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Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15reaggregation of active drug substances during preparation . Suspension of drug nanocrystals in liquid can bestabilized by adding surface active substances or polymers• Applicability to all poorly soluble drugs becauseall these drugs could be directly disintegrated into nanometersizedparticles. [10]Bottom up TechnologiesThere are two basic approaches to produce drug nanocrystals, the bottom up and the top downtechnologies. In the bottom up processes, one starts from the molecule in solution, the molecules are aggregated toform particles, being crystalline or amorphous. There are various bottom up technologies. [11]1. Precipitation methodA poor water-soluble drug is dissolved in an organic medium, which is water miscible. A pouring of thissolution into a non solvent, such as water, will cause a precipitation of finely dispersed drug nanocrystals. Aproblem associated with this technology is that the formed nanoparticles need tobe stabilized to avoid growth inmicrometer crystals. In addition, the drug needs to be soluble at least in one solvent , this creates problems for thenewly synthesized or discovered drugs, being poorly soluble in water and simultaneously in organic media.Lyophilization is recommended to preserve the particle size. Another approach to preserve the size of theprecipitated nanocrystals is the use of polymeric growth inhibitors, which are preferably solublein the aqueousphase. The increased viscosity of the aqueous phase can reduce particle growing. [12 ] A basic disadvantage of manyprecipitation processes is the use of organic solvents, which need to be removed again in most cases, increasing thecosts. Especially when large solvent volumes are required, being the case when the drug exhibits low solubility inwater and also in organic solvents. Therefore, for pharmaceutical industry, typically the top down technologies areemployed for the products introduced to the market. [13]2. SonocrystallizationRecrystallization of poorly soluble material using liquid solvents and antisolvents has also been employedsuccessfully to reduce particle size. The novel approach for particle size reduction on the basis of crystallization byusing ultrasound is sonocrystallization. Sonocrystallization utilizes ultrasound power characterized by a frequencyrange of 20-100 kHz for inducing crystallization. It not only enhances the nucleation rate but also an effectivemeans of size reduction & controlling size distribution of the active pharmaceutical ingredient (API). Mostapplications used ultrasound in the range 20 khz -5mhz.Sonocrystallization technique or technology has also beenstudied to modify the undesirables of NSAID’S I) i.e. poor solubility and dissolution rate and consequently the poorbioavailiability. Flubiprofen was poured in deionized water at 25°C and sonicated for 4 minutes at an amplituted of60% and cycle is 40 sec on and 10 sec off. The particle size of treated flubiprofen was significantly reduced and theincreased solubility of treated flurbiprofen was about 35%. The intrinsic dissolution rate of treated flubiprofenincreased by 2-fold. The dissolution studies obtained that 90% of the drug was released within 20 minutes fortreated flubiprofen as compared to untreated flubiprofen obtained 60% release of the drug.International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20114
Sneha V Sawant et al., IJSID 2011, 1 (3), 1-153. Gas antisolvent recrystallization-GASThis processing requires drug polymer mixture be solubilized via conventional means into a solvent i.e.then sprayed into an SCF (supercritical fluid), the drug should be miscible with the organic solvent. The SCFdiffuses into the spray droplets, causing expansion of the solvent present and precipitation of the drug particles.The low solubility of poorly water-soluble drugs and surfactants in supercritical CO2 and the high pressurerequired for these processes restrict the utility of this technology in the pharmaceutical industry. [14]Top Down TechnologiesIn the top down technologies, one starts from large crystals in the μm range and goes down to the nanodimension by diminuting the crystals.There are several top down technologies which are discussed below. [11]1. Media millingIn this protocol, the milling chamber is charged with milling pearls, dispersion media(e.g. water), drugpowders and stabilizers. The pearls are rotated at a very high speed to generate strong shear forces to disintegratedrug powders into nanoparticles. The pearls or balls consist of ceramics, stainless steel, glass, or highly crosslinkedpolystyrene resin-coated beads. [15] Physical characteristics of the resulting nanocrystals depend on thenumber of milling pearls, the amount of drug and stabilizer, and milling time, speed and temperature. Drugnanocrystals can be prepared by a wet milling procedure using a rotation/revolution mixer and zirconia balls. Thetechnique showed superior performance compared with the beads mill, enabling drug nanocrystals to be producedin a quick process (approximately 5 min) using a small amount of zirconia balls. The potential shortcomings ofmedia milling are difficulty in the removal of residual milling media fromthe final product and the loss of drugowing to adhesion to the inner surface of the milling chamber. [16] A problem associated with the pearl millingtechnology is the erosion from the milling material during the milling process. In order to reduce the quantity ofimpurities caused by an erosion of the milling media, the milling beads were coated with highly cross-linkedpolystyrene resin. [17] Furthermore, the method is not suitable for drug powders with elasticity. Despite theselimitations, the milling method is the most commonly used method in industry because of its low cost and capacityfor rapid production. [16]2. High Pressure Homogenization methods1. Microfluidization (IDD-P technology)The microfluidizer is a jet stream homogenizer of two fluid streams collided frontally with high velocity (upto1000m/sec) under pressures up to 4000 bar. There is aturbulent flow, high shear forces, particles collied leadingto particle diminution to the nanometer range.The high pressure applied and the high streaming velocity of thelipid can also lead to cavitation additionally, contributing to size diminution. To preserve the particle size,stabilization with phospholipids or other surfactants and stabilizers is required. A major disadvantage of thisprocess is the required production time. In many cases, 50 to 100 time- consuming passes are necessary for asufficient particle size reduction. SkyePharma Canada, Inc. (previously RTP, Inc.) applies this principle for its IDD-P technology toproduce submicron particles of poorly soluble drugs. [15]International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20115
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