Crystal Inhibition Research Articles

Development of amorphous solid dispersions of cannabidiol: Influence of the carrier, the hot-melt extrusion parameters and the use of a crystallization inhibitor

Hot-melt extrusion has been widely used to manufacture amorphous solid dispersion to enhance water solubility of molecules. In this study, the influence of the polymer, the extrusion parameters and the use of a crystallization inhibitor were investigated for the production of amorphous solid dispersions.Three polymers, namely Kollidon® VA 64, Parteck® MXP and Eudragit® EPO, were first investigated to manufacture amorphous solid dispersions with cannabidiol as a model poor water-soluble drug. Selected mixtures were extruded at three temperatures and two screw speeds. Eudragit® NM 30D, was added to the formulation which had the most appropriated dissolution behavior in order to highlight the prevention of the recrystallization.Dissolution tests first showed a difference between polymers regarding the dissolution of cannabidiol. Eudragit® EPO allowed the highest and the quickest dissolution of CBD (80% after 30 min), so it was selected for the rest of the study. The dissolution tests on the ASD produced with different extrusion parameters showed that the temperature had an influence on the cannabidiol concentration upkeep during the test.Finally, it was observed that Eudragit® NM 30D was able to maintain the elevated CBD concentration during at least 4 h, while the same formulation without this inhibitor was subjected to a drop of cannabidiol concentration.This study showed the importance of first, the choice of polymers for the manufacture of amorphous solid dispersions containing cannabidiol. Secondly, the influence of the extrusion temperature on the upkeep of the cannabidiol concentration was highlighted. Finally, it was shown that the use of a crystallization inhibitor prevents the cannabidiol recrystallization during at least 4 h of dissolution.

Research on numerical simulation method of salt dissolution and recrystallization of inter-salt shale oil reservoir

The Qianjiang inter-salt shale oil reservoir has a high content of salt minerals such as glauberite and halite. Salt dissolution and recrystallization will occur during the water injection development process, which will lead to changes in the porosity and permeability of the reservoir. At present, there is a lack of models and numerical simulation methods to characterize this phenomenon. Using theoretical derivation combined with laboratory experiments, programming and numerical simulation, a characterization model and reservoir numerical simulation method that can describe changes in reservoir porosity and permeability caused by salt dissolution and recrystallization have been established. Studies have shown that salt dissolution will increase the porosity and permeability of the reservoir, and the magnitude of the change is proportional to the amount of water passing, which can improve the flow ability of shale oil. To the contrary, recrystallization will cause the porosity and permeability of the reservoir to decrease, and therefore in the development process, salt crystallization inhibitors should be added to the injected water to avoid salt crystallization blocking the reservoirs around the well and wellbore and causing production decline or even shut-in.

The effectiveness of some crystallization inhibitors in preventing salt damage to limestone

The present paper studied the effectiveness of some crystallization inhibitors as a preventive method to limestone from salt damage. Amino trimethylene phosphonic acid (ATMP), polyacrylic acid (PA), and citric acid (CA) were evaluated as inhibitors against sodium sulfate and sodium chloride salts crystallizations into limestone (micrite). The modifiers that influenced the transport of Na2SO4 and NaCl solutions inside the limestone samples were evaluated by recording the changes with photography and daily report. USB-Digital microscope, scanning electron microscope SEM coupled with a microanalysis energy dispersive system (EDS), X-ray diffraction (XRD), and weight loss data were used to evaluate the efficiency of these inhibitors. The results revealed that the effectiveness of inhibitors of concentration 0.01 M was better than 0.05 M. 0.01 M polyacrylic acid and 0.05 M amino trimethylene phosphonic acid changed the sodium sulfate crystal habit. Only 0.05 M of polyacrylic transformed halite crystals from cube to octahedron, dodecahedron, and tetrahexahdron. The best inhibitors for salt crystallization and mitigates damages to limestone are polyphosphonate and polyacrylate for sodium sulfate salt and polyacrylic for sodium chloride salt.

Vitamin D and Calcium Supplementation Accelerate Vascular Calcification in a Model of Pseudoxanthoma Elasticum.

Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by ABCC6 mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries. Methods: we analyzed whether long-term exposure of Abcc6−/− mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6−/− and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining. Results: at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6−/− mice. Conclusions: vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.

Selection of Primer-Template Sequences That Bind with Enhanced Affinity to Vaccinia Virus E9 DNA Polymerase.

A modified SELEX (Systematic Evolution of Ligands by Exponential Enrichment) pr,otocol (referred to as PT SELEX) was used to select primer–template (P/T) sequences that bound to the vaccinia virus polymerase catalytic subunit (E9) with enhanced affinity. A single selected P/T sequence (referred to as E9-R5-12) bound in physiological salt conditions with an apparent equilibrium dissociation constant (KD,app) of 93 ± 7 nM. The dissociation rate constant (koff) and binding half-life (t1/2) for E9-R5-12 were 0.083 ± 0.019 min−1 and 8.6 ± 2.0 min, respectively. The values indicated a several-fold greater binding ability compared to controls, which bound too weakly to be accurately measured under the conditions employed. Loop-back DNA constructs with 3′-recessed termini derived from E9-R5-12 also showed enhanced binding when the hybrid region was 21 nucleotides or more. Although the sequence of E9-R5-12 matched perfectly over a 12-base-pair segment in the coding region of the virus B20 protein, there was no clear indication that this sequence plays any role in vaccinia virus biology, or a clear reason why it promotes stronger binding to E9. In addition to E9, five other polymerases (HIV-1, Moloney murine leukemia virus, and avian myeloblastosis virus reverse transcriptases (RTs), and Taq and Klenow DNA polymerases) have demonstrated strong sequence binding preferences for P/Ts and, in those cases, there was biological or potential evolutionary relevance. For the HIV-1 RT, sequence preferences were used to aid crystallization and study viral inhibitors. The results suggest that several other DNA polymerases may have P/T sequence preferences that could potentially be exploited in various protocols.

EDTA analogues – unconventional inhibitors of gypsum precipitation

In the current study, EDTA (ethylenediamine-N,N,N′,N′-tetraacetic acid) and three further structurally related analogues with various spacing between the amino groups - PDTA (1,3-Diaminopropane-N,N,N′,N′-tetraacetic acid), HDTA (1,6-Diaminohexane-N,N,N′,N′-tetraacetic acid) and EGTA (Ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid) - were tested as inhibitors of gypsum crystallization. The precipitation reactions were performed at high initial supersaturation and calcium ions were present in large excess relative to the amount of the inhibitor. This way the crystallization reaction was facilitated and the degree of supersaturation was not affected by the complexation. It was found that the structural differences between the inhibitors (i.e., the spacing between the amino groups) seem to exert only a secondary effect on the efficiency of the inhibition. The optimum pH for inhibition was found to be strongly dependent on the inhibitor used. The optimum conditions for inhibition were explained in terms of the concentration of the uncomplexed ligand, which is determined by the stability of the calcium complexes with 1:1 composition as well as with the extent of proton competition. The structure, composition and morphology of the precipitating solids isolated from equilibrium mixtures at the completion of the precipitation process were also studied and the crystal faces where adsorption is most likely to happen were identified.

Synthesis of stacked spherical hierarchical SAPO-34 zeolite and its methanol to olefin catalytic performance

In this paper, stacked spherical hierarchical SAPO-34 zeolite was synthesized by hydrothermal crystallization with tetraethylammonium hydroxide (TEAOH) and morpholine (MOR) as composite template by adding cetyltrimethylammonium bromide (CTAB) as mesoporogen and crystal growth inhibitor. The effects of different templates and CTAB amount on SAPO-34 zeolite was investigated by XRD, SEM, NH3-TPD, and BET. The results showed that hierarchical SAPO-34 zeolite with high MTO catalytic performance was synthesized. With the increase amount of CTAB, the morphology of SAPO-34 zeolite changed from cubic to stacked spherical. Furthermore, the use of composite template could also greatly reduce the synthesis cost of SAPO-34 zeolite, which was of significance for its industrial development.

Оценка кристаллогенной активности меда северных территорий Нижегородской области в различных разведениях

Crystallization of honey is one of its main properties. The component composition of honey has been studied for a very long time, but there are no express methods for examining its characteristics. For this reason, the issue of finding innovative methods for assessing the quality and safety of bee honey remains relevant at the present time. The aim of the study was to evaluate the effect of various honey dilutions on the crystallization of a model crystal-forming solution. Twenty samples of polyfler honey collected from apiaries located on the territory of the Shakhunya district of the Nizhny Novgorod region in the summer served as the material for the study. 4 samples were formed from each collected honey sample, the mass of each of which was 0.1 g, then homogenization of all samples was carried out. By adding an appropriate amount of saline solution to the honey samples, the following dilutions were obtained: 1:4, 1:8, 1:16, 1:32. A control sample representing 0.9% sodium chloride solution was also used. 100 μl of substrate from each sample was applied to a slide and dried in vivo. Facias were analyzed by microscopy using qualitative and quantitative criteria. It was found that in micro-preparations of diluted honey, the density of crystalline elements monotonically increases from the minimum dilution to the maximum. This is due to the high concentration of carbohydrates in honey, which are known inhibitors of crystallization. The use of this testing method during the examination will allow to identify the presence of honey adulterants with artificially increased sugar content.

Effect of a mixed-in crystallization inhibitor on the properties of hydraulic mortars

<abstract> <p>Porous building materials are often subjected to damage due to salt crystallization. In recent years, the addition of crystallization inhibitors in lime-based mortar, has shown promising results in improving durability of this material against salt decay. Lime-based mortars have low mechanical properties and slow setting. They are often replaced with hydraulic binders to overcome these limitations. However, the effect of crystallization inhibitors in mortars with hydraulic binders is still unknown. Incorporation of crystallization inhibitors in hydraulic mortars would widen the application field of this new technology. In this research, the possibility to develop hydraulic mortars with mixed-in sodium ferrocyanide, an inhibitor of sodium chloride crystallization, is explored. As an essential first step, the influence of this inhibitor addition on the properties of hydraulic mortars is investigated. Two common types of hydraulic binders, natural hydraulic lime (NHL) and ordinary Portland cement (CEM I), were studied; the inhibitor was added in different amounts (0%, 0.1% and 1% by binder weight) during mortar (and binder paste) preparation. Relevant mortar and binder paste properties, in fresh (hydration, workability, setting time) and hardened (mechanical strength, elastic modulus, pore size distribution, water absorption) state, were assessed using several complementary methods and techniques. The results indicate that the addition of ferrocyanide does not alter the studied properties of both NHL and CEMI-based mortar and binder pastes. These results are promising for the further development of hydraulic mortars with an improved durability with respect to salt decay.</p> </abstract>

Origin of Crystallization Suppression in a New Amorphous Molecular White-Light-Generating Material

The microscopic structure of a new infrared-driven amorphous white-light-generating material was explored by X-ray diffraction, EXAFS and Reverse Monte Carlo simulation. In this material, structural disorder appears to be prerequisite for this nonlinear optical effect. The results are consistent with quantum chemical predictions, but it is also found that the molecular cores are distorted, which is identified as a crystallization inhibitor. Sulfur atoms thereby form a uniform vibrational network, which may be responsible for the high capability of the material to absorb infrared radiation.

Synthesis of hierarchical nanocrystalline β zeolite as efficient catalyst for alkylation of benzene with benzyl alcohol.

To develop an efficient solid acid catalysts for the Friedel–Crafts alkylation reaction, especially for involving bulky molecules, the direct synthesis of hierarchical nanocrystalline β zeolites were achieved by using amphiphilic organosilane ([(CH3O)3SiC3H6N(CH3)2C18H37]Cl, TPOAC) as collaborative structure-directing agent (SDA). The growth evolution of β crystals and the influence of TPOAC/SiO2 molar ratio on the mesoporous structure, crystal size, and acidic properties of β zeolites were investigated and discussed in detail. The characterization results reveal that intracrystalline mesopores and intercrystalline mesopores/macropores via the stacking of β nanocrystals were generated over the hierarchical β zeolites. Moreover, most of the strong acid sites were well remained compared with the conventional microporous β zeolite. Consequently, the hierarchical nanocrystalline β zeolite synthesized under the optimized synthesis conditions shows improved specific catalytic activity of acid sites (turnover number, TON) in alkylation of benzene with benzyl alcohol, which can be attributed to the integrated balance of considerable mesoporosity, accessibility of the acid sites, and well-remained strong acid sites in the hierarchical β zeolite.

The genetics of kidney stone disease and nephrocalcinosis.

Kidney stones (also known as urinary stones or nephrolithiasis) are highly prevalent, affecting approximately 10% of adults worldwide, and the incidence of stone disease is increasing. Kidney stone formation results from an imbalance of inhibitors and promoters of crystallization, and calcium-containing calculi account for over 80% of stones. In most patients, the underlying aetiology is thought to be multifactorial, with environmental, dietary, hormonal and genetic components. The advent of high-throughput sequencing techniques has enabled a monogenic cause of kidney stones to be identified in up to 30% of children and 10% of adults who form stones, with ~35 different genes implicated. In addition, genome-wide association studies have implicated a series of genes involved in renal tubular handling of lithogenic substrates and of inhibitors of crystallization in stone disease in the general population. Such findings will likely lead to the identification of additional treatment targets involving underlying enzymatic or protein defects, including but not limited to those that alter urinary biochemistry.

High-Throughput in vitro Gel-Based Plate Assay to Screen for Calcium Oxalate Stone Inhibitors

Objective: Kidney stones are a common medical condition that is increasing in prevalence worldwide. Approximately, ∼80% of urinary calculi are composed of calcium oxalate (CaOx). There is a growing interest toward identifying therapeutic compounds that can inhibit the formation of CaOx crystals. However, some chemicals (e.g., antibiotics and bacterial metabolites) may directly promote crystallization. Current knowledge is limited regarding crystal promoters and inhibitors. Thus, we have developed an in vitro gel-based diffusion model to screen for substances that directly influence CaOx crystal formation. Materials and Methods: We used double diffusion of sodium oxalate and calcium chloride-loaded paper disks along an agar medium to facilitate the controlled formation of monohydrate and dihydrate CaOx crystals. A third disk was used for the perpendicular diffusion of a test substance to assess its influence on CaOx crystal formation. Results: We confirmed that citrates and magnesium are effective inhibitors of CaOx crystals. We also demonstrated that 2 strains of uropathogenic Escherichia coli are able to promote crystal formation. While the other tested uropathogens and most antibiotics did not change crystal formation, ampicillin was able to reduce crystallization. Conclusion: We have developed an inexpensive and high-throughput model to evaluate substances that influence CaOx crystallization.

Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient.

Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability, and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e., artemisinin-orcinol (ART-ORC) and artemisinin-resorcinol (ART2-RES), as oral dosage forms to deliver ART molecules for bioavailability enhancement. This is the first part of the study, aiming to develop a simple and effective formulation, which can then be tested on an appropriate animal model (i.e., mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. In the current work, the physicochemical properties (i.e., solubility and dissolution rate) of ART cocrystals were measured to collect information necessary for the formulation development strategy. It was found that the ART solubility can be increased significantly by its cocrystals, i.e., 26-fold by ART-ORC and 21-fold by ART2-RES, respectively. Screening a set of polymers widely used in pharmaceutical products, including poly(vinylpyrrolidone), hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose acetate succinate, based on the powder dissolution performance parameter analysis, revealed that poly(vinylpyrrolidone)/vinyl acetate (PVP-VA) was the most effective crystallization inhibitor. The optimal concentration of PVP-VA at 0.05 mg/mL for the formulation was then determined by a dissolution/permeability method, which represented a simplified permeation model to simultaneously evaluate the effects of a crystallization inhibitor on the dissolution and permeation performance of ART cocrystals. Furthermore, experiments, including surface dissolution of single ART cocrystals monitored by Raman spectroscopy, scanning electron microscopy and diffusion properties of ART in solution measured by 1H and diffusion-ordered spectroscopy nuclear magnetic resonance spectroscopy, provided insights into how the excipient affects the ART cocrystal dissolution performance and bioavailability.

Tailoring Release Profiles of BCS Class II Drugs Using Controlled Release Amorphous Solid Dispersion Beads with Membrane-Reservoir Design: Effect of Pore Former and Coating Levels.

Poor aqueous solubility is a major limiting factor during the development of BCS Class II drug candidates in a solid oral dosage form. Conventional amorphous solid dispersion (ASD) systems focus on maximizing the rate and extent of release by employing water-soluble polymeric crystallization inhibitors; however, they often encounter rapid supersaturation and solution-mediated phase transformation (SMPT). Therefore, in this work, a controlled release membrane was introduced onto ASD beads to mitigate the SMPT problem. A membrane-reservoir controlled release amorphous solid dispersion (CRASD) bead system was designed, and the effects of the coating thickness and pore former content on drug release profiles were investigated. CRASD beads were manufactured by spray-coating polyvinyl acetate with polyvinylpyrollidone (PVP) as a pore former onto sugar bead substrates layered with the ASD reservoir of celecoxib and PVP. Raising the pore former content and/or lowering the coating level imparted higher release rates and supersaturation levels. The extent of release, measured by the area under the curve, was greatest when an optimal balance between the release rate and peak concentration could be established, corresponding to a high pore former/high coating level combination. Attributed to a thicker membrane structure with a higher pore former, rapid initial release could be achieved, yet controlled gradually for several hours, avoiding the critical threshold where the onset of SMPT predominates. The greater membrane capacity to transiently immobilize drug molecules (i.e., preserve amorphicity) and gradually release drug over a prolonged duration may be key to balancing supersaturation on both sides of the membrane; hence coating variables should be tactfully selected to exploit this benefit.

Explicating the molecular level drug-polymer interactions at the interface of supersaturated solution of the model drug: Albendazole

Supersaturation as a formulation principle relates to the aqueous solubility of poorly soluble drugs in solution . However, supersaturation state of drugs tends to crystallize because of its thermodynamic instability thereby compromising the solubility and biopharmaceutical performance of drugs. The present study aims to investigate the supersaturation potential of albendazole (ABZ) and its precipitation via nucleation and crystal growth. We hypothesized the use of polymers will avoid ABZ precipitation by interacting with drug molecules. The drug polymer interactions are characterized using conventional methods of Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR) and Polarized light microscopy (PLM). We have used a novel approach of sum frequency generation (SFG) vibrational spectroscopic in exploring the drug polymer interactions at air-water interface. Recently we have reported the SFG for e rifaximin-polymer interactions (Singh et al., 2021). The supersaturation assay, saturation solubility studies and nucleation induction time analysis revealed polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP K30) as effective precipitation inhibitors thereby enhancing the ABZ equilibrium solubility and in vitro supersaturation maintenance of ABZ. Further, modification in the solid state of ABZ has confirmed the influence of polymers on its precipitation behaviour. We conclude that PVA and PVP K30 act as nucleation and crystal growth inhibitor, respectively for the precipitation inhibition of ABZ.

A novel modified LiCl solution for three-phase absorption thermal energy storage and its thermal and physical properties

• A novel LiCl solution for three-phase absorption thermal energy storage is proposed. • The energy storage density of the solution is enhanced by adding two types of additives. • The LiCl crystal slurry overcomes the fluidity problem caused by crystallization. • Thermal and physical properties of the modified solution are measured by experiments. Absorption thermal energy storage (TES) is gaining increasing attention due to its large energy storage density (ESD), mobility and long-term thermal storage capability. Expanding the working concentration difference of a solution can significantly enhance its ESD; however, this may result in crystallization, influencing fluidity and blocking flow channels in a TES device. Furthermore, bulky crystals are difficult to dissolve during energy discharge. In this paper, a novel modified LiCl solution is proposed for three-phase absorption TES, which allows the growth of fine crystals and the formation of well suspended slurry. For the first time, two types of additives with competing mechanism are introduced into the solution: ethylene glycol as a crystallization inhibitor and SiO 2 nanoparticles (SNPs) as a nucleating agent. Compared with traditional working fluids, the proposed solution has a larger ESD and good fluidity. The expanded concentration difference is determined by experiments on solubility and suspension. The optimal mass ratio of the LiCl solution, ethylene glycol and SiO 2 nanoparticles are obtained considering both ESD and fluidity. Heat and cold storage density using this novel LiCl crystal slurry can be enhanced by 24.8% and 156.0% respectively. Measurements on thermal and physical properties including vapor pressure, density and viscosity are also carried out.

Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug-Polymer Interactions.

Amorphous solid dispersions (ASDs) are of great interest due to their ability to enhance the delivery of poorly soluble drugs. Recent studies have shown that, in addition to acting as a crystallization inhibitor, the polymer in an ASD plays a role in controlling the rate of drug release, notably in congruently releasing formulations, where both the drug and polymer have similar normalized release rates. The aim of this study was to compare the solid-state stability and release performance of ASDs when formulated with neutral and enteric polymers. One neutral (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) and four enteric polymers (hypromellose acetate succinate; hypromellose phthalate; cellulose acetate phthalate, CAP; methacrylic acid-methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs with lumefantrine, a hydrophobic and weakly basic antimalarial drug. The normalized drug and polymer release rates of lumefantrine-PVPVA ASDs up to 35% drug loading (DL) were similar and rapid. No drug release from PVPVA systems was detected when the DL was increased to 40%. In contrast, ASDs formulated with enteric polymers showed a DL-dependent decrease in the release rates of both the drug and polymer, whereby release was slower than for PVPVA ASDs for DLs < 40% DL. Drug release from CAP and Eudragit L 100 systems was the slowest and drug amorphous solubility was not achieved even at 5% DL. Although lumefantrine-PVPVA ASDs showed fast release, they also showed rapid drug crystallization under accelerated stability conditions, while the ASDs with enteric polymers showed much greater resistance to crystallization. This study highlights the importance of polymer selection in the formulation of ASDs, where a balance between physical stability and dissolution release must be achieved.

Influence of additives on the crystallization and thermal conductivity of container glass cullet for foamed glass preparation

Foamed glass preparation is a complex combination of reactions, greatly influenced by the composition of the used glass and often hindered by simultaneous crystallization. The crystallization phenomenon is undesirable in foamed glass production since it decreases the quality of the final product. In this work the influence of different types of additives (foaming agents, flux agents, crystallization inhibitors and nucleating agent) on the crystallization of waste container glass and properties of the sintered samples (density and thermal conductivity) was studied. Results of our study confirmed partial crystallization during sintering stage. We found that waste container glass manifests complex crystallization with the formation of four main crystalline phases, which can be inhibited with the addition of fluxing agents (B2O3 and borax). Moreover, here we show that prevention of the crystallization can lead to a significant decrease of the thermal conductivity.

Critical Growth Rate of Hydrate Crystal Growth Inhibitors in the Low Growth Rate Region

Critical Growth Rate of Hydrate Crystal Growth Inhibitors in the Low Growth Rate Region