(32b) Optimization of API Attributes and Flow Properties Via Crystallization and Size Reduction Techniques

The flowability
of final Active Pharmaceutical Ingredients (APIs) is an important property that
very often impacts formulation process performance as well as Drug Product (DP)
performance. The more poorly the API flows, the more troublesome is its
behavior during formulation. Therefore, it is beneficial to develop
processes/protocols that result in API with optimized attributes and flow
properties. Bulk density is usually a good indicator of flow properties with
low values indicating poor flow. This paper describes our efforts to improve
bulk density and hence flow properties of a needle ?shape API with a very low
bulk density by a combination of controlled crystallization and different
milling techniques.

We attempted to increase
bulk density by exploring several alternative approaches. These included: 1)
attempts to alter crystal morphology by changing solvent composition, 2) control
of crystals aspect ratio (a) through pin-milling and (b) via controlled
crystallization coupled with different milling techniques and 3) change the crystal
aspect ratio and improve packing by using high pressure homogenization (HPH).
The last three of these methods increased API bulk density from its original
value. The most drastic impact was observed with HPH.

The original material,
obtained by seeded cooling crystallization, was needle like powder with very
poor flowability and ?Styrofoam-like? appearance. Its bulk and tap densities
were 0.10 g/ml and 0.28 g/ml respectively. The bulk density value is typical of
micronized materials, which generally tend to have very poor flow properties. Pin-milling
increased the bulk and tap densities to 0.14 g/ml and 0.34 g/ml respectively. Showing
some promising results, this milling approach was taken one step further. The
crystallization procedure was optimized to include temperature cycling, which
promoted crystal growth in length as well as in width. Size reduction of these
crystals resulted in API with reduced aspect ratio and ultimately higher bulk and
tap densities (0.25 g/ml and 0.50 g/ml respectively), a two-fold increase from
the original values. Flowability and formulation tests showed that the new
material exhibited acceptable properties for final formulation.

The last method
investigated for bulk density increase involved HPH and demonstrated the
biggest improvements. High pressure homogenization is a technique commonly used
in the pharmaceutical industry for cell breakage, emulsion generation or
particle size reduction. It can be also viewed as a wet micronization technique
capable to achieve micron and submicron particle sizes. When the slurry from
the API crystallization is run through the homogenizer, the original needles
are broken down to several microns in size. The resulting particles are so
small that the initial needle-like morphology ceases to exist and the resulting
aspect ratio is very close to one. During subsequent filtration and drying
these small particles agglomerate into well-packed hard solid blocks. Depending
on the degree of de-lumping during a co-milling step, the final bulk density
can be finely tuned. Using this approach the bulk density of the API under
development was increased to 0.34 g/ml ? a three-fold increase from the
original value and the highest ever achieved for this API.