(667c) High Pressure Homogenization As Particle Size Reduction Technology In the Pharmaceutical Industry: Optimization, Modeling and Isolation Techniques

Grigorov, P. - Presenter, Merck & Co. Inc.
Long, C. P. - Presenter, Cornell University
Lekhal, A. - Presenter, Merck and Co. Inc.

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.