Polymorphic Cocrystals Research Articles

Photoreactive Polymorphic Cocrystals Utilizing a Molecular Template with Dual Halogen and Hydrogen Bonding Capabilities

The ability of 1,2,4,5-tetrachloro-3-iodobenzene to act as a template to form a pair of polymorphic cocrystals with trans-1,2-bis(4-pyridyl)ethylene is reported. After exposure to ultraviolet light, a nearly quantitative yield for the [2 + 2] cycloaddition reaction was observed for both concomitant cocrystals. These crystalline solids engage in both I···N halogen bonds along with nontraditional C–H···N hydrogen bond which results in a one-dimensional chain. In addition, the components homogeneous π–π stack which positions the carbon–carbon double bond on the reactant molecule in a suitable orientation to undergo a photoinduced cyclization reaction.

Two Polymorphic Cocrystals of Theophylline with Ferulic Acid

In this study, the crystal structures of 1:1 theophylline–ferulic acid cocrystal polymorphs are reported for the first time. Interestingly, both forms crystallize in the same space group but with a different number of molecules in the asymmetric unit (form I = 2; form II = 4). The two polymorphs show distinct crystal morphology, demonstrating prism and rod single crystals, respectively. Theoretical calculations are performed to predict their morphology and thermodynamic stability (form I > form II). The prediction result agrees well with the measured pharmaceutical properties. Form I presents better hygroscopic stability (RH < 95%), slower dissolution, and lower solubility (1.06 ± 0.03, 1.63 ± 0.01, 1.30 ± 0.08 and 4.09 ± 0.05 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions) over form II (8.45 ± 0.33, 2.41 ± 0.17, 3.46 ± 0.26 and 28.71 ± 0.87 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions). In summary, this work elucidates the experimental findings with relevant predictions systematically and enriches our understanding of the structure–property relationship of the theophylline cocrystal system.

Chameleon Behavior of a New Salt of 3-(Aminocarbonyl) Pyridinium Malonate and Implications for Polymorphism on the Salt/Cocrystal Continuum

This contribution presents a previously unreported example and comparative study of a binary crystalline adduct which exhibits a salt form in a 1:1 stoichiometry. Specifically, a new salt form of a novel 1:1 form of 3-(aminocarbonyl) pyridinium malonate is reported, and the route to isolating it from aqueous solution and the crystal chemistry of the system are characterized. Structurally, the nicotinamide dimer motif present in the polymorphic cocrystals is absent in the salt, allowing an equimolar structure arising from a singly donated proton from one malonic acid carboxylic acid group. A comparative study of the solid form landscape is presented against its known polymorphic forms I and II, which form in a 2:1 ratio of bis(nicotinamide) malonic acid, wherein computational mapping reveals the order or stability as a 1:1 salt, 2:1 cocrystal polymorph II, and 2:1 cocrystal polymorph I, the latter being the metastable form. Intriguingly, on the basis of periodic DFT-D calculations, we also propose two tentative 2:1 salt forms of cocrystal polymorph II which would be of higher stability than both the hitherto explored 2:1 cocrystalline forms and linked crystal packing/interactions with crystal growth outcomes. This study demonstrates the importance of computational studies to explore the salt/cocrystal continuum and could highlight subtle isostructural changes that could yield novel solid forms and impact physiochemical properties and morphology, providing further impetus for screening activities/characterization.

Optical Waveguide and Photoluminescent Polarization in Organic Cocrystal Polymorphs.

Organic cocrystals whose unique polymorphic feature can provide a feasible way to investigate and understand the relationship between luminescence properties and aggregate structures have attracted increasing attention in the area of organic optoelectronics. Herein, we prepare polymorphic cocrystals (C1, C2) by using 9,10-bis((E)-2-(pyridin-3-yl)vinyl)anthracene (BP3VA) as chromophore and 1,3,5-trifluoro-2,4,6-triiodobenzene (FIB) as conformer. Both C1 and C2 stack with segregated stacking form, but different intermolecular interactions promote the formation of sheet cocrystals C1 and needle cocrystals C2. C1 exhibits anisotropic optical waveguide property and photoluminescent polarization, while C2 only exhibits the quasi-one-dimensional optical waveguide property. The different optical properties originate from the varieties of molecular packing modes and directions of the optical transition dipole in the two polymorphic cocrystals, which can be clarified through the structure analysis and theoretical calculation. The study can provide a deep understanding of the structure-property relationship of cocrystals and benefit the rational design of novel functional materials.

Mechanosynthesis of Eutectics of Anti‐Inflammatory Drug Ethenzamide – A Comparison with Analogous Cocrystals

AbstractMechanochemical milling of ethenzamide (ETZ), a nonsteroidal anti‐inflammatory drug, with substituted aromatic carboxylic acids as well as anti‐tuberculosis drug pyrazinamide (PZA) resulted in the formation of eutectics. Although a large number of cocrystals as well as polymorphic cocrystals are reported for ETZ, for the first time we have synthesized six eutectics including an instance of a drug‐drug eutectic system. Supramolecular synthon energy calculations validate the formation of eutectic mixtures over cocrystals with coformers considered in our study.

Solvent dependent 4-aminosalicylic acid-sulfamethazine co-crystal polymorph control

Despite polymorphism of crystalline active pharmaceutical ingredients (APIs) being a common phenomenon, reports on polymorphic co-crystals are limited. As polymorphism can vastly affect API properties, controlling polymorph generation is crucial. Control of the polymorph nucleation through the use of different solvents during solution crystallization has been used to obtain a desirable crystal polymorph. There have been two reported polymorphic forms of the 4-aminosalicylic acid-sulfamethazine co-crystals. These forms were found to have different thermodynamic stabilities. However, the control of co-crystal polymorph generation using preparation parameter manipulation has never been reported. The aim of this study was to establish the effect of different solvent parameters on the formation of different co-crystal polymorphic forms. Selection of the solvents was based on Hansen Solubility Parameters (HSPs) as solvents with different solubility parameters are likely to interact differently with APIs, ultimately affecting co-crystallization. Eight solvents with different HSPs were used to prepare co-crystals by solvent evaporation at two different temperatures. Through characterization of the co-crystals, a new polymorph has been obtained. The hydrogen bond acceptability seemed to affect the co-crystal form obtained more than the hydrogen bond donation ability. Furthermore, the use of HSPs can be utilized as an easy calculation method in screening and design of co-crystals.

Luminescent Polymorphic Co-crystals: A Promising Way to the Diversity of Molecular Assembly, Fluorescence Polarization, and Optical Waveguide.

The design of molecular optoelectronic materials based on fabricating polymorphs and/or co-crystals has received much recent attention in the fields of luminescence, sensors, nonlinear optics, and so on. If the advantages of the two crystal engineering strategies above were combined, the diversity of self-assembly fashions and the tuning of photofunctional performances would be largely extended. However, such multicomponent examples have still been very limited to date. Herein, we report the construction of luminescent polymorphic co-crystals by assembly of tris(pentafluorophenyl)borane (TPFB) with 9,10-dicyanoanthracene (DCA) and acridine (AC) as paradigms. Different stacking modes and arrangement styles based on identical building block units in polymorphic co-crystals result in adjustable crystalline morphologies and variant photophysical properties (such as fluorescence wavelength, lifetimes, and up-conversion luminescence). The optimized photoluminescence quantum yield (63.1%) and lifetime (57.1 ns) are much higher than those of the pristine assembled units. In addition, two polymorphic co-crystals (DCA@TPFB-1 and AC@TPFB-2) present prominent fluorescence polarization and optical waveguide behaviors due to the highly regulated molecular orientation. Their high one-dimensional luminescence anisotropy (0.652) and low optical waveguide loss (0.0079 dB/μm) outperform most state-of-the-art low-dimensional molecular systems and thus endow them with great opportunities for photonic materials and devices. Therefore, this work not only confirms that constructing polymorphic co-crystals can be an effective way to design new photofunctional materials for luminescence and photonic applications but also discloses a deep understanding on the relationship between variant self-assembled fashions and tunable photofunctional properties of new TPFB-based molecular materials.

A preformulation co-crystal screening case study: Polymorphic co-crystals of an imidazopyridazine antimalarial drug lead with the coformer succinic acid

A crystal engineering approach combined with experimental screening methods was employed as a preformulation step for producing expectedly useful forms of a novel antimalarial drug lead (MMV652103). In previous experiments, this drug lead had shown promise both in vitro and in vivo against the human malaria parasite Plasmodium falciparum. Various new forms of MMV652103 were produced earlier, including co-crystals, a salt, polymorphs and a hydrated form and these were reported elsewhere. Three distinct new forms are reported here, of which two are conformational and synthon (2:1) co-crystal polymorphs produced with the coformer succinic acid, while the third is a co-crystal with a different stoichiometric ratio (1:1) of the same components. The crystal structures of the co-crystal polymorphs were elucidated by single-crystal X-ray diffraction. The different forms were also characterised by powder X-ray diffraction, Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, hot stage microscopy, differential thermal analysis, differential scanning calorimetry, thermogravimetric analysis and in some cases variable-temperature powder X-ray diffraction. It was determined that the polymorphs are monotropically related. Methods were developed to prepare each of these forms reproducibly and rapidly identify each form.

Tuning the Apparent Stability of Polymorphic Cocrystals through Mechanochemistry

Mechanochemistry has become a valuable method for the synthesis of new materials and molecules, with a particular strength for screening and preparing multicomponent crystals. In this work, two nov...

X-Ray Diffraction and Theoretical Calculation–Supported Formation of Polymorphic Cocrystals Discovered Through Thermal Methods: A Case Study

Polymorphism commonly exists in the preparation of cocrystals and has attracted widespread attention from both the pharmaceutical industry and academia. However, few studies have examined how to discover polymorphic cocrystals and their potential formation mechanism. In this study, we report the novel discovery of salicylic acid: 3-nitrobenzamide (SA-3NBZ) polymorphic cocrystals by thermal methods. The formation mechanism is elucidated based on theoretical calculations. SA-3NBZ polymorphic cocrystals with molar ratio of 1:1 and 2:2 were discovered using the combination of differential scanning calorimetry and hot stage microscopy. Single-crystal X-ray diffraction analysis confirmed this discovery. Density functional theory calculations corrected with dispersion were conducted to illustrate the energetic stabilization of SA polymorphic cocrystals. Compared with the starting materials, formation of the cocrystals at 1:1 and 2:2 present a weak stabilization with overall energy reduction of −0.01 and −0.05 eV/molecule, respectively. The calculated noncovalent interactions index further suggests that intralayer hydrogen bonds and van der Waals forces contribute to these weak interactions. The density functional theory calculations are in good agreement with the X-ray diffraction data. Hence, thermal analysis is a simple and reliable method to discover polymorphic cocrystals.

Regioselective [2 + 2] cycloaddition reaction within a pair of polymorphic co-crystals based upon halogen bonding interactions

A pair of photoreactive polymorphic co-crystals that undergo a regioselective solid-state [2 + 2] cycloaddition reaction that yields exclusively the head-to-tail photoproduct is reported.

Exposing Key Vibrational Contributions to Properties of Organic Molecular Solids with High Signal, Low Frequency Neutron Spectroscopy and Ab Initio Simulations

Stability and response of supramolecular forms is important to many areas in materials science, and contributions from vibrations can be crucial. We have collected the first spectra of organic molecular crystals and polymorphic cocrystals using the next-generation, high-signal VISION spectrometer in the far-infrared (FIR) and mid-infrared (MIR) range. Unambiguously different spectral signatures were found for carbamazepine and two polymorphs of the carbamazepine-saccharin cocrystal, including numerous modes undetectable with optical methods. For FIR-range frequencies, in addition to correct calculation of peak positions, accurate line-shape features were reproducible by simulation using ab initio vibrational calculations. High confidence spectral assignments and thermochemical information for this region are thus expected, and a benchmark for vibrational ab initio calculations is provided, creating a significant addition to methods used in investigation and design of organic materials.

The urea-barbituric acid polymorphic co-crystal system: Characterization, thermodynamics and crystallization

Polymorphism in co-crystals is known to have a dramatic effect on physiochemical properties. The current contribution covers the characterization, thermodynamic analysis, and cooling seeded crystallization investigation of the urea-barbituric acid (UBA) polymorphic co-crystal system including urea (UA), barbituric acid (BA), and two polymorphic UBA (Forms I and III). Supramolecular synthesis of UBA Forms I and III have been conducted by cooling crystallization in methanol and then systematically characterized by powder X-ray diffraction (PXRD), thermal analysis (DSC and TGA), Raman and IR spectroscopy. Compared to the TGA results, the exothermic and endothermic peaks shown in DSC curves represent the decomposition of UBA and the melting of BA, respectively. Using the measured solubility data, the UBA polymorphs were found to be an enantiotropic polymorphic system, and the transition points in the water and methanol were determined at 35 °C and 33 °C, respectively. Subsequently, the modified Apelblat equation and van’t Hoff model were used to correlate the experimental data and to calculate the dissolution enthalpy and entropy of the different system. Moreover, cooling seeded crystallization of two polymorphic co-crystals in methanol was carried out to investigate the influence of process variables, such as seed amount, cooling rate, and stirring rate, on the crystal structure and crystal size distribution of final co-crystals.

Binary polymorphic cocrystals: an update on the available literature in the Cambridge Structural Database, including a new polymorph of the pharmaceutical 1:1 cocrystal theophylline-3,4-dihydroxybenzoic acid.

An analysis and classification of the 2925 neutral binary organic cocrystals in the Cambridge Structural Database is reported, focusing specifically on those both showing polymorphism and containing an active pharmaceutical ingredient (API). The search was confined to molecules having only C, H, N, O, S and halogens atoms. It was found that 400 out of 2925 cocrystals can be classified as pharmaceutical cocrystals, containing at least one API, and that of those, 56 can be classified as being polymorphic cocrystals. In general, the total number of polymorphic cocrystal systems of any type stands at 125. In addition, a new polymorph of the pharmaceutical cocrystal theophylline-3,4-dihydroxybenzoic acid (1/1), C7H8N4O2·C7H6O4, is reported.

Elusive Nonsolvated Cocrystals of Aspirin: Two Polymorphs with Bipyridine Discovered with the Assistance of Mechanochemistry

We report the discovery two nonsolvated polymorphic cocrystals of acetylsalicylic acid (ASA) and 4,4′-bipyridine (4,4′-bipy) in the form of 2(ASA)·(4,4′-bipy). Form I was discovered through mechanical dry grinding, and Form II was discovered through rapid cooling in ethanol. Both polymorphs consist of three-component hydrogen-bonded assemblies sustained by O–H···N hydrogen bonds. The components of the assemblies adopt an anti-conformation. The polymorphs differ in terms of relative twists of carboxylic acid groups and pyridyl rings. In Form I the ASA molecules are linked by discrete catemeric methyl C–H···O forces of the acetyl substituents, while in Form II the ASA molecules are linked by both infinite methyl C–H···O catemers and centrosymmetric dimers of the acetyl groups. Our results demonstrate the importance of neat mechanical grinding in the discovery and design of pharmaceutical cocrystals and polymorphs.

Polymorphism of Cocrystals: The Promiscuous Behavior of Agomelatine

It has been traditionally suggested that polymorphism of cocrystals is a phenomenon seen less frequently than in monocomponent crystals. However, since the research on cocrystals has recently experienced a big growth, the number of solved structures of polymorphic cocrystals in the Cambridge Structural Database has increased, which can help to understand better whether a lower impact of this phenomenon exists or not in multicomponent crystals. In this paper we describe the cocrystal landscape of agomelatine, a particularly promiscuous drug able to cocrystallize with up to nine different coformers. Interestingly, two of those coformers have produced polymorphic cocrystals during the screening, which converts agomelatine into a new example that questions the traditional belief of the lesser impact of polymorphism in cocrystals and highlights the importance of polymorphism studies in cocrystal screening. Our work is completed with the determination of the crystal structures of the new forms from combined sin...

Drug-drug co-crystallization presents a new opportunity for the development of stable vitamins.

Drug-drug co-crystallization could realize combination drugs at a molecular level. Two polymorphic co-crystals between VD2 and VD3 were successfully designed and synthesized. These enantiotropic polymorphs exhibit significantly different physicochemical stabilities.

Charge density studies on polymorphic co-crystals

Charge density studies on polymorphic co-crystals

Two New Polymorphic Cocrystals of Zafirlukast: Preparation, Crystal Structure, and Stability Relations

Two new cocrystals of zafirlukast with piperazine, existing in five different solid forms, have been discovered during a cocrystal screening. The crystal structure of one of these forms has been determined by single crystal X-ray diffraction, and the stability landscape of the crystalline forms of the new cocrystal has been studied. In the present article, we extend the knowledge about the solid state of this important pharmaceutical drug for the treatment of asthma by reporting the crystal structures of two new solvates (acetonitrile and butanol) and the elusive anhydrous Form X, which have been solved by single crystal X-ray diffraction.

Polymorphism in Sulfadimidine/4-Aminosalicylic Acid Cocrystals: Solid-State Characterization and Physicochemical Properties

Polymorphism of crystalline drugs is a common phenomenon. However, the number of reported polymorphic cocrystals is very limited. In this work, the synthesis and solid-state characterization of a polymorphic cocrystal composed of sulfadimidine (SD) and 4-aminosalicylic acid (4-ASA) is reported for the first time. By liquid-assisted milling, the SD:4-ASA 1:1 form I cocrystal, the structure of which has been previously reported, was formed. By spray drying, a new polymorphic form (form II) of the SD:4-ASA 1:1 cocrystal was discovered which could also be obtained by solvent evaporation from ethanol and acetone. Structure determination of the form II cocrystal was calculated using high-resolution X-ray powder diffraction. The solubility of the SD:4-ASA 1:1 cocrystal was dependent on the pH and predicted by a model established for a two amphoteric component cocrystal. The form I cocrystal was found to be thermodynamically more stable in aqueous solution than form II, which showed transformation to form I. Dissolution studies revealed that the dissolution rate of SD from both cocrystals was enhanced when compared with a physical equimolar mixture and pure SD. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1385-1398, 2015.