Designing robust crystallization processes in the presence of parameter uncertainty using attainable regions

We consider the influence of uncertainty in crystallization kinetics (i.e., in the nucleation and growth rates) in the context of process design. Specifically, we model continuous and batch crystallization processes using population balance equation models and investigate how the inherent uncertainty in kinetic parameters propagates through the crystallization processes and how it ultimately affects the distribution of process outcomes (yield and mean particle size). We incorporate the effect of uncertainty into the concept of attainable regions, i.e., we exhaustively investigate which combinations of particle size and total residence time (or batch time) can be attained with a certain probability. Avoiding regions of low probability allows the design of robust crystallization processes that can deliver a product with desired specifications, even when the original process was designed using inadequately characterized crystallization kinetics. The concepts presented in this article are illustrated by a case study on the cooling crystallization of paracetamol grown from ethanol as a solvent

Numerical computation of mass transport in microcavities by the finite element method

Thesis (B.S.) in Chemical Engineering--University of Illinois at Urbana-Champaign, 1991.Includes bibliographical references (leaves 52-53)Microfiche of typescript. [Urbana, Ill.]: Photographic Services, University of Illinois, U of I Library, [1991]. 2 microfiches (80 frames): negative.s 1991 ilu n

Detection of critical antibiotic resistance genes through routine microbiome surveillance.

Population-based public health data on antibiotic resistance gene carriage is poorly surveyed. Research of the human microbiome as an antibiotic resistance reservoir has primarily focused on gut associated microbial communities, but data have shown more widespread microbial colonization across organs than originally believed, with organs previously considered as sterile being colonized. Our study demonstrates the utility of postmortem microbiome sampling during routine autopsy as a method to survey antibiotic resistance carriage in a general population. Postmortem microbial sampling detected pathogens of public health concern including genes for multidrug efflux pumps, carbapenem, methicillin, vancomycin, and polymixin resistances. Results suggest that postmortem assessments of host-associated microbial communities are useful in acquiring community specific data while reducing selective-participant biases

Pharmaceutical Digital Design: From Chemical Structure through Crystal Polymorph to Conceptual Crystallization Process

A workflow for the digital design of crystallization processes starting from the chemical structure of the active pharmaceutical ingredient (API) is a multi-step, multi-disciplinary process. A simple version would be to first predict the API crystal structure and from it the corresponding properties of solubility, morphology, and growth rates, assume that the nucleation would be controlled by seeding, and then use these parameters to design the crystallization process. This is usually an over-simplification as most APIs are polymorphic, and the most stable crystal of the API alone may not have the required properties for development into a drug product. This perspective, from the experience of a Lilly Digital Design project, considers the fundamental theoretical basis of crystal structure prediction (CSP), free energy, solubility, morphology and growth rate prediction, and the current state of nucleation simulation. This is illustrated by applying the modeling techniques to real examples, olanzapine and succinic acid. We demonstrate the promise of using ab initio computer modeling for solid form selection and process design in pharmaceutical development. We also identify open problems in the application of current computational modeling and achieving the accuracy required for immediate implementation that are currently limiting the applicability of the approach

Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization

The design, development, and implementation of a pilot-scale continuous Schotten–Baumann amide bond formation and reactive crystallization to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The scalability of the reaction and crystallization processes was confirmed during the development process. The pilot-scale equipment set was contained in a walk-in fume hood and operated at a production rate of 3 kg/day in a 72 h continuous run. Significant technical and business drivers for running the process in continuous flow mode were proposed and examined during development. The continuous process provided for lab hood commercialization and provided for minimal material at risk in the process. The demonstration also confirmed the risk inherent to operation of a tubular reactor under supersaturated conditions, and fouling occurred in the plug flow reactor. Fouling also occurred in the crystallizer. Recognizing these deficiencies, the process operated within the footprint of a standard walk-in fume hood, providing a successful demonstration of the opportunities afforded by continuous processing for low volume pharmaceuticals