Accelerated Dissolution Rates Research Articles

Tea saponins as novel stabilizers for the development of diosmin nanosuspensions: Optimization and in vitro evaluation

Diosmin (DSN) is a plant-origin polyphenolic component that has attracted considerable interest for various physiological applications. Nevertheless, DSN shows high intersubject variation and poor oral absorption because of its poor solubility and permeability. This study examined the use of phytosaponins, specifically, tea saponins (TS), as novel stabilizers for optimizing and preparing diosmin nanosuspensions using top-down methods. The main formulation and process variables in particle size and polydispersity index were investigated by single-factor experiment optimization. The DSN nanocrystals were prepared and then characterized by electron microscopy, Fourier transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). Compared with conventional stabilizers, TS exhibited better stabilizing performance at low concentrations. The lyophilized powder, which had a particle size 478.4 ± 9.4 nm after redispersion, coupled with mannitol as lyoprotectant showed good redispersibility. Electron microscopy revealed that the nanocrystals had an irregular and lamellar morphology. PXRD and FT-IR spectroscopy indicated that the crystallinity of DSN was reduced during the production process. DSN nanosuspensions significantly enhanced the accelerated dissolution rate due to the amorphous status and decreasing particle size. Overall, this study presents an advantageous solution to poor solubility and offers a reasonable strategy for expanding the application range of DSN.

The Impact of Process and Formulation Parameters on the Fabrication of Efavirenz Nanosuspension to Improve Drug Solubility and Dissolution.

Efavirenz nanosuspensions (EZ-NSs) were developed by the wet milling method as the most promising top-down nanosizing technique. Different process and formulation parameters were studied and optimized to produce appropriate EZ-NS in suitable conditions to enhance drug dissolution. In the preliminary studies, various polymeric stabilizers, including Pluronic F68, sodium carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), and polyvinyl alcohol (PVA), as well as different sizes and weight of milling beads were used to prepare NSs. The effect of sodium lauryl sulfate (SLS) concentration on the NS properties was also evaluated. The influence of other formulation and process parameters, including polymer concentration, milling speed, and milling time, on the particle size and distribution of NSs were investigated using Box-Behnken design. The optimized freeze-dried nanosuspension was characterized by redispersibility, physicochemical properties, and stability. A combination of PVA and SLS was selected as steric and electrostatic stabilizers. The optimum EZ-NS displayed a uniform size distribution with a mean particle size and zeta potential of 254.4 nm and 21.1 mV, respectively. The solidified nanosuspension was well redispersed to the original nanoparticles. Significantly enhanced aqueous solubility (about 11-fold) and accelerated dissolution rate were observed for the optimized formulation. This could be attributed to the reduced particle size and partial amorphization of EZ during the preparation process, studied by X-ray diffraction. Accelerated studies confirmed the stability of the optimum freeze-dried formulation over the examined period of three months. Optimization of different variables led to the formation of EZ-NSs with desired properties through wet milling in a very short time compared to the previous study and therefore reduced production costs. This formulation seems to be a suitable approach for solubility and dissolution enhancement of EZ and may have a great potential to improve the drug's oral bioavailability.

Combination of Phospholipid Complex and Matrix Dispersion.

Phospholipid complexation, despite being a successful, versatile, and burgeoning strategy, stickiness of phospholipids leads to suboptimal dissolution rate of drugs. This work was undertaken to fabricate simvastatin-phospholipid complex (SIM-PLC)-loaded matrix dispersion (SIM-PLC-MD) using Soluplus® as carrier material, to augment dispersibility and dissolution of SIM-PLC without altering complexation between simvastatin (SIM) and phospholipid. SIM-PLC and SIM-PLC-MD were prepared using solvent evaporation and discontinuous solvent evaporation techniques, respectively. The successful complexation was substantiated by FTIR method. Besides, PXRD and SEM studies disclosed the absence of crystallinity of SIM in both SIM-PLC and SIM-PLC-MD. The TEM analysis monitored the self-assembly of SIM-PLC and SIM-PLC-MD into colloidal structures, which could be correlated with redispersion in GIT fluids upon oral administration. The considerable increase in hydrophilicity of SIM-PLC-MD and SIM-PLC as evident from partition coefficient experiment can further be correlated with their remarkably improved solubility profiles in the following pattern: SIM-PLC-MD˃SIM-PLC˃SIM. Correspondingly, improved dispersibility of SIM-PLC-MD in comparison to SIM-PLC can be accountable for accelerated dissolution rate by 2.53-fold and 1.5-fold in pH 1.2 and 6.8 conditions, respectively. The oral pharmacokinetic evaluation in Sprague Dawley (SD) rats revealed 3.19-fold enhancement in oral bioavailability of SIM through SIM-PLC-MD when compared with plain SIM, whereas 1.83-fold increment was observed in the case of SIM-PLC. Finally, the efficacy experimentation in SD rats revealed that SIM-PLC-MD significantly reduced triglycerides and cholesterol levels in comparison to SIM and SIM-PLC. These outcomes suggest that a matrix dispersion strategy improves oral bioavailability and hypolipidemic activity of SIM.

Assessment of Galvanostatic Anodic Polarization to Accelerate the Corrosion of the Bioresorbable Magnesium Alloy WE43

In the field of surgery, bioresorbable magnesium is considered a promising candidate. Its low corrosion resistance, which is disadvantageous for technical application, is advantageous for surgery since the implant fully degrades in the presence of the water-based body fluids, and after a defined time the regenerating bone takes over its function again. Therefore, knowledge of the corrosion behavior over several months is essential. For this reason, an in vitro short-time testing method is developed to accelerate the corrosion progress by galvanostatic anodic polarization without influencing the macroscopic corrosion morphology. The initial corrosion rate of the magnesium alloy WE43 is calculated by detection of the hydrogen volume produced in an immersion test. In a corresponding experimental setup, a galvanostatic anodic polarization is applied with a three-electrode system. The application range for the polarization is determined based on the corrosion current density from potentiodynamic polarization. To correlate the initial corrosion rate, and accelerated dissolution rate, the corrosion morphologies of both test strategies are characterized by microscopy images, as well as energy dispersive X-ray spectroscopy and Fourier-transform infrared spectroscopy. The results demonstrate that the dissolution rate can be increased in the order of decades with the limitation of a changed corrosion morphology with increasing polarization. With this approach, it is possible to characterize and exclude new unsuitable magnesium alloys in a time-efficient manner before they are used in subsequent preclinical studies.

Variation in Supersaturation and Phase Behavior of Ezetimibe Amorphous Solid Dispersions upon Dissolution in Different Biorelevant Media.

The delivery of poorly water-soluble drugs using amorphous solid dispersions (ASDs) has been widely acknowledged as a promising strategy for enhancing oral bioavailability. Upon dissolution, ASDs have accelerated dissolution rates and yield supersaturated solutions leading to higher apparent solubilities. Understanding the complex phase behavior of ASDs during dissolution is crucial for developing an effective formulation. Since the absorption of a lipophilic, high permeability drug is determined primarily by the intraluminal dissolution process and the final concentration achieved, there is a need for evaluation in biorelevant dissolution media that simulate both fasting and fed gastrointestinal states. In this study, using ezetimibe as a model drug, three different ASDs were prepared using poly(acrylic acid) (PAA), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose acetyl succinate (HPMC-AS). Dissolution of ASDs was carried out in sodium phosphate buffer, fed-state simulated intestinal fluid (FeSSIF), and Ensure Plus to evaluate the impact of different dissolution media on release profile, supersaturation, and phase behavior. The supersaturation level and crystallization kinetics varied among the dispersions and were found to be highly dependent on the medium employed. The presence of solubilizing additives in biorelevant media greatly affected the generation and stabilization of supersaturated solutions. Second harmonic generation microscopy was found to enable the detection of crystals in all media including the highly turbid Ensure Plus system. In conclusion, it is important to evaluate the impact of complex biorelevant media on the dissolution performance of ASDs to better design supersaturating formulations for oral delivery.

Nanocrystal Dissolution Kinetics and Solubility Increase Prediction from Molecular Dynamics: The Case of α-, β-, and γ-Glycine.

Nanocrystals are receiving increased attention for pharmaceutical applications due to their enhanced solubility relative to their micron-sized counterpart and, in turn, potentially increased bioavailability. In this work, a computational method is proposed to predict the following: (1) polymorph specific dissolution kinetics and (2) the multiplicative increase in the polymorph specific nanocrystal solubility relative to the bulk solubility. The method uses a combination of molecular dynamics and a parametric particle size dependent mass transfer model. The method is demonstrated using a case study of α-, β-, and γ-glycine. It is shown that only the α-glycine form is predicted to have an increasing dissolution rate with decreasing particle size over the range of particle sizes simulated. On the contrary, γ-glycine shows a monotonically increasing dissolution rate with increasing particle size and dissolves at a rate 1.5 to 2 times larger than α- or β-glycine. The accelerated dissolution rate of γ-glycine relative to the other two polymorphs correlates directly with the interfacial energy ranking of γ > β > α obtained from the dissolution simulations, where γ- is predicted to have an interfacial energy roughly four times larger than either α- or β-glycine. From the interfacial energies, α- and β-glycine nanoparticles were predicted to experience modest solubility increases of up to 1.4 and 1.8 times the bulk solubility, where as γ-glycine showed upward of an 8 times amplification in the solubility. These MD simulations represent a first attempt at a computational (pre)screening method for the rational design of experiments for future engineering of nanocrystal API formulations.

Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate.

The aim of this study was to prepare and evaluate solid dispersion tablets containing a poorly water-soluble drug using porous calcium silicate (PCS) by a wet granulation method. Nifedipine (NIF) was used as the model poorly water-soluble drug. Solid dispersion tablets were prepared with the wet granulation method using ethanol and water by a high-speed mixer granulator. The binder and disintegrant were selected from 7 and 4 candidates, respectively. The dissolution test was conducted using the JP 16 paddle method. The oral absorption of NIF was studied in fasted rats. Xylitol and crospovidone were selected as the binder and disintegrant, respectively. The dissolution rates of NIF from solid dispersion formulations were markedly enhanced compared with NIF powder and physical mixtures. Powder X-ray diffraction (PXRD) confirmed the reduced crystallinity of NIF in the solid dispersion formulations. Fourier transform infrared (FT-IR) showed the physical interaction between NIF and PCS in the solid dispersion formulations. NIF is present in an amorphous state in granules prepared by the wet granulation method using water. The area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) values of NIF after dosing rats with the solid dispersion granules were significantly greater than those after dosing with NIF powder. The solid dispersion formulations of NIF prepared with PCS using the wet granulation method exhibited accelerated dissolution rates and superior oral bioavailability. This method is very simple, and may be applicable to the development of other poorly water-soluble drugs.

Preparation and optimization of resveratrol nanosuspensions by antisolvent precipitation using Box-Behnken design.

Resveratrol, a natural polyphenolic component, has inspired considerable interest for its extensive physiological activities. However, the poor solubility of resveratrol circumscribes its therapeutic applications. The purpose of this study was to optimize and prepare resveratrol nanosuspensions using the antisolvent precipitation method. The effects of crucial formulation and process variables (drug concentration, stabilizer, and surfactant contents) on particle size were investigated by utilizing a three-factor three-level Box-Behnken design (BBD) to perform this experiment. Different mathematical polynomial models were used to identify the impact of selected parameters and to evaluate their interrelationship for predictive formulation purposes. The optimal formulation consisted of drug 29.2 (mg/ml), polyvinylpyrrolidone (PVP) K17 0.38%, and F188 3.63%, respectively. The morphology of nanosuspensions was found to be near-spherical shaped by scanning electron microscopy (SEM) observation. The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis confirmed that the nanoparticles were in the amorphous state. Furthermore, in comparison to raw material, resveratrol nanosuspensions showed significantly enhanced saturation solubility and accelerated dissolution rate resulting from the decrease in particle size and the amorphous status of nanoparticles. Meanwhile, resveratrol nanosuspensions exhibited the similar antioxidant potency to that of raw resveratrol. The in vivo pharmacokinetic study revealed that the C max and AUC0→∞ values of nanosuspension were approximately 3.35- and 1.27-fold greater than those of reference preparation, respectively. Taken together, these results suggest that this study provides a beneficial approach to address the poor solubility issue of the resveratrol and affords a rational strategy to widen the application range of this interesting substance.

3D hydrodynamics and shear rates’ variability in the United States Pharmacopeia Paddle Dissolution Apparatus

The 3D hydrodynamics and shear rates distributions within the United States Pharmacopeia Apparatus 2 have been investigated in this paper. With the help of a CFD package, several geometric modifications to the device were evaluated in this study. Specially, we examine the influence of impeller clearance, blade diameter, shape of the vessel base and shape of the lower part of blade. Increasing the impeller clearance was observed to exacerbate the heterogeneity in shear and would likely result in greater variability in dissolution measurements. Use of moderate blade diameter and dished bottom were observed to reduce shear heterogeneity in the regions where tablets are most likely to visit during testing. The comparative analysis shows better reproducibility and accelerated dissolution rates with the modified vessel shape, the dished bottom can enhance mixing near the vessel base when compared with the flat bottom. Increasing length of the lower edge of the paddle was observed to generate high radial pumping and to enlarge the dead zone located at the center of the vessel base.

Improvement of the Dissolution Rate of Poorly Soluble Drugs by Solid Crystal Suspensions

We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days.

Limestone Corrosion by Neutrophilic Sulfur-Oxidizing Bacteria: A Coupled Microbe-Mineral System

Subsurface karst aquifers receiving sulfidic water can host complex chemolithotrophic microbial communities that are capable of dissolving limestone, forming new karstic habitat. Neutrophilic sulfur-oxidizing bacteria use reduced sulfur compounds as energy rich substrate, potentially producing sulfuric acid as a geochemically reactive byproduct. The physicochemical relationship between a biofilm forming on a limestone surface and the extent of microbial influence on dissolution rate, however, are unknown. We investigated the rate of Madison limestone dissolution by sulfur-oxidizers both in the field at Lower Kane Cave, WY (LKC), and in the laboratory using continuous flow culture reactors and microbial mat collected from LKC. In the field, a microbial consortium rapidly colonized limestone chips forming a thick biofilm, with deep etching of mineral surfaces underneath. In the laboratory we found that a microbial biofilm oxidizing thiosulfate on the limestone surface accelerated dissolution rate up to 7 times faster than the abiotic baseline rate. In contrast, experiments done with H2S or a mixture of H2S and thiosulfate had no effect on dissolution rate. We hypothesize that the laboratory mat community dominated by Thiothrix sp. oxidizes thiosulfate to sulfate and H+, while H2S is partially oxidized to S°. When all sulfur substrate is withheld, the community oxidizes stored intracellular sulfur, briefly accelerating limestone dissolution even in the absence of external supplied substrate. Accelerated corrosion occurs only in the reactive micro-environment under the biofilm, disconnected from the bulk reactor solution. When experiments are repeated where the microbial population is separated from the limestone by a dialysis membrane barrier, measured pH drop is greater, but there is only slight enhancement of rate. This work confirms our working hypothesis that neutrophilic sulfur-oxidizers colonize and rapidly dissolve limestone surfaces, possibly to buffer the production of excess acidity.

Accelerated dissolution testing for improved quality assurance

In pharmaceutical production of controlled release tablets and capsules, a rapid and automated at-line dissolution test for quality assurance of semi-products is advantageous. For effective control of the production, the analysis should not take more than about an hour, without loss of correlation to the ordinary (USP) dissolution test of the final product. For almost a decade, the ACDRA apparatus (ACcelerated Dissolution Rate Analysis) have been used for this purpose at AstraZeneca Tablet Production Sweden (TPS). In this paper, we give examples on different ways to accelerate the dissolution process. We use the USP dissolution calibrator tablets of salicylic acid (non-disintegrating type) to illustrate the strategy. We investigate the accelerated dissolution of the dissolution calibrator tablets, and show how it can be correlated with the dissolution in the ordinary USP-II equipment. The dissolution process was accelerated by variation of temperature, solvent and stirring. For example, we show that by increasing the temperature to 70 °C, changing the solvent to water, and increasing the stirring, it is possible to accelerate the dissolution by a factor of 5, without any loss of correlation to the dissolution process in the ordinary test.

ACcelerated Dissolution Rate Analysis (ACDRA) for controlled release drugs. Application to Roxiam ®

Accelerated dissolution rate analysis by elevated temperature has been applied to the release of remoxipride from a controlled release drug, Roxiam ®, and compared to the standard USP method. A PLS model has been used in evaluating the factors of importance of the release as well as for the comparison to the standard USP method. ACelerated Dissolution Rate Analysis (ACDRA) offers the possibility of substantial reduction of analysis time. The time needed for one analysis with ACDRA is less than 5% of the USP-method. The automated analytical procedure is well suited for use in process control as well as in the early stages of the formulation development.

Corrosion Behavior of Ceramics in High Purity Water at 290°C

Recently, advanced ceramics with superior strength and corrosion resistance have been developed. They have a possibility for various engineering applications as structural materials used in high temperature water, such as steam turbine systems or water cooled reactors. Fundamental corrosion behaviors of 14 kinds of sintered polycrystalline ceramic were examined in oxygen-free (less than 20ppb dissolved oxygen) and oxygenated (about 32ppm dissolved oxygen) pure water at 290°C using a refleshed-type autoclave system. Change in weight and surface morphology detected by X-ray diffraction and scanning electron microscopy on the samples corroded for 72 hours were discussed. Silicon carbide showed the best corrosion resistance among the present ceramics. The corrosion resistance of alumina strongly depended on its purity. 99.99% purity alumina showed high corrosion resistance. For pressure-less sintered and hot-pressed silicon nitride and sialon ceramics, the preferential dissolution of crystalline phase occurred at the surface of the sample and the grain boundary phases remained near the surface. Aluminum nitride formed a thick boehmite layer in the tests. Partially stabilized zirconia, stabilized by 3mol% yttria, flaked away by accompanying a phase transformation from tetragonal to monoclinic. Many of the non-oxide ceramics, particularly silicon carbide, showed more accelerated dissolution rates in oxygenated water than in oxygen-free water.

The effect of chloride ion on the ferric chloride leaching of galena concentrate

Previous investigations of the ferric chloride brine leaching of galena concentrate have shown that additions of chloride ion result in accelerated dissolution rates. The current study has provided the necessary information to extend and modify these previous results by incorporating the important effect of chloride ion on the dissolution kinetics. As part of this study the solubility of lead chloride in ferric chloride-brine solutions has been determined and results indicate that additions of either FeCl3 or NaCl increase the PbCl2 solubility. This is attributed to the effect of complexing on the level of free chloride ion. In addition, the dissolution kinetics of elemental lead and lead chloride were also determined and compared with the kinetics of PbS dissolution. It is significant that the rate of dissolution of PbCl2 decreases as the concentration of Cl− is decreased and as the concentration of dissolved lead increases. These results along with SEM examination of partially reacted Pb shot show that solid PbCl2 forms on the surface long before the bulk solution is saturated with lead. The PbCl2 is proposed to form by a direct electrochemical reaction between Cl− and PbS prior to the formation of dissolved lead. The reaction was determined to be first order with respect to Cl− and closely obeys the following kinetic model based on a rate limiting charge transfer reaction at the surface: $$1 - (1 - a)^{1/3} \left[ {\frac{{5.01x10^{11} }}{{r_0 }}\left[ {Fe^{3 + } } \right]_T^{0.21} \left[ {Cl^ - } \right]_T^{1.0} \exp \left( {\frac{{ - 72100}}{{RT}}} \right)} \right]t$$ The model is in excellent agreement with experimental results up to about 95 pct reaction as long as the solubility of PbCl2 is greater than about 0.051 M. Where these conditions are not met, deviation from the surface reaction model occurs due to the extremely slow dissolution rate of PbCl2. Therefore the effect of Cl− on the brine leaching of PbS is attributed to two factors, the direct reaction of Cl− with the pbS surface and the effect of Cl− on the dissolution rate of PbCl2. The overall dissolution process is viewed as occurring in three stages; in the first stage the reaction is controlled by the surface reaction and described by the model above, then as solid PbCl2 is produced the diffusion of Cl− would be equal in importance with the surface reaction,i.e, the second stage. As the reaction proceeds further, a shift in the rate-limiting step from surface reaction to product layer or pore diffusion occurs, the third stage. Thus the rate-determining step would no longer be just the surface reaction as observed experimentally at longer reaction times. The practical implications of these results for the processing of a complex sulfide concentrate using sequential, selective, or total leach approaches are also discussed.

Inhibitor Development for Titanium Corrosion

Abstract An aromatic derivative study showed how corrosion inhibitors were developed for the control of titanium dissolution in sulfuric acid. Included were the effects of temperature and concentration on the corrosion rate of titanium. Test results indicated distinctly critical concentrations for effectiveness; lower concentrations accelerated dissolution rates. The more effective inhibitors apparently formed permanent complexes with the titanium atom within the lattice structure. Potentiodynamic polarization curves suggest that the class of derivatives were passivator type inhibitors. The root structures were: phenol, aniline, toluene, and nitrobenzene. The more effective structures were: 2,4, 6-trinitrophenol, 5-nitroquinoline, 8-nitroquinoline, o-dinitrobenzene, and m-nitroacetanilide.

A scanning electron microscope study of factors influencing etch patterns of human enamel

Facets were ground and polished in the outer third of the enamel thickness from 25 caries-free human molar teeth to produce enamel sub-surfaces cut perpendicularly to the prism direction. Under static conditions of acid dissolution, using 0.25 M formic, acetic or lactic acid solutions adjusted to pH 4.0, prism cores were preferentially dissolved. The predominant honeycomb acid-etch pattern, which showed an elevation of prism sheaths relative to adjacent unetched enamel surfaces, is interpreted as due to the precipitation of dissolution products. Vigorous agitation of the acid media caused preferential dissolution at prism junctions, a change of acid etch pattern attributed to the breakdown of diffusion barriers and accelerated dissolution rates which would tend to enhance the loss of enamel tissue from sites of greatest porosity, that is, the prism junctions. Therefore, the establishment of diffusion barriers with the potential for recrystallization of dissolution products may be a contributory factor in the formation of the honeycomb topography.