High Pressure Homogenization As Particle Size Reduction Technology In the Pharmaceutical Industry: Optimization, Modeling and Isolation Techniques

High pressure homogenization (HPH) is a technology widely used in various industries. In the pharmaceutical industry HPH is used in broad range of applications such as cell rupture, dispersions, emulsions and particle size reduction. Many of today's active pharmaceutical ingredients (APIs) exhibit low solubility and permeability. In order to improve their bioavailability, these APIs are often milled to small sizes. Milling techniques traditionally used in the pharmaceutical industry can be divided into two main categories: wet and dry. Each category has its benefits and drawbacks. Dry milling (e.g. jet milling) can achieve micron size particles with no agglomeration but it is not preferred for very potent compounds and can introduce amorphous content into the APIs. Wet milling on the other hand is safe for handling potent compounds but usually can not achieve very small particles (e.g. rotor-stator mills) or has potential for extraneous matter to be introduced (e.g. media mills). Producing small particles by a wet milling technique is also associated with particle aggregation and/or difficult isolation.

High pressure homogenization can be viewed as a wet micronization technique capable of achieving micron and sub-micron particle sizes. It is a top-down approach for controlling particles size during which slurry of API in a non-solvent media is forced through a very small nozzle under very high pressures. This enormous pressure drop causes cavitation, high shear forces and particle-particle collisions, which are the main factors for particle breakage. Proper selection of operation parameters (pressure, nozzle size, flow configuration, number of passes) and process parameters (non-solvent media, solid content) can yield very narrow particle size distributions (PSD).

In this paper we describe our investigational work evaluating HPH as a particle size reduction technique and its potential for use in API manufacturing. The work presented consists of three main parts. In the first part we investigate the effect of process and operation parameters on particle breakage performance. Very important process design considerations for API processing are also presented. In the second part we propose a mathematical model capable of describing particle breakage and HPH performance as a function of operation parameters for the specific equipment at hand. The proposed model helps with the answer of one very important question: how to scale-up HPH? In the third part we evaluate various particle isolation and drying techniques. These include the following: conventional filtration and drying, spray drying and freeze-drying. Investigated are the effects these isolation protocols have on the API's physical attributes such as final PSD, specific surface area (SSA) and bulk density. Finally, a simple decision tree is presented for the selection of these isolation techniques depending on final API formulation method.