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.     

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, pK_a 4.8), nicardipine HCl (salt of weak organic base, pK_a8.6), and acetaminophen (very weak organic acid, pK_a9.7, 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.     

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.     

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.     

Dissolution Characteristics of Interactive Powder Mixtures. Part One: Effect of Solubility and Particle Size of Excipients

Abstract

Interactive mixtures of fine cohesive drug powders and coarse free flowing excipients are reported to increase dissolution rates of poorly soluble drugs. However, dissolution rates are known to be affected by the solubility characteristics of the excipients as well as excipients surface characteristics after mixing with lubricant.

In this study the effects of solubility and particle size of excipients on dissolution of micronized griseofulvin from interactive powder mixtures were investigated. Quantitative assessment of dissolution from such mixtures showed that systems containing soluble excipients increased dissolution of the drug more efficiently than mixtures prepared using insoluble excipients. The role of the soluble excipient was more significant after mixing with magnesium stearate. Excipients of smaller particle sizes increased dissolution more efficiently than their large size counterparts. Effects of particle size were particularly significant in case of water insoluble excipients.     

Influence of formulation parameters on dissolution rate enhancement of glyburide using liquisolid technique

The aim of this study was to investigate the use of liquisolid technique in improving the dissolution of glyburide in a solid dosage form. This study was designed to evaluate the effects of different formulation variables, i.e. type of non-volatile liquid vehicles and drug concentrations, on drug dissolution rates. The liquisolid tablets were formulated with Propylene glycol, as liquid vehicle. Microcrystalline cellulose was used as a carrier material, silica as a coating material and croscaremellose as a disintegrant. In vitro drug dissolution profiles of the liquisolid formulations were studied and compared with direct compressed non-micronized and micronized tablets of glyburide using USP II, paddle apparatus at 50 rpm for 60 min using 900 ml of 0.05 M Phosphate Buffer, pH 7.5. The stability studies showed that the dissolution profiles of liquisolid tablets prepared with propylene glycol were not affected by ageing significantly, as f2 value found between aged and fresh samples was 51.92. Differential scanning calorimetry revealed that the drug has got solubilized in the liquid vehicle. This was further supported by the powder X-ray diffraction studies of pure drug and the liquisolid powder system. It can be concluded that it is possible to load poorly soluble drug into liquisolid tablets by addition of PVP to the liquid vehicle. This is valuable for the preparation of liquisolid tablets of poorly soluble drugs. The liquisolid tablets prepared with PVP showed a remarkably improved dissolution rate in comparison with DC tablet and other formulations.     

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.     

Standardized in vitro drug release test for colloidal drug carriers using modified USP dissolution apparatus I

Background: Recently the use of colloidal carriers as drug delivery systems is gaining more attention. Evaluation of the in vitro drug release is considered an important step during the development and quality control of such systems. Therefore, there is a need for a standard test technique to study in vitro drug release from colloidal systems. Methods: The glass basket dialysis method was performed by a modification to the USP dissolution apparatus I by replacing the baskets with glass cylinders closed at the lower end by dialysis membrane. This method was characterized for the essential test parameters and compared to the dialysis bags technique using different types of colloidal drug carriers, namely liposomes, polymeric, and lipid nanoparticles. Results: The method proved to be more discriminating than the conventional dialysis bag method and allowed for better comparison between different formulation parameters or experimental conditions. In general, the design is easy to perform, simple, and available in all pharmaceutical laboratories under the same setup. Conclusion: The described method is a step toward standardized dissolution tests on colloidal drug delivery systems and the possible comparability of results.     

Effect of powder substrate on the dissolution properties of methyclothiazide liquisolid compacts

The effects of powder substrate composition on the in vitro release properties of methyclothiazide liquisolid compacts were evaluated. The dissolution patterns of this water-insoluble drug formulated in liquisolid tablets were also compared to those of commercial products. According to the new liquisolid technique, liquid medications such as solutions or suspensions of water-insoluble drugs in suitable nonvolatile liquid vehicles can be converted into acceptably flowing and readily compressible powders by a simple admixture with certain powder substrates, which are selected powders referred to as the carrier and coating materials. Enhanced release profiles may be exhibited by such systems due to the increased wetting properties and surface of drug available for dissolution. Liquisolid tablets of methyclothiazide containing a 5% w/w drug solution in polyethylene glycol 400 were prepared using powder substrates of different excipient ratios. The release rates of such products were assessed using the USP dissolution test and were compared to those of their commercial counterparts. It was observed that maximum drug dissolution rates can be exhibited by systems that have powder substrates with optimum carrier-to-coating ratios. In addition, liquisolid tablets displayed significantly enhanced dissolution profiles compared to those of marketed products.     

Evaluation of Eudragit RS-PO and Ethocel 100 matrices for the controlled release of lobenzarit disodium

Lobenzarit disodium is a drug for the treatment of rheumatoid arthritis. In this work, inert matrix tablets of lobenzarit disodium were prepared by direct compression using Ethocel® 100 and Eudragit® RS-PO as polymeric materials in different ratios. The obtained powder mixtures and tablets were evaluated from the rheological and technological points of view. The dissolution test was performed to evaluate the in vitro release kinetic of the matrices. The obtained dissolution profiles demonstrated that the matrices containing Eudragit RS-PO showed a slower release rate and therefore were more suitable for controlling the release of drug. The fit to the Higuchi model indicates that the drug release mechanism from these matrices was controlled by the diffusion step.     

Preparation and dissolution characteristics of controlled release diltiazem pellets

Different series of Diltiazem pellets with slow release of the active substance were prepared, by pan coating technique, using different mixtures of acrylic polymers (Eudragit E, Eudragit L, Eudragit RL and Eudragit RS) as film coating agents. The thickness of the coatings were varied by different amounts of Eudragit. Release profiles of Diltiazem hydrochloride were investigated using USP XX rotating basket method (Erweka DT-D6) with 1000 ml buffer solution (pH values 1.5; 2.2; 5.5; 6.8; 7.0) at 37°C as solvent. In vitro dissolution findings showed that Eudragit coatings gave prolonged release of Diltiazem hydrochloride. The permeability of coatings in gastric and intenstinal juices was found to be influenced by the amount of Eudragit L in the formulation. Also, the drug release rate was found to be dependent on the amount of coating applied. In order to understand the drug release mechanism better, the release data were tested assuming common kinetic models. In the present study square - root of the time plots and Weibull plots were not sufficiently linear, although several correlation coefficients were high. When the goodness of fit of release data to first - order kinetics and Hixson - Crowell 's equation was evaluated, the difference between these two models was often noted to be minimal.     

Preparation and dissolution characteristics of controlled release diltiazem pellets

Abstract

Different series of Diltiazem pellets with slow release of the active substance were prepared, by pan coating technique, using different mixtures of acrylic polymers (Eudragit E, Eudragit L, Eudragit RL and Eudragit RS) as film coating agents. The thickness of the coatings were varied by different amounts of Eudragit. Release profiles of Diltiazem hydrochloride were investigated using USP XX rotating basket method (Erweka DT-D6) with 1000 ml buffer solution (pH values 1.5; 2.2; 5.5; 6.8; 7.0) at 37°C as solvent. In vitro dissolution findings showed that Eudragit coatings gave prolonged release of Diltiazem hydrochloride. The permeability of coatings in gastric and intenstinal juices was found to be influenced by the amount of Eudragit L in the formulation. Also, the drug release rate was found to be dependent on the amount of coating applied. In order to understand the drug release mechanism better, the release data were tested assuming common kinetic models. In the present study square - root of the time plots and Weibull plots were not sufficiently linear, although several correlation coefficients were high. When the goodness of fit of release data to first - order kinetics and Hixson - Crowell ‘s equation was evaluated, the difference between these two models was often noted to be minimal.     

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.     

Comparison of directly compressed vitamin B12 tablets prepared from micronized rotary-spun microfibers and cast films

Fiber-based dosage forms are potential alternatives of conventional dosage forms from the point of the improved extent and rate of drug dissolution. Rotary-spun polymer fibers and cast films were prepared and micronized in order to direct compress after homogenization with tabletting excipients. Particle size distribution of powder mixtures of micronized fibers and films homogenized with tabletting excipients were determined by laser scattering particle size distribution analyzer. Powder rheological behavior of the mixtures containing micronized fibers and cast films was also compared. Positron annihilation lifetime spectroscopy was applied for the microstructural characterization of micronized fibers and films. The water-soluble vitamin B₁₂ release from the compressed tablets was determined. It was confirmed that the rotary spinning method resulted in homogeneous supramolecularly ordered powder mixture, which was successfully compressed after homogenization with conventional tabletting excipients. The obtained directly compressed tablets showed uniform drug release of low variations. The results highlight the novel application of micronized rotary-spun fibers as intermediate for further processing reserving the original favorable powder characteristics of fibrous systems.     

Formulation of Controlled Release Matrices by Granulation with a Polymer Dispersion

The objective of this work was to incorporate an ethylcellulose-based controlled-release coating suspension (Surelease, Colorcon) within a tablet matrix to provide a release controlling mechanism. Anhydrous theophylline, chlorpheniramine maleate, and acetaminophen were selected as model drug entities. Surelease dispersion was incorporated as the granulating agent either to the drug entity alone or to a blended mixture of drug and filler. Control batches included simple aqueous granulations and direct compression mixtures. Tablets were prepared on a single stroke tablet press. Dissolution was performed by the USP Method I (rotating basket) in purified water for the granulations and the resulting tablets. The uncompressed granulations did not exhibit prolonged release. In general, tablets prepared with the polymer suspension as the granulating agent were non-disintegrating, and exhibited slower dissolution than the control tablets. Release profiles were affected by drug concentration and excipient levels. By the dissolution method selected, complete drug release for the various formulations ranged from less than 1 hour to greater than 12 hours. The use of the polymer dispersion appears to enhance the processing characteristics of some materials, and to provide the formulator with control over drug release.     

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.     

Investigation of dissolution behavior of diclofenac sodium extended release formulations under standard and biorelevant test conditions

Background: Dissolution characteristics of four extended release (ER) generic formulations of diclofenac sodium were examined. Aim: The aim of this study was to compare the drug dissolution behavior of diclofenac ER generics to clarify whether the products are characterized by comparable dissolution characteristics under the applied test conditions. Methods: The investigations were performed in the USP apparatus 2 and in the new biorelevant dissolution stress test device. Results: The experiments yielded striking differences between the generic formulations. Applying USP apparatus 2 it was noticed that the dissolution profiles of the products were distinctly affected by the stirring rate. Using the biorelevant dissolution stress test device susceptibility of the products to biorelevant stresses was observed. Change of pH within the experiments reduced the dissolution rates of all formulations and distinctly influenced their dissolution characteristics. Conclusion: The study demonstrates clearly the divergences in the dissolution behavior among the generic ER formulations of diclofenac sodium. The observed susceptibility of the tested dosage forms toward biorelevant stress bears in our interpretation the risk to cause unwanted fluctuations in drug plasma concentration profiles.     

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.