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.
Expected learning outcomes
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.
Lesson period: Second semester
(In case of multiple editions, please check the period, as it may vary)
Course program with the chronological order of the lessons: 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). 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.
Prerequisites for admission
Good knowledge of synthetic organic chemistry
Lectures and exercises on case studies taken from literature.
- Practical Process Research & Development - Neal G. Anderson - Academic Press, Elsevier - Green Chemistry in Pharmaceutical industry - Peter J. Dunn et al. Wiley-VCH 2010 - Lesson slides
Assessement methods and criteria
Written test. Duration: normally 2.5 hours The written test foresees a critical analysis of a single reaction step synthesis of an active pharmaceutical ingredient (API) or of a relevant intermediate taken from the recent literature. The ability to plan the development of the synthetic procedure, taking into account key parameters such as safety, environmental impact (atom economy and E-factor), reliability, and cost-effectiveness, and to prepare the corresponding block flow diagram will be evaluated. The final mark of the test will be expressed in thirtieths and the result published on the dedicated page of the UNIMI website, leaving the student the possibility of accepting it or not.