A review of Pharmaceutical Cocrystal Preparation ... - ACS Publications

(59) Moradiya, H.; Islam, M. T.; Woollam, G. R.; Slipper, I. J.; Halsey, S.; Snowden, M. J.;. Douroumis, D., Continuous Cocrystallization for Dissolut...
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Creating Cocrystals: A review of Pharmaceutical Cocrystal Preparation Routes and Applications Maryam Karimi-Jafari, Luis Padrela, Gavin M. Walker, and Denise M. Croker Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00933 • Publication Date (Web): 10 Aug 2018 Downloaded from http://pubs.acs.org on August 11, 2018

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Crystal Growth & Design

Creating Cocrystals: A review of Pharmaceutical Cocrystal Preparation Routes and Applications Maryam Karimi-Jafari, Luis Padrela, Gavin M. Walker, Denise M. Croker Synthesis & Solid State Pharmaceutical Centre (SSPC), Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland Abstract Originally discovered almost a century ago, cocrystals continue to gain interest in the modern day due to their ability to modify the physical properties of solid-state materials, particularly pharmaceuticals. Intensification of cocrystal research efforts has been accompanied by an expansion of the potential applications where cocrystals can offer a benefit. Where once solubility manipulation was seen as the primary driver for cocrystal formation, cocrystals have recently been shown to provide attractive options for taste masking, mechanical property improvement and intellectual property generation and extension. Cocrystals are becoming a commercial reality with a number of cocrystal products currently on the market, and more following in registration and clinical trial phases. Increased commercialisation of cocrystals has in turn necessitated additional research on methods to make cocrystals, with particular emphasis placed on emerging technologies that can offer environmentally attractive and efficient options. Methods of producing cocrystals and of harnessing the bespoke physical property adjustment provided by cocrystals are reviewed in this article, with a particular focus on emerging trends in these areas.

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Graphical Abstract

1.0 Introduction Cocrystals are solids that are neutral crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts1. If at least one of the coformers is an API and the other is pharmaceutically acceptable, then it is recognized as a pharmaceutical cocrystal2. Cocrystals of different stoichiometry with the same coformer are possible, as illustrated by the carbamazepine:4-aminobenzoic acid cocrystal system, which can exist in 1:1, 2:1 and 4:1 stoichiometric configurations3. A cocrystal has a different crystal structure to either of the starting materials and as a result different physicochemical properties.

Cocrystals are

attractive because the cocrystal solid can be designed to have superior physical properties to either of the pure starting molecules. Physical property improvement via cocrystal formation has been demonstrated for solid explosives4, agrochemicals5, pigments6 and, particularly, pharmaceuticals7-12. Physical property improvement is of particular interest to pharmaceuticals as the vast majority of medicines are delivered as solid forms. The physical properties of the solids contained within a pharmaceutical drug product will have a direct impact on the processing, delivery and, ultimately, performance of the medicine. To provide a classic example, crystal structure directly affects the solubility of a given solid in solution. Drug products require a certain solubility to be bioavailable in the body. It is estimated that 40 % of existing drug products and up to 90 % of new chemical entities have limited aqueous solubility

13

and

hence cannot be delivered to the body using conventional techniques. Cocrystal formation with a suitable coformer offers the potential of improved solubility via modification of the 2 ACS Paragon Plus Environment

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underlying crystal structure, thus potentially rendering the compound bioavailable. As cocrystal research has expanded so it has the range of application areas for physical property manipulation

through

cocrystal

formation.

Improvements

in

solubility,

bioavailability, and mechanical properties, have been well documented

14, 15

stability,

and emerging

applications such as taste masking and intellectual property extension are being explored. Research in cocrystal structure and applications has shown an exponential increase in the last decade, evident in the number of cocrystal structures deposited in the Cambridge Structural Database16 and cocrystal related patent applications. In light of this, it is surprising that cocrystal preparation methods have remained, until relatively recently, largely poorly defined. Limited research attention has been directed specifically at cocrystal preparation, and this topic receives little detail in the majority of existing publications. Initial cocrystal related research efforts centred on elucidation of the crystal structure of cocrystal and bonding mechanisms, requiring high quality single crystal from cocrystal samples. This was typically achieved using trial and error approaches based on solvent evaporation that serendipitously yielded cocrystals, on occasion.

A universal approach was lacking. As

experimentation with cocrystal systems increased, the demand for larger quantities of cocrystal material accompanied it. Solution based cocrystallization routes were employed, requiring knowledge of the solubility of both starting materials in the solvent of choice, often supplied in the format of a ternary phase diagram. Again, methods used were inconsistent from research paper to research paper and no universal approach was practiced. Today, a wide range of successful cocrystal preparation methods have been documented: solvent evaporation, solid state grinding, solution crystallization, slurry conversion, melt crystallization, hot melt extrusion, spray crystallization; but there is little consistency in the application of different preparation methods or even in the terminology used to describe same. Details such as solvent choice, concentration of target molecule/coformer, equilibration time and recovery process are often not provided. This makes it difficult to repeat or compare cocrystal preparation methods, and must be confusing to a newcomer to this research area16. The objective of this review is to systematically describe all reported cocrystal preparation routes and applications in a single location in an effort to standardise progress achieved todate in this evolving area.

2.0 Cocrystal production Cocrystal production routes can be broadly categorised as solid-state or solution based. Solidstate methods can be differentiated as methods using very little or no solvent, with solution 3 ACS Paragon Plus Environment

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based methods representing production routes that involve a large excess of solvent necessitating a subsequent isolation stage to separate the crystalline product from the mother liquor.

2.1 Solid State Methods 2.1.1 Contact Formation The spontaneous formation of cocrystals via mixing of pure API and coformer under controlled atmospheric environment has been reported17-19. In this method no mechanical forces are applied during cocrystallization20, 21. However, in some cases brief grinding of pure components individually before mixing has been done20. N. Rodriguez-Hornedo et al. studied the effect of pre-milling of the starting materials on cocrystallization rate of carbamazepine and nicotinamide20. It was shown that cocrystallization rate in case of pre-milled reactants was markedly faster than unmilled reactants (12 versus 80 days, respectively). Moreover, higher cocrystallization rates have been reported for the same system at higher temperature and relative humidity, regardless of the mechanical activation20. Sarcevica et al. reported the formation of isoniazid-benzoic acid cocrystal via spontaneous cocrystallization22. They reported that the rate of reaction was considerably increased at higher pre-milling frequencies of the pure reactants22. Moreover, A. Y. Ibrahim et al. studied the effect of particle size of starting materials on spontaneous cocrystallization of urea and 2-methoxybenzamide (2-MB). It has been shown that smaller particle size distributions lead to faster cocrystal formation. A rapid increase in cocrystallization rate was observed in case of the small particle size distribution of 20-45 µm, where no buried eutectic or amorphous intermediate phase was detected21.The mechanism of cocrystallization in the presence of moisture at deliquescent conditions consists of three stages of (1) moisture uptake, (2) dissolution of reactants, and (3) cocrystal nucleation and growth23 (Figure 1).

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Moisture sorption by deliquescent materials

Dissolution of cocrystal components in deliquesced solution

Cocrystallization

Figure 1. Illustration of the Moisture Uptake Process Leading to Deliquescence, Reactant Dissolution, and Cocrystal Formation A and B are cocrystal reactants, Ds is solid deliquescent additive, and Dl is the solution phase created by deliquescence at relative humidity greater than deliquescence relative humidity (reprinted with permission from23). David J. Berry et al. used hot-stage microscopy for cocrystal screening. They used Kofler method to successfully probe the binary phase behaviour of a given co-crystal system, revealing potential co-crystal phases in five API mixtures. In this work, nicotinamide was chosen as a molecular scaffold former with a series of APIs e. g. fenbufen, flubiprofen, ibuprofen, ketoprofen and salicylic acid. In this method, one component is melted then allowed to solidify, before another component is brought into contact with it and solubilized a proportion of the first component. Thus, after recrystallization of all materials a zone of mixing is created. This is comparable to the binary phase diagram of the two components. With this method, they were able to identify the formation of nicotinamide:ibuprofen, nicotinamide:salicylic acid, nicotinamide:flubiprofen and nicotinamide:fenbufen.

2.1.2 Solid State Grinding Solid state grinding methods have been used successfully to generate cocrystal powder samples. Two formats are practised: neat (dry) grinding, and liquid assisted grinding. Neat grinding involves the combination of target molecule and coformer in their dry solid forms with the application of pressure through manual (mortar and pestle) or mechanical (automated ball mill) means. Dry grinding is distinct from melt crystallization as the solid

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starting materials are not expected to melt during grinding. The temperature achieved during grinding is often monitored to ensure same, and will often be reported. Two sulphathiazole:carboxylic acid cocrystals were prepared by grinding stoichiometric equivalents of sulphathiazole with the required carboxylic acid for 90 minutes in a Retsch mixer mill at 25 Hz frequency with the temperature not allowed exceed 37 ºC24. There is an efficiency associated with solid state grinding, relative to solution based methods, in that yield is not lost to the solvent due to solubility25. Issues with dry grinding can include failure to form a cocrystal, incomplete conversion to cocrystal and crystalline defects with possible generation of some amorphous content. Incomplete conversion to cocrystal, resulting in a mixture of cocrystal and excess starting material in the product, is not desirable as it requires the use of addition purification steps to yield a pure cocrystal product. Increasing the grinding time can sometimes resolve this, but product mixtures can also be an indication of non-stoichiometric cocrystal formation. Dry grinding is typically attempted with stoichiometric mixtures of target and coformer solids. This requires formation of a stoichiometric cocrystal to consume all available starting materials. Formation of a non-stoichiometric cocrystal will thus lead to an excess of either remaining. Ideally dry grinding should be completed using molar equivalents, and an excess of each starting material respectively. This will also facilitate discovery of alternative cocrystals if they exist for a system. Liquid assisted grinding involves the addition of a solvent, typically in a very small amount, to the dry solids prior to the initiation of milling. The solvent has a catalytic role in assisting cocrystal formation and should persist for the duration of the grinding process. More efficient cocrystal formation is suggested for liquid assisted methods than with neat methods, with a tendency for the cocrystal formation kinetics to increase as the solvent added to the grinding media is increased26, but as yet this is inconclusive. The liquid component is thought to accelerate reaction kinetics by wetting the solid surface. Liquid assisted grinding has been reported in a number of different formats. Trask et al. applied caffeine and maleic acid to make a caf:ma cocrystal for the first time using neat and liquid assisted grinding (LAG) methods. Their research suggested that 1:1 or 2:1 caf:ma cocrystal could be manufactured after 30 and 60 min of grinding depending on the solvent selection27. But in 2010, another method (ultrasound assisted solution cocrystallization) was presented to form purer cocrystal of caf:ma, because the synthesized cocrystals by Trask et al. contained impurities and accompanied by different amount of caffeine28. Benzoic acid cocrystals were formed by wetting an equimolar mixture of benzoic acid and carboxilic acid coformer in a mortar with 6 ACS Paragon Plus Environment

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methanol and grinding it to dryness29. 50 µL of nitromethane were added to an equimolar mixture of caffeine and tetrafluorosuccinic acid with grinding for 30 mins at 30 Hz to form a 1:1 cocrystal; the same method for a 2:1 mixture of caffeine and octafluoroadipic acid yielded a 2:1 cocrystal30. 10 µL of ethanol or nitromethane facilitated the formation of a 2:1 cocrystal from a 2:1 molar mixture of pterostilbene and piperazine, whereas 10 µL of toluene of 2propanol facilitated the formation of a 1:1 cocrystal from a 1:1 molar mixture of pterostilbene and glutaric acid31. For generating highly water-soluble cocrystals of a poorly soluble nutraceutical Hesperetin (HESP), solvent drop grinding cocrystallization method was applied. Kunal Chadha et al. used different coformers such as picolinic acid (PICO), nicotinamide (NICO), and caffeine (CAFF). Their research has led to optimize the pharmacokinetic properties by improving the bioavailability. Also, the dissolution of prepared cocrystals in aqueous buffer showed that the hesperetin concertation is around 4-5 times higher than the pure one32 (Figure 2.).

Figure 2. An example of equilibrium solubility (24 h) of hesperetin, HESP-PICO, HESP-NICO, and HESP-CAFF. (reprinted with permission from 32.)

A wide range of carbamazepine cocrystals were generated using solvent drop grinding and solvent evaporation in a screening exercise by Weyna et al., and equivalent cocrystal hits achieved from either method33. In general, there is no clear logic proposed for solvent

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selection for liquid assisted grinding experiments, with limited justification for solvent choice provided in existing literature. 2.1.2.1. Cocrystallization mechanisms It has been suggested that the synthesis of new cocrystals is affected by many variables, which are mostly affected by the nature of solvent and the reactants. For examples, the presence of functional groups, the solubility of reactants in the solvent in addition to many experimental conditions such as stoichiometric ratio of coformer and API, temperature, stirring, pH, and type of glassware are just a few of the effective parameters34. On the other hand, the rules of hydrogen bonding, synthons and graph sets could be helpful in designing cocrystal systems. For instance, for an API containing carboxylic acid choosing coformers containing acidic moieties or amides could increase the chance of cocrystallization35. However, there is no guarantee for cocrystal formation. Thus, preparation of cocrystals is often a multistage and empiric process. As described above, many techniques are capable of cocrystal synthesis. However, the lack of control over the nucleation, crystallization and phase evolution of the cocrystals is still a significant scientific challenge36. Mechanochemical techniques are promising techniques for cocrystal production from a green chemistry and affordable synthetic pathway37. For the first time in 1893, grinding was used as one of the main techniques for cocrystal formation in order to produce quinhydrone cocrystal from equimolar amounts of p-benzoquinone and hydroquinone38. Since then, many other crystalline compounds have been formed through both mechanisms of neat and wet grinding. Despite all the technological improvements in the field, the underlying mechanism/s of cocrystal formation through these methods have not been understood fully. Thus, many efforts have been put into understanding the underlying mechanism of these techniques. P. G. Fox has proposed the formation of very high temperatures of around 1000 °C for a short period in the order of milliseconds39. P. Balaz has proposed the magma-plasma model which consider the formation of transient plasma at temperatures up to 10000 °C to activate the reaction37,

40

. However, no explanation is

provided for the stability of the coformer and API at these high temperatures. Cocrystallization is not a single mechanism process, as Jones and co-worker have mentioned41, but rather a series of mechanisms which include: molecular diffusion, eutectic formation42 and cocrystallization through an amorphous phase43. The common point in these three mechanisms is the presence of an intermediate bulk phase (gas, liquid, or amorphous solid) with improved mobility and/or higher energy of reactant molecules with respect to the starting crystalline forms. 8 ACS Paragon Plus Environment

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For each one of these mechanisms there are examples in the literature. It has been mentioned that molecular diffusion is more likely in cases where one or both reactants have significantly high vapour pressures in the solid state. The availability of fresh surfaces enhances the molecular diffusion on the reactant crystals44. Additionally, It has been suggested that mechanical force beaks down the intermolecular bonds of the crystals of the reactant molecules44. Error! Reference source not found. shows the schematic of cocrystal formation mechanism via grinding. The solid and vapour diffusion are both significant in some cases of cocrystallization, e.g. in cocrystals containing naphthalene. However, in heavier aromatic hydrocarbons surface diffusion is a more effective mechanism of cocrystal formation. In liquid phase assisted cocrystallization the formation of solid cocrystals is assisted by an intermediate liquid phase, e.g. when one of the reactants is liquid at ambient conditions45-47. Eutectic formation in cocrystal synthesis is also an increasingly significant mechanism in cocrystal formation48. The cocrystal formation at the interface of two colourless crystals of diphenylamine and benzophenone was revealed by microscopic observation, where the contact surface was converted into liquid. Incorporating grinding with eutectic-mediated cocrystallization enhances the process through two mechanisms: firstly, increasing the fresh reactant surfaces for eutectic formation and secondly, improving the cocrystal nucleation in the eutectic phase41. In cases where there is no special mass transfer pathway (i.e. liquid or gas phase), cocrystallization can take place through the formation of amorphous intermediates. This is possible in cocrystallization of molecular solids with strong intermolecular interactions (e.g. hydrogen bonds). Moreover, it has been reported that grinding at temperatures below the glass transition temperature of the reactants, results in amorphous phase formation, however grinding at higher than that would lead to metastable polymorphic forms49. In liquid assisted grinding, the mechanism of cocrystal formation has not been completely understood yet. In some cases it has been suggested that liquid just plays the role of lubricant by providing a medium to facilitate the molecular diffusion41. Since the cocrystals formed after neat and liquid assisted grinding are typically thermodynamically stable, the low solvent fraction during liquid assisted grinding is of little significance in controlling the outcome of process. The same rational behind the liquid assisted grinding can be applied to slurry cocrystallization as well. Moreover, the nature of the liquid phase used in grinding can be significantly influential during mechanochemical cocrystallization50.

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The mentioned mechanisms are the ones mostly involved with mechanochemical synthesis of cocrystals. As HME is a mechanochemical method of processing, each one of these mechanisms could be valid depending on the initial reactants, mechanical forces, temperature and liquids used during the process.

Figure 3.Schematic of cocrystal formation mechanism via mechanochemical reaction (grinding)(adapted from41)

2.1.3 Extrusion Distinct from Hot Melt Extrusion (HME), Twin Screw Extrusion (TSE) operates at temperatures below the melting point of either starting material, and takes place in a distinct piece of equipment – an aptly named twin screw extruder This unit consists of 2 co/counter 10 ACS Paragon Plus Environment

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rotating screw in a single barrel. Screw action provides simultaneous mixing and movement of material along the length of the barrel. Daurio et al. reported on the formation of 4 model cocrystals using a 16 mm twin screw extruder with four controllable temperature zones51. Carbamazepine:saccharin,

theophylline:citric

acid,

caffeine:oxalic

acid

and

nicotinamide:cinnamic acid cocrystals were prepared by passing stoichiometric blends of the dry powder of each starting material through the extruder. The impact of temperature on conversion to cocrystal was specific to the cocrystal system being studied, with no apparent temperature dependence for cocrystals of carbamazepine:saccharin and a strong temperature dependence for nicotinamide:cinnamic acid. In a separate study, the same authors compared a AMG-157:saccharin cocrystal prepared from TSE and solution crystallization52. Cocrystals from TSE were shown to have improved surface area, bulk density and flow properties relative to those produced from solution crystallization. In another case study, carbamazepine-trans-cinnamic acid cocrystals were extruded by both Single Screw Extrusion (SSE) and TSE. According to the DSC and XRD results, less crystallinity was observed for cocrystal which manufactured via single screw extruder compared to twin screw extruder. Moreover, the dissolution rate of TSE cocrystal was higher than SSE one53. Cesar Medina et al. applied TSE method for the first time to manufacture cocrystal of caffeine and AMG 517. Their research proved that TSE helps to have a highly efficient mixing and close material packing which lead to improvement of surface contact between cocrystal components. Consequently, cocrystal formation will be facilitated without adding any solvent54. Twin screw extrusion also was employed to manufacture of ibuprofen-nicotinamide cocrystal as a continuous process. Off-line PXRD demonstrated that purity of cocrystal to be variable between 20% to 99% with different extrusion conditions. This study showed that extrusion temperature, screw configuration and screw rotation speed are the three critical parameters to determine cocrystal purity. The optimum situations to reach the purest ibuprofennicotinamide cocrystal are highest residence time (lowest speed) and highest processing temperature with most intensive mixing screw55. 2.1.4 Hot Melt Extrusion Hot melt extrusion (HME) is a relatively recent addition to cocrystal preparation options. This specialist technique combines simultaneous melting and mixing of the target molecule 11 ACS Paragon Plus Environment

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and coformer via the use of a heated screw extruder (Figure 4). Typically, the starting materials are mixed in a molar ratio and fed to the heated extruder. Melting occurs, facilitating intimate mixing of the starting materials, the cocrystal nucleates directly in the melt and pure cocrystal extrudate is isolated from the extruder continuously. The advantages of the method are elimination of the use of organic solvents, fast operating times, increased conversion relative to solution based methods, reduced waste and the technology lend itself well to continuous pharmaceutical processing. Moradiya et al. described the production of carbamazepine:cinnamic acid cocrystals using single screw and twin screw extruder56. Cocrystals obtained from the twin screw extruder displayed enhanced dissolution properties relative to those obtained from the single screw/ solution based methods. Melt extrusion as a continuous manufacturing techniques was employed to produce indomethacin−saccharin cocrystals. Their studies proved that the temperature profile, feed rate, and screw speed were the three critical process parameters (CPP) which are needed for the engineering of high quality cocrystals. Moreover, they showed that temperature has no impact on dissolution rate of

cocrystals

57

. However, this is only valid in this case as the samples have same

crystallinity based on Rietveld analysis. It has been reported that in case of deviation in the crystalline quality by process temperature dissolution rate will be affected subsequently. In contrast, the particle size of cocrystals can have an influence on their dissolution profile 58, 59.

Figure 4. Schematic representation of a typical HME instrument.

Dhumal et al. manufactured the agglomerated cocrystal of ibuprofen and nicotinamide by hot melt extrusion. They have studied the effect of different processing parameters such as screw speed, temperature profile and screw configuration. It was depicted that for cocrystallization to happen, the barrel temperature must be above the eutectic point of physical mixture. Also, in order to get the purer cocrystal, the highest sheer screw configuration should be applied60. 12 ACS Paragon Plus Environment

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Additionally, it was shown that incorporating of polymeric matrix of xylitol in manufacturing of ibuprofen-isonicotinamide cocrystal has significant impact on the torque of extrusion and the residence time. They studied the effect of adding 10%, 30% and 50% xylitol as a polymer. It has been observed that with increasing the amount of xylitol, the torque decreased and hence the residence time increased61. Xu Liu et al. also selected carbamazepine (CBZ) and nicotinamide (NIC) as model drug and coformer, respectively, to manufacture amorphous CBZ-NIC cocrystal solid dispersion via HME method. The main scope of their study was to show cocrystallization as a considerable approach to prevent thermal degradation of heat sensitive drugs during HME. Firstly, they proved that CBZ and NIC could in-situ cocrystallization in PVP/VA during the process of heating in hot melt extrusion. The newly formed cocrystal completely melted around 160˚C. This temperature is 30˚C lower than the Tm of CBZ. Hence, the CBZ-NIC-polymer solid dispersion could be successfully prepared while preserving heat sensitive API from thermal degradation via HME62.

2.1.5 High shear wet granulation Typically employed for drug product formulation, high shear wet granulation has been investigated as a route to cocrystal preparation. This technique involves the agglomeration of powder particles via a liquid medium in the presence of a binder. Technically the procedure is carried out in a high shear granulator which imparts shear on the powder mixture through impellers and choppers. The mechanism of cocrystal formation by high shear granulation is not exactly known, but suspected to be either similar to liquid assisted grinding, or slurry transformation. Granules containing a 1:1 piracetam:tartaric acid cocrystal were successfully produced from a mixture of piracetam, tartaric acid and a variety of excipients in the presence of water using a Bohle mini granulator63. The extent of cocrystal formation was impacted by the volume of granulation liquid used, impeller speed and the excipient mixture used, with 95% conversion achieved within 5 minutes. In another case study, Veronika Sládková et al. studied vabradine hydrochloride (S)-mandelic acid 1:1 co-crystal (IClSM) and the effect of adding two different granulation liquids. First, lactose monohydrate was added as a common formulation filter to the mixture of API and coformer. Then water and ethanol were applied to granulate it. The results showed that no co crystal formation was observed when water was applied for granulation in presence of lactose monohydrate while, by adding ethanol the cocrystal was formed and PXRD depicted the cocrystal characteristic peaks64. 13 ACS Paragon Plus Environment

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2.2 Solution Based Methods A variety of methods exist to cocrystallize from solution, and each will be discussed in the subsequent section. At the outset it is worthwhile considering some universal solution crystallization concepts.

The driving force for crystallization is supersaturation, the

difference between the actual experimental concentration and the reported solubility concentration at that temperature in that solvent. With a cocrystal system, there are 2 concentrations to consider, that of the target molecule and the coformer. The concentrations of both relative to the solubility of the cocrystal (most accurately expressed in terms of target molecule and coformer) dictate the supersaturation for cocrystallization. A eutectic point will exist where at one fixed solution concentration, a mixture of cocrystal and the target molecule is the stable solid phase for the system; a second eutectic point exists for mixture of the cocrystal and coformer. The eutectics represent solution minima where the solvent content is at its lowest value, meaning solubility is at its highest value. The cocrystal will only be stable, less soluble than target molecule or coformer, at concentrations lying between the eutectic points. Knowledge of this concentration range, termed cocrystal operating range, is key to designing a successful solution cocrystallization. Operation outside of this range can fail to yield a cocrystal or can yield a cocrystal/target molecule or cocrystal/coformer mixture in the solid phase. The solubility of a cocrystal system is most accurately represented in a ternary phase diagram (TPD). This triangular diagram illustrates the solubility of the solid phases in a given solvent at fixed temperature and pressure, and also identifies regions of stability for different solid phases in the system65, 66. Figure 5 shows the typical ternary phase diagrams which describe the three-phase behaviour of a multicomponent system: API, coformer, cocrystal and solvent. It is also able to predict the pathway of cocrystal formation.

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S

S F

F A A

E C

E C

B

D

B

D

2 1

1

2 (b) Solubility differences

(a) Similar solubility

Figure 5. Schematic representation of isothermal ternary phase diagram (a) similar solubilities between API and coformer (1 and 2) in solvent S and (b) different solubilities of 1 and 2 in S. Region A, component 1 and solvent; B, component 1+cocrystal; C, cocrystal; D, component2 + cocrystal; E, component 2 and solvent; F, solution. modified from reference67. Crystallization from solution is an established unit operation for single component crystallizations and one would imagine that this technique has the greatest industrial potential for up-scaling cocrystal preparation without moving towards the specialist techniques. Screening cocrystal systems via solution cocrystallization in combination with grinding approaches can significantly enhance the exploration of variety of cocrystal systems. As an example, the potential of cocrystal formation of caffeine with dicarboxylic acids was investigated by the solution cocrystallization of caffeine/L-malic acid68.

2.2.1 Evaporative Cocrystallization Evaporative cocrystallization is a common method of generating cocrystals, typically employed for generating single crystal cocrystals suitable for diffraction studies to elucidate cocrystal structure. The technique involves the nucleation and growth of a cocrystal from a solution of both coformers in a solvent, with supersaturation provided by removal of solvent from the solution via evaporation. Individual cocrystals, or the bulk crystal sample, should be harvested before the solution evaporates to dryness to ensure recovery of a clean crystal(s). A slow rate of evaporation is usually desired so as to ensure formation of a small number of

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larger crystals as opposed to a high number of smaller crystals. As crystal structure identification is a necessary step in the discovery of new cocrystal forms, evaporative cocrystallization is evident in the majority of cocrystal related research papers and there are countless examples of it in the literature. It should be noted that identification of crystal structure is a necessity for defining whether the obtained crystal is a cocrystal, salt, hydrate or any other polymorphic form of the API or coformer. A classic example is provided by Basavoju et al. in the description of the generation of single crystals of a norflaxinisonicotinamide cocrystal from chloroform: 0.1 mmol of norflaxin and 0.1 mmol of isonicotinamide are dissolved in 8ml of chloroform. The chloroform was subsequently allowed to evaporate at room temperature yielding rod shaped single crystals of a 1:1 norfloxacin:isonicotinamide cocrystal10. Another example of making cocrystal with solvent evaporation method was shown by S.F. Chow et al for Ibuprofen-nicotinamide and flurbiprofen-nicotinamide cocrystals which exhibited higher intrinsic dissolution rate compared to the corresponding profens. Moreover, the synthesized cocrystals presented higher tabletability and less absorbed humidity compared to the individual precursors69. This method is typical in that most evaporative cocrystallizations are performed in stoichiometric solutions, typically 1:1 molar ratio of precursors. However, this is not recommended as it tends to only yield stoichiometric cocrystals and will not identify cocrystals with unequal API:coformer ratios when they do exist for a cocrystal system. Ideally evaporative cocrystallization should be performed from three solutions: 1:1 stoichiometric solution, solution where the coformer is in excess and a solution where the target molecule is in excess70. Not only will this increase the probability of obtaining a cocrystal, it will also identify cocrystals with unequal API:coformer ratios where they are possible. In studies to date, there is limited attention given to the role of the solvent in evaporative cocrystallization. In theory, there is no reason why evaporative cocrystallization could not be used at larger scales to produce bulk amounts of cocrystal product. In this case single crystal formation would not be required, and the cocrystallization could be optimised the same as any crystallization process. At lab scale, evaporative cocrystallization tends to occur from very dilute solutions. This is oftentimes due to a lack of solubility information on the precursor molecules in the solvent, but can also be a purposeful attempt to reduce the rate of supersaturation to promote the formation of larger crystals. Optimisation of these starting concentrations and process conditions could design an efficient large scale evaporative

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Crystal Growth & Design

cocrystallization. In practice this could be difficult to operate and control, possibly leading to the preferred selection of alternative cocrystallization routes at larger scales. Depending on the volatility of the solvent, evaporative cocrystallization can be very slow – evaporation times of up to six months have been reported71. While slow evaporation is desirable to generate single crystals, extended evaporation times are a hindrance to progress. Various techniques can be used to accelerate the rate of evaporation during evaporative cocrystallization, with the aim of decreasing the process time required to yield cocrystals. Elevated temperature has been employed, where evaporation of methanol from a stoichiometric solution of ezetimibe and methyl paraben in methanol was conducted at 35 ºC using a water bath. Evaporation (to dryness) of an unspecified organic solvent from a solution of curcumin and phloroglucinol was achieved under vacuum using a rotary evaporator at 60 ºC to generate a powder cocrystal sample72.

2.2.2 Cooling Crystallization A

designed

seeded cooling crystallization was

used to

prepare cocrystals of

carbamazepine:nicotinamide from ethanol, in an effort to establish a scalable solution cocrystallization strategy73. Solvent selection, identification of the thermodynamically stable cocrystal operating range, and desupersaturation kinetics were considered in design of the process, which was demonstrated at 1 L scale with 90 % yield and 14 l.kg-1 throughout. A similar approach was taken by Holaň et al. in the preparation of agomelatine:citric acid cocrystals, and the impact of cooling rate and seed amount of the crystal size distribution in the final product assessed74. 2.2.3 Reaction Cocrystallization Reaction cocrystallization was used to produce cocrystals of carbamazepine:saccharin by combining individual feed solutions of either of the starting material75. The method was informed by the ternary phase diagram and illustrated a robust operating range for cocrystal formation, and demonstrated the expected relationship between supersaturation and induction time. Formation of carbamazepine:nicotinamide cocrystal was also done by reaction cocrystallization under ambient conditions.76.

2.2.4 Isothermal slurry conversion This technique involves the suspension of the target molecule and coformer, usually in a fixed molar ratio, in a solvent with the solid fraction always remaining in excess. In practical terms, the technique can also operate by adding the target molecule to a solution or 17 ACS Paragon Plus Environment

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suspension of coformer in solvent. While this is a solution based method, it does not require generation of a clear (fully dissolved) starting solution as is the case with the previous methods described above. The rate at which slurry conversion occurs will differ based on the solubility driving force, the relative concentrations of the target molecule and coformer, and the nucleation and growth kinetics of the system. There have been limited kinetic accounts of isothermal slurry conversion for any cocrystal system. Zhang et al. investigated the transformation time for theophylline to convert to a 1:1 glutaric acid cocrystal. Times ranging from 15 minutes to 5 hours were recorded for complete conversion depending on solution concentration and solvent selection. It was proposed that the transformation time to cocrystal decreases with increasing solubility in a given solvent. A. Jayasankar et. al directly investigated the impact of coformer concentration on the outcome of slurry conversion for the carbamazepine: 4aminobenzoic acid cocrystal. This system forms two cocrystals, a 1:1 and a 2:1 form. Equilibration of excess carbamazepine at low (0.1M) 4-aminobenzoic acid (4-ABA) concentration for an unspecified equilibration time yielded no cocrystal, pure carbamazepine persisted. The same experiment at 0.6M 4-ABA yielded the 2:1 co-crystal, and with excess 4ABA present the 1:1 cocrystal was formed. This relates to the position of the experimental composition on the ternary phase diagram, again reflecting the importance of a well-defined ternary phase diagram for a cocrystal system. The yield and productivity of isothermal slurry conversion can vary widely based on the operating conditions and concentrations, and can also be optimised through use of the TPD77. M. L. Cheney et. al showed that 96 % cocrystal yield was achieved for a slurry conversion of meloxicam with aspirin in 3 ml of tetrahydrofuran (THF) at ambient conditions overnight78. Croker et al. demonstrated the purity and process efficiencies that can be achieved with isothermal slurry conversion for the toluenesulphonamide:triphenylphosphine oxide cocrystal system

79

. Although the slurry

conversion method typically requires a greater amount of starting materials and will incur some material loss due to residual solubility in the solvent, it is considered as one of the most promising screening techniques due to its high efficiency.

2.3 Supercritical Fluid Methods Cocrystals have been successfully produced using supercritical fluid technology, primarily with the use of supercritical carbon dioxide (CO2), by three different approaches which focus on distinct supercritical CO2 properties: solvent, antisolvent and atomization enhancement80.

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2.3.1 Cocrystallization with Supercritical Solvent Cocrystallization with Supercritical Solvent (CSS) technique uses the solvent power of supercritical CO2 to suspend the API and the coformer as a slurry in liquid or supercritical CO2, avoiding the use of toxic organic solvents81. By controlling the thermodynamic conditions of CO2 (e.g. temperature, pressure), it is possible to fine-tune its density and solvent power which provides control over the cocrystallization between cocrystal components. L. Padrela et al. have compared the cocrystallization outcome of distinct APIs (e.g. indomethacin, theophylline, carbamazepine, caffeine, sulfamethazine and acetylsalicylic acid) with saccharin in liquid and supercritical CO282. Those authors have suggested that despite the usual low solubility of most cocrystal components (API and coformer) in CO2, cocrystallization is mediated by their dissolution in it. In particular, they have observed that by increasing the concentration of the cocrystal components in the CO2 phase, the cocrystallization rate is increased. In addition to this, stirring of the cocrystal components in the CO2 slurry promotes intense mas transfer by convection which was found to be paramount to achieve complete cocrystallization and obtain cocrystalline products with no traces of their starting components.

2.3.2 Rapid Expansion of Supercritical Solvents The Rapid Expansion of Supercritical Solvents (RESS) technique consists of the saturation of the supercritical fluid (supercritical CO2) with a solid substrate (API and coformer in the case of producing cocrystals) prior to the depressurization of the CO2 phase through a nozzle into a drying chamber at atmospheric pressure. Müllers et al. have used this process to produce microparticles of ibuprofen-nicotinamide cocrystals83. The main drawback of this technique is that the starting components (API and coformer) have to be soluble in supercritical CO2, as unfortunately most pharmaceutical molecules have a very low solubility in it.

2.3.3 Supercritical Antisolvent Cocrystallization Using supercritical CO2 as an antisolvent for cocrystallization works on the principle that solubility of API and coformer is reduced in supercritical CO2, allowing them to precipitate together in a cocrystalline structure. This approach has the potential to control the polymorphic form of the API or cocrystals produced82,

84, 85

. It has been used for the

production of cocrystals by two distinct techniques: (1) a batch Gas Antisolvent (GAS) process which involves saturating a solution containing the dissolved API and coformer inside a high pressure vessel with CO2 until cocrystallization occurs82,

84

and (2) a semi19

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continuous Supercritical Antisolvent (SAS) process which involves forcing a solution containing the dissolved API and coformer molecules through a nozzle into a high pressure vessel containing supercritical CO280. In both techniques, the CO2 dissolves in the solvent simultaneously expanding its volume and reducing it solubilizing ability, ultimately resulting in precipitation. Ober et al. demonstrated GAS in the formation of itraconazole-succinic acid cocrystals and compared the properties of the cocrystals thus formed, to those formed from conventional solution antisolvent cocrystallization84,

86

. Cocrystal structure and habit were

equivalent from both preparation methods but agglomeration properties were modified. GAS resulted in the formation of rosette type agglomerates which demonstrated enhanced dissolution profile relative to the spherulite agglomerates formed from liquid antisolvent. L. Padrela et al. demonstrated the SAS process for the formation of micron-sized needle and block-shaped particles of indomethacin-saccharin cocrystals80. Other authors have used the SAS process to produce naproxen-nicotinamide and diflunisal-nicotinamide cocrystals and have observed the CO2/solution flow ratio to have a paramount importance in the production of cocrystal-pure powders86, 87.

2.3.4 Supercritical CO2-Assisted Spray Drying Using supercritical CO2 as an atomization enhancer is based on the supercritical fluids’ ability to enhance the breakup of liquid jets into fine droplets when depressurized simultaneously with liquid solutions (Figure 6). This is a single-step process which consists of spraying a solution containing the dissolved starting cocrystal components through a nozzle with supercritical CO2 into a drying chamber at atmospheric pressure. Padrela et al. have used the Supercritical Enhanced Atomization (SEA) technique to produce micro- to nanosized cocrystals of theophylline with several coformers and fine-tune the cocrystal particles morphology and dissolution properties88, 89. Interestingly, this technique was also successfully used to generate microcomposites of theophylline-saccharin cocrystals dispersed in hydrogenated palm oil as a controlled release formulation90.

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Fig ure 6. Sch em atic diagram of the SEA apparatus. (1) CO2 cylinder; (2) liquid solution flask; (3) temperature controlled CO2 storage cylinder; (4) precipitator; (5) filter; (6) solvent trap; (7) detail of the nozzle cap; P, T, F: instruments for, respectively, pressure, temperature and flow measurements; and Tc is for temperature control and measurement (reprinted with permission from88)

The above methods represent the majority of standard approaches to cocrystal formation and are summarised in Table 1. Recently emerging preparation methods, which are relatively uncommon, are reviewed in section 2.4.

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Crystal Growth & Design

Table 1: Standard titles and definitions for common cocrystal preparation methods Category Standard Title

Also known as

Definition of method

Dry grinding for a

Neat grinding;

Combination of solid forms of

fixed period of time

Mechanochemical

both coformers for grinding –

and frequency

synthesis

manual/mechanical for a fixed period of time.

Liquid

assisted Solvent drop grinding;

Combination of solid forms of

grinding for a fixed Wet grinding;

both coformers in the presence

period of time and Kneading

of a very small amount of

frequency

solvent for grinding – manual/mechanical, for a fixed

Solid State Methods

period of time. Extrusion

Combination of solid forms of both

coformers

in

bespoke

extruder equipment; may be single/twin screw; may involve liquid binder Hot Melt Extrusion

Cocrystallization via applying heat and pressure to melt of API and

coformer

in

bespoke

extruder equipment High

Shear

Wet

Agglomeration

Granulation

via

a

liquid

medium in presence of a binder by exerting high shear on powder

mixtures

through

impellers and choppers.

Solution Based Methods

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

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Isothermal slurry

Slurry method; excess

Addition of solid forms of both

conversion

slurry method; slurry

coformers to a solvent/solvent

equilibration; slurry

mixture for a fixed period of

transformation; slurry

equilibration

conversion

remaining in excess for the

with

the

solid

duration Evaporative

Solution crystallization; Removal of solvent from an 22 ACS Paragon Plus Environment

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Cocrystallization

slow evaporation.

undersaturated solution of both coformers via evaporation at ambient conditions

Assisted

Solution crystallization; Removal of solvent from an

evaporative

slow evaporation.

cocrystallization

undersaturated solution of both coformers via evaporation at elevated

temperature

and/or

reduced pressure Spray drying

Fast removal of solvent from an undersaturated solution of both coformers

by

dispersing

it

through a nozzle using nitrogen Reactive

Solution

cocrystallization

Precipitation

method- (i)

Combination of individual

solutions of either coformers, or (ii) the addition of one solid coformer to a solution of the other coformer in a solvent, with the result of sudden spontaneous cocrystallization.

Cooling

Solution method;

Cocrystallization

cocrystallization

Direct Solution

solution of both coformers as a

crystallization

direct result of cooling

Solution crystallization

Cocrystallization

Anti-solvent cocrystallization

from

from

a

a

solution of both coformers as a direct result of the addition of a

Fluid Methods

solvent

Supercritical

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

Crystal Growth & Design

Cocrystallization

Supercritical slurry

Addition of a supercritical fluid

with supercritical

crystallization

to a mixture of solid forms of

solvent

both coformers for a fixed period of time

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Supercritical

anti- Gas anti-solvent

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Cocrystallization

from

a

solvent

(GAS); Supercritical

solution of both coformers as a

cocrystallization

anti-solvent (SAS)

direct result of the addition of a supercritical anti-solvent

Supercritical

Supercritical enhanced

Fast removal of solvent from an

assisted spray

atomization (SEA);

undersaturated solution of both

drying

Atomization and anti-

coformers

solvent (AAS)

through

by a

dispersing nozzle

it

using

supercritical CO2

2.4 Miscellaneous Cocrystal preparation 2.4.1 Laser Irradiation This method consists of using a high-power CO2 laser to irradiate powder blends of cocrystal formers and induce their recrystallization to a cocrystal structure. Titapiwatanakun et al. have used this method to produce caffeine cocrystal with oxalic acid and malonic acid91. Interestingly, these authors have found that the cocrystal formers need to sublime to a considerable extent for the cocrystallization to take place, which indicated that the mechanism of the molecular re-arrangement between API and coformer molecules and the nucleation of the cocrystal is likely to take place in the vapour phase.

2.4.2 Electrochemically Induced Cocrystallization Urbanus et al. demonstrated the potential of using cocrystallization combined with electrochemistry for in situ product removal of carboxylic acids92. Proof-of-principle was established using a cinnamic acid and 3-nitrobenzamide cocrystal system. This work showed that electrochemistry can be used to locally shift the pH to obtain neutral carboxylic acids and generate a local driving force for cocrystallization.

2.4.3 Resonant Acoustic Mixing Resonant acoustic mixing has been used to mix target molecule and coformer in the presence of liquid to form a cocrystal in the absence of any grinding media. In this method, mechanical energy is transferred acoustically into a wetted powder mixture, encouraging intimate mixing

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Crystal Growth & Design

of the components. A range of carbamazepine cocrystals were successfully produced using a labRAM resonant acoustic mixer operating at 80 – 100G and 60Hz. The cocrystal products were isolated at a range of laboratory scales: 100mg, 1.5 g and 22 g, and the technology appeared amenable to scale-up93.

2.4.4 Spray drying Spray drying is a continuous single-step method of transformation of liquids (solutions, suspensions, slurries) to solid powders94-96. It is advantageous due to its continuous, highly controllable and fast process. Although spray drying has been widely used in formulating amorphous solid dispersions because of the fast solidification process, it has also been employed in synthesis of cocrystals97. Alhalaweh et al. spray dried several combinations of API-coformer with the aim of cocrystallization. They claim that cocrystallization has been observed in highly supersaturated regions of drug due to the rapid solvent evaporation, presence of coformer or interaction between drug and coformer in liquid form98. Another application of spray drying to generate pharmaceutical cocrystal was done to prepare Carbamazepine–Nicotinamide cocrystal (CNC) (1:1). Also, it was proved that TPD can be used for formation of cocrystals by industrially feasible spray drying methods99. Spray drying can also be used to produce cocrystals embedded in an excipient matrix with enhanced rheological properties. Walsh et al. have demonstrated the production of cocrystals (sulfadimidine as the poorly soluble model API and 4-aminosalicylic acid as the coformer) by spray drying in the presence of a third component (excipient matrix)100. It was found that a larger difference in HSP (Hansen Solubility Parameters) between the cocrystal components and the excipient promotes cocrystal formation during spray drying in the presence of a carrier excipient, as the cocrystal components will not be miscible with the excipient. This leads to the cocrystal components (API and coformer) remaining phase separated from the excipient but still interacting/cocrystallizing with each other, generating a cocrystal phase embedded in excipient matrix. The compaction properties of these co-spray dried (sulfadimidine and 4-aminosalicylic acid with excipient) cocrystal systems were notably improved compared to the spray dried (sulfadimidine and 4-aminosalicylic acid without excipient) cocrystals, due to less sticking characteristics.

2.4.5 Freeze Drying Freeze-drying, technically known as lyophilisation, has been mostly used as a processing technique to preserve a wide variety of products, which include food and pharmaceuticals. 25 ACS Paragon Plus Environment

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This process works by freezing the material and then reducing the surrounding pressure to allow the frozen water in the material to sublime directly from the solid phase to the gas phase. It has also has been demonstrated recently to be a feasible method for the preparation of new solid forms of cocrystal systems101. Eddleston et al. prepared a new form of the theophylline:oxalic acid cocrystal using freeze drying. Cocrystallization takes place via an amorphous phase that is generated as solvent sublimes during the freeze-drying process.

2.4.6 Electrospray Technology Electrospraying is a process of simultaneous droplet generation and charging by means of an electric field. In this process, a solution containing the dissolved substances flows out from a capillary nozzle, which is maintained at high potential, through an electric field, which causes elongation of the solution droplets to form a jet. The solution jet is dried and the generated particles are collected on a charged powder collector. Patil et al. demonstrated the potential of this process to generate cocrystals of carbamazepine and itraconazole with different coformers102.

3.0 Cocrystal Application Areas Cocrystal formation results in a new crystal structure, which is entirely independent to any of the starting materials. This new crystal structure imparts a new set of physical properties, also independent of and indifferent to the physical properties of any of the starting materials. Currently the crystal structure and resulting physical properties of a cocrystal cannot be predicted from any property of the starting materials. As a result of potential physical property improvements, cocrystal applications are many and continue to grow.

3.1 Solubility By far the most prolific utility of cocrystals to-date has been to improve the solubility of the starting material, particularly when that starting material is an active pharmaceutical ingredient. Low aqueous solubility is a barrier to satisfactory drug delivery, and, as such, often prevents a medicine from being fit for purpose. Inherently a cocrystal will have a different solubility that of either of the starting materials due to the altered underlying crystal structure. The solubility alteration can be in either direction. Enhanced solubility is desirable, as it will improve the bioavailability of the drug, but excessive enhancement can be problematic as it can lead to undesirable precipitation of the starting material due to the

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generation of a supersaturated solution23. This has been characterised for cocrystal materials as a “spring and parachute” effect103 (Figure 7).

Figure 7. The spring and parachute concept to achieve high apparent solubility for insoluble drugs. (1) The crystalline (stable) form has low solubility. (2) A short-lived metastable species (i.e., amorphous phase) shows peak solubility but quickly drops (within minutes to an hour) to the low solubility of the crystalline form. (3) Highly soluble drug forms are maintained for a long enough time (usually hours) in the metastable zone (reprinted with permission from 103).

Zheng et al. reported improved solubility of resveratol upon cocrystallization with 4aminobenzaamide and isoniazid104. Hu et al. demonstrated an increase in aqueous solubility from 7.5 mg/L febuxostat to 571 mg/L for a febuxostate:arginine cocrystal105, showcasing the potential physical property modification that can be achieved with cocrystals. Perlovich and co-authors demonstrated that cocrystals can improve or reduce solubility as a function of the coformer for 4 aminosalicyclic acid106. Cocrystallization with isoniazid, caffeine, pyranzinamide, nicotinamide and isonicotinamide resulted in cocrystals (sometimes hydrated) which increased aqueous solubility at pH 2.0 by at least a factor of 2, while cocrystallization with theophylline was found to reduce the solubility by half in the same

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solution. This was due to partial cocrystal disintegration back to original starting materials in solution. There are many other accounts of improved solubility upon cocrystal formation available in literature, but it is worth recalling the true nature of solubility as we consider the cocrystal solubility impact. Solubility is a thermodynamic measure of the amount of a solute that can be contained in a given volume of solvent at fixed conditions (temperature and pressure). The presence of impurities in the solvent or solute will affect solubility measurements. In the case of cocrystals, the coformer can be considered as an impurity, and therefore be expected to alter the solubility of the starting material. This is often not accounted for in reported solubility measurements where cocrystal solubility is compared to the starting material solubility in the pure solvent. To compare like with like, it is more accurate to compare the solubility of the cocrystal with the solubility recorded for the equivalent physical mixture, or at least in the presence of some known concentration of the coformer. The expected impact of the coformer on cocrystal solubility is lacking in the majority of published account. An extensive study by Pastore et al. addressed this exact issue in 2015 by comparing the solubility, dissolution and permeability characteristics of raw carbamazepine with three of its cocrystals (vanillin, succinc acid and nitropyridine N-oxide) and their respective physical mixtures. The authors concluded that the physical mixtures were distinct from the cocrystal material verifying the pharmacological impact of cocrystal materials107. The collective work of Rodriguez-Hornedo has also extensively addressed cocrystal solubility, and has proposed the concept of a solubility product, Ksp, which takes into account the relative concentrations of both cocrystal formers during cocrystal dissociation in a solvent 108.

‫ܭ‬௦௣ = [‫]ܣ‬௔ [‫]ܤ‬௕ when activity coefficients taken as unity;superscripts refer to the stoichiometric number of molecules of a/b in the cocrystal. The solubility product reflects the strength of cocrystal solid state interactions of drug and ligand relative to interactions with the solvent and is also correlated to solubility, with a higher Kspindictaing higher cocrystal solubility109.

3.2 Bioavailability Cocrystals bear the potential to enhance the delivery and clinical performance of drug products by modulating drug solubility, pharmacokinetics and bioavailability. Particularly, using cocrystals to improve oral drug absorption of BCS class II and IV drugs has been a strong focus of several case studies published in the literature. Stanton et al. have compared

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Crystal Growth & Design

the improvement on the solubility and pharmacokinetics of AMG 517, a potent and selective transient receptor potential vanilliod 1 (TRPV1) antagonist, when cocrystallizing this drug with carboxylic acid (cinnamic acid and benzoic acid and amide coformers (cinnamamide and benzamide))110. All four AMG517 cocrystals showed faster intrinsic and powder dissolution rates in fasted simulated intestinal fluid than the free base of AMG 517. The results on the pharmacokinetics showed a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations, which highlights the improvement in bioavailability of AMG 517 when in a cocrystalline form. Other studies have demonstrated the efficiency of cocrystallization in improving the solubility and bioavailability of poorly soluble APIs such as indomethacin111, baicalein 112and quercetin113. Interestingly, polymers and other excipients can provide a huge contribution to improving the bioavailability of cocrystals by acting as crystallization inhibitors and prolonging the supersaturation concentration of cocrystals during dissolution. This approach is particularly important in situations where the cocrystal transforms rapidly to a low-solubility form of the drug and is unable to maintain desired solubility levels necessary to ensure optimal absorption. Childs et al. improved the solubility and bioavailability of a danazol:vanillin cocrystal by using an appropriate formulation containing a combination of cocrystal, a solubilizer (1% vitamin E-TPGS (TPGS)) and a precipitation inhibitor (2% Klucel LF Pharm Hydroxypropylcellulose)114. This formulation resulted in a high improvement in the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. Another example of cocrystals that undergo rapid precipitation during dissolution and form a dihydrate form of the parent drug in aqueous media is dihydromyricetin-caffeine and dihydromyricetin-urea cocrystals. Wang et al have improved the bioavailability of these cocrystals by inhibiting the precipitation of dihydromyricetin using polyvinylpyrrolidone K30 as a crystallization inhibitor115. Approximately five-fold enhancement in oral bioavailability of dihydromyricetin was achieved when both cocrystals were dosed with 2.0 mg/mL polyvinylpyrrolidone K30 solution compared to dihydromyricetin dihydrate suspended in a similar same dissolution medium.

3.3 Controlled Release Cocrystallization provides an opportunistic approach to modulate the physicochemical properties of pharmaceutical drugs, which include solubility and dissolution rate. Particularly, depending on the coformer that cocrystallizes with the API, the dissolution rate of the API in water or a buffer solution can be increased or decreased over time. Carbamazepine-cinnamic 29 ACS Paragon Plus Environment

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acid cocrystals synthesized by solvent evaporation showed a higher dissolution rate, solubility and stability in water compared to carbamazepine

116

. Arenas-Garcia et al.

produced several cocrystals of acetazolamide (ACZ) with enhanced intrinsic dissolution rates when compared to pure ACZ in a medium simulating physiological conditions (HCl 0.01N, pH 2.0)117. The cocrystals which provided the largest dissolution rates were those which showed the poorest solid-state stability in the same medium by initially undergoing solvent mediated phase transformation. Cocrystals also bear the potential to reduce the dissolution rate of the original APIs. Chen et al. used the cocrystallization approach to sustain the dissolution behaviour of ribavirin, a water-soluble antiviral drug118. These authors demonstrated that the release rate of ribavirin can be manipulated over a wide range by the formation of cocrystals, which may subsequently help lower its peak-to-trough fluctuation in plasma concentrations. Padrela et al. used a supercritical fluid enhanced atomization (SEA) process, which is a nano spray drying method that uses the atomization potential of supercritical CO2 to disperse and dry a drug solution through a coaxial nozzle, to produce micro to nano-sized cocrystals of theophylline with several coformers

119

. The authors found that the solubility of each

coformer in the dissolution medium (phosphate-buffered saline, pH 7.4 at 25◦C) could determine the dissolving rate behaviour of the produced cocrystals. Consequently, lowsoluble coformers provided TPL cocrystals with slow-dissolving rates, while -highly-soluble coformers provided faster-dissolving TPL cocrystals. Tiago et al. reduced the dissolution behaviour and improved the solid state stability of theophylline by generating cocrystals of this drug with saccharin dispersed in a lipid using the SEA process90. The dissolution of theophylline was further improved when theophyllinesaccharin cocrystals (TPL-SAC) were formed and dispersed in hydrogenated palm oil (HPO) during the SEA processing. The SEA process provided improvement of TPL stability and delivery by single-step micronization, co-crystallization and encapsulation. Depending on the ratio of TPL-SAC to HPO, the dissolution rate of TPL could be further sustained over time with increasing proportions of HPO in the TPL-SAC-HPO microcomposites. In addition to this, the TPL-SAC-HPO microcomposite particles were able to attenuate the TPL burst effect. The presence of polymers in the dissolution media might also impact the supersaturation level and dissolution rate of cocrystals. Guo et al. have studied the impact of the presence of different polymers (polyethylene glycol (PEG), polyvinylpyrrolidone

(PVP), and

polyvinylpyrrolidone/vinyl acetate (PVP-VA)), which have been pre-dissolved in a solution 30 ACS Paragon Plus Environment

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media, have on the dissolution behaviour of flufenamic acid-theophylline (FFA-TPL) and flufenamic acid-nicotinamide (FFA-NCT) cocrystals120. It was demonstrated that by controlling the dissolution environment with the presence of a certain polymers, such as PVP or PVP-VA, which can interact with the crystal surface to alter its dissolution properties, the solubility and dissolution rates of FFA-TPL and FFA-NIC cocrystals is significantly improved.

3.4 Multidrug Cocrystals Combining multiple active pharmaceutical ingredients (APIs) into one unit dose has become a popular trend in drug formulation industry. The need to target multiple receptors for effective treatment of complex disorders such as HIV/AIDS, cancer and diabetes in addition to the increasing demand for facilitating the reduction of drug manufacturing costs are the two main reasons for this growing trend. Salts, mesoporous complexes, co-amorphous systems, and cocrystals are systems which have been used for combining multiple APIs in a single delivery system121. Multidrug cocrystals (MDCs) are advantageous compared to coamorphous systems in terms of their enhanced stability and in terms of their reduced payload compared to the mesoporous and cyclodextrin complexes. Thipparaboina et al. defined the MDCs as ‘dissociable solid crystalline supramolecular complexes comprising two or more therapeutically effective components in a stoichiometric ratio within the same crystal lattice, wherein the components may predominantly interact via nonionic interactions and rarely through hybrid inter- actions (a combination of ionic and nonionic interactions involving partial proton transfer and hydrogen bonding) with or without the presence of solvate molecules122-124. MDC could offer potential advantages compared to the pure drug components such as: enhanced solubility and dissolution of at least one of the components125, 78

126

, enhanced

bioavailability , improved stability of unstable APIs via intermolecular interactions127,

128

increased mechanical strength and flowability. MDC formulation of ethenzamide and gentinsic acid was reported with improved intrinsic dissolution rate. Meloxicam and aspirin containing MDC was developed with 12-times decrease in the time to reach the therapeutic concentrations and fourfold bioavailibity enhancement. An extensive list of MDCs can be found elsewhere129. On the other hand, there are examples of MDCs with lower intrinsic dissolution rates compared to pure APIs. Kaur et al. reported the MDC of two antoconvulsants, lamotrigine and phenobarbital. The two molecules form heterodimers through hydrogen binding. Dissolution studies in phosphate buffer (pH 7.2) revealed 31 ACS Paragon Plus Environment

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decreased dissolution rate of cocrystal in the order of pure phenobarbital > pure lamotrigine > cocrystal130. So far, no computational approach has been developed for predicting and/or screening of MDC formulations. Thus, prediction and screening of the potential MDC formulations mostly follows the knowledge-based approach which includes hydrogen-bond tendency, pKa studies, use of synthons and molecular descriptor. In synthon engineering is all about studying the structural units within the supermolecules that are capable of forming intermolecular interactions. Carboxylic acid dimers, acid-pyridine, phenol-pyridine, and phenol-carboxylic acid are the most frequently seen synthons131. Moreover, Cambridge Structural Database (CSD) could be used to screen the possible hydrogen-bondings and synthon competitions132. pKa was used as a simple tool for prediction of cocrystal formation. It was shown that generally difference between pKa base and pKa acid (∆pKa) >3 leads to the formation of salts, while ∆pKa < 0 results in cocrystal formation. More modifications have been made to the use of ∆pKa as a measure of cocrystal formation by Cruz Cabeza et al. where they studied 6465 crystalline structure in CSD and validating and measuring their ∆pKa. They found a linear relationship between the possibility of proton transfer between acid-base pairs and the ∆pKa 133

.

Main techniques of cocrystal synthesis have been used for preparing MDCs as well. These techniques include distillation, solvent evaporation, neat and liquid-assisted grinding, slurry reaction, melting and cooling crystallization. Scale-up techniques such as spray-drying 99, hot melt extrusion134, twin screw extrusion51 and high shear granulation63 have been used for scale-up production of cocrystals. The MDC formulation approach has been evolved a lot from exploring different combinations of APIs yet more efforts are required for selection for therapeutically relevant APIs that could be beneficial to the patients and pharmaceutical industry. Moreover, more efforts are required in terms of predictive modelling of the cocrystallization process of two APIs. 3.5 Mechanical Properties Enhancement Tableting is the most popular pharmaceutical dosage form due to its numerous technical and economic advantages. Low manufacturing cost, high production throughput, ease of consumption, storage and handling are some of these benefits135. However, several deficiencies caused by poor flowability and mechanical properties have always been a difficulty along the way of successful tablet production. 32 ACS Paragon Plus Environment

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Several strategies have been employed to address these issues during formulating process of APIs. Adding silicon dioxide for increasing mechanical strength of tablets and magnesium stearate for improved flowability are some of these techniques. Cocrystallization has been also investigated as a technique to improve chemical and physical properties of powders including mechanical strength and flow properties. For instance, compression properties of paracetamol form I has been improved by cocrystallization with theophylline, oxalic acid, naphthalene and phenazine136. Hiendrawan et al. obtained cocrystal of paracetamol and 5nitroisophtalic acid by solvent evaporation method. The tableting experiments showed that the formed cocrystal has superior tabletability properties compared to both paracetamol and coformer137. Carbamazepine and saccharin cocrystal was shown to be denser compared to pure carbamazepine. Moreover, higher tensile strength compared to pure carbamazepine was obtained at any compaction pressure. Heckel analysis of the carbamazepine and cocrystal revealed that plastic deformation in cocrystal was started at lower compression leading to higher compaction138.

3.6 Taste Masking Quick disintegrating tablets with rapid dissolution are required for preparing oral disintegrating tablets. This strategy enables the use of tablets without the need for chewing or water intake which broadens the spectrum of the drug users to geriatric, pediatric and travelling patients with no access to water. However, readily disintegrating tablets necessitate the use of taste masking agents to improve the patients’ experience. So far, the use of sugarbased excipients has been the main approach. On the other hand, poor dissolution rate can be another limiting factor in developing oral disintegrating formulations. Thus, greater advantage could be achieved using an approach for improving dissolution with tablet sweetening agents. Cocrystallization could be a promising strategy for improving dissolution rate using sugarbased coformers. Arafa et al. have done so by using sucralose as coformer for preparing cocrystals of hydrochlorothiazide. The produced cocrystal got the benefits of increased dissolution rate and taste masking, simultaneously139. Maeno et al. reported a new cocrystal of paracetamol with trimethylglycine (TMG) with improved tabletability, compression and dissolution properties. Moreover, the taste sensing experiments revealed the sweetness of the formulation due to the presence of TMG in the structure140. Theophelline is known for its bitter taste, hence current marketed solid and oral formulations have been formulated using artificial sweeteners such as vanilla, sodium glutamate, sodium saccharin and d-sorbitol. A 33 ACS Paragon Plus Environment

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1:1 stoichiometric cocrystal of theophelline and saccharine was prepared via liquid assisted grinding. The prepared cocrystal showed enhanced dissolution and sweetness at the same time based on the automated sweetness tasting machine used in this study141. Nine cocrystals of propiverine were generated by mixing it with organic acid solutions. The results of the use of taste sensor showed that propiverine salicylic acid cocrystals are less bitter than propiverine hydrochloride. The authors illustrated both improved aqueous solubility and taste masking, simultaneously142.

3.7 Enabling in process separation and purification Lee et al. demonstrated a continuous cocrystallization process at 90 ml/min scale for the manufacture of phenazine-vanillin cocrystals for the purpose of preferentially separating 143

vanillin from its mother liquor

. Billot et al. reported on an slurry based method for

manufacture of an API cocrystal at pilot plant scale to provide for purification of the API, with subsequent cleavage of the cocrystal to release the API product also demonstrated11.

3.8 Generation/Extension of Intellectual Property Intellectual property (IP) is vital for pharmaceutical companies. IP protection of new ideas, inventions, processes or products enable the exclusivity on the manufacture and commercialization of pharmaceutical services or products. IP is protected in law by, for example,

patents,

copyright

and

trademarks,

which

enable

individuals

or

organizations/companies to earn recognition or financial benefit from their own work or investment in a creation. Specifically, patents are a recognition for an invention, which must satisfy the criteria of global novelty, non-obviousness, and industrial or commercial application. Patent life cycle management of drugs or drug products is a critical activity that pharmaceutical companies have to deal with to ensure they keep their drugs in the market as long as possible. Screening of novel solid forms of marketed drugs, including polymorphs, salts and cocrystals provides the opportunity to grant new IP on those drugs and extend their patent life cycle144. Pharmaceutical cocrystals possess regulatory and IP advantages which confer them with unique opportunities, advantages and challenges

145, 146

. FDA has recently issued a revised

draft guidance on the classification of pharmaceutical cocrystals for industry, which states that from a regulatory perspective, drugs designed to contain a new co-crystal are considered analogous to a new polymorph of the API. This guidance takes novel cocrystals to be considered as new drug substances rather than drug product intermediates, which promotes 34 ACS Paragon Plus Environment

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their independent patentability as novel solid forms. Cocrystals bear also the potential to provide meaningful IP extension to existing drugs in the market after the expiration of the original patent, playing an important role in drug lifecycle management. Figure 8 shows an increasing trend in patent submissions for novel cocrystals and cocrystal preparation methods between 2004 and 2017.

Figure 8. Trend of co(-)crystals in WIPO patent database from 2004 until December 2017.

Cocrystals possess also important scientific advantages. Some of these advantages link to the availability of a wide number of potential complementary molecules (coformers) to cocrystallize with the drug molecules. This maximizes the number of new cocrystals that might be discovered for a particular drug with suitable physicochemical properties (e.g. solubility, bioavailability, physical stability) 2. As neither the API of coformer need to have ionisable functional groups in their molecular structures, which is a prerequisite for salt formation, this opens up a larger array of possibilities for the generation of novel solid state forms of APIs as cocrystals. That in turn promotes the possibility for IP extension of existing drugs currently in the market.

4.0 Conclusions Cocrystallization offers one of the most promising approaches to improve physicochemical properties of APIs. A wide range of options exist to prepare cocrystals ranging from routine 35 ACS Paragon Plus Environment

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lab scale synthesis methods to potentially large scale continuous production methods. This review offers standard descriptions and examples of established and emerging cocrystal preparation routes. Moreover, detailed insight is given on the proposed mechanisms of cocrystallization in different techniques. As cocrystals continue to gain interest and prove their value, the range of demonstrated cocrystal application areas continues to expand. All demonstrated application areas for pharmaceutical cocrystals are included in this review with the aim of highlighting the wide ranging potential of these materials. It is anticipated that cocrystals will become more and more routine in pharmaceutical development as their benefits continue to be demonstrated and routine routes of manufacturing are proven.

Acknowledgements The authors acknowledge Science Foundation Ireland for supporting the work undertaken at the Synthesis and Solid State Pharmaceutical Centre (Grants SFI SSPC2 12/RC/2275 and 15/US-C2C/I3133).

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(121) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N., Polymorphs, salts, and cocrystals: What’s in a name? Crystal growth & design 2012, 12, (5), 2147-2152. (122) Sarkar, A.; Rohani, S., Molecular salts and co-crystals of mirtazapine with promising physicochemical properties. Journal of pharmaceutical and biomedical analysis 2015, 110, 93-99. (123) Mahieux, J.; Gonella, S.; Sanselme, M.; Coquerel, G., Crystal structure of a hybrid salt– cocrystal and its resolution by preferential crystallization:((±) trans-N, N′dibenzyldiaminocyclohexane)(2, 3-dichlorophenylacetic acid) 4. CrystEngComm 2012, 14, (1), 103111. (124) Kelley, S. P.; Narita, A.; Holbrey, J. D.; Green, K. D.; Reichert, W. M.; Rogers, R. D., Understanding the effects of ionicity in salts, solvates, co-crystals, ionic co-crystals, and ionic liquids, rather than nomenclature, is critical to understanding their behavior. Crystal Growth & Design 2013, 13, (3), 965-975. (125) Sanphui, P.; Goud, N. R.; Khandavilli, U. R.; Nangia, A., Fast dissolving curcumin cocrystals. Crystal Growth & Design 2011, 11, (9), 4135-4145. (126) Aitipamula, S.; Chow, P. S.; Tan, R. B., Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs. CrystEngComm 2009, 11, (9), 1823-1827. (127) Chadha, R.; Saini, A.; Arora, P.; Jain, D. S.; Dasgupta, A.; Guru Row, T. N., Multicomponent solids of lamotrigine with some selected coformers and their characterization by thermoanalytical, spectroscopic and X-ray diffraction methods. CrystEngComm 2011, 13, (20), 6271-6284. (128) Luszczki, J. J.; Czuczwar, M.; Kis, J.; Krysa, J.; Pasztelan, I.; Swiader, M.; Czuczwar, S. J., Interactions of Lamotrigine with Topiramate and First-generation Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis. Epilepsia 2003, 44, (8), 1003-1013. (129) Thipparaboina, R.; Kumar, D.; Chavan, R. B.; Shastri, N. R., Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug discovery today 2016, 21, (3), 481-490. (130) Kaur, R.; Cavanagh, K. L.; Rodríguez-Hornedo, N.; Matzger, A. J., Multidrug Cocrystal of Anticonvulsants: Influence of Strong Intermolecular Interactions on Physiochemical Properties. Crystal Growth & Design 2017. (131) Desiraju, G. R., Supramolecular synthons in crystal engineering—a new organic synthesis. Angewandte Chemie International Edition 1995, 34, (21), 2311-2327. (132) Khan, M.; Enkelmann, V.; Brunklaus, G., O− H··· N heterosynthon: a robust supramolecular unit for crystal engineering. Crystal Growth and Design 2009, 9, (5), 2354-2362. (133) Cruz-Cabeza, A. J., Acid–base crystalline complexes and the p K a rule. CrystEngComm 2012, 14, (20), 6362-6365. (134) Dhumal, R. S.; Kelly, A. L.; York, P.; Coates, P. D.; Paradkar, A., Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharmaceutical research 2010, 27, (12), 27252733. (135) Perumalla, S. R.; Sun, C. C., Enabling Tablet Product Development of 5-Fluorocytosine Through Integrated Crystal and Particle Engineering. Journal of pharmaceutical sciences 2014, 103, (4), 1126-1132. (136) 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. Advanced materials 2009, 21, (38-39), 3905-3909. (137) Hiendrawan, S.; Veriansyah, B.; Widjojokusumo, E.; Soewandhi, S. N.; Wikarsa, S.; Tjandrawinata, R. R., Physicochemical and mechanical properties of paracetamol cocrystal with 5nitroisophthalic acid. International journal of pharmaceutics 2016, 497, (1), 106-113. (138) Rahman, Z.; Samy, R.; Sayeed, V. A.; Khan, M. A., Physicochemical and mechanical properties of carbamazepine cocrystals with saccharin. Pharmaceutical development and technology 2012, 17, (4), 457-465.

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(139) Arafa, M. F.; El-Gizawy, S. A.; Osman, M. A.; El Maghraby, G. M., Sucralose as co-crystal coformer for hydrochlorothiazide: development of oral disintegrating tablets. Drug development and industrial pharmacy 2016, 42, (8), 1225-1233. (140) Maeno, Y.; Fukami, T.; Kawahata, M.; Yamaguchi, K.; Tagami, T.; Ozeki, T.; Suzuki, T.; Tomono, K., Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former. International journal of pharmaceutics 2014, 473, (1), 179-186. (141) Aitipamula, S.; Wong, A. B.; Kanaujia, P., Evaluating Suspension Formulations of Theophylline Cocrystals with Artificial Sweeteners. Journal of Pharmaceutical Sciences 2017. (142) Ogata, T.; Tanaka, D.; Ozeki, T., Enhancing the solubility and masking the bitter taste of propiverine using crystalline complex formation. Drug development and industrial pharmacy 2014, 40, (8), 1084-1091. (143) Lee, T.; Chen, R. H.; Lin, H. Y.; Lee, H. L., Continuous co-crystallization as a separation technology: The study of 1:2 co-crystals of phenazine-vanillin. Crystal Growth & Design 2012, 12, (5897-5907). (144) Newman, A.; Wenslow, R., Solid form changes during drug development: good, bad, and ugly case studies. AAPS Open 2016, 2, (1), 2. (145) Trask, A. V., An Overview of Pharmaceutical Cocrystals as Intellectual Property. Molecular pharmaceutics 2007, 4, (3), 301-309. (146) Gadade, D. D.; Pekamwar, S. S., Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development. Advanced Pharmaceutical Bulletin 2016, 6, (4), 479-494.

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For Table of Contents Use Only



Creating Cocrystals: A review of Pharmaceutical Cocrystal Preparation Routes and Applications Maryam Karimi-Jafari, Luis Padrela, Gavin M. Walker, Denise M. Croker Synthesis & Solid State Pharmaceutical Centre (SSPC), Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick, Ireland

Cocrystallization through various methodologies leads to improved physicochemical properties of active pharmaceutical ingredients. Different solution based and solid based techniques can be used for preparing cocrystals. This process will most likely result in enhanced bioavailability, flowability, solubility and tabletability.

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