Adel Sakr

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.

Application of multiple response optimization technique to extended release formulations design

The purpose of the present study was to apply response surface methodology and multiple response optimization utilizing superimposed contour diagrams to design extended release formulations with a preplanned release profile. Bumetanide solution was layered on sugar pellets followed by coating with various coating formulations according to a central composite statistical design using a Glatt GPCG 1 Wurster Fluid Bed. The coated pellets were tested for their release profiles and the percent of drug released after 1, 4 and 8 h were used to describe and optimize the release process. Statistical models describing the percent bumetanide released after 1, 4 and 8 h were developed and the corresponding contour diagrams were superimposed to predict the coating formulation parameters expected to produce target release profile. The pellets coated with the designed coating formulation were tested for their release profiles in comparison to the target profile. According to the model-independent approach using similarity factor (F2), the dissolution profile of the designed formulation and the expected target profile were found to be similar. It was concluded that response surface methodology and multiple response optimization could be successfully used to design and optimize extended release formulations with desired preplanned release profile.

Characterization of Esterase and Alcohol Dehydrogenase Activity in Skin. Metabolism of Retinyl Palmitate to Retinol (Vitamin A) During Percutaneous Absorption

Retinyl palmitate, a widely used ingredient in cosmetic products, is promoted for its beneficial effects on the appearance of skin. Previous studies suggest that enzymes are available in skin to metabolize this ingredient during skin absorption. Esterase activity hydrolyzes retinyl palmitate to retinol (vitamin A), which is oxidized in many tissues to retinoic acid primarily by alcohol dehydrogenase. The activities of esterase and alcohol dehydrogenase were characterized in hairless guinea pig skin by using flow-through diffusion cells and radiolabeled model compounds (methyl salicylate and benzyl alcohol) previously shown to be metabolized by these enzymes. Methyl salicylate was hydrolyzed by esterase to a greater extent in viable skin than in nonviable skin. Glycine conjugation of salicylic acid and benzoic acid occurred only in viable skin. The metabolism of methyl salicylate and benzyl alcohol occurred to a greater extent in male guinea pig skin than in female guinea pig skin. The percutaneous absorption of both radiolabeled compounds was similar in viable and nonviable skin. About 30 and 18% of topically applied retinyl palmitate were absorbed from an acetone vehicle by hairless guinea pig skin and human skin, respectively. Less than 1% of the applied dose of this lipophilic compound diffused from skin into the receptor fluid. Retinol was the only detectable metabolite of retinyl palmitate in both hairless guinea pig and human skin. In human skin, 44% of the absorbed retinyl palmitate was hydrolyzed to retinol. The use of retinyl palmitate in cosmetic formulations may result in significant delivery of retinol into the skin.

The effect of excipients on the stability of levothyroxine sodium pentahydrate tablets

Levothyroxine tablets, 50 microg, have been marketed for many decades but have had numerous recalls due to degradation and failure to meet potency. These experiments were devised to study the effects of various excipients on the stability of levothyroxine sodium pentahydrate in aqueous slurries and in formulated tablets. The active alone was found to be stable in the solid state for 6 months at 40 degrees C/75% RH whether stored in open or closed containers, and was found to be non-hygroscopic under normal processing conditions (>30% RH). In aqueous slurries with an excipient, the stability of the active improved as the pH of the slurry was increased from pH 3 to 11. Tablets manufactured with lactose anhydrous, starch, or microcrystalline cellulose failed to meet USP assay requirements at 3 months at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate or mannitol met USP assay requirements at 3, but not 6 months when stored at 40 degrees C/75% RH. Tablets manufactured with dibasic calcium phosphate and a basic pH modifier, such as sodium carbonate, sodium bicarbonate, or magnesium oxide, met the USP assay requirements at both 3 and 6 months. Thus, the use of basic pH modifiers is a potential technique for improving the stability of levothyroxine sodium pentahydrate tablets.

Predicting dissolution via hydrodynamics : salicylic acid tablets in flow through cell dissolution

A model was established for the dissolution of non-disintegrating salicylic acid tablets as a function of hydrodynamic conditions in the Flow Through Cell system (USP Apparatus 4). The approach was to model the dissolution rate of the material as a function of the Reynolds number, the dimensionless engineering term that describes the degree of turbulence. The dissolution rate of USP calibrator salicylic acid tablets was measured as a function of tablet size, orientation within the cell, dissolution media flow rate, and cell size. All of these variables were found to have an effect on dissolution rate, consistent with theory. An equation to predict this dissolution was established as: N(SH)=-21.1+12.6xN(RE)(0.5), R(2)=0.99; 10

Modeling of a roller-compaction process using neural networks and genetic algorithms.

In this study, roller-compaction of acetaminophene was studied to model the effect of binder type (hydroxypropyl methyl cellulose (HPMC), polyethylene glycol (PEG), Carbopol), binder concentration (5, 10 and 20%), number of roller-compaction passes (one or two), and extragranular microcrystalline cellulose addition on the properties of compressed tablets. Forty-two batches resulted from the experimental design. The artificial neural network methodology (ANN) along with genetic algorithms were used for data analysis and optimization. ANN and genetic models provided R2 values between 0.3593 and 0.9991 for measured responses. When a set of validation experiments was analyzed, genetic algorithm predictions of tablet characteristics were much better than the ANN. Optimization based on genetic algorithm showed that using HPMC at 20%, with two roller-compaction passes would produce mechanically acceptable acetaminophene tablets. PEG and carbopol would also produce acceptable tablets perhaps more suitable for sustained release applications. Using PEG as a binder had the additional advantage of not requiring an external lubricant during tablet manufacturing.

Studies of the mechanical properties of free films prepared using an ethylcellulose pseudolatex coating system

Free films produced using a commercially available ethylcellulose (EC) pseudolatex coating system (Aquacoat®) were prepared by a spraying method. The effect of either of 10 different plasticizers representing three chemical classes (citrate esters, di-acid esters and fatty acids/alcohols) on free film mechanical properties was determined using an Instron tensile testing apparatus. The plasticizers were each added to the EC pseudolatex formula at levels of 25, 30 or 35% (w/w), respectively. Increasing the amount of plasticizer led to an increase in free film elongation and a decrease in modulus and stress. Differences among the individual plasticizers and classes of plasticizers evaluated were correlated with their molecular structure and a rank order could be identified. Selected films containing 30% plasticizer were evaluated under conditions of elevated temperature and humidity for storage times of up to 1 month. The results indicated that plasticizer type and amount and elevated storage temperature and humidity influence free film mechanical behavior, particularly free film elongation and toughness. These changes probably arise from further gradual coalescence of EC pseudolatex particles.

The effects of packaging on the stability of a moisture sensitive compound.

Packages that provided stability (less than a 10% loss in potency) of a moisture sensitive compound (PGE-7762928) in tablet form at accelerated conditions for 6 months were identified. The equilibrium moisture content of the tablets at 25 degrees C/60%RH, 30 degrees C/60%RH and 40 degrees C/75%RH were 2.3,2.4, and 2.9%, respectively. The tablet equilibrium moisture content, degradation rate of unpackaged product, and the moisture barrier properties of the packages were used to predict the stability of the packaged product. The physical and chemical stability (HPLC assay) of the products were measured after 2,4,6,8,12, and 24 weeks at ICH conditions. The Containers-Permeation(1) of polyvinyl chloride blisters, cyclic olefin blisters, aclar blisters, cold-form aluminum blisters was 0.259, 0.040, 0.008 and 0.001 mg per blister per day, respectively. At 6 months at 40 degrees C/75%RH, the percent active was 84% in polyvinyl chloride blisters, 91% in cyclic olefin blisters, 97% in aclar blisters, 100% in cold-form aluminum blisters and 99% in an high density polyethylene bottle with a foil induction seal. The stability results for the packaged product were fairly consistent with the predictions based on the moisture sensitivity of the product and the moisture barrier properties of the respective package. To gain a better prediction, the flux value determined by the Containers-Permeation procedure was adjusted for the internal moisture concentration of the blister.

In Vitro Skin Absorption and Metabolism of Benzoic Acid, p-Aminobenzoic Acid, and Benzocaine in the Hairless Guinea Pig

The percutaneous absorption and metabolism of three structurally related compounds, benzoic acid, p-aminobenzoic acid (PABA), and ethyl aminobenzoate (benzocaine), were determined in vitro through hairless guinea pig skin. Benzocaine was also studied in human skin. Absorption of benzocaine was rapid and similar through both viable and nonviable skin. The absorption of the two acidic compounds, benzoic acid and PABA, was greater through nonviable skin. A small portion (6.9%) of absorbed benzoic acid was conjugated with glycine to form hippuric acid. Although N-acetyl-benzocaine had not been observed as a metabolite of benzocaine when studied by other routes of administration, both PABA and benzocaine were extensively N-acetylated during percutaneous absorption. Thus, the metabolism of these compounds should be considered in an accurate assessment of absorption after topical application.

Determination of levothyroxine and its degradation products in pharmaceutical tablets by HPLC-UV-ICP-MS

A new analytical methodology using high-performance liquid chromatography (HPLC) coupled to inductively coupled plasma mass spectrometry (ICP-MS) was applied to study the presence of possible degradation products in levothyroxine tablets. The analytical methodology takes advantage of the element-specific and highly-sensitive I detection provided by ICP-MS and is applied to the speciation of: 3,3′,5,5′-tetraiodothyronine (T4); 3,3′,5-triiodothyronine (T3); 3,5-diiodothyronine (T2); 3,3′,5,5′-tetraiodothyroacetic acid (TTAA4); 3,3′,5-triiodothyroacetic acid (TTAA3); and 3,5-diiodothyroacetic acid (TTAA2). Chromatographic conditions were optimized by using UV absorption at 225 nm and ICP-MS detection of 127I. Complete chromatographic resolution of the levothyroxine degradation products within 25 min was obtained using 22% (v/v) acetonitrile at pH 2.3, adjusted with 0.08% (v/v) trifluoroacetic acid. The introduction of the mobile phase containing acetonitrile was performed by post column on-line dilution (1∶3.3) of the chromatographic eluent with a 2% (v/v) nitric acid solution using a PTFE tee. The separations with either detector were good with little detector effect on the resolution. The peak broadening caused by on-line dilution was insignificant. The detection limits obtained with UV detection ranged from 28.9 to 34.5 µg l−1, whereas those obtained with the plasma detector were about 175–375 times better (lower). Finally, the analytical methodology was applied to the determination of possible iodine species originated by degradation of T4 in synthetic and commercial levothyroxine sodium tablets.