Dissolution performance related to particle size distribution for cohpiercially available prednisolone acetate suspensions

Dissolution performance for three commercially available parenteral prednisolone acetate suspensions was analyzed using a diffusion based model. Physicochemical properties of the drug and particle size characteristics of the formulation were included in the model as important determinants of dissolution performance.

The model describes the dissolution profile for each formulation with a single characteristic value, the dissolution rate constant. For Products I and II with similar particle size characteristics, the model sufficiently describes the dissolution profile for each formulation but does not provide conclusive evidence about reasons for differences in dissolution performance between the two products. For Product III, the model sufficiently describes the dissolution profile and adequately includes the effect of a bimodal distribution of larger drug particles .

This approach to the analysis of dissolution data for suspension formulations is suggested as being useful during the formulation process to provide for predetermined dissolution characteristics, as an evaluative tool in quality assurance, assurance, and for correlating in-vivo and in-vitro product performance.     

Optimization of Slow-Release Tablet Formulations Containing Montmorillonite II. Factors Affecting Drug Release

Abstract

The influence of electrolytes, surfactants in the dissolution medium, and particle size of drug and montmorillonite on the in vitro release of the soluble model drug sodium sulfathiazole from directly compressed slow-release tablets containing 20% drug and 30% magnesium aluminum silicate was investigated. The presence of electrolytes in the dissolution media decreased the release from the tablets. A decrease in release was also observed in deionized water when sodium chloride was included in the tablet formulation. The surface tension of the media appeared to have little influence on the dissolution rate of the drug. Varying the particle size of the drug had a greater effect on release rates than varying the particle size of the montmorillonite clay.     

Development of a Clinical Capsule Formulation Containing a Marginally Water Soluble Drug

Abstract

A good clinical development program maximizes the clinical efficacy of a new drug product and, in addition, requires only minimal formulation changes in the transition from clinical to market image product. This study demonstrates the development design as well as the technology utilized to improve the dissolution characteristics of a marginally water soluble drug to be administered in a capsule dosage form for clinical trials. A satisfactory formulation was achieved by controlling drug particle size, selecting an appropriate diluent and incorporating a surfactant.     

Dissolution Characteristics of Interactive Powder Mixtures. Part One: Effect of Solubility and Particle Size of Excipients

Abstract

Interactive mixtures of fine cohesive drug powders and coarse free flowing excipients are reported to increase dissolution rates of poorly soluble drugs. However, dissolution rates are known to be affected by the solubility characteristics of the excipients as well as excipients surface characteristics after mixing with lubricant.

In this study the effects of solubility and particle size of excipients on dissolution of micronized griseofulvin from interactive powder mixtures were investigated. Quantitative assessment of dissolution from such mixtures showed that systems containing soluble excipients increased dissolution of the drug more efficiently than mixtures prepared using insoluble excipients. The role of the soluble excipient was more significant after mixing with magnesium stearate. Excipients of smaller particle sizes increased dissolution more efficiently than their large size counterparts. Effects of particle size were particularly significant in case of water insoluble excipients.     

Effects of Particle Size of Bulk Drug and food on the Bioavailability of U-78875 in Dogs

Abstract

The effects of particle size and food on the absolute bioavailability of U-78875 in dogs after oral administration of either a suspension or tablet dosage form were investigated. A reduction of particle size caused a significant increase in bioavailability along with an increase in dissolution rate. Additionally, both suspension and tablet dosage forms administered after food caused an increase in bioavailability. Thus, to accelerate drug dissolution, a reduction of U-78875 particle size from the unmilled state is important for the optimization of formulation compositions. To increase the bioavailability of U-78875, postprandial dosing should be considered.     

A Review of: “Evaluation of Enzyme Inhibitors in Drug Discovery”

Abstract

The preparation of a new scored 250 mg theophylline tablet is described, for which effects of particle size of the active principle, aspects of granulation and changes in tabletting settings were investigated.

In vitro studies showed the dissolution rate from tablets prepared from theophylline of commercial quality (50 μm) or of selected particle size (30 μm) to be faster than that from tablets prepared from micronized theophylline (10 μm). In vivo studies in dog showed that only the tablet from theophylline of selected particle size has the same bioavailability as an aqueous solution.

The scale up study showed that the characteristics of the tablets, including dissolution rate, are independent of the formulation factors.     

Reprocessing of Microcrystalline Cellulose Spheres with Low Drug Concentrations

Abstract

Spherical dosage forms have been reported to be an efficient and effective method for delivering drugs into the body and controlling their dissolution rate. Substantial work has been conducted in these laboratories illustrating the advantages of microcrystalline cellulose-based spheres for these purposes. Through various methodologies, but most routinely the extrusion and marumerization technique, it has been determined by Funck, et al. that not more than 50% drug can be incorporated into a sphere formulation without the addition of other binders.

Because of the nature of the extrusion and marumerization manufacturing process, the type of drug being processed and the resultant particle size requirements of the spheres, the percent of spheres falling outside the desired particle size can range from between 3% and 20%. For this reason and the possibility of operator errors, our objective was to determine the parameters which needed monitoring when reprocessing was necessary.     

Influence of extrusion-spheronization processing on the physical properties of d-Indobufen pellets containing pH adjusters

Abstract

d-Indobufen pellets containing pH adjusters (acids, buffer, salt) were prepared by extrusion-spheronization technology.

The interaction effect between some processing variables (feeding/agitator speeds of extruder, plate speed and residence time of spheronizer) was evaluated by comparing the basic formulation pellets with the pellets in which the soluble filler (lactose) was substituted by fumaric, tartaric and citric acids and also sodium citrate.

The criteria of formulation and process evaluation were the reproducibility of the particle size distribution, the density, the hardness and morphological properties, in addition to the reproducibility of the drug dissolution rates.

In all cases, the physical/technological characteristics were not influenced very much by pH adjuster incorporation, but the drug dissolution profiles showed some significant variations in the first hour. As a logical extension of this work, wet granulations with aqueous ethylcellulose and acrylic resin dispersions instead of only water were tested to evaluate the wetting effect of the release modifier inclusion. The results confirmed the validity of polymeric systems in the preparation of pellets and their ability to produce a further delay of d-Indobufen release.     

Effect of Particle Size on the Dissolution Rate of Monophenylbutazone Solid Dispersion in Presence of Certain Additives

Abstract

Monophenylbutazone is a very sparingly soluble drug. The effect of particle size on the dissolution characteristics of monophenylbutazone in a dissolution medium of 0.1 N hydrochloric acid and 0.1 N hydrochloric acid to which was added 0.005% Tween 80, was carried out. The enhancement of the dissolution rate of the medicament was attained by formulating the drug in both solid dispersion and physical mixture using urea and polyethylene glycol 4000 as carriers. A comparative dissolution behaviour of the medicament in different solid dispersion and physical mixture ratios were investigated at particle, size of < 63 μ. Drug-urea solid dispersion of a ratio 5:95% produced the highest dissolution rate.     

Development and optimization of locust bean gum and sodium alginate interpenetrating polymeric network of capecitabine

Objective: The objective of the study was to develop interpenetrating polymeric network (IPN) of capecitabine (CAP) using natural polymers locust bean gum (LBG) and sodium alginate (NaAlg).

Significance: The IPN microbeads were optimized by Box–Behnken Design (BBD) to provide anticipated particle size with good drug entrapment efficiency. The comparative dissolution profile of IPN microbeads of CAP with the marketed preparation proved an excellent sustained drug delivery vehicle.

Methods: Ionotropic gelation method utilizing metal ion calcium (Ca²⁺) as a cross-linker was used to prepare IPN microbeads. The optimization study was done by response surface methodology based Box–Behnken Design. The effect of the factors on the responses of optimized batch was exhibited through response surface and contour plots. The optimized batch was analyzed for particle size, % drug entrapment, pharmacokinetic study, in vitro drug release study and further characterized by FTIR, XRD, and SEM. To study the water uptake capacity and hydrodynamic activity of the polymers, swelling studies and viscosity measurement were performed, respectively.

Results: The particle size and % drug entrapment of the optimized batch was 494.37?±?1.4?µm and 81.39?±?2.9%, respectively, closer to the value predicted by Minitab 17 software. The in vitro drug release study showed sustained release of 92% for 12?h and followed anomalous drug release pattern. The derived pharmacokinetic parameters of optimized batch showed improved results than pure CAP.

Conclusion: Thus, the formed IPN microbeads of CAP proved to be an effective extended drug delivery vehicle for the water soluble antineoplastic drug.     

Effect of Granulating Method on Dissolution Rate of Compressed Tablets. III

Abstract

The dissolution rates of dexamethasone granules prepared by all the methods were slower than the dissolution rates of the corresponding tablets. This was shown to be the result of a reduction of the average particle size on compaction. The dissolution rates of sulfadiazine tablets prepared by microgranulating and slugging were slower than the corresponding granules. This was demonstrated to be the result of enlargement of the granules on compaction. For both drugs the microgranulating procedure gave the most rapid dissolution of tablets and granules. In case of the dexamethasone formulation, direct compression exhibited the slowest dissolution rate. The dissolution rates of sulfadiazine granules and tablets prepared by the wet granulating method were also unsatisfactory.     

Evaluation of Chitosan Citrate Complexes as Matrices for Controlled Release Formulations Using a 32 full Factorial Design

Abstract

Chitosan citrate complexes of several viscocity grades were synthesized, isolated, purified and identified. These complexes were found to form viscous gels of varying viscosities, upon dispersion in water. The ability of these complexes in sustaining drug release from matrix tablets was evaluated using a two factor three level full factorial design with theophylline as the model drug. Viscosity and concentration of the polymer complexes were optimized to achieve the desired in-vitro release profile. In-vitro dissolution characteristics were evaluated in deionized water as the dissolution medium. Data were fit to a quadratic model and polynomial equations were generated and used to predict the optimum formulation composition with desired release characteristics. These complexes were found to be very effective in sustaining the release of theophylline and were directly compressible. The release mechanism appears to be diffusion controlled. Excellent correlation was obtained between predicted and actual release profiles of the optimum formula.     

The Use of Fractal Geometry in Pharmaceutical Systems

Abstract

The nature of surface irregularity affects many phenomena including adsorption/desorption, catalysis, crystal growth, drug dissolution and chromatography. Many excellent models have been developed with the oversimplified assumption that all particles are smooth spheres; fractal geometry allows these models to be expanded to irregular surfaces by providing a quantitative means of assessing surface roughness.

An overview of fractal analysis is presented in the following, and the state of the art, as far as pharmaceutical systems are concerned are outlined. Erroneous approaches, as well as the directions pharmaceutical research and technology might take in the area of fractal analysis are suggested.

From a historical perspective, micromeritics (the science of particle size, shape and surface area) were first developed with the assumptions that all particles were smooth spheres.

Much excellent work has been developed with such an oversimplified model. For example, numerous workers have shown that particle flow through an orifice is a function of “particle diameter”, and experiments have most often been carried out on particles as close to spherical as possible, and as monodisperse as possible.

The science of micromeritics, the science of small particles, is the making of Dalla Valle (1943) who coined the term in a book of the same name which describes methods of particle size measurement, mostly used by soil scientists.¹     

Influence of dispersion method on particle size and dissolution of grisgofulvin-silicon dioxide tripurations

Abstract

Dissolution rate and particle size distribution of griseofulvin were determined after simple blending or solvent deposition using colloidal silicon dioxide. Griseofulvin deaggregation in simple blends and micro-particulate drug dispersion in solvent deposited samples, both determinants of drug dissolution rate, were a function of silicon dioxide content. Solvent deposited samples scored impressively highly initial dissolution rates compared to corresponding simple blends. However, dissolution data thereafter were not encouraging. Drug particle size enlargment in griseofulvin rich samples and incomplete drug recovery from silicon dioxide rich samples were notable drawbacks in solvent deposition systems. Viscosity effects of silicon dioxide dispersion on griseofulvin dissolution were demonstrated. Simple blending with silicon dioxide was recommended as a means of promoting dissolution rate of griseofulvin. Limitation of average particle size data determined by methods which do not discriminate between drug and insoluble carrier is discussed.     

The Influence of Drug Solubility and Particle Size on the Pellet Formulation in a Rotoprocessor

ABSTRACT

Pellets containing drugs of different properties were prepared in a Rotoprocessor in order to study changes in the formulation process and resulting pellet characteristics. Diltiazem hydrochloride, diclofenac sodium, and theophylline were chosen as model drugs. Pellet size distribution, sphericity, density, hardness, friability, and repose angle were determined using standard methods. The amount of water as a wetting agent necessary for successful pellet formulation was observed for each sample and changed depending on drug solubility, concentration, and particle size. The pelletization of freely soluble diltiazem hydrochloride required 24.8–23.1% of the wetting agent and its amount decreased as the drug concentration increased. The demand for water in the formulation of theophylline pellets was 31.0–34.4% and it increased with increasing drug concentration. The pellet samples containing both drugs were easy to prepare. However, the cohesion of micronized diclofenac sodium particles negatively influenced both the pellet size distribution and the formulation process itself. When the drug concentration exceeded 40%, it was not possible to produce pellets of an appropriate size and the process was not reproducible.     

Design of selegiline-loaded bio-nanosuspension for the management of depression using novel bio-retardant from Manilkara zapota

Objective: Depression is one of the most frequent psychiatric and potentially life-threatening disorders. This research work can offer a potential for delivery of selegiline moiety via ocular route in bio-nanosuspension mode for the effective management of depression after preclinical performance screening.

Methods: The selegiline-loaded bio-nanosuspension was prepared using novel bio-retardant isolated from fruit pulp of Manilkara zapota (Sapodilla) by sonication solvent evaporation method with different ratios (0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and 1%) and with standard polymer HPMC (0.1%, 0.2%, 0.3%, 0.4%, and 0.5%). The prepared formulations were evaluated for pH stability studies, %entrapment efficiency, in vitro drug release, particle size, polydispersity index (PDI), zeta potential, and stability studies.

Results: The prepared bio-nanosuspension was subjected to the best formulation based on comparison of above-mentioned evaluation parameters, so Fb2 (0.1%) formulation was found to be the best formulation showing an R² value of 0.9814, T50% of 29.7?h, and T80% of 65.25?h. According to the release kinetics, the best fit model was found to be the Korsmeyer–Peppas with the Fickian diffusion (Higuchi matrix) as the mechanism of drug release. Manilkara zapota (Sapodilla) provided excellent stability for the formulation and resulting particle size for the best formulation was found to be 252?nm. The bio-nanosuspension had PDI of 0.35 with zeta potential of –8.91?mV.

Conclusion: The prepared bio-nanosuspension was found to be safe and compatible with the ophthalmic delivery for treatment of depression.     

Microencapsulation by Emulsion Non-Solvent Additicin Method

Abstract

Cellulose acetate butyrate microcapsules containing propranolol were prepared by emulsion non-solvent addition method. The effects on drug release of different polyethylene glycols (PEG), various concentrations of PEG 4000, and particle size of the drug to be encapsulated were investigated. In vitro dissolution of microcapsules in simulated intestinal fluid and buffers at different pH was also studied. PEGs were found to increase drug release for this system. The pH dissolution profiles of the microcapsules indicated that dissolution was slightly pH dependent during the first 8 hours of dissolution.     

Relationship Between Particle Size and Dissolution Rate of Bulk Powders and Sieving Characterized Fractions of two Qualities of Orthoboric Acid

Abstract

We have carried out a study of the particle size distribution and aqueous dissolution rate of two commercially available qualities of orthoboric acid, labeled “crystal” (ABC) and “powder” (ABP). In a previous work, we have shown that the two commercial qualities of orthoboric acid chosen as model compound (“powder” and “crystal”) are related to the same crystal network in spite of their dvferent names. However, these two qualities have very different size particle distributions, as previously determined by sieving and confirmed by the present laser light scattering study. Dissolution testing is performed under sink conditions and show that the bulk ABC quality dissolves far more rapidly that the bulk ABP quality, For each quality, dissolution rates of four sieved particle size fractions (0-90 μm; 90-125 μm; 125-180 μm; 180-250 μm) were compared. Concerning the ABC quality, comparisons were also done with three other particles size fractions: 250-355 μm, 355-500 μm, and 500-710 μm. This study used the dQ/dt versus t profile. Dissolution profiles of the fractions enclosing particles with a size superior to 125 μm are very close. On the other hand, fractions enclosing particles with a size smaller than 90 μm present a different profile and a slower rate of dissolution.