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.     

Dissolution Characteristics of Capsule Shells and Drug Release from Commercial Tetracycline-Hcl Capsules

Abstract

The dissolution characteristics of the gelatin shells of four brands of tetracycline-HCl capsules were examined by measuring the shell rupture time (t_r) in a modified version of two-blade stirrer apparatus under various stirrer depth, ionic strength, and pH conditions. The dissolution rate of tetracycline-HCl from these capsules was also determined using the U.S.P. XIX dissolution apparatus. While no significant effect of stirrer depth on t_r was found, increasing the basket-stirrer distance from the bottom of the flask from 0.2 to 2 cm was found to increase the dissolution rate of tetracycline-HCl from capsules significantly (p < 0.001). As the ionic strength was increased, the dissolution rates of both gelatin shell and tetracycline-HCl content were increased, however, increasing the ionic strength from 0.6 to 1.5 failed to produce any further increase in t_r. The pH of the dissolution fluid significantly (p < 0.01) influenced the dissolution rate of the capsule shell and t_r was longest at pH = 4. A linear, inverse relationship between pH and tetracycline-HCl dissolution rate constant (k_s) was obtained. While a good correlation between t_r and k_s was obtained under certain conditions, capsule shell and tetracycline-HCl content showed different dissolution behaviour under other conditions. It is expected therefore, that under the latter conditions capsule shells had their maximum effect on drug release from the capsules studied.     

SiCp/Al复合材料搅拌铸造新型搅拌器流场及工艺研究

SiCp/Al复合材料搅拌铸造法虽然具有制备成本低、近终成型的优点,但是实现SiC颗粒在铝合金熔体的均匀分散难度很大,这与搅拌器结构及搅拌工艺有直接关系。采用数值模拟和实验相结合的方法开展了新型桨栅复合搅拌器设计及其工艺研究,比较了桨栅复合搅拌器与单一搅拌器的流场结构和速度场分布,并在此基础上进行了搅拌铸造工艺研究。结果表明:(1)桨栅复合搅拌器能够较好地实现复合材料大体积熔体的均匀搅拌和高速剪切,复合搅拌器内熔体的流场为较好的轴向和径向循环,液面更为平稳,搅拌转速500r/min时熔体最大速度为3.9m/s,流场结构和剪切速度均优于单一形式搅拌器;(2)用桨栅复合搅拌器进行20%(质量分数)SiCp/A357复合材料搅拌铸造工艺实验,在搅拌温度610℃、搅拌转速500r/min、搅拌时间20min的工艺条件下,SiC颗粒分布均匀且无气孔缺陷。     

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.     

A new rapidly absorbed paracetamol tablet containing sodium bicarbonate. II. Dissolution studies and in vitro/in vivo correlation

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.     

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.     

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.     

Dissolution rates of limestones of different sources

The dissolution characteristics of limestones from six sources in Taiwan have been studied by using the pH-stat method in a stirred tank at 60 degrees C, pH values of 4 and 6, stirrer speeds of 500-1000 rpm, and a particle size of 75-125 microm aperture width. The dissolution rates of the limestones were found to be controlled by the mass transfer of hydrogen ions with chemical reactions in the liquid film surrounding the limestone particle. The measured value of mass transfer coefficient increases with an increasing pH value and stirrer speed and remains constant with particle size. For the six limestones at the same particle size, the measured dissolution rates per unit area are the same due to the mass-transfer control kinetics; however, the time taken to reach a certain fraction of dissolution is proportional to the molar concentration of the soluble species in the limestone and the initial particle size.     

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.     

Comparative pH-Gradient Dissolution of Several Oral Dosage Forms of Iron

A comparative pH - gradient dissolution study was conducted for several brands of oral iron dosage forms on the Canadian market. The commercially available dissolution apparatus employed in the study met the requirements of the variety of pH media conditions necessary for conducting dissolution of conventional, enteric coated and slow release iron preparations. The reproducibility of the dissolution system was evaluated using the USP's non-disintegrating salicylic acid tablets. Dissolution results are discussed in reference to a recent bioavailability report concerning oral iron preparations. The applicability of the procedure in studying the dissolution of solid dosage forms of iron is discussed.     

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.     

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.     

Autohated Deterhination of Dissolution Rate: Effect of Particle Size Distribution

The effect of particle size distribution on the dissolution of salicylic acid in an automated dissolution apparatus has been studied. Tablets were prepared by individually weighing 200 mg of the drug particles having a narrow size distribution, compressing the tablets using a hydraulic press and employing identical compression force for the same time period for each tablet. The results showed that the range values obtained were not significantly different from those obtained when the particle size was not controlled. However, the range values obtained from the dissolution of drug particles recovered from the tablet formulation were found to be similar to the range values obtained from the dissolution of the tablet formulation, indicating that compression during tabletting was responsible for observed differences.     

Comparative pH-Gradient Dissolution of Several Oral Dosage Forms of Iron

Abstract

A comparative pH - gradient dissolution study was conducted for several brands of oral iron dosage forms on the Canadian market. The commercially available dissolution apparatus employed in the study met the requirements of the variety of pH media conditions necessary for conducting dissolution of conventional, enteric coated and slow release iron preparations. The reproducibility of the dissolution system was evaluated using the USP's non-disintegrating salicylic acid tablets. Dissolution results are discussed in reference to a recent bioavailability report concerning oral iron preparations. The applicability of the procedure in studying the dissolution of solid dosage forms of iron is discussed.     

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.     

Practical Aspects of Dissolution Testing

The introduction of in vitro dissolution tests into the British Pharmacopoeia necessitated a considerable programs of laboratory investigation and collaborative testing. The importance of minimising variation and identifying and controlling some of the factors causing variation was an important aspect of this programme. Factors which were identified were sampling position, temperature of the dissolution medium, dissolved air, filter adsorption and filter release of interfering substances, drive motor speed variation, stirrer shaft eccentricity, basket dimensions, displacement vibration, and flask shape. Reference is made to automated sampling systems and to the use of Dissolution Calibrators.     

Suppository Dissolution Testing: Apparatus Design and Release of Aspirin

Present methods of in vitro dissolution testing for suppositories were found to be lacking in universal acceptance, reproducibility, and difficult to perform. Initially a USP basket for tablet dissolution with one-hundred milliliters of phosphate buffer of pH 8 to approximate rectal pH was used. A slow constant stirring speed was maintained by means of a Hanson dissolution drive control and hollow spindle-stirrer apparatus as well as a constant temperature of 37.5±0.1° Aspirin in polyethylene glycol bases gave plausible, reproducible results with this apparatus. However, oil bases (i.e. cocoa butter) gave unacceptable, irreproducible results since the base blocked the openings of the basket mesh. This report describes a modified basket method where the basket is polyurethane of the same size and configuration as the USP basket. The basket described has twelve linear vertical slots of 0.25 mm width allowing for a porosity of 52%. Results of aspirin release from four PEG bases prepared in this laboratory are presented and discussed. The results were reproducible. Five commercially available suppositories were also tested in the above described manner.

Dissolution, or drug release has been extensively studied and reported for only a few selected tablets and other oral solid dosage forms. Dissolution has been shown to be the best in vitro parameter to correlate release of drug to bioavailability. Dissolution of drug from non-oral dose forms however, has not been extensively investigated. Past research into drug release from suppository bases has taken a number of approaches, some of which are not very scientifically sound or reproducible. Gibaldi and Gundhofer in 1975 studied bioavailability of aspirin from commercially available suppositories (1). These researchers reported “the rate of absorption of aspirin was sufficiently slow to raise considerable doubt as to whether efficaceous body levels of aspirin or salicylate are obtained after a single dose” (1). Other reports also question the absorption of aspirin from suppositories (2, 3).

Because present methods of in vitro dissolution testing appeared lacking in universal acceptance and reproducibility or were difficult to perform, this study was undertaken to develop an apparatus for suppository dissolution. To test the reproducibility of the devised method, four PEG base blends were used as vehicle for aspirin. Several commercially available products were also tested to determine their release patterns.     

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.     

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.     

A Combination Disintegration-Dissolution Apparatus for Fast-Disintegrating

Abstract

A combination disintegration-dissolution apparatus for fast disintegrating tablets is described. Preliminary investigation using sodium carboxymethyl starch as the disintegrant indicated that the apparatus was capable of detecting differences in the disintegration time both due to disintegrant concentration as well as due to the intensity of agitation used in the apparatus. No difference in the disintegration times could be observed when similar tablets were evaluated using the existing disintegration apparatus.

The combination apparatus described is simple in construction and design and can be fabricated quite easily and economically in the laboratory. Due to the anticipated increase in the availability of fast-disintegrating tablets, this apparatus will be useful to the pharmaceutical formulator as a valuable quality control tool. In addition, the apparatus is adaptable to various other agitational systems in common usage and can be used by laboratories carrying out combined disintegration and dissolution tests using automated equipment.