Recent advancements in mechanical reduction methods: particulate systems

• Published in: Drug development and industrial pharmacy Vol. 40; no. 3; pp. 289 - 300
• Main Authors: Leleux, Jardin, Williams, Robert O.
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare USA, Inc 01-03-2014; Taylor & Francis
• Subjects: Chemistry, Pharmaceutical - methods; Drug Approval; Homogenization; milling; nanocrystal; nanonization; nanoparticle; Nanoparticles; Particle Size; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - chemistry; poorly water soluble; Solubility; United States; United States Food and Drug Administration; United States
• ISSN: 0363-9045; 1520-5762
• DOI: 10.3109/03639045.2013.828217

Abstract
The screening of new active pharmaceutical ingredients (APIs) has become more streamlined and as a result the number of new drugs in the pipeline is steadily increasing. However, a major limiting factor of new API approval and market introduction is the low solubility associated with a large percentage of these new drugs. While many modification strategies have been studied to improve solubility such as salt formation and addition of cosolvents, most provide only marginal success and have severe disadvantages. One of the most successful methods to date is the mechanical reduction of drug particle size, inherently increasing the surface area of the particles and, as described by the Noyes-Whitney equation, the dissolution rate. Drug micronization has been the gold standard to achieve these improvements; however, the extremely low solubility of some new chemical entities is not significantly affected by size reduction in this range. A reduction in size to the nanometric scale is necessary. Bottom-up and top-down techniques are utilized to produce drug crystals in this size range; however, as discussed in this review, top-down approaches have provided greater enhancements in drug usability on the industrial scale. The six FDA approved products that all exploit top-down approaches confirm this. In this review, the advantages and disadvantages of both approaches will be discussed in addition to specific top-down techniques and the improvements they contribute to the pharmaceutical field.