Expedited Crystallization Processes Development from Automated Experiments

Crystallization has gained increased interest for continuous pharmaceutical manufacturing, primarily for
intermediate purification and isolation of Active Pharmaceutical Ingredients (APIs). The reason for this
is that continuous manufacturing of pharmaceuticals can produce products faster than the current batch
manufacturing method, even at a much smaller scale. The biggest challenge, however, is the amount of
time and materials required for process development, which often entails dozens of labor-intensive
experiments to assess solubility and kinetics. In the early stages of pharmaceutical development, these
experiments can become hindered due to limited available material and a development cycle that must
be quick yet accurate due to limited patent time.

As a solution for the early characterization of crystallization processes, we have developed a set of
recipes, data analysis spreadsheets, and generalized mathematical models to automate this process with
minimal human input using commercial and widely-available equipment. Compared to the currently
used methods, this approach requires only a few grams of a model system, approximately one work day
of a scientist’s time, and less than a week (total time) to obtain the necessary data. The experimental
data collection is automated using the novel imaging tools of the Technobis Crystalline, collecting
approximately 12 crystallization experiments per day to give us information on properties such as the
number of crystals, and crystal size. Experimental data analysis is automated using Excel which will
trim down and calculate data that’s required by our models. Further data analysis is assisted using the
gPROMS Formulated Products software, which outputs the parameters needed to design a continuous or
batch crystallizer based on known crystallization equations. This process has been demonstrated for two

well-researched model compounds. These methods will aid in the early process characterization of new
compounds and provide valuable information to drive future crystallization research.