Solvent-drop Grinding Research Articles

Acceleration under solvent-drop grinding: Synthesis of bis(indolyl)methanes using small amounts of organic solvents or ionic liquids

The reactions for the synthesis of bis(indolyl)methanes were accelerated by the addition of a few drops of solvents. Solvent effect for the addition of organic solvents and ionic liquids was examined. The yields of bis(indolyl)methanes increased by the addition of THF, 1-ethyl-3-ethylimidazolium bis(trifluoromethylsulfonyl)imide ([emim]NTf2), and 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF6). Solvent-drop grinding methodology was quite useful for the reactions of “solid + liquid” as well as “solid + solid”.

Preparation, characterization and evaluation of fenofibrate: benzoic acid cocrystals with enhanced pharmaceutical properties

BackgroundCocrystallization process involved the understanding of interaction at molecular level between two molecules in context to their crystal packing and designing of new solids having improved physicochemical as well as pharmaceutical properties. In the present research, an attempt to increase the aqueous solubility and dissolution rate of a poorly aqueous soluble drug fenofibrate (FB) by formulation and evaluation of its cocrystals with benzoic acid (BZ) as a coformer was carried out.ResultsThe drug and coformer were cocrystallized by using the solvent drop grinding method. For prediction of cocrystals formation, CSD (Cambridge Structure Database) software was utilized. Fourier transformation infrared spectroscopy (FTIR), X-ray diffraction (XRD) and differential scanning calorimetry (DSC) techniques were used for analysis of cocrystals. Albino rats were procured from institution as per IAEC guidelines for in vivo anti-hyperlipidaemic studies. The in vitro dissolution profile of cocrystals, pure drug, their physical mixture and marketed formulation was found to be 89%, 39%, 47% and 61%, respectively.ConclusionsAn enhanced anti-hyperlipidaemic activity of cocrystals was found compared to pure drug. The FB: BZ cocrystals also compared to the pure drug showed better dissolution profile and improved in vivo anti-hyperlipidaemic activity in rats. The study proved that cocrystals can promise to improve in vitro dissolution rate of poorly aqueous soluble drugs, which in turn can lead to better in vivo activities.

Toward an Understanding of the Propensity for Crystalline Hydrate Formation by Molecular Compounds. Part 2.

The propensity of molecular organic compounds to form stoichiometric or nonstoichiometric crystalline hydrates remains a challenging aspect of crystal engineering and is of practical relevance to fields such as pharmaceutical science. In this work, we address the propensity for hydrate formation of a library of eight compounds comprised of 5- and 6-membered N-heterocyclic aromatics classified into three subgroups: linear dipyridyls, substituted Schiff bases, and tripodal molecules. Each molecular compound studied possesses strong hydrogen bond acceptors and is devoid of strong hydrogen bond donors. Four methods were used to screen for hydrate propensity using the anhydrate forms of the molecular compounds in our library: water slurry under ambient conditions, exposure to humidity, aqueous solvent drop grinding (SDG), and dynamic water vapor sorption (DVS). In addition, crystallization from mixed solvents was studied. Water slurry, aqueous SDG, and exposure to humidity were found to be the most effective methods for hydrate screening. Our study also involved a structural analysis using the Cambridge Structural Database, electrostatic potential (ESP) maps, full interaction maps (FIMs), and crystal packing motifs. The hydrate propensity of each compound studied was compared to a compound of the same type known to form a hydrate through a previous study of ours. Out of the eight newly studied compounds (herein numbered 4–11), three Schiff bases were observed to form hydrates. Three crystal structures (two hydrates and one anhydrate) were determined. Compound 6 crystallized as an isolated site hydrate in the monoclinic space group P21/a, while 7 and 10 crystallized in the monoclinic space group P21/c as a channel tetrahydrate and an anhydrate, respectively. Whereas we did not find any direct correlation between the number of H–bond acceptors and either hydrate propensity or the stoichiometry of the resulting hydrates, analysis of FIMs suggested that hydrates tend to form when the corresponding anhydrate structure does not facilitate intermolecular interactions.

Screening and Preparation of Cocrystals: A Comparative Study of Mechanochemistry vs Slurry Methods.

Cocrystals of biologically active molecular compounds have potential utility in drug products thanks to their effect upon physicochemical properties such as aqueous solubility. The fact that control of cocrystallization can be more challenging than crystallization of single-component crystals means that systematic studies that address the methodology of cocrystal screening, production, and purification are a topical subject. We previously reported a comparison of slow evaporation vs mechanochemistry for a library of 25 molecular cocrystals. Herein, we compare the previously reported mechanochemistry results (solvent-drop grinding (SDG) with eight solvents) with new results obtained from slurrying in five preferred solvents using the same library of 25 cocrystals. Overall, both methods were found to be effective with slurrying and SDG being 94 and 78.5% successful, respectively. Importantly, 96% of the cocrystals formed via slurrying were observed to be free of starting materials (coformers) according to powder X-ray diffraction (PXRD), whereas this was the case for only 72% of the cocrystals prepared by SDG. Slurrying therefore compared favorably with mechanochemistry, which tends to leave small amounts of unreacted coformer(s) as byproducts, and solution crystallization, which often affords crystals of the least soluble coformer because it can be difficult to control the saturation of three or more solids. Perhaps the most interesting and surprising result of this study was that water slurrying proved to be highly effective, even for low-solubility coformers. Indeed, water slurrying was found to be effective for 21 of the 25 cocrystals studied.

Review: Effect of Different Methods on the Multicomponents Crystal Formation from Medicinal Natural Ingredient Compounds

Solubility is an important parameter for the bioavailability of drugs that are difficult to dissolve. Natural compounds that are included in class II in the Biopharmaceutics Classification System (BCS) are Apigenin, Quercetin, Genistein, Curcumin, and Piperin. These drugs have low solubility in water and high permeability so that they affect the dissolution rate and as well as their bioavailability, to increase the solubility they are made with multicomponent crystals. This review aims to provide information on the method of making crystal multicomponent to increase the solubility and dissolution rate of BCS II drugs. Several methods that can be used in multicomponent are solvent drop grinding, solvent evaporation, assisted grinding, and slurry. The results showed that multicomponent crystals using several methods could increase the solubility and dissolution rates.

Unusual Thermal Expansion in Hydrogen Bonded Network of an Organic Salt Induced by Large Transverse Vibration of Atoms

Thermal expansion of an organic salt, prepared by solvent-drop grinding of terephthalic acid and imidazole in a 1:2 ratio, has been studied over a wide range of temperature 100–430 K. Restricted mo...

Novel cocrystals of brexpiprazole with improved solubility

Brexpiprazole (BPZ) is a typical antipsychotic drug used for the treatment of schizophrenia and depression. It is classified under BCS class-II with low aqueous solubility and high intestinal permeability. In the present investigation, we reported novel solid forms of brexpiprazole with acid coformers such as glutaric acid (GLU), fumaric acid (FUM), malonic acid (MAL) and succinic acid (SUC) via solvent drop grinding method. All the cocrystals were completely characterized by PXRD (Powder X-ray Diffraction), DSC (Differential Scanning Calorimetry) and FTIR (Fourier Transform Infrared Spectroscopy). The crystal structure is determined for malonic acid cocrystal by single-crystal X-ray diffraction method. The crystal structure revealed that the cocrystal crystallized in the triclinic crystal system with space group P-1 and the malonic acid molecules are sandwiched by brexpiprazole molecules. The solubility studies for brexpiprazole and cocrystals are established in 0.05 M acetate buffer with pH 4.3 at 25 ± 2 °C. Among all solid forms BPZ:FUM cocrystal shown 2.6 times higher solubility than parent drug whereas other cocrystals such as BPZ:GLU, BPZ:SUC and BPZ:MAL improved by 1.77, 1.59 and 1.37 times.

Clean Grinding Technique: A Facile Synthesis and In Silico Antiviral Activity of Hydrazones, Pyrazoles, and Pyrazines Bearing Thiazole Moiety against SARS-CoV-2 Main Protease (Mpro).

A novel series of some hydrazones bearing thiazole moiety were generated via solvent-drop grinding of thiazole carbohydrazide 2 with various carbonyl compounds. Also, dehydrative-cyclocondensation of 2 with active methylene compounds or anhydrides gave the respective pyarzole or pyrazine derivatives. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Additionally, the anti-viral activity of all the products was tested against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MDS). The average binding affinities of the compounds 3a, 3b, and 3c (−8.1 ± 0.33 kcal/mol, −8.0 ± 0.35 kcal/mol, and −8.2 ± 0.21 kcal/mol, respectively) are better than that of the positive control Nelfinavir (−6.9 ± 0.51 kcal/mol). This shows the possibility of these three compounds to effectively bind to SARS-CoV-2 Mpro and hence, contradict the virus lifecycle.

Solid State Characterization and Dissolution Enhancement of Nevirapine Cocrystals.

Purpose: Novel cocrystals of nevirapine (NP) were designed and prepared with salicylamide and 3-hydroxy benzoic acid (3-HBA). Methods: The cocrystals were prepared by solvent drop grinding method by adding few drops of acetone to enhance the solubility and dissolution. The drug and cocrystals were characterized by differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD). The solubility of NP, its wet ground form, and cocrystals were investigated at different pH. Moreover, the effect of surfactant on solubility of cocrystals was also studied. Finally, intrinsic dissolution rate (IDR) and stability of cocrystals was examined. Results: The characterization of cocrystals by DSC and PXRD revealed formation of new solid forms due to changes in thermogram and PXRD pattern. The cocrystal of NP with 3-HBA showed 4.5 folds greater solubility in pH 1.2 buffer and 5.5 folds in 1% Tween 80 as compared to original drug. IDR of cocrystals was higher than the pure drug in 0.1 N hydrochloric acid (HCl). Moreover, cocrystals were found physically stable after 3 months as evident from unchanged IDR. Conclusion: Hence, the present research indicates the new stable solid forms of NP with improved dissolution rate than pure drug.

Solvent Drop Grinding Approach Assisted Development of Glimepiride Co-crystals: Solubility Enhancement Journey of BCS Class-II Product

Solvent Drop Grinding Approach Assisted Development of Glimepiride Co-crystals: Solubility Enhancement Journey of BCS Class-II Product

DISSOLUTION ENHANCEMENT OF LANSOPRAZOLE USING COCRYSTALLIZATION

Objective: Lansoprazole (LPZ) is a Biopharmaceutics Classification System Class II drug. It has low solubility and high permeability, so its rate ofdissolution is a rate-limiting step for drug absorption. This study aimed to improve the dissolution rate of LPZ by forming cocrystals, using nicotinamide(NCT) as the conformer.Methods: Cocrystals of LPZ were produced using the solvent evaporation and solvent-drop grinding methods with a molar ratio of 1:1 and 1:2.The cocrystals were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), and differential scanningcalorimetry (DSC). The solubility and dissolution of the LPZ cocrystals were examined in distilled water.Results: FTIR was used to confirm the formation of hydrogen bonds between LPZ and NCT. DSC and XRD studies showed the formation of crystalsfrom cocrystals and a decrease of the melting point of the cocrystals. The dissolution study revealed that the cocrystals could increase the LPZdissolution rate by up to 8.4-fold compared with pure LPZ.Conclusion: LPZ cocrystal formation with NCT was successful in increasing the dissolution rate of LPZ.

Perbaikan Kelarutan Albendazol Melalui Pembentukan Kristal Multikomponen dengan Asam Malat

An effort to improve the solubility of albendazole (ABZ), an anthelmintic drug has been successfully carried out through the formation of multicomponent crystal with dl-malic acid (MAL). Construction of phase solubility curve of ABZ in MAL solution and crystal morphological observations after recrystallization in the acetone-ethanol (9:1) mixture were performed for initial prediction of multicomponent crystal formation. ABZ-MAL multicomponent crystal was prepared by wet grinding or also known as solvent-drop grinding (SDG) with acetone-ethanol (9:1) mixture as a solvent followed by characterization of the multicomponent crystal formation by powder X-ray diffraction and Fourier transform infrared (FTIR) methods. The solubility of ABZ-MAL multicomponent crystal was tested in water at ambient temperature and in pH 1.2, 4.5 and 6.8 of buffered solutions at 37°C. The phase solubility curve of the ABZ in the MAL solution showed type Bs. The ABZ-MAL mixture has a different crystalline morphology than pure ABZ and MAL after recrystallization in the acetone-ethanol mixture (9:1). The powder X-ray diffraction pattern and the FTIR spectrum of ABZ-MAL from SDG different from intact ABZ and MAL powder X-ray diffraction patterns and these results can indicate the ABZ-MAL multicomponent crystal formation. The ABZ-MAL multicomponent crystal has better solubility than pure ABZ in all media used. These results can be concluded that ABZ-MAL multicomponent crystal can be prepared by solvent-drop grinding method with acetone-ethanol (9:1) mixture as a solvent and can increase the solubility of albendazole.

Solubility Enhancement of Clozapine Through Co-Crystal Formation with Isonicotinamide

Clozapine (CLO) is an effective atypical antipsychotic to control the symptoms of psychosis and schizophrenia. Clozapine has low solubility and high permeability, so it is classified as a class II in the biopharmaceutical classification system. The aim of this study was to improve the solubility and dissolution rate of clozapine by clozapine-isonicotinamide (CLO-INA) co-crystal formation. CLO-INA co-crystal was prepared by solvent-drop grinding (SDG) method using water as a solvent. Characterization of SDG result was conducted by powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR). Solubility test was performed in water at room temperature. The dissolution test was performed in 900 mL of pH 6.8 phosphate buffer solution, 50 rotation per minute of paddle rotation, and at 37±0.5 °C. The PXRD pattern of SDG result of CLO-INA has many different peaks from its parent components, and this may indicate the co-crystal formation. The solubility of the co-crystal clozapine was fifteen folds higher than pure clozapine. The dissolution rate of CLO-INA co-crystal increased in the first 10 minutes compared to pure clozapine. Percentage of clozapine dissolved after 10 minutes from CLO-INA co-crystal and pure CLO were 10.2 and 2.4%, respectively. CLO and INA can form co-crystal by SDG method that can improve the solubility and dissolution rate of clozapine.Keywords: Clozapine, Isonicotinamide, Co-crystal, Solubility, Dissolution

IMPROVEMENT OF SIMVASTATIN DISSOLUTION RATE USING DERIVATIVE NON-COVALENT APPROACH BY SOLVENT DROP GRINDING METHOD

Objective: This study aimed to enhance the solubility of simvastatin using noncovalent derivatives (NCDs) with oxalic acid (OA), fumaric acid (AF), and nicotinamide (NK) as conformers.
 Methods: NCDs were prepared using by a solvent drop grinding (SDG). The NCDs formed were evaluated for saturated solubility test, NCDs with the highest saturation solubility were then characterized by Fourier transform infrared spectrophotometry (FT-IR), differential scanning calorimeter (DSC), powder x-ray diffractometry (PXRD) and the particulate dissolution using type II of USP test.
 Results: SV-OA NCDs showed the highest solubility; thus NCDS of SV-OA were characterized by X-ray diffraction showing a new peak at 2ϴ = 28.96 °C and differential scanning calorimeter showed a change of endothermic peak from 134.3 °C to 69 °C. Infrared spectroscopy indicated that there were no functional group changes from simvastatin, while the dissolution rate increased from 68.22% to 76.08%.
 Conclusion: SV-OA NCDs show an increased profile of solubility and dissolution compared to pure simvastatin.

Dissolution Enhancement of Atorvastatin Calcium by Cocrystallization.

Purpose: To enhance the dissolution rate of the poorly soluble drug atorvastatin calcium (ATC) by cocrystallization with selected coformers. Enhancement of the dissolution rate and solubility of the drug, which is classified as Class II of the Biopharmaceutical Classification System (BCS), is expected to enhance the bioavailability.Methods: Two methods were used for preparing the cocrystals, solvent drop grinding (SDG) and solvent evaporation (SE) method using 1:1, 1:3, and 1:10 drug-coformer molar ratios. Glucosamine hydrochloride (GluN) and nicotinamide (NIC) were investigated as coformers. The cocrystals, their physical mixtures, and the raw ATC were characterized by fourier transform infrared (FTIR spectroscopy), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), mass spectroscopy (MS), scanning electron microscopy (SEM), solubility, and dissolution rate studies. Results: SDG and SE were effective in improving the dissolution rate of ATC with both coformers. Drug: coformer ratio 1:3 was optimum. The solubility values for ATC, GluN-, and NIC-cocrystals were 26, to 35 and 50 µg/mL, respectively. The dissolution rate of ATC from cocrystals was > 90% after 5 minutes, compared to 41% untreated ATC. Conclusion: Cocrystallization significantly improved the solubility and dissolution, in comparison to the untreated ATC.

THE DEVELOPMENT OF GLIBENCLAMIDE-SACCHARIN COCRYSTAL TABLET FORMULATIONS TO INCREASE THE DISSOLUTION RATE OF THE DRUG

Objective: Cocrystallisation is a promising method in order to increase the solubility and dissolution of poorly water-soluble drugs. The aim of this study was to prepare, formulate and evaluate glibenclamide (GCM) cocrystal in direct compress tablet dosage form using saccharin (SAC) as the coformer.
 Methods: GCM cocrystal with various stoichiometric ratios were prepared by the solvent drop grinding method. The co-crystal was characterized by a saturated solubility test and dissolution rate test, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Powder X-Ray Diffraction (PXRD). The tablet dosage form of GCM was formulated and evaluated compare with the conventional dosage form.
 Results: The solubility and disso­lution rate of GCM-SAC cocrystals increased significantly compared with pure GCM, especially for 1:2 of ratio. The dissolution rate of cocrystal with ratio 1:2 increased by almost 91.9% compared with pure GCM. Based on the FTIR analysis, it showed the shifting of characteristic bands of GCM in the spectrum and there was no chemical reaction in GCM cocrystal. In PXRD measurement, the new crystalline peak was detected in the crystal habit of cocrystal compared with pure GCM and coformer. The new single melting of GCM-SAC cocrystal also was detected in DSC measurement. The tablets of GCM-SAC cocrystal were successfully prepared by direct compression method which rapidly disintegrated (1 min) and has higher dissolution compared with its pure form (32.36% greater than glibenclamide after 45 min).
 Conclusion: The tablet dosage form of GCM cocrystal with SAC as coformer was successfully prepared, formulated and improved its solubility and dissolution rate.

The effect of surfactant and polymer on solution stability and solubility of tadalafil-methylparaben cocrystal

Cocrystal formation is a novel method to enhance physicochemical properties of pharmaceuticals. However, instability in solution is one of the challenging issues of cocrystals and surfactants/polymers could have a positive effect on cocrystal solubility and stability. In this study, tadalafil cocrystal was prepared via the solvent drop grinding method with methylparaben as a cocrystal former. The thermodynamic solubility of cocrystal was determined in phosphate buffer solution (pH = 6.8) and in the presence of different concentrations of sodium lauryl sulfate (SLS) and polyvinylpyrrolidone (PVP), followed by investigating their effects on solution stability of cocrystal. The prepared cocrystal showed enhancement in solubility compared with tadalafil, but the solution stability analysis indicated it is an incongruently saturating cocrystal that could transform to a less soluble solid form during slurring and dissolution. Moreover, PVP and SLS improved the cocrystal solution stability, however, the solubility advantage for the prepared cocrystal is not obtained because of preferential solubilization for tadalafil that is less soluble than methylparaben. Overall, the results showed that cocrystal formation of tadalafil with methylparaben has the ability to change its physicochemical properties. In addition, polymer and surfactant could have a significant effect on the solubility and the stability of the cocrystal.

KLi(HC3N3O3)·2H2O: Solvent-drop Grinding Method toward the Hydro-isocyanurate Nonlinear Optical Crystal.

A novel mixed alkali hydro-isocyanurate, KLi(HC3N3O3)·2H2O was first prepared in AOH-BOH-H3C3N3O3 (A/B = Li/Na/K/Rb/Cs) system via a solvent-drop grinding method. KLi(HC3N3O3)·2H2O shows a large second harmonic generation response (5.3 × KH2PO4) with an ultraviolet cutoff edge of 237 nm. More importantly, the bulk single crystal can be readily grown through water solution technique. Characterization of these crystals indicates that KLi(HC3N3O3)·2H2O has a high laser damage threshold (LDT) (4.76 GW/cm2) and exhibits a large birefringence (Δ n = 0.186@514 nm), which reduces Type I phase-matching to 246 nm.

Succinic, fumaric, adipic and oxalic acid cocrystals of promethazine hydrochloride

Novel cocrystals of promethazine hydrochloride [PTZ-Cl; systematic name: N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-aminium chloride] with succinic acid (PTZ-Cl-succinic, C17H21N2S+·Cl-·0.5C4H6O4), fumaric acid (PTZ-Cl-fumaric, C17H21N2S+·Cl-·0.5C4H4O4) and adipic acid (PTZ-Cl-adipic, C17H21N2S+·Cl-·0.5C6H10O4) were prepared by solvent drop grinding and slow evaporation from acetonitrile solution, along with two oxalic acid cocrystals which were prepared in tetrahydrofuran (the oxalic acid hemisolvate, PTZ-Cl-oxalic, C17H21N2S+·Cl-·0.5C2H2O4) and nitromethane (the hydrogen oxalate salt, PTZ-oxalic, C17H21N2S+·C2HO4-). The crystal structures obtained by crystallization from tetrahydrofuran and acetonitrile include the Cl- ion in the lattice structures, while the Cl- ion is missing from the crystal structure obtained by crystallization from nitromethane (PTZ-oxalic). In order to explain the formation of the two types of supramolecular configurations with oxalic acid, the intermolecular interaction energies were calculated in the presence of the two solvents and the equilibrium configurations were determined using density functional theory (DFT). The cocrystals were studied by X-ray diffraction, IR spectroscopy and differential scanning calorimetry. Additionally, a stability test under special conditions and water solubility were also investigated. PTZ-Cl-succinic, PTZ-Cl-fumaric and PTZ-Cl-adipic crystallized having similar lattice parameter values, and showed a 2:1 PTZ-Cl to dicarboxylic acid stoichiometry. PTZ-Cl-oxalic crystallized in a 2:1 stoichiometric ratio, while the structure lacking the Cl atom belongs has a 1:1 stoichiometry. All the obtained crystals exhibit hydrogen bonds of the type PTZ...Cl...(dicarboxylic acid)...Cl...PTZ, except for PTZ-oxalic, which forms bifurcated bonds between the hydrogen oxalate and promethazinium ions, along with an infinite hydrogen-bonded chain between the hydrogen oxalate anions.

Synthesis of cocrystals of sulfonyl urea class drug using suitable coformers for enhancement of aqueous solubility

The pharmaceutical cocrystals and its engineering is widely accepted phenomenon regarding to the enhancement of aqueous solubility of poorly soluble drugs. The pharmaceutical cocrystals have the great ability to improve the physicochemical properties of drug substance. Cocrystals are formed by the stoichiometric combination of drug substance and the coformer. The drug glimepiride is a third generation oral hypoglycemic sulfonylurea class. Glimepiride is a drug which is get classified as biopharmaceutical classification system (BCS) class II which indicates the glimepiride having low aqueous solubility and high permeability. Cocrystal engineering is a perfect way to increases glimepiride solubility without changing its therapeutic property. The cocrystals were synthesized by the solvent drop grinding as a green chemistry approach. The coformers used to form the cocrystals are succinic acid (SA), Theobromine (TB), caffeine (CF). The synthesized cocrystals are get characterized by vibrational spectroscopy, thermal analysis, molecular crystallography, and optical microscopy. The obtained results shows the formation of cocrystal phase between the drug glimepiride and its coformers.