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

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.     

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.     

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 Dissolution Versus In Vivo Evaluation of Four Different Aspirin Products

Abstract

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.     

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.     

A Flow-Through Dissolution Approach to In Vivo/In Vitro Correlation of Adinazolam Release from Sustained Release Formulations

Abstract

A Copley? fraction collector and a Disotest? flow-through system were coupled to provide an automatic discrete sampling flow-through dissolution system for use both in the “open-loop” and “closed-loop” mode. The system was used to investigate the release characteristics of adinazolam in sustained release formulations using a pH 1.2 simulated gastric fluid (without enzymes) dissolution medium (USP XXI). These experimental formulations are designed to provide relatively slow to rapid drug release. The dissolution effluent was analysed off-line by reverse phase HPLC to determine the adinazolam concentration at programmed timed intervals. The differential dissolution profiles produced when the system is used in the “open-loop” configuration are more discriminating in describing the release characteristics of the formulations according to the relative release rates than the “closed-loop” cumulative profiles. Using the characteristic dissolution time parameter from the Weibull function, a better correlation with in vivo bioavailability data was achieved for the data from the system in the “open-loop” mode than when it was used in the “closed-loop” mode. In the “open-loop” mode the Weibull function characteristic dissolution time parameter yielded the best quantitative correlation with a correlation coefficient of 0.92 compared to a value of 0.85 for the “closed-loop” configuration     

A Flow-Through Dissolution Approach to In Vivo/In Vitro Correlation of Adinazolam Release from Sustained Release Formulations

A Copley^TM fraction collector and a Disotest^TM flow-through system were coupled to provide an automatic discrete sampling flow-through dissolution system for use both in the “open-loop” and “closed-loop” mode. The system was used to investigate the release characteristics of adinazolam in sustained release formulations using a pH 1.2 simulated gastric fluid (without enzymes) dissolution medium (USP XXI). These experimental formulations are designed to provide relatively slow to rapid drug release. The dissolution effluent was analysed off-line by reverse phase HPLC to determine the adinazolam concentration at programmed timed intervals. The differential dissolution profiles produced when the system is used in the “open-loop” configuration are more discriminating in describing the release characteristics of the formulations according to the relative release rates than the “closed-loop” cumulative profiles. Using the characteristic dissolution time parameter from the Weibull function, a better correlation with in vivo bioavailability data was achieved for the data from the system in the “open-loop” mode than when it was used in the “closed-loop” mode. In the “open-loop” mode the Weibull function characteristic dissolution time parameter yielded the best quantitative correlation with a correlation coefficient of 0.92 compared to a value of 0.85 for the “closed-loop” configuration     

A New Rapidly Absorbed Paracetamol Tablet Containing Sodium Bicarbonate. II. Dissolution Studies and In Vitro/In Vivo Correlation

ABSTRACT

The objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH 5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel® worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro–in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH 5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r = 0.773; p<.00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro–in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration–time profiles.     

Correlation Between Tablet Disintegration and In Vitro Dissolution

The effect of aging on the mechanical properties of tablets has not been thoroughly investigated in the past. A recent article (1) addresses this problem in respect to tries Icium phosphate tablets and exhibits the parameters of importance in tablet storage. Two of the aspects studied were dissolution and disintegration.     

Lonidamine Solid Dispersions: In Vitro and In Vivo Evaluation

ABSTRACT

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Preparation and In Vitro/In Vivo Evaluation of Gliclazide Loaded Eudragit Nanoparticles as a Sustained Release Carriers

ABSTRACT

The aim of this study was to formulate and optimize gliclazide-loaded Eudragit nanoparticles (Eudragit L100 and Eudragit RS) as a sustained release carrier with enhanced efficacy. Eudragit L 100 nanoparticles (ELNP) were prepared by controlled precipitation method whereas Eudragit RSPO nanoparticles (ERSNP) were prepared by solvent evaporation method. The influence of various formulation factors (stirring speed, drug:polymer ratio, homogenization, and addition of surfactants) on particle size, drug loading, and encapsulation efficiency were investigated. The developed Eudragit nanoparticles (L100 and RS) showed high drug loading and encapsulation efficiencies with nanosize. Mean particle size altered by changing the drug:polymer ratio and stirring speed. Addition of surfactants showed a promise to increase drug loading, encapsulation efficiency, and decreased particle size of ELNP as well as ERSNP. Dissolution study revealed sustained release of gliclazide from Eudragit L100 as well as Eudragit RSPO NP. SEM study revealed spherical morphology of the developed Eudragit (L100 and RS) NP. FT-IR and DSC studies showed no interaction of gliclazide with polymers. Stability studies revealed that the gliclazide-loaded nanoparticles were stable at the end of 6 months. Developed Eudragit NPs revealed a decreased t_min (ELNP), and enhanced bioavailability and sustained activity (ELNP and ERSNP) and hence superior activity as compared to plain gliclazide in streptozotocin induced diabetic rat model and glucose-loaded diabetic rat model. The developed Eudragit (L100 and RSPO) NP could reduce dose frequency, decrease side effects, and improve patient compliance.     

Comparative Evaluation of Four Dissolution Apparatus

Four dissolution methods, the rotating basket, the rotating paddle, the rotating basket with paddle and the stationary basket-rotating paddle, were evaluated using capsules and non-disintegrating pellets of salicylic acid. The agitation intensity produced by the rotating basket method was very low and differed significantly throughout the vessel. However, it did not differ significantly at different positions in the stationary basket-rotating paddle method. This method offered considerable advantages and hence appears to be a suitable alternative to the existing compendial methods which have limitations for evaluation of dosage forms which tend to float on the dissolution medium.     

Comparative Evaluation of Four Dissolution Apparatus

Abstract

Four dissolution methods, the rotating basket, the rotating paddle, the rotating basket with paddle and the stationary basket-rotating paddle, were evaluated using capsules and non-disintegrating pellets of salicylic acid. The agitation intensity produced by the rotating basket method was very low and differed significantly throughout the vessel. However, it did not differ significantly at different positions in the stationary basket-rotating paddle method. This method offered considerable advantages and hence appears to be a suitable alternative to the existing compendial methods which have limitations for evaluation of dosage forms which tend to float on the dissolution medium.     

In Vitro and In Vivo Evaluation of Glibenclamide in Solid Dispersion Systems

The purpose of this work is to improve the dissolution and bioavailability characteristics of glibenclamide as compared to Daonil® tablets (Hoechst). Solid dispersions of glibenclamide in Gelucire 44/14 (Formula 1) and in polyethylene glycol 6000 (PEG 6000) (Formula 2) were prepared by fusion method. In vitro dissolution studies showed that the dispersing systems containing glibenclamide and Gelucire 44/14 or PEG 6000 gave faster dissolution rates than the reference product Daonil. The in vivo bioavailability study was assessed in six healthy male volunteers in crossover design with a 1‐week washout period. Both formulas were found to be significantly different from Daonil with regard to the extent of absorption as indicated by the area under serum concentration‐time curve. Both formulas are not significantly different from Daonil with respect to time of peak plasma concentration (T_max). It is concluded from this pilot study that the ranking of the in vitro dissolution is similar to the ranking of in vivo availability. The ranking of the three preparations in term of dissolution rate and extent of absorption is as follows: Formula 2?>?Formula 1?>?Daonil.     

Development of Sustained-Release Tablets Containing Sodium Valproate: In Vitro and In Vivo Correlation

ABSTRACT

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

Critical Dissolution Tests of Oral Systems Based on Statistically Designed Experiments. II. In Vitro Optimization of Screened Variables on ER-Coated Spheres for the Establishment of an in Vitro/In Vivo Correlation

Abstract

The study was designed to optimize the effects of the screened in vitro dissolution variables agitation, temperature, osmolality, and polarity on the release of the neuroleptic compound remoxipride from extended release coated spheres. The variables were varied independently by means of a fractional factorial design. The in vitro tests were performed with the Basket method (USP). The polarity and the osmolality of the medium had significant effects on the dissolution rate of remoxipride. A statistical model was calculated based on the obtained dissolution in vitro. The model was then used to predict the in vitro conditions that most closely correlated with the dissolution rate of remoxipride in vivo, after administration of the formulation to 16 volunteers. The predicted in vitro conditions were experimentally verified, and an excellent association with the in vivo behavior of the formulation was found. Validation of the optimal in vitro conditions was performed on another batch of the formulation. The dissolution profile obtained showed a significant association with the corresponding dissolution profile in vivo. The use of statistically designed experiments in the development of critical dissolution tests for the establishment of in vitro/in vivo correlations seems to be a useful working approach, and supports further application to other oral solid systems.     

Evaluation of an in Vitro Dissolution and Permeation Apparatus for Oral Solid Pharmaceutical Dosage Forms

An apparatus based in the USP dissolution test, the F-C-SL apparatus (Ferreira-Costa-Sousa Lobo), was developed that allowed the simultaneous evaluation of the in vitro release and permeation of oral solid pharmaceutical dosage forms. The release rate in both dissolution devices (USP and F-C-SL apparatus) was evaluated with acetaminophen tablets. Different test conditions (stirring rate and solvent volume ratio) were investigated and no significant differences in acetaminophen release rate were found between these apparatuses. In the F-C-SL apparatus, the in vitro permeation kinetics of acetaminophen were evaluated using synthetic membranes and followed a zero-order kinetic.     

Relating In Vitro/In Vivo Data of Two Controlled-Release Metformin Formulations

This study was conducted to compare the bioavailability of two controlled-release metformin preparations (Diabetmin Retard and Glucophage Retard) and also to correlate the in vitro and in vivo data obtained with the two preparations. Twelve healthy volunteers participated in the study, conducted according to a completely randomized, two-way crossover design. The preparations were compared using area under the plasma concentration–time curve AUC_0?∞, time to reach peak plasma concentration T_max, and peak plasma concentration C_max, while correlation was determined between in vitro release and in vivo absorption. Diabetmin Retard demonstrated a slower rate of in vitro release, but a faster rate of in vivo absorption than Glucophage Retard. However, the in vivo absorption of both products was found to be slower than that of drug released in vitro. A satisfactory relationship could be established between the in vitro and in vivo results, but there was no rank order correlation. No statistically significant difference was observed between the two preparations in the parameters AUC_0?∞ and C_max. However, a slight but statistically significant difference was observed between the T_max values, but it may not be therapeutically significant. Moreover, the 90% confidence interval for the ratio of the logarithmic transformed AUC_0?∞ values, as well as the logarithmic transformed C_max values, of Diabetmin Retard over those of Glucophage Retard was within the acceptance criteria of 0.80–1.25.     

In Vitro/in Vivo Evaluation Of A Liquid Sustained Release Dosage Form Of Chlorpheniramine

Chlorpheniramine-resin complexes were coated with cellulose acetate butyrate to yield microcapsules with a geometric mean diameter of 346 μm. In vitro release rate of chlorpheniramine declined with increasing microcapsule size. Release of chlorpheniramine from the micropcapsules was faster in simulated gastric fluid (pH 1.2) than in simulated intestinal fluid (pH 7.5). A Chlorpheniramine solution administered by rapid intravenous injection to dogs exhibited a two phase decline in plasma drug concentration. A peroral solution resulted in a rapid rise to a peak followed by a sharp decline in plasma chlorpheniramine concentration. Peroral administration of a microcapsule suspension caused a rapid rise in plasma concentration, but prevented the fast decline.