Overview of milling techniques for improving the solubility of poorly water-soluble drugs

TLDR

Milling applies mechanical energy to break down coarse drug particles into finer ones, producing micro‑ and nano‑particles that improve processability and solubility, especially for poorly water‑soluble drugs and formulations for parenteral, respiratory, and transdermal use. This review aims to give an overview of milling and to introduce the common techniques used for micronization and nanonization of drugs. Milling enhances dissolution and solubility by reducing particle size, increasing specific surface area, altering shape, and inducing amorphization or structural disorder through mechanochemical activation. The review extracts and summarizes key examples to provide researchers with a concise reference for applying these techniques to improve drug solubility and bioavailability.

Abstract

Milling involves the application of mechanical energy to physically break down coarse particles to finer ones and is regarded as a “top–down” approach in the production of fine particles. Fine drug particulates are especially desired in formulations designed for parenteral, respiratory and transdermal use. Most drugs after crystallization may have to be comminuted and this physical transformation is required to various extents, often to enhance processability or solubility especially for drugs with limited aqueous solubility. The mechanisms by which milling enhances drug dissolution and solubility include alterations in the size, specific surface area and shape of the drug particles as well as milling-induced amorphization and/or structural disordering of the drug crystal (mechanochemical activation). Technology advancements in milling now enable the production of drug micro- and nano-particles on a commercial scale with relative ease. This review will provide a background on milling followed by the introduction of common milling techniques employed for the micronization and nanonization of drugs. Salient information contained in the cited examples are further extracted and summarized for ease of reference by researchers keen on employing these techniques for drug solubility and bioavailability enhancement.