Liquid-assisted Grinding Method Research Articles

Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Recently, favipiravir, as a broad-spectrum antiviral drug, has gain more attention because it might be a candidate to remedy the coronavirus disease 2019 (COVID-19). To improve its poor permeability and tabletability, four multicomponent crystals of favipiravir (FPV) were prepared by a slow evaporation or liquid-assisted grinding method, including three cocrystals (FPV-theophylline, 1:1;FPV-saccharin, 1:1;FPV-5-fluorouracil, 1:1) and one salt (FPV-piperazine, 2:1). All of the crystal structures were solved by single-crystal X-ray diffraction. Interestingly, FPV-theophylline has a crystal structure similar to that of FPV, leading to similar properties, such as solubility, permeability, and tabletability. Except for FPV-theophylline, all of the other multicomponent crystals exhibit an enhanced permeability and tabletability. Our studies provide a new insight in overcoming the shortcomings of the important antiviral drug FPV. ©

Venlafaxine Caffeic Acid Salt: Synthesis, Structural Characterization, and Hypoglycemic Effect Analysis.

Depression is a recurrent and chronic mental disorder requiring long-term treatment. Major depressive disorder is present in 15–20% of patients with type 1 or type 2 diabetes. Large-scale evidence revealed that depression and depressive symptoms are independent risk factors for the development of type 2 diabetes, and they may contribute to hyperglycemia and even accelerate the premature onset of diabetes complications. Venlafaxine is a clinical first-line antidepressant used for more than 30 years. Recently, clinical reports showed that venlafaxine overdose might cause hypoglycemia. Venlafaxine is insoluble and salt formation technology is the most appropriate method to improve the physicochemical properties and the pharmacokinetic profile of the drug. In the present work, the use of the solvent evaporation method, slurry, and the liquid-assisted grinding method resulted in the crystalline salt venlafaxine–caffeic acid (1:1). The compounds were characterized using a series of solid-state techniques, viz., powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and solid-state nuclear magnetic resonance, and the crystal structure was determined by single-crystal X-ray diffraction. Besides, a comparative study of solubility, dissolution, and hypoglycemic activity of the parent drug and the new salt has been carried out. The tested venlafaxine–caffeic acid salt showed about 16-fold higher solubility than the pure drug. Moreover, the glucose consumption assay results showed that the novel salt possesses potent hypoglycemic activity in vitro, suggesting that it is a promising candidate effective for major depressive disorder patients with type 2 diabetes.

Сocrystals of betulin with suberic acid: mechanochemical synthesis and thermal behavior

In this work, the cocrystals of betulin with suberic acid were prepared by liquid-assisted grinding method using solvents of different polarity. The formation of cocrystals was confirmed by means of powder X-ray diffraction, IR spectroscopy and thermal analysis. It was shown that under heating, a structural transformation occurred after water removal, followed by cocrystal dissociation.

Mechanochemical Synthesis of Cocrystals of Betulin with Adipic Acid

The cocrystal of betulin with adipic acid was prepared using a liquid-assisted grinding method. The formation of cocrystal was confirmed by powder X-ray diffraction and IR spectroscopy methods. In order to choose a liquid for preparing cocrystal, solvents of different polarity were compared. It was shown that cocrystal of betulin with adipic acid was formed if solvents were used during mechanical treatment, in which the increased solubility of adipic acid was observed

Simvastatin-Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and in vivo Profile.

PurposeTo enhance the solubility and dissolution profile of simvastatin (SIM) through co-crystallization with varying ratios of nicotinamide (NIC) using various co-methods.Materials and MethodsTwelve SIM:NIC co-crystal formulations (F01–F12) were prepared using dry grinding, slurry, liquid-assisted grinding, and solvent-evaporation methods, and their properties compared. Optimized formulations were selected on the basis of dissolution profiles and solubility for in vivo studies. The angle of repose, Carr Index and Hausner ratio were calculated to evaluate flow properties. Differential light scattering (DLS) was used to estimate particle-size distribution. Scanning electron microscopy (SEM) was employed to evaluate surface morphology. Thermal analyses and Fourier-transform infrared (FTIR) spectroscopy were used to determine the ranges of thermal stability and physical interaction of formulated co-crystals. X-ray powder diffraction (XPD) spectroscopy was used to determine the crystalline nature. Solubility and dissolution studies were undertaken to determine in vitro drug-release behaviors.ResultsMicromeritic analyses revealed the good flow properties of formulated co-crystals. DLS showed the particle size of co-crystals to be in the nanometer range. SEM revealed that the co-crystals were regular cubes. Thermal studies showed the stability of co-crystals at >300°C. FTIR spectroscopy revealed minor shifts of various peaks. XPD spectroscopy demonstrated co-crystal formation. The formulations exhibited an improved dissolution profile with marked improvements in solubility. In vivo studies showed a 2.4-fold increase in Cmax whereas total AUC(0–∞) was increased 4.75-fold as compared with that of SIM tablets.ConclusionCo-crystallization with NIC improved the solubility and dissolution profile and, hence, the bioavailability of the poorly water-soluble drug SIM.

Novel Aceclofenac Cocrystals with l-Cystine: Virtual Coformer Screening, Mechanochemical Synthesis, and Physicochemical Investigations.

Current work focuses on the improvement of the solubility and dissolution of ACF by the cocrystal approach. Aceclofenac (ACF) is one of the commonly used Nonsteroidal Anti-Inflammatory Drug (NSAID) representing a variety of therapeutic applications including management of pain, inflammation, rheumatoid arthritis, and osteoarthritis, etc. But very low solubility and dissolution rate of ACF compromise its therapeutic utility. Now a day's cocrystallization technique has emerged as a novel technique for modulation of the said problems. The Specific objectives of this research work were mechanochemical synthesis, characterization, and performance evaluation of aceclofenac cocrystal. ACF was screened with various pharmaceutically acceptable coformers (Selected from GRAS and EAFUS list) using MOPAC software and physical screening method to find out novel cocrystals of ACF with enhanced solubility and dissolution rate. Novel cocrystals (multi-component crystalline solid) of ACF with l-cystine were prepared by a neat grinding method and by liquid assisted grinding method. The synthesized cocrystals (ACF-l-CYS NG and ACF-l-CYS LAG) were characterized carefully by Differential Scanning Calorimetry (DSC), Infrared Spectroscopy (IR), and Powder XRay Diffraction (PXRD) to verify the formation of the cocrystals. Pharmaceutically significant properties such as powder dissolution rate, solubility, and stability of the prepared cocrystals were evaluated. Compared to pure ACF, the prepared cocrystals showed superior solubility and dissolution rate. The prepared cocrystals were found to be stable and non-hygroscopic under study conditions. The cocrystallization technique was successfully utilized to increase the solubility and dissolution rate of aceclofenac.

Spectroscopic, Structural, DFT and Molecular Docking Studies on Novel Cocrystal Salt Hydrate of Chromotropic Acid and Its Antibiofilm Activity

A novel organic cocrystal salt hydrate (CTPTH) of Chromotropic acid with 1,10-phenanthroline was successfully obtained using both traditional solution method and liquid-assisted grinding method, a green approach. The formation and characterization were done by Powder x-ray diffraction, Fourier-transform infrared spectroscopy, thermogravimetric analysis, and the structural confirmation by single crystal x-ray diffraction. The molecular properties were studied using density functional theory, B3LYP/def2-SVP including dispersion correction (D3) to calculate the HOMO and LUMO energies using Orca and Gaussian packages. The calculated geometric parameters were in good agreement with those of experimentally observed. The non-bonding interaction between the CTPTH and active site of the crystal structure of quorum-quenching N-Acyl homoserine lactone lactonase (PDB: 2BR6) in bacterium was studied by molecular docking. The total energy of ligand interaction of CTPTH with the receptor is found to be − 42.78 kcal mol−1. The Hirshfeld surfaces were mapped over dnorm for the identification and quantification of robust synthons for a better understanding of the overall packing pattern of CTPTH. In addition, the antibiofilm efficacy of CTPTH against the pathogenic bacterium Pseudomonas aeruginosa was also determined.

Exploring potential coformers for oxyresveratrol using principal component analysis.

Oxyresveratrol (OXY) exhibits poor bioavailability due to its low solubility. Cocrystals are effective in improving solubility of OXY. In this study, principal component analysis (PCA) was employed for coformer selection using 5 variables (solubility parameter, logP, hydrogen bonding acceptor, hydrogen bonding donor and molecular volume). According to PCA analyses, nicotinamide (NCT) and proline (PRO) were grouped as the potential coformers. OXY-PRO and OXY-NCT cocrystals were obtained using a liquid assisted grinding method. The thermal and diffraction characteristics of both cocrystals were different from their starting materials. Based on FTIR and Raman spectroscopy, both interactions between the amide group of NCT and the phenolic hydroxyl groups of OXY, as well as π-π interactions between the aromatic rings of OXY and the pyridine ring of NCT were involved in the cocrystal formation. For OXY-PRO cocrystal, the carboxylate group of PRO interacted with the hydroxyl groups of OXY, OXY-NCT and OXY-PRO cocrystals enhanced the solubility and dissolution of OXY. Accordingly, PCA proved to be an effective technique in screening potential coformers for OXY and probably for other compounds. The improved solubility and dissolution of OXY in the form of cocrystal may provide a benefit for the use of OXY for pharmaceutical applications.

Crystal Structures, Stability, and Solubility Evaluation of a 2:1 Diosgenin\u2013Piperazine Cocrystal

A cocrystal of diosgenin with piperazine in 2:1 stoichiometry was successfully synthesized. The solid form was prepared by liquid assisted grinding, slurry and crystallization methods. The cocrystal was characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and structure determined by single crystal X-ray diffraction, the hydrogen bonds formed into fish bone structure along the [010] direction and all the molecules packed into 3D layer structure along a axis. After formation of cocrystal, the solubility of diosgenin was improved, and the solubility value in 0.2% SDS solution was approximately 1.5 times as large as that of the parent material.Graphic

Improving solubility and intrinsic dissolution rate of ofloxacin API through salt formation via mechanochemical synthesis with diphenic acid

The study focusses on the effect of solubility and intrinsic dissolution rate on the pharmaceutical salt of ofloxacin, a new generation fluoroquinolone antibacterial marketed drug, with the organic acid coformer, diphenic acid produced via mechanochemical synthesis using liquid assisted grinding method. The synthesized cocrystal salt was characterized by single crystal and powder X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy techniques. The crystal structure reveals that, there is proton migration from the coformer to the drug leading to the formation of salt via charge assisted N–H+···O hydrogen bond interactions. The aqueous solubility of the drug and its corresponding salt were determined in neutral phosphate buffer medium (pH = 7) at 25 °C using UV–Vis absorption spectroscopy, while dissolution experiments were carried out at 37 °C bath temperature and neutral phosphate buffer conditions. Interestingly it has been observed that the aqueous solubility and intrinsic dissolution rate of the salt form of ofloxacin has enhanced significantly compared to the parent drug and this is expected to have implications in the bioavailability of the drug in different formulations related to the utilization of this drug.

Co-Amorphous Telmisartan-Pimelic Acid with Improved Solubility

Telmisartan (TEL), a type of antihypertensive drug, has poor solubility. To improve its solubility, the co-amorphous telmisartan with pimelic acid (PA) in molar ratio of 1:1 and 2:1, respectively, were obtained using a liquid-assisted grinding method. The co-amorphous system was characterized by the powder X-ray diffraction and differential scanning calorimetry. The molecular interactions of the co-amorphous were studied by the infrared spectra. After the formation of co-amorphous, the solubility of TELwas much improved, and the apparent solubility values were approximately 9-15 times as high as that of crystalline TEL. Moreover, the co-amorphous TEL-PA was stored under 25 °C/20% RH for a month without any evidence of conversion by powder X-ray diffraction analysis.

A new salt of clofazimine to improve leprosy treatment

In this work, a new salt of clofazimine (CFZ) with 4-aminobenzoic acid (PABA is described. CFZ is an antibiotic drug used in the treatment of leprosy. This drug has low absorption when administered orally because of its low water solubility, contributing to the reduction of bioavailability, limiting its application. Towards the augmentation of the bioavailability of CFZ, we propose in this work the development of a salt. The new product CFZ+–PABA– (1:1) was synthesized through liquid assisted grinding method and characterized by powder X-ray diffraction, mid-infrared spectroscopy, and differential scanning calorimetry. The investigations provided evidence of the formation of a new salt. The interaction involves proton transfer between PABA and CFZ forming R21(7) motif in carboxylate region (COO−) of PABA and imines regions (N–H/N+–H) of CFZ. According to the analyses, the stoichiometric ratio of salt formation is 1:1. The salt dissolution profile shows the product is 5.0 folds more soluble than the CFZ free base.

Tuning Solid-State Luminescence in Conjugated Organic Materials: Control of Excitonic and Excimeric Contributions through π Stacking and Halogen Bond Driven Self-Assembly.

Two polymorphs with distinctly different fluorescence emission (green and yellow; G, Y) emanating from excitonic and excimeric contributions were prepared from solution as well as by using physical vapour transport. Based on crystal structure investigations, the vibrationally-resolved excitonic emission is found to originate from a β-Sheet arrangement (G), whereas a sandwich herringbone structure is responsible for the excimer emission (Y). The intermolecular interactions and energies were quantified to have a complete picture of the decisive factors that controls the self-assembly. Halogen-bond directed self-assembly was explored to fine-tune the intermolecular interactions through co-crystallization as well as a commercially viable liquid assisted grinding method. A smooth fluorescence shift from G to Y was achieved by co-assembly due to substantial differences in the π orbital overlap in the molecular packing. Our investigation provides a comprehensive understanding of the origin of excitonic and excimeric contributions of emission behaviour in conjunction with the molecular packing and π-π orbital overlap, and might provide a directive towards the engineering of fluorescent functional molecular materials.

NOVEL PHARMACEUTICAL COCRYSTAL OF TELMISARTAN AND HYDROCHLOROTHIAZIDE

Objective: Telmisartan (TEL), commonly used antihypertensive, is poorly soluble in water and has limited and variable bioavailability. Commercially, TEL is available as a single drug and in combination with hydrochlorothiazide (HYZ). Researchers have developed cocrystals of TEL with coformers, namely, oxalic acid, glutaric acid, and saccharin. An attempt was made to prepare the cocrystals of TEL with HYZ, an active pharmaceutical ingredient (API) itself so that both the APIs are available in a single tablet. The present study was aimed at enhancement in solubility of TEL by formation of its cocrystals.
 Methods: The cocrystals of TEL with HYZ, in different stoichiometric ratios (1:0.5, 1:1, and 1:2), were prepared by solvent coevaporation and liquid-assisted grinding methods. The cocrystals, consisting of TEL:HYZ (in 1:0.5 ratio and 1:1 ratio), depicted maximum yield, drug content, saturation solubility, and flow properties. These cocrystals were characterized by X-ray analysis, infrared spectroscopy, and thermal analysis.
 Results: The crystal structure of TEL-HYX revealed that it was a cocrystal, since no proton was transferred between the TEL and HYZ molecules. It was predicted that two molecules are associated through a hydrogen bond between an acidic group of TEL and sulfonamido group of HYZ. The cocrystallization improved the solubility of TEL 7 times. In vitro release rate of tablets of cocrystals was higher than that of marketed TEL tablets. HYZ has a potential to form the cocrystals of TEL.
 Conclusion: The objective of improvement in the solubility of TEL was successfully achieved by the formation of cocrystals of TEL: HYZ.

Screening and characterization of cocrystal formation between betulin and terephthalic acid

The pharmaceutical cocrystals are nowdays intensively studied due to the improvements of solubility, stability, processability, etc. of the drugs. In this work, the cocrystals of betulin with terephthalic acid as a coformer were prepared by liquid-assisted grinding method. The formation of cocrystals was confirmed by powder X-ray diffraction, IR spectroscopy and thermal analysis methods. HPLC analysis showed that in the case of betulin – terephthalic acid cocrystals, solubility of betulin was significantly improved compared to the initial betulin as well as betulin from cocrystals with aliphatic dicarboxylic acids which were earlier prepared.

H5PV2Mo10O40 encapsulated into Cu3(BTC)2 as an efficient heterogeneous nanocrystalline catalyst for styrene epoxidation

The nanocrystalline catalyst HPMoV@Cu3(BTC)2 prepared using a liquid-assisted grinding method showed excellent catalytic activity for the epoxidation of styrene in O2.

Preparation and evaluation of pharmaceutical co-crystals for solubility enhancement of atorvastatin calcium

Co-crystallization is one of the methods to enhance the solubility of hydrophobic drugs that belong to BCS class II. Preparation and characterization of atorvastatin calcium co-crystals by liquid-assisted grinding method using citric acid and nicotinamide as co-formers for solubility enhancement were the objective of the current research. All the prepared formulations were characterized by powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), zeta size analysis, dissolution and solubility studies. Solubility studies were performed in distilled water, pH 1.2 and pH 6.8. PXRD revealed the structural nature of the co-crystals formulations. FTIR, TGA and DSC confirmed the complex formation and have better thermal stability than individual components. SEM images exhibited the prism-like crystals with irregular and rough surfaces. Zeta size analysis showed the small particle size having large surface area that facilitates to improve the solubility. Dissolution and solubility studies of the formulations confirmed that solubility enhanced several folds in all media as compared to the solubility of available market drug. From all these studies, it can be concluded that co-crystallization technique enhanced the solubility of atorvastatin calcium by using liquid-assisted grinding method.

Design and Preparation of Zaltoprofen-Nicotinamide Pharmaceutical Cocrystals via Liquid Assisted Grinding Method

Abstract: Introduction: Pharmaceutical cocrystal is an endowed approach to augment solubility and dissolution of drugs with limited aqueous solubility. Zaltoprofen is a nonsteroidal anti-inflammatory drug with prevailing solubility problem. The present study deciphers preparation of cocrystals of lipophilic drug zaltoprofen to improve the solubility and dissolution by screening various coformers. Methods: Cocrystals of zaltoprofen were prepared in 1:1 and 1:2 molar ratio of drug: coformer by liquid assisted grinding method. The crystalline phase was subjected to evaluation by melting point and solubility. The potential cocrystals were characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). Dissolution rate and stability of cocrystals was also investigated. Results: Zaltoprofen-nicotinamide (ZFN-nicotinamide) cocrystals revealed variation in melting point and solubility. Two cocrystals were obtained in 1:1 and 1:2 ratios with nicotinamide. IR spectrum distinctly showed the shifting of typical absorption bands of zaltoprofen. Crystallinity of cocrystals was clear from the PXRD pattern and noteworthy difference in 2θ value of intense peaks. DSC spectra of cocrystals revealed altered endotherms analogous to melting point. Cocrystals exhibited rapid dissolution rate and 56% increase in the extent of dissolution compared to pure drug. The cocrystals were found stable at stability conditions. SEM revealed difference in the crystal morphology. Conclusion: Hence, it can be concluded that ZFN-nicotinamide cocrystal could present an improved drug design approach to surmount dissolution and bioavailability related challenges linked with lipophilic drug zaltoprofen. Key words: Cocrystal, Zaltoprofen, Liquid assisted grinding, Solubility, Dissolution.

Role of Structure, Microenvironmental pH, and Speciation To Understand the Formation and Properties of Febuxostat Eutectics.

Cocrystallization studies were undertaken to improve the solubility of a highly water-insoluble drug, febuxostat (FXT), used in the treatment of gout and hyperuricemia. A liquid-assisted grinding (LAG) method was successfully employed, starting with the screening of various coformers for obtaining cocrystals. However, in this process, three eutectic systems with coformers (probenecid, adipic acid, and α-ketoglutaric acid) were formed. Affinities of the different functional groups to form a hydrogen bond and ΔpKa differences, leading to the eutectic formation, were discussed. The eutectic systems thus formed were further characterized and analyzed using a differential scanning calorimeter (DSC) and powder X-ray diffraction (PXRD). Binary thermal phase diagrams were plotted using different ratios of the systems to confirm the formation of eutectics, and pH-dependent solubility studies exhibited a significant decrease in the solubility in comparison to that of the drug for all three eutectic systems. The solubility of FXT reduced from 46.53 μg/mL (pH 5.63) to 46.03 μg/mL, 28.53 μg/mL, and 18.88 μg/mL; 770.58 μg/mL (pH 8.21) to 307.574 μg/mL, 116.63 μg/mL, 113.40 μg/mL; and from 13165.97 μg/mL (pH 10.13) to 1409.737 μg/mL, 854.51 μg/mL, and 1218.99 μg/mL for FXT-probenecid, FXT-adipic acid, and FXT-α-ketoglutaric acid eutectic systems, respectively. Furthermore, the microenvironmental pH studies were carried out to understand the effect of the microenvironment on the solubility of these eutectic systems. The contribution to solubility from lattice and nonlattice forces considering the microenvironment was also discussed.

Rapid Synthetic Routes to Bipyridine-Based Metal–Organic Frameworks for Highly Selective Solvent Sensing

A series of known Pb(II) metal–organic frameworks (MOFs) have been synthesized from the reaction of PbX2 (X = Cl, NO3 and OAc) with bpy (where bpy = 4,4-bipyridine) using three synthetic methods, namely solvothermal, mechanochemical and liquid-assisted grinding (LAG). The synthesized compounds were characterized with powder X-ray diffraction (PXRD) patterns and matched with calculated X-ray diffraction patterns of reported crystal structures of Pb(II)-based MOFs. Interestingly, most of the compounds can be easily prepared by solvent-free methods either mechanochemically or by LAG methods. Finally, the successfully synthesized MOFs were subjected to photoluminescence study. Solid-state photoluminescence of the selected MOFs has been studied by suspending the MOFs particles in various solvents. Although they are not soluble in the solvents used, the MOFs show a fair amount of solvent-dependent emission quenching that roughly correlate with solvent polarity. With further exploration and investigations, the observed solvatochromic emission behavior of these compounds may find importance in solvent sensing applications.