Protonic Speaking ~ Powerfully Express your Potential

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On the continuum of long-range order, however, eutectics and cocrystals occupy opposite positions. A crystal is defined by its long-range order. In contrast, the eutectic lacks long-range order. Whether a cocrystal or a eutectic will result from a non-covalent derivatization depends on the predominant thermodynamic force. A cocrystal will result when the enthalpic advantage outweighs any entropy loss due to ordering.

On the other hand, the eutectic will predominate when the entropy gain outweighs the potential enthalpy gain of an ordered crystal. The conditions for this entropic vs. In cases where the functional groups are compatible for effective non-covalent bonding and the size and shape of the parent molecules favor crystal packing, a cocrystal will result.

In cases where the non-covalent bonding is favored but there is little or no packing shape compatibility of the parent molecules, then the binding forces predominate and a eutectic is produced [ 18 ]. Compared to traditional synthetic modifications, the preparation of NCDs is an alternative that can be less toxic, produce less waste, be less labor-intensive and more economical when used to affect the same types of property changes [ 3 ]. A variety of solvent methods can be used to prepare NCDs.

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Cocrystal preparation has been reported using traditional methods of precipitation [ 19 , 20 , 21 , 22 ], cooling crystallization [ 23 , 24 ] and slurry formation [ 25 ]. Evaporation [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] has emerged as the most common solvent-based method for the preparation of cocrystals [ 34 ]. The preparation of eutectics has also been reported using solvent evaporation [ 35 , 36 ]. Solvent-based preparation methods for NCDs have significant limitations.

All the NCD partners are required to have a solubility relationship with the solvent that allows for effective dissolution followed by concurrent precipitation as the solution cools or evaporates. Since those first works, solid-state grinding has become a well-established method for the preparation of NCDs. A large number of examples can be found in the literature describing the grinding of neat solids via mortar and pestle or automated grinders to produce cocrystals [ 20 , 37 , 38 , 39 , 40 ] and eutectics [ 41 , 42 ].

There are three mechanisms recognized to be in effect during grinding in the solid state: grind molecular diffusion, eutectic formation, and cocrystallization mediated by amorphous phase [ 43 ]. Grind molecular diffusion is described as a process by which the surface of the solid is made mobile either by vaporization or energy transfer to the surface of the solids.

In the case of the eutectic, the eutectic liquid is first formed which then crystallizes to the final solid. Lastly, the cocrystal is described as coalescing out of the amorphous phase of the parent solids. The addition of catalytic amounts of solvent to the grinding matrix has been shown to improve the efficiency of preparation [ 44 ] and increase the crystallinity of the final cocrystal product [ 45 ].

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These observations and subsequent studies [ 43 ] have led to the common practice of liquid-assisted grinding LAG , originally referred to as solvent drop grinding, for the preparation of NCDs [ 46 , 47 , 48 ]. In a study comparing method preparations, it was demonstrated that it was possible to prepare the same carbamazepine cocrystals achieved with evaporation by means of solvent-assisted grinding [ 49 ]. In addition, grinding can produce cocrystals that are not available by solvent-based methods [ 20 , 50 ].


The spray-dry evaporation technique has also been used to produce different cocrystal forms from the same parent compounds [ 51 ]. Cocrystals of urea and succinic acid when prepared with spray drying produced a previously unidentified cocrystal structure, having a 1-to-1 molar ratio and a laminar sheet form.

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These same materials, with other preparation methods, produced a 2-to-1 urea-to-succinic acid structure with a complex three-dimensional structure that contains two ring-structure repeat units. The two cocrystal forms had different stabilities and dissolution rates. This study is indicative of the versatility of NCD formation, not only in choice of materials, but also in the choice of method in order to produce tailored NCDs.

The practical industrial manufacture of cocrystals has yet to be fully exploited because the most common methods for the preparation of cocrystals, solid-state grinding or slow evaporation, do not lend themselves easily to scaling up. Several references discuss large batch cooling crystallization for the preparation of cocrystals facilitated by the preparation of ternary phase diagrams for the interaction of coformers and the solvent [ 52 , 53 ]. In another promising example, the formation of carbamazepine CBZ -trans-cinnamic acid cocrystals, in stoichiometric ratios, was reported using continuous hot melt extrusion [ 54 ].

In a similar set of studies, CBZ-nicotinamide cocrystals were prepared in the presence of a polymer matrix using hot melt extrusion [ 55 ].

Another interesting option for large scale production is demonstrated through the preparation of cocrystals through vapor deposition of triiodotrifluorobenzene onto a layer of 1,4-bis- E pyridinyl vinyl benzene [ 56 ]. A wide variety of single crystal structures of cocrystals can be found in the literature [ 26 , 57 , 58 , 59 , 60 , 61 , 62 ]. This crystal structure analysis is the most direct and conclusive method for NCD characterization. However, a cocrystal of the appropriate size for single crystal analysis is oftentimes not achievable, particularly when grinding is used for preparation.

In these cases, powder X-ray diffraction PXRD has been used as an alternative characterization technique. Indexing software was used to identify the crystal structures from the PXRD data of theobromine cocrystals with either trifluoroacetic acid or malonic acid [ 63 ]. Because PXRD alone cannot differentiate between hydrates, solvates, and cocrystals, the data is often considered in conjunction with another analysis method [ 64 ].

For example, by combining PXRD, nuclear magnetic resonance NMR and theoretical calculations, theophylline-nicotinamide cocrystal structures were solved from the powder cocrystal data [ 65 ].

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These methods are not generally predictive of the structure of the cocrystal or eutectic, but can, by the appearance of novel peaks in the spectra, indicate the presence of novel interactions in the NCD that are not seen in the pure parent compounds. In one example, terahertz spectroscopy was used to follow the mechanochemical construction of a two-component cocrystal that was made by grinding together phenazine and mesaconic acid [ 38 ].

In some cases, especially those where the coformer is a carboxylic acid, infrared IR spectroscopy can be used because the frequency of some stretches will change when in a cocrystal environment [ 66 ]. Raman spectroscopy has also proven to be an effective tool for NCD analysis as exemplified by the analysis of cocrystals prepared from salicylic acid and a series of coformers [ 67 ]. DSC thermal data for eutectic mixtures results in a classic V shape where the minimum point of the V represents the molar ratio and temperature at the eutectic point.

By contrast, the binary-phase diagram for a cocrystal exhibits a more complex behavior which contains two eutectic points and a region of cocrystal at the maximum between the two eutectic points. This results in a typical W-shaped phase diagram for cocrystals [ 69 , 70 , 71 ]. Microscopy has also been used to indicate the formation of a cocrystal, though this method can only indicate a significant change in morphology. In one example, the interface of cocrystal preparation for lamotrigine and phthalimide was observed by hot-stage microscopy [ 72 ].

In another study, atomic force microscopy AFM was used to differentiate between two forms of caffeine-glutaric acid cocrystals [ 73 ]. Because of their versatility, NCDs have useful applications in a wide variety of areas.

In the early s, one of the earliest industrial patents with NCDs demonstrates the use of non-covalent derivatives applied to the development process of instant film [ 74 ]. NCDs were used to alleviate the problem of labile hydroquinone that leads to premature aging and diffusion between photographic film layers.

Based on the naturally occurring quinhydrone NCD, cocrystals between hydroquinone and diamides were used to reduce the hydroquinone solubility and diffusion. This early NCD work also included a series of studies exploring the hydroquinone NCD system via changes to the coformer structure [ 2 , 76 , 77 ]. Even relatively minor changes in the coformer structure have significant effect. In a similar example, hydroquinone and tris- N , N -diethyl trimesamides formed a complex while tris- N , N -dimethyl trimesamides formed a complex of hydroquione to trimesamide [ 76 ].

These studies speak to the enormous capacity to tailor NCD systems for specific properties. Much attention has shifted to the potential utility of cocrystals in the pharmaceutical industry. A variety of active pharmaceutical ingredients APIs have been incorporated into cocrystals and eutectics, with the result being remarkable changes in physical properties without the loss of pharmaceutical activity. Improvements to solubility [ 78 , 79 , 80 , 81 , 82 , 83 ] and hydro-stability [ 20 ] have been reported for cocrystals with APIs.

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Dovetailing with the changes in solubility, preparation of pharmaceuticals as cocrystals has been hailed as one of the most effective methods available for the challenging task of improving bioavailability [ 84 ]. A number of review articles are in print on pharmaceutical NCD cocrystals [ 13 , 66 , 85 , 86 , 87 , 88 ]. Likewise, pharmaceutical eutectics have been recognized as a powerful means for altering API properties [ 88 ].

In an illustrative and often referenced study, several cocrystals were prepared from fluoxetine hydrochloride and the solubility was measured. The fluoexetine hydrochloride solubility was determined to be The benzoic acid cocrystal solubility was measured at 5. Both the fumaric acid and succinic acid cocrystals were found to increase the solubility to In a similar study, the cocrystal formed from the chemotheraphy agent, Tegafure, was shown to have solubility comparable to that of Tegafure in its pure amorphous phase and much higher than in its pure crystalline phase.

The advantage of the cocrystal in this case was the improvement in solubility without the loss of stability associated with the amorphous phase [ 86 ]. A number of similar examples showing changes in solubility and dissolution for cocrystals can be found in the literature and several reviews have been published on the subject [ 87 , 88 , 89 , 90 ].

The literature on eutectics and API solubility is less plentiful, but in one example the binary eutectic formed from two anti-tubercular drugs, pyrazinamide and isoniazid, showed significantly improved intrinsic dissolution [ 42 ]. Ibuprofen-menthol eutectics for use in suppositories also showed improved solubility over pure ibuprofen [ 92 ].

This change in solubility has implied effects on the bioavailability of APIs. This can be seen in glutaric acid cocrystals prepared with the API, 2-[4- 4-chlorofluorophenoxy phenyl] pyrimidinecarboxamide.