Novel cocrystals of the potent 1,2,4-thiadiazole-based neuroprotector with carboxylic acids: virtual screening, crystal structures and solubility performance (original) (raw)
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Three new hydrochlorothiazide cocrystals: Structural analyses and solubility studies
Journal of Molecular Structure, 2017
Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform-infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P2 1 /n, P2 1 /c and P2 1 /n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after four hours in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs.
Computational and Theoretical Chemistry, 2016
Intrinsic solubility of the isoniazid-carboxylic acid cocrystals is explored using thermodynamic cycle of transferring from crystal to gas and then to solution. The enthalpy/Gibbs free energy of phase transitions is computed by solid-state DFT (crystal) and DFT methods with/without accounting for polar solvent (aqueous solution/gas). The dissolution process of the isoniazid-dicarboxylic acid 2:1 cocrystals is found to be enthalpy-determined. The linear correlation between the theoretical sublimation enthalpies and experimental Gibbs energy of solution is established. According to it, the increase of stability causes the decrease of the considered cocrystals solubility. We conclude that a soluble and relatively stable cocrystal of isoniazid should be characterized by the sublimation enthalpy varying from 185 to 200 kJÁmol À1. Bader analysis of theoretical periodic electron density enables us to quantify the noncovalent interactions and clarify their role in formation of the isoniazid cocrystals. The sublimation enthalpy of the cocrystals is defined by the structure of the coformer molecule. Its value is less 150 kJÁmol À1 in the case of aromatic acids and larger than 180 kJÁmol À1 for the aliphatic dicarboxylic acids. The sublimation enthalpy increases with the increase of the dicarboxylic acid hydrocarbon chain.
Novel Synthons in Sulfamethizole Cocrystals: Structure−Property Relations and Solubility
The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH 2 and imine NH; acceptors: sulfonyl O, thiazolidine N and S, and imidine N), which makes it a functionally diverse molecule to form cocrystals. A cocrystal screen of sulfamethizole (SMT) with COOH, NH 2 , pyridine, and CONH 2 functional group containing coformers, e.g., p-aminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), 4,4-bipyridine (BIP), suberic acid (SBA), oxalic acid (OA), and adipic acid (ADP), resulted in six cocrystals and one salt, namely, SMT−ADP (1:0.5), SMT−PABA (1:1), SMT−VLA (1:1), SMT−ABA (1:1), SMT−BIP (1:1), SMT−SBA (1:0.5), and SMT−OA (1:1). The novel crystalline adducts were synthesized by liquid-assisted cogrinding and isothermal solvent crystallization. In addition to single-crystal X-ray diffraction, the phase composition of the powder samples was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Hydrogen bonding interactions between the coformers and SMT are analyzed as six different synthons. In addition to strong N−H···O and O−H··· N hydrogen bonds, the cocrystal structures are sustained by weak C−H···O hydrogen bonds. The not so common chalcogen− chalcogen (S···O) type II intermolecular interaction in SMT−ADP cocrystal and chalcogen−nicogen (S···N) type II interaction in SMT−BIP cocrystal were observed. The products were characterized by vibrational spectroscopy to obtain information on the strengths of the intermolecular interactions. Solubility and dissolution experiments on SMT−ADP, SMT−SBA, and SMT−OA showed a lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1 N HCl medium, which is ascribed to stronger N−H···O, N−H···N, and O−H···O hydrogen bonds and better crystal packing. The decreased IDR could be useful in controlled/extended release of SMT to improve therapeutic activity of the drug by minimizing its fast systemic elimination in vivo. Furthermore, we observed that SMT−OA salt is formed spontaneously when the components were mixed in acidic medium (0.1 N HCl), whereas in neutral medium (phosphate buffer) no SMT−OA salt formation was observed.
International Journal of Applied Pharmaceutics, 2018
Objective: Pharmaceutical cocrystal is a promising method to improve the solubility of active pharmaceutical ingredients (APIs). Itraconazole (ITZ) is a BCS class II antifungal drug with poor aqueous solubility, therefore an attempt was made to improve the solubility of ITZ using cocrystallization technique. In this work, six novel pharmaceutical cocrystals of ITZ with various coformers, including 4-hydroxybenzoic acid (4HBA), trans-cinnamic acid (TCA), suberic acid (SUB), sebacic acid (SBC), 1-hydroxy-2-naphthoic acid (1H2N), and benzamide (BZD) were prepared. Methods: ITZ cocrystals was prepared by solvent evaporation process. The cocrystals produced were characterized using powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and fourier transform infrared (FTIR) spectroscopy. Solubility analysis was performed to evaluate the cocrystals. Results: PXRD and DSC analysis revealed that the pattern of all ITZ cocrystals was distinguishable from the individual compounds which indicates the formation of new phase. The solubility of ITZ and its cocrystals from highest to lowest after 24 h in 0.1 N HCl solution (pH 1.2) follows the order ITZ-TCA (1.97-fold), ITZ-SBC (1.09-fold), ITZ, ITZ-1H2N (0.58-fold) and ITZ-4HBA (0.46-fold). Conclusion: This study demonstrates that the selection of coformers has pronounced an impact on the physicochemical properties of ITZ. Based on this study, it can be concluded that cocrystallization offers a valuable way to improve the solubility of ITZ.
International Journal of Pharmaceutics, 599, 120441, 2021
In this work, the cocrystallization approach was applied to itraconazole (ITR), a very slightly soluble triazole antifungal drug, which led to the formation of two new solid forms of ITR with 4-aminobenzoic acid (4AmBA) and 4-hydroxybenzamide (4OHBZA). A thermodynamic analysis of the solid-liquid binary phase diagrams for the (ITR + 4AmBA) and (ITR + 4OHBZA) systems provided conclusive evidence of the cocrystal stoichiometry: 1:1 for the cocrystal with 4-aminobenzoic acid, and 1:2 for the cocrystal with 4-hydroxybenzamide. Powder X-Ray diffraction analysis confirmed the formation of two different polymorphic forms of the [ITR + 4OHBZA] (1:2) cocrystal obtained either through solution or melt crystallization. Cocrystal formation and polymorphic transition processes were investigated in detail by the DSC and HSM methods. The thermodynamic functions of cocrystal formation were estimated from the solubility of the cocrystals and the corresponding solubility of the pure compounds at different temperatures. The combination of ITR and 4OHBZA was found to be more favorable than the reaction between ITR and 4AmBA in terms of both Gibbs energy and enthalpy. The pH-solubility behavior of the cocrystals was investigated at different pH values using eutectic concentrations of the components and the cocrystal solubility advantage was estimated. It was found that the cocrystallization of itraconazole with 4OHBZA and 4AmBA can potentially increase the drug solubility at pH1.2 and 37 • C by 225 and 64 times, respectively. The cocrystal dissolution behavior in biorelevant media was analyzed in terms of C max , σ max parameters (the maximum ITR concentration and supersaturation), and AUC (the concentration area under the curve during the dissolution-supersaturation-precipitation process). The cocrystals had similar σ max values during the dissolution and sustained supersaturation for up to 6 h, which gave them an advantage in the AUC values (13-37 times higher) over the drug. The differences in the dissolution profiles of the cocrystals were rationalized in terms of their dissolution rate values.
Polimery w medycynie, 2019
Background. Tinidazole (TNZ) is an anti-parasite drug used in the treatment of a variety of amebic and parasitic infections. It has low solubility in aqueous media and is categorized under Class II of the Biopharmaceutical Classification System. Objectives. The aim of this research was to study the potential for enhancing the solubility of TNZ using carboxylic acid co-crystals. Material and methods. The solubility of TNZ was determined individually using 6 carboxylic acids for forming co-crystals at a 1:1 stoichiometric ratio. Three carboxylic acids-namely tartaric acid (TA), oxalic acid (OA) and glutaric acid (GA)-resulted in the formation of co-crystals with enhanced solubility. An equilibrium solubility study of TNZ co-crystals at 1:1.5 and 1:2 stoichiometric ratios was also carried out. The co-crystals which developed were evaluated using X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC) to study the drug-co-crystal former interactions. Results. The solubility of TNZ in distilled water was found to be 0.014 mg/mL. The highest enhancement ratio was obtained with TNZ and TA at a ratio of 1:1. Differential scanning calorimetry thermograms suggested that the drug and carboxylic acids had undergone interactions such as hydrogen bonding. The XRD and DSC results confirmed the formation of co-crystals. Conclusions. It was concluded that the results of enhanced solubility of TNZ using co-crystals is a clear indication of the potential for co-crystals to be used in the future for other poorly water-soluble drugs, considering that co-crystals are a safe and cost-effective approach.
The bronchodilator drug theophylline (THP), though a BCS class-I drug, is considered as a representative compound to prepare variable stoichiometry cocrystals with isomeric aminobenzoic acids (o-ABA, m-ABA, and p-ABA) as coformers. Cocrystals are synthesized using crystal engineering principles through liquid-assisted mechanochemical grinding. Four different stoichiometry cocrystals of THP are isolated with o-ABA. Coformers m-ABA and p-ABA afforded only 1:1 cocrystals irrespective of crystallization media and different starting materials ratios. All cocrystal materials were subjected to aqueous solubility and diffusion/membrane permeability to examine drug biopharmaceutic properties to predict the in vivo performance of the drug. They exhibited different but improved solubility and modulated diffusion/membrane permeability when compared with pure THP. The interplay of drug solubility and membrane permeability that predicts the overall bioavailability is emphasized based on hydrogen bond synthons and solute···solvent interactions. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between permeability and drug−coformer interactions.
Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement
MRS Bulletin, 2006
Pharmaceutical cocrystals are crystalline molecular complexes containing therapeutic molecules. They represent an emerging class of pharmaceutical materials offering the prospect of optimized physical properties. This article highlights important opportunities and challenges associated with the design and synthesis of pharmaceutical cocrystals. Cocrystallization is first placed into context with the more established approaches to physical property optimization of polymorph, hydrate, and salt selection. A directed, intermolecular-interaction-based approach to cocrystal design is described. The enhancement of specific physical properties, such as dissolution rate and physical stability, is illustrated by summarizing several recent reports. Synthetic approaches to cocrystallization are considered; in particular, the selectivity and screening-related opportunities afforded by solid-state grinding and solvent-drop grinding methods are discussed. Finally, an outlook on future developments...
Halogen and Hydrogen Bonding in Multicomponent Crystals of Tetrabromo-1H-Benzotriazole
Crystals, 2017
Tetrabromo-1H-benzotriazole (TBBT) is still considered a reference inhibitor of casein kinase II (CK2), a valuable target for anticancer therapy, even though the poor solubility in water of this active pharmaceutical ingredient (API) has prevented its implementation in therapy. We decided to explore the interactions preferentially formed by TBBT in crystalline solids in order to obtain information helpful for the development of new TBBT cocrystals possibly endowed with improved bioavailability. In this paper, we describe the synthesis and the structural characterization of the TBBT methanol solvate and of the TBBT salt with N,N,N',N'-tetramethylethylenediamine. It is shown that TBBT can give rise to several competing interactions. This API is clearly a good halogen bond (XB) donor, with bromine atoms adjacent to the triazole ring possibly better donors than the two others. TBBT is also a good hydrogen bond (HB) donor, with the triazole hydrogen forming an HB with the acceptor or being transferred to it. Interestingly, one of the triazole nitrogens was proven to be able to work as a hydrogen bond acceptor.
2019
Through cocrystallization of the broad-spectrum antifungal agent fluconazole (FLZ) with a number of nutraceuticals, we have isolated three distinct solid forms of the drug, namely, anhydrous cocrystal with vanillic acid (VA) and anhydrous and hydrated cocrystals of 4-hydroxybenzoic acid (4OHBA). The new cocrystals have been thoroughly investigated by different analytical techniques, including powder and single crystal X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravi-metric analysis (TG), scanning electron microscopy (SEM), and dissolution and solubility methods. Analysis of hydrogen bond patterns in the crystals has shown structural similarity in the packing of FLZ molecules between the new crystal forms and the structures taken from the CSD. Comparing the theoretical lattice energies of multicomponent crystals and their constituents, we have found that hydrated crystal forms are more energetically preferable than the anhydrous cocrystals. Analysis of noncovalent interaction energies performed within the framework of quantum theory of atoms in molecules and crystals (QTAIMC) has confirmed the structure-forming role of water molecules in the hydrated cocrystal of FLZ with 4OHBA. Thermal analysis and SEM investigations have shown that the dehydration behavior of FLZ monohydrate (FLZ·H 2 O) is highly sensitive to particle size and morphology of crystals. The pH-solubility behavior of the cocrystals has been investigated at different pH values using eutectic concentrations of the components, and the driving force of the cocrystal formation process for each solid phase has been estimated. Possible cocrystallization pathways between FLZ and 4OHBA have been examined under mechanochemical conditions. A two-step formation mechanism of cocrystallization reaction, which includes generation of an anhydrous [FLZ+4OHBA] (1:1) cocrystal as an intermediate, has been proposed.