Solvent Drop Research Articles

Solubility Enhancement and Characterization of Tamoxifen Citrate Using Co-crystallization

Tamoxifen citrate (TC) is one of the anti-estrogen agents which has low solubility in the water. As TC is still used as the main therapy in breast cancer treatment, modifications are still being made to increase the solubility of TC for a successful treatment. In this research, co-crystallization of TC was performed using Nicotinamide (NIC), Isonicotinamide (ISO), Saccharin (SAC), Aspartame (ASP), and Benzoic Acid (BNZ) as a coformer with the molar ratio of 1:1, 1:2, and 2:1. Co-crystal was prepared by solvent drop grinding (SDG) and solvent evaporation (SE) methods using methanol. The results of the solubility test showed that TC-NIC and TC-ISO co-crystals with a 1:2 molar ratio made using the SDG and SE methods gave the best results. Meanwhile, the best dissolution test results were shown by TC-ISO co-crystals with a ratio of 1:2. Based on the characterization of physical stability, the SDG method resulted in more stable TC co-crystals than the SE method. Therefore, in this case, the SDG method could be more advantageous to be used for development in the field of co-crystallization.

New Sodium Mefenamate - Nicotinamide Multicomponent Crystal Development to Modulate Solubility and Dissolution: Preparation, Structural, and Performance Study.

A cocrystal of mefenamic acid (MA) - nicotinamide (NA) has been reported to increase the solubility of MA, but it still does not exceed the solubility of sodium mefenamate (SM). Accordingly, this research dealt with a new salt cocrystal arrangement of SM - NA. Cocrystal screening was performed, followed by powder and single-crystal preparation. Solvent drop grinding and slow evaporation at cold and ambient temperatures were employed to produce the multicomponent crystal. Two new salt cocrystals were found as hemihydrates and monohydrates, named SMN-HH and SMN-MH, respectively. SMN-MH single crystals were successfully isolated and structurally analyzed using a single crystal X-ray diffractometer. Pharmaceutical properties were investigated, including hydrate stability, solubility, and intrinsic dissolution. The experiments showed that the hemihydrate was stable under ambient humidity and temperature, and that the monohydrate rapidly changed to hemihydrate. Both hydrates improved the solubility and intrinsic dissolution of SM, but SMN-HH was superior. The data showed that SMN salt cocrystals combine the advantages of salt and cocrystals and show potential for dosage form development.

Cocrystals, Salts, and Salt-Solvates of olanzapine; selection of coformers and improved solubility

Pharmaceutical cocrystals and salts are extensively researched in recent years due to their ability to tune the physicochemical properties of active pharmaceutical ingredients (APIs). A model API, olanzapine, an atypical antipsychotic drug classified as Biopharmaceutical Classification System class II, is used in this study. Cocrystals and salts of olanzapine are discovered using solvent drop grinding and ball milling. Appropriate coformers were selected based on a combination of hydrogen-bond propensity (HBP) and hydrogen-bond coordination (HBC) calculations. Eight new multicomponent phases of olanzapine, including one cocrystal hydrate with phenol; four anhydrous salts with salicylic acid, terephthalic acid, anthranilic acid, 3-hydroxybenzoic acid, and 2-aminoterephthalic acid; one salt dihydrate with terephthalic acid; and one salt solvate with 3-hydroxybenzoic acid and acetonitrile, have been discovered and characterized by PXRD and DSC. One reported cocrystal (olanzapine-resorcinol) has also been considered for the dissolution test. All these newly formed solid phases followed the “ΔpKa rule of 3”. The crystal structures of cocrystal/salts were determined by single-crystal X-ray (sc-XRD) diffraction. With the collected single-crystal data, the crystal packings were found to be primarily stabilized via strong hydrogen bonds between carboxyl, phenolic hydroxyl of co-formers/salt-formers with the piperazine and diazepine nitrogen of olanzapine, which confirmed the predicted result from the HBP and HBC calculations. HPLC coupled with UV–vis detector was used in the solubility and dissolution test instead of UV–vis spectroscopy, to avoid the peak overlap between olanzapine and co-formers/salt-formers. A threefold increase in the solubility was observed in olanzapinium 3-hydroxybenzoate and olanzapinium anthranilate, and an almost fivefold increase in solubility of olanzapinium 2-aminoterephthalate.

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.

Drop Spreading and Confinement in Swelling-Driven Folding of Thin Films.

Surface instabilities are a versatile method for generating three-dimensional (3D) surface microstructure. When an elastomeric film weakly bonded to a substrate is swollen with solvent, buckle delamination and subsequent sliding of the film on the substrate lead to the formation of tall, self-contacting, and permanent folds. This paper explores the mechanics of fold development when such folding is induced by placing a drop on the surface of the film. We show that capillary effects can induce a strong coupling between folding and drop spreading: as folds develop, they wick the solvent toward the periphery of the drop, further propagating radially aligned folds. Accordingly, a solvent drop spreads far more on films that are weakly adhered to the substrate. As drop size reduces and folding becomes increasingly confined, debonding propagates along the perimeter of the wetted region, thus leading to corral-shaped fold patterns. On the other hand, as drop size increases and confinement effects weaken, isotropically oriented folds appear at a spacing that reduces as swelling increases. The spacing between the folds and the size of the corrals are both determined by the extent to which a single fold relieves compressive stress in its vicinity by sliding. We develop a model for folding which explicitly accounts for the fact that folds must initiate with near-zero volume under the buckle. The model shows that folds can appear even at very low swelling if there are large pre-existing debonded regions at the film-substrate interface.

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.

Delamination and Wrinkling of Flexible Conductive Polymer Thin Films

AbstractPolymer based conductive and transparent thin films are an important class of functional materials at the heart of flexible organic electronic devices. These flexible films are prone to degradation and to mechanical instability leading to the formation of blisters, wrinkles, and cracks. This is detrimental to their use especially in the case of multilayer devices. Here, it is shown that a simple water or solvent drop deposited on such films gives rise to a buckling instability and the formation of several folds due to the tendency of these films to swell in contact with the solvent. A phase diagram of the instability portraying its domain of existence, and thus the means to inhibit it, is proposed. By depositing drops on such films and observing the instability, material parameters such as the elastic modulus of the thin films or their energy of adhesion to the substrate can be estimated reliably. Further, the instability can be harnessed to pattern surfaces at low cost giving rise to percolated and more conductive pathways in the conductive polymer films under scrutiny.

Formulation And In-Vitro Evaluation Of Cocrystals Of Pantoprazole Sodium For Immediate Release

Pantoprazole is extensively metabolized in the liver and has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 L/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance, and volume of distribution are independent of the dose. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The clearance of pantoprazole is only slightly affected by age, with its half-life being approximately 1.25 h in the elderly. Pantoprazole is an acid labile drug that requires protection from degradation in acidic media. Hence, co-crystallization of pantoprazole sodium with appropriate co-formers will inhibit its degradation in acidic medium ensuring fast release in the stomach. The acid-labile drugs for oral administration may also be protected from gastric acidity by inhibiting its degradation upon entering into acidic environment. So, the current approach includes co-crystallization of the provided drug with appropriate co-former which prevents degradation of drug by quick absorption and protects the drug from low pH. Apart from that, the formulations also modulate or control the drug release for an immediate action.
 Keywords: Pantoprazole sodium, Co-crystal, solvent drop method, Co-former.

Effect of Lipopolysaccharide Extracted from Enterobacter cloacae on some Pathogenic Bacteria

A 106 different specimen were collected to isolate and diagnose some gram negative and gram-positive bacteria, as it was performed for the period from 15 August to 30 November 2019 from AL-Salam and Al-Khansaa educational hospitals in Mosul. Lipopolysaccharide (LPS) was extracted from Enterobacter cloacae by using the Methanol - Chloroform method. extract was diagnosed, using some biochemical tests such as the Molisch test to detect carbohydrate content and Folin reagent in order to determine proteins concentration, lipid solubility in organic solvent and Bio drop technique as well as to detect nucleic acid concentration. The extraction methods showed its efficiency with low protein and nucleic acids concentration in the extract. Lipopolysaccharide demonstrated its efficiency inhibiting microbial growth on all test isolates at concentrations 1100, 1000 µg ml while its lipopolysaccharide showed its inhibition of Proteus mirabilis at all concentrations used. LPS showed possibility used as inhibitory, antimicrobial growth

A novel direct-immersion single-drop microextraction combined with digital colorimetry applied to the determination of vanadium in water

In this study, a method based on direct-immersion single-drop microextraction was developed for the determination of vanadium in water. The detection system uses digital images obtained directly from the solvent drop after the sorption of V(V). The extraction solvent used was the ionic liquid 1-hexyl-3-methylimidazolium hexafluorophosphate ([C6MIM][PF6]). The images were obtained directly from the solvent drop, with the aid of a camera. The digital images were stored, and the RGB (red, green, and blue) data were obtained. The data collected by the red channel were used to construct the analytical curve since it showed higher sensitivity compared with green and blue channels. Under optimized conditions, the method presented an enrichment factor of 50 and a limit of detection of 0.6 μg L−1 for 3.5 mL sample volume. The limit of quantification and the relative standard deviation (50.0 μg L−1) obtained were 1.8 μg L−1 and 4.8%, respectively. Certified reference material (Plankton) was used to assess the accuracy of the method. The simple, fast, efficient, and low-cost procedure was successfully applied to the determination of V(V) in water samples. The proposed method is also following the principles of green chemistry since it uses minimal volumes of samples, reagents, and solvents and yields a small amount of waste.

Dynamics of an elastoviscoplastic droplet in a Newtonian medium under shear flow

The dynamics of a single elastoviscoplastic (EVP) drop immersed in plane shear flow of a Newtonian fluid is studied by 3D direct numerical simulations using a finite-difference and level-set method combined with the Saramito model for the EVP fluid. This model gives rise to a yield stress behavior, where the unyielded state of the material is described as a Kelvin-Voigt viscoelastic solid and the yielded state as a viscoelastic Oldroyd-B fluid. Yielding of an initially solid drop of Carbopol is simulated under successively increasing shear rates. We proceed to examine the roles of nondimensional parameters on the yielding process; in particular, the Bingham number ($Bi$), capillary number ($Ca$), Weissenberg number ($Wi$), and ratio of solvent and total drop viscosity. We find that all of these parameters, and not only $Bi$, have a significant influence on the drop dynamics. Numerical simulations predict that the volume of the unyielded region inside the droplet increases with $Bi$ and $Wi$, while it decreases with $Ca$ at low $Wi$ and $Bi$. A new regime map is obtained for the prediction of the yielded, unyielded, and partly yielded modes as a function of $Bi$ and $Wi$. The drop deformation is studied and explained by examining the stresses in the vicinity of the drop interface. The deformation has a complex dependence on $Bi$ and $Wi$. At low $Bi$, the droplet deformation shows a nonmonotonic behavior with an increasing $Wi$. In contrast, at moderate and high $Bi$, droplet deformation always increases with $Wi$. Moreover, it is found that the deformation increases with $Ca$ and with the solvent to total drop viscosity ratio. A simple ordinary differential equation model is developed to explain the various behaviours observed numerically. The presented results are in contrast with the heuristic idea that viscoelasticity in the dispersed phase always inhibits deformation.

Buckling and snapping of a thin polymeric membrane exposed to a solvent drop

We report the behavior of a thin and flat rectangular polymeric membrane, fixed at both ends, in contact with a solvent droplet. Depending on the solvent type and volume, and membrane thickness, three different regimes —no buckling, buckling, and snapping— are observed. Our study reveals that the behavior depends on the solubility parameter of the solvent and the ratio of the sum of swelling-induced force and capillary force to the elastic restoring force, i.e., the force ratio. We attempt to explain the phenomenon using the poroelastic and elastic recoil timescales. Using correlations from simple scaling, our model can estimate the maximum force ratio in terms of known quantities and predict the operating regime and maximum deflection. We expect our study will find significance in the design and analysis of systems involving flexible microbeams.

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.

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.

How to obtain kinetic information in thin-film voltammetry from the comparison of SCV and SWV responses

Abstract Thin-film voltammetry (TFV) has one of the simplest experimental setups for studying the electrochemical processes that take place at liquid/liquid interfaces. This is because in TFV it is possible to neglect the iR drop of the non-aqueous solvent, when it corresponds to an organic thin film attached to the working electrode. In this manuscript the theory of TFV is used for describing how the electrochemical responses of staircase cyclic voltammetry (SCV) and square-wave voltammetry (SWV) are affected by the confinement of electroactive species in a thin film that is in contact with the working electrode. The reason for comparing the responses of these two techniques is established on the different concentration profiles that the electroactive species present within the thin-film and the implications that it has on the voltammetric responses of each technique. According to our analysis, the presence of the so-called “quasi-reversible maximum” cannot be used in TFV for estimating kinetic parameters since it would lead to erroneous results. This is because both the apparent kinetic and the apparent thickness change simultaneously with the variation of the scan-rate of each technique. Instead of this, it is proposed a strategy based on the variation of the scan-rate of SCV and SWV. Thus, it is possible to obtain 2 sets of voltammograms whose peak currents and peak potentials characterize the kinetic and thickness of the system. The estimation can be made when all the peak parameters fit properly to the theoretical data provided in this manuscript. Besides, it is shown that the results of SCV and SWV complement each other providing the way for estimating the formal charge transfer rate constant and the thickness of this kind of systems.

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

Simultaneous determination of curcuminoids in Curcumae Longae Rhizoma and turmeric tea using liquid-phase microextraction based on solidification of floating deep eutectic solvent drop

A simple and efficient liquid-phase microextraction procedure has been developed based on solidification of floating deep eutectic solvent (DES) drop for simultaneous separation and preconcentration of active curcuminoids in Curcumae Longae Rhizoma and turmeric tea. In this work, a hydrophobic and low-density DES prepared from tetrabutylammonium chloride and decanoic acid as extractant was injected into the sample phase, and a cloudy solution was formed by magnetic stirring at 40 °C. After extraction, the floating and reaggregated DES drop was recovered through solidification for high performance liquid chromatography analysis. The important extraction variables were optimized including extraction solvent type and consumption, sample phase pH, salt amount, stirring rate, extraction time and temperature. Under the optimal conditions, good responses were presented with detection limits of 7.0 × 10−5, 7.0 × 10−5, 9.0 × 10−5 mg/L, and enrichment factors of 608, 621, and 848 for bisdemethoxycurcumin, demethoxycurcumin and curcumin, respectively. Satisfactory accuracies (recoveries 84.6–116.8%) and precisions (relative standard deviations 1.4–4.2%) were also obtained. The proposed method was successfully applied for extraction and determination of three curcuminoids in real herbal and dietary supplement samples.

Control by one drop of solvent: selective preparation of guest release/trap-triggered interconvertible molecular crystals.

Interconvertible molecular crystals 1close and 1open composed of 4-pyridyl-1,3-indanedione dimer 1 were selectively obtained. Thermal removal of solvent molecules in 1open afforded 1close. Further dipping of 1close in a specific solvent reproduced 1open. No crystallinity loss was observed even though both processes involved a drastic change of molecular packing arrangements.

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.