Dissolution Kinetics and Rate-Controlling Mechanisms

The kinetics and mechanisms of dissolution in a newly designed diffusion cell were investigated. It was found that benzoic acid is an ideal compound to calibrate the fluid hydrodynamics in the diffusion cell when the mass transfer at the boundary layer is the primary contributor for its dissolution process. The dissolution of a very lipophilic drug, progesterone was also studied and the mechanisms of its dissolution process appear to be diffusion controlled. Using the dimensionless Sh-Re-Sc relationship developed earlier, it became possible to study the kinetics and mechanisms of dissolution of a solid drug. A reciprocal plot was established to obtain the kinetic constant of dissolution at the interface. This approach could be applied to investigate the kinetics of dissolution and diffusional resistance of other drugs     

Studies on Drug Release from a Carbomer Tablet Matrix

Abstract

The purpose of this investigation was to study the drug release mechanisms for tablet matrices of carbomer. Carbomer is a polymer of acrylic acid which is cross-linked with polyalkenyl polyether. The drug and the carbomer were blended and directly compressed into tablets using a laboratory Carver press. The influence of the level of carbomer, the type of drug, and the pH of dissolution media were investigated by measuring drug release kinetics. In general, the release of a relatively neutral molecule (e.g. theophylline) in the pH 7.2 phosphate buffer solution appears to exhibit nearly zero-order kinetics via a diffusion-controlled mechanism for all polymer levels studied (10-85%).

The drug release process based on diffusion can be described by the general expression:

M_t = k₁t^1/2 + k₂t

where M, represents the amount of the drug released at time t, and k₁, k₂ are related to kinetic constants characteristic of the drug delivery systems. The release kinetics are modified when an ionic species, such as sodium salicylate, is incorporated into the tablet matrix.     

Use of CACO-2 Cells as an in vitro Intestinal Absorption and Metabolism Model

Abstract

The Caco-2 cell line, a human colorectal carcinoma cell line, is an established in vitro model for the study of drug transport in the human intestine. We have routinely utilized this in vitro model to 1) elucidate intestinal absorption mechanisms of small drug molecules and peptide-like therapeutic agents (e.g. paracellular/transcellular passive diffusion and carrier-mediated active transport), 2) screen and select orally active therapeutic agents, 3) identify optimum luminal pH's for drug absorptions, 4) address dissolution rate-related absorption problems, 5) assess mucosal toxicity of therapeutic agents, and 6) evaluate prodrug approaches for enhanced drug absorptions. We have also utilized this in vitro model to assess the metabolic stability of therapeutic agents in the intestinal epithelium. Demonstrated in this report are primarily the techniques for the elucidation of absorption mechanisms. Examples of the characterization of paracellular/ transcellular passive diffusion pathways and carrier-mediated active transport will be given. Application of the Caco-2 model to the process of drug development will also be discussed.     

Effect of Polymer Loading on Drug Release from Film-Coated Ibuprofen Pellets Prepared by Extrusion-Spheronization

Abstract

Many factors are capable of influencing the mechanism of drug release from pellets prepared by extrusion-spheronization. This study was designed to elucidate the effect of polymer type and loading and the effect of processing variables on the rate and mechanism of drug release from ibuprofen pellets coated using aqueous polymeric dispersions. Qualitative and quantitative assessment of the success of the film coating process and the quality of the resultant films is made using scanning electron microscopy and in-vitro dissolution testing. The importance of plasticizer in polymeric film formation is also discussed. Uncoated pellets containing 60, 70 and 80% ibuprofen were coated with aqueous polymeric dispersions of polymethacrylates, ethylcellulose and silicone elastomer films. The high drug loading of these pellets adds special interest to this study. Drug release from uncoated pellets appears to follow first-order kinetics. The application of a polymeric membrane to uncoated cores has the effect of retarding drug release. There appears to be a critical coating level below which core coverage by the polymer is incomplete, drug release is diffusion controlled and first-order release kinetics are observed. Above a defined polymer level, drug release appears to be membrane controlled and zero-order kinetics are observed. The presence of plasticizer in the polymeric film imparts a hydrophilic component to an otherwise hydrophobic membrane. This enhances the penetration of aqueous solvent into the pellet core during in-vitro dissolution testing, increasing the rate of drug release. Scanning electron micrographs reveal the nature of these hydrophilic pores, beneath which a fine tortuous skeletal network of drug-depleted core is exposed.     

Dissolution Profiles of Long-Acting Quinacrine Hydrochloride Pellets II

Abstract

Quinacrine hydrochloride is a well known drug used safely as an antimalarial agent and also could be used for permanent non-surgical female sterilization. In the present investigation the dissolution studies of the long-acting quinacrine hydrochloride pellets were carried by U.S.P. basket method. And it is seen that the drug release is principally through leaching and drug diffusion from the matrix. The plot of drug dissolved against time in the semilogaritmic presentation showed that the release kinetics is of first order.     

Effect of Formulation Variables on Dissolution Profile of Diclofenac Sodium from Ethyl- and Hydroxypropylmethyl Cellulose Tablets

Abstract

The effects of formulation variables on the release profile of diclofenac sodium from ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC) matrix tablets were investigated. With increase in viscosity of ethyl cellulose used in nonaqueous granulation, a decrease in drug release from the tablets was observed, while the percentage of fines articles passed through 60 mesh) in the granulation had a significant effect on the dissolution profile. Granules containing 15% fines exhibited slow release of the drug in comparison to those containing 30% fines with EC matrices. An analysis of kinetics of drug release from hydrophobic EC matrix showed Fickian diffusion regulated dissolution. Drug release from HPMC tablets followed an apparent zero-order kinetics.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

Abstract

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

Relationship Between the Swelling Process and the Release of a Water-Soluble Drug from a Compressed Swellable-Soluble Matrix of Poly(Vinyl Alcohol)

An attempt was made in this study to relate the release of a highly water-soluble model drug from tablet matrices of poly(vinyl alcohol) (PVAL) with the factors that may affect the release behavior. Swelling was evaluated using a simple projection method. The swollen layer was photographed to monitor its thickness. The polymer and drug dissolution were determined simultaneously by spectrophotometric methods. The resulting change of tablet area showed that the process of swelling occurred in three different stages that were intimately related to polymer dissolution: (a) a rapid initial swelling, resulting in an increased area; (b) a period with an approximately constant area; and (c) a decrease of the tablet area. In spite of the significant dissolution of PVAL during the release process, the thickness of the gel layer gradually increased. Thus, the delivery was governed by the drug concentration gradient along the diffusional path length. The drug release appeared to be controlled by a diffusion process according to Higuchi-type kinetics. The data analysis of drug and polymer profiles confirmed the diffusional mechanism.     

Relationship Between the pH of the Diffusion L'Ayer and the Dissolution Rate of Furosemide

Abstract

Sodium bicarbonate and ascorbic acid, both highly water-soluble materials, were used to modify the initial dissolution rate of furosemide from tablet formulations in various dissolution media. The observed differences in the initial dissolution rates of the drug have been correlated with changes in the pH of the diffusion layer brought about by the diluents. The initial dissolution rate of furosemide was shown to be dependent on and controlled by the pH of the diffusion layer while the bulk exerted only a secondary effect by controlling the magnitude of the pH-change through its buffer capacity.     

Development of a Formulation of Sustained Release Potassium Chloride

Abstract

The purpose of this work has been the designing and “in vitro” evaluation of a potassium chloride tablet using a wax matrix.

Camauba wax, stearyl alcohol and stearic acid ware employed to prepare granulates at different drug/wax ratios. Fran dissolution kinetic studies and technological performances a 75/25 – KCl/camauba wax granulates was selected. The rheolqgical properties of granulates were characterized and tablets were manufactured employing ccrrmun tablets excipients. Also a coating procedure was developed. The coated tablet formulation selected release the potassium chloride according to the USP requirements.

The dissolution kinetics of the potassium chloride from both coated and uncoated tablets fit the Higuchi diffusion model, giving a straight line when the amount dissolved is plotted against the square root of time.     

Comparison of Diffusion Studies of Hydrocortisone Between the Franz Cell and the Enhancer Cell

Abstract

The Franz diffusion cell remains a popular method to study diffusion of transdermal drug delivery systems through membranes. Recently, VanKel Industries, Inc., (Edison, NJ) developed the “Enhancer Cell,” a new device for in vitro transdermal drug diffusion testing. The purpose of this study was to evaluate the enhancer cell for in vitro transdermal diffusion of hydrocortisone from an ointment using a synthetic membrane and a biological membrane and compare it to the traditionally employed Franz cell. The Enhancer cell utilizes existing USP dissolution equipment (USP Apparatus II). Results show a higher cumulative release from the Enhancer cell as compared to the Franz cell. The Enhancer cell demonstrated more durability and was easier to use during experimentation and after completion of the experiment no apparent change was observed in the condition of the ointment or the skin when compared to the Franz cell.     

Preparation and Evaluation of Sustained-Release Solid Dispersions of Drugs with Eudragit Polymers

Abstract

Coevaporates of paracetamol and rifampicin with Eudragit polymers of different natures (anionic, cationic, and zwitterionic) were prepared. Determination of dissolution rate of these coevaporates in dissolution media simulating those of the gastrointestinal tract (GIT) revealed that the release rate of paracetamol is retarded from all the coevaporates studied. In this respect, Eudragit L100-SS shows the highest sustainment of drug release, while Eudragit E100 shows the lowest. Conversely, the release of rifampicin from its coevaporates with the anionic Eudragit S100 polymer is more retarded than the corresponding coevaporate with the zwitterionic Eudragit RL100 or from coevaporates with equal mixtures of the two polymers.

Increasing the polymer weight fraction in rifampicin coevaporates with Eudragit S100 up to 0.5 resulted in a corresponding decrease in the dissolution rate. However, beyond this weight fraction, the polymer effect on the dissolution rate of the drug becomes minimized. The results confirmed that the process of dissolution of the two drugs from their coevaporates is a diffusion-controlled release process.

The biological performance of paracetamol coevaporates was monitored in rabbits; paracetamol level in plasma was found to follow first-order kinetics. for all the investigated paracetamol coevaporates, the peak plasma level was less than 50 μg/ml compared to a value of 60, μg/ml for the drug per se. The coevaporates of the drug with Eudragit L100-55 showed slowest rates of absorption and elimination as well as greatest half-peak and half-life times. Biological peformance of rifampicin coevaporates was assessed in human subjects receiving a single oral dose equivalent to 300 mg of the drug. The results depicted sustainment of drug release as a function of polymer weight fraction. A strict correlation was shown to exist between the total amount of drug excreted during 24 hr post dosing of the coevaporates and its in vitro dissolution rate.

The results depicted that paracetamol can be formulated in the form of a coevaporate with Eudragit L100-55 to prepare a more safe sustained-release formulation with minimal side effects, and also revealed the advantages of administration of rifampicin in the form of a coevaporate with Eudragit S100 (4:1) at a single oral dose equivalent to 600 mg of drug.     

The Kinetics of Drug Release from Ethylcellulose Solid Dispersions

Abstract

Sulphadiazine - ethylcellulose (EC) solid dispersions with different drug: carrier ratios were prepared and fractionated. In vitro drug release followed an apparent zero-order kinetics rate constant being dependent on the thickness of the coat which was the rate controlling step in the process. Drug release was found to increase as the granule size was decreased. The amount of drug released was found to be pH dependent thus showing the existence of pores in the coat surrounding the drug particles. Inclusion of polyethylene glycol or sodium lauryl sulphate in the coat material or dissolution medium resulted in increased dissolution, an effect which was attributed to increase in porosity, reduction of interfacial tension and increase in wettability which was associated with the presence of these compounds.     

Injection moulding of alumina with partially water soluble binder system and solvent debinding kinetics

Abstract

A partially water soluble binder system was successfully derived and tested for injection moulding of alumina powder. The major binder of the binder system was comprised of poly(2-ethly-2-oxaline) and polyethylene glycol and these constituents formed the water soluble fraction of the system. The rheological properties of the feedstock were investigated systematically over a temperature range of 120 to 160°C and a shear rate range of 100 to 1000 s^?1. Binder removal was accomplished using a two stage process. The water soluble constituents were removed by water leaching. The remaining binder constituents were removed by thermal pyrolysis. The solvent debinding kinetics of the water leaching process were studied as a function of temperature, ranging from 40 to 80°C. Solvent debinding is a two stage process consisting of dissolution and diffusion. In this study, dissolution was the rate limiting step during the first stage of water leaching over a leaching time of 90 min at 40°C. As the process proceeds, it is shown that diffusion becomes the rate limiting step.     

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

Abstract

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.     

Polyethyelene Glycols and Drug Release

Abstract

The dissolution rates of several drugs may be increased by incorporation into solid polyethylene glycols1. These dispersions are usually manufactured by heating a physical mixture of the drug and polymer to the fluid state and subsequently cooling to room temperature.

The physical structure of both the drug and the polyethylene glycol will be discussed, as these factors may affect the rate of drug release from the dispersions2,3. The solid state properties of both components have traditionally been studied by X-ray diffraction and/or by differential scanning calorimetry (DSC). The latter technique has facilitated the use of phase diagrams in the investigation of the melting properties of the dispersions, these usually indicating the presence of eutectics, monotectics, solid solutions or glasses. The application of a further technique, dielectric spectroscopy, in the study of molten and solid dispersions will be described.

The mechanisms by which drug dissolution rate may be enhanced will be described. Furthermore, the kinetics of drug release will be discussed in terms of the non-interactive and interactive models proposed by Corrigan4.     

Using the Percolation Theory to Explain the Release Behavior from Inert Matrix Systems

Abstract

A novel analysis of drug release process from binary matrix systems has been realized and a study of the initial stage of the process has been carried out. A fast and easy technique has allowed the acquisition of one experimental datum per second. Release data have been analyzed by means of a detailed statistical study. The dissolution profiles were studied applying different kinetic models (zero order, logarithmic, and Higuchi equation). In all the cases studied, a starting process of zero or first order, indicative of a surface-dependent mechanism, has been found. Then, a parameter, named as critical time of kinetic change (t_c), has enabled the authors to establish the instant at which a diffusion release mechanism, according to Higuchi equation, is consolidated. From this time until the end of the process, release mechanism of matrices was shown to be diffusion controlled. The influence of the drug loading and the particle size over the release properties of tablets has also been investigated and it has been evaluated on the basis of percolation theory. The results show a major significance of particle size over the initial drug release and a decrease of its influence along the time. On the other hand, the drug loading variable shows an important influence over the release properties along the whole process.     

Effect of Eudragit Type Polymers on the Drug Release from Magnesium Oxide Granules Produced by Laboratory Fluidization

Abstract

The differences in the bioavailability of different drug products are most frequently caused by differences in the dissolution rates of the active ingredient. In case of magnesium oxide the drug release can be directly determined by reaction kinetics method based on acid neutralization.

For a more precise study of the factors influencing the kinetical characteristics of the neutralization rates it is advisable to use homogeneous granule fractions. Before the granulation the substance was pretreated with silicone oil. The granulation of the obtained grains having hydrophobe surface was carried out in an AEROMATIC STREA-I type laboratory fluidization equipment with Eudragit polymer solved in isopropyl alcohol.

For determining the acid neutralization kinetics of the granules the “constant pH” method and the Rossett-Rice test were used.

As a result of the granulation the neutralization rate decreased. The granules can be considered as an Eudragit matrix which contains the pretreated magnesium oxide in embedded form. During the chemical reaction the resulted salt (magnesium chloride) leaves the surface of the unreacted magnesium oxide unless having a chemical reaction with the polymer. Meanwhile the residual matrix forms a mesh which increases the viscosity of the solution and the thickness of the diffusion layer. The dissolution rate decreases in both cases.

Under the same conditions the kinetic values of the neutralization change by several magnitudes depending on the utilized methods. In this way different systems of medicine, which alter their reaction capacity according to the expected physiological purposes, can be created.     

Preparation and evaluation of ethylcellulose microcapsules with bacampicillin

Abstract

Ethylcelluloses of different types were used to microencapsulate bacampicillin. Polymer deposition from cyclohexane was performed by temperature change. As coacervation - inducing agent different polyisobutylenes (Oppanol B - 200, B - 100, B - 50, B -3) were used. Fine products with slower drug release were obtained. Average diameters of prepared microcapsules were determined with sieve analysis and it was shown that the particle size of the microcapsules follows log - normal distribution. Scanning electron microscopy was used to examine the shape and the surface characteristics of the microcapsules. HPLC method was developed for testing drug content and its dissolution. Drug content in the microcapsules was in all cases over 80% regarding the amount added. Dissolution of bacampicillin from microcapsules was retarded comparing to the dissolution of bacampicillin itself. The experimental values of dissolution were fitted with different model kinetics. To describe the dissolution profiles we suggested the combined zero and first order kinetics. The bitter taste was quite satisfactory disguised in all prepared microcapsules.     

Mechanisms of Dissolution of Fast Release Solid Dispersions

Abstract

Drug dissolution from a solid dispersion is dependent on the technology employed to prepare the dispersion and on the proportion and properties of the carrier used. The diffusion models describing dissolution from multi-component solids seem to adequately describe drug release from non-disintegrating systems in the weight fraction range where the drug phase is expected to control dissolution. When solid dispersions have higher dissolution rates than corresponding mechanical mixtures, solid state changes during the formation of the dispersion are indicated. These increases in rate may result from the formation of higher energy phases of either component or from interactions between the components. The carrier may play an important role in the formation of these phases and in stabilizing them during subsequent dissolution. When a large relative solubility difference exists between the carrier and the drug, deviations from theory can be expected to occur at high carrier weight fractions. The model fails because insufficient drug phase is present to form a viable surface drug layer. Drug release then becomes controlled by dissolution of the carrier. In polymer based systems the presence of drug retards dissolution of the carrier, possibly through effects on binding and polymer swelling. These effects need to be quantified in order to allow prediction of drug release from high carrier weight fraction systems.