Dissolution Rates of Commercial Phenylbutazone Tablets: Inter-And Intra-Brand Effects

Abstract

A study has been carried out to investigate the dissolution rate profiles of twelve batches of sugar-coated phenylbutazone tablets belonging to four commercial brands. Using the rotating basket method, significant inter-brand and inter-batch variations in dissolution rates were found. Only two batches of one brand passed the B.P. dissolution limit whilst other batches had percentages dissolution between 0.3 and 58 after 45 min. Batches with poor dissolution characteristics exhibited significant tablet-to-tablet variations in dissolution rates; a finding which was not observed in the relatively fast-dissolving batches. When the paddle method was substituted for the B.P. basket method, the dissolution rates were relatively faster but similar dissolution failure was found. However, the tablet-to-tablet dissolution variability was decreased in some of the batches. The observed differences in dissolution rates of the batches examined were unrelated to their disintegration times. Inspite of the poor dissolution characteristics of most of the batches studied, no apparent chemical degradation was found. It is recommended that when evaluating the dissolution rates of brands of phenylbutazone tablets, a number of batches from each brand should be tested.     

Dissolution Rates of Commercial Phenylbutazone Tablets: Inter-And Intra-Brand Effects

A study has been carried out to investigate the dissolution rate profiles of twelve batches of sugar-coated phenylbutazone tablets belonging to four commercial brands. Using the rotating basket method, significant inter-brand and inter-batch variations in dissolution rates were found. Only two batches of one brand passed the B.P. dissolution limit whilst other batches had percentages dissolution between 0.3 and 58 after 45 min. Batches with poor dissolution characteristics exhibited significant tablet-to-tablet variations in dissolution rates; a finding which was not observed in the relatively fast-dissolving batches. When the paddle method was substituted for the B.P. basket method, the dissolution rates were relatively faster but similar dissolution failure was found. However, the tablet-to-tablet dissolution variability was decreased in some of the batches. The observed differences in dissolution rates of the batches examined were unrelated to their disintegration times. Inspite of the poor dissolution characteristics of most of the batches studied, no apparent chemical degradation was found. It is recommended that when evaluating the dissolution rates of brands of phenylbutazone tablets, a number of batches from each brand should be tested.     

Dissolution of Manganese Oxides of Various Compositions in Sulfuric Acid Solutions Studied by Kinetic Methods

The dissolution of manganese oxides in sulfuric acid solutions of various concentrations has been studied by kinetic methods. We have investigated the dissolution of manganese oxides of various compositions in sulfuric acid solutions of various concentrations. The composition of the manganese oxides and the sulfuric acid concentration have been shown to influence the dissolution rate. We have calculated kinetic parameters of the dissolution of manganese oxides in sulfuric acid solutions (dissolution rate, activation energy for dissolution, and reaction orders) and proposed a model for the dissolution of manganese oxides in sulfuric acid solutions.     

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     

Influence of selected water soluble carbohydrates on the dissolution profile of prednisolone

The utilization of three water soluble carbohydrates as carrier to improve the dissolution rate of prednisolone was studied. Coprecipitates and physical mixtures of the drug and the carriers in three different proportions were prepared and their dissolution profile was compared with the dissolution profile of the pure drug. The remarkably fast and erratic dissolution of prenisolone observed from the coprecipitates was possible due to the conversion of prednisolone into its metastable or amorphous form durning the coprecipitation process. The dissolution rate of the drug from the physical mixtures was much higher than from the pure drug itself. Effect of aging of the coprecipitate on the dissolution profile showed an increasing tendency of the dissolution curve to match with that of the corresponding physical mixture.     

Influence of selected water soluble carbohydrates on the dissolution profile of prednisolone

Abstract

The utilization of three water soluble carbohydrates as carrier to improve the dissolution rate of prednisolone was studied. Coprecipitates and physical mixtures of the drug and the carriers in three different proportions were prepared and their dissolution profile was compared with the dissolution profile of the pure drug. The remarkably fast and erratic dissolution of prenisolone observed from the coprecipitates was possible due to the conversion of prednisolone into its metastable or amorphous form durning the coprecipitation process. The dissolution rate of the drug from the physical mixtures was much higher than from the pure drug itself. Effect of aging of the coprecipitate on the dissolution profile showed an increasing tendency of the dissolution curve to match with that of the corresponding physical mixture.     

Retardation of Polymeric Carrier Dissolution by Dispersed Drugs: Factors Influencing the Dissolution of Solid Dispersions Containing Polyethlene Glycols

Molecular weight is an important determinant of plyethylene glycol (PEG) dissolution rate: the rate decreasing as the molecular weight is increased. PEG samples of equivalent nominal. molecular weight had different dissolution properties. Intrinsic viscosity and differential scanning calorimetry suggested that the observed differences my be related to molecular weight variation between samples. The dissolution rate of PEG from solid dispersions is retarded, the effect being dependent on the chemical nature of the drug and its concentration. Phenobarbitone was particularly potent in retarding PEG dissolution. Phenobarbitone dissolution rate was retarded from dispersions of high phenobarbitone content. However drug dissolution from solid dispersions low in phenobarbitone were greater than that of pure phenobarbitone. The low dissolution rates were explained in terms of formation of the 2:1 PEG monomer: phenobarbitone complex during solid dispersion formation. At high PEG weight fractions (i.e. 30:1, 50:1) drug dissolution was carrier controlled and although PEG dissolution was greatly suppressed, it was sufficiently large to transport the drug into solution at a rate greater than that of pure phenobarbitone.     

Retardation of Polymeric Carrier Dissolution by Dispersed Drugs: Factors Influencing the Dissolution of Solid Dispersions Containing Polyethlene Glycols

Molecular weight is an important determinant of plyethylene glycol (PEG) dissolution rate: the rate decreasing as the molecular weight is increased. PEG samples of equivalent nominal. molecular weight had different dissolution properties. Intrinsic viscosity and differential scanning calorimetry suggested that the observed differences my be related to molecular weight variation between samples. The dissolution rate of PEG from solid dispersions is retarded, the effect being dependent on the chemical nature of the drug and its concentration. Phenobarbitone was particularly potent in retarding PEG dissolution. Phenobarbitone dissolution rate was retarded from dispersions of high phenobarbitone content. However drug dissolution from solid dispersions low in phenobarbitone were greater than that of pure phenobarbitone. The low dissolution rates were explained in terms of formation of the 2:1 PEG monomer: phenobarbitone complex during solid dispersion formation. At high PEG weight fractions (i.e. 30:1, 50:1) drug dissolution was carrier controlled and although PEG dissolution was greatly suppressed, it was sufficiently large to transport the drug into solution at a rate greater than that of pure phenobarbitone.     

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     

Preparation and in Vitro Dissolution Profiles of Tolazamide-Polyethylene Glycol Solid Dispersions

The objective of this study is to prepare solid dispersions of tolazamide (TLZ) using polyethylene glycol (PEG) and measure the dissolution of TLZ. PEG 8000 was used as carrier to prepare solid dispersions by melt and solvent methods. Dissolution studies indicated a remarkable increase in the rate of dissolution of TLZ when dispersed in PEG as well as with physical mixture of TLZ and PEG. The rate of dissolution of TLZ was faster with solid dispersions containing TLZ:PEG (1:5) and (1:10) compared to physical mixtures and pure TLZ. The effect of buffer on dissolution was studied. In general the dissolution of TLZ was less in phosphate buffered saline (PBS, pH 7.4) compared to Tris buffer. However, there was no significant difference in the extent of dissolution of TLZ from solid dispersions and physical mixture compared to pure TLZ. Solid dispersions prepared by solvent method showed faster dissolution rates compared to melt method. These results suggest that the rate of dissolution can be increased by improving the wetting property of tolazamide.     

Comparison of Three Dissolution Devices for Evaluating Drug Release

Abstract

The dissolution studies are usually conducted on “official” USP dissolution devices or “non-official” dissolution devices like the Rotating Bottle Apparatus. The recent introduction of the Bio-Dis® Tester exacerbates a difficult situation : no comparative dissolution studies have been done regarding the results for a drug and/or dosage form using these three different instruments. The purpose of this investigation was to evaluate and compare three dissolution devices - USP XXI Dissolution Apparatus II, Rotating Bottle Apparatus, and Bio-Dis® Tester -taking into account pertinent factors that can affect dissolution. Dissolution profiles were obtained for two drugs - theophylline and phenylpropanolamine HCI. Three dosage forms of each drug were evaluated at different agitation intensities using two different dissolution media (simulated gastric fluid and simulated intestinal fluid) on all three dissolution devices. Various advantages/limitations for each device were observed depending on the drug, dosage form, agitation speed and dissolution medium.     

Multivariate chemometric approach to fiber-optic dissolution testing

The use of fiber optics in in vitro dissolution testing opens up new possibilities for more powerful data evaluation since an entire UV-Vis spectrum can be collected at each measuring point. This paper illustrates a multivariate chemometric approach to the solution of problems of interfering absorbance of excipients in in vitro dissolution testing. Two different chemometric approaches are tested: multivariate calibration using partial least squares (PLS) regression and curve resolution using multivariate curve resolution alternating least squares (MCR-ALS), generalized rank annihilation (GRAM), and parallel factor analysis (PARAFAC). Multivariate calibration (PLS) can, following the construction of a calibration model from a calibration sample set, give selective and accurate determinations of the active ingredient in dissolution testing despite the presence of interfering absorbance from excipients. Curve resolution (MCR-ALS, GRAM, or PARAFAC) can be applied to dissolution testing data in order to determine the dissolution rate profiles and spectra for the interfering excipients as well as for the active ingredient without any precalibration. The concept of the application of these chemometric methods to fiber-optic dissolution testing data is exemplified by analysis of glibenclamide tablets enclosed in hard gelatin capsules. The results show that, despite highly overlapping spectra and unresolved raw data, it is possible with PLS to obtain an accurate dissolution rate profile of glibenclamide. Applying curve resolution makes it possible to obtain accurate estimates of both dissolution rate profiles and spectra of both the gelatin capsule and the glibenclamide. The application of multivariate chemometric methods to fiber-optic dissolution testing brings a fresh scope for a deeper understanding of in vitro dissolution testing, solving the problem of interfering absorbance of excipients and making it possible to obtain dissolution rate profiles and spectra of these. Obtaining dissolution rate profiles of multiple active pharmaceutical ingredients in tablets consisting of several active compounds is another possibility.     

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

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.     

Tablet-to-Tablet Dissolution Variability and its Relationship to the Homogeneity of a Water Soluble Drug

The homogeneity of a water soluble drug in a tablet granulation was studied by mixing the granulated drug with excipients in a V-shaped tumbling mixer. Samples were withdrawn from five different locations of the mixer for homogeneity and dissolution studies at different mixing times. For dissolution studies, tablets were compressed at a constant compression load. Qualitatively, the coefficient of variation of mixing and dissolution looked similar, suggesting that the mixing homogeneity may have some relationship to the tablet-to-tablet dissolution variability. The addition of magnesium stearate resulted in an increase in the coefficient of variation of mixing and a decrease in the dissolution rate. A large decrease in the dissolution rate occured during the first minute of mixing with the magnesium stearate. The tablet crushing strength continuously decreased during the first 10 minutes of mixing with the magnesium stearate. The results suggested that the formulation in which a major portion of the excipients was not wet granulated with the drug resulted in higher tablet-to-tablet dissolution variability. The addition of sodium starch glycolate or sodium carboxymethyl cellulose to starch for enhancing disintegration neither improved the tablet-to-tablet dissolution variability nor increased the rate of drug dissolution.     

Effect of Dissolution Rate and Food on Oral Bioavailability of Bropirimine Tablets in Dogs

Abstract

Three different tablet formulations of bropirimine were evaluated in an in vitro dissolution study. Further, the effect of dissolution rate of bropirimine and food on the bioavailability after oral administration of the tablets was investigated in dogs. A tablet formulation with lower bropirimine content percent and smaller tablet size showed faster in vitro dissolution rate due to the larger tablet surface area per unit mass of bropirimine and the higher ratio of hydrophilic excipients in a tablet. In the fasted state, the bioavailability of bropirimine after oral administration of tablets tended to reflect the in vitro dissolution characteristics. The bioavailability after administration of tablets with slow in vitro dissolution rate was increased by food intake due to the in vivo dissolution increased in the fed state, while the postprandial effect on the bioavailability of tablets with fast in vitro dissolution rate was not clearly observed. In the fed state, there were no differences in the plasma concentration profile and pharmacokinetic parameters of bropirimine between the tablets with a slow and a fast in vitro dissolution rate. This suggests that the postprandial administration of bropirimine tablets may maximize the bioavailability without distinction of the in vitro dissolution rate.     

Dissolution Rate of Polymorphs and Two New Pseudopolymorphs of Sulindac

This study reports the enhancement of sulindac dissolution rate by using the acetone and chloroform solvated forms. me intrinsic dissolution rates of potymorphs I and II and the influence of crystal habit on the drug dissolution process have also been studied. The dissolution properties were studied by calculating the intrinsic dissolution rate (k) by linear regression analysis from the amount dissolved versus time. The results indicated that the intrinsic dissolution rates of solvates in acetone and chloroform were much higher (k = 0.076 mg min^-1cm-², respectively) than those of polymorphs I and II (k = 0.036 mg min^-1cm^-2). However, the dissolution rates of the two solvates were found to be essentially the same and independent of the solvent nature. The intrinsic dissolution rates of form II recrystal-lized in methanol and ethanol differed (k = 0.031 and 0.036 mg min^-1cm^-2, respectively), which confirms the influence of crystal habit on sulindac dissolution rate. No significant difference in dissolution profiles were observed between forms I and II, in agreement with the similar values of fusion cemperature (1187 and 183°C respectively.     

Effect of Granulating Method on Dissolution Rate of Compressed Tablets. III

The dissolution rates of dexamethasone granules prepared by all the methods were slower than the dissolution rates of the corresponding tablets. This was shown to be the result of a reduction of the average particle size on compaction. The dissolution rates of sulfadiazine tablets prepared by microgranulating and slugging were slower than the corresponding granules. This was demonstrated to be the result of enlargement of the granules on compaction. For both drugs the microgranulating procedure gave the most rapid dissolution of tablets and granules. In case of the dexamethasone formulation, direct compression exhibited the slowest dissolution rate. The dissolution rates of sulfadiazine granules and tablets prepared by the wet granulating method were also unsatisfactory.     

Dissolution or disintegration – substitution of dissolution by disintegration testing for a fixed dose combination product

According to International Council for Harmonisation (ICH) guideline Q6A, dissolution testing can be replaced by disintegration testing if it can be shown that the active pharmaceutical ingredient is highly soluble and the formulation is rapidly releasing. In addition, a relationship between dissolution and disintegration has to be established. For a fixed-dose combination tablet of empagliflozin and linagliptin, this relationship was established by applying two different approaches. In the first approach, the extent to which the disintegration process of the film-coated tablets contributes to the release of the active ingredients was investigated. In the second approach, the mean disintegration times in a disintegration tester were correlated with the mean dissolution rates at a selected sampling time point. By correlating disintegration times in the dissolution vessel with the dissolution rate at selected sampling times it is demonstrated that the disintegration into primary particles is the rate limiting step for the dissolution process. A direct correlation of disintegration times in the disintegration tester with dissolution rate at a selected sampling time is established supporting a relationship between dissolution and disintegration testing for this type of formulation. Additionally, it could also be shown that the disintegration test method exhibits at least a similar discriminatory power compared to the proposed dissolution method. Based on a statistical approach and data from a bioavailability study, a clinical relevant specification for the disintegration time was established. All presented data support the replacement of dissolution by disintegration testing according to ICH Q6A for the selected fixed-dose combination product.     

Effect of Granulating Method on Dissolution Rate of Compressed Tablets. III

Abstract

The dissolution rates of dexamethasone granules prepared by all the methods were slower than the dissolution rates of the corresponding tablets. This was shown to be the result of a reduction of the average particle size on compaction. The dissolution rates of sulfadiazine tablets prepared by microgranulating and slugging were slower than the corresponding granules. This was demonstrated to be the result of enlargement of the granules on compaction. For both drugs the microgranulating procedure gave the most rapid dissolution of tablets and granules. In case of the dexamethasone formulation, direct compression exhibited the slowest dissolution rate. The dissolution rates of sulfadiazine granules and tablets prepared by the wet granulating method were also unsatisfactory.     

Influence of Dissolution Medium Agitation on Release Profiles of Sustained-Release Tablets

Reaching nearly perfect sink conditions is very important in the determination of drug dissolution rates. Many times, the only factor that is taken into consideration in achieving sink conditions is the relation between the drug concentration and its solubility. The analytical conditions of the dissolution assay, as well as the dissolution apparatus, stirring speed, and nature and volume of the dissolution fluid may also influence the dissolution results. The main objective of this work was to study the influence of the stirring rate conditions and of the dissolution apparatus in the diltiazem hydrochloride release from tablets. Diltiazem hydrochloride sustained-release (SR) tablets were tested and the following dissolution parameters were evaluated: t_10%, t_25%, t_50%, dissolution time, mean dissolution time (MDT), and dissolution efficiency (DE) at t₁₂₀, and at t₃₆₀. To analyze the release mechanism, several release models were tested, such as Higuchi, zero order, first order, Baker-Lonsdale, Hixson-Crowell, Weibull, and Korsmeyer-Peppas. The similarities between two in vitro dissolution profiles were assessed by the similarity factor f₂. The in vitro release kinetics of diltiazem hydrochloride sustained-release tablets were evaluated using the USP 2 (paddle) and USP 4 (flow-through) apparatus.