interactions, which define also synthon variation based on amidine to imidine tautomerism in the cocrystals upon proton transfer from sulfonamide NH to one of the pyrimidine nitrogen atoms (Figure 5)50. Structures of the cocrystals have been characterized based on SCXRD with respect to hydrogen bonding competition between various acceptors and donors, in the presence of competing functional groups. For example, SUL forms with Theophylline (THE) into a unique cocrystal in a 2:1 molar ratio featuring a similar synthon via mutual N−H•••O and N−H•••N interactions51. Enhanced water solubility, stability, as well as hygroscopicity have been observed for some cocrystals by contrast to the pure form of SUL.

16


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Figure 5. View of the various supramolecular synthons of Sulfadimidine (a) and hydrogen–bonded network of Sulfadimidine−Theophylline (b). Nitrofurantoin Nitrofurantoin (NIT) is clinically used as an antiseptic drug for urinary system infection, which has been cataloged as class IV drugs according to the biopharmaceutics classification system (BCS) issued by the Food and Drug Administration (FDA, USA). NIT has particularly poor water solubility (ca. 82 mg L−1, 25 ºC), due to the formation of monohydrate, and membrane permeability, further to the low bioavailability52. Moreover, NIT is barely soluble in common organic solvents. Vangala and co−workers have prepared and structurally characterized the 1:1 cocrystal of NIT with 4−hydroxybenzoic acid (HYD), in which two types of molecular synthons formed by N−H•••O, O−H•••O, and C−H•••O are observed53. The cocrystal displays superior physicochemical and photo−stability compared to NIT. The NIT−HYD cocrystal exhibits significantly enhanced stability to various temperatures and humidity, as well as superior photostability over the commercial β−NIT polymorph. Moreover, the hydration stability and dissolution rate of some NIT cocrystals are compared with that of the stable β−NIT and hydrate form by Cherukuvada and co−workers54. Upon room−temperature evaporation of the acetonitrile solution of equal molar NIT and p−aminobenzoic acid (AMI), a stable NIT−AMI cocrystal with enhanced water solubility (ca. 216 mg L−1, 25 ºC) has been formed, which does not transform easily (over a period of three days stirring in water at room

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temperature) into the less soluble monohydrate as the other NIT polymorphs do, and shown good solubility. The IDR of NIT−AMI cocrystal is higher in buffer solution compared with pure water, and the least in acidic medium, indicating that the pH is important in drug dissolution. Further study based on cocrystallization of NIT and CCFs with different functionalization indicates that heterosynthons have the privilege over homosynthons55. Caffeine Caffeine (CAF) is by far one of the most extensively used drug substances, either as APIs or CCFs, in the PCCs preparation. CAF is capable of adapting into various PCCs systems, similar to norfloxacin, and meanwhile, it is compatible to different synthetic methods. Cocrystals of CAF and citric acid (CIT) in various stoichiometric ratios have been evaluated via liquid−assisted grinding, resulting in CAF−CIT cocrystals with different melting points and thermodynamic stability56,57. The kinetics of cocrystal formation has been assessed by calculating the ball impact energy and force using the distinct element method (DEM) simulations. Furthermore, the formation kinetics of the cocrystals with precise crystal structure is to be completely revealed, which can be explained according to a 3D diffusion mechanism. In the case of CAF−glutaric acid (GLU) cocrystallization, a dimorphic cocrystal system (1:1) has been recently revealed through in situ structural analysis, by which the metastable (at ambient conditions) Form I and the stable Form II are identified58,59. Further, the dimorphs are enantiotropically related with a transition temperature around 80 ºC, although the transformation from Form I to the thermodynamically stable Form II appears below the transition point during cooling. Notably the heterosynthons built by O−H•••N and C−H•••O hydrogen bonds are responsible for the molecular cocrystallization. CAF forms cocrystals with MAL spontaneously upon the contact of these two materials60,61. 18


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Nartowski and co−workers have studied the formation process of CAF−MAL cocrystals from a mechanistic point of view. The spontaneous conversion rate from starting materials to cocrystals is able to be manipulated by tuning moisture additions, as such, moisture sorption can be crucial for the growth of CAF−MAL cocrystals. The stoichiometrically diverse CAF−MAE cocrystals (1:1 and 2:1) have been successfully isolated by the selection of appropriate solvents by using the kinetic screening methods, in which the carboxyl groups are oriented in a manner to promote intermolecular formation of hydrogen−bonded synthons62−64. Specifically, the 2:1 CAF−MAE cocrystal has been isolated by an ultrasound−assisted solution crystallization method63, while the microwave radiation has been used to prepare the 1:1 and 2:1 CAF−MAE cocrystals from different solvent systems64. The supersaturation condition at the reacting interface of CAF and MAE in solution is thus achieved through ultrasound or microwave−assisted solution crystallization, which might favor the generation of cocrystal nuclei. Of special note is the utilization of the powerful cocrystal screening method has revealed the formation of CAF−adipic acid (ADI) cocrystal that remains unexplored over the years, although ADI has been considered as a promising component to explore the cocrystal formation with imidazolyl−containing drug substances65. The discovery of CAF−ADI cocrystal establishes the significance of the cocrystal screening method which effectively avoids the time−consuming crystallization trials.

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Figure 6. View of the molecular synthons (a) and Caffeine−n−hydroxy−2−naphthoic acid cocrystals (b) and (c).

hydrogen–bonded

structure

of

CAF cocrystallizes also with various aromatic acids, i.e. benzoic acid, hydroxybenzoic acid or nitro−benzoic acid, by means of the viable binary O−H•••N and C−H•••O imidazolyl−carboxyl heterosynthons (Figure 6a)66–68. For example, in most cases of CAF−n−hydroxybenzoic acids and CAF−n−hydroxy−2−naphthoic acids, similar heterosynthons have been observed69, with an exception that carboxyl−carboxyl homosynthons are formed in the case of n−hydroxy−2−naphthoic acids (Figure 6b)70. In this context, new and unknown phases of CAF PCCs may be expected with dicarboxylic acid as CCFs in virtue of the possibility to form simultaneously hetero− and homosynthons71,72.

It

is

somehow

interesting

to

note

that

two

polymorphs

of

CAF−4−chloro−3−nitrobenzoic acid cocrystals which display similar 2D layered structures but surprisingly distinct mechanical behaviors73. As some metastable drug forms are normally softer and transformable

to

stable

and

harder

forms

upon

stressing,

one

form

of

the

CAF−4−chloro−3−nitrobenzoic acid cocrystals is fragile, but shows shear−induced phase instability and converts to the soft and plastically shearable form upon grinding. It is the relative strength of

20


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specific weaker C−H•••O and π−stacking interactions, in a way, deciding the mechanical property of the cocrystals. Indeed, computational study also shows that the CAF−4−chloro−3−nitrobenzoic acid cocrystal, in the form of methanol solvate, is remarkably flexible and elastically bendable so that the cocrystal is able to maintain its cocrystal structure at temperature range of 100−400 K74. Moreover, the remarkable elasticity of the cocrystal is developmental to the design of high−performance supramolecular materials with excellent self−healing or efficient stress dissipating property. Cocrystallization of CAF and anilines is relatively unexplored, despite of the great potentials of amine groups to be involved in hydrogen bonding synthons for achieving new PCCs. Ghosh et al. has performed somehow pioneering work based on the isolation of a series of CAF−anilines cocrystals, by which a structure–mechanical property relationship is rationalized by using a simple mechanical deformation (qualitative) method75. In general, cocrystals with robust intralayer and weak interlayer interactions exhibit shear deformation behavior, whereas those with comparable intralayer and interlayer interactions show brittle fracture on application of mechanical stress. Moreover, the formation of flat layer is desirable, by contrast to those of corrugated layers or 3D interlocked packing layers. Carbamazepine Carbamazepine (CAR), cataloged as class II drugs according to the BCS, has been used for the treatment of trigeminal neuralgia and anticonvulsant since its approval by FDA (UDS). CAR shows poor water solubility and high membrane permeability. In order to improve the physicochemical properties of CAR, various synthetic methods, including solution cooling, solvent evaporation, low temperature grinding, and resonant acoustic mixing (RAM)76−81, have been applied to prepare CAR−NIC cocrystals. The cocrystals obtained by aforementioned pathways have shown comparable 21



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physical properties to the pure CAR in terms of water solubility, IDR, and compressibility, however, the chemical stability in relatively humid environment has been noticeably enhanced. Liu and co−workers have placed equal molar of CAR and NIC between two polyamide films and allowed them to melt at 160 ºC, which leads to the formation of CAR−NIC cocrystals dispersed onto polymer78. The polymer supported cocrystals exhibit enhanced dissolution rate than the pure CAR (75% vs 60%) in distilled water. Schultheiss and colleagues have studied the stability of CAR−pterostilbene (PTE) cocrystals at extremely humid conditions (98% humidity) and found CAR turns from extremely unstable to stable for up to 4 weeks upon cocrystallization with PTE79. IDR of the CAR polymorphs and cocrystals with NIC has been studied, by which phase transition of cocrystals is observed during dissolution80. The IDR of CAR–NIC cocrystal decreases slowly during dissolution, indicating the rate of crystallization of CAR dihydrate from the solution is slow. In situ solid–state characterization has shown the evolutional conversion of CAR–NIC cocrystals and polymorphs to the dihydrate form82,83. The cocrystal of CAR–SAC also exhibits a higher aqueous solubility than the dihydrate form. Using this model system, Ullah and co−workers have demonstrated an efficient and material–sparing tablet formulation screening approach that is enabled by intrinsic dissolution rate measurements84. Three tablet formulations capable of stabilizing the cocrystal, both under accelerated condition of 40 ºC and 75% relative humidity and during dissolution, have been achieved. Moreover, the polymer systems designed for tableting exhibit better bioavailability in comparison with a marketed product, Epitol®. On the other hand, the crystallization method for industrial production of CAR−SAC cocrystals, including the determination of the supersaturation, has been studied by Kudo and Takiyama based on the ternary phase diagram85. The cocrystals can be successfully obtained under a 22


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fairly wide range of mixing ratios. Moreover, the relationship between the supersaturation and the induction time for nucleation has been revealed86,87. Study of the varied stoichiometric ratios of CAR−AMI cocrystals indicates the cocrystal dissolution behavior is complex, and cocrystallization with appropriate coformers does not guarantee an improved drug dissolution88,89. In particular, the intermolecular interactions within the crystal lattice can be crucial for cocrystal dissolution in case that the difference of solubility between APIs and CCFs is minor90. Likewise, the kinetic growth methods can be promising for cocrystal screening in attempting to optimize bioavailability of poorly soluble drug substances, since crystal dissolution is benefited from the weak intermolecular interactions in the thermodynamically unstable forms91. AMG 517 AMG 517 (AMG), as analgesics candidate, is a small molecule inhibitor of the capsaicin receptor (TRPV1) and is hardly soluble in water92. The salt formation method has been used to improve the water solubility of AMG, and the ether linkage in the molecule turns to be unstable in water. Bak and co−workers have used solution cocrystallization method to prepare AMG−sorbic acid (SOR) cocrystals in different solvent systems with varied stoichiometric ratios of starting materials, which feature similar supramolecular synthons as those observed in CAF−based cocrystals (Figure 6a)93. The in vivo pharmacokinetics reveals that the bioavailability of AMG−SOR cocrystal is 17 times of pure AMG 517. The twin screw extrusion (TSE) technique has been applied in the scale−up production of AMG−SOR cocrystals by which formation of the cocrystal is found to be strongly dependent to temperatures94. Moreover, AMG−SOR cocrystals made by the TSE process have shown superior mechanical property over those solution growths of cocrystals. By exploiting the same method, cocrystals of AMG with carboxyl−based and amide−based CCFs are isolated and 23



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possess generally enhanced dissolution and pharmacokinetics in simulated intestinal liquid solutions95−97. Agomelatine Agomelatine (AGO) has been a blockbuster for the treatment of psychiatric disorders, particularly effective for adult depression with little drug adverse reaction. In order to improve the solubility of AGO in water, Zheng and co−workers have prepared AGO−based cocrystals by means of various synthetic methods in different solvent systems98. The solubility of AGO−glycol (GLY) cocrystals is approximately doubled to pure AGO (Form II), however, it is unstable in water and converts into Form I and III. In addition, AGO can form cocrystals with glycolic acid, urea, i–NIC, and methyl−p−hydroxybenzoate, with enhanced water solubility and stability99. 4.3. PCCs of hydroxyl–functionalized APIs Most hydroxyl–functionalized, alcoholic and phenolic, APIs involved in the study of PCCs are natural products, such as Curcumin, Quercetin, and Silibinin. Curcumin Curcumin (CUR) is an anti–inflammatory, anti–cancer, anti–proliferation, and antimitotic drug substance extracted from the tuber of herbal Curcuma. The water solubility of CUR is as low as 8.7 mg L–1, while this can be improved in alkaline environment which conversely affects the bioavailability of CUR due to the decrease of stability100. The solubility and dissolution rate of two crystalline polymorphs and an amorphous phase of CUR have been studied101. In general, an inverse relation exists between the stability and solubility of polymorphic crystals, that is, the less stable polymorph is more soluble or has faster dissolution rate102. The dissolution rate of a new crystalline 24


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form is higher (about three times) than that of a known form and the amorphous phase behaves in between the former two. On the other hand, stabilization of the crystalline and amorphous forms through additives and excipients could lead to advances of CUR as a more bioavailable active drug substances103,104. By means of liquid–assisted grinding, CUR forms 1:1 cocrystals with resorcinol (RES), pyrogallol (PYR), or phloroglucinol (PHL)105,106. The cocrystals are generally sustained by O−H•••O hydrogen bonds between the phenolic hydroxyl groups in RES/PYR to the carbonyl group in CUR. As mentioned earlier, the melting point of cocrystals is in between that of CUR and the CCFs, and the lower melting cocrystal form is more soluble than higher melting one. The dissolution rates of CUR–RES and CUR–PYR in 40% EtOH–water mixture are ca. 5 and 12 times faster than that of the common curcumin tablets. Meanwhile, the CUR–PHL cocrystal displays reduced hygroscopicity and superior tableting performance that may be applied in the formulation development and manufacture of high–quality curcumin products. Thus, cocrystals of CUR are probably viable platforms to provide faster dissolving solid forms with enhanced stability for drug development. Quercetin Quercetin (QUE) is an active ingredient of natural medicine, which displays a variety of pharmacological activities, such as antitussive, expectorant, and antiasthetic action etc. as confirmed by in vitro experiments. However, the bioavailability of QUE is considerably low due to its poor water solubility. Smith et al. has demonstrated that the water solubility and bioavailability of QUE can be significantly increased upon the formation of cocrystals with CAF, i−NIC, as well as pentoxifylline107. The hydroxyl groups in QUE are the main hydrogen bond donating sites and the 25



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carbonyl groups in CAF and pyridyl groups in i−NIC are dominant hydrogen bond accepting sites. Of note, the solubility of QUE−CAF cocrystals in 1:1 ethanol−water is nearly 10 times of QUE dihydrate. Furthermore, the in vivo pharmacokinetics indicates that the bioavailability of QUE−CAF cocrystals has outperformed QUE dihydrate with increment up to about 10−fold. It is also interesting that Desiraju and co−workers have developed a combinatorial synthesis strategy for the isolation of binary and ternary cocrystals of QUE with dibasic coformers ， through the selection of both molecular configuration and supramolecular synthon108. With the use of templating molecules to reduce molecular and supramolecular ‘confusion’ which are inherent for QUE, and at the same time, it defines an alternative means to the synthesis of ternary and higher component cocrystals. Silibinin Silibinin (SIL), which has been used as anti−tumor and hepatoprotective drugs in clinical treatment, is a racemic flavonoids extracted from the skin of thistle seeds109,110. SIL is nearly insoluble in water and cocrystal formation may well improve its water solubility. However, the racemate of SIL is difficult to form cocrystals with conformers such as RES, PYR, and PHL that have worked for CUR. In this context, cocrystallization of enantiomers of SIL upon chiral resolution might be a feasible route, which leaves an open question to chemical and pharmaceutical researchers, also to crystallographers. 4.4. PCCs of heterocyclic APIs Artemisinin As one of the most recent eye−catching drug substances, artemisinin (ART) crystallizes as a colorless needle−shaped crystals extracted originally from the leaves of Artemisia annua L. and

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shows predominant antimalarial activity by means of the generation of radicals upon activation. Due to the presence of peroxide group in the molecular structure of ART which is unstable in acidic or alkaline conditions, traditional methods commonly used to improve the stability of the drug substances (such as salt formation) are no longer suitable. Meanwhile, it is also problematic to apply the conventional cocrystallization method due to the lack of dominant molecular hydrogen bonding sites (a single carbonyl group) in ART. Jones and co−workers have isolated and characterized ART−RES and ART−ORC (orcinol) cocrystals constructed via O−H•••N hydrogen bonds via mechanochemical synthesis111. DSC analysis shows that the melting points of ART−RES and ART−ORC cocrystals are about 40 ºC lower than that of the amorphous ART. Spironolactone Spironolactone (SPI) is a steroidal aldosterone agonist with low aqueous solubility and high permeability52. Salt formation is unlikely a feasible means to improve its solubility since SPI is nonionizable. SPI has long been known to crystallize in two polymorphs and a number of solvates112,113, while it is only recent that the hydrated and dehydrated cocrystals of SPI–SAC (1:1) are structurally characterized114. SCXRD and PXRD indicate that the hydrate cocrystal retains its crystal lattice or three–dimensional (3D) packing arrangements upon dehydration and the hydrate cocrystal shows enhanced solubility of about two–fold the maximum supersaturated concentration with respect to the most stable form of SPI. However, the high solubility of the hydrate cocrystal unexpectedly initiates nucleation of the SPI hydrate (1/3) that is even less soluble than the most stable form of SPI and thus supersaturation is reduced in this case. On the other hand, there is certainly a margin to maximize the potentials of hydrate cocrystals so as to further improve solubility, as long as nucleation of SPI hydrates can be effectively inhibited. 27



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Figure 7. A view of the molecular synthons in Meloxicam PCCs. Meloxicam Meloxicam (MEL) is a nonsteroidal anti–inflammatory drug with low aqueous solubility and high permeability. Pharmaceutical cocrystallization of MEL represents a promising approach to generate new crystalline forms with improved physicochemical and/or pharmacological property. Cocrystals of MEL with SUC and MAE are first obtained by solvent–assisted grinding technique, yet the solid state structures of the cocrystals have been unrevealed115. In fact, MEL molecule is functionalized with amide, carbonyl, and hydroxyl groups in its structure; however, the ability of those groups to be involved in viable hydrogen bonding interactions has been somehow restricted by the steric hinderance of heterocyclic and π–conjugated rings. Moreover, the carbonyl and hydroxyl groups in MEL also take part in the formation of intramolecular hydrogen bonds. Thus, coformers with strong hydrogen bond donating/accepting groups might be rational candidates for cocrystallization with MEL. For this reason, some carboxyl–functionalized CCFs, including SUC, terephthalic acid (TP), and Aspirin (ASP), have been used for pharmaceutical cocrystallization with MEL10,116. SCXRD has revealed that a same synthon is formed amongst carboxyl groups in CCFs and amide and thiazolyl groups in MEL via mutual O−H•••N and N−H•••O hydrogen bonding 28


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interactions (Figure 7). As expected, the carbonyl and hydroxyl groups form intramolecular hydrogen bonds (Figure 8). The improved dissolution observed for the pharmaceutical cocrystals as compared to the poorly soluble MEL is explained by the presence of molecular dimers linked through strong hydrogen bonds in the crystalline form of MEL while the absence of such dimers in cocrystals.

Figure 8. View of the cocrystal structures of Meloxicam and carboxyl–functionalized CCFs: (a) hexanoic acid and (b) terephthalic acid. 5. CHALLENGES AND OPPORTUNITIES Versatile conventional and newly developed methods, such as solution and solid state crystallization, liquid−assisted grinding, microwave radiation, ultrasound−assisted synthesis etc. coupled to the progressive improvement of design strategies have been applied and advanced greatly the preparation of pharmaceutical cocrystals (PCCs)117,118. In particular, the concepts of supramolecular synthesis and crystal engineering contribute overwhelmingly to the development of PCCs in recent years. It is certainly an ever−increasing research realm representing a successful paradigm that creates opportunities for the development and innovation of drug substances. Therefore, there is a clear demand for better understanding and control over crystal forms of PCCs that are crucial for drug formulation and pharmaceutical development.

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The crystal engineering of PCCs has been well−established by chemists, materials and pharmaceutical scientists and used for viable means to improve and tailor the physicochemical properties of active pharmaceutical ingredients (APIs) and as a consequence of sustainable research aimed at gathering a better knowledge of the supramolecular forces that direct and uphold crystal structures119,120. Furthermore, a handful of research has also extended the scopes more extensively by using a larger range of cocrystallizing components (coformers) in order to take the full advantage of those current advancements in API cocrystals to create exotic supramolecular architectures121–124. Supramolecular assembly and structural analysis of PCCs can be somehow straightforward in view of the existing knowledge systems. To this end, viable supramolecular synthons facilitate to determine the molecular structures of PCCs. It is clear that certain heteromolecular aggregates might well persist in soluble amorphous forms leading to a higher persistence of the drug substances in solution. Meanwhile, the choice of solvents is of great importance for cocrystal identification in solution, with an increasing possibility to observe different stoichiometric phases of PCCs showing comparable solubility towards APIs/CCFs. PCCs with higher solubility normally show higher values of initial diffusion. However, more complex systems might arise to satisfy some practical demands related to for example drug optimization. Controlled synthesis of API−API cocrystals, i.e. NOR−CIP, IND−CAR, FUR−CAF, QUE−CAF, CAR−PTE, MEL−ASP etc., may realize medicinal ‘cocktail’ on the molecular level21. Moreover, the isolation of ternary PCCs or hidden cocrystals that have been predicted or known to exist for long can be extremely challenging from both the synthetic and theoretical point of view65,106. In fact, some APIs, e.g. norfloxacin and caffeine, have been demonstrated to be widely compatible in forming PCCs with a wide variety of CCFs including aliphatic and aromatic acids and

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amides, while for the others, some promising cocrystal phases have proven to be intractable for synthetic targets. This includes also the expansion of APIs with promising potentials, preferably with well−defined functionalizations as docks for recognition of CCFs/APIs via supramolecular interactions in the formation of PCCs112,125. It seems more ground rules and practical experience are necessary but there is no doubt that, with the advance of new techniques, qualitative determination on the improvement of physicochemical pharmacokinetic and pharmaceutical property of PCCs may become possible at a more advanced stage67. The research on pharmaceutical cocrystals (PCCs) has aroused considerable attention due to the effectiveness of the cocrystallization methods to improve some key properties of drug substances. Preliminary experimental results show that physicochemical and/or pharmacological properties, as well as bioavailability of the active pharmaceutical ingredients (APIs) have been significantly improved, which guarantees wide application prospect in the field of pharmacy. In comparison with the traditional methods, such as the preparation of drug polymorphs and salt forms, the PCCs means is highly feasible, even for nonionizable drug molecules (e.g. artemisinin and spironolactone). Moreover, PCCs can be prepared by means of modified and rationalized processes, so as to achieve the aim of property improvement of the drug substances. In addition, it should be pointed out that current research in this area and related is largely limited to structural identification and analysis of PCCs, as well as the selection criteria of cocrystal formers (CCFs) based on the existing experience, concepts, and fundamentals. Purposeful research targeting on the applications of PCCs, for example the bioactivity and pharmacokinetics, remains scarce at the present stage. It is particularly promising though that more PCC drugs will become practically applicable, with the further development of PCCs study, to further advance the application of PCCs in the pharmaceutical fields.

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AUTHOR INFORMATION Corresponding Authors *E–mail: [email protected] (J.L.). *E–mail: [email protected] (R.C.).

Competing financial interests The authors declare no competing financial interests.

ACKNOWLEDGEMENTS The authors acknowledge the 973 program (Grant 2014CB845605), the NSFC (Grants 91622114, 21520102001, and 21521061), the Strategic Priority Research Program (Grant XDB20000000) and the “Strategic Priority Research Program” (XDA09030102) of the Chinese Academy of Sciences, the New Century Excellent Talents in Fujian Province University, and the International Science and Technology Cooperation and Exchange Project of Fujian Agriculture and Forestry University (Grant KXGH17010) for funding. J.L. thanks Prof. Davide M. Proserpio (Universita' degli Studi di Milano, Italy) for his valuable suggestions. We are grateful to all colleagues, co−workers, and peer scientists who have contributed and inspired us in the research area of pharmaceutical cocrystals. Some of their names are mentioned in the REFERENCES.

REFERENCES

32


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(1)


Almarsson, O.; Zaworotko, M.J. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co–crystals represent a new path to improved medicines? Chem. Commun. 2004, 40, 1889–1896.

(2)

Brittain, H.G. Cocrystal systems of pharmaceutical interest: 2007–2008. Elsevier Academic Press: Amsterdam 2010, 35, 373–390.

(3)

Qiao N.; Li M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Pharmaceutical cocrystals: an overview. Int. J. Pharm. 2011, 419, 1–11.

(4)

Remenar, J.F.; Morissette, S.L.; Peterson, M.L.; Moulton, B.; MacPhee, J.M.; Héctor, R.; Guzmán, H.R.; Almarsson, Ö. Crystal engineering of novel cocrystals of a triazole drug with 1,4–dicarboxylic acids. J. Am. Chem. Soc. 2003, 125, 8456–8457.

(5)

Vishweshwar, P.; Mcmahon, J.A.; Bis, J.A.; Zaworotko, M.J. Pharmaceutical co–crystal.

J.

Pharm. Sci. 2006, 95, 499–516. (6)

Shan, N.; Zaworotko, M.J. The role of cocrystals in pharmaceutical science. Drug Discov. Today 2008, 13, 440–446.

(7)

Brittain, H.G. Vibrational spectroscopic studies of cocrystals and salts. 4. Cocrystal products formed by benzylamine, α–Methylbenzylamine, and their chloride salts. Cryst. Growth Des. 2011, 11, 2500–2509.

(8)

Brittain, H.G. Cocrystal systems of pharmaceutical interest: 2011. Cryst. Growth Des. 2012, 12, 5823–5832.

(9)

Aakeröy, C.B.; Salmon, D.J. Building co–crystals with molecular sense and supramolecular sensibility. CrystEngComm 2005, 7, 439–448.

33



Page 34 of 51

(10) Cheney, M.L.; Weyna, D.R.; Shan, N.; Hanna, M.; Wojtas, L.; Zaworotko, M.J. Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J. Pharm. Sci. 2011, 100, 2172–2181. (11) Li, Z.; Matzger, A.J. Influence of coformer stoichiometric ratio on pharmaceutical cocrystal dissolution: three cocrystals of carbamazepine/4−aminobenzoic acid. Mol. Pharmaceutics 2016, 13, 990−995. (12) P.C. Vioglio, M.R. Chierotti, R. Gobetto, Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges. Adv. Drug Deliver. Rev. 2017, 117, 86−110. (13) Karki, S.; Friščić, T.; Fábián, L.; Laity, P.R.; Day, G.M.; Jones, W. Improving mechanical properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv. Mater. 2009, 21, 3905–3909. (14) Chen, A.M.; Ellison, M.E.; Peresypkin, A.; Wenslow, R.M.; Variankaval, N.; Savarin, C.G.; Natishan, T.K.; Mathre, D.J.; Dormer, P.G.; Euler, D.H.; Ball, R.G.; Ye, Z.; Wang, Y.; Santos, I. Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid. Chem. Commun. 2007, 43, 419–421. (15) Aitipamula, S.; Chow, P.S.; Tan, R.B.H. Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs. CrystEngComm, 2009, 11, 1823–1827. (16) Du, M.; Zhang, Z.–H.; Guo, W.; Fu, X.–J. Multi–component hydrogen–bonding assembly of a pharmaceutical agent pamoic acid with piperazine or 4,4'–bipyridyl: a channel hydrated salt

34


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


with multiple–helical motifs vs a bimolecular cocrystal. Cryst. Growth. Des. 2009, 9, 1655–1657. (17) Aitipamula, S.; Chow, P. S.; Tan, R. B. Polymorphism in cocrystals: a review and assessment of its significance. CrystEngComm 2014, 16, 3451−3465. (18) Padrela, L.; Rodrigues, M.A.; Velaga, S.P.; Fernandes, A.C.; Matos, H.A.; de Azevedo, E.G. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J. Supercrit. Fluids 2010, 53, 156–164. (19) Padrela, L.; Rodrigues, M.A.; Velaga, S.P.; Matos, H.A.; de Azevedo, E.G. Formation of indomethacin–saccharin cocrystals using supercritical fluid technology. Eur. J. Pharm. Sci. 2009, 38, 9–17. (20) Dhumal, R.S.; Biradar, S.V.; Paradkar, A.R.; York, P. Particle engineering using sonocrystallization: salbutamol sulphate for pulmonary delivery. Int. J. Pharm. 2009, 368, 129–137. (21) Yamamoto, K.; Tsutsumi, S.; Ikeda, Y. Establishment of cocrystal cocktail grinding method for rational screening of pharmaceutical cocrystals. Int. J. Pharm. 2012, 437, 162–171. (22) Karki, S.; Friščić, T.; Jones, W.; Motherwell, W.D.S. Screening for pharmaceutical cocrystal hydrates via neat and liquid−assisted grinding. Mol. Pharmaceutics 2007, 4, 347−354. (23) Li, Z.; Yang, B.–S.; Jiang, M.; Eriksson, M.; Spinelli, E.; Yee, N.; Senanayake, C. A practical solid form screen approach to identify a pharmaceutical glutaric acid cocrystal for development. Org. Process Res. Dev. 2009, 13, 1307–1314.

35



Page 36 of 51

(24) Goyal, S.; Thorson, M.R.; Zhang, G.G.Z.; Gong, Y.; Kenis, P.J.A. Microfluidic approach to cocrystal screening of pharmaceutical parent compounds. Cryst. Growth Des. 2012, 12, 6023−6034. (25) Barbas, R.; Martí, F.; Puigjaner, C. Polymorphism of norfloxacin: evidence of the enantiotropic relationship between polymorphs A and B. Cryst. Growth Des. 2006, 6, 1463–1467. (26) Hu, T.–C.; Wang, S.–L.; Chan, T.–F.; Lin, S.–Y. Hydration–induced proton transfer in the solid state of norfloxacin. J. Pharm. Sci. 2002, 91, 1351–1357. (27) Velaga, S.P.; Basavoju, S.; Boström, D. Norfloxacin saccharinate–saccharin dihydrate cocrystal – a new pharmaceutical cocrystal with an organic counter ion. J. Mol. Struct. 2008, 889, 150–153. (28) Vitorino, G.P.; Sperandeo, N.R.; Caira, M.R.; Mazzieri, M.R. A supramolecular assembly formed by heteroassociation of ciprofloxacin and norfloxacin in the solid state: co−crystal synthesis and characterization. Cryst. Growth Des. 2013, 13, 1050−1058. (29) Fabbiani, F.P.A.; Arlin, J.−B.; Buth, G.; Dittrich, B.; Florence, A.J.; Herbst−Irmer, R.; Sowa, H. Intermolecular interactions, disorder and twinning in ciprofloxacin−2,2−difluoroethanol (2/3) and ciprofloxacin−water (3/14.5). Acta Crystallogr. 2011, C67, o120−o124. (30) Shen, L.L.; Mitscher, L.A.; Sharma, P.N.; O’Donnell, T. J.; Chu, D.W.T.; Cooper, C.S.; Rosen, T.; Pernet, A.G. Mechanism of inhibition of DNA gyrase by quinolone antibacterials – a cooperative drug–DNA binding model. Biochemistry 1989, 28, 3886−3894. (31) Basavoju, S.; Boström, D.; Velaga, S.P. Indomethacin–saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization. Pharm. Res. 2008, 25, 530–541.

36


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


(32) Ferretti, V.; Dalpiaz, A.; Bertolasi, V.; Ferraro, L.; Beggiato, S.; Spizzo, F.; Spisni, E.; Pavan, B. Indomethacin co–crystals and their parent mixtures: does the intestinal barrier recognize them differently? Mol. Pharmaceutics 2015, 12, 1501−1511. (33) Chun, N.–H.;

Wang, I.–C.; Lee, M.–J.; Jung, Y.–T.; Lee, S.; Kim, W.–S.; Choi, G.J.

Characteristics of indomethacin–saccharin (IMC–SAC) co–crystals prepared by an anti–solvent crystallization process. Eur. J. Pharm. Biopharm. 2013, 85, 854–861. (34) Chun, N.–H.; Lee, M.–J.; Song, G.–H.; Chang, K.–Y.; Kim, C.–S.; Choi, G.J. Combined anti–solvent and cooling method of manufacturing indomethacin–saccharin (IMC–SAC) co–crystal powders. J. Cryst. Growth 2014, 408, 112–118. (35) Lin, H.−L.; Zhang, G.−C.; Lin, S.−Y. Real–time co–crystal screening and formation between indomethacin and saccharin via DSC analytical technique or DSC–FTIR microspectroscopy. J. Therm. Anal. Calorim. 2015, 120, 679–687. (36) Lin, S.−Y. Simultaneous screening and detection of pharmaceutical co–crystals by the one–step DSC–FTIR microspectroscpic technique. Drug Discov. Today 2017, 22, 718–728. (37) Sun, X.; Yin, Q.; Ding, S.; Shen, Z.; Bao, Y.; Gong, J.; Hou, B.; Hao, H.; Wang, Y.; Wang, J.; Xie, C. (Solid + liquid) phase diagram for (indomethacin + nicotinamide)−methanol or methanol/ethyl acetate mixture and solubility behavior of 1: 1 (indomethacin + nicotinamide) co−crystal at T = (298.15 and 313.15) K. J. Chem. Thermodyn. 2015, 85, 171−177. (38) Maruyoshi, K.; Iuga, D.; Antzutkin, O.N.; Alhalaweh, A.; Velagad, S.P.; Brown, S.P. Identifying

the

intermolecular

hydrogen–bonding

supramolecular

synthons

in

an

indomethacin–nicotinamide cocrystal by solid–state NMR. Chem. Commun. 2012, 48, 10844–10846.

37



(39) Lin,

H.−L.;

Zhang,

G.−C.;

Huang,

Y.−T.;

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Lin,

S.−Y.

An

investigation

of

indomethacin–nicotinamide cocrystal formation induced by thermal stress in the solid or liquid state. J. Pharm. Sci. 2014, 103, 2386–2395. (40) Majumder, M.; Buckton, G.; Rawlinson–Malone, C.; Williams, A.C.; Spillman, M.J.; Shankland, N.; Shankland, K. A carbamazepine–indomethacin (1:1) cocrystal produced by milling. CrystEngComm 2011, 13, 6327–6328. (41) Sangtani, E.; Sahu, S.K.; Thorat, S.H.; Gawade, R.L.; Jha, K.K.; Munshi, P.; Gonnade, R.G. Furosemide cocrystals with pyridines: an interesting case of color cocrystal polymorphism. Cryst. Growth Des. 2015, 15, 5858−5872. (42) Srirambhatla, V.K.; Kraft, A.; Watt, S.; Powell, A.V. A robust two–dimensional hydrogen–bonded network for the predictable assembly of ternary co–crystals of furosemide. CrystEngComm 2014, 16, 9979–9982. (43) Banik, M.; Gopi, S.P.; Ganguly, S.; Desiraju, G.R. Cocrystal and salt forms of furosemide: solubility and diffusion variations. Cryst. Growth Des. 2016, 16, 5418−5428. (44) Ueto, T.; Takata, N.; Muroyama, N.; Nedu, A.; Sasaki, A.; Tanida, S.; Terada, K. Polymorphs and a hydrate of furosemide–nicotinamide 1:1 cocrystal. Cryst. Growth Des. 2012, 12, 485−494. (45) Kerr, H.E.; Softley, L.K.; Suresh, K.; Nangia, A.; Hodgkinson, P.; Evans, I.R. A furosemide–isonicotinamide cocrystal: an investigation of properties and extensive structural disorder. CrystEngComm 2015, 17, 6707–6715.

38


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


(46) Goud, N.R.; Gangavaram, S.; Suresh, K.; Pal, S.; Manjunatha, S.G.; Nambiar, S.; Nangia, A. Novel furosemide cocrystals and selection of high solubility drug forms. J Pharm Sci. 2012, 101, 664–680. (47) Pal, S.; Roopa, B.N.; Abu, K.; Manjunath, S.G.; Nambiar, S. Thermal studies of furosemide–caffeine binary system that forms a cocrystal. J. Therm. Anal. Calorim. 2014, 115, 2261–2268. (48) Shan, N.; Toda, F.; Jones, W. Mechanochemistry and co–crystal formation: effect of solvent on reaction kinetics. Chem. Commun. 2002, 20, 2372–2373. (49) Lu, J.; Li, Y.P.; Wang, J.; Li Z.; Rohani S.; Ching C.−B. Pharmaceutical cocrystals: a comparison of sulfamerazine with sulfamethazine. J. Cryst. Growth. 2011, 335, 110−114. (50) Ghosh, S.; Bag, P.P.; Reddy, C.M. Co–crystals of sulfamethazine with some carboxylic acids and amides: co–former assisted tautomerism in an active pharmaceutical ingredient and hydrogen bond competition study. Cryst. Growth Des. 2011, 11, 3489−3503. (51) Lu J.; Rohani S. Synthesis and preliminary characterization of sulfamethazine–theophylline co–crystal. J. Pharm. Sci. 2010, 99, 4042–4047. (52) Kasim N.A.; Whitehouse M. Ramachandran C.; Bermejo M. Lenernas H.; Hussain A.S.; Junginger H.E.; Stavchansky S.A.; Midha K.K.; Shah V.P. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol. Pharmaceutics 2004, 1, 85−96. (53) Vangala V.R.; Chow P.S.; Tan R.B.H. Characterization, physicochemical and photo–stability of a co–crystal involving an antibiotic drug, nitrofurantoin, and 4–hydroxybenzoic acid. CrystEngComm 2011, 13, 759–762.

39



Page 40 of 51

(54) Cherukuvada S.; Babu N.J.; Nangia A. Nitrofurantoin–p–aminobenzoic acid cocrystal: hydration stability and dissolution rate studies. J. Pharm. Sci. 2011, 100, 3233–3244. (55) Vangala V.R.; Chow P.S.; Tan R.B.H. Co–crystals and co–crystal hydrates of the antibiotic nitrofurantoin: structural studies and physicochemical properties. Cryst. Growth Des. 2012, 12, 5925−5938. (56) Shimono K.; Kadota K.; Tozuka Y.; Shimosaka A.; Shirakawa Y.; Hidaka J. Kinetics of co–crystal formation with caffeine and citric acid via liquid–assisted grinding analyzed using the distinct element method. Eur. J. Pharm. Sci. 2015, 76, 217–224. (57) Mukaida M.; Watanabe Y.; Sugano K.; Terada K. Identification and physicochemical characterization of caffeine–citric acid co–crystal polymorphs. Eur. J. Pharm. Sci. 2015, 79, 61–66. (58) Vangala V.R.; Chow P.S.; Schreyer M.; Lau G.; Tan R.B.H. Thermal and in situ X–ray diffraction analysis of a dimorphic co–crystal, 1:1 caffeine–glutaric acid. Cryst. Growth Des. 2016, 16, 578−586. (59) Chow, P.S.; Lau, G.; Ng, W.K.; Vangala, V.R. Stability of pharmaceutical cocrystal during milling: a case study of 1:1 caffeine–glutaric acid. Cryst. Growth Des. 2017, 17, 4064−4071. (60) Ibrahim A. Y.; Forbes R.T.; Blagden N. Spontaneous crystal growth of co–crystals: the contribution of particle size reduction and convection mixing of the co–formers. CrystEngComm 2011, 13, 1141–1152. (61) Nartowski K.P.; Khimyak Y.Z.; Berry D.J. Tuning the spontaneous formation kinetics of caffeine: malonic acid co–crystals. CrystEngComm 2016, 18, 2617–2620.

40


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


(62) Leyssens T.; Springuel G.; Montis R.; Candoni N.; Veesler S. Importance of solvent selection for stoichiometrically diverse cocrystal systems: caffeine/maleic acid 1:1 and 2:1 cocrystals. Cryst. Growth Des. 2012, 12, 1520−1530. (63) Aher S.; Dhumal R.; Mahadik K.; Paradkar A.; York P. Ultrasound assisted cocrystallization from solution (USSC) containing a non–congruently soluble cocrystal component pair: caffeine/maleic acid. Eur. J. Pharm. Sci. 2010, 41, 597–602. (64) Pagire S.; Korde S.; Ambardekar R.; Deshmukh S.; Dash R.C.; Dhumal R.; Paradkar A. Microwave assisted synthesis of caffeine/maleic acid co–crystals: the role of the dielectric and physicochemical properties of the solvent. CrystEngComm 2013, 15, 3705–3710. (65) Bučar D.–K.; Henry R.F.; Lou X.; Borchardt T.B.; Zhang G.G.Z. A 'hidden" co–crystal of caffeine and adipic acid. Chem. Commun. 2007, 5, 525–527. (66) Bučar D.−K.; Day G.M.; Halasz I.; Zhan G.G.Z.g; SanderJ.R.G.; Reid D.G.; MacGillivray L.R.; Duer M.J.; Jones W. The curious case of (caffeine)•(benzoic acid): how heteronuclear seeding allowed the formation of an elusive cocrystal. Chem. Sci. 2013, 4, 4417–4425. (67) Singaraju A.B.; Iyer M.; Haware R.V.; Stevens L.L. Caffeine co–crystal mechanics evaluated with a combined structural and spectroscopic ppproach. Cryst. Growth Des. 2016, 16, 4383−4391. (68) Aitipamula S.; Chow P.S.; Tan R.B.H. Co–crystals of caffeine and piracetam with 4–hydroxybenzoic acid: unravelling the hidden hydrates of 1: 1 co–crystals. CrystEngComm 2012, 14, 2381–2385.

41



Page 42 of 51

(69) Habgood M.; Price S.L. Isomers, conformers, and cocrystal stoichiometry: insights from the crystal energy landscapes of caffeine with the hydroxybenzoic acids. Cryst. Growth Des. 2010, 10, 3263−3272. (70) Bučar D.−K.; Henry R.F.; Lou X.; Duerst R.W.; Borchardt T.B.; MacGillivray L.R.; Zhang G.G.Z. Co–crystals of caffeine and hydroxy–2–naphthoic acids: unusual formation of the carboxylic acid dimer in the presence of a heterosynthon. Mol. Pharmaceutics 2007, 4, 339−346. (71) Leyssens T.; Tumanova N.; Robeyns K.; Candoni N.; Veesler S. Solution cocrystallization, an effective tool to explore the variety of cocrystal systems: caffeine/dicarboxylic acid cocrystals. CrystEngComm 2014, 16, 9603–9611. (72) Das B.; Baruah J.B. Water bridged assembly and dimer formation in co–crystals of caffeine or theophylline with polycarboxylic acids. Cryst. Growth. Des., 2011, 11(1), 278–286. (73) Ghosh S.; Mondal A.; Kiran M.S.R.N.; Ramamurty U.; Reddy C.M. The role of weak interactions in the phase transition and distinct mechanical behavior of two structurally similar caffeine co–crystal polymorphs studied by nanoindentation. Cryst. Growth Des. 2013, 13, 4435−4441. (74) Chen C.−T.; Ghosh S.; Reddy C.M.; Buehler M.J. Molecular mechanics of elastic and bendable caffeine co–crystals. Phys. Chem. Chem. Phys. 2014, 16, 13165−13171. (75) Ghosh S.; Reddy C.M. Co–crystals of caffeine with substituted nitroanilines and nitrobenzoic acids: structure–mechanical property and thermal studies. CrystEngComm 2012, 14, 2444–2453.

42


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


(76) Rahman Z.; Agarabi C.; Zidan A.S.; Khan S.R.; Khan M.A. Physico–mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech 2011, 12, 693–704. (77) Chieng, N.; Hubert, M.; Saville, D.; Rades, T.; Aaltonen, J. Formation kinetics and stability of carbamazepine–nicotinamide cocrystals prepared by mechanical activation. Cryst. Growth Des. 2009, 9, 2377–2386. (78) Liu, X.; Lu, M.; Guo, Z.; Huang, L.; Feng, X.; Wu, C. Improving the chemical stability of amorphous solid dispersion with cocrystal technique by hot melt extrusion. Pharm. Res. 2012, 29, 806–817. (79) Schultheiss, N.; Bethune, S.; Henck, J.O. Nutraceutical cocrystals: utilizing pterostilbene as a cocrystal former. CrystEngComm 2010, 12, 2436–2442. (80) Qiao N.; Wang K.; Schlindwein W.; Davies A.; Li M. In situ monitoring of carbamazepine–nicotinamide cocrystal intrinsic dissolution behaviour. Eur. J. Pharm. Biopharm. 2013, 83, 415–426. (81) Michalchuk, A.A.L.; Hope, K.S.; Kennedy, S.R.; Blanco, M.V.; Boldyreva, E.V.; Pulham, C.R. Ball–free mechanochemistry: in situ real–time monitoring of pharmaceutical co–crystal formation by resonant acoustic mixing. Chem. Commun. 2018, 54, 4033–4036. (82) Martins, D.; Stelzer, T.; Ulrich, J.; Coquerel, G. Formation of crystalline hollow whiskers as relics of organic dissipative structures. Cryst. Growth Des. 2011, 11, 3020–3026. (83) Dette, S.S.; Stelzer, T.; Jones, M.J.; Coquerel, G.; Ulrich, J. Fascinating control of crystalline microstructures. Chem. Eng. Res. Des. 2010, 88, 1158–1162.

43



Page 44 of 51

(84) Ullah M.; Hussain I.; Sun C.C. The development of carbamazepine–succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance. Drug. Dev. Ind. Pharm. 2016, 42, 969–976. (85) Kudo S.; Takiyama H. Production method of carbamazepine/saccharin cocrystal particles by using two solution mixing based on the ternary phase diagram. J. Cryst. Growth 2014, 392, 87–91. (86) Qiu S.; Lai J.; Guo M.; Wang K.; Lai X.; Desai U.; Juma N.; Li M. Role of polymers in solution and tablet–based carbamazepine cocrystal formulations. CrystEngComm 2016, 18, 2664–2678. (87) Hickey M.B.; Peterson M.L.; Scoppettuolo L.A.; Morrisette S.L.; Vetter A.; Guzmán H.; Remenar J.F.; Zhan Z.; Tawa M.D.; Haley S.; Zaworotko M.J.; Almarsson Ö. Performance comparison of a co–crystal of carbamazepine with marketed product. Eur. J. Pharm. Biopharm. 2007, 67, 112–119. (88) Rahim S.A.; Hammond R.B.; Sheikh A.Y.; Roberts K.J. A comparative assessment of the influence of different crystallization screening methodologies on the solid forms of carbamazepine co–crystals. CrystEngComm 2013, 15, 3862–3873. (89) Buanz A.B.M.; Parkinson G.N.; Gaisford S. Characterization of carbamazepine–nicatinamide cocrystal polymorphs with rapid heating DSC and XRPD. Cryst. Growth Des. 2011, 11, 1177–1181. (90) He, H.; Jiang, L.; Zhang, Q.; Huang, Y.; Wang, J.–R.; Mei, X. Polymorphism observed in dapsone−flavone cocrystals that present pronounced differences in solubility and stability. CrystEngComm 2015, 17, 6566−6574.

44


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


(91) Arora K.K.; Tayade N.G.; Suryanarayanan R. Unintended water mediated cocrystal formation in carbamazepine and aspirin tablets. Mol. Pharmaceutics 2011, 8, 982–989. (92) Gavva, N.R.; Bannon, A.W.; Hovland, D.N.; Lehto S.G.; Klionsky L.; Surapaneni S.; Immke D.C.; Henley C.; Arik L.; Bak A.; Davis J.; Ernst N.; Heve G.; Kuang R.; Shi L.; Tamir R.; Wang J.; Wang W.; Zajic G.; Zhu D.; Norman M.H.; Louis J.C.; Magal E.; Treanor J.J. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade. J. Pharmacol. Exp. Ther. 2007, 323, 128−137. (93) Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A. The co−crystal approach to improve the exposure of a water−insoluble compound: AMG 517 sorbic acid co−crystal characterization and pharmacokinetics. J. Pharm. Sci. 2008, 97, 3942−3956. (94) Daurio D.; Nagapudi K.; Li L.; Quan P.; Nunez F.–A. Application of twin screw extrusion to the manufacture of cocrystals: scale–up of AMG 517–sorbic acid cocrystal production. Faraday Discuss. 2014, 170, 235–249. (95) Stanton, M.K.; Bak, A. Physicochemical properties of pharmaceutical co−crystals: a case study of ten AMG 517 co−crystals. Cryst. Growth Des. 2008, 8, 3856−3862. (96) Stanton, M.K.; Kelly, R.C.; Colletti, A.; Kiang, Y.−H.; Langley, M.; Munson, E.J.; Peterson, M.L.; Roberts, J.; Wells, M. Improved pharmacokinetics of AMG 517 through co−crystallization part 1: comparison of two acids with corresponding amide co−crystals. J. Pharm. Sci. 2010, 99, 3769−3778.

45



Page 46 of 51

(97) Stanton, M.K.; Kelly, R.C.; Colletti, A.; Langley M.; Munson E.J.; Peterson M.L.; Roberts J.; Wells M. Improved pharmacokinetics of AMG 517 through co−crystallization part 2: analysis of 12 carboxylic acid co−crystals. J. Pharm. Sci. 2011, 100, 2734−2743. (98) Zheng, S.L.; Chen, J. M.; Zhang, W.X.; Lu T.B. Structures of polymorphic agomelatine and its cocrystals with acetic acid and ethylene glycol. Cryst. Growth Des. 2011, 11, 466−471. (99) Yan, Y.; Chen, J.M.; Geng, N.; Lu T.B. Improving the solubility of agomelatine via cocrystals. Cryst. Growth Des. 2012, 12, 2226−2233. (100) Tønnesen H.H.; Másson M.; Loftsson T. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int. J. Pharm. 2002, 244, 127–135. (101) Sanphui P.; Goud N.R.; Khandavilli U.B.R.; Bhanoth S.; Nangia A. New polymorphs of curcumin. Chem. Commun. 2011, 47, 5013–5015. (102) Pudipeddi M.; Serajuddin A.T.M. Trends in solubility of polymorphs. J. Pharm. Sci. 2005, 94, 929–939. (103) Lakshman J.P.; Cao Y.; Kowalski J.; Serajuddin A.T.M. Application of melt extrusion in the development of a physically and chemically stable high–energy amorphous solid dispersion of a poorly water–soluble drug. Mol. Pharmaceutics 2008, 5, 994–1002. (104) Lee E.H.; Byrn S.R. Stabilization of metastable flufenamic acid by inclusion of mefenamic acid: solid solution or epilayer? J. Pharm. Sci. 2010, 99, 4013–4022. (105) Sanphui P.; Goud N.R.; Khandavilli U.B.R.; Nangia A. Fast dissolving curcumin cocrystals. Cryst. Growth Des. 2011, 11, 4135–4145.

46


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


(106) Chow S.F.; Shi L.; Ng W.W.; Leung K.H.Y.; Nagapudi K.; Sun C.C.; Chow A.H.L. Kinetic entrapment of a hidden curcumin cocrystal with phloroglucinol. Cryst. Growth Des. 2014, 14, 5079–5089. (107) Smith A.J.; Kavuru P.; Wojtas L.; Zaworotko M.J.; Shytle R.D. Cocrystals of quercetin with improved solubility and oral bioavailability Mol. Pharmaceutics 2011, 8, 1867–1876. (108) Dubey R.; Desiraju G.R. Combinatorial selection of molecular conformations and supramolecular synthons in quercetin cocrystal landscapes: a route to ternary solids. IUCrJ 2015, 2, 402–408. (109) Singh R.P.; Raina K.; Deep G.; Chan D.; Agarwal R. Silibinin suppresses growth of human prostate carcinoma PC–3 orthotopic xenograft via activation of extracellular signal–regulated kinase 1/2 and inhibition of signal transducers and activators of transcription signaling. Clin. Cancer Res. 2009, 15, 613–621. (110) Tyagi A.; Singh R.P.; Ramasamy K.; Raina K.; Redente E.F.; Dwyer–Nield L.D.; Radcliffe R.A.; Malkinson A.M.; Agarwal R. Growth inhibition and regression of lung tumors by silibinin: modulation of angiogenesis by macrophage–associated cytokines and nuclear factor–kappa B and signal transducers and activators of transcription 3. Cancer Prev. Res. 2009, 2, 74–83. (111) Karki, S.; Friščić, T.; Fábián, L.; Jones, W. New solid forms of artemisinin obtained through cocrystallisation. CrystEngComm 2010, 12, 4038–4041. (112) Tao Q.; Chen J.−M.; Ma L.; Lu T.−B. Phenazopyridine cocrystal and salts that exhibit enhanced solubility and stability. Cryst. Growth Des. 2012, 12, 3144−3152.

47



Page 48 of 51

(113) Agafonov, V.; Legendre, B.; Rodier, N.; Wouessidjewe, D.; Cense, J.M. Polymorphism of spironolactone. J. Pharm. Sci. 1991, 80, 181–185. (114) Takata, N.; Takano, R.; Uekusa, H.; Hayashi, Yoshiki; Terada, K. A spironolactone–saccharin 1:1 cocrystal hemihydrate. Cryst. Growth Des. 2010, 10, 2116–2122. (115) Myz S.A.; Shakhtshneider T.P.; Fucke K.; Fedotov A.P.; Boldyreva E.V.; Boldyreva V.V.; Kuleshova N.I. Synthesis of co–crystals of meloxicam with carboxylic acids by grinding. Mendeleev Commun. 2009, 19, 272–274. (116) Tumanov, N.A.; Myz, S.A.; Shakhtshneider, T.P.; Boldyreva, E.V. Are meloxicam dimers really the structure–forming units in the ‘meloxicam–carboxylic acid’ co–crystals family? relation between crystal structures and dissolution behavior. CrystEngComm 2012, 14, 305–313. (117) Trask A.V.; Motherwell W.D.S.; Jones W. Pharmaceutical cocrystallization: engineering a remedy for caffeine hydration. Cryst. Growth Des. 2005, 5, 1013–1021. (118) Hong C.; Xie Y.; Yao Y.; Li G.; Yuan X.; Shen H. A novel strategy for pharmaceutical cocrystal generation without knowledge of stoichiometric ratio: myricetin cocrystals and a ternary phase diagram. Pharm. Res. 2015, 32, 47−60. (119) Vishweshwar, P.; McMahon, J.A.; Peterson, M.L.; Hickey, M.B.; Shattock, T.R.; Zaworotko, M.J. Crystal engineering of pharmaceutical co−crystals from polymorphic active pharmaceutical ingredients. Chem. Commun. 2005, 39, 4601−4603. (120) Khan, M.; Enkelmann, V.; Brunklaus, G. Crystal engineering of pharmaceutical co−crystals: application of methyl paraben as molecular hook. J. Am. Chem. Soc. 2010, 132, 5254−5263.

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


(121) Aakeröy, C. B.; Desper, J.; Scott, B.M.T. Balancing supramolecular reagents for reliable formation of co−crystals. Chem. Commun. 2006, 40, 1445−1447. (122) Bhogala,

B.R.;

Nangia,

A.

Ternary

and

quaternary

co−crystals

of

1,3−cis,5−cis−cyclohexanetricarboxylic acid and 4,4'−bipyridines. New J. Chem. 2008, 32, 800−807. (123) Chiarella, R.A.; Davey, R.J.; Peterson, M.L. Making co−crystals − the utility of ternary phase diagrams. Cryst. Growth Des. 2007, 7, 1223−1226. (124) Nechipadappu, S.K.; Tekuri, V.; Trivedi, D.R. Pharmaceutical co−crystal of flufenamic acid: synthesis and characterization of two novel drug−drug co−crystal. J. Pharm. Sci. 2017, 106, 1384−1390. (125) Paluch K.J.; Tajber L.; Elcoate C.J.; Corrigan O.I.; Lawrence S.E.; Healy A.M. Solid−state characterization of novel active pharmaceutical ingredients: cocrystal of a salbutamol hemiadipate salt with adipic acid (2:1:1) and salbutamol hemisuccinate salt. J. Pharm. Sci. 2011, 100, 3268−3283.

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For Table of Contents Use Only Two–Component Pharmaceutical Cocrystals Regulated by Supramolecular Synthons Comprising Primary N•••H•••O Interactions Hai–Lei Cao, Jun–Ru Zhou, Feng–Ying Cai, Jian Lü* and Rong Cao*

This Perspective focuses on binary cocrystals of APIs regulated by supramolecular synthons comprising primary N•••H•••O interactions and showing enhanced physicochemical property.

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This Perspective focuses on binary cocrystals of APIs regulated by supramolecular synthons comprising primary N•••H•••O interactions and showing enhanced physicochemical property. 80x46mm (150 x 150 DPI)


Two-Component Pharmaceutical Cocrystals Regulated by

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