Liquid-assisted Grinding Research Articles

SYNTHESIS OF COCRYSTALS OF BETULIN WITH SUBERIC ACID AND STUDY OF THEIR PROPERTIES

Lupane triterpenoids, betulin and its derivatives, are attracting great interest due to their wide range of biological and pharmacological activities. However, the poor solubility of betulin and its derivatives in aqueous media significantly reduces their bioavailability. Obtaining cocrystals, that is, multicomponent crystal systems containing active pharmaceutical ingredients and non-toxic partner molecules in their structure, is used in pharmacy to change the physicochemical properties of drugs, including the rate of dissolution and solubility. In this study, cocrystals of betulin with suberic acid were obtained by liquid-assisted grinding method using organic solvents of different polarity: ethanol, acetone, ethyl acetate, chloroform, toluene, dioxane. The formation of cocrystals was confirmed by X-ray diffraction analysis, IR spectroscopy, and thermal analysis. It has been shown that cocrystals of betulin with suberic acid contain water molecules in their structure; anhydrous cocrystals can be obtained by heating a physical mixture of reagents until the acid melts. The results of experiments on the dissolution of cocrystals of betulin with suberic acid in comparison with the data for cocrystals of betulin with adipic acid showed that an increase in the length of the aliphatic acid chain leads to a decrease in the rate of betulin release into solution.

Salts of 2-hydroxybenzylamine with improvements on solubility and stability: Virtual and experimental screening

2-Hydroxybenzylamine (2-HOBA) is a drug used to effectively treat oxidative stress. To improve its aqueous solubility and thermal stability, salt screening and synthesis was carried out. The conductor-like screening model for the real solvents model (COSMO-RS) was applied to virtual screening of coformers among 200 commonly used candidates for salification of 2-HOBA. As a result, 40 hit compounds were subjected to experimental liquid-assisted grinding (LAG) with 2-HOBA, then 21 systems were characterized as new solid phases by PXRD. Nine multicomponent single crystals of 2-HOBA with succinic acid, p-aminobenzoic acid, p-nitrobenzoic acid, o-nitrobenzoic acid, p-toluic acid, 2,3-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, p-nitrophenol, and 5-hydroxyisophthalic acid were obtained and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. All of them were salts and exhibited higher decomposition temperatures compared with pure 2-HOBA. The apparent aqueous solubility of three new salts, i.e., those with succinic acid, p-aminobenzoic acid, and p-nitrophenol were higher than the equilibrium solubility of 2-HOBA. The accelerated stability test indicated that all salts show excellent stability under conditions (40 °C and 75% RH) for 4 weeks. Overall, this work introduced a protocol that combined the virtual screening tool based on the COSMO-RS model and the experimental LAG method to screen new salts for a target compound. The feasibility of this protocol was confirmed in the case of 2-HOBA whose new salts were successfully obtained and represented an improvement for aqueous solubility and thermal stability.

ZIF-8-based oxygen reduction reaction catalyst prepared from one-pot and stepwise ion- and liquid-assisted grinding modified with tris-1,10-phenanthroline iron (II) perchlorate

In this study, a one-pot ion- and liquid-assisted grinding (ILAG) synthesis of ZIF-8-based catalysts was proposed and compared with a conventional stepwise synthesis to determine an appropriate method for proton exchange membrane fuel cells (PEMFCs). The performance characteristics of one-pot- and stepwise-synthesis catalysts were measured by various physicochemical and electrochemical characterization methods. In lab-scale production, the material cost of the one-pot-synthesis catalyst was seven times lower than that of the stepwise-synthesis catalyst. The surface structural characteristics of the one-pot- and stepwise-synthesis catalysts were identical, and the two catalysts showed similar onset potentials that were close to that of a Pt/C. However, based on PEMFC tests, the maximum power density of the one-pot-synthesis catalyst was lower than that of the stepwise-synthesis catalyst owing to the smaller micropore area of one-pot-synthesis catalyst. Nonetheless, the difference between maximum power densities was only 9.6% despite the large disparity in the material cost. Thus, the proposed one-pot-synthesis catalyst can be recommended as a promising non-platinum group metal (PGM) catalyst, but further research to improve its micropore area and performance is required.

Engineering a Remedy to Modulate and Optimize Biopharmaceutical Properties of Rebamipide by Synthesizing New Cocrystal: In Silico and Experimental Studies.

Rebamipide (REB) a potent anti-ulcer agent, has not been exploited to its full potential, owing to it extremely poor solubility, leading to highly diminutive bioavailability (<10%). The purpose is to carry out its solid-state modification. Cocrystallisation was done with three GRAS coformers namely citric acid (CA), 3,4-dihydroxybenzoic acid (DHBA) and oxalic acid (OXA) employing the liquid-assisted grinding method. Cocrystal formation was based upon amide-carboxyl and amide-hydroxyl supramolecular synthons. Characterization of novel cocrystals i.e. RCA, RDHBA and ROXA was carried out by DSC, PXRD and additionally by FT-IR spectroscopy. Chemical structures have been determined utilizing the PXRD pattern by Material Studio®. Furthermore, cocrystals were subjected to solubility and intrinsic dissolution rate (IDR) evaluation. Also, pharmacodynamic and pharmacokinetic studies were performed and compared with pure rebamipide. The appearances of a single sharp melting endotherm in DSC, along with novel characteristic peaks in PXRD infer the existence of a new crystalline form. Shifting in characteristic vibrations in FT-IR spectroscopy supports the establishment of distinct hydrogen-bonded networks. Structural determination revealed that RCA crystallizes in 'Bb2b' space groups whereas RDHBA in 'P1' and ROXA crystallize out in the 'P-1' space group. All the cocrystals exhibited superior apparent solubility and almost 7-13 folds increase in IDR. Furthermore, 1.6-2.5 folds enhancement in relative bioavailability and remarkable amplification in anti-ulcer, anti-inflammatory and the antioxidant potential of these cocrystals were observed. The study ascertains the advantages of cocrystallization, with RCA showing greatest potential and suggests a viable alternative approach for improved formulation of rebamipide.

Structure-Property Relationships of Inorganic-Organic Hybrid Semiconducting Se-Fe-Cu-CO Polymers.

A novel family of inorganic-organic-hybrid SeFe3(CO)9-dipyridyl two- and one-dimensional Cu polymers was synthesized via the three-component liquid-assisted grinding (LAG) of [Cu(MeCN)4]+, inorganic cluster [SeFe3(CO)9]2- (1), and rigid conjugated dipyridyls 4,4'-dipyridyl (dpy) and 1,2-bis(4-pyridyl)ethylene (bpee) or flexible conjugation-interrupted dipyridyls 1,2-bis(4-pyridyl)ethane (bpea) and 1,3-bis(4-pyridyl)propane (bpp). They included a cluster-linked 2D polymer, [(μ4-Se)Fe3(CO)9Cu2(MeCN)(dpy)1.5]n (1-dpy-2D), a cluster-pendant 1D chain, [(μ3-Se)Fe3(CO)9Cu2(dpy)3]n (1-dpy-1D), cluster-blocked 1D polymers, [(μ3-Se)Fe3(CO)9Cu2(L)]n (1-L-1D, L = bpee, bpea), and a cluster-linked 2D polymer, [(μ4-Se)Fe3(CO)9Cu2(bpp)2]n (1-bpp-2D). The reversible dimensionality transformations of these three types of polymers accompanied by the change in coordination modes of 1 were achieved by the LAG addition of 1/[Cu(MeCN)4]+ or dipyridyl ligands. These polymers were found to possess tunable low-energy gaps (1.49-1.72 eV) that increased in the order regarding their structural features: cluster-linked 1-dpy-2D and 1-bpp-2D, cluster-blocked 1-bpea-1D and 1-bpee-1D, and cluster-pendant 1-dpy-1D and [(μ3-Se)Fe3(CO)9Cu2(L)2.5]n (L = bpee, 1-bpee-2D; bpea, 1-bpea-2D), indicative of the importance of the participation of cluster 1. The measured electrical conductivities of 1-bpp-2D, 1-bpea-1D, and 1-dpy-1D were 3.13 × 10-7, 2.92 × 10-7, and 2.30 × 10-7 S·cm-1, respectively, which were parallel for the trend in their energy gaps, revealing semiconducting behaviors, supported by XPS, XANES, and DFT calculations. The surprising semiconductivity of the conjugation-interrupted bpp-linked 1-bpp-2D was mainly ascribed to electron transport via C-H···O(carbonyl) hydrogen bonds and aromatic C-H···π contacts within its closely packed 2D layers. Water-/light-stable polymers 1-bpp-2D, 1-bpea-2D, and 1-dpy-1D were also demonstrated to exhibit excellent pseudo-first-order photodegradation toward nitroaromatics and organic dyes, where cluster-linked polymer 1-bpp-2D performed the best, as predicted by its structural features and narrow energy gap.

A New Reasonable Interpretation of Azilsartan Form II: a Hydrate

In this study, a new reasonable interpretation of azilsartan form II was suggested which had been reported as a 1,4-dioxane solvate in the literature. Multiple evidence has indicated that azilsartan form II obtained in this study was not a 1,4-dioxane solvate. Results of single crystal diffraction showed that the chemical formula of azilsartan form II was C 25 H 20 N 4 O 5 •1.25H 2 O. The apparent solubility and intrinsic dissolution rate of azilsartan form II were greater than that of form I in pH 6.8 phosphate buffer solution at 37 °C. Results of dynamic vapour sorption indicated that azilsartan form I was hardly hygroscopic. Results of accelerated stability test showed that azilsartan form I and II remained stable after 6 months of storage. Differential scanning calorimetry results showed that azilsartan form II had a lower melting point than form I. A cleaner and more efficient preparation method for azilsartan form II was provided. Azilsartan form II could be prepared through the liquid-assisted grinding method by using a very small amount of tetrahydrofuran (η = 0.2 μL mg −1 ) or acetone (η = 0.3 μL mg −1 ). Azilsartan form II presents an alternative solid form for pharmaceutical preparation. • A new reasonable interpretation of azilsartan form II was suggested. • Properties of azilsartan form II was investigated. • A cleaner and more efficient preparation method was provided.

Pharmaceutical salt hydrates of vortioxetine with maleic acid and fumaric acid: Crystal structures, characterisation and solubility performance

Vortioxetine (VOT) is a serotonin (5-HT) receptor antagonist used for the treatment of major depressive disorder, but its poor solubility limits its absorption in vivo. This study aimed to improve the solubility properties of VOT and modify its physicochemical properties by combining it with pharmaceutically acceptable coformer molecules. In this work, two pharmaceutical salt hydrates of VOT with maleic acid (MA) and fumaric acid (FA) were successfully prepared by solvent evaporation and the liquid-assisted grinding method. The obtained salt hydrates were systematically investigated by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis techniques. The solubility of the salt hydrates was evaluated in water and pH 6.86 phosphate buffer medium. The results suggested that the two VOT salt hydrates exhibited increased solubility compared to VOT. The intrinsic dissolution rates (IDRs) of each salt hydrates was also determined, indicting that MA and FA were dissolution accelerators in water.

Implications of Thermodynamic Control: Dynamic Equilibrium Under Ball Mill Grinding Conditions

AbstractWe report a powerful example of subtle dynamic equilibrium control under milling conditions using the base catalysed solid state disulfide exchange reaction between two homodimers (bis‐2‐nitrophenyldisulfide and bis‐4‐nitrophenyldisulfide) to produce the heterodimer (4‐nitrophenyl‐2‐nitrophenyl‐disulfide). Under ball mill neat grinding conditions, the equilibrium is reproducibly represented by homodimers and Form A of the heterodimer in a molar ratio of 1 to 4. The heterodimer crystallizes in two different polymorphic forms, Form A and Form B, which can be interconverted by changing the milling conditions between neat grinding and liquid assisted grinding with a number of solvents. Because such milling equilibria are reversible and dynamic in nature, we interpret these end points as existing in local thermodynamic wells. Moreover, homodimer bis‐2‐nitrophenyldisulfide also shows two polymorphs, Form I and Form II, depending on the milling conditions, further complicating the picture. Because of the nanocrystalline nature of these solid forms, we suggest that surface effects are responsible for the switch in polymorph stabilities in the milling jar.

Improved pharmaceutical properties of ritonavir through co-crystallization approach with liquid-assisted grinding method

Ritonavir is a BCS class II antiretroviral agent which shows poor aqueous solubility and low oral bioavailability. The cocrystallization approach was selected to overcome these problems and to improve the physicochemical and mechanical properties of Ritonavir. The novel pharmaceutical Ritonavir-L-tyrosine cocrystals (RTC at a molar ratio of 1:1) were synthesized using the liquid assisted grinding (LAG) method. The possibility of molecular interactions between drug and coformer were studied using Gold software version 5.2. The newly formed crystalline solid phase was characterized through Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform-infrared spectroscopy (FT-IR), Scanning electron microscopy (SEM), and Solid-State Nuclear magnetic resonance (SSNMR). The improved pharmaceutical properties were confirmed by solubility, dissolution, and powder compaction study. The prepared cocrystals exhibited an 11.24-fold increase in solubility and a 3.73-fold increase in % of drug release at 1 h compared to pure drug. Tabletability and compaction behavior of the pure drug and cocrystal with added excipients assessed. The tabletability profile of cocrystals showed enhanced tabletting performance as compared to pure drug. The stability studies revealed that cocrystals were stable for at least one month when stored at 40 °C/75 % RH and 25 °C/60 % RH conditions. The cocrystallization approach was found to be very promising and showed an overall improved performance of Ritonavir.

Peptide bond formation using unprotected N-carboxyanhydrides under green chemistry conditions

Peptide bond forming reactions are fundamental to the synthesis of peptides and peptidomimetics. Unfortunately, the chemistry of the peptide bond rouses much concern in terms of economic cost, environmental impact, and production of wastes, especially toxic organic solvents. In a Green Chemistry perspective, we reconsidered the use of unprotected N-carboxy anhydrides (NCAs) of standard α-amino acids under minimal liquid-assisted grinding (LAG) conditions. NCAs are very attractive in peptide synthesis for their simplicity and atom economy. Indeed, the molecular bulk of these N-protected/C-activated bidentate reactants remains with the newly formed peptide. However, the NCAs are prone to polymerization, a formidable obstacle to the development of mechanochemical conditions. Nevertheless, polymerization can be prevented by operating under controlled basic conditions. In this work, we describe peptide bond forming reactions from NCAs and amino partners by LAG in amalgam with nanocrystalline hydroxyapatite (HAp) powder as a bio-compatible, reusable inorganic base. The experiments supported the combination of HAp and the green solvent γ-valerolactone, and highlighted the importance of NCAs’ purity and crystallinity, as studied by NMR, SEM, and XRD. The efficacy of the procedure was assessed by the synthesis of the 13-mer cytotoxic peptide PTP7.

Four Novel Pharmaceutical Cocrystals of Oxyresveratrol, Including a 2 : 3 Cocrystal with Betaine

Cocrystal engineering can alter the physicochemical properties of a drug and generate a superior drug candidate for formulation design. Oxyresveratrol (ORV) exhibits a poor solubility in aqueous environments, thereby resulting in a poor bioavailability. Extensive cocrystal screening of ORV with 67 cocrystal formers (coformers) bearing various functional groups was therefore conducted using grinding, liquid-assisted grinding, solvent evaporation, and slurry methods. Six cocrystals (ORV with betaine (BTN), L-proline (PRL), isonicotinamide, nicotinamide, urea, and ethyl maltol) were found, including four novel cocrystals. Powder X-ray diffraction, low frequency Raman spectroscopy, and thermal analysis revealed unique crystal forms in all obtained samples. Conventional Raman and infrared data differentiated the cocrystals by the presence or absence of a hydrogen bond interacting with the aromatic ring of ORV. The crystal structures were then elucidated by single-crystal X-ray diffraction. Two new cocrystals consisting of ORV : BTN (2 : 3) and ORV : PRL : H2O (1 : 2 : 1) were identified, and their crystal structures were solved. We report novel cocrystalline solids of ORV with improved aqueous solubilities and the unique cage-like crystal structures.

Role of Mechanochemistry in Solid Form Selection and Identification of the Drug Praziquantel

Identification of all possible polymorphs for a pharmaceutical compound is vital for the better formulation of medicine with desired properties. This study demonstrates the application of a mechanochemical approach to reveal new polymorphs of a drug and the potential of variable amounts of solvent in liquid-assisted grinding for solid form screening. Without solvent and by varying the amount of solvent added, we found two new polymorphs and an amorphous form, which were not reported previously. The finding portrays the advantage of the mechanochemical approach as a means of the polymorph screening strategy. While the focus here was on praziquantel, a similar approach is applicable to other pharmaceutical systems. This study also contributed to reinvestigate the solid-state behavior of the chiral praziquantel system, including the melt phase diagram and the role of experimental conditions on its phase behavior.

Ionic Liquid-Assisted Grinding: An Electrophilic Fluorination Benchmark.

We demonstrated the influence of liquid additives on the rate and selectivity of mechanochemical fluorination of aromatic and 1,3-dicarbonyl compounds with F-TEDA-BF4. Substoichiometric catalytic quantities of ionic liquids speed up the reaction. We proposed an improved protocol for ionic liquids-assisted fluorination that allows easy and efficient isolation of fluorinated products by vacuum sublimation. A careful choice of additive results in high yields of fluorinated products and low E-factor for the overall process. Here, we report a benchmarking study of various ionic liquids in comparison with representative molecular solvents. A lower viscosity of ionic liquid additive is typically associated with higher yields and a higher degree of difluorination. Ionic liquids with fluorous anions (triflate and triflimide) are shown to be the most efficient catalysts for ionic liquid-assisted grinding.

Modafinil Cocrystals for Altered Physicochemical Properties

The present investigation was designed to prepare and characterize BCS class II drug modafinil cocrystals for its solubility enhancement and other properties. Hansen solubility parameter (HSP) was used for prediction of cocrystal formation. Coformers/excipients namely boric acid, cinnamic acid, salicylic acid, and tartaric acid were used in the preparation of cocrystals by liquid assisted grinding method with 1:1 molar ratio of drug and coformer. The prepared cocrystals were subjected to characterization by performing melting point determination, solubility analysis at its saturation point, and drug release by in vitro method. Furthermore, characterization was also done by Fourier Transform IR spectroscopy, Differential Scanning Calorimetry, PXRD and Scanning Electron Microscopy. The formation of modafinil cocrystals by using cinnamic acid and salicylic acid and the formation of modafinil complexes with boric acid and tartaric acid were confirmed by collectively assessing the results. Moreover, a drastic improvement in the solubility revealed the importance of preparing pharmaceutically useful cocrystals of marketed active pharmaceutical ingredients (APIs). However, the increased dissolution rates were seen with cocrystals but not with the complexes. Thus solid state manipulation technique can be used to improve the physicochemical properties of an API using HSP as a successful tool for the prediction of cocrystal formation among the partners.

Mechanochemical synthesis insights and solid-state characterization of quininium aspirinate, a glass-forming drug-drug salt.

Quinine (an antimalarial) and aspirin (a nonsteroidal anti-inflammatory drug) were combined into a new drug-drug salt, quininium aspirinate, C20H25N2O2+·C9H7O4-, by liquid-assisted grinding using stoichiometric amounts of the reactants in a 1:1 molar ratio, and water, EtOH, toluene, or heptane as additives. A tetrahydrofuran (THF) solution of the mechanochemical product prepared using EtOH as additive led to a single crystal of the same material obtained by mechanochemistry, which was used for crystal structure determination at 100 K. Powder X-ray diffraction ruled out crystallographic phase transitions in the 100-295 K interval. Neat mechanical treatment (in a mortar and pestle, or in a ball mill at 20 or 30 Hz milling frequencies) gave rise to an amorphous phase, as shown by powder X-ray diffraction; however, FT-IR spectroscopy unambiguously indicates that a mechanochemical reaction has occurred. Neat milling the reactants at 10 and 15 Hz led to incomplete reactions. Thermogravimetry and differential scanning calorimetry indicate that the amorphous and crystalline mechanochemical products form glasses/supercooled liquids before melting, and do not recrystallize upon cooling. However, the amorphous material obtained by neat grinding crystallizes upon storage into the salt reported. The mechanochemical synthesis, crystal structure analysis, Hirshfeld surfaces, powder X-ray diffraction, thermogravimetry, differential scanning calorimetry, FT-IR spectroscopy, and aqueous solubility of quininium aspirinate are herein reported.

Co-amorphous solids of dasatinib and olanzapine by saccharin with promising physicochemical properties

Two co-amorphous compounds of poorly water-soluble drugs dasatinib (DAS) and olanzapine (OLA) were formed, dasatinib-saccharin (DAS-SAC), and olanzapine-saccharin (OLA-SAC) with saccharin (SAC) as the co-former through liquid assisted grinding method, and at large scale, by rapidly evaporating the solvent (ethanol) from a rota-vapor at 60 °C under vacuum. The co-amorphous solids showed improved dissolution rates in phosphate-buffered saline (PBS, pH 7.2) and glycine-HCl buffer (pH 3.6) at 37 °C compared to the freeform. For example, the dissolution rate of DAS-SAC in PBS in first 10 min was 0.12 mg/mL (30-times faster than DAS) compared to 0.004 mg/mL of DAS. The dissolution rate of OLA-SAC in PBS in 10 min was 1.72 mg/mL and more than OLA (~21 times faster) as opposed to 0.08 mg/mL of OLA. Thermal analysis of the DAS-SAC and OLA-SAC showed single glass transition temperature (Tg) with the onsets of 132.8 °C and 161.7 °C, respectively indicating the amorphous nature of solids. The co-amorphous forms were stable at various temperatures (6 °C, 25 °C and 40 °C) and relative humidity (11%, 75% and dry condition) for up to eight weeks. Importantly, no amorphous forms were able to produce with DAS and OLA through grinding or quick evaporation without the use of SAC.

Cocrystallization of gliclazide with improved physicochemical properties

BackgroundCocrystallization is one of the crystal engineering strategies used to alter the physicochemical properties of drugs that are poorly water-soluble. Gliclazide (GLZ), an antidiabetic drug, belongs to Biopharmaceutical Classification System class-II (low solubility and high permeability) and has low bioavailability, resulting in poor therapeutic effects in patients. Therefore, to impart better solubility and bioavailability of GLZ, the study was carried out by preparing GLZ cocrystals using liquid-assisted grinding method with three coformers [3,5-dinitrosalicylic acid (DNS), 2,6-pyridine dicarboxylic acid (PDA), and L-proline (LPN)], and these were characterized using Differential Scanning Colorimetry (DSC), Powder X-ray diffraction (PXRD), Fourier Transform Infra-red spectroscopy (FTIR), and Raman spectral studies. Further, Scanning electron microscopy (SEM) analysis, accelerated stability, solubility, in vitro dissolution studies, and in vivo pharmacokinetic studies were performed in male Wistar rats.ResultsDSC and PXRD analysis confirmed the formation of the GLZ cocrystals. Hydrogen bonding between pure GLZ and its coformers was demonstrated based on FTIR and Raman analysis. SEM data showed morphological images for GLZ cocrystals differed from those of pure GLZ. In comparison with pure GLZ, these GLZ cocrystals have greatly improved solubility, in vitro dissolution, and in vivo profiles. Among the three, GLZ–DNS cocrystals outperformed the pure drug in terms of solubility (6.3 times), degradation (1.5 times), and relative bioavailability (1.8 times).ConclusionHence, cocrystallization of GLZ leads to improved physicochemical properties of poorly soluble drug gliclazide.

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. ©

Mechanochemically Assisted Synthesis of Hexaazatriphenylenehexacarbonitrile.

1,4,5,8,9,11-hexaazatriphenylenehexacarbonitrile (HAT CN) was synthesized mechanochemically at room temperature. The coupling of hexaketocyclohexane and diaminomaleonitrile was conducted in 10 min by vibratory ball milling. The effects of milling parameters, acids, dehydrating agents, and liquid-assisted grinding were rationalized. With 67%, the yield of this mechanochemical approach exceeds that of state-of-the-art wet-chemical syntheses while being superior with respect to time-, resource-, and energy-efficiency as quantified via green metrics.

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.