Power Ultrasound and the Production of Mesoscopic Particles and Aqueous Dispersions

The authors discuss advanced sonocrystallization particle-engineering techniques for manufacturing mesoscopic particles.
Aug 31, 2008


PROSONIX
The control of the crystal particle size of an active pharmaceutical ingredient (API) is necessary when the final product's performance depends on well defined and, ideally, engineered mesoscopic particles. The size of the particle and the crystal form of the API can influence behavior such as dissolution rate in a biological system. This influence is of particular importance because more than 40% of new molecules being developed are poorly water soluble.

The technology available for particle engineering to improve therapeutic performance has grown rapidly in popularity and sophistication and has created a need for technology that can tailor particles for various applications. The need for improved and efficient drug delivery systems for many new drugs has become apparent, especially when the drugs are administered in a particulate form (1).

In respiratory drug delivery, effective deep-lung deposition is achieved with 1–5-μm particles. Pulmonary administration of various drug substances, particularly small molecules, whether for systemic or local delivery, is especially appealing because of the thin alveolar epithelium wall's large surface area and absorption ability. Local delivery of therapeutics to the lung is an appropriate method for treating conditions such as asthma, chronic obstructive pulmonary disease (COPD), infections, and disease states such as cystic fibrosis. Other important therapeutics areas that pulmonary delivery can address include those where a rapid onset of action is required (e.g., diabetes, neuropathic pain, migraine), and systemic action of peptides, proteins, and oncolytics.

Top-down and bottom-up methods

Size reduction, or "top-down," destructive methods for preparing mesoscopic particles such as fluid-energy milling, also known as micronization (including jet milling and fluidized-bed jet mills), achieve the target size range, but the high energy required for such processes often damages the crystal's surface. This damage leads to highly charged and cohesive particles, which result in the chemical and physical instability of the drug. A significant proportion of micronized particles may be too fine and of an unsuitable shape for a given use. These qualities lead to undesirable surface polymorphological transformation, which may form amorphous structures that are undesirable for applications such as inhaled treatments. In addition, the particle properties can vary from batch to batch, thus causing problems in downstream processing and product formulation. Micronization can also generate considerable heat, which may be incompatible with the material of interest (e.g., a low-melting solid API).

Constructive "bottom-up" or "molecule-to-particle" techniques provide a way to avoid these destructive techniques and appear to offer superior alternative production methods that yield better products. The US Food and Drug Administration would theoretically favor constructive techniques because they are consistent with its quality by design initiative aimed at improving the invention, development, and commercialization of structured products using technologies that provide superior product quality, per the ICH Q8 guidelines of 2004.

One such technology, sonocrystallization, uses the excellent dispersive and crystal-nucleation properties of transient cavitation to produce microcrystalline particles when a drug–solute solution makes contact with an antisolvent. The literature offers a review of particle-engineering technologies (2). Sonocrystallization can also be applied to the preparation of aqueous nanosuspensions or submicrometer colloidal dispersions of a pure drug. These dispersions are ideal formulations to improve bioavailability (3, 4).

Nanosizing reduces the size of the API to the submicrometer range (typically 100–200 nm) in an aqueous media. Surfactants or polymers stabilize the API concurrently (5). Nanosuspensions can be dried using conventional techniques such as spray drying or lyophilization.

Prosonix (Oxford, UK) has developed advanced sonocrystallization particle-engineering techniques for manufacturing mesoscopic particles. This article discusses these techniques, including the proprietary Solution Atomization and Crystallization by Sonication (SAX) and Dispersive Crystallization with Ultrasound (DISCUS) methods. The DISCUS method involves recirculation and miscible and immiscible (emulsion-oriented) systems. The article also reviews the factors that affect the production of tailor-made particles suitable for efficient delivery and improved therapeutic performance.