Crystal Inhibition Research Articles

Suppressing the effect of cullet composition on the formation and properties of foamed glass

The process of foaming glass is very dependent on the chemical composition of the glass. In this study we used a foaming-agent/oxidizing-agent couple and a crystallization inhibitor to foam cullets of flat, container and CRT-panel glass. Foamed glass with a density of 110–120 kg m–3, a thermal conductivity of 50–52 mW m–1 K–1 and a homogeneous pore structure was obtained from a mixture of panel glass, 0.33 wt% carbon and 4.45 wt% Fe2O3. We also showed that it is possible to fabricate foamed glass with the same density or pore structure as mentioned above by adding up to 50 wt% container cullet or 70 wt% flat glass to the mixture. In the foamed samples with a low content of panel glass, crystals form, resulting in an increased open porosity, density and inhomogeneous pore structure. The crystallization can, however, be inhibited by adding calcium phosphate, so enabling the preparation of high-quality foamed glass from flat glass or flat/container-glass mixture. The pore gas is predominantly CO2 and the pressure inside the pores is 0.36–0.47 bar. The reduced effect of the composition on the foaming process suggests that there is a great potential for stabilizing the production of foamed glass and ensuring the product's quality.

Sodium Acetate Trihydrate–Crystallization Inhibitor System for Seasonal Latent Heat Storage

AbstractStable supercooling of phase change materials benefits the long-term latent heat storage. Various crystallization inhibitors were adopted to improve the stability of the supercooled sodium ...

Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria

To overcome the chemical and metabolic stability issues of l-cystine dimethyl ester (CDME) and l-cystine methyl ester (CME), a series of l-cystine diamides with or without Nα-methylation was designed, synthesized, and evaluated for their inhibitory activity of l-cystine crystallization. l-Cystine diamides 2a–i without Nα-methylation were found to be potent inhibitors of l-cystine crystallization while Nα-methylation of l-cystine diamides resulted in derivatives 3b–i devoid of any inhibitory activity of l-cystine crystallization. Computational modeling indicates that Nα-methylation leads to significant decrease in binding of the l-cystine diamides to l-cystine crystal surface. Among the l-cystine diamides 2a–i, l-cystine bismorpholide (CDMOR, LH707, 2g) and l-cystine bis(N′-methylpiperazide) (CDNMP, LH708, 2h) are the most potent inhibitors of l-cystine crystallization.

Evaluation of Pazopanib Phase Behavior Following pH-Induced Supersaturation.

Salts of weakly basic active pharmaceutical ingredients are widely used to improve aqueous solubility and/or dissolution rate. However, these compounds are prone to precipitation due to the lower solubility of the un-ionized species at the higher pH in the intestinal region, and this can result in poor and/or variable absorption. The goal of this study was to investigate the degree of supersaturation achieved following dissolution of different amounts of pazopanib hydrochloride at low pH, followed by rapid pH increase. Using pH solubility profiles, phase boundaries were defined for crystalline and amorphous free base forms. The resultant phase diagram was used to rationalize the observed supersaturation and phase behavior of pazopanib following pH adjustment. In the presence of a crystallization inhibitor, hydroxypropylmethyl cellulose (HPMC), the degree of supersaturation was found to be very high, approximately 600-fold, at pH 6.5. At a dose equivalent to the clinical dose, the maximum free drug concentration observed at pH 6.5 was dictated by the amorphous solubility. Solutions that exceeded the amorphous solubility upon pH increase were found to undergo glass-liquid phase separations (GLPS) with the formation of amorphous colloidal drug-rich particles. Microscopic observations confirmed that HPMC delayed the appearance of pazopanib free base crystals. The phase behavior upon pH change is thus well predicted by the phase diagram, after taking into consideration the initial dose, the extent of supersaturation generated upon pH change, and the presence or absence of a crystallization inhibitor.

Pyrophosphate-Inhibition of Apatite Formation Studied by In Situ X-Ray Diffraction

The pathways to crystals are still under debate, especially for materials relevant to biomineralization, such as calcium phosphate apatite known from bone and teeth. Pyrophosphate is widely used in biology to control apatite formation since it is a potent inhibitor of apatite crystallization. The impacts of pyrophosphate on apatite formation and crystallization kinetics are, however, not fully understood. Therefore, we studied apatite crystallization in water by synchrotron in situ X-ray diffraction. Crystallization was conducted from calcium chloride (0.2 M) and sodium phosphate (0.12 M) at pH 12 where hydrogen phosphate is the dominant phosphate species and at 60 °C to allow the synchrotron measurements to be conducted in a timely fashion. Following the formation of an initial amorphous phase, needle shaped crystals formed that had an octacalcium phosphate-like composition, but were too small to display the full 3D periodic structure of octacalcium phosphate. At later growth stages the crystals became apatitic, as revealed by changes in the lattice constant and calcium content. Pyrophosphate strongly inhibited nucleation of apatite and increased the onset of crystallization from minute to hour time scales. Pyrophosphate also reduced the rate of growth. Furthermore, when the pyrophosphate concentration exceeded ~1% of the calcium concentration, the resultant crystals had reduced size anisotropy suggesting that pyrophosphate interacts in a site-specific manner with the formation of apatite crystals.

Hyperuricosuric calcium urolithiasis.

Hyperuricosuric calcium urolithiasis is a condition of mixed calcium oxalate stones characterized by hyperuricosuria either in isolation or in conjunction with other risk factors for calcium oxalate stones such as hypercalciuria, hyperoxaluria, and hypocitraturia. There are three proposed physicochemical models of pathogenesis where urate in its crystalline phase via heterogeneous nucleation, in its colloidal phase via removal of crystallization inhibitors, and in solution via precipitation crystallization, can all increase propensity to calcium oxalate precipitation. Regardless of the model, the phenomenologic observation of urate increasing calcium oxalate precipitation appears solid. Another supporting factor are retrospective data analysis and prospective trials showing uric acid lowering reduces stones events in hyperuricosuric calcium stone formers. Due to the heterogeneity of pathogenesis of calcium oxalate stones in the unselected stone-formers, association cannot be demonstrated between uric acid excretion rate and risk of kidney stone the general population. In calcium oxalate stoners with isolated hyperuricosuria or hyperuricosuria in combination with other calcium stone risks where treatment of these traditional risks fails to reduce stone formation, urate acid lowering should be cautiously attempted. More refinement of pathogenic models and prospective controlled trials in phenotypically defined subgroups of subjects with calcium oxalate urolithiasis will be informative.

Phosphate-Free Inhibition of Calcium Carbonate Dishwasher Deposits

This article reports the characterization of the composition and morphology of mineral formation on glass and plastic (poly(methyl methacrylate)) substrates in a dishwasher environment and the identification of suitable phosphate-free mineral crystallization inhibitors as environmentally benign candidates to replace the currently used phosphate-containing inhibitor 1-hydroxyethane 1,1-diphosphonic acid (HEDP). Screening of the calcium carbonate crystallization inhibition performance of 28 different compounds resulted in the identification of two phosphate-free, cyclic poly(carboxylic acid) inhibitors, which were found in combination to be effective replacements. Each inhibitor proved to be highly substrate specific with all-cis-cyclohexane-1,2,3,4,5,6-hexacarboxylic acid (CHHCA) preventing deposition on glass (where calcite is the dominant polymorph) and cis,cis,cis,cis-cyclopentane-1,2,3,4-tetracarboxylic acid (CPTCA) inhibiting aragonite deposition on poly(methyl methacrylate) (PMMA). When used in combi...

SNF472, a novel inhibitor of vascular calcification, could be administered during hemodialysis to attain potentially therapeutic phytate levels

BackgroundCardiovascular calcification (CVC) is a major concern in hemodialysis (HD) and the loss of endogenous modulators of calcification seems involved in the process. Phytate is an endogenous crystallization inhibitor and its low molecular mass and high water solubility make it potentially dialyzable. SNF472 (the hexasodium salt of phytate) is being developed for the treatment of calciphylaxis and CVC in HD patients. We aimed to verify if phytate is lost during dialysis, and evaluate SNF472’s behaviour during dialysis.MethodsDialyzability was assessed in vitro using online-hemodiafiltration and high-flux HD systems in blood and saline. SNF472 was infused for 20 min and quantified at different time points.ResultsPhytate completely dialyzed in 1 h at low concentrations (10 mg/l) but not when added at 30 or 66.67 mg/l SNF472. In bypass conditions, calcium was slightly chelated during SNF472 infusion but when the system was switched to dialysis mode the calcium in the bath compensated this chelation.ConclusionPhytate dialyses with a low clearance. The administration of SNF472 as an exogenous source of phytate allows to attain supra-physiological levels required for its potential therapeutic properties. As SNF472 is infused during the whole dialysis session, the low clearance would not affect the drug’s systemic exposure.

Small-Molecule Povidone Analogues in Coamorphous Pharmaceutical Phases

The crystallization inhibitor polyvinylpyrrolidone (PVP) is commonly used as a stabilizer in the formation of amorphous polymer dispersions of poorly soluble pharmaceuticals. In this work we examine the use of a range of PVP-inspired small-molecule bis(lactams) as coformers in the stabilization of amorphous pharmaceutical phases creating coamorphous materials. The dimer of N-vinyl(caprolactam) (bisVCap, 3) was found to be an effective coamorphous-former at relatively low loading for carisoprodol, carbamazepine, isoniazid, and 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY).

A trade-off between solubility enhancement and physical stability upon simultaneous amorphization and nanonization of curcumin in comparison to amorphization alone

The numerous health benefits of curcumin (CUR) have not been fully realized due to its low aqueous solubility, resulting in poor bioavailability. While amorphization of CUR via amorphous solid dispersion (ASD) represents a well-established CUR solubility enhancement strategy, simultaneous amorphization and nanonization of CUR via amorphous CUR nanoparticles (or nano-CUR in short) have emerged only recently as the plausibly superior alternative to ASD. Herein we examined for the first time the amorphous nano-CUR versus the ASD of CUR in terms of their (1) in vitro solubility enhancement capability and (2) long-term physical stability. The ASD of CUR was prepared by spray drying with hydroxypropylmethylcellulose (HPMC) acting as crystallization inhibitor. The amorphous nano-CUR was investigated in both its (i) aqueous suspension and (ii) dry-powder forms in which the latter was prepared by spray drying with adjuvants (i.e. HPMC, trehalose, and soy lecithin). The results showed that the amorphous nano-CUR (in both its aqueous suspension and dry-powder forms) exhibited superior solubility enhancement to the ASD of CUR attributed to its faster dissolution rates. This was despite the ASD formulation contained a larger amount of HPMC. The superior solubility enhancement, however, came at the expense of low physical stability, where the amorphous nano-CUR showed signs of transformation to crystalline after three-month accelerated storage, which was not observed with the ASD. Thus, despite its inferior solubility enhancement, the conventional ASD of CUR was found to represent the more feasible CUR solubility enhancement strategy.

Preliminary results on tartaric stabilization of red wine by adding different carboxymethylcelluloses

Despite being natural phenomena of physical-chemical stabilization of young wines, tartrate precipitations in bottled wines are often understood as a quality fault. Carboxymethylcellulose (CMC) is an inhibitor of tartaric salts crystallization, authorized as oenological additive, which application is currently limited to white and sparkling wines by OIV. The aim of this exploratory research was to study the effect of different CMC on a (tartaric) unstable red wine, in terms of tartrate stability, colouring matter stability, turbidity, comprehensive phenolic composition, and chromatic characteristics. All the CMC tested were able to inhibit potassium bitartrate crystallization in the red wine, promoting its tartaric stability. Slight increase in the colour intensity, coloured anthocyanins concentration, and turbidity of the wine were observed. No colouring matter precipitation was verified. The study seems to indicate that the CMC can be an efficient alternative to other tartaric stabilization treatments, also in red wines, opening new prospective and scenarios concerning the use of CMC in this type of wines.

Pediatric renal stone disease

Pediatric renal stone disease is manifested as nephro/urolithiasis (UL) and/or nephrocalcinosis (NC). Compared to adults, UL in childhood is less common, and it is believed to be around 5% in industrialized countries, while the incidence of NC is even lower except for critically ill premature infants in whom it may reach 64%. The formation of UL and NC is caused by increased concentration of relevant solutes, and their aggregations and adherence to the renal tubules cell is facilitated by factors such as urine pH, inability of natural crystallization inhibitors, stasis of urine as well as renal tubule damage. UL is associated with significant morbidity because of pains, susceptibility to urinary tract obstruction and infections, and the necessity of surgical procedures. NC is usually asymptomatic but is frequently progressive, and more often than UL, leads to chronic renal failure. Although other imaging modalities can be used in the diagnosis of renal stone disease, ultrasound has the least risk and is most cost-effective. The majority cases of UL and NC in children are of metabolic origin and thus they are prone to recurrence and may cause chronic renal damage. Therefore, they deserve, even after their initial presentation a detailed metabolic evaluation. Genetic source of renal stone disease is suspected in the following conditions: early onset, familial prevalence, familial consanguinity, multiple or recurrent stones, and NC. For all UL/NC etiologies early identification and personalized treatment of the basic disorder is the most important.

Treatment and Prevention of Urolithiasis in patients with stones of various locations

The study goal was to find the most optimal approach to the treatment of patients with urolithiasis. The study involved 4014 patients with stones of different localization. Patients with benign prostatic hyperplas-ia (BPH) were investigated with IPSS, PSA, and uroflowmetry. 3175 ureteropyeloscopies were performed. Separately, we studied the results of treatment of 427 patients with ureterolithiasis in combination with BPH, which underwent ureterolithotripsy. Percutaneous nephrolithotrip-sy was performed in 412 patients, most of the procedures were per-formed according to the classical technique. The other research purpose was prophylaxis optimization of the recurrent urolithiasis. 152 patients participated in the experimental part. Some of the patients were taken from the clinical part of the study. All patients were with recurrent calci-um oxalate urolithiasis. Patients were divided into two groups: the 1st group (74 patients) did not receive treatment during the follow-up peri-od, the second group (42 patients) received treatment in the volume of thiazide diuretics, water load, citrate mixtures, calcium preparations in-side. During the entire follow-up (6 months), all patients underwent a comprehensive urological examination. Eventually have been estimated that surgery should not be the final stage of treatment of the urolithiasis. Urolithiasis requires constant monitoring of patients, and the priority task of a urologist is to prevent recurrent stone formation. This is achieved through the appointment of adequate conservative therapy, which includes thiazide diuretics, citrate mixtures, calcium preparations, water intake in adequate amount, and if necessary, magnesium prepara-tions. The final choice of conservative treatment depends on the type of stone. The change in the concentration of crystallization inhibitors (biku-nin and osteopontin) is a predictor of an early relapse of the urolithiasis, which can be used in monitoring patients in the postoperative period.

The Effect of Eu Doping on Microstructure, Morphology and Methanal-Sensing Performance of Highly Ordered SnO₂ Nanorods Array.

Layered Eu-doped SnO2 ordered nanoarrays constructed by nanorods with 10 nm diameters and several hundred nanometers length were synthesized by a substrate-free hydrothermal route using alcohol and water mixed solvent of sodium stannate and sodium hydroxide at 200 °C. The Eu dopant acted as a crystal growth inhibitor to prevent the SnO2 nanorods growth up, resulting in tenuous SnO2 nanorods ordered arrays. The X-ray diffraction (XRD) revealed the tetragonal rutile-type structure with a systematic average size reduction and unit cell volume tumescence, while enhancing the residual strain as the Eu-doped content increases. The surface defects that were caused by the incorporation of Eu ions within the surface oxide matrix were observed by high-resolution transmission electron microscope (HRTEM). The results of the response properties of sensors based on the different levels of Eu-doped SnO2 layered nanoarrays demonstrated that the 0.5 at % Eu-doped SnO2 layered nanorods arrays exhibited an excellent sensing response to methanal at 278 °C. The reasons of the enhanced sensing performance were discussed from the complicated defect surface structure, the large specific surface area, and the excellent catalytic properties of Eu dopant.

In vivo controlled release of fenretinide from long-acting release depots for chemoprevention of oral squamous cell carcinoma recurrence

Local, long-acting release fenretinide (4HPR) millicylindrical implants were prepared and evaluated for their release kinetics in vivo and their ability to suppress oral cancer tumor explant growth. Poly(lactic-co-glycolic acid)(PLGA) implants were prepared as a function of drug loading and the presence of various excipients (pore-formers, solubilizers, crystallization inhibitors) to enhance release of the insoluble 4HPR. Release kinetics and bioerosion of PLGA were monitored both in vitro in a PBS/Tween 80 buffer and in vivo by recovery of the drug remaining at the injection site. 4HPR was released from PLGA implants much slower in vivo than in the drug solubilizing media in vitro, with a 3-week lag phase and continuous release of >2 months, but showed some release enhancement by addition of solubilizers. Water-soluble PVA/sucrose implants for release of 4HPR served to determine if drug dissolution provided suitable controlled release without the PLGA, and this formulation showed continuous drug release over 6 weeks in vivo. Placement of PLGA-4HPR implants adjacent to oral cancer tumor murine xenografts showed inhibition of tumor growth relative to sham implants, indicating the potential for the local 4HPR delivery approach to be useful for oral cancer chemoprevention.

Formulation, Characterization, and In Vitro Evaluation of Transdermal Patches for Inhibiting Crystallization of Mefenamic Acid.

The crystallization of mefenamic acid in transdermal patch is a major problem that makes the patch unstable and decreases the drug release. The additive was used to inhibit crystallization of a mefenamic acid. Among the different types of additives, polyvinylpyrrolidone (PVP) K30 and PVP K90 were studied and found to be highly effective in inhibiting the crystallization of the drug. The PVP presented as a solubilizer agent for mefenamic acid in matrix patches at the different ratio between drug : PVP, 1 : 2 and 1 : 2.5 for using PVP K30 and 1 : 1.5 and 1 : 2 for using PVP K90. The characterizations showed the homogeneous patches without the crystal form of the mefenamic acid in matrix patches. The release profiles of the mefenamic acid from the patches were investigated by Franz diffusion cells. Over the first 1 h, the release behavior of mefenamic acid from the patches obviously increased when PVP was used as a crystallization inhibitor. However, the ratio between drug : PVP K90 at 1 : 2 was found to be the most effective in increasing the drug release from patch. Thus, the PVP could be used as a crystallization inhibitor for mefenamic acid in matrix patches which will increase the drug release.

Improving Solubility and Oral Bioavailability of Febuxostat by Polymer-Coated Nanomatrix.

Here, the mesoporous silica (Sylysia 350) was selected as mesoporous material, hydroxypropyl methylcellulose (HPMC) was selected as crystallization inhibitor, and febuxostat (FBT) was selected as model drug, respectively. The FBT-Sylysia-HPMC nanomatrix (FBT@SHN) was prepared. The characteristics of FBT@SHN were investigated in vitro and in vivo. Our results indicated that the FBT in FBT@SHN was in amorphous form. The solubility and dissolution of FBT in FBT@SHN were significantly increased. The oral bioavailability of FBT in FBT@SHN was greatly improved 5.8-fold compared with that in FBT suspension. This nanomatrix could be used as a drug delivery platform for improving the oral bioavailability.

A MoO3–Metal–Organic Framework Composite as a Simultaneous Photocatalyst and Catalyst in the PODS Process of Light Oil

Photo-oxidative desulfurization (PODS) properties of MoO3–metal–organic framework composite photocatalysts were investigated by introducing the proper weight percent of MoO3 into a Zn(II)-based MOF, [Zn(oba)(4-bpdh)0.5]n·1.5DMF (TMU-5), for the mineralization of dibenzothiophene from model oil. The addition of 3 wt % of MoO3 into a TMU-5 host acting as a crystal growth inhibitor was confirmed by PXRD and BET results. For the first time, under mild and green reaction conditions, 5 wt % MoO3–TMU-5 composite (MT-5) exhibited good photocatalytic activity in the model oil PODS reaction, which has no limitations in the current oxidative desulfurization catalytic systems. Only 3% of the total amount of MoO3 content in the MT catalyst is leached during the reaction. In addition, the rate of PODS of MT-5 obeys a pseudo-first-order equation with an apparent rate constant of 0.0305 min–1 and half-life t1/2 of 22.7 min. Radical scavenger experiments and terephthalic acid fluorescence techniques confirmed that OH• and...

PVP-assisted synthesis and photocatalytic properties of magnetic Fe3O4/SiO2/BiOBr composite

In this study, a magnetic Fe3O4/SiO2/BiOBr composite photocatalyst was controllably synthesized a PVP-assisted solvothermal method. The Fe3O4/SiO2/BiOBr composites are composed of many three-dimensional (3D) flower-like BiOBr microspheres loaded with many spherical Fe3O4 particles. The formation mechanism and effect of PVP’s concentration on the products were investigated and proposed. Experimental results showed that PVP might act as a potential crystal plane inhibitor in the system as well as the stabilizer on the surface of BiOBr nanoplates. The Fe3O4/SiO2/BiOBr displayed high photocatalytic activity for the degradation of RhB under visible light irradiation, after which it can be easily recovered by applying an external magnetic field. Moreover, the as-prepared photocatalyst exhibited excellent stability and reusability in the cycled experiments.

A novel pharmacodynamic assay to evaluate the effects of crystallization inhibitors on calcium phosphate crystallization in human plasma

Cardiovascular calcification (CVC) is a progressive complication of chronic kidney disease and a predictor of CV events and mortality. The use of biomarkers to predict CV risk and activities of potential or current treatment drugs in these patients could have a crucial impact on therapeutic approaches. Our aim was to develop a novel assay for measurement of the rate of calcium phosphate crystallization in human plasma and provide a tool to evaluate the effects of crystallization inhibitors. The efficacy of inhibitors was determined by adding inhibitory compounds (polyphosphates, fetuin-A, sodium thiosulfate or citrate) to control samples. The assay was additionally validated for SNF472, an experimental formulation of phytate being developed for the treatment of calciphylaxis and CVC in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). The method was repeatable and reproducible. The plasma crystallization rate was reduced up to 80% in a concentration-dependent manner following treatment with inhibitors in vitro, among which SNF472 was the most potent. This method appears beneficial in evaluating and discriminating between inhibitory activities of compounds such as polyphosphates on calcium phosphate crystallization, which present a novel therapeutic approach to treat CVC in ESRD patients.