Optimization of Slow-Release Tablet Formulations Containing Montmorillonite II. Factors Affecting Drug Release

The influence of electrolytes, surfactants in the dissolution medium, and particle size of drug and montmorillonite on the in vitro release of the soluble model drug sodium sulfathiazole from directly compressed slow-release tablets containing 20% drug and 30% magnesium aluminum silicate was investigated. The presence of electrolytes in the dissolution media decreased the release from the tablets. A decrease in release was also observed in deionized water when sodium chloride was included in the tablet formulation. The surface tension of the media appeared to have little influence on the dissolution rate of the drug. Varying the particle size of the drug had a greater effect on release rates than varying the particle size of the montmorillonite clay.     

Effect of Some Formulation Additives on the Oral, Absorption of Indomethacin

Higher dissolution rates of indomethacin were noted in glycerin-water mixtures, sucrose solutions, sod.-cmc mucilage, from a fabricated capsule containing a buffer and also from drug crystals obtained by precipitation in presence of a physiological surfactant solution. Dogs fed with the drug along with these additives and in the form of a lipid-containing dosage form shoved significantly increased plasma-indomethacin levels. The magnitude of plasma-drug levels from aqueous and oily suspensions and from the prepared capsule was found to be significantly greater than that obtained from the marketed preparation.     

Optimization of Slow-Release Tablet Formulations Containing Montmorillonite II. Factors Affecting Drug Release

Abstract

The influence of electrolytes, surfactants in the dissolution medium, and particle size of drug and montmorillonite on the in vitro release of the soluble model drug sodium sulfathiazole from directly compressed slow-release tablets containing 20% drug and 30% magnesium aluminum silicate was investigated. The presence of electrolytes in the dissolution media decreased the release from the tablets. A decrease in release was also observed in deionized water when sodium chloride was included in the tablet formulation. The surface tension of the media appeared to have little influence on the dissolution rate of the drug. Varying the particle size of the drug had a greater effect on release rates than varying the particle size of the montmorillonite clay.     

Rectal Absorption of Phenytoin in Rabbits from Polyethylene Glycol Suppositories

Abstract

Various suppositories containing phenytoin and phenytoin sodium were formulated with different polyethylene glycol combinations. The three formulae that had the best in vitro release rate were administered to rabbits. Phenytoin was well absorbed from the suppositories, and the results show that rectal administration of phenytoin can be an alternative to oral administration.     

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30°C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.     

Enhanced oral bioavailability of piroxicam in rats by hyaluronate microspheres

To enhance the dissolution and oral bioavailability of poorly water soluble piroxicam, the piroxicam-loaded hyaluronic microspheres were prepared with various ratios of piroxicam, sodium hyaluronate and polyethylene glycol 4000 (PEG) using a spray dryer, and their physicochemical properties such as shape, size, drug-loading efficiency and dissolution were investigated. The pharmacokinetic study of piroxicam-loaded hyaluronic micropheres in rats was then performed compared to piroxicam powder. The piroxicam-loaded hyaluronic microspheres, spherical in shape, had the geometric mean diameters of about 1.5 μm and drug loading efficiency of about 90%, irrespective of ratio of piroxicam/sodium hyaluronate/PEG. The hyaluronic microspheres containing PEG gave significantly higher dissolution rates of drug than did piroxicam powder, PEG-based solid dispersion system and hyaluronic microspheres without PEG, suggesting that the hyaluronic microsphere with sodium hyaluronate and PEG was more useful for improving the dissolution rate of poorly water soluble piroxicam. The piroxicam-loaded hyaluronic microcapsule composed of (piroxicam/sodium hyaluronate/PEG; 2: 20: 1) gave about threefold improved dissolution of drug in water for 4 h compared to piroxicam powder. It showed higher plasma concentrations of drug compared to piroxicam powder. It gave significantly higher AUC and faster T_max of piroxicam than did piroxicam powder. In particular, the AUC of piroxicam from hyaluronic microsphere was about twofold higher than that from piroxicam powder, suggesting that it could enhance the oral bioavailability of piroxicam. Thus, the hyaluronic microsphere developed using spray-drying technique with sodium hyaluronate and PEG was a more effective oral dosage form for poorly water soluble piroxicam.     

Enhanced Oral Bioavailability of Piroxicam in Rats by Hyaluronate Microspheres

ABSTRACT

To enhance the dissolution and oral bioavailability of poorly water soluble piroxicam, the piroxicam-loaded hyaluronic microspheres were prepared with various ratios of piroxicam, sodium hyaluronate and polyethylene glycol 4000 (PEG) using a spray dryer, and their physicochemical properties such as shape, size, drug-loading efficiency and dissolution were investigated. The pharmacokinetic study of piroxicam-loaded hyaluronic micropheres in rats was then performed compared to piroxicam powder. The piroxicam-loaded hyaluronic microspheres, spherical in shape, had the geometric mean diameters of about 1.5 μm and drug loading efficiency of about 90%, irrespective of ratio of piroxicam/sodium hyaluronate/PEG. The hyaluronic microspheres containing PEG gave significantly higher dissolution rates of drug than did piroxicam powder, PEG-based solid dispersion system and hyaluronic microspheres without PEG, suggesting that the hyaluronic microsphere with sodium hyaluronate and PEG was more useful for improving the dissolution rate of poorly water soluble piroxicam. The piroxicam-loaded hyaluronic microcapsule composed of (piroxicam/sodium hyaluronate/PEG; 2: 20: 1) gave about threefold improved dissolution of drug in water for 4 h compared to piroxicam powder. It showed higher plasma concentrations of drug compared to piroxicam powder. It gave significantly higher AUC and faster T_max of piroxicam than did piroxicam powder. In particular, the AUC of piroxicam from hyaluronic microsphere was about twofold higher than that from piroxicam powder, suggesting that it could enhance the oral bioavailability of piroxicam. Thus, the hyaluronic microsphere developed using spray-drying technique with sodium hyaluronate and PEG was a more effective oral dosage form for poorly water soluble piroxicam.     

Chitosan and sodium sulfate as excipients in the preparation of prolonged release theophylline tablets

The major objectives of this study were to monitor the effect of cross-linking of cationic chitosan in acidic media with sulfate anion during granules preparation by wet granulation method prior to tableting using theophylline (TPH) as a model drug. The prepared granules and the compressed tablets were subjected to in vitro evaluation. The properties of the prepared matrix granules and the compressed tablets were dependent on chitosan:sodium sulfate weight ratios, chitosan content, and molecular weight of chitosan. The prepared granules of all batches showed excellent to passable flowability and were suitable for compression into tablets. Most of the granules were hard and expected to withstand handling during the subsequent compression into tablets. Granules with high friabilities were only those prepared with a high amount of sodium sulfate or low amount of chitosan. Compression of granule batches yield nondisintegrating tablets that showed a decrease in tensile strength with the increase of sodium sulfate content at high chitosan:sodium sulfate weight ratio or with decrease of chitosan content. On the other hand, friability of tablets was increased in the presence of an excessive amount of sodium sulfate and low chitosan content as observed with granules. Slow TPH release from the formulated tablets was achieved at 1:0.5 and 1:1 chitosan:sodium sulfate weight ratios where all or most of the cationic chitosan and sulfate anions were used in a cross-linking reaction during wet granulation. Ratios of 1:2 and 1:3 showed fast drug release, which support the hypothesis that excessive unreacted water-soluble sodium sulfate might increase the porosity of the nondesintegrating tablets during dissolution. Slow drug release was also obtained with high molecular weight chitosan, whereas changing the hardness of the tablets did not significantly change the release profile of the drug as long as the tablets are intact during dissolution. Furthermore, slow drug release was observed as the total amount of chitosan was increased in the formulated tablets. A comparative in vivo study between the chosen formulated tablets (1:1 chitosan:sodium sulfate ratio that contains 10% high molecular weight chitosan) and the commercial Quibron tablets indicated prolonged appearance of the drug in dogs' plasma for both formulations with no significant differences (p > 0.05) in rate and extent of drug absorption. The formulated tablets showed 103.16% bioavailability relative to that of the commercial tablets.     

Chitosan and Sodium Sulfate as Excipients in the Preparation of Prolonged Release Theophylline Tablets

The major objectives of this study were to monitor the effect of cross-linking of cationic chitosan in acidic media with sulfate anion during granules preparation by wet granulation method prior to tableting using theophylline (TPH) as a model drug. The prepared granules and the compressed tablets were subjected to in vitro evaluation. The properties of the prepared matrix granules and the compressed tablets were dependent on chitosan:sodium sulfate weight ratios, chitosan content, and molecular weight of chitosan. The prepared granules of all batches showed excellent to passable flowability and were suitable for compression into tablets. Most of the granules were hard and expected to withstand handling during the subsequent compression into tablets. Granules with high friabilities were only those prepared with a high amount of sodium sulfate or low amount of chitosan. Compression of granule batches yield nondisintegrating tablets that showed a decrease in tensile strength with the increase of sodium sulfate content at high chitosan:sodium sulfate weight ratio or with decrease of chitosan content. On the other hand, friability of tablets was increased in the presence of an excessive amount of sodium sulfate and low chitosan content as observed with granules. Slow TPH release from the formulated tablets was achieved at 1:0.5 and 1:1 chitosan:sodium sulfate weight ratios where all or most of the cationic chitosan and sulfate anions were used in a cross-linking reaction during wet granulation. Ratios of 1:2 and 1:3 showed fast drug release, which support the hypothesis that excessive unreacted water-soluble sodium sulfate might increase the porosity of the nondesintegrating tablets during dissolution. Slow drug release was also obtained with high molecular weight chitosan, whereas changing the hardness of the tablets did not significantly change the release profile of the drug as long as the tablets are intact during dissolution. Furthermore, slow drug release was observed as the total amount of chitosan was increased in the formulated tablets. A comparative in vivo study between the chosen formulated tablets (1:1 chitosan:sodium sulfate ratio that contains 10% high molecular weight chitosan) and the commercial Quibron® tablets indicated prolonged appearance of the drug in dogs' plasma for both formulations with no significant differences (p > 0.05) in rate and extent of drug absorption. The formulated tablets showed 103.16% bioavailability relative to that of the commercial tablets.     

Evaluation of solid dispersions of Clofazimine

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Dissolution Characteristics of Benzoic Acid and Salicylic Acid Mixtures in Reactive Media

The dissolution rates of mixtures of the two acids, benzoic acid and salicylic acid were determined in a phosphate buffered medium. Dissolution properties from compressed discs under sink conditions were essentially linear. Plots of dissolution rate versus compact composition deviated from the two component models for both non-interacting and interacting components. Dissolution rates, particularly for benzoic acid at intermediate weight fractions, were lower than predicted by the theory for two non-interacting components. These lower than expected rates were explained in terms of the physicochemical changes occurring in the microenvironment at the solid liquid interface.     

Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs – a case study with valsartan

Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30?min against the plain drug which showed only 11.31% of drug release in 30?min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher C_max compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs.     

Effect of Agitation Intensity on the Dissolution Rate of Indomethacin and Indomethacin-Citric Acid Compressed Discs

Abstract

The dissolution rates of indomethacin (IMC) and indomethacin-citric acid (monohydrate) 1:1 mixtures under various hydrodynamic conditions were determined in a phosphate buffered medium Dissolution profiles of the γ form of IMC were nonlinear the rates decreasing with time The dissolution rates increased with increasing stirring speed In contrast α-IMC gave linear dissolution profiles the rates being higher and more sensitive to agitation intensity than those obtained using the γ-form. The slope of a log dissolution rate versus log stirring speed plot had a value of 0.598 for γ-IMC and 0.171 for γ-IMC Indomethacin dissolution rates from the mixed discs were 5-10 times lower than those of pure γ-IMCin the stirring speed range 180-60 rpm respectively The dissolution profiles of IMC showed positive curvature at low stirring speed while at high stirring speed the dissolution profiles became linear The slope of the log dissolution rate versus log stirring speed plot was nonlinear and ranged from >1 at low stirring speed to <0.5 at high stirring speed.     

Effect of amorphous content on dissolution characteristics of rifampicin

Rifampicin, one of the main first line anti-TB drugs, shows variable bioavailability in different marketed preparations and reasons cited include physiological, degradation, manufacturing/ processing, solid state, and bioavailability assessment procedure. Although the amorphous form of a drug is expected to exhibit higher solubility, the amorphous rifampicin has been reported to have a solubility disadvantage as compared to crystalline form II, which is used in marketed preparations. Amorphous form was generated and characterized by solid-state characterization techniques. Physical powder mixtures of form II with varying amounts of amorphous form were prepared, which were then subjected to solid-state characterization techniques and further evaluated for their dissolution behavior. Differential scanning calorimetry (DSC) scans show that area enclosed by integral of melting endotherm can be used for quantification of crystalline component, which can then be used to estimate amorphous content. No definite trend was evident in powder dissolution of mixtures that could implicate solubility difference of amorphous form. Intrinsic dissolution rate (IDR) results indicate that amorphous content has no effect on dissolution profiles of crystalline rifampicin.     

Effect of Amorphous Content on Dissolution Characteristics of Rifampicin

Rifampicin, one of the main first line anti-TB drugs, shows variable bioavailability in different marketed preparations and reasons cited include physiological, degradation, manufacturing/ processing, solid state, and bioavailability assessment procedure. Although the amorphous form of a drug is expected to exhibit higher solubility, the amorphous rifampicin has been reported to have a solubility disadvantage as compared to crystalline form II, which is used in marketed preparations. Amorphous form was generated and characterized by solid-state characterization techniques. Physical powder mixtures of form II with varying amounts of amorphous form were prepared, which were then subjected to solid-state characterization techniques and further evaluated for their dissolution behavior. Differential scanning calorimetry (DSC) scans show that area enclosed by integral of melting endotherm can be used for quantification of crystalline component, which can then be used to estimate amorphous content. No definite trend was evident in powder dissolution of mixtures that could implicate solubility difference of amorphous form. Intrinsic dissolution rate (IDR) results indicate that amorphous content has no effect on dissolution profiles of crystalline rifampicin.     

Ketorolac Tromethamine Bioavailability Via Tablet, Capsule, and Oral Solution Dosage Forms

The single-dose mean pharmacokinetic characteristics and relative bioavailability of 10-mg ketorolac tromethamine tablet, capsule, and oral solution dosage forms were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The tablet and the capsule formulations used were shown to have similar in vitro dissolution profiles. Ketorolac tromethamine was rapidly absorbed from all three dosage forms. The tablet and capsule were not significantly different with respect to any of the mean pharmacokinetic parameters: time to maximum plasma concentration (T_max) (35 and 42 min for the tablet and capsule, respectively), peak plasma concentration (C_max) (0.865 and 0.809 μg/ml for the tablet and capsule, respectively), area under the curve (AUC) (3.50 and 3.43 μg/ml × hr for the tablet and capsule, respectively), and half-life (t1/2) (5.2 and 4.8 hr for the tablet and capsule, respectively). Ninety-five percent fiducial (confidence) limits supported the equivalence of all of the tablet and capsule pharmacokinetic characteristics except for T^max, because of the higher variability of this parameter. The solution was absorbed significantly faster than the tablet (the time to maximum plasma concentration was 23 min for the solution versus 35 min for the tablet), but was not significantly different from the tablet in any other pharmacokinetic aspect. The fiducial intervals supported these tablet versus solution findings. Therefore, when functional or anatomical abnormality make tablet administration inadvisable, the solution or capsule formulations employed in this study may be used as alternatives to the commercially marketed tablet without adversely impacting the absorption profile of the drug substance.     

Dissolution Characteristics of Benzoic Acid and Salicylic Acid Mixtures in Reactive Media

Abstract

The dissolution rates of mixtures of the two acids, benzoic acid and salicylic acid were determined in a phosphate buffered medium. Dissolution properties from compressed discs under sink conditions were essentially linear. Plots of dissolution rate versus compact composition deviated from the two component models for both non-interacting and interacting components. Dissolution rates, particularly for benzoic acid at intermediate weight fractions, were lower than predicted by the theory for two non-interacting components. These lower than expected rates were explained in terms of the physicochemical changes occurring in the microenvironment at the solid liquid interface.     

In-vitro and in-vivo study of amorphous spironolactone prepared by adsorption method using supercritical CO2

Objective: The aim of this study was to improve the oral bioavailability of spironolactone (SP).

Method: SP was adsorbed on the fumed silica using supercritical CO₂ (scCO₂) technology and further compressed into tablets. The morphology was observed by scanning electron microscopy (SEM), and the crystalline form was investigated by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution test was performed in water, 0.1?M HCl solution, pH 4.5 acetate buffers and pH 6.8 phosphate buffers using the paddle method. The pharmacokinetics was undertaken in six dogs in a crossover fashion.

Results: SP was successfully prepared into tablets and presented in amorphous state. SP-silica scCO₂ tablets displayed higher dissolution profiles than SP-silica physical mixtures tablets in different media. The AUC_0–t and C_max of SP-silica supercritical CO₂ was 1.61- and 1.52-fold greater than those of SP-silica physical mixtures (p?Conclusion: It is a promising method in improving dissolution and bioavailability by adsorbing SP, a poorly soluble drug, on the fumed silica using rapid expansion of supercritical solutions.     

The impact of food components on the intrinsic dissolution rate of ketoconazole

To accurately predict the in vivo performance of drugs from an in vitro dissolution test, the dissolution conditions used are supposed to be similar to those present in the gastrointestinal milieu. Post-prandial gastric fluid contains partially digested food mixtures consisting of fat, protein and carbohydrate. Despite this, the compendia dissolution medium recommended to simulate the gastric fluid is still composed of a simple solution of hydrochloric acid and sodium chloride with or without the addition of pepsin. Therefore, in this investigation, biorelevant dissolution media were developed to evaluate the impact of food constituents; milk with different fat contents, egg albumin, gelatin, casein, gluten, carbohydrates and amino acids on the intrinsic dissolution behavior of ketoconazole. Most of the food additives that were evaluated enhanced the apparent solubility of the drug but to different extents. The greatest enhancement in dissolution was observed in media containing either neutral amino acids or media based on milk mixtures. The formation of complexes between the drug and the additives most likely accounted for the solubilizing effect and in milk-containing media, the effect was attributed to the whole complex structure of milk rather than simply its fat content. These results highlight the potential effect of the type of ingested meal on drug dissolution and subsequent bioavailability.     

The in vitro dissolution of theophylline from different types of hard shell capsules

The in vitro dissolution of theophylline from two-piece hard shell capsules has been investigated using different types of capsule shells (gelatin, gelatin/polyethylene glycol, hydroxypropyl methylcellulose), different formulations, different capsule fill weights, and different tamping forces. Analysis of variance confirmed that the formulation and the capsule shell materials were the most important factors influencing drug dissolution. The maximum extent of drug dissolution was significantly increased when hydroxypropyl methylcellulose (HPMC) capsules were used. The mean dissolution time (MDT) was significantly reduced, indicating a faster dissolution rate of the drug from HPMC capsules. The addition of microfine cellulose to the formulations as filler reduced the MDT in all cases, whereas the addition of lactose monohydrate did not enhance drug dissolution. The study confirmed that a change from gelatin hard shell capsules to gelatin/PEG or HPMC hard shell capsules should not pose problems with respect to drug absorption or bioavailability.