Process Development

Goals
The goal of this course is to provide an insight into Organic Process Research and Development for the preparation of Active Pharmaceutical Ingredients (APIs) and relevant intermediates from laboratory to commercial scale. In particular, emphasis will be put on the theoretical basis for a correct approach to a safe, green, reliable, reproducible and cost-effective process.


acquired skills
At the end of the course, the students will be able to plan the development of a synthetic procedure taken from the literature, to design and fill the corresponding block flow diagram.


Course content
Scale-up issues: reaction vessels, separation, volume measurements, sampling, evaporation to dryness, temperature control, isolation of solid products, etc. Route selection: Green Chemistry and chemistry metrics (yields, conversion, selectivity, E-factor, atom economy theory, reaction mass efficiency, molecular complexity, etc.), telescoping, number of steps, productivity, catalytic vs. stoichiometric approaches, linear and convergent syntheses. Solvents and reagents for large scale operation: toxicity and flammability. Standards of choice. Alternative to classical solvents. Process development and analytical issues: determination of purity and assay of starting materials, solvents, intermediates, APIs, and In-process controls. Safety issues related to thermochemistry in view of designing intrinsically safe processes thus avoiding runaway reactions, thermal decompositions. Methods and instruments for thermal-hazard testing (DSC; TGA; ARC; RC) and data analysis. Work-up. Different synthetic practical approaches (chirality pool, separation of stereoisomers: resolution, crystallization and racemization, use of enzymes and catalytic asymmetric synthesis). Economics: direct, indirect, fix and variable costs to design a competitive process. Exercises on case studies taken from literature. Use of worksheet and block diagram.


Suggested prerequisites
Good knowledge of synthetic organic chemistry


Reference material
- Practical Process Research & Development - Neal G. Anderson - Academic Press, Elsevier
- Green Chemistry in Pharmaceutical industry - Peter J.Dunn et al. Wiley-VCH 2010


Prerequisites
Good knowledge of synthetic organic chemistry


Assessment method
Written examination. The written examination foresees a critical analysis of a single reaction step of an API synthesis or of a relevant intermediate taken from the recent literature, with particular emphasis to the experimental procedure in view of the scale-up and development. The students will then fill a block flow diagram taking into account key parameters relevant to each unit operation. Green metrics (atom economy and E-factor) will be calculated.


Language of instruction
English


Attendance Policy:
Recommended


Mode of teaching:
Traditional

Website:
https://amanfredipd.ariel.ctu.unimi.it