Preparation and characterization of highly porous direct compression carrier particles with improved drug loading during an interactive mixing process.

The aim of this study was to prepare highly porous carrier particles by emulsion solvent evaporation and compare the loading capacity of these beads with two traditional carriers, sugar beads, and microcrystalline cellulose granules during an interactive mixing process. The porous carrier particles were prepared by an emulsion solvent evaporation process using cellulose propionate as a binder, anhydrous dibasic calcium phosphate, and ion exchange resins as a fillers, and polyethylene glycol as a pore inducer. Micronized furosemide or griseofulvin powder was mixed with the same volume of each carrier in an interactive mixing process. The tableting properties, drug loading per unit volume of carrier, content uniformity of the mixtures, and dissolution of the drugs from the mixtures were measured. The results showed that highly porous microcapsules with desirable hardness equivalent to that of sugar beads and MCC granules were successfully prepared. On average the loading capacity of the new carrier was 310% that of sugar beads and 320% that of MCC granules during an interactive mixing process with very good content uniformity. The tableting properties of the microcapsules were equivalent to that of microcrystalline cellulose granules, and the dissolution of the drugs from interactive mixtures prepared with the new carrier was equivalent to that of drug suspensions. This showed that the prepared microcapsule carrier could be used to improve the loading capacity during an interactive mixing and to prepare tablets by direct compression.

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis.

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.

Variable-temperature X-ray powder diffraction analysis of the crystal transformation of the pharmaceutically preferred polymorph C of mebendazole.

Mebendazole is a common benzimidazole anthelmintic that is water insoluble. It is reported to exist in three different polymorphic forms in the solid state, i.e. polymorph A, B and C. Form C is the pharmaceutically preferred form because of its increased aqueous solubility. This paper deals with the use of variable-temperature X-ray powder analysis (VTXRPD) to study the transformation of Form C. Results showed that Form C was stable and transformed to the more stable polymorph A at high temperature (>180 degrees C). This transformation is a first-order process with activation energy of 238 +/- 16 kJ/mole. Further studies showed that compression did not cause any significant changes in the crystal structure of polymorph C.

Effect of processing variables on the release and particulate properties of sustained release amoxicillin microcapsules prepared by emulsion solvent evaporation.

This study reports the preparation of amoxicillin microcapsules by an emulsion solvent evaporation process. In particular the effect of processing variables including the dimension and position of stirring paddle and container; volume of continuous phase versus dispersion phase; stirring speed and encapsulation temperature on the release and particulate properties of the amoxicillin microcapsules were determined. When the diameter of the paddle was half of that of the container and the clearance between the paddle and the bottom of the vessel was 1/4 of the total volume in the vessel, almost no material stuck to the inside wall of the beaker and uniform microcapsules were prepared. Very uniform, round microcapsules were also prepared with a high yield when V(acetone): V(light mineral oil) = 1 : 3 and 1 : 5 because these systems ensured the formation of uniform emulsions. Physical evaluation of the microcapsules also showed that optimum drug release was achieved when the microcapsules were round, did not aggregate, were protected from the burst effect, the stirring speed for preparation was between 600-800 rpm and evaporation temperature was 25 degrees C. Microcapsules prepared using these ideal conditions achieved constant amoxicillin release for up to 12 h.

Effect of viscosity and concentration of wall former, emulsifier and pore-inducer on the properties of amoxicillin microcapsules prepared by emulsion solvent evaporation.

This study reports the laboratory optimization for the preparation of sustained release amoxicillin (AMX) ethylcellulose microcapsules by an emulsion solvent evaporation process by adjusting the viscosity and concentration of ethylcellulose, ratio of amoxicillin to ethylcellulose, and concentration of emulsifier and pore inducer. When ethylcellulose with a viscosity of 45 mPa.s was used, almost no material stuck to the inside wall of the beaker and uniform microcapsules were prepared. The average diameter of microcapsules increased and yield and release rate decreased as the concentration of ethylcellulose increased from 1% to 8%. The release of amoxicillin from microcapsules was influenced by the ratio of the weight of drug to that of ethylcellulose and ratios of 2:1 and 4:1 were most suited for optimum amoxicillin release. The average diameter of microcapsules decreased and the release rate increased as the concentration of the emulsifier increased from 1.5% to 6.0%, however, the size distribution became significantly wider with the increase in the concentration of sorbitan monooleate. Addition of small amounts of a water-soluble agent sucrose improved the release of active ingredient from the microcapsule matrix without influencing the morphology and particulate properties of the microcapsules.

Effect of a change in crystal polymorph on the degree of adhesion between micronized drug particles and large homogenous carrier particles during an interactive mixing process.

This study reports the effect of a change in crystal form on the quality of interactive mixtures prepared with homogenous sugar beads and the three polymorphs of chloramphenicol palmitate (CAP). Six mixtures containing micronized CAP polymorph powder (0.5%) and sugar beads (99.5%) were mixed in a Turbula mixer at 27 rpm or 54 rpm for 2.5, 5, 10, or 20 min. Three of the six mixtures was screened to remove the unmixed drug powder. The content uniformity (CV %) of the three screened and three unscreened mixtures was determined by determining the variation in drug content of 10 randomly taken samples from each mixture. Comparison of the amount of drug screened and the content uniformity of the mixtures showed that at short mixing times and 27 rpm and longer mixing times of 10 and 20 min at 54 rpm, the three crystal forms formed interactive mixtures with statistically the same content uniformity. In contrast at 54 rpm and mixing for 5 min and shorter, form A formed less homogeneous interactive mixtures compared with forms B and C. Consistently at both mixing speeds a larger amount of form A, compared with forms B and C, was screened from the mixtures. The results showed that the affinity between forms B and C and the carrier sugar beads is higher than that between form A and the sugar beads. Therefore, changing the crystal form of a drug influences the affinity between the drug and a carrier when preparing interactive mixtures.

Structural characterization, physicochemical properties, suspension stability, and adsorption properties of four solid forms of amitraz.

This paper reports the identification and preparation of three crystalline (A-C) and one metastable form (D) of amitraz. These were identified by their crystal morphology, crystal structures, aqueous solubility, and thermal properties. Form C was the least soluble (7 mug/mL) and had the highest melting point (115 degrees C). The differences in melting point (82 vs 72 degrees C) and solubility (20 vs 23 mug/mL) of forms A and B were not significant. The metastable noncrystalline form D (Tg = 38 degrees C, transition temperature = 62 degrees C, and melting point = 78 degrees C) was obtained by deposition on the surface of activated carbon from acetonitrile solutions. When the anionic surfactant sodium lauryl sulfate was added to the solubility medium, the solubilities of forms A and B were increased 10-11-fold and that of form C was increased 28-fold. Changing the crystal form had an effect on the stability of amitraz suspensions. Form C was the most stable with a t(1/2) of 136 days, and form B was the least stable with a t(1/2) of 28 days. The stability correlated with solubility differences. The addition of sodium lauryl sulfate to the suspensions increased the rate of hydrolysis (mean t(1/2) = 17 h), and because of increased solubility, there was no difference in the stability of the crystal forms in the anionic surfactant solution.

Preparation and physicochemical characterization of 5 niclosamide solvates and 1 hemisolvate.

The purpose of the study was to characterize the physicochemical, structural, and spectral properties of the 1:1 niclosamide and methanol, diethyl ether, dimethyl sulfoxide, N,N' dimethylformamide, and tetrahydrofuran solvates and the 2:1 niclosamide and tetraethylene glycol hemisolvate prepared by recrystallization from these organic solvents. Structural, spectral, and thermal analysis results confirmed the presence of the solvents and differences in the structural properties of these solvates. In addition, differences in the activation energy of desolvation, batch solution calorimetry, and the aqueous solubility at 25 degrees C, 24 hours, showed the stability of the solvates to be in the order: anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > methanol solvate > dimethyl sulfoxide solvate > N,N' dimethylformamide solvate. The intrinsic and powder dissolution rates of the solvates were in the order: anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > N,N' dimethylformamide solvate > methanol solvate > dimethyl sulfoxide solvate. Although these nonaqueous solvates had higher solubility and dissolution rates than the monohydrous forms, they were unstable in aqueous media and rapidly transformed to one of the monohydrous forms.

Preparation and physicochemical properties of niclosamide anhydrate and two monohydrates.

The intent of the study was to prepare and characterize three crystal forms of niclosamide namely the anhydrate and the two monohydrates and to investigate the moisture adsorption and desorption behavior of these crystal forms. The crystal forms were prepared by recrystallization and were characterized by differential scanning calorimetry, thermogravimetric analysis, isoperibol solution calorimetry, Karl Fischer titration, and X-ray powder diffractometry. Moisture adsorption by the anhydrate at increased relative humidities and two temperatures, 30 and 40 degrees C, was measured while the desorption from the monohydrates was determined at 45, 55, and 65 degrees C for monohydrate H(A) and 75, 90, and 100 degrees C for monohydrate H(B). Thermal analysis and solution calorimetry showed that monohydrate H(B) is more stable than monohydrate H(A) and solubility measurements showed the solubility of the crystal forms decreased in the order: anhydrate>>monohydrate H(A)>monohydrate H(B). With an increase in temperature and relative humidity niclosamide anhydrate adsorbed moisture to form monohydrate H(A) by a random nucleation process. Dehydration of monohydrate H(A) at increased temperatures followed zero order kinetics and resulted in a change to the anhydrate. Monohydrate H(B) was transformed to the anhydrate at higher temperatures by a three-dimensional diffusion mechanism.

Structural characterization, physicochemical properties, and thermal stability of three crystal forms of nifedipine.

In this study the single-crystal X-ray structure of the solvated species (nifedipine)2. 1,4-dioxane is reported for the first time. Included solvent molecules are located in isolated cavities in the crystal, yielding a very stable solvate. Desolvation of this species involves complete disruption of the crystal structure at the relatively high temperature of 150-153 degrees C, i.e., 50 degrees above the boiling point of 1,4-dioxane, and yields a monoclinic polymorph (Modification I) with a melting point of 174 degrees C. When exposed to an aqueous medium for 48 h, the solvate transformed into a dihydrate. The aqueous solubilities of the above species were in the order: 1,4-dioxane solvate >or= Modification I > dihydrate. The solubility of nifedipine was increased sixfold when transformed into an amorphous form by quenched fusion. This amorphous form was relatively stable at room temperature but converted to Modification I when suspended in water at pH 1. The fused materials also converted to Modification I through an intermediate, Modification III, within 6 days when kept at 40 degrees C for 6 days. XRPD analysis showed that grinding increased the crystallinity of the amorphous form due to partial transformation to Modification I. The pulverized amorphous powder was more stable at 40 degrees C and was approximately three times as soluble as Modification I.