Controlling Particle Size of a Poorly Water-Soluble Drug Using Ultrasound and Stabilizers in Antisolvent Precipitation

Abstract

The objective of this work was to develop a better understanding of a potentially scalable, liquid antisolvent (LAS) precipitation process, for the preparation of stable aqueous suspensions of ultrafine particles of poorly watersoluble active pharmaceutical ingredients (APIs). A novel combination of jets, ultrasound, polymers, and surfactants was used for the precipitation and stabilization of ultrafine particles of griseofulvin (GF). Use of ultrasound and high stream velocities enhances micromixing, whereas addition of polymers/surfactants inhibits/lowers the particle growth. A combination of ultrasound, high jet velocities, and stabilizers decreased the GF particle size to 1.04 µm ((0.46 µm) from 30.8 µm ((14.2 µm), when none of the treatments were used. A rational understanding was developed for predicting process performance and selecting suitable particle growth inhibitors/stabilizers. Favorable process conditions and combinations of polymer and surfactants were also identified experimentally for the precipitation of ultrafine particles of GF with a narrow particle size distribution (PSD).

Surfactant Free Preparation of Celecoxib Microcrystals by a Controlled Precipitation Process

“…In similar works it has also been shown that the particle size decreases as the solvent content is reduced by increasing the AS to S ratio. [21][22][23][24] The shift from a larger crystal size at lower volume ratio to a smaller crystal size at higher volume ratio can be elucidated as follows. Keeping the same solute content in the system, if the ratio of AS/S is increased, the degree of supersaturation ratio is raised.…”

“…When the degree of supersaturation is increased by a higher drug concentration, the particle size is increased above a certain limit because of higher availability of solute molecules near the nascent surface favoring the particle growth. 28 These results can also be elucidated by considering the dependency of the micromixing between the multiphases on the solution concentration. Higher solute molecules in solution results in higher viscosity which in turn hinders the diffusion of nuclei between the solvent and the antisolvent phases.…”

“…Similar results have been reported in literature of previous studies that an optimum drug concentration is needed to achieve the smallest particle size and use of drug concentration above this level results in larger particles. 21,29 Cosolvents system It was concluded from above results that the viscosity for solution with the increasing of drug concentration should be concerned cautiously because of its negative effect on diffusion between S and AS and non-homogenous supersaturation. To avoid the negative effect of increasing drug concentration, the cosolvents system was taken into consideration, which was mixture of acetone and ethanol.…”

Unusual anti-leukemia activity of nanoformulated naproxen and other non-steroidal anti-inflammatory drugs

“…This lack of availability of sufficient amount of stabilizers to control the growth of the particles resulted in larger particles [54]. At higher than optimum concentrations of the polymers, increase in osmotic pressure leads to increased attraction among colloidal particles leading to agglomeration [55]. When the concentration of stabilizers was optimum, the particle growth was controlled by stabilizers resulting in smaller particles.…”

Agglomeration Control during Ultrasonic Crystallization of an Active Pharmaceutical Ingredient

“…On the other hand, these characteristics also provide the opportunity to control the drug release profile after intake into the human body. As a result, industrial processes exploit numerous particle engineering techniques in combination with crystallization to produce crystals that meet both the bioavailability and processing requirements [1][2][3][4][5][6].…”