Acid Cocrystal Research Articles

Quercetin-Glycolic Acid Cocrystalization Using Solvent Evaporation and Slurry Methods

Quercetin is a flavonoid compound with the highest antioxidant activity and has the potential to treat various diseases. However, quercetin has poor solubility in water which causes low bioavailability of the drug in the body. One of the modifications that can be made to improve the solubility of a drug is solid modification, for example cocrystals. Cocrystal is a crystalline system between drug and coformer which interacts through hydrogen bonding. Glycolic acid is a compound that can function as a coformer because it has functional groups that have the potential to interact through hydrogen bonds with quercetin molecules. Quercetin-glycolic acid cocrystals were prepared in two molar ratios, namely 1:1 and 1:2, and through two methods of preparation, namely solvent evaporation and slurry. The results of the crystallinity analysis and thermal analysis of the sample indicated that a new solid phase was formed in the sample that was specific and different from the two constituent components. Samples with a molar ratio of 1:2 and the slurry preparation method are known to be samples with the most optimal new crystalline phase formation.

Cocrystal screening of benznidazole based on electronic transition, molecular reactivity, hydrogen bonding, and stability.

Screening of cocrystals of active pharmaceutical ingredients is important in the development of pharmaceutical compounds because it improves bioavailability, stability, solubility, and many other physicochemical properties. In this work, quantum chemical calculations were utilized for the computational evaluation of the cocrystal screening of benznidazole (BZN) API via hydrogen bonding with four coformers (maleic acid, malonic acid, oxalic acid, and salicylic acid), and they contain carboxylic groups. The nitrogen of the imidazole ring in benznidazole and the carboxylic group of the coformer form a hetero-synthon connected by a strong hydrogen bond. The strength of the hydrogen bonding interaction O-H…N was measured using various tools. It was found that in comparison to BZN cocrystals with malonic acid, oxalic acid, and salicylic acid, the O-H…N interaction in the BZN-maleic acid cocrystal had higher interaction energy, indicating it had stronger hydrogen bonding. The strength of the hydrogen bond O-H…N for synthons was discovered to be more beneficial than the C-H…O interaction, as confirmed by ESP analysis. The BZN-salicylic acid cocrystal was found to be more reactive and polarizable, whereas the BZN-malonic acid cocrystal was more stable. Cocrystals of benznidazole exhibited better physicochemical characteristics than API benznidazole, as indicated by electron transition properties between the most significant orbitals. The computational evaluation for the screening of benznidazole cocrystals was performed in Gaussian 16 software using density functional theory (DFT) with the hybrid functional B3LYP and the basis set 6-311 + + G(d,p). The UV-Vis absorption spectrum in solvent water was analyzed using the TD-DFT/6-311 + + G(d,p) method to determine the influence of the solvent in cocrystals using a polarizable continuum model. The strength of the hydrogen bonding interactions O-H…N in each of those mentioned cocrystals was used to screen the cocrystals using tools such as thermodynamic probability, ESP analysis, QTAIM analysis, and NBO analysis. The pairing energy of interaction was measured by determining H-bond donor ( ) and H-bond acceptor ) parameters for hydrogen bonds from maxima and minima on the ESP surface. GaussView 06 software was used to create, visualize, and plot the optimized structure of the cocrystal and HOMO-LUMO orbitals. The AIMALL (10.05.04) software package generated the molecular graph for intra- and intermolecular interactions. The RDG-scatter plot, MEP map, and ELF plot were rendered from Multiwfn 8.0 and VMD 1.9.1 software.

Insight into the phase equilibrium of mycophenolic acid cocrystals

In this study, mycophenolic acid-nicotinamide (MPA-NAM) and mycophenolic acid-acetoguanamine (MPA-AGA) cocrystals were synthesized and characterized using single-crystal X-ray diffraction, Fourier transform spectroscopy and thermal analysis. Intrinsic intermolecular interactions were investigated through Hirshfeld surface and electrostatic potential surface analysis. The results indicated that MPA-NAM and MPA-AGA cocrystals possessed the same types of hydrogen bonds but different hydrogen bond connectivity. Thermodynamic studies revealed that MPA-NAM and MPA-AGA cocrystals exhibited incongruent dissolution behaviors in the chosen solvent. Model regression results indicate that the 1:1 complex formation existed during the dissolution of the MPA-NAM cocrystal, whereas 1:1 and 1:2 solution complexes presented in the MPA-AGA cocrystal. The complicated complexation in the MPA-AGA cocrystal induced all fragments of MPA-AGA to possess higher energies, facilitating MPA-AGA cocrystal precipitation from the solution, which was testified by Energy calculations.

Influence of solvent selection and RESS processing conditions on formation of a praziquantel-malonic acid cocrystal in supercritical CO2

Praziquantel (PZQ) is an anthelmintic drug with low solubility, therefore cocrystallization and particle size reduction is desirable to improve bioavailability. In this study, a PZQ-malonic acid cocrystal was micronized by rapid expansion of supercritical solution (RESS). Due to low solubility in scCO2, four cosolvents were screened as RESS modifiers. While addition of acetone or THF yielded mixtures of PZQ and its cocrystal, MeOH and EtOH produced pure cocrystal. Impact of pressure (15–30 MPa), temperature (35–55 °C), and cosolvent loading (3–10 volumes) on phase-purity, yield, and particle size were investigated. Adding cosolvent to RESS facilitated dissolution of cocrystal formers in scCO2 and crystallization of the cocrystal with yields up to 68.5 wt% and particle size as low as 600 nm. Results show that for APIs with low solubility in scCO2, cosolvent-modified RESS is a suitable approach for simultaneous crystallization and micronization.

Development and Evaluation of Flurbiprofen-Ferulic Acid Co-crystal With Enhanced Solubility and Dissolution Rate.

Flurbiprofen, a BCS class II NSAID, was combined with GRAS molecules to create new co-crystal forms using crystal engineering techniques such as solvent drop grinding and evaporation. Analysis with XRD, DSC, and FTIR confirmed purity and co-crystal formation. X-ray crystal data revealed hydrogen bonding and interactions, while DSC showed changes in thermal behavior. The co-crystals, particularly the flurbiprofen-ferulic acid co-crystals, had increased solubility and faster dissolution than pure drug.

Ternary phase diagram and investigation of slurry conversion of 1:1 sulfamethazine-acetylsalicylic acid cocrystal

Successful production of 1:1 sulfamethazine-acetylsalicylic acid (SMZ-ASA) cocrystal was achieved through slow solvent evaporation, liquid-assisted grinding, and slurry conversion method. SCXRD, PXRD, DSC, FTIR, and Raman spectroscopy were employed to characterize the cocrystal. Ternary phase diagrams (TPD) for SMZ and ASA in acetonitrile (ACN) and deionized water (DIW) has been constructed at 25 ℃. Using TPD of the incongruent system, slurry compositions for stable production of cocrystal was determined in both the solvents. The cocrystal conversion process in slurry was monitored using in-situ Raman spectroscopy. Intermittent sampling was also carried out to determine the purity of the solid phase from the slurry using offline PXRD. In-situ Raman and offline PXRD measurements confirmed fast conversion of the pure coformer crystals to the cocrystal in ACN, within a span of 5 minutes. However, the conversion in DIW was much slower and the in-situ Raman measurements significantly underpredicted the transformation time in comparison to offline PXRD analysis. The study highlights the utilization of TPD for developing the cocrystallization process and the need for multiple characterization techniques for monitoring cocrystallization.

Formulation and optimization of olanzapine-carboxylic acid cocrystals orodispersible tablets: In-vitro/ In-vivo study

Oromucosal delivery of olanzapine (OLZ) is an optimal strategy to overcome low oral bioavailability as well as improve medication adherence. However, its poor aqueous solubility may hinder its absorption through the buccal mucosa. The aim of the study is to enhance OLZ solubility and dissolution via cocrystal formation, followed by incorporation into an orodispersible tablet (ODT) based on an effervescent mixture and crospovidone as a superdisintegrant mixture. OLZ was cocrystallized with different carboxylic acids using slow solvent evaporation, and the optimal cocrystal formula was subjected to solid state characterization. Central composite design (CCD) was used in the modeling and optimization of the ODT independent variables (amounts of crospovidone and effervescent mixture). The optimized OLZ cocrystal ODTs were subjected to microenvironmental pH, stability, and in-vivo studies. The results revealed that the OLZ:itaconic acid at 1:1 M ratio showed a 7.86 fold increase in OLZ solubility and 86.71 ± 1.07 % dissolution efficiency (DE60 %) with FTIR, XRPD, and DSC diffractograms that confirmed the cocrystal formation. The optimized OLZ cocrystal ODTs exhibited hardness of 3.6 ± 0.1 kg/cm2, disintegration time of 11.66 ± 1.52 s, wetting time of 36.33 ± 2.51 s, and 94.26 ± 2.77 % OLZ released within 15 min with a DE60 % of 91.65 ± 0.98 %. Finally, the optimized OLZ cocrystal ODTs showed a significant (p < 0.01) higher Cmax and AUC with a relative bioavailability of 139.08 % compared to the Schisolazine©10 mg ODTs. These results suggest that OLZ:itaconic acid cocrystal incorporated into an ODT containing a superdisintegrant mixture of effervescence mixture and crospovidone is a potential approach for enhancement of oromucosal delivery of OLZ.

Multi-component Crystal Strategy for Improving Water Solubility and Antifungal Activity of Climbazole.

The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects. In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques. The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.

Unveiling spectroscopic behaviour and molecular features (DFT studies) of Exemestane-maleic acid cocrystal as model multicomponent system

The present study aimed to investigate the Exemestane - maleic acid (Ex-Mal) cocrystal using Fourier-transform Raman (FT-Raman), Fourier-transform Infrared (FT-IR), Powder X-ray Diffraction (PXRD) and Differential Scanning Calorimeter (DSC) experimental techniques and quantum chemical calculations. Exemestane (Ex) is an irreversible aromatase inhibitor, clinically used for the treatment of postmenopausal women having primary or advanced breast cancer. Maleic acid (Mal), a dicarboxylic acid is found in many vegetables and fruits and is used as a food additive and sweetener. Solution crystallization of Ex and Mal was done in the generation of Ex-Mal cocrystal (1:1). PXRD and DSC analysis confirmed the successful generation of Ex-Mal Cocrystal. Intermolecular hydrogen bonding (O4-H12···O13 & C8-O3···H36) also suggested the formation of a multi-component system, Ex-Mal cocrystal (1:1), as the respective modes shifted in the vibrational (Raman & IR) spectra of cocrystal than the Ex. Further, the quantum theory of atoms in molecules (QTAIM) has been done to analyze the strength and nature of inter-/intra molecular hydrogen bonding. Natural bond orbital (NBO) analysis was performed to check the stabilization energy of the system. The frontier molecular orbital (FMO) analysis predicted that Ex-Mal cocrystal is more reactive and less stable than Ex. Molecular electrostatic potential (MEP) surface showed that electrophilic (C16-H36)/(O4-H12), and nucleophilic (C8=O3)/(C17=O13) reactive groups in Ex/Mal and Mal/Ex, respectively, neutralized after the formation of Ex-Mal cocrystal, confirming the presence of hydrogen bonding interactions (C16-H36∙∙∙O3=C8) and (C17=O13∙∙∙H12-O4). Molar Refractivity (MR) was calculated to check the drug-likeness behaviours of Ex-mal cocrystal. This study provided a comparison of experimental and theoretical results to understand the hydrogen bonding interactions and structural activity of the system.

Harvesting of shear piezoelectricity in a molded multicomponent crystal disc

Biomolecular piezoelectrics, such as amino acids and peptides, exhibit significant shear piezoelectric responses in single crystal form. However, naturally occurring longitudinal piezoelectricity is rare and, when present, is dampened due to the multi-directional self-assembly in polycrystalline device layers. Here we utilise cocrystallisation to engineer a multicomponent crystalline salt hydrate of S(+)Mandelic Acid and LLysine, S-Mand•L-Lys•5H2O (1). This material exhibits a predicted single crystal longitudinal piezoelectric response of d33 = 3.5 pC/N. In polycrystalline form, 1 grows as an assembly of plates which increases the measured longitudinal piezoelectricity to 11 pC/N in its macroscopic solid-state. This is due to contributions from the shear piezoelectric response d36 = 10.8 pC/N, originating from the presence of plates oriented at acute angles relative to the surface. The brittleness of the crystals (E = 37 GPa) is overcome by reinforcing the substrate-free piezoelectric disc with a thin polymer coating to prevent flaking. Structural analysis confirms that the triclinic structure of 1 gives rise to this increased response due to the relative orientations of individual crystallites. Confined crystallisation of this multi-component form with a plate-like morphology, results in macroscopic self-assembly of an amino acid cocrystal that allows for the harvesting of higher shear piezoelectricity, but in a facile longitudinal configuration.

Stoichiometric Diversity of Caffeine and 4-Hydroxybenzoic Acid Cocrystals in Batchelor Vortex Flow

Stoichiometric Diversity of Caffeine and 4-Hydroxybenzoic Acid Cocrystals in Batchelor Vortex Flow

A Comparison Study between Green Synthesis of Microwave Irradiation and Solvent Evaporation Methods in The Formation of p-Methoxycinnamic Acid-Succinic Acid Cocrystals

Cocrystal of p-Methoxycinnamate acid-succinic acid has been produced by microwave irradiation and solvent evaporation methods. Cocrystals are formed using succinic acid as the coformer at a molar ratio of 1:1. The formation of cocrystal can be done by solvent evaporation method and microwave radiation method. Physicochemical properties have been studied by FT-IR, DSC, PXRD, and SEM analysis. The solubility test was carried out with pH 6.8 phosphate buffer at a temperature of 25±0.5°C for 5 hours and the dissolution test was carried out with 900 mL pH 6.8 phosphate buffer at a temperature of 37±0.5°C with the speed of 75 rpm using a paddle-type dissolution test apparatus. The solubility of PMCA has increased its solubility in cocrystals by the solvent evaporation method by 1.19 times and by the microwave radiation method by 1.16 times compared to PMCA. The dissolution rate of the cocrystals of the solvent evaporation method increased by 3.50 times and the cocrystals of the microwave radiation method increased by 2.29 times compared to PMCA.

Relative Bioavailability Assessment of Solid Forms by An Artificial Stomach and Duodenum Apparatus

In this work, the ability of the artificial stomach and duodenum (ASD) model to predict bioavailability in rats was investigated using a poorly soluble model compound, BI-639667. A solution and four suspensions of different solid forms of BI-639667 were tested both in an ASD and rats. Rank order of the bioavailability estimated from an ASD apparatus is consistent with that of in vivo result in rats, i.e., solution > salicylic acid cocrystal > malate salt > maleate salt > monohydrate, which correlates with the ability of the different solid forms to maintain supersaturation with respect to the stable form in aqueous solution. The results support the use of an ASD for characterizing dissolution performance of solid forms to aid their selection for tablet formulation development.

Noncovalent and Covalent O-H···O Interactions in PPh3O Cocrystals: A Correlation Study Involving QTAIM, SAPT, NBO, and IBSI Methods.

PPh3O.hemihydrate polymorphs and 11 assorted PPh3O cocrystals collectively constitute a reliable stock to pursue a systematic analysis aiming to investigate the impacts of some vital issues on the TPPO.H-bond donor aggregates. The issues highlighted herein are (i) effect of varying acidity of H-bond donors on the degeneracy of lone pairs of the H-bond acceptor (PPh3O), (ii) effectiveness of the |V(r)|/G(r) and H(r)/ρ(r) parameters as a covalency metric, (iii) 3c-4e bonding in the covalent PPh3O.nitric acid cocrystal, (iv) salient features of H-bond interaction energy and an interplay of its components, (v) an intrinsic bond strength scale for the PPh3O cocrystals, and (vi) reliable empirical relations between several bond descriptors for a quick estimation of interaction energy. To be specific about point (vi), we have propounded two promising avenues for a fast semiquantitative calculation of interaction energy from an endearing nonenergetic parameter, viz., bond length: dO-H···O → ρBCP (MAPE = 2.36%) → ESAPT0 (MAPE = 9.26%), and dO-H···O → IBSI (MAPE = 1.87%) → ESAPT0 (MAPE = 9.66%). All the aforesaid issues have been explored in detail through the QTAIM, NBO, and IBSI analyses (M06-2X-D3/def2-TZVP level), as well as by the SAPT study at the SAPT0/aug-cc-pVDZ platform. The statistically valid correlation studies can be particularly conducive for practical purposes as a transformative extension of the established facts into postulates for the unknown cocrystals.

Relationship between synthesis method-crystal structure-melting properties in cocrystals: the case of caffeine-citric acid.

The influence of the crystal synthesis method on the crystallographic structure of caffeine-citric acid cocrystals was analyzed thanks to the synthesis of a new polymorphic form of the cocrystal. In order to compare the new form to the already known forms, the crystal structure of the new cocrystal (C8H10N4O2·C6H8O7) was solved by powder X-ray diffraction thanks to synchrotron experiments. The structure determination was performed using `GALLOP', a recently developed hybrid approach based on a local optimization with a particle swarm optimizer, particularly powerful when applied to the structure resolution of materials of pharmaceutical interest, compared to classical Monte-Carlo simulated annealing. The final structure was obtained through Rietveld refinement, and first-principles density functional theory (DFT) calculations were used to locate the H atoms. The symmetry is triclinic with the space group P-1 and contains one molecule of caffeine and one molecule of citric acid per asymmetric unit. The crystallographic structure of this cocrystal involves different hydrogen-bond associations compared to the already known structures. The analysis of these hydrogen bonds indicates that the cocrystal obtained here is less stable than the cocrystals already identified in the literature. This analysis is confirmed by the determination of the melting point of this cocrystal, which is lower than that of the previously known cocrystals.

Posaconazole-glutaric acid cocrystal tablet with improved Dissolution rate

Posaconazole is used to prevent fungal infections in patients having severely weakened immune system and has poor aqueous solubility which impairs its dissolution in upper gastric fluid producing problems in different formulations. These characteristics hinder its therapeutic application by delaying absorption rate and thereby onset of action. In the present study, an attempt was made to prepare posaconazole cocrystals with improved physicochemical properties for better therapeutic activity. Cocrystals were prepared with glutaric acid in 1:1 molar using ethanol by solvent drop grinding technique. The co-crystals formed were characterized by melting point determination, fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and dissolution studies. Posaconazole-glutaric acid co-crystals were further formulated as fast disintegrating tablets. The IR study revealed the shifting of characteristic bands of posaconazole. The PXRD pattern indicated cocrystal crystallinity and a considerable difference in 2θ value of intense peaks. The variation in fusion endotherm, which is in agreement with melting point, was designated by DSC spectra of posaconazole cocrystal. A significant improvement in the dissolution rate was observed in the case of cocrystals based tablets than pure posaconazole tablets.

Combined experimental and quantum computational studies on 5-Fluorouracil salicylic acid cocrystal: Assessment on anti-breast cancer potential through docking simulation

5-fluorouracil salicylic acid (5FUSA) cocrystal was synthesised via mechanochemical and solution evaporation technique and spectroscopic experiments and theoretical research were conducted. Methods for the experiments included XRD, FTIR, and UV spectroscopy. Following that, 5FUSA was the subject of quantum chemistry investigations employing the DFT/B3LYP/6–311++G (d, p) basis level. First, the resultant simulated XRD pattern was compared to the relevant experimental pattern. The estimated FT-IR frequencies were gathered from the same level of theory and compared to the experimental data. To learn more about the reactive properties of the 5FUSA, the molecular electrostatic potential plot was generated, and Fukui function calculations were also performed. In order to examine intramolecular interactions and verify the bioactivity of the 5FUSA molecule, the natural bond orbital study was also carried out. We examined the UV–Vis absorption wavelengths (λ) via theoretical (TD-DFT) and experimental methods. The non-linear optical properties were identified, and it was discovered that it had three times the NLO activity of urea. The inter- and intramolecular interactions of the 5FUSA were explored using the Hirshfeld surface and finger print approaches. At various temperatures thermodynamic parameters were calculated and topological analyses were conducted using the (ELF, LOL, and RDG). The anticancer activity of 5FUSA cocrystal was studied using molecular docking and the docking scores ranges between -8.1 to -9.0 Kcal/mol against breast tumor proteins.

Phase Diagrams of Praziquantel and Vanillic Acid Cocrystals: Racemic Compound and Conglomerate System

Phase Diagrams of Praziquantel and Vanillic Acid Cocrystals: Racemic Compound and Conglomerate System

In Silico Coformer Screening for Mefenamic Acid Cocrystallization

Cocrystallization is a widely used approach to enhance the solubility and dissolution characteristics of poorly soluble drugs. A pharmaceutical cocrystal is a multicomponent system composed of a solid active pharmaceutical ingredient (API) and a coformer, governed by non-covalent interactions. Screening for suitable coformers is essential to obtain an optimal cocrystal for specific drugs. This study aims to determine the drug-coformer interactions to select the most suitable coformer for cocrystal formation using the molecular docking method. Mefenamic acid, classified as a class II drug in the biopharmaceutical classification system (BCS), was used as the model drug. Two-dimensional structures of mefenamic acid (PubChem CID: 4044) and potential coformers were sourced from PubChem. Geometric optimization of all compounds was performed using GaussView 5.0.8 and Gaussian09 with the 3-21G basis set and Density Functional Theory (DFT) B3LYP method. The optimized compounds were prepared by adding hydrogen atoms and calculating Kollman partial charges using AutoDock 4.2. A grid box of size 40 Å × 40 Å × 40 Å was generated, with a maximum radius of 0.375 Å set as the surface distance in each simulation. A hundred conformations were run using the Lamarckian Genetic Algorithm. Interaction types and binding energies were analyzed using VMD 1.9.2 and BIOVIA Discovery Studio 2020 to compare interactions between mefenamic acid and each coformer. The results revealed that most coformer compounds formed interactions with mefenamic acid via hydrogen bonding and π–interactions. Saccharin demonstrated the most optimal interaction with mefenamic acid, with a binding free energy of –3.1 kcal/mol. Saccharin was identified as the most suitable coformer for mefenamic acid cocrystal formation based on the molecular docking study. Further experimental validation of saccharin is recommended to confirm its effectiveness in cocrystallization with mefenamic acid.

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.