Evaluation of In Vitro/In Vivo Correlation Utilizing a Rotating Basket-Paddle Dissolution Apparatus

Abstract

The desirability of good correlations of parameters derived from in vitro dissolution study with parameters derived from in vivo bioavailability study is well established in biopharmaceutics. Reports on several in vitro dissolution apparatus, including the two official USP/NF methods, have appeared in the literature over the years. However, none have been accepted as universal because each apparatus is useful only for the dissolution testing of a specific group of drugs or dosage forms. Comparative dissolution testing was performed using the rotating basket-paddle apparatus and the two official USP/NF apparatus.

A comparative bioavailability study was carried out on four batches of rapidly disintegrating tablets (Formulations A to D) of nitrofurantoin and perphenazine using rabbit as an animal model. Excellent rank order (qualitative) correlations were observed among all combinations of in vitro and in vivo parameters. With the drug nitrofurantoin, an excellent quantitative correlation was found between the dissolution halftime and Cmax or Tmax or AUC. Yet, a repeated run with perphenazine yielded excellent correlation between dissolution halftime and Cmax or Tmax, but poor correlation between dissolution halftime and AUC.     

In Vitro Dissolution Versus In Vivo Evaluation of Four Different Aspirin Products

The single dose pharmacokinetic characteristics of four aspirin formulations in humans were compared with their in vitro dissolution properties. The pharmacokinetic parameters were determined by measuring salicylate concentrations in the plasma. Dissolution was measured by using the USP XX single time point dissolution test. The four aspirin products were a commercial tablet, a commercial capsule, a capsule filled with a commercial granulation, and a slow dissolving capsule formulation that failed the USP dissolution specification. It was found that there was a poor correlation between the in vitro dissolution results and the in vivo computed pharmacokinetic parameter statistics. In vivo testing in humans showed that all of the formulations were bioequivalent in terms of half-life and AUC, and the capsule that failed to pass the dissolution specification was bioequivalent to two of the three products that did pass the specification with respect to the maximum plasma concentration. None of the products could be demonstrated to be bioequivalent with regard to the time to maximum plasma concentration. However, none of the in vivo differences between the four aspirin formulations were judged to be clinically significant. Therefore, while there was a poor relationship between the in vitro USP XX dissolution test results and the bioequivalence test results, from a practical viewpoint the dissolution test is a satisfactory manufacturing quality control test, since it can detect differences in in vitro dissolution prior to their having a significant clinical impact.     

Relationship Between Dissolution Rate and Bioavailability of Sustained-Release Ibuprofen Capsules

Dissolution studies of three marketed brands of ibuprofen sustained-release (SR) capsules were conducted on USP XIX dissolution apparatus 1, using buffers simulating the gastrointestinal tract (GIT) pHs. The products showed almost identical drug release pattern in dissolution studies. A single-dose crossover oral bioavailability study revealed statistically significant differences in C_max, T_max, AUC and percent bioavailability values among the SR products but no such differences are evident in the t_1/2a, K_a, t_1/2e, and K_e. Retard quotient values were used to evaluate the sustained-release nature of the products. Statistical moment parameters such as MRT, MAT, and MDT were related with the dissolution parameters. Statistically significant correlations were observed between MRT_{in vitro} and MRT_{in vivo} or MDT_{in vivo} T_50% and T_max; and T_90%, and C_max, or AUC¹²₀. The determination of MRT_{in vitro}, T_50%, and T_90%, may be useful as quality control parameters to which each batch of the ibuprofen SR products could be submitted.     

Testing of “In Vitro” Dissolution Behaviour of Microparticulate Drug Delivery Systems

No official dissolution method exists concerning microparticulate drug delivery systems. The purpose of this work is the evaluation of different dissolution methods commonly used to test the in vitro release behaviour of microparticulate drug delivery systems. The influence of different environmental conditions, as stirring speed, ionic strength and presence of surfactant, on drug release is also evaluated.

Four dissolution methods, based on different equipments (USP dissolution test apparatus, rotating bottle apparatus, shaker incubator, recycling flow through cell), are performed on the same batch of indomethacin loaded poly-D, L-lactide (PDLLA) microspheres prepared by spray drying. The results obtained with the methods tested show the influence of in vitro dissolution method employed and of the environmental conditions on drug release profile.     

Characterization of the In Vitro Dissolution of Some Commercial Sustained Release Theophylline Dosage Forms

A dissolution study of five commercial sustained release theophylline dosage forms, concerning their pH dependency, is described. The experiment was carried out in a flow through dissolution apparatus, at constant pH and at pH gradient, being the pH values of 1, 2, 6, 5 and 7, 5. In both cases, they were treated in terms of the dissolution profile and the dissolution rate, complemented with the dissolution efficiency at pH gradient in order to make a correlation with the in vivo experiments that will be done in the future. The absorbance was measured at a wavelength of 264 nm. According to the results obtained, was selected the best pharmaceutical form, concerning the pH dependency and taking as a basis, just, the in vitro experiments.     

Comparison of In VitroRelease Rates of Multisource Sustained-Release Papaverine Hydrochloride Products

The extent of differences in the In vitro release rate among 24 lots of 150 mg sustained-release papaverine hydrochloride products from six manufacturers was investigated.

The rotating bottle method for timed-release capsules, official in N.F. XIV, was used. Quantitation of papaverine hydrochloride in solution was done using ultra-violet spectrophotometry at two wavelengths to assure that there was no interference from other components of the formulation.

While in vitro dissolution data by itself cannot predict in vivo performance, variations from one manufacturer to another and also for the same manufacturer were observed. These included variations in the amount released both in the first hour and also in the total amount released.

Of the six products tested, Pavabid and Cerespan demonstrated the most consistent release patterns with slightly better consistency observed for the former. Observed differences may or may not be of clinical significance.     

Correlation of Urinary Excretion with in Vitro Dissolution Using Four Dissolution Methods for Aiipicillin Capsules

The in vitro release of ampicillin from 8 brands of ampicillin capsules, using four dissolution apparatus, was determined. These apparatus were the USP dissolution apparatus, the USP paddle stirrer apparatus, the USP disintegration apparatus and the spiral—stirrer apparatus. Significance of the differences in dissolution between brands and between methods were tested. Analysis of variance of the dissolution data showed statistically significant differences between brands and between methods at selected time. The paddle method showed superior discriminating capacity than the other methods. Correlation between the present in vitro data and the previously reported in vivo data, in order to find the apparatus capable to mimic in vivo release of ampicillin from capsules, was also determined.     

An Application of Transdermal Antiviral Delivery Systems to the Establishment of a Novel Animal Model Approach in the Efficacy Evaluation for Dermatological Formulations

This report described the establishment and the examination of a novel hairless mouse model in the efficacy evaluation for topical antiviral dosage forms with a focus on the relationship between the in vitro dermal flux of the antiviral agent and the in vivo antiviral efficacy. A unique dose/flux-efficacy relationship in topical antiviral treatment was obtained by applying a series of transdermal acyclovir delivery systems (TADS) for the treatment of cutaneous herpes simplex virus type 1 infected hairless mouse in our earlier study. By konwing the pharmacokinetic parameters of acyclovir in hairless mouse and the flux (J) of a suitable TADS, the skin target site concentration (C*) could be calculated for that patch. With the corresponding C* value, the in vivo permeability coefficient (P_{d,in vivo}) of that patch could be calculated from P_{d,in vivo} = J/C*. The difference between this in vivo permeability coefficient and the in vitro permeability coefficient (P_{d,in vivo}. obtained from in vitro diffusion experiment) was considered due to the blood flow effect in the in vivo condition. This P_{d,in vivo} can be further applied to calculate the C* value of any acyclovir topical formulation with flux, J', from C'*=J'/P_{d,in vivo}, where the C'* represents the calculated skin target site concentration for any acyclovir topical formulation. After knowing different C* values of different dermatological formulations of acyclovir, the efficacy of each formulation can be estimated from the dose/flux-efficacy relationship. Two formulations with different fluxes were examined under this study. The results showed very good correlation between the in vitro acyclovir flux and the in vivo antiviral efficacy and the applicability of this model approach was validated.     

A Critical Assessment of the Usp Dissolution Apparatus Suitability Test Criteria

This report describes results of a survey conducted to assess the variability in drug release from the USP calibrators and its dependence on various deaeration methods. The calibrator data submitted by 33 laboratories, involved tests of 1659 sets (6 or 12 tablets/set) from four lots of prednisone and salicylic acid each, using apparatuses 1 & 2 run at 50 and 100 rpm. Overall variabilityranges for the individual sets, which met the USP dissolution apparatus Suitability Criteria, were 0.5-31.3% for prednisone/apparatus 1, 0-13.2% for salicylic acid/apparatus 1, 0.3-10.2% for prednisone/apparatus 2 and 0.7-20.2% for salicylic acid/apparatus 2. The results of this survey suggest that variability levels are dependent on apparatus/calibrator combination. Although deaeration of dissolution media tends to reduce the failures i.e. not meeting the Suitability Criteria, its effect on reducing the variability appears to be minimal. Among the various deaeration methods reported, degassing the media by a combination of heating with helium sparging or with filtering under vacuum tend to give the lowest failure rate. From our findings, a variability of up to 31% CV (coefficient of variation) in percent drug release for the calibrator can occur with the samples still meeting the USP criteria. However, if the apparatus/calibrator combination is taken into consideration with appropriate deaeration method, the maximum expected variability can be reduced to 10% or less. The results of this survey show that rather than an eight point dissolution calibration test criteria, a four point evaluation system i.e. testing non-disintegrating tablets with apparatus 1 and disintegrating tablets with apparatus 2 may provide sufficient information for system suitability. It is also recommended that a similar formulation/apparatus combination should be considered for drug products evaluation which might yield less variable results with an improved potentials of in vitro/in vivo correlations particularly for modifieddrug release products.     

In Vitro Release of Hydrochlorothiazide from Capsule Formulations

Five different hydrochlorothiazide (50mg. per capsule) capsule formulations were prepared with one of the following diluents: corn starch, dibasic calcium phosphate, lactose, microcrystalllne cellulose, or sodium carboxymethyl starch. A comparative dissolution study was conducted using the USP procedure. Significant differences (p = 0.05) were found among the formulations relative to in vitro dissolution rates over a two-hour sampling period. The formulations prepared with lactose consistently ranked near the top (Newman-Keuls multiple range test) while the formulation prepared with sodium carboxymethyl starch ranked last at each sampling time except 3 min.     

Evaluation of Pharmaceutical Quality of Prednisone Tablets from Multinational Market

This report describes results of a collaborative study in which samples of the 5 mg strength of prednisone tablets were evaluated following a common protocol based on European (Ph. Eur.) and US Pharmacopeial (USP) specifications. Several tests including, identification, content uniformity and dissolution were performed. Laboratories from 16 countries submitted data representing 42 products obtained from the respective local markets. There were no reported abnormalities in general appearance and identification of the products evaluated. Most products met the requirements for assay and content uniformity. Dissolution results showed that 11 lots did not meet the USP S1 stage Tolerance Criterion, whereas products from Greece (one lot) and Sweden (two lots) would not meet the dissolution requirement of USP even at the S3 stage, i.e. these lots would be rejected. Overall variability (% CV) in percent drug release values at different sampling times for the tested products and those of USP calibrator tablets were not significantly different from each other. To assess the potential effect of dissolution characteristics on in vivo bioavailability, the percent drug release values were also evaluated using a logarithmic-probability     

Evaluation of dosage forms. VI. Studies of commercial oxyphenbutazone tablet dosage forms.

Dissolution-dialysis studies of commercial tablets of oxyphenbutazone were carried out to establish the applicability of this technique for the in vitro evaluation of oxyphenbutazone dosage form. While disintegration time and dissolution rate studies did not give a true indication of bioavailability, an excellent correlation was obtained between the dialysis rate constant K and the pharmacokinetic parameters AUC and Cmax.     

The Effect of Formulation on 1-131 Dissolution In Vitro from Sodium Iodide Capsules

Because of the importance of the bioavailability of 1-131 for thyroid uptake studies and thyroid therapy, the present investigation was conducted to determine the influence of diluents, type of lubricant and the concentration of lubricant on the in vitro release rate of 1-131 from 1-131 sodium iodide capsules. Formulations and 1-131 sodium iodide capsules were prepared in-house and dissolution profiles determined using the U.S.P. XXII Dissolution Test. Distilled water was employed as the solvent. Lactose only, calcium phosphate only, a mixture of dicalcium phosphate—Avicel PH 101 and a sodium phosphate formulation consisting of lactose, L-cysteine hydrochloride and sodium phosphate were chosen as diluents. Several concentrations of the lubricant magnesium stearate were employed. The influence of 3% or 5% talc as the lubricant was studied using the sodium phosphate formulation.

The results of the study demonstrated the influence of the formulation on the dissolution of 1-131 when the concentration of magnesium stearate was held constant. This was particularly noted at a 3% concentration and to a lesser degree at a 1% concentration of magnesium stearate. The dissolution rate for 1-131 from capsules prepared with the sodium phosphate—Avicel PH 101 formulation was slow and not influenced by varying the concentration of magnesium stearate. Using talc as the lubricant resulted in 1-131 dissolution rates that were rapid for the sodium phosphate formulation. Based upon the findings it is apparent that the diluent and the lubricant can influence the dissolution rate of 1-131 from sodium iodide labeled capsules. The relationship of in vitro dissolution profiles should be compared to the bioavailability of 1-131 in animals to ascertain the importance of formulation in thyroid function studies and treatment.     

A new in vitro/in vivo kinetic correlation method for nitrofurantoin matrix tablet formulations

The kinetic distributions of in vitro percentage release and in vivo percentage urinary excretion rates of nitrofurantoin from matrix tablets were plotted using a kinetic program. In vitro release rates were determined using the USP paddle and half-change methods. Urinary excretion curves of the drug were characterized by means of the statistical moments. The individual linear correlations between each in vitro and in vivo kinetic distribution were established, and regression equations were calculated. The application results of the best correlations obtained were evaluated according to in vivo results. A reversed kinetic procedure was applied for transformation of the correlated kinetic values to the drug percentage release rates. The modified Langenbucher kinetic showed excellent linear correlation (r = .9985). The method that is proposed in this study, the kinetic correlation program, is simple, independent of time, and suggests that it is possible to use kinetic distributions in the in vitro/in vivo correlation. This study also suggests using kinetic correlation to investigate the suitability of the in vitro dissolution methods with the in vivo drug dissolution.     

Advances in Dissolution Technology: Design, Pros and Cons

To date dissolution tests are considered to be the most reliable predictors of bioavailability of drugs. Dissolution tests are critical and difficult to carry out properly. A review of different dissolution apparatii currently in use or employed in the past is present along with the advantages and disadvantages offered by each. Criteria as to design, operation, sensitivity, etc. of an in vitro dissolution system are outlined which would assist in fabrication of a more efficient and reliable apparatus. If one is to obtain meaningful results, care and attention must be given to those aspects that have been identified as crucial. To date no universal dissolutiuon test has yet been devised that in every instance gives the same rank order for in vitro dissolution and in vivo availability for different formulation and batches.     

Moment Analysis for the Evaluation of In Vitro Drug Release and In Vivo Bioavailability of Theophylline Microcapsules

Abstract

Statistical moment analysis has been used to establish an in vitro-in vivo correlation for five types of theophylline ethylcellulose microcapsules prepared by using various concentrations of ethylene-vinyl acetate (EVA) copolymer as a coacervation-inducing agent. The concentration of EVA copolymer was found to be played an important function in the controlled release of theophylline microcapsules. Correlations were found between the in vitro dissolution behavior, e.g., MDT _0→7, in vitro' and the rate of bioavailability, e.g., Cmax, Tmax, MDT _{in vivo} or MRT_0→2, although there was no valid correlation with the extent of bioavailability, e.g., AUC_0→27. Thus, moment analysis by studying the quantitative in vitro-in vivo correlations relating to drug release was validated.     

Design and Evaluation of a Rotating Basket-Paddle Dissolution Apparatus

The rotating basket-paddle dissolution apparatus is a combination of the USP/NF rotating basket and rotating paddle. A comparative dissolution study was performed utilizing this new apparatus and the two USP/NF apparatus at various stirring speeds using non-disintegrating oxalic acid tablets and disintegrating aspirin tablets. The amount of drug released using the new apparatus was significantly higher than the rotating basket but significantly lower than the rotating paddle at each of the stirring speeds studied. The results obtained using this new apparatus were highly reproducible compared to the USP/NF apparatus.     

Assessment of Transport Barriers Using Cell and Tissue Culture Systems

The delivery of the next generation of drugs, particularly polar peptides and proteins, will represent a major challenge to the pharmaceutical scientists. To successfully deliver these potential drugs to specific targets, strategies will have to be developed to circumvent epithelial (e.g., intestinal, buccal, nasal, epidermal) and endothelial (e.g., vascular) cells, which represent both physical and metabolic barriers. This presentation will focus on the possible utility of cultured epithelial and endothelial cells to screen the permeability properties of potential drug candidates, to elucidate transcellular transport mechanisms, to evaluate the potential cellular site of metabolism, and to test strategies to prevent metabolism and/or to enhance the permeability properties of drug candidates. Topics to be discussed include: (a) advantages and disadvantages of cell culture systems; (b) factors important in selecting an appropriate cell culture system which will mimic the in vivo biological barrier; (c) characterization and validation of in vitro cell culture model systems; (d) factors important in selecting a porous membrane and a diffusion apparatus for transcellular transport studies; (e) the effect of cell culturing conditions on the transport characteristics of cultured cells; and (f) factors important in interpretation of in vitro cell culture data.     

Design and Evaluation of a Rotating Basket-Paddle Dissolution Apparatus

Abstract

The rotating basket-paddle dissolution apparatus is a combination of the USP/NF rotating basket and rotating paddle. A comparative dissolution study was performed utilizing this new apparatus and the two USP/NF apparatus at various stirring speeds using non-disintegrating oxalic acid tablets and disintegrating aspirin tablets. The amount of drug released using the new apparatus was significantly higher than the rotating basket but significantly lower than the rotating paddle at each of the stirring speeds studied. The results obtained using this new apparatus were highly reproducible compared to the USP/NF apparatus.     

“In Vitro” - “In Vivo” Correlations of Eight Nitrofurantion Tablet Formulations: Effect of Various Technological Factors

The bioavailability of eight nitrofurantoin tablet formulations differing in technological respects has been evaluated and correlated with de dissolution curves obtained using USP XXI Ed methods I and II. Method I was found incapable of predicting bioavailability of formulations when Carbopol 934 is used as binder. The influence of the technological factors varied is discussed.