Solid Dispersion Controlled Release: Effect of Particle Size, Compression Force and Temperature

Solid dispersions are dynamic systems, a careful control of processing variables is required to produce desired physicochemical properties of these systems.

The influence of drug particle size, dispersion temperature and compression force on the release rate of theophylline from solid dispersed system tablets was studied. Theophylline base (micronized and granulate) were embedded into a polymeric mixture of PEG and acrylic/methacrylic esters at controlled temperature and shock cooled. Tablets were made at two compressional forces and drug release was measured spectrophotometrically over a period of fifteen hours.

The release rate of drug dispersed in these insoluble matrices was independent of particle size but not of hardness.

However, variations in ratios of polymeric mixture and dispersion temperature controls the drug release rate from inert matrix more effectively than such factors as drug particle size and lower range of tablet hardness. The fast cooling produced excellent reproducibility of drug content throughout the entire entrapment product. X-ray diffraction study demonstrated no changes in crystalline form of theophylline.     

Use of Proteins to Minimize the Physical Aging of EUDRAGIT® Sustained Release Films

ABSTRACT

The objective of this study was to investigate the influence of two proteins, albumin and type B gelatin, on the physical aging of EUDRAGIT® RS 30 D and RL 30 D coated theophylline pellets. The physicomechanical properties of sprayed films, thermal properties of cast films, influence of proteins on the zeta potential and particle size of the dispersion, and the release of proteins from cast films under simulated dissolution conditions were investigated. The release rate of theophylline decreased significantly over time from pellets coated with an acrylic dispersion containing 10% albumin when there was no acidification of the acrylic dispersion; however, when pellets were coated with an acidified EUDRAGIT®/albumin dispersion, the theophylline release rate was stable for dosage forms stored in the absence of humidity. The drug release rate was faster for pellets coated with acrylic dispersions containing 10% gelatin compared to the albumin–containing formulations. When sprayed films were stored at 40°C/75% RH, the water vapor permeability decreased significantly for both EUDRAGIT® films and those containing EUDRAGIT® and albumin; however, there was no significant change in this parameter when 10% gelatin was present. Albumin was released from the acrylic films when the pH of the dissolution media was below the isoelectric point of the protein while no quantitative release of gelatin was observed in pH 1.2 or 7.4 media. The effect of gelatin to prevent the decrease in drug release rate was due to stabilization in water vapor permeability of the film. Acidification of the polymeric dispersion resulted in electrostatic repulsive forces between albumin and the acrylic polymer, which stabilized the drug release rate when the dosage forms were stored in aluminum induction sealed containers at both 40°C/75% RH and 25°C/60% RH.     

Lysozyme-loaded lipid-polymer hybrid nanoparticles: preparation,characterization and colloidal stability evaluation

Context: Lipid-polymer hybrid nanoparticles (LPNPs) are polymeric nanoparticles enveloped by lipid layers, which have emerged as a potent therapeutic nanocarrier alternative to liposomes and polymeric nanoparticles.

Objective: The aim of this work was to develop, characterize and evaluate LPNPs to deliver a model protein, lysozyme.

Materials and methods: Lysozyme-loaded LPNPs were prepared by using the modified w/o/w double-emulsion-solvent-evaporation method. Poly-?-caprolactone (PCL) was used as polymeric core material and tripalmitin:lechitin mixture was used to form a lipid shell around the LPNPs. LPNPs were evaluated for particle size distribution, zeta potential, morphology, encapsulation efficiency, in vitro drug release, stability and cytotoxicity.

Results: The DLS measurement results showed that the particle size of LPNPs ranged from 58.04?±?1.95?nm to 2009.00?±?0.52?nm. The AFM and TEM images of LPNPs demonstrate that LPNPs are spherical in shape. The protein-loading capacity of LPNPs ranged from 5.81% to 60.32%, depending on the formulation parameters. LPNPs displayed a biphasic drug release pattern with a burst release within 1?h, followed by sustained release afterward. Colloidal stability results of LPNPs in different media showed that particle size and zeta potential values of particles did not change significantly in all media except of FBS 100% for 120?h. Finally, the results of a cellular uptake study showed that LPNPs were significantly taken up by 83.3% in L929 cells.

Conclusion: We concluded that the LPNPs prepared with PCL as polymeric core material and tripalmitin:lechitin mixture as lipid shell should be a promising choice for protein delivery.     

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.     

Preparation and Properties of Tablets Prepared from Furosemide-PVP Solid Dispersion Systems

Abstract

Tablets were prepared from the solid dispersion of furosemide: PVP by using different techniques such as direct compression and double compression. The results were compared with similar tablets prepared by physical mixture. Direct compression was much prefered, as it provided tablets with acceptable mechanical and physical qualities. On the other hand, the choice of disintegrant is very important in the formulation of furosemide: PVP solid dispersed tablets. With Kollidon CL, the best result was obtained. Disintegration mechanism of this system was also discussed. The other effective factor is the particle sizes of coprecipitates. Fine particle exhibited compression difficulty. The drug release from these tablets was 17 times greater than that from tablets prepared from physical mixture.     

Release of Theophylline from Ethyl Cellulose Mecrocapsues Alone and in Conjuction with Fat Embedded (Precirol®) Granules and Hydroxypropyl Methycellulose

Abstract

Microcapsules of theophylline with ethyl cellulose were prepared by coacervation technique using cabosil® (silicon dioxide) as separant. Tablets were prepared from microcapsules, microcapsules + theophylline fat embedded granules, and microcapsules and hydroxypropyl methylcellulose 4000 (HPMC). Release was studied in vitro by the rotating basket method. Prolonged release of theophylline was observed from microcapsules with no drug dumping. The release from microcapsules was of first-order whereas that from all the tablet formulation was diffusion controlled according to the Higuchi model. Good correlation was found between release rate and core:wall ratio for all the systems. Decrease in hardness of tablets made from microcapsules alone decreased the release rate, indicating damage of microcapsules during compression. The tablets compressed from fat embedded granules, microcapsules with fat embedded granules, and microcapsules with HPMC gave a desired release for a 74 hour sustained release preparation.     

Entrapment of Phenytoin into Microspheres of Oleaginous Materials: Process Development and in Vitro Evaluation of Drug Release

Abstract

A novel multiparticulate preparation of the antiepileptic agent phenytoin (1) was developed and evaluated in vitro. The preparation consists of gastroresistant microparticulate drug delivery system formulated with oleaginous material (lipospheres) to minimize unwanted effects of l on gastric apparatus. The drug was dispersed in a spherical micromatrix consisting of a mixture of stearyl alcohol and glycerol esters of various fatty acids. The best mixture to obtain discrete, reproducible, free-flowing lipospheres consisted of glyceryl monostearate dilaurate and stearyl alcohol (ratio 3: 17). The lipospheres were obtained by a technique involving melting and dispersion of drug-containing oleaginous material in aqueous medium. The oily droplets of the resulting emulsion after cooling under rapid stirring were transformed into solid. About 99% of the lipospheres were of particle size range 100–800 pm. The lipospheres were analyzed to determine the drug content in various particle sizes and to characterize the in vitro release profile. The average drug content was 23.8% w/w. Drug encapsulation efficiency was about 93.6% and the yield of production ranged from 94 to 98%. The drug discharge pattern from the microparticulate system in the intestinal environment was evaluated. Kinetic results were analyzed to distinguish between various release models. The matrix diffusion-controlled equation was the most appropriate one in describing drug release.     

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.     

Prolonged Release of Theophylline from Aqueous Suspensions

Abstract

The dissolution of theophylline from aqueous suspensions was measured by the U.S.P. paddle method. Theophylline release was retarded in the presence of xanthan gum, 1%, sodium alginate, 0.5%, and equi-weight mixtures of gelatin type B and iota carrageenan, 1%. These suspensions formed gels in situ in Simulated Gastric Fluid, U.S.P. Diffusion cell studies suggested that theophylline transport within the formed matrix was due to diffusion through immobilized liquid water. Evidence in support of a diffusion controlled dissolution mechanism in these systems were linearity of the initial section of plots of dissolution against the square route of time, the lack of effect of theophylline particle size on dissolution rate, and the tendency for release from a particular system to become independent of polymer concentration once a sufficiently high concentration was reached.     

Manufacture of Slow-Release Matrix Granules by Wet Granulation with an Aqueous Dispersion of Quaternary Poly(meth)acrylates in the Fluidized Bed

ABSTRACT

Slow-release matrix granules were manufactured in the fluidized bed using an aqueous dispersion of quaternary poly(meth)acrylates (Eudragit® RS 30 D) as binder for granulation. A factorial design was carried out to investigate the influence of the following parameters, spraying rate, applied polymer amount, and inlet air temperature, on various granule properties. Prerequisites for a slow release of the model drug theophylline are high spraying rate, high amount of polymer, and low inlet air temperature. No considerable decrease of the drug release rate can be achieved without a subsequent curing of the dry granules. A clear correlation exists between the moisture content of the fluidized bed, indicated by the terminal moisture content (TMC), and the mean dissolution time for 80% of the drug (MDT₈₀).     

Development and in Vitro Evaluation of a Novel Multiparticulate Matrix Controlled Release Formulation of Theophylline

Abstract

A novel multiparticulate matrix controlled release preparation of theophylline was formulated and evaluated in-vitro. The preparation which consisted of spherical drug pellets in a size range of 1.18-1.70 mm diameter was produced using an extrusion-spheronisation technique. The drug was embedded in a mixture of nonsoluble matrix materials forming the pellets to control the drug release. For this purpose, microcrystalline cellulose (MCC) and its mixture with glyceryl monostearate (GMS) were evaluated. When microcrystalline cellulose was used alone, the drug release was not sufficiently sustained and was essentially complete within 6 hours. However, incorporation of glyceryl monostearate significantly retarded the rate of drug release. Moreover, the rate of drug release could be readily modified in a predictable manner by varying the amount of glyceryl monostearate. The rate of the drug release was relatively insensitive to changes in the drug to matrix ratio. Drying of the drug pellets at temperatures below the melting point of glyceryl monostearate (approximately 57°C) has no effect on the rate of drug release. In addition, the rate of drug release was found to be stable after storage for 6 months and was essentially independent of pH and agitation rate.     

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.     

Use of proteins to minimize the physical aging of EUDRAGIT sustained release films

The objective of this study was to investigate the influence of two proteins, albumin and type B gelatin, on the physical aging of EUDRAGIT® RS 30 D and RL 30 D coated theophylline pellets. The physicomechanical properties of sprayed films, thermal properties of cast films, influence of proteins on the zeta potential and particle size of the dispersion, and the release of proteins from cast films under simulated dissolution conditions were investigated. The release rate of theophylline decreased significantly over time from pellets coated with an acrylic dispersion containing 10% albumin when there was no acidification of the acrylic dispersion; however, when pellets were coated with an acidified EUDRAGIT®/albumin dispersion, the theophylline release rate was stable for dosage forms stored in the absence of humidity. The drug release rate was faster for pellets coated with acrylic dispersions containing 10% gelatin compared to the albumin-containing formulations. When sprayed films were stored at 40°C/75% RH, the water vapor permeability decreased significantly for both EUDRAGIT® films and those containing EUDRAGIT® and albumin; however, there was no significant change in this parameter when 10% gelatin was present. Albumin was released from the acrylic films when the pH of the dissolution media was below the isoelectric point of the protein while no quantitative release of gelatin was observed in pH 1.2 or 7.4 media. The effect of gelatin to prevent the decrease in drug release rate was due to stabilization in water vapor permeability of the film. Acidification of the polymeric dispersion resulted in electrostatic repulsive forces between albumin and the acrylic polymer, which stabilized the drug release rate when the dosage forms were stored in aluminum induction sealed containers at both 40°C/75% RH and 25°C/60% RH.     

Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Abstract

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50–75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Studies on solid dispersions of nifedipine

Abstract

Nifedipine-Polyethylene glycol solid dispersions were prepared by melting or fusion method in order to improve nifedipine solubility in the aqueous body fluids. The dissolution rate of the drug was markedly increased in these solid dispersion systems. The increase in dissolution was a function of the ratio of drug to polyethylene glycol used and the molecular weight of polyethylene glycol. The dissolution rate was compared with a 10% w/w physical mixture of drug with polyethylene glycol.

The physical state of nifedipine after fusion was determined by X-ray crystallography on the pure drug and on the solidified melts. The X-ray diffraction studies indicated that nifedipine in the solid dispersion which was obtained by sudden cooling of the melt, was in the thermodynamically unstable metastable form. It was established that the slow cooling of the melt as well as powdering of solid dispersion resulted in the emergence of crystallinity.

The effect of aging on nifedipine-polyethylene glycol 6000 solid dispersions has been investigated. After storage at room temperature for six months, solid dispersions showed no change in the dissolution rate and the X-ray diffraction pattern showed slight enhancement in crystallinity.     

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.     

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.     

Influence of technological factors on formulation of sustained release tablets

Abstract

Theoretically expected rates of release of solid drugs incorporated into solid matrices have been derived for several model systems. Mathematical relations have been obtained for cases (a) where the drug particles are dispersed in a homogeneous, uniform matrix which acts as the diffusional medium and (b) where the particles are incorporated in an essentially granular matrix and released by the leaching action of the penetrating solvent. A number of technological factors are influencing the formulation of sustained release tablets. It was found that the choice of matrix material, amount of drug incorporated in matrix, matrix additives, the hardness of the tablet, density variation, and tablet shape could markedly affect the release rate and also the formulation.     

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.     

Carnauba Wax Microspheres Loaded with Valproic Acid: Preparation and Evaluation of Drug Release

Abstract

To minimize unwanted toxic effects of valproic acid (1) by the kinetic control of drug release, gastroresistant carnauba wax microspheres loaded with the antiepileptic agent were prepared. The preparation was based on a technique involving melting and dispersion of drug-containing wax in an aqueous medium. The resulting emulsion after cooling under rapid stirring produced solid, discrete, reproducible free flowing microspheres which converted the liquid drug droplets into solid material. About 94% of the isolated microspheres were of particle size range 200-425 μm. The microspheres were analyzed to determine the drug content in various particle size range and to characterize the in vitro release profile. The average drug content was 26% w/w. The intestinal drug discharge of 1 from the carnauba wax microspheres was studied and compared with the release patterns observed for white beeswax and hexadecanol microspheres previously described. The drug release performance was greatly affected by the material used in the microencapsulation process. In the intestinal environment carnauba wax microspheres exhibited more rapid initial rate of release and about 80% of the entrapped drug was discharged in 120 min while complete release occurred in about 8 h.