Nanosizing: a formulation approach for poorly-water-soluble compounds

Authors: Elaine Merisko-Liversidge , Gary G. Liversidge, Eugene R. Cooper

European Journal of Pharmaceutical Sciences 18 (2003) 113–120

By: Ehsan Moaseri – Behzad Changalvaie


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Schematic diagram of the nanosizing process using milling technology. The chamber (with milling media) is charged with the crude slurry of a poorly water soluble compound. As the motor activated the impeller, the media, drug particles and the chamber walls bring significant shearing/impaction forces resulting in particle size reduction from 100s of microns to the nanometer scale. 

There is a very high percentage of active substances, which are poorly water soluble and therefore, efficient delivery of the drug into human body is quite challenging. One of the favorite approaches to address this issue is generating a salt to enhance the solubility. However, in most of the cases, the substance is found to be non-ionizable and consequently other techniques such as gelatin capsules or complexing agents have been employed.

In the past decade, a new drug delivery approach for poorly water soluble compounds has attracted lots of attention. In this technique, the drug is presented in the form of nanometer-sized particles/crystals that can be dispersed in a colloidal solution by having a stabilizer on the surface of the nanoparticles. This stabilizer prevent the aggregation of nanoparticles and keep them separate from each other by providing some electrostatic/steric repulsion on the surface of the nanoparticles. The essence of nanosizing these substances is basically increasing the surface area of the drug and therefore enhancing the dissolution rate of the drug. The ability to form stable nanoparticles of poorly water soluble drugs can have a huge effect on performance, such as enhancing bioavailability, allowing for dose escalation and hence improving efficacy and safety.

The nanoparticles are usually made using media milling process. The applied shear force during the impaction of the milling process on the micron size drug crystals results in nanometer-sized particles of the drug that can be dispersed in water and stabilized by the surface ligands introduced to their surface. It’s a great advantage of this technique that the drug can be stored in the powder form and dispersed in water before use.

The formed nano drugs can be delivered both orally or through injection. The dissolution rate of the drugs is the main factor in oral delivery of the drug which depends on the intrinsic solubility of the drug and the size of the nanoparticles. It should be noted that the acidic environment of the intestine with the high concentration of enzymes greatly enhances the dissociation and solubility of the drugs compared to the dissolution kinetics in pure water.

The nanometer-sized poorly soluble drugs can be also injected to human body. It is a great advantage of these drugs, compared to water soluble drugs, that can be injected in significantly higher dosage because they do not have any toxic solvents or co-solvents, present frequently in traditional drugs, that limits the injectable dosage.

The use of milling technology to synthesize nanometer-sized particles of poorly water soluble compounds can be a great way of delivering these type of drugs at high dosage both orally or through injection into human body. In the past decade, this technology has been tried to be implemented on various drugs and in many cases successful results have been reported in the literature.

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