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.