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.     

Dissolution Behaviour of Indomethacin Capsule Formulations: Comparison of Two Types of Usp Apparatus

Abstract

The dissolution behaviour of indomethacin from six commercial brands of indomethacin capsules, using the USP rotating basket apparatus and the USP paddle apparatus have been studied. The products showed marked differences in their dissolution profiles. The dissolution rates have been different in different brands, and variation has also been observed depending on the method of testing used. The rotating basket apparatus showed superior discriminating capacity than the paddle method.     

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.     

Studies on the Delivery Mechanisms of Theophylline from a Sustained Release Tablet

The in-vitro and in-vivo release of theophylline from an oral sustained release tablet (Theograd^R) was studied.

The in-vitro release profiles were determined by means of the rotating basket method, the paddle method and the modified disintegration method, described in the USP XX as apparatus 1, 2 and 3 respectively. Besides a stationary basket-rotating paddle method was used.

It was demonstrated that in the stationary basket-rotating paddle apparatus and in the paddle apparatus at low rotational speeds of the paddle, mild agitation conditions were created. Under these conditions the release of theophylline from the sustained release tablet appeared to be matrix controlled. The leached matrix was found to be structurally very weak. For a matrix type of sustained release tablet this is probably beneficial as it would be less likely to cause accumulation and gastro-intestinal obstruction. In contrast the conditions of agitation in the rotating basket apparatus and in the disintegration apparatus were found to be rather severe. This was partly due to mechanical abrasion of the dosage form caused by the gauze of the basket and the basket-rack respectively, and partly the result of high solvent agitation, especially in the disintegration apparatus. Under these conditions it appeared that the empty matrix of the sustained release tablet eroded during the release process. This was confirmed by the results of studies under non-dissolving circumstances of the drug which showed that in this case only the leached matrix of the sustained release dosage form eroded and not that part of the dosage form from which the drug had not yet been dissolved. The in-vivo absorption appears to relate to the in-vitro release. When the Theograd tablet was taken on an empty stomach, it appeared that the absorption rate could succesfully be simulated by means of the stationary basket-rotating paddle method and the paddle method, both at low rotational speeds of the paddle. It was very likely that in this case the in-vivo release from the sustained release tablet was matrix controlled too. Under these conditions the bioavailability was found to be 65% compared with an oral solution of the drug. In contrast, when the Theograd tablet was taken after a meal, a relative bioavailability of 90% was observed. It was made plausible, that the greatly enhanced bioavailability, observed on postprandial administration of the tablet, was due to partial erosion of the leached matrix. This erosion was caused by the food induced increased motility of the gastro-intestinal tract. Based on the results of this study it is recommended to take Theograd^R tablets after a meal.     

Effect of pH on Theophylline Release from Partially Esterifted Alginic Acid Matrices

The effect of dissolution medium pH on theophylline release from co-compressed matrices composed of a 40% benzyl ester of alginic acid was investigated using both the USP rotating paddle method and a modification of the USP rotating basket method. Release rates for each pH were compared using a measure of the time for approximately 80% release (t80%). Results show release of theophylline from these matrices to be significantly slower at pH 1 than at pH 2 and above. Beyond pH 2, drug release is relatively insensitive to dissolution medium pH but is affected by dissolution method because of the tendency of the alginate to form an adhesive, gel-like layer at pH values higher than four. The drug release characteristics of this polymer, under various pH conditions, make it potentially suitable for use in delayed/controlled release oral delivery systems containing compounds that are acid labile or irritating to the gastric mucosa.     

Effect of pH on Theophylline Release from Partially Esterifted Alginic Acid Matrices

The effect of dissolution medium pH on theophylline release from co-compressed matrices composed of a 40% benzyl ester of alginic acid was investigated using both the USP rotating paddle method and a modification of the USP rotating basket method. Release rates for each pH were compared using a measure of the time for approximately 80% release (t80%). Results show release of theophylline from these matrices to be significantly slower at pH 1 than at pH 2 and above. Beyond pH 2, drug release is relatively insensitive to dissolution medium pH but is affected by dissolution method because of the tendency of the alginate to form an adhesive, gel-like layer at pH values higher than four. The drug release characteristics of this polymer, under various pH conditions, make it potentially suitable for use in delayed/controlled release oral delivery systems containing compounds that are acid labile or irritating to the gastric mucosa.     

Disintegration and Dissolution Parameters of Compressed Tablets Prepared by Direct Compression-Wet Granulation Process and Compression of Wet Granulation of Both Sections

Hardness, disintegration and dissolution of compressed tablets were assessed by compressing tablets from granulations prepared by dry and wet granulation process of two sections and by composite wet granulation process. Modified USP XVIII apparatus for disintegration, rotating basket apparatus USP XVIII and constant circulation apparatus were employed for measuring dissolution. The constant circulation apparatus was used in the studies as only it proved to be sensitive to reflect the differences in the dissolution rates and was a close analog of physiological situation. Four types of tablets containing acetylsalicylic acid, codeine phosphate and propoxyphene hydrochloride were prepared. Tablets prepared by partial dry and wet granulation process did not show significant differences in the rates of dissolution as compared to those prepared by complete wet granulation process.     

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.     

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.     

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.     

Disintegration and Dissolution Parameters of Compressed Tablets Prepared by Direct Compression-Wet Granulation Process and Compression of Wet Granulation of Both Sections

Abstract

Hardness, disintegration and dissolution of compressed tablets were assessed by compressing tablets from granulations prepared by dry and wet granulation process of two sections and by composite wet granulation process. Modified USP XVIII apparatus for disintegration, rotating basket apparatus USP XVIII and constant circulation apparatus were employed for measuring dissolution. The constant circulation apparatus was used in the studies as only it proved to be sensitive to reflect the differences in the dissolution rates and was a close analog of physiological situation. Four types of tablets containing acetylsalicylic acid, codeine phosphate and propoxyphene hydrochloride were prepared. Tablets prepared by partial dry and wet granulation process did not show significant differences in the rates of dissolution as compared to those prepared by complete wet granulation process.     

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.     

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.     

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.     

Captopril floating and/or bioadhesive tablets: design and release kinetics

Two viscosity grades of hydroxypropylmethylcellulose (HPMC 4000 and 15000 cps) and Carbopol 934P were used to prepare captopril floating tablets. In vitro dissolution was carried out in simulated gastric fluid (enzyme free) at 37°C ± 0.1°C using the USP apparatus 2 basket method. Compared to conventional tablets, release of captopril from these floating tablets was apparently prolonged; as a result, a 24-hr controlled-release dosage form for captopril was achieved. Drug release best fit both the Higuchi model and the Korsmeyer and Peppas equation, followed by first-order kinetics. While tablet hardness and stirring rate had no or little effect on the release kinetics, tablets hardness was found to be a determining factor with regard to the buoyancy of the tablets.     

Captopril Floating and/or Bioadhesive Tablets: Design and Release Kinetics

Two viscosity grades of hydroxypropylmethylcellulose (HPMC 4000 and 15000 cps) and Carbopol 934P were used to prepare captopril floating tablets. In vitro dissolution was carried out in simulated gastric fluid (enzyme free) at 37°C ± 0.1°C using the USP apparatus 2 basket method. Compared to conventional tablets, release of captopril from these floating tablets was apparently prolonged; as a result, a 24-hr controlled-release dosage form for captopril was achieved. Drug release best fit both the Higuchi model and the Korsmeyer and Peppas equation, followed by first-order kinetics. While tablet hardness and stirring rate had no or little effect on the release kinetics, tablets hardness was found to be a determining factor with regard to the buoyancy of the tablets.     

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.     

The development of a modified dissolution method suitable for investigating powder mixtures

A novel dissolution method was developed, suitable for powder mixtures, based on the USP basket apparatus. The baskets were modified such that the powder mixtures were retained within the baskets and not dispersed, a potential difficulty that may arise when using conventional USP basket and paddle apparatus. The advantages of this method were that the components of the mixtures were maintained in close proximity, maximizing any drug: excipient interaction and leading to more linear dissolution profiles. Two weakly acidic model drugs, ibuprofen and acetaminophen, and a selection of pharmaceutical excipients, including potential dissolution-enhancing alkalizing agents, were chosen for investigation. Dissolution profiles were obtained for simple physical mixtures. The f1 fit factor values, calculated using pure drug as the reference material, demonstrated a trend in line with expectations, with several dissolution enhancers apparent for both drugs. Also, the dissolution rates were linear over substantial parts of the profiles. For both drugs, a rank order comparison between the f1 fit factor and calculated dissolution rate, obtained from the linear section of the dissolution profile, demonstrated a correlation using a significance level of P = 0.05. The method was proven to be suitable for discriminating between the effects of excipients on the dissolution of the model drugs. The method design produced dissolution profiles where the dissolution rate was linear for a substantial time, allowing determination of the dissolution rate without mathematical transformation of the data. This method may be suitable as a preliminary excipient-screening tool in the drug formulation development process.     

Ibuprofen Tablets Dissolution Versus Bioavailability

Abstract

Dissolution studies and a 24 patient randomized double-blind crossover bioavailability study were performed using two commercially-sized batches of an ibuprofen 200 mg tablet formulation (sugar-coated). The batches were equivalent with respect to the USP dissolution test, but differed, particularly from tablet-to-tablet, when a paddle at 50 rpm was substituted, one batch consistently giving a high dissolution and the other consistently giving a low dissolution.

The bioavailability study showed the batches to be bioequivalent, thus prompting an investigation as to why the substitution of a paddle at 50 rpm gave no correlation with bioavailability and should therefore be unsuitable as a standard dissolution test. It was found that soaking tablets in acid prior to using the paddle at 50 rpm (thus simulating more closely the in vivo pH sequence) increased the dissolution rate. The increase is such that the maximum dissolution rate, which also approximates that given by the USP method, is achievable within five minutes, even when the presoak medium is an unbuffered solution of hydrochloric acid at pH 4. A standard presoak procedure was then developed consisting of soaking each tablet for five minutes in 5 ml of USP gastric fluid without pepsin at room temperature and with no agitation. A comprehensive application of this procedure to both batches consistently produced results equivalent to those obtained by the USP method. In particular, there was very little tablet to tablet variation. Studies with formulations of varying bioavailability will be necessary before it can be determined whether this new acid presoak procedure will provide a more meaningful dissolution test compared with the current USP method.     

Drug release from spray layered and coated drug-containing beads: effects of pH and comparison of different dissolution methods.

Based on dissolution profiles of three model drugs on spray layered beads with the same percentage of Aquacoat coating, it was concluded that in vitro dissolution of oral controlled-release formulations should be performed in both gastric and intestinal media for ionizable drugs. Ketoprofen (weak acid, pKa 4.8), nicardipine HCl (salt of weak organic base, pKa 8.6), and acetaminophen (very weak organic acid, pKa 9.7, not ionized at physiologic pH) provided different dissolution characteristics in enzyme-free simulated gastric fluid (pH 1.4) and enzyme-free simulated intestinal fluid (pH 7.4), indicating that the rate of drug release was pH dependent and related to drug ionization even though the solubility of the coating (ethylcellulose) is pH independent. In acidic media, ketoprofen release from the beads containing low-level coating (3%) was slower than that of nicardipine HCl, with the opposite holding true in basic media. Acetaminophen was released at approximately the same rate in both acidic and basic media. A comparison of drug release profiles for nicardipine HCl nude beads was also investigated among three different dissolution methods: USP dissolution apparatus I (basket method, 50 rpm), USP dissolution apparatus II (paddle method, 50 rpm), and USP dissolution apparatus III (Bio-Dis, Van-Kel Industries, 5 and 10 dpm). Release profiles obtained from all methods were similar, indicating that the three dissolution methods were comparable.