Preparation J characterization and in vivo evaluation of amorphous atorvastatin calcium nanoparticles using supercritical antisolvent (SAS) process

Chungnam National University, Daejeon, Republic of Korea.
European Journal of Pharmaceutics and Biopharmaceutics (Impact Factor: 3.38). 07/2008; 69(2):454-65. DOI: 10.1016/j.ejpb.2008.01.007
Source: PubMed


In this work, amorphous atorvastatin calcium nanoparticles were successfully prepared using the supercritical antisolvent (SAS) process. The effect of process variables on particle size and distribution of atorvastatin calcium during particle formation was investigated. Solid state characterization, solubility, intrinsic dissolution, powder dissolution studies and pharmacokinetic study in rats were performed. Spherical particles with mean particle size ranging between 152 and 863 nm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration and feed rate ratio of CO2/drug solution. XRD, TGA, FT-IR, FT-Raman, NMR and HPLC analysis indicated that atorvastatin calcium existed as anhydrous amorphous form and no degradation occurred after SAS process. When compared with crystalline form (unprocessed drug), amorphous atorvastatin calcium nanoparticles were of better performance in solubility and intrinsic dissolution rate, resulting in higher solubility and faster dissolution rate. In addition, intrinsic dissolution rate showed a good correlation with the solubility. The dissolution rates of amorphous atorvastatin calcium nanoparticles were highly increased in comparison with unprocessed drug by the enhancement of intrinsic dissolution rate and the reduction of particle size resulting in an increased specific surface area. The absorption of atorvastatin calcium after oral administration of amorphous atorvastatin calcium nanoparticles to rats was markedly increased.

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Available from: Reinhard H H Neubert, Apr 03, 2015
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    • "Due to low solubility of most drug molecules in ScCO 2 , use of RESS process is mostly limited, whereas, amorphization [23] [24], recrystallization [25] [26], micronization [27] [28] [29] and nanonization [23] [24] [30] through SAS process have been successfully achieved. SAS is a one-step efficient process leading to completely dry, smaller particles with narrow size distribution, controlled crystals with preferred morphology and better flow-ability, and organic solvent-free product justifying their industrial applications. "
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    ABSTRACT: The biomedical applications of curcumin (CUR) are limited due to its poor oral bioavailability. In this work, CUR nanoparticles were successfully prepared by combining the supercritical anti-solvent (SAS) process with Tween 80 as a solubilizing agent and permeation enhancer. Different processing parameters that can govern the mean particle size and size distribution of nanoparticles were well investigated by manipulating the types of solvents, mixing vessel pressure, mixing vessel temperature, CO2 flow rate, solution flow rate and solution concentration. Solid state characterization was done by Fourier Transform infrared spectroscopy, differential scanning calorimetry, dynamic light scattering, scanning electron microscopy, and powder X-ray diffraction study. Solubility and dissolution profile of SAS-processed CUR were found to be significantly increased in comparison with native CUR. Further, a validated ultra-performance liquid chromatographic method with quadrupole-time of flight-mass spectrometry was developed to investigate the pharmacokinetic parameters after a single oral dose (100 mg/kg) administration of CUR (before/after SAS-processed) in male Wistar rats. From the plasma concentration vs. time profile graph, oral bioavailability of SAS-processed CUR was found to be increased approximately 11.6-fold (p < 0.001) as compared to native CUR.
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    • "However, as per biopharmaceutical classification system (BCS), ATV calcium belongs to Class II category and has an aqueous solubility of about 100 μg/ml[2]; exhibiting dissolution rate limited oral bioavailability. In order to improve solubility and/or dissolution rate of the drug, strategies like particle size reduction and amorphisation were explored[345]. Though the abovementioned approaches were appealing in enhancing solubility of the drug, its amorphous form, in fact, tends to revert to the stable polymorph during storage because of its inherent thermodynamic properties and the studies were not found to be effective on stabilisation of metastable amorphous form of the processed drug, which would ensure unaltered solubility characteristics over the period of its storage. "
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    • "Apart from solubilization, the presence of lipid in the formulation further helps to improve bioavailability by affecting the drug absorption [1]. Selection of a suitable self-emulsifying formulation thus depends upon the assessment of the solubility of the drug in various components, the area of the self-emulsifying region as obtained in the phase diagram, and the droplet size distribution of the resultant emulsion following self-emulsification [7]. "
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