Industrial pharmacy

CHAPTER 1. DRUG METABOLISM 1.1. ENZYMES AND COENZYMES IN DRUG METABOLISM (8 hours) Introduction. Mechanisms of enzyme catalysis. Coenzyme catalysis. Pyridoxal 5’-phosphate (PLP): reactions catalyzed by PLP-dependent enzymes. Mechanism and Dunathan hypothesis. Racemases, decarboxylases, aminotransferases, B-elimination. Tetrahydrofolate: reactions catalyzed by tetrahydrofolate -dependent enzymes. Mechanism of carbon unit transfer. Flavins: reactions catalyzed by flavin-dependent enzymes. Mechanisms of regeneration of the oxidized coenzymes. Heme: reactions catalyzed by heme-dependent enzymes. Activation of the coenzyme and reactions of hydroxylation and epoxidation. Adenosine triphosphate (ATP) and coenzyme A (CoA): reactions and mechanisms. 1.2. PHASE I TRANSFORMATIONS (10 hours) Introduction. Analytical methods in drug metabolism. Synthesis of radioactive compounds. Oxidative reactions. Enzymatic involved systems. Aliphatic and aromatic hydroxylation.Alkene epoxidation. Oxidations of carbons adjacent to sp2 center. Oxidations of carbon-nitrogen, carbon-oxygen, carbon-sulfur systems. Other oxidative reactions. Reductive reactions. Introduction. Carbonyl, nitro and azo reduction. Reductive dehalogenation. Hydrolytic reactions. 1.3. CONJUGATION REACTIONS (6 hours) Introduction. Reactions of glucuronic acid, sulphate, methyl, acetyl conjugation. Mechanisms and involved substrates. Conjugation reactions that involved CoA. Reactions of conjugation and redox with glutathione. Other conjugation reactions. 1.4. DRUG METABOLISM AND PHARMACEUTICAL SYNTHESIS (2 hours) Structural modifications to modulate drug metabolism. Hard and soft drugs. CHAPTER 2. PRODUGS (8 hours) Utility of prodrugs. Types of prodrugs. 2.1. MECHANISMS OF ACTIVATION Carrier-linked prodrugs. Carrier-linkages for various functional groups. Examples of carrier-linked bipartite prodrugs. Prodrugs for increase water solubility, for improved absorption and distribution, for site specificity, for stability, slow and prolonged release, for minimize toxicity, to encourage patient acceptance, to eliminate formulation problems. Macromolecular drug carrier systems. General strategy. Synthetic polymers. Poli-aminoacids. Other macromolecular supports. Tripartate prodrugs. Mutual prodrugs. Bioprecursor prodrugs: origins. Oxidative activation. N- and O-dealkylations, oxidative deamination, N-oxidation, other oxidations. Reductive activation: azo, azido, sulfoxide, disulfide, nitro reduction. Nucleotide, phosphorylation, sulfatation, decarboxylation activation. CHAPTER 3. DRUG STABILITY (6 hours) Introduction. Chemical and physical decomposition. Kinetics of chemical decomposition in solution. Order of reaction. Determination of the order of reactions. Complex reactions. Kinetics of chemical decomposition in solid dosage forms. Stability testing and prediction of shelf-life. Effect of temperature on stability. Protocol for stability testing. CHAPTER 4. POLYMERS AND MACROMOLECULES (6 hours) Pharmaceutical polymers. Definitions. Polydispersity. Solubility.Water-soluble polymers. General properties of polymer solutions. Viscosity. Gelling water-soluble polymers. Polymer complexes. Binding of ions to macromolecules. Some water-soluble polymers used in pharmacy and medicine. Carboxypolymethylene, cellulose, dextran. Water-insoluble polymers and polymer membranes. Some applications of polymeric systems in drug delivery. Matrices. Microcapsules and microspheres. CHAPTER 5. FUNDAMENTAL PROCESSES IN PHARMACEUTICAL INDUSTRY 5.1. FILTRATION (4 hours) Introduction. Objectives. Types of materials to be filtered. Theory. Equations of Poiseuille, Darcy, Kozeny. Types of filters. Materials employed in filtration. Gravity filters. Rotative filter. Oliver filter. Pressure filters. 5.2 STERILIZATION (5 hours) Physical means. Heat sterilization. Dry heat sterilization .Flame system. Equipment to air dry. Moist heat sterilization. Flowing steam, saturated steam under pressure. Advantages of the use of steam. Autoclaves. UV rays. Gamma rays. Beta rays. Advantages and disadvantages. Other physical methods: ultrasound, x-ray sterilization. Parameters for the evaluation of sterilization processes: D value, Z value, factor inactivation. Bactericides, disinfectants. Gas sterilization: ethylene oxide, beta - propiolactone. Mechanical methods: filtration. Filter Berkefeld, Chamberland and Selas, Seitz filters, Pal cartridges. Glass filters. Membrane filters. Aseptic preparation. Air treatment. Laminar flow hoods. 5.3 FREEZE-DRYING (5 hours) Freezing rate and type of lyophilized obtained. Noyes -Whitney equation. Eutectic point. Drying under vacuum. State of aggregation of water. Heat of sublimation: Clapeyron equation. Heating of the sample. Vacuum pumps. Rotary pumps. Use of gas - ballast. Rotary pumps at one and two stages. Rotary piston pumps. Roots pumps. Elimination of water vapor chemical fixation, capacitors cold. Law Knudsen. Refrigerant mixtures. Final drying. Measuring equipment. Vacuum and temperature. Static and dynamic freezing. Pre-cooling in layers. Control cards. Residual moisture. Final treatment. 6. ANTIBODY-DRUG CONJUGATES (2 hours) Key components of an antibody-drug conjugate. N-hydroxysuccinimide (NHS) or maleimide-mediated cross-linking: Doxorubicin-based antibody-drug conjugate. Evolution of monoclonal antibodies. Type of drug to be conjugated. Characteristics of conjugates Selection of linker: cleavable and non-cleavable linkers. Drug release strategies for antibody-drug conjugates. Chemically labile linkers: hydrazone, disulfide, peptide, glucuronide. Chemically stable linkers: thioether. Conjugation involving the amino group of lysine. Conjugation involving thiol groups: Michael reaction and related problems. Alternative strategies: unnatural amino acid with a bio-orthogonal reactive group, enzymatic conjugation and insertion or mutation of cysteine residues. Click-chemistry. 7. DISTILLATION (2 hours) Definition of distillation and evaporation. Volatility. Temperature-composition diagram. Theoretical plate. Relative volatility. Rectification distillation. Continuous and batch processes. Number of plates required for a separation. Distillation of petroleum. Extractive and azeotropic distillation. Modified relative volatility. Production of absolute ethyl alcohol. Steam distillation.

Essential preconditions: Organic Chemistry, Biochemistry Important: Physiology, Pharmacology and Toxicology Useful: Inorganic Chemistry, Drug analyses, Food Chemistry.

1) R. B. Silverman "The Organic Chemistry of Drug Design and Drug Action" Academic Press, 2a edizione, 2004. 2) "Burger's Medicinal Chemistry and Drug Discovery" - 5a edizione, Volume I-M. E. Wolff editore - J. Wiley, 1995 3) G. S. Banker - C. T. Rhodes "Modern Pharmaceutics" 3a edizione- M. Dekker, 1996.

The teaching of Applied Pharmaceutical Chemistry consists of frontal lessons and one or two seminars. The lessons are interactive. The teacher tries to stimulate the students, highlighting the contact points among the different teachings, in order to give a full and homogeneous vision of the degree course. The multidisciplinary is a characteristic of the graduate in Drug Chemistry and Technology that makes him suitable for different jobs in the pharmaceutical world. The students get the teaching materials necessary for the study during the first lesson (program, books…). The teacher during the frontal lessons presents the arguments and practical examples of drugs formulations. The frequency of the lessons is not mandatory but is recommended.

The frequency of the lessons is not mandatory but is recommended.

At the end of the teaching, the student has to pass an oral examination. Eight exam appeals are fixed on Infostud in one year; one of each is opened for ten days, so that students can avoid overlaps with other examinations of the same period. The students that do not pass the examination can recur it during the following appeal. The time of the exam is variable. If the student is able to range over the arguments of the program, and to carry out connections among the different aspects of the proposed subject the examination time can be of about half an hour. Otherwise, more than one hour can be necessary to help the student to have a full vision of the drug problems. The aim of the test is to verify the knowledge and understanding of the students about drug problems and the modifications that is possible to introduce on the molecule in order to overcome them. The students have to communicate their knowledge clearly and with adequate language. The valuation elements are: knowledge of the subjects, suitable language, involvement at the lessons, ability to connect the arguments of the teaching to the already studied ones, ability to solve a specific problem related to the formulation of a specific drug, ability to study autonomously. A sufficient knowledge of the arguments is required to pass the examination with the minimum mark. To obtain the maximum mark, the student has to show a very good knowledge of all the arguments and to be able to present them logically and with suitable scientific language. A sufficient knowledge of the arguments is required to pass the examination with the minimum mark. To obtain the maximum mark, the student has to show a very good knowledge of all the arguments and to be able to reply to the required questions clearly and with suitable scientific language.

The teaching of Applied Pharmaceutical Chemistry consists of frontal lessons and one or two seminars. The lessons are interactive. The teacher tries to stimulate the students, highlighting the contact points among the different teachings, in order to give a full and homogeneous vision of the degree course. The multidisciplinary is a characteristic of the graduate in Drug Chemistry and Technology that makes him suitable for different jobs in the pharmaceutical world. The students get the teaching materials necessary for the study during the first lesson (program, books…). The teacher during the frontal lessons presents the arguments and practical examples of drugs formulations. .