Andy Koswara

Nanocrystal Dissolution Kinetics and Solubility Increase Prediction from Molecular Dynamics: The Case of α-, β-, and γ-Glycine

Nanocrystals are receiving increased attention for pharmaceutical applications due to their enhanced solubility relative to their micron-sized counterpart and, in turn, potentially increased bioavailability. In this work, a computational method is proposed to predict the following: (1) polymorph specific dissolution kinetics and (2) the multiplicative increase in the polymorph specific nanocrystal solubility relative to the bulk solubility. The method uses a combination of molecular dynamics and a parametric particle size dependent mass transfer model. The method is demonstrated using a case study of α-, β-, and γ-glycine. It is shown that only the α-glycine form is predicted to have an increasing dissolution rate with decreasing particle size over the range of particle sizes simulated. On the contrary, γ-glycine shows a monotonically increasing dissolution rate with increasing particle size and dissolves at a rate 1.5 to 2 times larger than α- or β-glycine. The accelerated dissolution rate of γ-glycine relative to the other two polymorphs correlates directly with the interfacial energy ranking of γ > β > α obtained from the dissolution simulations, where γ- is predicted to have an interfacial energy roughly four times larger than either α- or β-glycine. From the interfacial energies, α- and β-glycine nanoparticles were predicted to experience modest solubility increases of up to 1.4 and 1.8 times the bulk solubility, where as γ-glycine showed upward of an 8 times amplification in the solubility. These MD simulations represent a first attempt at a computational (pre)screening method for the rational design of experiments for future engineering of nanocrystal API formulations.

Application of feedback control and in situ milling to improve particle size and shape in the crystallization of a slow growing needle-like active pharmaceutical ingredient

Control of crystal size and shape is crucially important for crystallization process development in the pharmaceutical industries. In general crystals of large size and low aspect ratio are desired for improved downstream manufacturability. It can be extremely challenging to design crystallization processes that achieve these targets for active pharmaceutical ingredients (APIs) that have very slow growth kinetics and needle-like morphology. In this work, a batch cooling crystallization process for a GlaxoSmithKline patented API, which is characterized by very slow growth rate and needle morphology, was studied and improved using process analytical technology (PAT) based feedback control techniques and in situ immersion milling. Four specific approaches were investigated: Supersaturation control (SSC), direct nucleation control (DNC), sequential milling-DNC, and simultaneous milling-DNC. This is the first time that immersion wet milling is combined with feedback control in a batch crystallization process. All four approaches were found to improve crystal size and/or shape compared to simple unseeded or seeded linear cooling crystallizations. DNC provided higher quality crystals than SSC, and sequential and simultanesou milling-DNC approaches could reduce particle 2D aspect ratio without generating too much fines. In addition, an ultra-performance liquid chromatography (UPLC) system was used online as a novel PAT tool in the crystallization study.

ON–OFF Feedback Control of Plug-Flow Crystallization: A Case of Quality-by-Control in Continuous Manufacturing

Plug-flow crystallization (PFC) is a promising candidate to realizing the paradigm shift from batch-to-continuous pharmaceutical manufacturing. While PFC has been recently touted as the ideal continuous crystallizer due to its compact design, proper mixing, and flexible cooling and antisolvent control, it is prone to surface fouling or encrustation. In this letter, a model of encrustation growth and dissolution dynamics coupled with PFC is discussed and a novel method of ON–OFF feedback control of PFC with antifouling control is proposed. The study illustrates a quintessential example of quality-by-control concept, which is complementary to the quality-by-design and essential in ensuring desired control performance and product quality.