Dissolution rate enhancement of the anti-inflammatory drug diflunisal by coprecipitation with a biocompatible polymer using carbon dioxide as a supercritical fluid antisolvent

Dissolution rate enhancement of the anti-inflammatory drug diflunisal was achieved using for the first time a supercritical fluid technology. The supercritical fluid antisolvent (SAS) method was applied to precipitate diflunisal alone and to coprecipitate the drug together with the biocompatible polymer polyvinylpyrrolidone (PVP K-30 and K-10). The untreated and SAS processed diflunisal, and the coprecipitates were characterized in terms of size, morphology, crystallinity, compositions, drug-polymer interactions, and drug release. SAS processed diflunisal exhibited a polymorphic form different from that of the untreated drug. Diflunisal crystallinity disappeared in the coprecipitates. Three different drug: polymer mass ratios were studied: 75:25, 50:50, and 25:75. Microparticle size decreased and aggregation disappeared as the relative amount of polymer increased. The 25:75 coprecipitate consisted of loose spherical particles exhibiting mean particle size of 410 nm while the 75:25 coprecipitate consisted of bigger aggregated particles. The SAS method was shown to be a suitable technology to form solid dispersions of a poorly soluble drug.     

Grey and black-box modelling based on neural networks and artificial immune systems applied to solid dissolution by rotating disc method

The dissolution rates of urea, sodium bicarbonate, and sodium carbonate in water and aqueous solutions were determined using the rotating disc technique. The experiments showed that the dissolution rate increases with increasing disc surface area, temperature, and rotating speed, while it decreases with the solute concentration increase in the dissolution medium. The comparison between experimental values for the dissolution rate and those calculated from Levich equation evidenced a satisfactory agreement in the case of the urea dissolution and poor compliance for the sodium bicarbonate and sodium carbonate dissolution. This poor results and the lack of a good model for making predictions in different situations determined the generation of empirical and semiempirical models (black and grey box approaches) which include neural networks developed with Clonal Selection algorithm (belonging to the Artificial Immune System class) and combination between neural network and phenomenological model. Satisfactory results were obtained with neural networks (black box models) and hybrid models (grey box models).     

Dissolution and Solubility Behavior of Fenofibrate in Sodium Lauryl Sulfate Solutions

The solubility of fenofibrate in pH 6.8 McIlvaine buffers containing varying concentrations of sodium lauryl sulfate was determined. The dissolution behavior of fenofibrate was also examined in the same solutions with rotating disk experiments. It was observed that the enhancement in intrinsic dissolution rate was approximately 500-fold and the enhancement in solubility was approximately 2000-fold in a pH 6.8 buffer containing 2% (w/v) sodium lauryl sulfate compared to that in buffer alone. The micellar solubilization equilibrium coefficient (k*) was estimated from the solubility data and found to be 30884 ± 213 L/mol. The diffusivity for the free solute, 7.15 × 10^{? 6} cm²/s, was calculated using Schroeder's additive molal volume estimates and Hayduk-Laurie correlation. The diffusivity of the drug-loaded micelle, estimated from the experimental solubility and dissolution data and the calculated value for free solute diffusivity, was 0.86 × 10^{? 6} cm²/s. Thus, the much lower enhancement in dissolution of fenofibrate compared to its enhancement in solubility in surfactant solutions appears to be consistent with the contribution to the total transport due to enhanced micellar solubilization as well as a large decrease ( ～ 8-fold) in the diffusivity of the drug-loaded micelle.     

Use of crospovidone as pelletization aid as alternative to microcrystalline cellulose: effects on pellet properties

Background: Microcrystalline cellulose (MCC) is the most important pelletization aid in extrusion/spheronization. Because of known disadvantages, the search for substitutes is ongoing. In this context, crospovidone has proven to offer substantial advantages as pelletization aid because of its ability to turn low-soluble active ingredients into fast-dissolving stable pellets. Method: Pellets from crospovidone with different amounts of paracetamol, hydrochlorothiazide, and spironolactone as model drugs were prepared by extrusion/spheronization. For comparison, pellets with MCC as extrusion aid were also produced. The pellets of different formulations were evaluated in terms of yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength, disintegration, and drug release profile. Results: Only crospovidone types exhibiting small particle sizes are suitable as pelletization aid. While maintaining the pharmaceutical quality aspects, it was possible to incorporate up to 60% (w/w) active pharmaceutical ingredients (API) into pellets with crospovidone. The most distinguished differences between pellets based on crospovidone and MCC are the disintegration and drug release behavior. The pellets containing binary mixtures of the low-soluble APIs and crospovidone resulted in fast release in contrast to the pellets with MCC as pelletization aid, which exhibited a slow release. Conclusion: Crospovidone shows an excellent behavior as pelletization aid and produces fast-releasing pellets even with low-soluble APIs.     

Development of stabilized itraconazole nanodispersions by using high-gravity technique

Purpose: For large scale preparation of stabilized itraconazole (ITZ) nanodispersions to improve the dissolution rate.

Method: High-gravity technique was employed to produce ITZ nanodispersions.

Results: Stabilizer had a significant effect on the stability of drug nanoparticles. Hydroxypropylmethylcellulose was found to be the most effective stabilizer to prevent drug nanoparticles from aggregation. ITZ nanoparticles with an average size of 210?nm were obtained. Mannitol was the suitable carrier matrix for improving the flowability and the dissolution rate of ITZ nanodispersion. The effects of operating variables on the particle size distribution were investigated in detail. The stability of ITZ nanodispersions was characterized by scanning electron microscopy, X-ray diffraction, Fourier transform-infrared spectroscopy, differential scanning calorimetry, and in vitro dissolution studies. After 6 months storage, the nanodispersion showed unchanged particles size, morphology, crystal state, chemical structure, and dissolution. In vitro dissolution rate indicated that the nanodispersion could significantly enhance the dissolution rate when compared to the commercial available Sporanox capsules. The nanodispersion achieved 70% of drug dissolution in 10?min, whereas the Sporanox capsules only dissolved 20% during the same period.

Conclusion: This study demonstrated that high-gravity technique is a promising method for large scale production of nanodispersions to enhance the dissolution rate of poorly water-soluble drugs.     

Key Production Parameters to Obtain Transparent Nanocellular PMMA

Transparent nanocellular polymethylmethacrylate (PMMA) with relative density around 0.4 is produced for the first time by using the gas dissolution foaming technique. The processing conditions and the typical characteristics of the cellular structure needed to manufacture this novel material are discovered. It is proved that low saturation temperatures (−32 °C) combined with high saturation pressures (6, 10, 20 MPa) allow increasing the solubility of PMMA up to values not reached before. In particular, the highest CO₂ uptake ever reported for PMMA, (i.e., 48 wt%) is found for a saturation pressure of 20 MPa and a saturation temperature of −32 °C. Due to these processing conditions, cell nucleation densities of 10¹⁶ nuclei cm⁻³ and cell sizes clearly below 50 nm are achieved. The nanocellular polymers obtained, with cell sizes ten times smaller than the wavelength of visible light and very homogeneous cellular structures, show a significant transparency.     

Measurement of the amount and rate of methane dissolution in pure water and aqueous solution of SDS + multi-wall carbon nanotubes + β-cyclodextrin

In this paper, the impact of the mixture of sodium dodecyl sulfate (SDS) + multi-wall carbon nanotubes (MWCNTs) + β-cyclodextrin on the quantity and initial rate of methane dissolved in water is investigated. The experiments were performed at a temperature range of 278.15–303.15 K and an initial pressure of 0.5 MPa. The experimental results show that simultaneous utilization of β-cyclodextrin (0.01 mass fraction), MWCNTs (0.0005 mass fraction), and SDS (0.001 mass fraction) at 278.15 K increases the amount and the rate of methane dissolution in water by 29.90% and 173.78%, respectively, compared to pure water. An increase in the temperature decreases the quantity and the initial rate of methane dissolution in all solutions containing additives. However, no consistent relationship is observed between the temperature and the enhancement percentage of solubility of methane in solutions containing additives.     

Dissolution of multicomponents during hydrothermal leaching of LF desulfurization slag

In light of the multicomponent dissolution equilibrium during the hydrothermal leaching of LF desulfurization slag, thermodynamic calculations were made and the dissolution equilibrium curves of calcium, aluminum and sulfur were plotted to analyze the interactions between these components and their influence on sulfur leaching. Furthermore, slag leaching experiments were conducted to investigate variation of pH and concentration of major components in the leaching solution. The results show that CaS(s) is easily soluble in water, and when pH>11. 4, CaS(s) dissolves to form Ca(OH)2(s). Use of hydrothermal leaching for sulfur removal from LF desulfurization slag is theoretically feasible. CaSO4(s) is difficult to dissolve and its solubility is always lower than that of CaS(s); therefore, slag oxidation affects negatively sulfur leaching. However, when the pH of the leaching environment is controlled to be above 12. 3, CaSO4(s) is gradually transformed into Ca(OH)2(s). Al2(SO4)3(s) is easily soluble, and it is unlikely that Al will react with sulfur in the solution to form a precipitate. The pH of the leaching solution rises with time and remains at about 12. Calcium concentration in the leaching solution is high, while Al concentration is low. Sulfur concentration in the solution increases with time, and Al in the slag has little effect on sulfur leaching. It is thus concluded that hydrothermal leaching is effective in removing sulfur from LF desulfurization slag.