Melgardt M. de Villiers

Nano-encapsulation of furosemide microcrystals for controlled drug release

Furosemide microcrystals were encapsulated with polyions and gelatin to control the release of the drug in aqueous solutions. Charged linear polyions and gelatin were alternatively deposited on 5-microm drug microcrystals through layer-by-layer (LbL) assembly. Sequential layers of poly(dimethyldiallyl ammonium chloride) (PDDA) and poly(styrenesulfonate) (PSS) were followed by adsorption of two to six gelatin/PSS bilayers with corresponding capsule wall thicknesses ranging from 45 to 115 nm. The release of furosemide from the coated microparticles was measured in aqueous solutions of pH 1.4 and 7.4. At both pH values, the release rate of furosemide from the encapsulated particles was reduced by 50-300 times (for capsules coated with two to six bilayers) compared to uncoated furosemide. The results provide a method of achieving prolonged drug release through self-assembly of polymeric shells on drug microcrystals.

Controlled Release of Dexamethasone from Microcapsules Produced by Polyelectrolyte Layer-by-Layer Nanoassembly

Purpose.In an effort to expand the application of core-shell structures fabricated by electrostatic layer-by-layer (LbL) self-assembling for drug delivery, this study reports the controlled release of dexamethasone from microcrystals encapsulated with a polyelectrolyte shell.Methods.The LbL self-assembly process was used to produce dexamethasone particles encapsulated with up to five double layers formed by alternating the adsorption of positively charged poly(dimethyldiallyl ammonium chloride), negatively charged sodium poly(styrenesulfonate) and depending on the pH positively or negatively charged gelatin A or B onto the surface of the negatively charged dexamethasone particles. The nano-thin shells were characterized by quartz crystal microbalance measurements, microelectrophoresis, microcalorimetry, confocal microscopy, and scanning electron microscopy. In vitro release of dexamethasone from the microcapsules suspended in water or carboxymethylcellulose gels were measured using vertical Franz-type diffusion cells.Results.Sonication of a suspension of negatively charged dexamethasone microcrystals in a solution of PDDA not only reduced aggregation but also reduced the size of the sub-micrometer particles. Assembly of multiple polyelectrolyte layers around these monodispersed cores produced a polyelectrolyte multilayer shell around the drug microcrystals that allowed for controlled release depending on the composition and the number of layers.Conclusions.Direct surface modification of dexamethasone microcrystals via the LbL process produced monodispersed suspensions with diffusion-controlled sustained drug release via the polyelectrolyte multilayer shell.

Effect of 4-Sulphonato-Calix(n)Arenes and Cyclodextrins on the Solubilization of Niclosamide, a Poorly Water Soluble Anthelmintic

The present study investigated the effect of water-soluble 4-sulphonato-calx[n]arenes, cyclodextrins, and combinations of these macromolecules on the aqueous solubility of a poorly water-soluble drug, niclosamide. Complexation between the macromolecules and niclosamide was confirmed by thermal analysis and phase solubility studies in a pH 7.0 McIlvaine buffer kept at 30°C. Results show that the increase in solubility ranked as follows: 4-sulphonato-calix [6]arene+hydroxypropyl-β-cyclodextrin (HP-β-CD)> 4-sulphonato-calix[6]arene+β-cyclodextrin > 4-sulphonato-calix[6]arene +γ-cyclodextrin=HP-β-CD>4-sulphonato-calix[6]arene >4-sulphonato-calix[8]arene=4-sulphonato-calix[4]arene>β-cyclodextrin. Type B phase solubility profiles were observed, indicating a decrease in solubility at concentrations > 0.004 to 0.005 mol/L of the 4-sulphonato-calix[n]arenes or combinations of 4-sulphonato-calix[6]arene and the cyclodextrins. However, below this concentration, the greatest increase in the aqueous solubility niclosamide was observed when 4-sulphonato-calix[6]arene and HP-β-CD were combined. This increase in solubility was additive.

Characterization of the solubility and dissolution properties of several new rifampicin polymorphs, solvates, and hydrates.

Based on reports that tuberculosis is on the increase, this investigation into the physicochemical properties of rifampicin when recrystallized from various solvent systems was undertaken. Rifampicin is an essential component of the currently recommended regimen for treating tuberculosis, although relatively little is known about its solubility and dissolution behavior in relation to its solid-state properties. A rifampicin monohydrate, a rifampicin dihydrate, two amorphous forms, a 1:1 rifampicin:acetone solvate, and a 1:2 rifampicin:2-pyrrolidone solvate were isolated and characterized using spectral, thermal, and solubility measurements. The crystal forms were relatively unstable because except for the 2-pyrrolidone solvate, all the hydrated or solvated materials changed to amorphous forms after desolvation. Fourier transform infrared (FTIR) analysis confirmed the favorable three-dimensional organization of the pharmacophore to ensure antibacterial activity in all the crystal forms except the 2-pyrrolidone solvate. In the 2-pyrrolidone solvate, the strong IR signals of 2-pyrrolidone interfered with the vibrations of the ansa group. The 2-pyrrolidone solvate was the most soluble in phosphate buffer at pH 7.4. This solvate also had the highest solubility (1.58 mg/ml) and the fastest dissolution in water. In 0.1 M HCl, the dihydrate dissolved the quickest. A X-ray amorphous form (amorph II) was the least soluble and had the slowest dissolution rate because the powder was poorly wettable and very electrostatic.

Aqueous solubilization of furosemide by supramolecular complexation with 4-sulphonic calix[n]arenes.

The solubilization of the practically water insoluble drug furosemide by guest:host inclusion complexation with 4‐sulphonic calix[n]arenes has been reported. The 4‐sulphonic calix[n]arenes are water‐soluble phenolic cyclooligomers that form inclusion complexes with neutral molecules. The solubility of furosemide in acidic (pH < 4) aqueous solutions containing increasing concentrations of the calixarenes was determined at 30°C and the concentration of furosemide in solution was determined by HPLC. Results showed that the molecular size of the 4‐sulphonic calix[n]arenes and the concentration of the calix[n]arenes significantly influenced the increase in the solubility of furosemide. 4‐Sulphonic calix[6]arene improved the solubility of furosemide the most (± 104%) followed by 4‐sulphonic calix[8]‐arene (±84–102%), while 4‐sulphonic calix[4]arene increased the solubility of furosemide the least (±73–81%). The increase in furosemide solubility afforded by the calixarenes was most probably the result of the incorporation of the non‐polar portions of the furosemide molecule into the non‐polar cavities of the calixarenes similar to furosemide:cyclodextrin complexes. The driving force for this interaction was the reduction in the non‐polar‐water interfacial surface area when the furosemide (guest) molecules were inserted into the 4‐sulphonic calix[n]arenes (host).

Quality evaluation of generic drugs by dissolution test: changing the USP dissolution medium to distinguish between active and non-active mebendazole polymorphs

Mebendazole is practically insoluble in water and studies of its polymorphism has led to the identification and characterization of three polymorphic forms (A, B, C) displaying solubility and therapeutic differences that show that polymorph C is therapeutically favored. The objective of this study was to adjust the USP dissolution test for mebendazole so that it was able to distinguish between the dissolution properties of three mebendazole polymorphs. This would provide generic manufacturers with one more test to ensure that the therapeutically active polymorph C is used. The results obtained in this study show that the USP dissolution test conditions were not able to distinguish between the dissolution properties of completely dispersed mebendazole polymorphs with comparable particle sizes. When sodium lauryl sulfate was removed from the dissolution medium, the percentage dissolved versus time profiles changed so that polymorph C dissolved faster (70% within 120 min) compared to polymorph B (37% within 120 min) and polymorph A (20% within 120 min).

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.

Comparison of the Physical and Chemical Stability of Niclosamide Crystal Forms in Aqueous Versus Nonaqueous Suspensions

In an effort to produce physically stable and pharmaceutically acceptable suspensions of niclosamide, this study reports the differences in physical and chemical stability of aqueous vs. nonaqueous suspensions of a niclosamide anhydrate, two monohydrates HA and HB, a 1:1 niclosamide N,N‐dimethylformamide solvate, a 1:1 niclosamide dimethyl sulfoxide solvate, a 1:1 niclosamide methanol solvate, and a 2:1 niclosamide tetraethylene glycol hemisolvate. Evaluation of aqueous and nonaqueous suspensions showed that in aqueous suspensions anhydrous, and solvated niclosamide crystal forms were transformed to a monohydrate, HA, which was reasonably stable but which did eventually transform to the most stable monohydrate HB. The order in which these crystal forms transformed to monohydrate HB were: Anhydrate > N,N‐dimethylformamide > dimethyl sulfoxide > methanol > tetraethylene glycol > monohydrate HA. In a nonaqueous propylene glycol vehicle, the transformation to the monohydrous forms was not observed and on desolvation the solvated crystals transformed to the anhydrous form. In all cases, immediately upon desolvation or dehydration, the crystal structures of the desolvated materials were similar to that of the solvated materials. However, the isomorphic structures, formed after desolvation, were unstable and rehydrated or resolvated when exposed to the solvent or converted to the anhydrous form in a dry environment. The crystal forms remained chemically stable in both aqueous and nonaqueous suspensions for the length of the study.

Solvent and Surfactant Enhanced Solubilization, Stabilization, and Degradation of Amitraz

Abstract In an effort to help with the development of effective dip vat management and waste disposal strategies this study determined how solution properties such as pH, buffer composition, ionic strength, temperature, solubility in organic solvents and the addition of commonly used solubilizing agents influenced the hydrolysis of amitraz. Amitraz degrade by means of hydrolysis described by a pseudo-first order rate process and a type ABCD pH rate profile. Hydrolysis increased with temperature and was fastest at low pH, slowest at neutral to slightly alkaline pH, and slightly increased above pH 10. However, buffer concentration and ionic strength influenced the hydrolysis rate and had to be accounted for before constructing a pH rate profile. Hydrolysis seems to depend on the dielectric constant of solvent mixtures and was fastest in water, slower in propylene glycol and ethanol solutions, and slowest in DMSO mixtures. In surfactant solutions, anionic micelles enhanced and cationic micelles retarded the hydrolysis rate. The magnitude of micellar effects decreased with increasing concentrations of the surfactants. The increased solubility and faster hydrolysis of amitraz in the sodium lauryl sulfate solutions showed that anionic surfactants potentially could be used for cleaning up amitraz spills, because it both solubilized the drug and catalyzed hydrolysis.

A Comparison of Interaction and Solvent Deposition Mixing

AbstractThe mixing of microingredients with diluents may be conducted by various methods. The purpose of this report is to compare the uniformity of mixing of finely powdered reserpine after mixing by an interactive and a solvent deposition method. Reserpine was used in concentrations of 0.25% with Avicel PH 102 and Sorbit Instant as carrier materials. The uniformity of the mixtures was compared by coefficients of variation (CV) of the content of powder or tablet samples. The dissolution of powder samples was measured in a rotating bottle apparatus. Interactive mixing with Avicel produced samples with larger variation in reserine content compared to solvent deposition. The variation in content was not significantly different when the drug was mixed interactively or by solvent deposition on Sorbit. Smaller coefficients of variation in content were observed for tablet samples compared to powder samples in most cases. The CVs obtained with powder samples for all the mixtures. except for solvent deposition on...