Sustained-Release Dosage Form of Nicardipine Hydrochloride: Application of Factorial Design and Effect of Surfactant on Release Kinetics

Microcapsules of nicardipine hydrochloride with core:wall ratios of 1:1, 2:1, and 1:2 were prepared by the coacervation-phase separation method, using ethyl-cellulose as the coating material. Two batches of nicardipine hydrochloride microscapsules were divided into size fraction by using standard sieves ranging from 840 μm to 476 pn. Dissolution rate studies from microcapsules were performed using the USP XXII basket method. The kinetic model according to the Rosin-Rammler-Sperling-Bennet-Weibull (RRSBW) distribution was applied for the parametric representation of the dissolution curves. Preparation and dissolution rate studies on the nicardipine hydrochloride microcapsules were pellformed and the influence of particle size, core:wall ratio, and the amount of nicardipine hydrochloride on the release rate was examined by 2³ factorial design. The sign@cance of the observed effects was tested with the F test. A surface active substance was added in the dissolution medium to understand how this substance effects the release of drug from ideal microcapsule form which is found by the findings of the 2³ factorial design. Dissolution studies were repeated with this ideal formulation using different ratio of Tween 20.

The results of this study suggested that the solubility and bioavailability of the sustained-release dosage forms of nicardipine hydrochloride using sullface active substances could be increased.     

A Study on the Manufacture and in Vitro Dissolution of Terbutaline Sulfate Microcapsules and their Tablets

Abstract

Microcapsules of terbutaline sulfate with cellulose acetate butyrate and ethylcellulose were prepared using an emulsion-solvent evaporation technique. The in vitro dissolution of terbutaline sulfate was studied using the USP rotating basket method. As the polymer to drug ratio increased, the microcapsule size distribution shifted to the smaller size and the release of terbutaline sulfate decreased. The release of terbutaline sulfate was independent of the dissolution medium pH for both polymers. The release kinetics from the microcapsules was dependent on the polymer type and polymer to drug ratio. The release of terbutaline sulfate from cellulose acetate butyrate and ethylcellulose microcapsules formulated with a 1:1 polymer to drug ratio was complex and could not be differentiated between the square-root of time and first-order release models. However, the square-root of time model was followed by microcapsules formulated with a 2:1 or a 3:1 cellulose acetate butyrate to drug ratio. When the ethylcellulose to drug ratio was increased to 2:1 the square-root of time model was followed. At an ethylcellulose to drug ratio of 3:1 the release kinetics could not be differentiated between the Hixon-Crowell and first-order release models. The T50% from ethylcellulose microcapsules was decreased when the microcapsules were compressed into tablets with the addition of Avicel^R/Emcompress^R (2:1) or Avicel^R.     

Evaluation of hydrophilic,hydrophobic and waxy matrix excipients for sustained release tablets of Venlafaxine hydrochloride

Objective: Venlafaxine is freely soluble In water and administered orally as hydrochloride salt In two to three divided doses. In the present investigation different release retarding matrices have been evaluated for sustained release of venlafaxine hydrochloride (VH) from the formulated tablets.

Materials and methods: Sustained release matrix tablets were formulated using different hydrophilic, hydrophobic and waxy materials as matrix formers. Tableting was done by pre-compression, direct compression and hot melt granulation depending on the type of matrix material used and evaluated for different tests. The formulated tablets were compared with commercial venlafaxine products. In vitro drug dissolution profiles were fitted In different mathematical models to elucidate the release mechanism.

Results: Dissolution data showed that commercial formulations Venlor XR^® and Venfax PR^® released the entire drug withIn 8?h where as the formulated tablets with hydroxypropylmethylcellulose (HPMC) and cetyl alcohol as matrix formers provided sustained release of drug for 14–15?h. The release was found to follow Hixson Crowel and Higuchi kinetics for HPMC and cetyl alcohol tablets, respectively.

Conclusion: The developed matrix tablet formulations with HPMC and cetyl alcohol provided sustained release profiles for prolonged periods than commercial formulations.     

In Vitro Release of Disopyramide from Cellulose Acetate Butyrate Microspheres

Abstract

Disopyramide was microencapsulated with cellulose acetate butyrate (CAB) using an emulsion-solvent evaporation process. Drug dissolution from microcapsules was studied in both simulated gastric (SGF) and intestinal fluids (SIF) under sink conditions using the USP paddle method. There was no significant difference between drug release into SIF and SGF. As the CAB to drug ratio decreased from 3:1 to 2:1 at constant polymer mass, the drug release rate increased and the T50Y0 decreased from 2.3 hr to 0.3 hr for 303 pm particles. Dissolution T50% increased from 0.4 hr to 2 hr when the mean microcapsule size was increased from 153 to 428 μm (26% drug loading). The addition of acetone to the external phase during preparation shifted the size distribution toward larger particles, but resulted in a higher drug dissolution rate for a given particle size range. A shift to smaller particles was obtained upon increasing the concentration of surfactant. The dissolution profiles were described by the Higuchi and Baker-Lonsdale equations for drug release from spherical matrices up to 90% of the drug release.     

Preparation of dendrimer-loaded microcapsules by a layer-by-layer deposition of polyelectrolytes

Poly(amidoamine) dendrimer-loaded microcapsules were prepared by a layer-by-layer deposition of poly(allylamine hydrochloride) and poly(vinyl sulfate) on the surface of calcium carbonate (CaCO₃) microparticles that contain poly(amidoamine) dendrimer, followed by dissolution of CaCO₃ core. A fluorescence spectroscopy revealed that a fluorescent dendrimer labeled with trimethylrhodamine is successfully encapsulated in the microcapsules. The leakage of the dendrimer out of the microcapsule was negligible at pH 4.0, while 7% and 25% of dendrimer were released after 6 h in the media at pH 7.0 and 9.0, respectively. The binding and release properties of the dendrimer-loaded microcapsules were evaluated using two kinds of organic dyes Rose Bengal (RB) and 1-anilinonaphthalene-8-sulfonic acid (ANS). RB was accommodated in the microcapsules and released rapidly into buffer solution at pH 8.0, while the release was suppressed at pH 7.0 probably due to binding of RB to dendrimer in the capsules. A fluorescence emission of ANS was highly enhanced in the presence of dendrimer-loaded microcapsules, suggesting a successful binding of ANS to dendrimer in the microcapsules because the fluorescence intensity was not enhanced in the presence of dendrimer-free microcapsules. The kinetic studies revealed that the rate of uptake of ANS in the dendrimer-loaded microcapsules was determined by the rate of transport of ANS across the capsule wall. On the other hand, the dissociation of ANS from PAMAM is the rate-determining step for the release of ANS from the microcapsules.     

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.     

Film Coated Pellets Containing Verapamil Hydrochloride: Enhanced Dissolution into Neutral Medium

Abstract

Weakly basic drugs, such as verapamil hydrochloride, that are poorly soluble in neutral/alkaline medium may have poor oral bioavailability due to reduced solubility in the small intestine and colon. Film coated pellets were prepared using two strategies to enhance drug release at high pH values. Firstly, pellets were coated with Eudragit® RS/hydroxypropyl methylcellulose acetate succinate (HMAS) mixtures in proportions of 10:1 and 10:3, respectively. The enteric polymer, HMAS, would dissolve in medium at pH>6 creating pores through the insoluble Eudragit RS membrane to increase drug release. Secondly, an acidic environment was created within the core by the inclusion of fumaric acid at concentrations of 5 and 10% in order to increase drug solubility. Both strategies enhanced drug release into neutral medium in dissolution studies using the pH change method to simulate GIT transit. Dissolution profiles of samples tested in pH 1.2 for 12 hr were compared with those using the pH change method (pH 1.2 for first 1.5 hr, pH raised to 6.8 for remaining 10.5 hr) using the area under the dissolution curve (AUC), the dissolution half-life (t_50%), and the amount of drug released in 3 hr (A_{3 hr}) values. Both strategies enhanced drug release into neutral medium although the strategy using HMAS in the film was more effective. The formulation least affected by pH change was a combination of the two strategies, i.e., pellets containing 5% fumaric acid coated with Eudragit RS 12% w/w and HMAS 1.2% w/w.     

Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

In Vitro Release of Disopyramide from Cellulose Acetate Butyrate Microspheres

Disopyramide was microencapsulated with cellulose acetate butyrate (CAB) using an emulsion-solvent evaporation process. Drug dissolution from microcapsules was studied in both simulated gastric (SGF) and intestinal fluids (SIF) under sink conditions using the USP paddle method. There was no significant difference between drug release into SIF and SGF. As the CAB to drug ratio decreased from 3:1 to 2:1 at constant polymer mass, the drug release rate increased and the T50Y0 decreased from 2.3 hr to 0.3 hr for 303 pm particles. Dissolution T50% increased from 0.4 hr to 2 hr when the mean microcapsule size was increased from 153 to 428 μm (26% drug loading). The addition of acetone to the external phase during preparation shifted the size distribution toward larger particles, but resulted in a higher drug dissolution rate for a given particle size range. A shift to smaller particles was obtained upon increasing the concentration of surfactant. The dissolution profiles were described by the Higuchi and Baker-Lonsdale equations for drug release from spherical matrices up to 90% of the drug release.     

Preparation and evaluation of ethylcellulose microcapsules with bacampicillin

Abstract

Ethylcelluloses of different types were used to microencapsulate bacampicillin. Polymer deposition from cyclohexane was performed by temperature change. As coacervation - inducing agent different polyisobutylenes (Oppanol B - 200, B - 100, B - 50, B -3) were used. Fine products with slower drug release were obtained. Average diameters of prepared microcapsules were determined with sieve analysis and it was shown that the particle size of the microcapsules follows log - normal distribution. Scanning electron microscopy was used to examine the shape and the surface characteristics of the microcapsules. HPLC method was developed for testing drug content and its dissolution. Drug content in the microcapsules was in all cases over 80% regarding the amount added. Dissolution of bacampicillin from microcapsules was retarded comparing to the dissolution of bacampicillin itself. The experimental values of dissolution were fitted with different model kinetics. To describe the dissolution profiles we suggested the combined zero and first order kinetics. The bitter taste was quite satisfactory disguised in all prepared microcapsules.     

Formulation,in vitro evaluation and study of variables on tri-layered gastro-retentive delivery system of diltiazem HCl

Context: Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs.

Objective: To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ).

Methods: Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate. Design of formulation to obtain 12?h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate. Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism. Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied.

Results and discussion: The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3–4?min. Drug release was faster from low molecular weight (MW) PEO as compared to high MW. With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO₂ gas formation. Drug release followed zero-order and gave a good fit to the Korsmeyer–Peppas model, which suggested that drug release was due to diffusion through polymer swelling.

Conclusion: Zero-order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer. The tri-layered system shows promising delivery of DTZ, and possibly other water-soluble drugs.     

Formulation and evaluation of floating tablet of H2-receptor antagonist

Context: Conventional sustained dosage form of ranitidine hydrochloride (HCl) does not prevent frequent administration due to its degradation in colonic media and limited absorption in the upper part of GIT.

Objectives: Ranitidine HCl floating tablet was formulated with sublimation method to overcome the stated problem.

Methods: Compatibility study for screening potential excipients was carried out using Fourier transform infrared spectroscopy (FT-IR) and differential scanning chromatography (DSC). Selected excipients were further evaluated for optimizing the formulation. Preliminary screening of binder, polymer and sublimating material was based on hardness and drug release, drug release with release kinetics and floating lag time with total floatation time, respectively. Selected excipients were subjected to 3² factorial design with polymer and sublimating material as independent factors. Matrix tablets were obtained by using 16/32” flat-faced beveled edges punches followed by sublimation.

Results: FT-IR and DSC indicated no significant incompatibility with selected excipients. Klucel-LF, POLYOX WSR N 60?K and l-menthol were selected as binder, polymer and sublimating material, respectively, for factorial design batches after preliminary screening. From the factorial design batches, optimum concentration to release the drug within 12?h was found to be 420?mg of POLYOX and 40?mg of l-menthol. Stability studies indicated the formulation as stable.

Conclusion: Ranitidine HCl matrix floating tablets were formulated to release 90% of drug in stomach within 12?h. Hence, release of the drug could be sustained within narrow absorption site. Moreover, the dosage form was found to be floating within a fraction of second independent of the pH of media ensuring a robust formulation.     

Effect of Temperature of Dissolution on The Release Kinetics of Phenobarbitone from Poly (Dl-Lactic Acid) Microcapsules: Calculation of Activation Energy.

Abstract

Poly (DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone (core:polymer, 1:2) were prepared using three different molecular weight polymers, 20,500, 13,300 and 5,200. Buffer pH 9 ware used to study dissolution rate at temperatures of 10°, 15°, 20°, 25°, 30° and 37°C. The release mechanism followed “Higuchi's” square root of time relationship at all these temperatures and allowed calculation of release rate from the straight line portion of release curve. These microcapsules showed an initial burst phase release followed by a lag phase; both of these phases are affected by the temperature of dissolution and polymer molecular weight. The normalized release rate [K_h2/SSA] was found to lower linearly with the lowering of temperature with all three polymers. Arrhenius plot of the normalized release rate allowed calculation of the activation energy (Ea) for the polymers. It was found to lower linearly with the increase in DL-PLA polymer molecular weight.     

Crystal engineering to improve physicochemical properties of mefloquine hydrochloride

Background: Pharmaceutical cocrystallization is a promising alternative for improving the solubility and dissolution rate or manipulating other physical properties of active pharmaceutical ingredients. The objective of this investigation was to study the effect of cocrystallization with different cocrystal formers on physicochemical properties of mefloquine hydrochloride. Method: Cocrystals were prepared by solution crystallization method – mefloquine hydrochloride (414.8 mg, 1 mmol) and different cocrystal formers (1/2 mmol) were dissolved in 20 mL of ethanol with warming. Solution was cooled in ice bath for 6 hours. The crystals were isolated by filtration through a membrane (0.45 μm) and dried in the air. The pure drug and the prepared cocrystals were characterized in terms of saturation solubility, drug content, infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, in vitro dissolution studies, and stability studies. Results: The cocrystals showed enhanced solubility and dissolution rate. The cocrystals were found to be stable over the period of 6 months confirmed from stability studies. Conclusion: Cocrystals resist the conversion of anhydrous form of drug into its hydrate which is responsible for the drugs less solubility and dissolution rate.     

Development and optimization of press coated tablets of release engineered valsartan for pulsatile delivery

The present work is aimed to develop and optimize pulsatile delivery during dissolution of an improved formulation of valsartan to coordinate the drug release with circadian rhythm. Preliminary studies suggested that β cyclodextrin could improve the solubility of valsartan and showed A_L type solubility curve. A 1:1 stoichiometric ratio of valsartan to β cyclodextrin was revealed from phase solubility studies and Job’s plot. The prepared complex showed significantly better dissolution efficiency (p?<?0.05) compared to pure drug, which could be due to the formation of inclusion complex as revealed from FTIR and DSC studies. Continuous dissolution-absorption studies revealed that absorption of drug from valsartan β cyclodextrin complex was significantly higher (p?2 full factorial design was used to measure the response of HPMC K4M and EC on lag time and time taken for 90% drug release (T90). The optimized batch prepared according to the levels obtained from the desirability function had a lag time of 6?h and consisted of HPMC K4M:ethylcellulose in a 1:1.5 ratio with 180?mg of coating and revealed a close agreement between observed and predicted value (R^2?=?0.9694).     

Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies

Objective: A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug’s low solubility in water and to conduct proof-of-concept clinical studies.

Significance: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug’s suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride.

Methods: Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15–25?°C, +2–8?°C and ?20?°C.

Results: The ASD powder was composed of freeze dried elacridar hydrochloride–povidone K30–sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25?mg elacridar hydrochloride and were stable for at least 12 months at –20?°C.

Conclusions: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.     

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.     

A Study of the Effects of Sucrose Concentration,Lacquer Concentration and Coating Time on the Formulation of Stable and Effective Carbenicillin Indanyl Sodium Microcapsules

Abstract

Carbenicillin indanyl sodium, commonly known as Geocillin (GC), is an orally effective derivative of carbenicillin employed in the treatment of gram negative infections of the urinary tract. GC exhibits an extremely bitter taste which affects patient compliance upon oral dosing (1). A novel coating approach allows Geocillin to be prepared as a suspension for oral administration. GC is available only as a tablet.

Eudragit E100^R [EE] is a tasteless, acid soluble cationic polymer. Encapsulation of GC with [EE] inhibited its release in the mouth, thus overcoming its bitter taste. Dissolution studies were carried out in simulated gastric fluid and simulated intestinal fluid. Three factors, viz. sucrose concentration, lacquer concentration and coating time were evaluated to arrive at an optimally acceptable formulation.

The formulation containing GC and sucrose in the ratio of 1:3, suspension coated using a 5% w/w lacquer solution for 40 mins. yielded taste free microcapsules with optimal release characteristics.     

In vitro and in vivo evaluation of sustained-release and enteric-coated microcapsules of diclofenac sodium

Abstract

This work examines the release of diclofenac sodium from ethylcellulose (EC) microcapsules made up of different drug to polymer ratios. The release process was found to follow the Higuchi square root equation and not the zero-order or first order equations. However, for drug to polymer ratio of 1:1, a critical time (θ) was reached beyond which the release rate was lower than that predicted on the basis of the Higuchi square root equation. Dissolution experiments in 0.1N HCL revealed that less than 1.5% of the encapsulated drug was released in 6 h. This finding indicates the suitability of the EC microcapsules for enteric-coated preparations. The in vitro release of diclofenac sodium from microcapsules of different drug to polymer ratios was compared with that from a commercial sustained-release product. A distinct similarity between the release profile of the commercial product with that obtained for the 1:2 drug to polymer microcapsules was noted. The in vivo work included determination of the serum drug profile following oral administration of the microcapsules and the commercial product to rabbits. The obtained serum concentration time profile of the EC microcapsules exhibited a sustained-release pattern similar to the commercial product and consistent with the in vitro results.     

Dissolution of Suppositories III: Effect of Insoluble Polyvinylpyrrolidone on Acetaminophen Release

Abstract

Previously reported studies from this laboratory have demonstrated the usefulness of a new apparatus for suppository dissolution study. Acetaminophen suppositories gave slow release and it was posited that addition of a disintegrating agent commonly used in tablet manufacture would increase this release rate. To test the hypothesis, four PEG blends were used as bases as in the previous studies. Each contained 320 mg acetaminophen and 1%, 5%, or 10% of insoluble polyvinylpyrrolidone (Polyplasdone XL^R). One thousand milliliters of phosphate buffer, pH 8.0 to approximate rectal pH was employed as the dissolution media and maintained at 37.5°. A constant agitation rate of 2 5 and 50 rpm was used. Acetaminophen was assayed spectrophotometrically at 243 nm. Comparative dissolution profiles at the various agitation rates and with the concentrations of polyvinylpyrrolidone were developed. Addition of insoluble polyvinylpyrrolidone increased the dissolution rate constant and dissolution half-times at the two agitation rates. While the disintegration aid increased release, this release was not linear with respect to disintegrating agent concentration.

Release of acetaminophen from suppositories and the bioavailability of acetaminophen Erom suppository bases have not received much study. Feldman reported that the rate of bioavailability of suppositories was extremely variable and might not produce a clinically noted response (1). Maron and Ickes, however, reported that acetaminophen suppositories were clinically as effective an antipyretic as were tablets (2).

Pagay, et al. studied the influence of the vehicle on the bioavailability of acetaminophen suppositories using a modified beaker method with a media of pH 7.0 and an agitation of 25 rpm (3). These researchers correlated the dielectric constant of the base to acetaminophen bioavailability. Commercial suppositories were not discussed.

A recent report by Palmieri (4) discussed release of acetaminophen from laboratory prepared PEG bases and commercially available suppositories. Dissolution half-times for laboratory prepared suppositories at 50 rpm ranged from 8 minutes for Base A to 22 minutes for Base D. The commercially available acetaminophen suppositories had a dissolution half-time of 90 minutes at 50 rpm. Because of these apparently slow release rates, it was posited that addition of a disintegrating agent would increase the release of acetaminophen from the polyethylene glycol base sup-positores. Polyplasdone XLR, (5) a crosslinked insoluble homopolymer of n-vinyl-2-pyrrolidone was used in an attempt to increase the release rate.