Process Development
A.Y. 2023/2024
Learning objectives
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
Assessment methods: Esame
Assessment result: voto verbalizzato in trentesimi
Single course
This course can be attended as a single course.
Course syllabus and organization
Single session
Responsible
Lesson period
Second semester
Course syllabus
Course program with the chronological order of the lessons:
Aim of the course, course content, assessment method. Scale-up issues: reaction vessels, separation, volume measurements, sampling, evaporation to dryness, temperature control, isolation of solid products, etc. Characteristics of cost-effective route: convergent vs. linear syntheses, telescoping, number of steps, productivity, catalytic vs. stoichiometric approaches, linear and convergent syntheses. Different synthetic practical approaches (chirality pool, separation of stereoisomers: resolution, crystallization and racemization). The SELECT criteria: Safety, Environmental, Legal, Economics, Control, Throughput issues. 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. Reaction criticality class: the Stoessel diagram and its interpretation. Route selection: Green Chemistry and chemistry metrics (yields, conversion, selectivity, E-factor, atom economy theory, reaction mass efficiency, molecular complexity, etc.). Sustainable processes: the development of awarded environmentally benign syntheses. Solvents for large scale operation: toxicity and flammability. Standards of choice. Alternative to classical solvents: water, supercritical CO2, ionic liquids, deep eutectic solvents, reaction without solvent. Solvent recycles. Solvent swap (replacement, chase). Process development and analytical issues: determination of purity and assay of starting materials, solvents, intermediates, APIs. In-process controls (IPC)s. Choosing the appropriate, reliable and reproducible IPC. Reagents for large scale operation: toxicity and flammability, ease of handling. Standards of choice. Pharmaceutical company Reagent Selection Guides. Work-up: definition and purposes. Aspect of work-up: quench, extraction, activated carbon treatment, filtration, concentrating solution and solvent displacement, deionization and metals removal, process stream destruction, derivatization. Economics: direct, indirect, fix and variable costs to design a competitive process. Exercises on case studies taken from literature. Use of worksheet and block flow diagram.
Aim of the course, course content, assessment method. Scale-up issues: reaction vessels, separation, volume measurements, sampling, evaporation to dryness, temperature control, isolation of solid products, etc. Characteristics of cost-effective route: convergent vs. linear syntheses, telescoping, number of steps, productivity, catalytic vs. stoichiometric approaches, linear and convergent syntheses. Different synthetic practical approaches (chirality pool, separation of stereoisomers: resolution, crystallization and racemization). The SELECT criteria: Safety, Environmental, Legal, Economics, Control, Throughput issues. 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. Reaction criticality class: the Stoessel diagram and its interpretation. Route selection: Green Chemistry and chemistry metrics (yields, conversion, selectivity, E-factor, atom economy theory, reaction mass efficiency, molecular complexity, etc.). Sustainable processes: the development of awarded environmentally benign syntheses. Solvents for large scale operation: toxicity and flammability. Standards of choice. Alternative to classical solvents: water, supercritical CO2, ionic liquids, deep eutectic solvents, reaction without solvent. Solvent recycles. Solvent swap (replacement, chase). Process development and analytical issues: determination of purity and assay of starting materials, solvents, intermediates, APIs. In-process controls (IPC)s. Choosing the appropriate, reliable and reproducible IPC. Reagents for large scale operation: toxicity and flammability, ease of handling. Standards of choice. Pharmaceutical company Reagent Selection Guides. Work-up: definition and purposes. Aspect of work-up: quench, extraction, activated carbon treatment, filtration, concentrating solution and solvent displacement, deionization and metals removal, process stream destruction, derivatization. Economics: direct, indirect, fix and variable costs to design a competitive process. Exercises on case studies taken from literature. Use of worksheet and block flow diagram.
Prerequisites for admission
Good knowledge of synthetic organic chemistry. Students are required to have at least attended and passed the Organic Chemistry I and Organic Chemistry II courses.
Teaching methods
Lectures and exercises on case studies taken from literature.
Teaching Resources
- Practical Process Research & Development - Neal G. Anderson - Academic Press, Elsevier (available at the Biological sciences, Computer science, Chemistry and Physics Library)
- Green Chemistry in Pharmaceutical industry - Peter J. Dunn et al. Wiley-VCH 2010 (available online in Minerva, the University library catalogue)
- Lesson slides uploaded on https://ariel.unimi.it
- Green Chemistry in Pharmaceutical industry - Peter J. Dunn et al. Wiley-VCH 2010 (available online in Minerva, the University library catalogue)
- Lesson slides uploaded on https://ariel.unimi.it
Assessment 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: 1) 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 2) 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.
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: 1) 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 2) 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.
CHIM/04 - INDUSTRIAL CHEMISTRY - University credits: 6
Lessons: 48 hours
Professor:
Albanese Domenico Carlo Maria
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