Christy M. Wyandt

Sustained Release of Acetaminophen from Heterogeneous Matrix Tablets: Influence of Polymer Ratio, Polymer Loading, and Co-active on Drug Release

The aim of this research was to investigate the effect of pseudoephedrine (PE), polymer ratio, and polymer loading on the release of acetaminophen (APAP) from hydroxypropyl methyl cellulose (HPMC)/polyvinylpyrrolidone (PVP) matrices. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and PVP were compressed into tablets at varying compression forces ranging from 2000 to 6000 Ib. In vitro drug release from the matrix tablets was determined and the results correlated with those of tablet water uptake and erosion studies. Drug release from the formulations containing both APAP and PE was slower than those containing only APAP (P < 0.05, F = 3.10). Drug release from tablets formulated with APAP only showed an initial burst at pH 1.16 or 7.45, and at high total polymer loading (> or = 9.6%). Formulations containing both APAP and PE showed slower drug release at pH 1.16 than at pH 7.45. At pH 1.16, a decline in the percentage of APAP released occurred after 18 hours. This was due to the hydrolysis of APAP to p-aminophenol. The drug dissolution data showed good fit to the Korsmeyer and Peppas model, and the values of the release exponents ranged from 0.20 to 0.62, indicating a complex drug release pattern. Tablet erosion studies indicated that the amount of APAP released was linearly related to the percentage of tablet weight loss. The kinetics of tablet water uptake was consistent with a diffusion and stress relaxation controlled mechanism. Overall, the results of this study indicated that PE, as a co-active in the formulation, modified the matrix, and hence retarded APAP release.

Carrier-Mediated Partitioning of Artemisinin into Plasmodium falciparum-Infected Erythrocytes

ABSTRACT The purpose of the present study was to characterize the partitioning of artemisinin into both uninfected and Plasmodium falciparum-infected red blood cells (RBCs). The partitioning of [14C](+)-artemisinin into RBCs was studied at four different hematocrit levels and eight time periods. At the optimum time of 2 h, the partitioning process was investigated with eight different drug concentrations ranging from 0.88 to 3.52 μM at 37 and 4°C. The effect of the presence of unlabeled artemisinin on the partitioning of the same concentration of [14C]artemisinin was studied. About 35 to 40% of the drug was seen to partition into uninfected RBCs at a hematocrit of 33%, irrespective of the incubation period or the drug concentration used. In contrast, infected RBCs showed an increase in partitioning of the drug with time until saturation was achieved at 1 h. While the partitioning of artemisinin into parasitized RBCs at 37°C was found to be significantly higher than that in nonparasitized RBCs, at 4°C both parasitized and nonparasitized RBCs showed identical partitioning of the drug. The partitioning of [14C]artemisinin into parasitized RBCs was completely inhibited in the presence of the same concentration of unlabeled artemisinin. However, no such effect was observed in nonparasitized cells, and no evidence suggesting that binding of the drug in parasitized RBCs is reversible was found. The partitioning of artemisinin into parasitized RBCs was found to be rapid, saturable, temperature dependent, irreversible, and subject to competitive inhibition with unlabeled artemisinin. The results obtained suggest the involvement of carrier mediation in the partitioning of artemisinin across the parasitized RBC membrane. In contrast, simple passive diffusion of artemisinin was seen in nonparasitized RBCs.

Effect of drug, formulation and process variables on granulation and compaction characteristics of heterogeneous matrices. Part 1: HPMC and HPC systems

Abstract The purpose of this study was to investigate the effects of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) ratios, total polymer loading and the use of pseudoephedrine as a co-active on the physical properties of acetaminophen granulation as well as that of the compressed tablets. The incorporation of pseudoephedrine to the acetaminophen–polymer formulations resulted in a decreased amount of water required for the wet granulation process. Moreover, the particle size of the granules decreased and the tablet hardness increased. Increasing the HPMC-to-HPC ratio increased both the particle size of granules and the tablet hardness. No clear trend in the particle size of granules and the tablet hardness was seen when the total polymer loading was varied at a given HPMC-to-HPC ratio. The tablet disintegration time was not influenced by the presence of pseudoephedrine; however, it decreased for the formulations containing a lower total polymer content. All the matrix systems investigated showed good compressibility. The effect of pseudoephedrine on the physical properties of wet granulated or compressed acetaminophen tablets was attributed to interference in the hydration characteristics of the matrix polymers.

Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique II. In vitro drug release studies and release mechanisms.

A novel freeze pelletization technique was evaluated for the preparation of wax-based sustained release matrix pellets. Pellets containing water-soluble drugs were successfully prepared using a variety of waxes. The drug release significantly depended on the wax type used and the aqueous drug solubility. The drug release decreased as the hydrophobicity of wax increased and the drug release increased as the aqueous drug solubility increased. In glyceryl monostearate (GMS) pellets, drug release rate decreased as the loading of theophylline increased. On the contrary, the release rate increased as the drug loading of diltiazem HCl increased in Precirol pellets. Theophylline at low drug loads existed in a dissolved state in GMS pellets and the release followed desorption kinetics. At higher loads, theophylline existed in a crystalline state and the release followed dissolution-controlled constant release for all the waxes studied. However, with the addition of increasing amounts of Brij 76, theophylline release rate increased and the release mechanism shifted to diffusion-controlled square root time kinetics. But the release of diltiazem HCl from Precirol pellets at all drug loads, followed diffusion-controlled square root time kinetics. Therefore, pellets capable of providing a variety of release profiles for different drugs can be prepared using this freeze pelletization technique by suitably modifying the pellet forming matrix compositions.

Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique: I. Formulation and process variables affecting pellet characteristics

A novel freeze pelletization technique was evaluated for the preparation of wax-based matrix pellets. Pellets containing either theophylline or diltiazem HCl were prepared using various waxes. In this technique, molten waxes along with a dispersed active ingredient were introduced as droplets into an inert and immiscible column of liquid to form pellets. An 80% (w/w) aqueous glycerol solution was found to be the most suitable column liquid for preparing spherical wax pellets. The physical stability of the molten wax suspensions was substantially improved by the addition of a 5% (w/w) colloidal silica gel. Pellet size obtained was directly proportional to the cubic root of the outer radius of the needle tip used to form pellets. Pellet size increased as the ratio of interfacial tension (gamma(LL)) to the density difference (Deltarho) between the molten matrix and the column liquid increased. Moreover, an increase in the drug load of theophylline increased the pellet size. However, an addition of a surfactant to the matrix slightly decreased the pellet size. Microscopic studies indicated that theophylline was homogenously dispersed throughout the matrix and existed in a crystalline state at higher drug loads. The percent drug recoveries ranged from 90.7 to 102.3% with acceptable drug loads up to 20% (w/w). Therefore, wax pellets containing drugs of varying aqueous solubility were successfully prepared using this technique.

Development and evaluation of a novel dissolution apparatus for medicated chewing gum products.

A novel dissolution apparatus was developed for medicated chewing gum products. A prototype gum product containing phenylpropa-nolamine hydrochloride (PPA) was used to evaluate the apparatus. The apparatus consists of a conical Teflon base and a rotating, ribbed Teflon plunger suspended in a dissolution vessel. Parameters evaluated were rotation speed, plunger frequency, medium volume, medium type, medium sampling location, number of plunger ribs, and number of gum pieces. Samples were taken over a 20-min period and samples were analyzed by HPLC. Cumulative percentage re-leased-versus-time profiles were obtained for each parameter evaluated. Statistical analysis of the gum product indicated that the only significant differences occurred at the lowest rotation speed and lowest plunger frequencies. A Level A correlation was found between the in vitro release profile for the 20-rpm and 30-cycles/min plunger frequency and the in vivo chew-out study.

Content Analysis and Stability Evaluation of Selected Commercial Preparations of St. John's Wort

Content analysis and stability studies were performed for the commercial products of St. Johns wort. Six marketed formulations were analyzed for their hypericin and pseudohypericin content. These products were standardized to contain 0.3% hypericin. Results revealed total hypericin as 7.72–38.57% of the labeled claim with varying concentrations of pseudohypericin. Stability studies were carried out under three different storage conditions: 1) 25 ± 2°C, 60 ± 5%RH for six months, 2) 40 ± 2°C, 75 ± 5%RH for six months, and 3) 50°C for one month. Tablet formulations were also analyzed for their hardness and friability. Stability studies revealed significant decrease in the content of the marker compounds with time.

Characterization of Drug Release from Liposomal Formulations in Ocular Fluid

The successful application of liposomes in topical ophthalmic drug delivery requires knowledge of vesicle stabilization in the presence of tear fluid. The release of procaine hydrochloride (PCH) from large unilamellar liposomes in the presence of simulated tear fluid was studied in vitro as a function of bilayer lipid content and tear protein composition. Reverse-phase evaporation vesicles were prepared from egg phosphatidylcholine, stearylamine or dicetyl phosphate, and cholesterol. The relationship between lipid composition and encapsulation efficiency, vesicle size, drug leakage upon storage at 4 degrees C, and the release of PCH-loaded liposomes was studied. The encapsulation efficiency was found to be dependent upon the lipid composition used in the liposome preparation. In particular, phosphatidylcholine vesicles containing cholesterol and/or charged lipids had a lower entrapment efficiency than liposomes prepared with phosphatidylcholine alone. However, the drug release rate was reduced significantly by inclusion of cholesterol and/or charged lipids in the liposomes. The release kinetics of the entrapped agent seemed to be a biphasic process and the drug-release in both simulated tear fluid (STF) and pH 7.4 phosphate buffered saline (PBS) solutions followed pseudo first-order kinetics in the early stage of the release profile. The drug-release appeared to be diffusion and/or partition controlled. Drug release from liposomes into STF, pH 7.4 PBS, and five different modified tear formulations was also evaluated. While serum-induced leakage is attributed to high-density lipoprotein-mediated destabilization, it was determined that lactoferrin might be the protein component in tear fluid that has the primary influence on the liposome-entrapped drug release rate. Five local anesthetics, benoxinate, proparacaine, procaine, tetracaine, and benzocaine were entrapped in liposomal vesicles by a reverse-phase evaporation (REV) technique. The release of these structurally similar topical anesthetics entrapped in positively charged liposomes (egg phosphatidylcholine, stearylamine, and cholesterol in a 7:2:1 molar ratio) was evaluated in a simulated tear fluid and pH 7.4 phosphate buffered saline solution. The liposomes appeared to be useful carriers for these drugs to retard their in vitro release in tear fluid and perhaps sustain or control their release in the eye for better therapeutic efficacy. An analysis of the release data demonstrated that for this series of drugs, drug partition coefficient has the largest effect on release rate, with molecular weight exhibiting a smaller effect. Release rate was found to decrease with increased lipophilicity or increased molecular weight.

Effect of Drug, Formulation, and Process Variables on Granulation and Compaction Characteristics of Heterogeneous Matrices: Part II. HPMC and PVP Systems

AbstractA heterogeneous matrix comprising hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) at various ratios was granulated using acetaminophen and pseudoephedrine as model drugs. The effect of drug, polymer ratio, total polymer loading, and volume of the granulating fluid on granule growth, granule size distribution, compaction, and tablet properties of the matrix was studied. Formulations containing both acetaminophen and pseudoephedrine required less water to granulate than those containing only acetaminophen. Moreover, the particle sizes of granules prepared with acetaminophen and pseudoephedrine were smaller than those containing only acetaminophen. Tablet hardness increased and friability decreased considerably in all formulations containing pseudoephedrine. In general, the tablet hardness and tablet disintegration time varied with changes in total polymer loading, fraction of HPMC in the matrix, and composition of the model drug(s). All the matrix systems studied showed good flow...

Physico chemical characterization of a novel anti-cancer agent and its comparison to Taxol®

Every year several thousand compounds are screened for their anti-cancer activity by a general test procedure amongst which only few selected move past the in vitro screening process. This may be due to the intrinsic property of the drug substance. Therefore, a complete physicochemical characterization of a New Chemical Entity (NCE) is essential to understand the effect of these properties on the in vitro and possibly in vivo behavior of these compounds. Various physicochemical properties such as dissociation constant, octanol-water partition co-efficient, pH solubility, stability, thermal characterization and membrane permeability were evaluated for a novel tubulin-binding agent JCA112 and were compared to that of Taxol®. The drug exhibited a pKa value of 10.9, log P value of 2.3, pH dependent solubility, and low artificial membrane permeability. Stability of the drug substance in the in vitro screening media suggested a significant degradation during the 48-hour study duration. The results demonstrate that due to low aqueous solubility, limited membrane permeability and due to insufficient stability of JCA112 in the in vitro screening media, the drug exhibited limited anti-cancer activity. Along with challenging physicochemical characteristics, a generalization of the in vitro testing procedure may also result in loss of important anti-cancer agents. As a result, a complete understanding of the physico-chemical properties of the drug leading to prototype formulation with acceptable physico-chemical properties may be required for successful in vitro screening.