Yuan Le

Micronization of atorvastatin calcium by antisolvent precipitation process

Amorphous atorvastatin calcium (AC) ultrafine powder has been successfully prepared by antisolvent precipitation and spray drying process, in which hydroxypropyl methylcellulose (HPMC) was employed to control the particle size and morphology. The effects of experimental parameters, such as stirring time, drug concentration and drying methods, on particle size and morphology were investigated. The average particle size of AC obviously increased from 410 nm to 1200 nm as the stirring time changed from 30s to 60 min. The enhancement of drug concentration favored to decrease the particle size from 410 nm to 240 nm. After spray drying process, ultrafine AC powder was obtained, which had good dispersibility and narrow particle size distribution of 1-3 microm. The as-prepared ultrafine AC was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, thermal gravimetric analysis (TG), differential scanning calorimetry (DSC), specific surface area and dissolution test. The XRD analyses indicated that the ultrafine AC was amorphous. In the dissolution tests, the amorphous AC ultrafine powder exhibited enhanced dissolution property when compared to the raw material.

Formation of bicalutamide nanodispersion for dissolution rate enhancement

Bicalutamide was loaded on hydrophilic excipients to form nanodispersions via a combination of anti-solvent precipitation and spray drying method. The particle size, BET surface area, contact angles and dissolution rate of the nanodispersions were analyzed. The results indicated that lactose was a suitable matrix to prevent the bicalutamide particles growth and aggregation. The lactose loaded particles had a mean size of 330 nm within a narrow distribution. X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) characterization indicated the nanodispersion exhibited unchanged crystalline and chemical structure. Dissolution rate of bicalutamide nanodispersion was significantly faster than that of commercial products. It increased to 94% in 10 min while both commercial formulas Casodex and bicalutamide tablets dissolved 60% and 38% respectively at the same period. It was proposed that the enhanced dissolution rate of bicalutamide nanodispersion contribute to high surface area and well-wetted state of drug particles.

Nanosized bicalutamide and its molecular structure in solvents

Nanosized bicalutamide particles have been obtained by anti-solvent precipitation after screened DMSO and EtOH as co-solvents. The produced nanoparticles have been characterized by scanning electron microscopy (SEM), Fourier transform infrared spectrophotometry (FTIR), X-ray diffraction (XRD) and a dissolution test. The mean particle size of bicalutamide is about 450nm with a narrow distribution. The results of the dissolution test show that dissolution rate of the produced nanoparticles are higher than that of the raw material. Besides, DFT calculations of the bicalutamide conformers have firstly been presented. It is found that the calculated geometry structure of lower-energy conformer is very similar to the experimental structure existing within the crystal lattice. The solvent effects have been taken into account based on the polarizable continuum model (PCM). The computed results appear that the introduction of dielectric medium has obvious effect on the molecular geometry of bicalutamide.

Electronic structure and UV spectrum of fenofibrate in solutions

The structure and UV spectra of fenofibrate have been evaluated in gas phase and in solutions using time dependent density functional theory (TDDFT) method at the B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) levels. The solvent effects have been taken into account based on the polarizable continuum model (PCM). The computed results appear that the introduction of dielectric medium has slight effect on the molecular geometry of fenofibrate. There is one allowed excited state presenting the strongest oscillator strength in the UV region, which is associated with the HOMO-->LUMO and HOMO-1-->LUMO transition both in gas phase and in solutions. The prediction of the lambda(max) in THF, ethanol and DMSO is 285 nm, 286 nm and 287 nm, respectively, which are in a good agreement with experimental data of 284 nm, 285 nm and 288 nm. The results demonstrate that TDDFT-PCM is a useful tool for study of the electronic absorption in solutions.

Poly(lactic acid)/chitosan hybrid nanoparticles for controlled release of anticancer drug.

Poly(lactic acid) (PLA) is a kind of non-toxic biological materials with excellent absorbability, biocompatibility and biodegradability, which can be used for drug release, tissue engineering and surgical treatment applications. In this study, we prepared chitosan modified PLA nanoparticles as carriers for encapsulation of docetaxel by anti-solvent precipitation method. The morphology, particle size, zeta potential and composition of the PLA/chitosan were characterized by SEM, DLS, FTIR and XPS. As-prepared PLA/chitosan particles exhibited average size of 250 nm and showed very narrow distribution with polydispersity index of 0.098. Their large surface charge-ability was confirmed by zeta potential value of 53.9 mV. Docetaxel was released from PLA/chitosan nanoparticles with 40% initial burst release in 5 h and 70% cumulative release within 24 h, while from PLA nanoparticles 65% of docetaxel was released in 5h. In vitro drug release study demonstrated that PLA/chitosan nanoparticles prolonged drug release and decreased the burst release over the unmodified PLA nanoparticles. These results illustrated high potential of chitosan modified PLA nanoparticles for usage as anticancer drug carriers.

Studies of Bicalutamide–Excipients Interaction by Combination of Molecular Docking and Molecular Dynamics Simulation

While the effects of hydrophilic excipients in enhancing the dissolution rate of water-insoluble drugs have been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. In this work, a combination of docking calculations and MD simulations was applied to investigate the molecular interactions between bicalutamide (BIC) and each of three excipients: lactose (LAC), hydroxypropyl methylcellulose (HPMC), and mannitol (MAN). The calculated results indicated that BIC interacted with HPMC and MAN mainly by Lennard-Jones (LJ) interactions but with LAC mainly by Coulomb (Coul) interactions. There was no hydrogen bond formed between BIC and excipient. It was shown that BIC/LAC had the biggest total solvent accessible surface area with the biggest hydrophilic area and formed the most hydrogen bonds between excipient and water. In addition to the structure analyses, BIC/LAC had both the lowest interaction energy between BIC and excipient and the lowest interaction energy between BIC/excipient and water. All these led to the best dissolution performance of BIC/LAC, which could correspond to the experimental results of dissolution test. The present study suggests that a combination of docking calculations and MD simulations, which aims at complementing the experimental work, could provide a molecular insight into the interaction between drug and excipient. It also holds the great potential to simplify the optimization process of drug delivery system and reduce both time and costs.

Preparation of azithromycin nanosuspensions by reactive precipitation method

Purpose: The aim of this work was to prepare azithromycin (AZI) nanosuspensions to increase the solubility and dissolution rate. Method: AZI nanosuspensions were prepared by the combination of reactive precipitation and freeze-drying in presence of biocompatible stabilizer. Formulation and process variables affecting the characteristics of nanosuspensions were optimized. Various tests were carried out to study the physicochemical characteristics of AZI nanosuspensions. Results: The nanosuspensions were parenterally acceptable and autoclavable, because soybean lecithin was the stabilizer of choice and no organic solvents were used during the preparation. The mean particle size and zeta potential of the AZI nanosuspensions were about 200 nm (±20 nm) and −36.7 mV (±7.6 mV), respectively. Solid nanoparticles were obtained by lyophilization of the nanosuspensions and nanosuspensions rapidly reconstituted when the nanoparticles were dispersed in water. X-ray diffraction and differential scanning calorimetry analysis showed that the crystal state of nanoparticles was amorphous. Solubility and in vitro release studies indicated that the saturated solubility and dissolution rate increased obviously in comparison of raw AZI. The nanoparticles were physically stable over a period of 5 months as demonstrated by unchanged crystallinity and stable particle size when stored at room temperature and protected from humidity. Conclusion: The results suggested that reactive precipitation is an effective way to prepare AZI nanosuspensions with increased solubility and dissolution rate.

A systematic study of solvent effect on the crystal habit of dirithromycin solvates by computer simulation

Abstract The crystal habits of five dirithromycin solvates were employed to unravel the solvent effect by using the modified attachment energy (AE) model. Solvents with different polarity and hydrogen bond donor/acceptor ability (acetone, 1-propanol, acetonitrile, water and cyclohexane) were studied. The good consistency between experimental results and predictions confirmed the applicability of modified AE model. Simulation results showed that all solvates underwent a change in morphological importance (MI) of crystal faces except for the cyclohexane trisolvate. A detailed analysis of the results indicated that the polar solvent had a stronger interaction with crystal face than the non-polar solvent due to the formation of hydrogen bond. Furthermore, crystals with similar structure in different solvents exhibited different aspect ratios. The computer-aided study approach in this work could be helpful to control the morphology of crystal by tailor-made solvents or additives.

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.

Dual-responsive star-shaped polypeptides for drug delivery

Core cross-linked star-shaped polypeptides based on poly(L-glutamic acid)-poly(L-phenylalanine-co-L-cystine) copolymer have been successfully synthesized and thoroughly characterized. The star polypeptides can self-assemble to form 50 nm micelles in aqueous medium, which respond rapidly to both pH change within the physiologically relevant pH range and a reduction environment mimicking the intracellular space. Water-soluble doxorubicin hydrochloride and hydrophobic resveratrol are loaded into the star polypeptides micelles through electrostatic and hydrophobic interactions respectively. The drug loading content can be controlled by tuning the composition of the star polypeptides. The in vitro release studies indicate dual sensitivity enabled rapid drug release at pH 5.5 and 10 mM dithiothreitol (DTT), mimicking the intracellular environment. Furthermore, the star polypeptides are biocompatible and interact well with cells in vitro. Confocal fluorescence microscopy and flow cytometry assays show these star polypeptides can be quickly internalized and effectively deliver the drugs into HeLa cells to inhibit cell growth.