Cocrystal Polymorphs Research Articles

Mechanochemical Transformations of Pharmaceutical Cocrystals: Polymorphs and Coformer Exchange.

Transformations of solid samples under solvent-free or minimal solvent conditions set the future trend and define a modern strategy for the production of new materials. Of the various technologies tested in recent years, the mechanochemical approach seems to be the most promising.The aim of this review article is to present the current state of art in solid state research on binary systems, which have found numerous applications in the pharmaceutical and materials science industries. This article is divided into three sections. In the first part, we describe the new equipment improvements.A brief description of techniques dedicated to ex-situ and in-situ studies of progress and the mechanism of solid matter transformation is presented. In the second section, we discuss the problem of cocrystal polymorphism highlighting the issue related with correlation between mechanochemical parameters (time, temperature, energy, molar ratio,liquid assistant, surface energy, crystal size, crystal shape) and preference for the formation of requested polymorph. The last part is devoted to the description of the processes of coformer exchange in binary systems forced by mechanical and/or thermal stimuli. The influence of the thermodynamic factor on the selection of the best-suited partner for the formation of a two-component structure is presented.

Hesperetin–4,4′-bipyridine cocrystal: Polymorphism, crystal structures, and thermodynamic relationship

The investigation of cocrystal polymorphism remains relatively limited compared to that of single-component crystals. This study focuses on the cocrystallization of hesperetin (HES), a typical flavonoid substance, with 4,4′-bipyridine (BPY), resulting in the formation of two distinct 1:1 cocrystal phases. Single crystal X-ray diffraction analysis reveals that the O—H···N hydrogen interaction serves as the hetero-synthon of the cocrystals, driving the formation of featured 1D molecular chains in both structures. The presence of rotatable C—C bonds in both HES and BPY introduces the possibility of the molecular conformational variations, contributing to differing molecular stacking arrangements between the two structures. Thermal analysis, solvent-mediated polymorphic transformation, and theoretical calculations confirm a monotropic relationship between the two cocrystals.

Polymorph selection of pharmaceutical cocrystals via bench-top and continuous production techniques

Polymorphism can be a valuable tool as well as an impediment in the development and approval of pharmaceuticals, providing an opportunity to tune active pharmaceutical ingredient (API) physicochemical properties. The control of polymorphism in cocrystalline systems and other multicomponent forms remains underexplored. The study herein aims to investigate the potential of several techniques, liquid-assisted grinding (LAG), solvent evaporation (SE), supercritical enhanced atomization (SEA) and electrospraying, to control the cocrystal polymorphic outcome of three cocrystals: isonicotinamide-citric acid (IsoCa), ethenzamide-saccharin (EthSac) and ethenzamide-gentisic acid (EthGa). Solvent selection employing LAG and SE showed little effect on polymorphic outcome. Electrospraying and SEA primarily produced the α form of IsoCa, with process parameter variations leading to the β form during SEA, and a mixture of α and γ from electrospraying. Electrospraying led to the stable form I of EthSac, while SEA could produce pure form II, and a mixture. Electrospraying produced the form I of EthGa while SEA could produce form II, with an unknown polymorphic impurity. Density functional theory (DFT) computed electron density (ED) maps of cocrystal polymorph binary systems further rationalised the polymorphic predominance observed through the electrospraying. Ultimately this study provides a general road map for polymorph selection via atomization-based methodologies.

Green Mechanochemical Preparation of Cocrystal Polymorphs: Significant Effect of Intermediates and Solvents

Green Mechanochemical Preparation of Cocrystal Polymorphs: Significant Effect of Intermediates and Solvents

Flavone Cocrystals: A Comprehensive Approach Integrating Experimental and Virtual Methods.

The dapsone/flavone cocrystal system served as a benchmark for both experimental and virtual screening methods. Expanding beyond this, two additional active pharmaceutical ingredients (APIs), sulfanilamide and sulfaguanidine, structurally related to dapsone were chosen to investigate the impact of substituents on cocrystal formation. The experimental screening involved mechanochemical methods, slurry experiments, hot-melt extrusion, and the contact preparation method. The virtual screening focused on crystal structure prediction (CSP), molecular complementarity, hydrogen-bond propensity, and molecular electrostatic potentials. The CSP studies not only indicated that each of the three APIs should form cocrystals with flavone but also reproduced the known single- and multicomponent phases. Experimentally, dapsone/flavone cocrystals ACC, BCC, CCC, and DCC were reproduced, CCC was identified as a nonstoichiometric hydrate, and a fifth cocrystal (ECC), a t-butanol solvate, was discovered. The cocrystal polymorphs ACC and BCC are enantiotripically related, and DCC, exhibiting a different stoichiometric ratio, is enthalpically stabilized over the other cocrystals. For the sulfaguanidine/flavone system, two novel, enantiotripically related cocrystals were identified. The crystal structures of two cocrystals and a flavone polymorph were solved from powder X-ray diffraction data, and the stability of all cocrystals was assessed through differential scanning calorimetry and lattice energy calculations. Despite computational indications, a diverse array of cocrystallization techniques did not result in a sulfanilamide/flavone cocrystal. The driving force behind dapsone's tendency to cocrystallize with flavone can be attributed to the overall strength of flavone interactions in the cocrystals. For sulfaguanidine, the potential to form strong API···API and API···coformer interactions in the cocrystal is a contributing factor. Furthermore, flavone was found to be trimorphic.

Synthon Approach in Crystal Engineering to Modulate Physicochemical Properties in Organic Salts of Chlorpropamide.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

Repurposing of Antifungal Drug Flucytosine/Flucytosine Cocrystals for Anticancer Activity against Prostate Cancer Targeting Apoptosis and Inflammatory Signaling Pathways.

This study aimed to repurpose the antifungal drug flucytosine (FCN) for anticancer activity together with cocrystals of nutraceutical coformers sinapic acid (SNP) and syringic acid (SYA). The cocrystal screening experiments with SNP resulted in three cocrystal hydrate forms in which two are polymorphs, namely, FCN-SNP F-I and FCN-SNP F-II, and the third one with different stoichiometry in the asymmetric unit (1:2:1 ratio of FCN:SNP:H2O, FCN-SNP F-III). Cocrystallization with SYA resulted in two hydrated cocrystal polymorphs, namely, FCN-SYA F-I and FCN-SYA F-II. All the cocrystal polymorphs were obtained concomitantly during the slow evaporation method, and one of the polymorphs of each system was produced in bulk by the slurry method. The interaction energy and lattice energies of all cocrystal polymorphs were established using solid-state DFT calculations, and the outcomes correlated with the experimental results. Further, the in vitro cytotoxic activity of the cocrystals was determined against DU145 prostate cancer and the results showed that the FCN-based cocrystals (FCN-SNP F-III and FCN-SYA F-I) have excellent growth inhibitory activity at lower concentrations compared with parent FCN molecules. The prepared cocrystals induce apoptosis by generating oxidative stress and causing nuclear damage in prostate cancer cells. The Western blot analysis also depicted that the cocrystals downregulate the inflammatory markers such as NLRP3 and caspase-1 and upregulate the intrinsic apoptosis signaling pathway marker proteins, such as Bax, p53, and caspase-3. These findings suggest that the antifungal drug FCN can be repurposed for anticancer activity.

Polymorphs of praziquantel–succinic acid cocrystal: Crystal structure, thermodynamic relationship, and improved pharmaceutical performance

Polymorphism is a ubiquitous phenomenon of critical significance for the pharmaceutical industry, yet reports on cocrystal polymorphs are scarce. This study elucidates the crystal structure of the praziquantel (PZQ)-succinic acid (SUC) cocrystal polymorph, α-PZQ-SUC. The dominant supramolecular interaction in the cocrystal polymorph is the O − H···O hydrogen bond between SUC and PZQ, consistent with the supramolecular interaction in the previously reported β-PZQ-SUC polymorph. Comprehensive analysis, including thermal analysis, theoretical calculations, and solvent-mediated polymorphic transformation experiments, established a monotropic relationship between the two polymorphs, with α-PZQ-SUC demonstrating greater stability than β-PZQ-SUC. Both α-PZQ-SUC and β-PZQ-SUC enhance the solubility and dissolution behavior of PZQ, indicating their suitability for pharmaceutical applications based on improved pharmaceutical performance.

Isomorphism, Polymorphism, and Stoichiomorphism of Cocrystals Derived from 1,4-Diiodotetrafluorobenzene and an Isomorphous Series of N-(4-Halobenzyl)-3-halopyridinium Halogenides

Isomorphism, Polymorphism, and Stoichiomorphism of Cocrystals Derived from 1,4-Diiodotetrafluorobenzene and an Isomorphous Series of <i>N</i>-(4-Halobenzyl)-3-halopyridinium Halogenides

Metronidazole Cocrystal Polymorphs with Gallic and Gentisic Acid Accessed through Slurry, Atomization Techniques, and Thermal Methods.

In this study, key features of metronidazole (MNZ) cocrystal polymorphs with gallic acid (GAL) and gentisic acid (GNT) were elucidated. Solvent-mediated phase transformation experiments in 30 solvents with varying properties were employed to control the polymorphic behavior of the MNZ cocrystal with GAL. Solvents with relative polarity (RP) values above 0.35 led to cocrystal I°, the thermodynamically stable form. Conversely, solvents with RP values below 0.35 produced cocrystal II, which was found to be only 0.3 kJ mol-1 less stable in enthalpy. The feasibility of electrospraying, including solvent properties and process conditions required, and spray drying techniques to control cocrystal polymorphism was also investigated, and these techniques were found to facilitate exclusive formation of the metastable MNZ-GAL cocrystal II. Additionally, the screening approach resulted in a new, high-temperature polymorph I of the MNZ-GNT cocrystal system, which is enantiotropically related to the already known form II°. The intermolecular energy calculations, as well as the 2D similarity between the MNZ-GAL polymorphs and the 3D similarity between MNZ-GNT polymorphs, rationalized the observed transition behaviors. Furthermore, the evaluation of virtual cocrystal screening techniques identified molecular electrostatic potential calculations as a supportive tool for coformer selection.

Investigation into polymorphism within ethenzamide-ethylmalonic acid cocrystal using Raman and terahertz vibrational spectroscopy

Two cocrystal polymorphs of ethenzamide (ETZ) and ethylmalonic acid (EMA) were synthesized by solvent evaporation. Crystal structure analysis revealed that the main amide − carboxyl heterosynthon in ETZ-EMA cocrystal Form I and Form II are the same, but the crystal structure of these two polymorphs are different. Terahertz (THz) and Raman vibrational spectroscopy were used to characterize ETZ, EMA, ETZ-EMA cocrystal polymorph Form I and Form II respectively. The experimental results showed that ETZ, EMA, ETZ-EMA cocrystal Form I and ETZ-EMA cocrystal Form II exhibited completely different characteristic peaks. Both THz and Raman vibrational spectroscopy can be used to distinguish ETZ-EMA cocrystal Form I from Form II. Furthermore, the investigation of phase transition induced by temperature and solid-state grinding was also performed. In the temperature phase transition experiments, when the powder sample was heated to a temperature range of 80–82 °C, the metastable ETZ-EMA cocrystal Form I transformed into the more stable ETZ-EMA cocrystal Form II. Solid-state grinding analysis revealed that the results of the ETZ-EMA cocrystal polymorph synthesis in grinding experiments depended on the polarity of the solvents used. Grinding without solvent or with high polarity solvents tended to result in the stable ETZ-EMA cocrystal Form II. Moreover, the metastable ETZ-EMA cocrystal Form I would transform into Form II after further grinding process. These results demonstrate that THz and Raman vibrational spectroscopy have high sensitivity and accuracy in the detection of both cocrystal synthesis and cocrystal polymorph phase transitions.

Effect of functional group position in co-formers and solvent on cocrystal polymorphism/stoichiomorphism: a case study

In recent years, there has been an increase in the number of reports on cocrystal polymorphism and stoichiomorphism. However, the research on the factors that influence these phenomena is limited. Herein, picolinamide (PAM), nicotinamide (NAM), and isonicotinamide (INA) were selected as co-formers to form multicomponent solids with 4-chloro-3-sulfamoylbenzoic acid (CSBA). Six new cocrystal forms of CSBA were discovered and their crystal structures were determined. It was found that PAM and NAM can only form one cocrystal with CSBA, while INA can form up to four cocrystals, including both cocrystal polymorphism and stoichiomorphism. Molecular electrostatic potential analysis and crystal structure analysis showed that the functional group position of PAM limited the diversity of cocrystal synthons, while the lattice energy limited the diversity of cocrystal synthons when NAM acted as a co-former. Only INA was not subject to these restrictions when forming cocrystals. Finally, the influence of solvents on cocrystals was illustrated by determining the ternary phase diagrams. The mechanism of two similar solvents, ethyl acetate and acetone, controlling the crystallization of cocrystal polymorphism was analyzed by molecular simulations.

Continuous Manufacturing of Cocrystals Using 3D-Printed Microfluidic Chips Coupled with Spray Coating.

Using cocrystals has emerged as a promising strategy to improve the physicochemical properties of active pharmaceutical ingredients (APIs) by forming a new crystalline phase from two or more components. Particle size and morphology control are key quality attributes for cocrystal medicinal products. The needle-shaped morphology is often considered high-risk and complex in the manufacture of solid dosage forms. Cocrystal particle engineering requires advanced methodologies to ensure high-purity cocrystals with improved solubility and bioavailability and with optimal crystal habit for industrial manufacturing. In this study, 3D-printed microfluidic chips were used to control the cocrystal habit and polymorphism of the sulfadimidine (SDM): 4-aminosalicylic acid (4ASA) cocrystal. The addition of PVP in the aqueous phase during mixing resulted in a high-purity cocrystal (with no traces of the individual components), while it also inhibited the growth of needle-shaped crystals. When mixtures were prepared at the macroscale, PVP was not able to control the crystal habit and impurities of individual mixture components remained, indicating that the microfluidic device allowed for a more homogenous and rapid mixing process controlled by the flow rate and the high surface-to-volume ratios of the microchannels. Continuous manufacturing of SDM:4ASA cocrystals coated on beads was successfully implemented when the microfluidic chip was connected in line to a fluidized bed, allowing cocrystal formulation generation by mixing, coating, and drying in a single step.

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.

Structural and thermal analyses of metaxalone cocrystals with succinic, adipic and salicylic acids

Metaxalone (MTX) is a skeletal muscle relaxant drug, crystallized with carboxylic acid coformers like succinic acid (SUC), adipic acid (ADP) and salicylic acid (SAL). Their molecular structure, crystal packing and thermal analysis were studied. In the crystallization screening, two polymorphic forms of MTX-SAL were discovered. Form I of MTX-SAL was obtained from ethanol while form II was obtained concomitantly along with form I in ethyl acetate. All four structures form MTX homodimer of R22(8) motif. In MTX-SUC, the N-H⋅⋅⋅O, O-H⋅⋅⋅N and C-H⋅⋅⋅O hydrogen bonds are involved in the crystal packing and generate a three-dimensional hydrogen-bonded network. In MTX-ADP, the coformer bridges the adjacent MTX homodimers and forms an extended chain. In both the polymorphs of MTX-SAL, the MTX molecule forms a homodimer, which is further connected by SAL coformer. Solvent assisted grinding and slurry techniques were employed to obtain phase pure bulk material. The results obtained in different trials were compared using powder X-ray diffraction (PXRD) and the process was optimized for bulk solid form preparation of MTX-SUC, MTX-ADP and MTX-SAL form I. MTX-SUC exhibits a higher melting point than the other two cocrystals. The close packing indices, crystal densities and melting temperatures between both the MTX-SAL cocrystal polymorphs resulted in the concomitant existence of form II with form I.

Polymorphism in cocrystals of metronidazole benzoate

Two polymorphic cocrystals from the metronidazole benzoate with salicylic acid and fumaric acid as coformers are reported in this work.

Polymorphism in parabanic acid-urea cocrystals governed by supramolecular synthons: a comparative analysis

A new polymorph of parabanic acid-urea cocrystal (PA-UA Form II) has been discovered. An experimental and theoretical investigation is conducted to compare PA-UA Form II cocrystal with PA-UA Form I cocrystal.

Controlling polymorphism in molecular cocrystals by variable temperature ball milling.

Mechanochemistry offers a unique opportunity to modify and manipulate crystal forms, often providing new products as compared with conventional solution methods. While promising, there is little known about how to control the solid form through mechanochemical means, demanding dedicated investigations. Using a model organic cocrystal system (isonicotinamide:glutaric acid), we here demonstrate that with mechanochemistry, polymorphism can be induced in molecular solids under conditions seemingly different to their conventional thermodynamic (thermal) transition point. Whereas Form II converts to Form I upon heating to 363 K, the same transition can be initiated under ball milling conditions at markedly lower temperatures (348 K). Our results indicate that mechanochemical techniques can help to reduce the energy barriers to solid form transitions, offering new insights into controlling polymorphic forms. Moreover, our results suggest that the nature of mechanochemical transformations could make it difficult to interpret mechanochemical solid form landscapes using conventional equilibrium-based tools.

Exploring the influence of crystal packing on the optical-physical property of quercetin-based binary and ternary solid forms

The co-crystallization of quercetin (Qur) with a flexible molecule 4-(4-pyridinyldisulfanyl) pyridine (DPDS) in different solvents and conditions was investigated, yielded five multi-component crystalline phases and characterized with X-ray diffractions and thermal analysis. Although the crystal system of Qur-DPDS-MeOH and Qur-DPDS-Dioxane is the same, the desolvation results revealed that Qur-DPDS-MeOH transformed to Qur-DPDS when MeOH solvent molecules escape from the lattice, while Qur-DPDS-Dioxane transformed to Qur-DPDS-II through a similar process, which is same with Qur-DPDS-THF. These two cocrystal polymorphs Qur-DPDS and Qur-DPDS-II obey an enantiotropic relationship. Moreover, the formation of cocrystal solvates improves the packing efficiency of crystals. Crystal structure analysis showed that hydrogen bonds and conformations of the corresponding parent molecules play a major role in molecular assembly and crystal packing patterns, thus bring different physicochemical properties. Finally, the fluorescence spectra and quantum-chemical calculations were carried out to explore the difference in the optical-physical properties.

Inhibiting Sublimation of Thymol by Cocrystallization

A thymol:4,4’-dipyridyl (2:1) cocrystal (Form I) is reported to suppress thymol sublimation. The cocrystal was prepared via solution-mediated phase transformation and its structure is sustained by O-H (phenol) ··· N (pyridyl) hydrogen bonds between two individual components. A cocrystal polymorph (Form II) was formed via solid state transformation or via vapor phase upon heating. Using gravimetry analysis, it was demonstrated that cocrystal Form I decreased the sublimation rate of thymol by 38-fold. This study demonstrates that cocrystallization is an effective approach to reduce vapor pressure and sublimation of solids, thus achieving odor-masking.