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.     

Preformulation Studies on Solid Dispersions Containing Triamterene or Temazepam in Polyethylene Glycols or Gelucire 44/14 for Liquid Filling of Hard Gelatin Capsules

Abstract

Solid dispersions of triamterene or temazepam in polyethylene glycols or gelucire 44/14 have been investigated. The phase equilibria of the drugs and carriers were determined by Differential Thermal Analysis and Hot Stage Microscopy. Particle Size Analysis was carried out using double image microscopy, whilst phase solubility techniques and dissolution methods were used to study solubility, dissolution and ageing.

It has been shown that triamterene forms monotectics with polyethylene glycols and gelucire 44/14 and temzepam shows partial solubility. The effect of the carriers on particle size depends on the solubility of the drug in the carrier and size reduction is observed where the drug is soluble in the carrier.     

Influence of the Drug and Ezcipient Solubility on the Antibiotic Release from Polymethacrylic Implants

Abstract

Polymethacrylic implants were prepared by use the monomer (Kallocryl^R) and a polymerization extrusion technique. The antibiotics used were gentamicine, streptomycine and chloramphenicol. The excipients used were amino acids with various solubilities and titan dioxyde as an inert and insoluble matrix filler. The drug release examined in vitro by use a modified pitcher/half change method was dependent on the mechanical strength of the matrix, the concentration and the solubility of the amino acid used and the drug concentration and solubility.

The water inflow into the matrix was of effect on the volume of pores and may be influenced by the drug and excipient particle size and solubility.

There was a relationship between the time dependent volume of pores in the matrix and the amount of drugs released from the implants.     

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.     

Requirements for the Production of Microtablets: Suitability of Direct-Compression Excipients Estimated from Powder Characteristics and Flow Rates

Abstract

Eleven direct-compression excipients, namely 3 microcrystalline celluloses, 4 lactoses, 4 co-processed excipients, and 4 mixtures of lactoses with Avicel PHI02 SCG were evaluated for possible use in micro tableting. Powder-technological parameters, namely particle size distributions, true and apparent densities, densification behaviour, and mass flow rates from a funnel through very narrow orifices, were determined.

Flow rates required on modern high-speed rotary tableting machines were calculated.

Flow rates may be estimated even for very narrow orifices, and such studies aid in selection of suitable excipients.

Mainly spray-dried lactose preparations with certain, definite upper limits in size distribution, seem to comply with the prerequisites for the production of micro tablets.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.     

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.     

Technological Evaluation of Three Enteric Coating Polymers II. With a Soluble Drug

Abstract

Three enteric coating polymers, cellulose acetate phthalate (CAP), hydroxy propylmethylcellulose phthalate (HP55) and cellulose acetate trimellitate (CAT) were evaluated on two different chemical substrates (soluble and insoluble). Gastric juice resistance was tested by dissolution using USP apparatus (paddle) in Britton buffer at different pH, under sink conditions over 5 hours. It can be said that the resistance of tablets depends on the coating formulation considered and the drug solubility. From our tests it results that CAP is more resistant than CAT for two drugs in intestinal medium and the resistance of HP55 depends on the solubility of the drugs. More, only CAT allows the release in the proximal small intestine for drugs whatever solubiliy.     

Preparation and Evaluation of SEDDS and SMEDDS Containing Carvedilol

ABSTRACT

A new self-emulsifying drug delivery system (SEDDS) and self-microemulsifying drug delivery system (SMEDDS) have been developed to increase the solubility, dissolution rate, and, ultimately, oral bioavailability of a poorly water soluble drug, carvedilol. Ternary phase diagrams were used to evaluate the self-emulsification and self-microemulsfication domains. The self-emulsification time following introduction into an aqueous medium under gentle agitation was evaluated. The minimum self-emulsification time was found at a Tween 80 content of 40%. The particle size distribution and ζ-potential were determined. Benzoic acid had a dual function, it improved the self-emulsification performance of SEDDS and SMEDDS in 0.1 N HCl and lead to a positively charged emulsion. The in vitro dissolution rate of carvedilol from SEDDS and SMEDDS was more than two-fold faster compared with that from tablets. The developed SEDDS formulations significantly improved the oral bioavailability of carvedilol significantly, and the relative oral bioavailability of SEDDS compared with commercially available tablets was 413%.     

Preparation and Characterization of Quercetin and Rutin Cyclodextrin Inclusion Complexes

ABSTRACT

The objective of the present study is to prepare and characterize cyclodextrin inclusion complexes of quercetin and rutin to improve their aqueous solubility and dissolution properties. Inclusion complexes of quercetin and rutin with ß-cyclodextrin (ß-CD) and hydroxyl propyl-ß-cyclodextrin (HP-ß-CD) were prepared by kneading and coevaporation methods. Characterization of inclusion complexes was done by phase solubility analysis and was supported by X-ray powder diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier-transform infra red spectroscopy (FT-IR) analysis. Inclusion complexes exhibited higher rates of dissolution than the corresponding physical mixtures and pure drug. Higher dissolution rates were observed with HP-ß-CD kneaded complexes in comparison to the products with ß-CD.     

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.     

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems

Context: Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability.

Objective: Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison.

Methods: The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated.

Results: The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2?h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine.

Conclusion: Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.     

Surface Characterisation df Sucrose and Antibiotics Powder Mixes with Relevance to Mixing Theories

Adhesional ordered mixing is not applicable in real systems because ordered interaction between drug and excipient particles can not be achieved. In contrary, Interactive Mixture approach is more applicable because it allows the powder mixtures to be described according to the state of homogeneity achieved which is dependent on mixing variables.

Surface characteristics of powder mixture particles are important to study in order to understand the interparticulate interactions between drug and excipient particles.

Indentations on excipient particles act as mechanical entrapment sites for drug particles which result in areas containing highly localised drug content. Consequently, the state of homogeneity of powder mixtures is possibly affected. Furthermore, the release of particles which are entrapped will be different from those held by interparticulate forces on the plain surfaces of excipient particles. This is particularly important when the excipient particles are insoluble and drug particles are poorly soluble.     

Properties of Solid Dispersions of Naproxen in Various Polyethylene Glycols

Abstract

Solid dispersions of naproxen in polyethylene glycol 4000, 6000, and 20000, aimed at improving the drug dissolution characteristics, were prepared by both the solvent and melting methods. The drug-polymer interaction in the solid state was investigated using differential scanning calorimetry, hot-stage microscopy, Fourier-transform infrared spectroscopy, and x-ray diffraction analysis. Interaction in solution was studied by phase solubility analysis and dissolution experiments. Computer-aided molecular modeling was used to supplement the results from phase solubility studies. No important chemical interaction was found between naproxen and polyethylene glycol, either in solution or in the solid state, apart from the formation of weak drug-polymer hydrogen bonds. The increase of naproxen dissolution rate from its binary systems with polyethylene glycol could be attributed to several factors such as improved wettability, local solubilization, and drug particle size reduction. No influence of polymer molecular weight or of the solid dispersion preparation method on drug dissolution properties was found.     

Effect of Aging on the Dissolution Rate of Nalidixic Acid Tablets

Abstract

Investigation of the dissolution rate profiles of nalidixic acid tablets of three commercial brands was carried out. Using the U.S.P. paddle method, significant inter-brand variations in dissolution rates were found and the tablets did not pass the U.S.P. dissolution test. The dissolution of the tablets was also found to be adversely affected on aging. The observed differences in dissolution rates of the tablets examined were unrelated to their disintegration times. An attempt was made to improve the dissolution rate of nalidixic acid tablets through hydrophilization of nalidixic acid powder and use of tablet excipients with high aqueous solubility were found to yield tablets of good physical qualities which were unaffected on aging.     

Film Coated Pellets Containing Verapamil Hydrochloride: Enhanced Dissolution into Neutral Medium

Abstract

Weakly basic drugs, such as verapamil hydrochloride, that are poorly soluble in neutral/alkaline medium may have poor oral bioavailability due to reduced solubility in the small intestine and colon. Film coated pellets were prepared using two strategies to enhance drug release at high pH values. Firstly, pellets were coated with Eudragit® RS/hydroxypropyl methylcellulose acetate succinate (HMAS) mixtures in proportions of 10:1 and 10:3, respectively. The enteric polymer, HMAS, would dissolve in medium at pH>6 creating pores through the insoluble Eudragit RS membrane to increase drug release. Secondly, an acidic environment was created within the core by the inclusion of fumaric acid at concentrations of 5 and 10% in order to increase drug solubility. Both strategies enhanced drug release into neutral medium in dissolution studies using the pH change method to simulate GIT transit. Dissolution profiles of samples tested in pH 1.2 for 12 hr were compared with those using the pH change method (pH 1.2 for first 1.5 hr, pH raised to 6.8 for remaining 10.5 hr) using the area under the dissolution curve (AUC), the dissolution half-life (t_50%), and the amount of drug released in 3 hr (A_{3 hr}) values. Both strategies enhanced drug release into neutral medium although the strategy using HMAS in the film was more effective. The formulation least affected by pH change was a combination of the two strategies, i.e., pellets containing 5% fumaric acid coated with Eudragit RS 12% w/w and HMAS 1.2% w/w.     

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.     

Amorphous nanoparticle complex of perphenazine and dextran sulfate as a new solubility enhancement strategy of antipsychotic perphenazine

Objective: The objective of this study is to develop a new solubility enhancement strategy of antipsychotic drug – perphenazine (PPZ) – in the form of its amorphous nanoparticle complex (or nanoplex) with polyelectrolyte dextran sulfate (DXT).

Significance: Poor bioavailability of PPZ necessitated the development of fast-dissolving PPZ formulations regardless of delivery routes. Existing fast-dissolving formulations, however, exhibited low PPZ payload. The high-payload PPZ-DXT nanoplex represents an attractive fast-dissolving formulation, as dissolution rate is known to be proportional to payload.

Methods: The nanoplex was prepared by electrostatically driven complexation between PPZ and DXT in a simple process that involved only ambient mixing of PPZ and DXT solutions. We investigated the effects of key variables in drug-polyelectrolyte complexation (i.e. pH and charge ratio R_DXT/PPZ) on the physical characteristics and preparation efficiency of the nanoplex produced. Subsequently, we characterized the colloidal and amorphous state stabilities, dissolution enhancement, and supersaturation generation of the nanoplex prepared at the optimal condition.

Results: The physical characteristics of nanoplex were governed by R_DXT/PPZ, while the preparation efficiency was governed by the preparation pH. Nanoplex having size of ≈80?nm, zeta potential of ≈(-) 60?mV, and payload of ≈70% (w/w) were prepared at nearly 90% PPZ utilization rate and ≈60% yield. The nanoplex exhibited superior dissolution than native PPZ in simulated intestinal juice, resulting in high and prolonged apparent solubility with good storage stabilities.

Conclusions: The simple yet efficient preparation, excellent physical characteristics, fast dissolution, and high apparent solubility exhibited by the PPZ-DXT nanoplex established its potential as a new bioavailability enhancement strategy of PPZ.     

The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

Abstract

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

Dissolution Characteristics of Polycaprolactone-Polylactide Microspheres of Chlorpromazine

Abstract

Studies were conducted on the preparation of controlled release polycaprolactone-polylactide microcapsules of chlorpromazine and on release of the drug from the microcapsules in pH 7.0 buffer medium. A wide range of release rates of the drug was obtained by simple change in the polymer system. Chlorpromazine was released from the microspheres in a biphasic manner consisting of an initial fast release phase followed by a slow-release phase. Increasing the drug content increased the initial drug release rate but no significant drug loading effect on the second stage dissolution rate was noted. There was no significant effect of particle size on the drug release rate from the microspheres. The swelling property of the microspheres and the agglomerate nature of the sieve fractions may complicate the drug release kinetics and obscure the particle size effect on dissolution rate.