Impact of Leucine and Magnesium Stearate on the Physicochemical Properties and Aerosolization Behavior of Wet Milled Inhalable Ibuprofen Microparticles for Developing Dry Powder Inhaler Formulation.

This study investigated the development and characterization of leucine and magnesium stearate (MgSt) embedded wet milled inhalable ibuprofen (IBF) dry powder inhaler (DPI) formulations. IBF microparticles were prepared by a wet milling homogenization process and were characterized by SEM, FTIR, DSC, XRD and TGA. Using a Twin-Stage Impinger (TSI), the in vitro aerosolization of the formulations with and without carrier lactose was studied at a flow rate of 60± 5 L/min and the IBF was determined using a validated HPLC method. The flow properties were determined by the Carr's Index (CI), Hausner Ratio (HR) and Angle of Repose (AR) of the milled IBF with 4-6.25% leucine and leucine containing formulations showed higher flow property than those of formulations without leucine. The fine particle fraction (FPF) of IBF from the prepared formulations was significantly (p = 0.000278) higher (37.1 ± 3.8%) compared to the original drug (FPF 3.7 ± 0.9%) owing to the presence of leucine, which enhanced the aerosolization of the milled IBF particles. Using quantitative phase analysis, the XPRD data revealed the crystallinity and accurate weight percentages of the milled IBF in the formulations. FTIR revealed no changes of the structural integrity of the milled IBF in presence of leucine or MgSt. The presence of 2.5% MgSt in the selected formulations produced the highest solubility (252.8 ± 0.6 µg/mL) of IBF compared to that of unmilled IBF (147.4 ± 1.6 µg/mL). The drug dissolution from all formulations containing 4-6.25% leucine showed 12.2-18.6% drug release in 2.5 min; however, 100% IBF dissolution occurred in 2 h whereas around 50% original and dry milled IBF dissolved in 2 h. The results indicated the successful preparation of inhalable IBF microparticles by the wet milling method and the developed DPI formulations with enhanced aerosolization and solubility due to the presence of leucine may be considered as future IBF formulations for inhalation.

Physicochemical, Pharmacodynamic and Pharmacokinetic Characterization of Soluplus Stabilized Nanosuspension of Tacrolimus.

BACKGROUND: Tacrolimus, an immunosuppressive drug has a variable pharmacokinetic and poor oral bioavailability due to poor solubility. The aim of the present study was enhancing the solubility and oral bioavailability of this drug. METHODS: Tacrolimus nanoparticles were prepared by precipitation anti-solvent evaporation method. The effect of different parameters including: surfactant type, solvent to nonsolvent ratio and drug to surfactant ratio were studied on the particle size, saturated solubility and dissolution rate of the drug. The solid state characterization was done by fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and scanning electron microscopy. The untreated drug (5 mg.kg-1day-1), nanoparticles or physical mixture of the drug and the stabilizers were administered to rats and blood levels of tacrolimus were assessed by electrochemiluminence method. The oral drug administration was done for 10 days then the changes in white blood cells (WBC) and percent lymphocyte count were determined before drug administration, 5 and 10 days after drug administration. RESULTS: FTIR spectroscopy showed no interaction between the drug and stabilizers. XRPD and DSC studies indicated the amorphous state of the drug in nanosuspensions. The solvent to nonsolvent ratio of 1:20 and drug to surfactant ratio of 1:3 enhanced 185 fold the saturated solubility and 17 fold dissolution rate of the drug. In vivo studies also showed tacrolimus nanoparticles significantly reduced the lymphocyte and WBC, enhanced 66 and 34 fold the AUC0-24 and Cmax of the drug, respectively. CONCLUSION: The precipitation anti-solvent evaporation is a nano-crystalization technique which showed to be an effective approach for enhancing water solubility and bioavailability of tacrolimus.

Estimating Maximal In Vitro Skin Permeation Flux from Studies Using Non-sink Receptor Phase Conditions.

PURPOSE: This study explored the impact of non-sink receptor conditions on the in vitro skin permeation test (IVPT) and sought to estimate equivalent sink condition IVPT data. METHODS: Simulated diffusion model and experimental IVPT data were generated for ethyl salicylate across human epidermal membranes in Franz diffusion cells using six different receptor phases, with a 10 fold variation in ethyl salicylate solubility. RESULTS: Both simulated and experimental IVPT - time profiles were markedly affected by receptor phase solubility and receptor sampling rates. Similar sink condition equivalent estimated maximum fluxes were obtained by nonlinear regression and adjustment of linear regression estimates of steady state flux for relative saturation of the receptor phase over time for the four receptor phases in which the ethyl salicylate was relatively soluble. The markedly lower steady - state fluxes found for the other two phases in which ethyl salicylate was less soluble was attributed to an aqueous solution boundary layer effect. CONCLUSIONS: Non-sink receptor phase IVPT data can be used to derive equivalent sink receptor phase IVPT data provided the receptor phase solubility and hydrodynamics are sufficient to minimise the impact of aqueous diffusion layers on IVPT data.

Comparison of ultrasonic-assisted and regular leaching of germanium from by-product of zinc metallurgy.

A major source of germanium recovery and also the source of this research is the by-product of lead and zinc metallurgical process. The primary purpose of the research is to investigate the effects of ultrasonic assisted and regular methods on the leaching yield of germanium from roasted slag containing germanium. In the study, the HCl-CaCl2 mixed solution is adopted as the reacting system and the Ca(ClO)2 used as the oxidant. Through six single factor (leaching time, temperature, amount of Ca(ClO)2, acid concentration, concentration of CaCl2 solution, ultrasonic power) experiments and the comparison of the two methods, it is found the optimum collective of germanium for ultrasonic-assisted method is obtained at temperature 80 °C for a leaching duration of 40 min. The optimum concentration for hydrochloric acid, CaCl2 and oxidizing agent are identified to be 3.5 mol/L, 150 g/L and 58.33 g/L, respectively. In addition, 700 W is the best ultrasonic power and an over-high power is adverse in the leaching process. Under the optimum condition, the recovery of germanium could reach up to 92.7%. While, the optimum leaching condition for regular leaching method is same to ultrasonic-assisted method, except regular method consume 100 min and the leaching rate of Ge 88.35% is lower about 4.35%. All in all, the experiment manifests that the leaching time can be reduced by as much as 60% and the leaching rate of Ge can be increased by 3-5% with the application of ultrasonic tool, which is mainly thanks to the mechanical action of ultrasonic.