Dissolution of Some Lithium Dosage Forms and Correlation with Enslin Number

Abstract

The biopharmaceutic parameters of six conventional and one sustained release lithium carbonate commercial products were determined. From the dissolution data mean residence time, dissolution rate constants, and percent dissolved at 5 and 10 minutes were obtained. The ENSLIN numbers were compared with mean residence time and percent dissolved at 5 and 10 minutes. A good correlation was obtained between ENSLIN number and mean residence time for the conventional preparations.     

Solvothermal treatment of starch for the production of glucose and maltooligosaccharides

Starch was hydrothermally degraded without any additives over the temperature range from 453 to 563 K at a constant pressure of 10 MPa and the fluid residence times up to 6 min in a semi-batch reactor to produce glucose and maltooligosaccharides. The effects of reaction temperature, flow rate of hot water and residence time of water-soluble components on the product distribution in the solvothermal degradation of starch were investigated. Even at the lowest reaction temperature studied, the loaded starch was partially degraded and dissolved within 8 min by contacting high-temperature and high-pressure water in a semi-batch reactor. By installing a plug-flow reactor at the exit of the first reactor to increase and control precisely the residence time, the maximum glucose yield of 43.8% on the carbon weight basis of the starting material was obtained at 3.64 min and 513 K. The comparison of yields of glucose and 5-hydroxymethyl furfural (HMF), which is a major secondary product, indicates that adjusting the residence time was the most effective to increase the glucose yield and to suppress the 5-HMF production.     

Development of Fast-Dissolving Tablets of Flurbiprofen-Cyclodextrin Complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Dissolution of Suppositories V: Influence of Aging on Aspirin Release from Polyethyleneglycol Suppositories with and Without Crospovidone

This report details the effect of aging on release of aspirin from four PEG blends containing crospovidone as a disintegrant in concentrations of 0, 0.5, 1 and 5%. It has been reported in the literature that release from suppository formulations is often altered upon aging. In this experiment, suppositories containing 350 mg aspirin were dissolved in 1,000 mls of pH 8.0 dissolution fluid, at 37.5° with an agitation rate of 50 rpm. Suppositories were designated as fresh (less than 10 days old), 4 months old and 6 months old. Aspirin was assayed at 265 nm. Dissolution profiles as well as dissolution half-times were reported. Aging had little effect on Base A and Base B. However, Ease C exhibited an ambiguous effect in that the dissolution half-times were inconsistent. Base D exhibited a dramatic change in release upon aging in that the dissolution half-times increased from 23 minutes to 55 minutes with 1/22 crospovidone. It is hypothesized that Base D stabilized when larger amounts of crospovidone are used although the exact mechanism of this stabilization is unknown     

Sugars as solid dispersion carrier to improve solubility and dissolution of the BCS class II drug: clotrimazole

Solid dispersion of poorly soluble BCS class II drug, clotrimazole, was prepared with the aim of enhancing its dissolution profile. Solid dispersions were prepared using various sugars as carriers at different weight ratio to drug-like d-mannitol, d-fructose, d-dextrose and d-maltose by fusion method. The solubility of plain clotrimazole in different percent of sugar solutions was measured. Also, its solubility in solid dispersion and their physical mixture were assessed. The dissolution of all the prepared SD tablets, direct compressed clotrimazole tablet and plain drug were tested using the U.S. Pharmacopeia convention (USP) apparatus II. The dissolution profiles were characterized by parameters like area under curve (AUC), mean residence time (MRT), mean dissolution time (MDT) and percent dissolution efficiency (% DE). The release kinetics study was performed using DD Solver TM software. The selected solid dispersions (SDs) were evaluated for antifungal activity. A 100% solution of mannitol showed 806-fold increases in solubility as compared with plain clotrimazole in water. It was observed that the dissolution profile of clotrimazole was improved by mannitol SD at drug to sugar ration of 1:3. The percent DE value for mannitol SD tablet was found to be 77.3516% as against plain drug and directly compressed tablet of clotrimazole at 50.9439% and 31.33%, respectively. Also the antifungal activity indicated by inhibition zone was found to be 54?mm indicating enhance activity against Candida albicans as compared with plain CTZ at 6.6?mm. Thus, it can be concluded that the sugar alcohol, that is, mannitol is a more promising hydrophilic carrier for solid dispersion preparation to improve the solubility and dissolution of poorly soluble drugs.     

Short Column Chromatography for a Robotic Dissolution Assay of Adinazolam Mesylate Tablets

Abstract

The use of robotics can potentially increase the productivity of pharmaceutical quality control laboratories, especially in areas such as dissolution testing. However, if the speed of the assay is limited by factors other than the speed of the robot, such as chromatography, the productivity of the assay is less than optimal. A robotic dissolution assay for adinazolam mesylate tablets is currently under development. One of the obstacles to implementation is that the productivity of the assay is limited by a chromatographic analysis time of six minutes per sample. This report descibes the application of short column chromatography to reduce the analysis for dissolved drug to under two minutes. Three short columns were evaluated for use in dissolution rate assay of adinazolam mesylate tablets. In this case, the application of short column technology allows for a potential increase in productivity of about 75 percent. Similar productivity gains may be achieved for other robotic assays that are limited by the speed of the chromatography.     

Investigations on Factors Affecting Chitosan for Dissolution Enhancement of Oxcarbazepine by Spray Dried Microcrystal Formulation With an Experimental Design Approach

In the present work effect of chitosan on microcrystal formulation for dissolution enhancement of oxcarbazepine using controlled crystallization technique coupled with spray drying was explored. The work was extended for exploration of simplified approach for stable particle size reduction. The study was performed with an experimental design approach i. e. a fractional factorial design of resolution 5 (with all 2 factor interaction) for the screening of predefined independent variables drug concentration, chitosan concentration, feed rate, inlet temperature and percent aspiration for spray drying. Whereas percent drug dissolved, wettability time, flowability in terms of angle of repose and particle size were designated as response variables. Resultant models were analyzed using multiple linear regression analysis, which generated equation to plot response surface curves along with desirability function. Results showed that chitosan concentration had significant effect on dissolution enhancement of oxcarbazepine at a level of 2% w/v. Increase in drug concentration showed decreased dissolution rate however on particle size it did not show statistically significant effect. Topographical characterization was carried out by SEM which showed that feed rate, percent aspiration and inlet temperature had significant effect on particle morphology. For deriving optimized formulation results were analyzed using desirability function for the maximum percent drug dissolved and least drug polymer matrix particle size. DSC studies showed that drug was molecularly associated with chitosan matrix or particles.     

Investigations on factors affecting chitosan for dissolution enhancement of oxcarbazepine by spray dried microcrystal formulation with an experimental design approach

In the present work effect of chitosan on microcrystal formulation for dissolution enhancement of oxcarbazepine using controlled crystallization technique coupled with spray drying was explored. The work was extended for exploration of simplified approach for stable particle size reduction. The study was performed with an experimental design approach i. e. a fractional factorial design of resolution 5 (with all 2 factor interaction) for the screening of predefined independent variables drug concentration, chitosan concentration, feed rate, inlet temperature and percent aspiration for spray drying. Whereas percent drug dissolved, wettability time, flowability in terms of angle of repose and particle size were designated as response variables. Resultant models were analyzed using multiple linear regression analysis, which generated equation to plot response surface curves along with desirability function. Results showed that chitosan concentration had significant effect on dissolution enhancement of oxcarbazepine at a level of 2% w/v. Increase in drug concentration showed decreased dissolution rate however on particle size it did not show statistically significant effect. Topographical characterization was carried out by SEM which showed that feed rate, percent aspiration and inlet temperature had significant effect on particle morphology. For deriving optimized formulation results were analyzed using desirability function for the maximum percent drug dissolved and least drug polymer matrix particle size. DSC studies showed that drug was molecularly associated with chitosan matrix or particles.     

Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Dissolution of Suppositories V: Influence of Aging on Aspirin Release from Polyethyleneglycol Suppositories with and Without Crospovidone

Abstract

This report details the effect of aging on release of aspirin from four PEG blends containing crospovidone as a disintegrant in concentrations of 0, 0.5, 1 and 5%. It has been reported in the literature that release from suppository formulations is often altered upon aging. In this experiment, suppositories containing 350 mg aspirin were dissolved in 1,000 mls of pH 8.0 dissolution fluid, at 37.5° with an agitation rate of 50 rpm. Suppositories were designated as fresh (less than 10 days old), 4 months old and 6 months old. Aspirin was assayed at 265 nm. Dissolution profiles as well as dissolution half-times were reported. Aging had little effect on Base A and Base B. However, Ease C exhibited an ambiguous effect in that the dissolution half-times were inconsistent. Base D exhibited a dramatic change in release upon aging in that the dissolution half-times increased from 23 minutes to 55 minutes with 1/22 crospovidone. It is hypothesized that Base D stabilized when larger amounts of crospovidone are used although the exact mechanism of this stabilization is unknown     

Characterization of the absorption of theophylline from immediate- and controlled-release dosage forms with a numerical approach using the in vitro dissolution-permeation process using caco-2 cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10(- 6)-5.28 10(- 6) cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (F(a)) against experimental dissolved fractions (F(d)) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed F(a)/F(d) relationships and theoretical F(a)/F(d) relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.     

Characterization of the Absorption of Theophylline From Immediate- and Controlled-Release Dosage Forms With a Numerical Approach Using the In Vitro Dissolution-Permeation Process Using Caco-2 Cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10^- 6-5.28 10^- 6 cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (F_a) against experimental dissolved fractions (F_d) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed F_a/F_d relationships and theoretical F_a/F_d relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.     

Validation of a Computer Spreadsheet Used to Perform Dissolution Calculations

Abstract

Dissolution testing for various pharmaceutical dosage forms is an integral part of release and stability testing requirements. In order to assist in such testing, a spreadsheet has been written and validated to perform dissolution calculations using Microsoft Excel software. The spreadsheet has been written for a dissolution experiment where the volume of the dissolution medium is held constant for the vessel by replacing removed dissolution medium with fresh dissolution medium at each time point. The spreadsheet corrects for the amount of dissolved drug substance removed at each time point and reports results in terms of percent of label claim dissolved for each vessel. The use of computer software to assist in data manipulation in the pharmaceutical industry requires adequate documentation, and therefore a validation protocol has been written and is described. An example of the formulas used to generate the spreadsheet is also given and can be easily used by readers to implement design of their own spreadsheets for dissolution calculations.     

Validation of a Computer Spreadsheet Used to Perform Dissolution Calculations

Dissolution testing for various pharmaceutical dosage forms is an integral part of release and stability testing requirements. In order to assist in such testing, a spreadsheet has been written and validated to perform dissolution calculations using Microsoft Excel software. The spreadsheet has been written for a dissolution experiment where the volume of the dissolution medium is held constant for the vessel by replacing removed dissolution medium with fresh dissolution medium at each time point. The spreadsheet corrects for the amount of dissolved drug substance removed at each time point and reports results in terms of percent of label claim dissolved for each vessel. The use of computer software to assist in data manipulation in the pharmaceutical industry requires adequate documentation, and therefore a validation protocol has been written and is described. An example of the formulas used to generate the spreadsheet is also given and can be easily used by readers to implement design of their own spreadsheets for dissolution calculations.     

Itraconazole formation using supercritical carbon dioxide

A new method of preparing Itraconazole (C₃₅H₃₈Cl₂N₈O₄), a synthetic triazole antifungal agent, was developed using supercritical carbon dioxide (SC CO₂) while eliminating the use of toxic solvents. Dissolution amounts of the product were measured in gastric fluid and compared to those of conventional drug formulations. Different operating conditions (five levels of treatment temperature ranging between 110-140°C, four levels of treatment pressure ranging between 30-400 atm, and four different treatment times ranging from 10-60 minutes) were tested in order to produce a desired Itraconazole product, which does not degrade during the product formation and has the highest extent of dissolution in gastric fluid after one hour. Itraconazole dissolution of 100% at one-hour was achieved for the drug produced at the optimum treatment condition: 135°C, 300 atm, and 30 minutes. Extent of dissolution obtained from this solvent and detergent-free process is 10% higher than that of the conventional method involving toxic organic solvents. Itraconazole produced using SC CO₂ should provide minimal side effects in human body.     

Characterization of the Absorption of Theophylline From Immediate- and Controlled-Release Dosage Forms With a Numerical Approach Using the In Vitro Dissolution-Permeation Process Using Caco-2 Cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10^{? 6}–5.28 10^{? 6} cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (F_a) against experimental dissolved fractions (F_d) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed F_a/F_d relationships and theoretical F_a/F_d relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.     

Itraconazole Formation Using Supercritical Carbon Dioxide

A new method of preparing Itraconazole (C₃₅H₃₈Cl₂N₈O₄), a synthetic triazole antifungal agent, was developed using supercritical carbon dioxide (SC CO₂) while eliminating the use of toxic solvents. Dissolution amounts of the product were measured in gastric fluid and compared to those of conventional drug formulations. Different operating conditions (five levels of treatment temperature ranging between 110–140°C, four levels of treatment pressure ranging between 30–400 atm, and four different treatment times ranging from 10–60 minutes) were tested in order to produce a desired Itraconazole product, which does not degrade during the product formation and has the highest extent of dissolution in gastric fluid after one hour. Itraconazole dissolution of 100% at one‐hour was achieved for the drug produced at the optimum treatment condition: 135°C, 300 atm, and 30 minutes. Extent of dissolution obtained from this solvent and detergent‐free process is 10% higher than that of the conventional method involving toxic organic solvents. Itraconazole produced using SC CO₂ should provide minimal side effects in human body.     

Formulation of Nitrofurantoin Tablets Fulfilling the Pharmacopoeial Specifications

The USP XXII specifies that the disintegration time for nitrofurantoin tablets must be not less than 30 minutes, not less than 25% of the drug is dissolved in 60 minutes and not less than 85% is dissolved in 120 minutes. These specifications were done to minimize the side effects and to achieve a proper bioavailability for the drug.

On testing the market tablet preparation (Furadantin), it was found that it does not fit to the [JSP specifications, Nine nitrofurantoin tablet formulations were then tried and each was studied for disintegration time and % dissolution in the first and second hours. The best formula was found to be consisted of adding 2% of collodion in 40% of the starting granules, coated with 4% CAP and adding another 2% of collodion to the remaining 60% of the granules.     

Bioequivalence study of paracetamol tablets: in vitro-in vivo correlation

The bioequivalence of three chemically equivalent paracetamol generic Mexican products (500 mg tablets) was evaluated in 12 healthy volunteers using the American innovator product (Tylenol, McNeil, Fort Washington, PA), as the reference. Single oral doses of each product were administered at 1-week intervals using a 4 x 4 Latin square design balanced for the first residual effect. The total amount of paracetamol excreted in urine in 24 hr was taken as a measure of bioavailability. In addition, moment analysis was used to estimate in vitro mean dissolution time (MDT) from dissolution profiles obtained following the USP 23 dissolution test specified for paracetamol tablets and to estimate in vivo mean residence time (MRT) from urinary excretion data. Significant differences in the dissolution performance and in the cumulative amount of paracetamol excreted in urine up to 24 hr were observed when the data were analyzed by analysis of variance (ANOVA) (p < .05). Classical and Westlake 90% confidence limits, as well as the two-sided t test proposed by Schuirmann, and the Anderson-Hauck power analysis supported the final conclusion that only one of the three generic paracetamol products studied can be considered equivalent to the reference product Tylenol. A linear correlation between in vitro MDT and in vivo MRT was found.     

The prediction of the dissolution rate constant by mixing rules: the study of acetaminophen batches

The purpose of this article is to promote two simple and scalable methods to accelerate the formulation development of formulated granules using acetaminophen as a model system. In method I, formulated granules made from the batch of small particle-sized acetaminophen (1) by ball milling the batch of large particle-sized acetaminophen (2), and the mixture of the two batches at equal weights (mix) gave the dissolution rate constants (k) of k(1) = 0.43 +/- 0.15 minutes(-1), k(2) = 0.18 +/- 0.01 minutes(-1), and k(mix) = 0.30 +/- 0.03 minutes(-1) for 75 wt percent formulation; k(1) = 0.75 +/- 0.01 minutes(-1), k(2) = 0.18 +/- 0.01 minutes(-1), and k(mix) = 0.34 +/- 0.03 minutes(-1) for 62 wt percent formulation; and k(1) = 0.28 +/- 0.01 minutes(-1), k(2) = 0.16 +/- 0.01 minutes(-1), and k(mix) = 0.22 +/- 0.02 minutes(-1) for 30 wt percent formulation. In method II, the mixture of the formulated granules produced by mixing the formulated granules from the two batches at equal weights gave dissolution rate constants of k(mix) = 0.30 +/- 0.03 minutes(-1), 0.30 +/- 0.02 minutes(-1), and 0.22 +/- 0.01 minutes(-1) for 75 wt percent, 62 wt percent, and 30 wt percent formulations, respectively. After fitting the three data points of k(1), k(2), and k(mix) to the 10 mixing rules in materials science--series mixing rule, Hashin and Shtrikman upper bound, logarithmic mixing, Looyenga mixing rule, effective media approximation (EMA), three-point lower bound, Torquato approximation, three-point upper bound, Maxwell mixing rule, and parallel mixing rule--we found that the selection of the best suited mixing rules based on k(1), k(2), and k(mix) was solely dependent on the formulations under a given operating condition and regardless of whether the system was a powder mixture or a granular mixture. The values of k(1), k(2), and k(mix) in both the 75 wt percent and 30 wt percent formulations were enveloped by the parallel mixing rule and Maxwell mixing rule, whereas the values of k(1), k(2), and k(mix) for the 62 wt percent formulation were encompassed by the logarithmic mixing rule, Hashin and Shtrikman upper bound, and the series mixing rule. Apparently, the best suited mixing rules could be used to predict the right proportions of either the powder mixture (Method I) or the granular mixture (Method II) for obtaining any other desired dissolution rate constant, k(mix), whose value fell in between the values of k(1) and k(2).