Current research activities include:

Crystallization Process Control with Process Analytical Technology
The purpose of this work is to implement modern process engineering and sensor technologies to monitor and determine critical variables in the crystallization process such as supersaturation profile, nucleation, crystal size distribution and polymorphic form. This research can aid in the development of data reduction methods and design process control schemes through the use of online sensor technologies such as (but not limited to) Focused Beam Reflectance Measurement (FBRM), vibrational spectroscopy, turbidity and x-ray diffraction.

Seeding Technology
Research in seed technology concentrates on the development of quantitative methods and experimental procedures to allow optimization of the amount and size of seed added, methods of seed preparation, strategies for addition, and exploration of the role of seed morphology. Other areas include exploration of final crystal morphology and the use of seed to insure desired crystal size distribution, crystal shape and correct solid form.

Defining API as a Drug Substance plus Additive/Excipients
There is substantial interest in developing strategies and approaches to redefining the active pharmaceutical ingredient (API) as a drug substance, plus additives or excipients. This interest is based on the desire to prepare API with desirable properties including amorphous material with high solubility and crystals with optimum morphology and shape. For example, it may be possible to alter the needle like character of the drug substance so that the crystals are more equi-dimensional improving flow and handling. By defining the API as drug substance plus additives/excipients, one can avoid problems that may arise from having to perform the combination step during formulation. A future purpose of this work is to address the regulatory implications of this strategy and to establish methods of validation of redefined APIs.

Investigation of Relationship between Prenucleation Aggregation and Eventual Polymorphic Form
This project is designed to test the hypothesis that the polymorph that crystallizes is the one with the most similar structure to solution aggregates or the liquid phase in the case of crystallization from amorphous phases. Model compounds which have polymorphic forms with distinctly different hydrogen bonding motifs will be identified, e.g., the enantiotrophic captopril system. The solution speciation in each of these systems will be determined using a combination of molecular spectroscopies. These data will be used to establish if there is a predictive link between molecular assembly in solution and eventual polymorphic form. As an alternative approach, crystallization from supercooled melts will be investigated for polymorphic compounds.

The Use of Computational Fluid Dynamics (CFD) for Analysis and Scale-up of Crystallization Processes
A CFD model will be used to simulate the anti-solvent crystallization process in order to investigate the effect of process operational parameters, e.g., stirrer type, stirrer size, agitation rate, addition rate and addition location, on the anti-solvent dispersion and supersaturation distribution. A sensitivity analysis based on these simulations will be used to guide optimization of process conditions to avoid unfavorable high local supersaturation as a result of poor mixing and subsequent scale-up. Scale-up of batch crystallizers with agitators can not enforce similarity between prototype and models in all aspects, geometric, dynamic and kinematic. Simulations will reveal the important few operating factors and point to which similarities are critical.

The Role of Supersaturation and Kinetics on Polymorphism
Many pharmaceutical compounds crystallize as multiple polymorphs depending on the conditions of crystallization. The control of the final form is essential for both product performance and compliance reasons. The critical crystallization conditions include temperature, supersaturation, solvent employed and impurities present. Supersaturation is a key controllable parameter, which can have a major effect on the “energetic selection” of the polymorph that will form. Traditional wisdom says that crystallization from higher supersaturation will preferentially produce meta-stable forms first. However, the range of supersaturation levels necessary and the time that the meta-stable form will persist in the crystallizer before transforming to the stable form are only qualitatively understood. The relationship between the supersatruation levels necessary to produce or avoid a high energy form will be compared to the relative free energies of the form to develop a response surface for the critical crystallization factors.