Cocrystal Coformers Research Articles

Machine learning approach to predict Hansen solubility parameters of cocrystal coformers via integrating group contribution and COSMO-RS

Hansen Solubility Parameters (HSPs) have been a hot topic on predicting the tendency of pharmaceutical cocrystals formation and cocrystal coformers (CCFs) screening. However, the limitation of such application is the lack of models to accurately predict the values of HSPs for drug CCFs with more structural complexity. Accordingly, three ML (machine learning) models, i.e. ANN (Artificial Neural Network), XGBoostRegressor (Extreme Gradient Boosting Regressor) and LGBMRegressor (Light Gradient Boosting Machine Regressor), were developed for predicting the HSPs on CCFs screening for drugs. The HSPs database for 181 CCFs (containing alcohols, alkenes, aromatics, haloalkanes, amines, ketones, ethers, amides, esters, pharmaceuticals, alkanes, acids, nitroalkanes) were established and classified into the training set (140 compounds) and the test set (41 compounds with various functional polarity and groups, covering solid reagents and solvents). The prediction molecular descriptors were combined from the GC (Group Contribution) methods, the COSMO-RS (the Conductor-like Screening Model for Real Solvents) sigma-moments and energy descriptors. The results showed that ANN and XGBoostRegressor beat out LGBMRegressor in predicting HSPs for CCFs. Finally, SHapley Additive exPlanations (SHAP) was employed to visualize and explain the most important characteristics and effects on predicting HSPs via XGBoostRegressor, indicating that CH3, M2 and MHbdon3 had a significant influence and high contribution to the prediction of δd, δp and δh, respectively. The coupled GC and COSMO-RS strategy had been proven as a promising tool to predict HSPs through XGBoostRegressor for screening, designing, and selecting CCFs for drugs.

The curious case of proton migration under pressure in the malonic acid and 4,4'-bipyridine cocrystal.

In the search for new active pharmaceutical ingredients, the precise control of the chemistry of cocrystals becomes essential. One crucial step within this chemistry is proton migration between cocrystal coformers to form a salt, usually anticipated by the empirical ΔpKa rule. Due to the effective role it plays in modifying intermolecular distances and interactions, pressure adds a new dimension to the ΔpKa rule. Still, this variable has been scarcely applied to induce proton-transfer reactions within these systems. In our study, high-pressure X-ray diffraction and Raman spectroscopy experiments, supported by DFT calculations, reveal modifications to the protonation states of the 4,4'-bipyridine (BIPY) and malonic acid (MA) cocrystal (BIPYMA) that allow the conversion of the cocrystal phase into ionic salt polymorphs. On compression, neutral BIPYMA and monoprotonated (BIPYH+MA-) species coexist up to 3.1 GPa, where a phase transition to a structure of P21/c symmetry occurs, induced by a double proton-transfer reaction forming BIPYH22+MA2-. The low-pressure C2/c phase is recovered at 2.4 GPa on decompression, leading to a 0.7 GPa hysteresis pressure range. This is one of a few studies on proton transfer in multicomponent crystals that shows how susceptible the interconversion between differently charged species is to even slight pressure changes, and how the proton transfer can be a triggering factor leading to changes in the crystal symmetry. These new data, coupled with information from previous reports on proton-transfer reactions between coformers, extend the applicability of the ΔpKa rule incorporating the pressure required to induce salt formation.

A New Look at the Mechanism of Cocrystal Formation and Coformers Exchange in Processes Forced by Mechanical and/or Thermal Stimuli - ex situ and in situ Studies of Low-Melting Eutectic Mixtures.

Three different devices: ball mill, hot stage melting, and magic angle spinning (MAS) NMR rotor were used for the preparation of ethenzamide (ET) cocrystals with glutaric acid (GLU), ethylmalonic acid (EMA) and maleic acid (MAL) as coformers. In each case, well-defined binary systems (ET:EMA, ET:GLU, ET:MAL) were obtained. The common features of the two solvent free methods of cocrystal formation (grinding, melting) are presented on the basis of arguments obtained by solid state NMR spectroscopy. Thermal analysis (Differential Scanning Calorimetry) proved that the eutectic phase arises over a wide range of molar ratios of components for each of the binary systems. NMR techniques, supported by theoretical calculations, allowed to provide details about the pathway of the reaction mechanism with atomic accuracy. It was found that the formation of ET cocrystals is a complex process that requires five steps. Each step has been recognized and described. Variable temperature 1D and 2D MAS NMR experiments allowed to track physicochemical processes taking place in a molten state. Moreover, it was found that in a multicomponent mixture consisting of all four components, ET, EMA, GLU, and MAL, ET in the molten phase behaves as a specific selector choosing only one partner to form binary cocrystals according to energy preferences. The process of exchange of coformers in binary systems during grinding, melting, and NMR measurements is described. The stabilization energies (Estab ) and molecular electrostatic potential (MEP) maps computed for the cocrystals under discussion and their individual components rationalize the selection rules and explain the relationships between individual species.

Cocrystals of carbamazepine: Structure, mechanical properties, fluorescence properties, solubility, and dissolution rate

Carbamazepine (CBZ) is an anticonvulsant with very low water solubility, presenting as a white crystalline powder with poor mechanical properties and is hard to bend. To enhance CBZ’s physicochemical properties, such as water solubility and mechanical properties, we selected six cocrystal coformers (CCFs): nicotinamide (NIC), benzamide (BZM), salicylic acid (SCA), fumaric acid (FMA), trimesic acid (TMA), and hesperetin (HPE). Six CBZ cocrystals were successfully prepared using the solution method. Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and single crystal X-ray diffraction (SCXRD) were used to characterize the crystal structures and gain comprehensive insights into the six cocrystals. The mechanical, fluorescence, and solubility properties of the six cocrystals were tested. The results reveal that most of the prepared cocrystals exhibit improved water solubility and mechanical properties when compared to CBZ. Among them, the dissolution rate of cocrystals excluded from CBZ-HPE has increased by an average of 3 or 4 times compared to CBZ, while CBZ-HPE exhibits superior mechanical properties. Moreover, all six cocrystals possess better fluorescence performance than CBZ. We thoroughly evaluated the mechanical properties of the cocrystals through both experimental and theoretical approaches. This work provides a new direction for studying drug cocrystals to improve the physicochemical properties of drugs.

Theoretical and experimental cocrystal screening of temozolomide with a series of phenolic acids, promising cocrystal coformers

The virtual cocrystal screening approach based on molecular electrostatic potential surface (MEPS) maps is a fast and feasible computational method to estimate the probability of cocrystal formation by calculating the difference in the interaction site pairing energies of monomers and that of their assemblies prior to experimental screening. In this paper, we report 12 cocrystal forms of temozolomide with mono-, di-, and trihydroxy benzoic acids, namely, 3‑hydroxy-, 2,4-dihydroxy-, 2,5-dihydroxy-, 2,6-dihydroxy-, 3,4-dihydroxy-, and 3,4,5-trihydroxy-benzoic acids, as well as benzoic acid, as pharmaceutical coformers for the first time. 10 single crystals out of the 12 cocrystal forms were obtained and unequivocally determined by single-crystal X-ray diffraction, which clarified spatial arrangements, molecular conformations, and supramolecular synthons. MEPS further gains some insights into the sites of hydrogen bonding interactions for exploring combination patterns in these assemblies. Modulated stability of TMZ was successfully achieved by cocrystallization with these acids.

Cocrystal Synthesis through Crystal Structure Prediction.

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all the possible crystalline solid forms of small-molecule active pharmaceutical ingredients. We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. For MK-8876, the CSP-based cocrystal prediction was performed retrospectively and successfully predicted the maleic acid cocrystal as the most likely cocrystal to be observed. The triol is known to form two different cocrystals with 1,4-diazabicyclo[2.2.2]octane (DABCO), but a larger solid form landscape was desired. CSP-based cocrystal screening predicted the triol-DABCO cocrystal as rank one, while a triol-l-proline cocrystal was predicted as rank two. Computational finite-temperature corrections enabled determination of relative crystallization propensities of the triol-DABCO cocrystals with different stoichiometries and prediction of the triol-l-proline polymorphs in the free-energy landscape. The triol-l-proline cocrystal was obtained during subsequent targeted cocrystallization experiments and was found to exhibit an improved melting point and deliquescence behavior over the triol-free acid, which could be considered as an alternative solid form in the synthesis of islatravir.

Co-crystallization of sofosbuvir with sugars for enhanced dissolution rate

Sofosbuvir is one of the direct acting antiviral agents which is approved in the treatment of chronic HCV in combination with other agents. The low aqueous solubility of sofosbuvir resulted in slow dissolution which is supposed to be responsible for its low and variable bioavailability after oral administration. Accordingly, the objective of this work was to investigate the effect of co-crystallization of sofosbuvir with hydrophilic sugars on its crystalline structure and dissolution rate. Mixtures of sofosbuvir with hydrophilic sugars at various molar ratios were prepared by ethanol assisted kneading followed by drying. The dry products were then characterized by attenuated total reflectance fourier transform infrared spectroscopy (ATR FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and in vitro dissolution studies. Combined instrumental analysis reflected development of new crystalline species of co-crystal type. This was evidenced by the existence of hydrogen bonding as shown from FTIR spectra, change in the thermal behaviour and appearance of new diffraction peaks in the diffractograms recorded by XRD. The co-crystallization was associated by weakening of intermolecular bonds which resulted in significant increase in the dissolution rate of sofosbuvir. The study introduced hydrophilic sugars as co-crystal co-formers for enhanced dissolution of sofosbuvir.

Structural diversity of cocrystals formed from acridine and two isomers of hydroxybenzaldehyde: 3-hydroxybenzaldehyde and 4-hydroxybenzaldehyde.

Cocrystals formed from acridine and two isomers of hydroxybenzaldehyde: 3-hydroxybenzaldehyde (1) and 4-hydroxybenzaldehyde (2) were synthesized and structurally characterized. Single-crystal X-ray diffraction measurements show that compound 1 crystallizes in the triclinic P1̄ space group, whereas compound 2 crystallizes in the monoclinic P21/n space group. In the crystals of title compounds, the molecules interact via O-H⋯N and C-H⋯O hydrogen bonds, and C-H⋯π and π-π interactions. DCS/TG measurements indicate that compound 1 melts at a lower temperature than the separate cocrystal coformers, whereas compound 2 melts at a higher temperature than acridine but at a lower temperature than 4-hydroxybenzaldehyde. The FTIR measurements reveal that the band attributed to the stretching vibrations of the hydroxyl group of hydroxybenzaldehyde disappeared, but several bands appeared in the range of 3000-2000 cm-1.

Solubility behaviour of CL-20 and HMX in organic solvents and solvates of CL-20

2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) and 1,3,5,7-tetranitro-1,3,5,7-tetrazoctane (HMX) are promising cocrystal coformers, but only little solubility data are available. Knowledge about their solubility and solvate formation is essential for the development of cocrystallisation experiments. This paper provides the solubility values of HMX and CL-20 in 29 solvents at 293.15 ​K and 333.15 ​K as well as the solubility in five 2-propanol solvent mixtures at 293.15 ​K. Novel CL-20 solvates of 5-methyloxolan-2-one, 1,3-dioxolan-2-one, tetrahydrotiophene 1-oxide, 1,3-dioxolane, furan-2-carbaldehyde and butane-2,3-dione have been isolated and characterised. For all new solvates, single crystal data were obtained, except for furan-2-carbaldehyde. The novel ϑ-conformation of CL-20 was observed in the tetrahydrotiophene 1-oxide solvate. It was found that none of the tested solvents and likely no existing solvent exhibits a beneficial solubility ratio of CL-20 and HMX in the tested temperature range, exceptionally good solubility ratios are most likely the result of solvate formation, and that solvate forming solvents cannot be categorically excluded from consideration as solvent for cocrystallisation of HMX and CL-20.

A combined theoretical and experimental investigation into the high-throughput screening of cocrystal coformers

A combined theoretical and experimental investigation into the high-throughput screening of cocrystal coformers

Designing of Stable Co-crystals of Zoledronic Acid Using Suitable Coformers.

In this present study a new co-crystals of zoledronic acid with DL-tartaric acid and nicotinamide has been developed with improved solubility. Zoledronic acid is a class III drug with poor oral bioavailability due to its poor permeability and low aqueous solubility; hence an attempt has been made to improve its solubility by co-crystallization technology. Pharmaceutical cocrystals are multi-component crystals with a stoichiometric ratio of active pharmaceutical ingredients (APIs) and cocrystal coformers (CCFs) that are assembled by noncovalent interactions such as hydrogen bonds, π-π packing, and Vander Waals forces. In this study the coformers selected were DL-tartaric acid and nicotinamide based on ease of hydrogen bond formation. The co-crystal of zoledronic acid with DL-tartaric acid were prepared in three ratios (1 : 1, 1 : 2 and 2 : 1) by slow solvent evaporation method and with nicotinamide in 1 : 1 ratio by dry grinding method. The formation of co-crystal was confirmed by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and Fourier transform (FT)IR. The dynamic solubility of co-crystals with DL-tartaric acid in the ratios 1 : 1, 1 : 2 and 2 : 1 increased by fold as compared to pure drug.

Naringenin Cocrystals Prepared by Solution Crystallization Method for Improving Bioavailability and Anti-hyperlipidemia Effects.

Naringenin exerts anti-inflammatory, hypolipidemic, and hepatoprotective effects; however, it shows low oral bioavailability because of poor water solubility. In this work, cocrystals of naringenin were formed to address these issues. Using the solution crystallization method, various naringenin cocrystals were prepared with different cocrystal coformers, including naringenin-nicotinamide, naringenin-isonicotinamide, naringenin-caffeine, naringenin-betaine, and naringenin-L-proline. The formation of these cocrystals was assayed by using DSC, XRD, and FT-IR spectroscopy. The stoichiometric ratio of naringenin and the CCFs in the corresponding cocrystals was investigated by NMR. The solubility of naringenin, as well as its dissolution rate, was markedly improved by forming cocrystals. The oral bioavailability of naringenin administered as naringenin-L-proline and naringenin-betaine cocrystals was achieved significantly greater than that of pure naringenin (p < 0.05). In particular, the Cmax of naringenin-L-proline and naringenin-betaine cocrystals were 2.00-fold and 3.35-fold higher, and the AUC of naringenin-L-proline and naringenin-betaine cocrystals were 2.39-fold and 4.91-fold, respectively, higher than pure naringenin in rats. With the naringenin-betaine cocrystals for oral delivery, the drug distribution in the liver was significantly increased compared to pure naringenin. Accordingly, the naringenin-betaine cocrystals showed improved anti-hyperlipidemia effects on the C57 BL/6J PNPLA3 I148M transgenic mouse hyperlipidemia model. Collectively, cocrystal formation is a promising way to increase the bioavailability of naringenin for treating hyperlipidemia.

Pharmaceutical Cocrystal Formation of Pyrazinamide with 3-Hydroxybenzoic Acid: A Terahertz and Raman Vibrational Spectroscopies Study.

Vibrational modes of pyrazinamide (PZA), 3-hydroxybenzoic acid (3-hBA), and their cocrystal were characterized using terahertz time-domain (THz-TDS) and Raman vibrational spectroscopic techniques. In experimental THz spectra, the cocrystal has characteristic absorption bands at around 0.81, 1.47, and 1.61 THz, respectively, meanwhile the raw materials are absolutely different in this region. Raman spectra also show similar results about differences between the cocrystal and corresponding starting parent materials. Density functional theory (DFT) was used to simulate both optimized structures and vibrational modes of the cocrystal formed between PZA and 3-hBA. The vibrational modes of such cocrystal are assigned through comparing the simulation DFT frequency results with experimental vibrational spectra. The calculation of the theoretical THz spectrum shows that the hydrogen bonding effect established between H11–N12–H13 and the carboxyl group -COOH makes contributions to the formation of absorption peaks in 0.49, 0.62, 0.83, and 1.61 THz, which agrees pretty well with experimental results. The theoretical Raman result also matches well with experimental observations. The results provide a fundamental benchmark for the study of pharmaceutical cocrystal formation and also inter-molecular hydrogen bonding interactions between active pharmaceutical ingredients and various cocrystal coformers based on Raman and terahertz vibrational spectroscopic techniques combined with theoretical simulations.

Mechanochemical Synthesis and Crystal Structure of the Lidocaine-Phloroglucinol Hydrate 1:1:1 Complex

Molecular complexation is a strategy used to modify the physicochemical or biopharmaceutical properties of an active pharmaceutical ingredient. Solvent assisted grinding is a common method used to obtain solid complexes in the form of cocrystals. Lidocaine is a drug used as an anesthetic and for the treatment of chronic pain, which bears in its chemical structure an amide functional group able to form hydrogen bonds. Polyphenols are used as cocrystal coformers due to their ability to form O–H···X (X = O, N) hydrogen bond interactions. The objective of this study was to exploit the ability of phloroglucinol to form molecular complexes with lidocaine by liquid assisted grinding. The formation of the complex was confirmed by the shift of the O–H and C=O stretching bands in the IR spectra of the polycrystalline ground powders, suggesting the formation of O–H···O=C hydrogen bonds. Hydration of the complexes also was confirmed by IR spectroscopy and by powder X-ray diffraction. The molecular structure was determined by single crystal X-ray diffraction.

Experimental and Theoretical Study of Selectivity in Mechanochemical Cocrystallization of Nicotinamide with Anthranilic and Salicylic Acid

Selectivity in mechanochemical cocrystal formation between nicotinamide and anthranilic acid or salicylic acid was studied using tandem in situ reaction monitoring by powder X-ray diffraction (PXRD) and Raman spectroscopy. Selectivity was probed by offering a competing cocrystal coformer to a previously prepared cocrystal or under competitive reaction conditions where all cocrystal coformers, in different stoichiometric ratios, were introduced together in the starting reaction mixture. Reaction paths were dependent on the starting mixture composition, and we find that the formation of intermediates and the final product can be predicted from solid-state ab initio calculations of relative energies of possible reaction mixtures. In some cases, quantitative assessment revealed different reaction profiles derived from PXRD and Raman monitoring, directly indicating, for the first time, different mechanochemical reactivity on the molecular and the bulk crystalline level of the reaction mixture.

Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

Multicomponent solids such as cocrystals have emerged as a way to control and engineer the stability, solubility, and manufacturability of solid active pharmaceutical ingredients (APIs). Cocrystals are typically formed by solution- or solid-phase reactions of APIs with suitable cocrystal coformers, which are often weak acids. One key structural question about a given multicomponent solid is whether it should be classified as a salt, where the basic API is protonated by the acid, or as a cocrystal, where the API and coformer remain neutral and engage in hydrogen bonding interactions. It has previously been demonstrated that solid-state NMR spectroscopy is a powerful probe of structure in cocrystals and salts of APIs; however, the poor sensitivity of solid-state NMR spectroscopy usually restricts the types of experiments that can be performed. Here, relayed dynamic nuclear polarization (DNP) was applied to reduce solid-state NMR experiment times by 1–2 orders of magnitude for salts and cocrystals of a compl...

Preparation and Characterization of Cabamazepine Cocrystal in Polymer Solution.

In this study, we attempted to prepare carbamazepine (CBZ) cocrystal through the solution method in ethanol-water solvent mixture (volume ratio 1:1) and polyvinyl pyrrolidone (PVP) solution. Nicotinamide (NIC) and saccharin (SAC) were selected as cocrystal coformers. Cocrystal screening products were characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction (PXRD) techniques. Characterization results show that in ethanol-water solvent mixture, pure CBZ-NIC cocrystal can be prepared, while CBZ-SAC cocrystal cannot be obtained. The addition of PVP can inhibit CBZ-NIC cocrystal formation and facilitate CBZ-SAC cocrystal formation.

Crystal Engineering: A Remedy To Tailor the Biopharmaceutical Aspects of Glibenclamide

New cocrystals of glibenclamide (GCM), namely, glibenclamide–hippuric acid, glibenclamide–nicotinic acid, glibenclamide–theophylline, and glibenclamide–succinic acid, were prepared using solvent assisted grinding. The formation of a new crystalline phase was preliminarily characterized by differential scanning calorimetry and powder X-ray diffraction (PXRD), which was further supported by Fourier transform infrared (FT-IR) spectroscopy and 13C solid state NMR analysis. The crystal structures of these cocrystals were determined from PXRD using BIOVIA material studio software. The data revealed the existence of new hydrogen bond interactions between -NH and the oxygen atom of the sulphamoyl group of GCM with carboxylic -C═O, aromatic N (Naromatic), imidazolic -NH, and carboxylic -OH of cocrystal coformers. Equilibrium solubility and intrinsic dissolution rate studies of cocrystals in phosphate buffer of pH 7.4 showed almost 1.5–3.5 times higher solubility as compared to that of pure of GCM. This further led...

Rationalization of the Color Properties of Fluorescein in the Solid State: A Combined Computational and Experimental Study.

Fluorescein is known to exist in three tautomeric forms defined as quinoid, zwitterionic, and lactoid. In the solid state, the quinoid and zwitterionic forms give rise to red and yellow materials, respectively. The lactoid form has not been crystallized pure, although its cocrystal and solvate forms exhibit colors ranging from yellow to green. An explanation for the observed colors of the crystals is found using a combination of UV/Vis spectroscopy and plane‐wave DFT calculations. The role of cocrystal coformers in modifying crystal color is also established. Several new crystal structures are determined using a combination of X‐ray and electron diffraction, solid‐state NMR spectroscopy, and crystal structure prediction (CSP). The protocol presented herein may be used to predict color properties of materials prior to their synthesis.

Directly Insight Into the Inter- and Intramolecular Interactions of CL-20/TNT Energetic Cocrystal through the Theoretical Simulations of THz Spectroscopy.

Compared with cocrystal coformers, an explosive cocrystal has distinctive packing arrangements and complex intermolecular interactions. Identifying the spectral signatures of an explosive cocrystal and understanding the molecular low-frequency modes by means of the spectrum in the terahertz range are of great worth to the explicit mechanism of cocrystal formation. In this work, on the basis of the joint molecular dynamics (MD) simulations and solid-state density functional theory (DFT) calculations, we have investigated the terahertz (THz) absorption spectra of the CL-20/TNT cocrystal and its different directions as well as cocrystal coformers and determined the systematic and all-sided assignments of corresponding THz vibration modes. The THz spectral comparison of the cocrystal with different directions and the cocrystal coformers indicates that the CL-20/TNT cocrystal has five fresh low-frequency absorption features as unique and discernible peaks for identification, in which 0.25, 0.73, and 0.87 THz are attributed to intensive crystalline vibrations; 0.87 THz is also caused by C-H···O hydrogen-bonding bending vibrations; 1.60 and 1.85 THz features originate from C-H···O hydrogen-bond stretching vibrations. Additionally, the THz spectrum of the (001) direction of the CL-20/TNT cocrystal verifies that the molecular conformation of the CL-20 is the same as that in the β-polymorph, other than the initial conformation of raw material ε-CL-20.