Dissolution Kinetics and Rate-Controlling Mechanisms

Abstract

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     

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.     

Studies on Drug Release from a Carbomer Tablet Matrix

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.     

Optimization of Slow-Release Tablet Formulations Containing Montmorillonite III. Mechanism of Release

The release of sodium sulfathiazole from slow-release tablet dosage forms containing 30% colloidal aluminum silicate and 20% drug, appears to follow first-order kinetics. Analysis of the data however, suggests that several mechanisms including hydration of the clay, diffusion of drug through a hydrated gelatinous barrier and attrition of the gel layer may contribute to the dissolution of sodium sulfathiazole from the tablet matrix. The influence of tablet shape and size on the dissolution properties of drug from the dosage forms was also examined.     

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.     

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

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.     

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.     

Interfacial chemistry of powdered barium ferrites immersed in aqueous solutions: leaching in acidic chloride media

The kinetics of leaching and dissolution of barium mono- and hexa-ferrite in acidic chloride media are presented and discussed. The monoferrite is appreciably more reactive, and dissolves in a nearly congruent way in low pH media. In the case of barium hexaferrite, iron and barium dissolution are independent processes. Initially, fast barium leaching is observed, which is followed by a slower process controlled by diffusion through a growing iron oxide layer. Iron dissolves at nearly constant rates that are a function of pH; the apparent kinetic order on H⁺ is 0.66, typical of acid dissolution mechanisms. The differing reactivities of the mono- and the hexa-ferrite relates to their crystal chemistry.     

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

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.     

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.     

Etching and dissolution kinetics of MoSe2 single crystal

Etching and dissolution kinetics of MoSe₂ single crystals in aqueous chromic acid at different concentrations and temperatures have been studied. The dependence of the etch rate upon the concentration and temperature of the etchant has been established. The mechanism of the process of dissolution has been explained on the basis of an oxidation-reduction process. The process of etching has been found to be purely diffusion controlled.     

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

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.     

7050铝合金第二相溶解行为EI北大核心CSCD

研究热轧态7050铝合金在固溶过程中的平衡态η(MgZn2)相、T(Al2Mg3Zn3)相、S(Al2CuMg)相及含铁Al7Cu2Fe难溶相的溶解行为。采用原位扫描的组织检测方法获得上述平衡相的溶解动力学实测数据。在体扩散控制的溶解动力学模型基础上,引入曲率和界面反应对原子迁移速率的作用,建立η,T和S相溶解动力学模型。结果表明:在7050铝合金常规固溶温度(470℃)条件下,η和T相在2 min内即可完全溶解,S相保温较长的时间才能完全溶解,含Fe相不发生溶解;曲率对溶解行为影响较小,界面反应会大幅度降低溶解速率;本工作建立的η,T和S等第二相溶解动力学模型预测结果与实测结果吻合,能够为优化Al-Zn-Mg-Cu合金固溶工艺提供指导作用。     

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

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.     

Sustained-release pellets prepared by combination of wax matrices and double-layer coatings for extremely water-soluble drugs

This study was performed in order to develop a sustained-release pellet formulation containing venlafaxine hydrochloride (VEN), an extremely water-soluble drug, prepared by combination of wax matrices and double-layer coatings. The influence of both double-layer polymeric coats and wax matrices on the release of VEN from sustained-release pellets was investigated. The pellets were prepared by wet mass extrusion spheronization methods and then coated with a fluidized bed coater. For the pellets coated with Eudragit NE30D alone, a coating level of nearly 40% was required to pass the dissolution test compared with commercial product, and it was accompanied by an unacceptable lag time. The application of an alcohol-soluble polymeric subcoat, Opadry I, was added before the Eudragit NE30D coating process, which resulted in a marked delay in drug release. However, a faster release was observed for the formulation coated with a high subcoat level (10%) at the end of the dissolution test. A further delay in drug release was observed when a wax matrix, octadecanol, was added to the core pellet formulation. The kinetics of drug release changed from the Higuchi model to a zero order model and the predominant mechanism controlling drug release changed from diffusion to dissolution upon increasing the amount of octadecanol within the matrix pellets. In addition, the drug release was markedly influenced by the drug to matrix ratio. In conclusion, the 40% drug-loaded core pellets with double-layer coatings (8% Opadry I and 12% Eudragit NE30D) and 20% octadecanol matrix produced the desired profile for once-daily sustained release compared with the commercial product, and these pellets remained stable during storage.     

Interaction of InAs and InSb with aqueous solutions of nitric acid

InSb dissolution in 7.8–15.6 N HNO₃ is controlled by the oxidizer diffusion to the surface. InAs dissolution in 15.6 N HNO₃ is controlled by diffusion in solution; at low acid concentrations, the dissolution rate is limited by diffusion through the loose oxide layer forming on the sample surface. The different dissolution kinetics of InAs and InSb in HNO₃ can be explained by the different properties of the surface layers of hydrous arsenic and antimony oxides.     

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

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.     

Influences of Osmotic Agents in Diffusion Layer on Drug Release from Multilayer Coated Pellets

Nonpareil beads were coated with three different functional layers, namely inner chlorpheniramine maleate‐loaded hydroxypropylmethylcellulose (HPMC, 4 mPa · s) deposition layer, middle HPMC (400 mPa · s) diffusion layer, and outer polyacrylic polymer (Eudragit RS30D) retention layer. The osmotic agents, including sodium chloride, glycine, citric acid, and disodium hydrogen phosphate, were incorporated in different amounts into the diffusion layer and the influences on drug release were studied. The osmotic agent competed with HPMC for imbibed water and subsequently caused more water influx owing to the osmotic pressure gradient. An appropriate amount of osmotic agent in the diffusion layer was necessary to exert its effect on retarding drug release. The osmotic effect on drug release was compromised with pellets at a higher coating level of the diffusion layer due to the extensive swelling and rupture of coat. The release parameters, including dissolution T_50% and mean dissolution time, showed linear relationship with osmolalities of osmotic agents studied. The effect of the osmotic agent in the diffusion layer played an important role in determining the unique multiphase drug release profiles, particularly in the initial phase of dissolution, and reduced with depletion of the osmotic agent in the later phase of dissolution.