PF1010 Physicochemical Basis of Pharmaceuticals PDF

PF1010 Physicochemical Basis of Pharmaceuticals Dr. Humphrey Moynihan ([email protected]) & Prof. Abina Crean ([email protected])  Material on Canvas Canvas → 2025-PF1010 Module (i.e., Canvas module): Dr. Humphrey Moynihan Materials Will contain:...

PF1010 Physicochemical Basis of Pharmaceuticals Dr. Humphrey Moynihan ([email protected]) & Prof. Abina Crean ([email protected])  Material on Canvas Canvas → 2025-PF1010 Module (i.e., Canvas module): Dr. Humphrey Moynihan Materials Will contain: – PDFs of lecture slides and tutorial question slides – PDFs of tutorial answers – Recordings of lectures if possible  PF1010 Objective Module objective: Introduction to the physicochemical principles of pharmaceutical systems. Pharmaceutical systems, examples include: Formulations of APIs and excipients – API: Active Pharmaceutical Ingredient, i.e., active drug molecule – Excipients: other non-active ingredients of the medicine Drugs binding to receptors in tissues – Receptors: proteins which act as binding sites for drugs Enzymes binding substrates Cellular structures, etc.  PF1010 Objective Module objective: Introduction to the physicochemical principles of pharmaceutical systems. Physicochemical principles: any aspect of: Chemistry Physics or physical chemistry which… …determines or affects the structure, stability and function of pharmaceutical systems.  Textbooks Entry level – Any 3rd level general chemistry textbook (e.g: ‘Chemistry’, C. E. Housecroft & E. C. Constable) – Principles and problems in physical chemistry for biochemists, Price & Dwek Intermediate – Pharmaceutics; The Science of Dosage Form Design, Aulton (Ed.) Advanced – Physical Pharmacy and Pharmaceutical Science, Martin – Physical Chemistry, Atkins & de Paula  H. Moynihan PF1010 Topics Introduction to thermodynamics: equilibrium, ideal gases HM First law of thermodynamics: enthalpy, thermochemistry HM Second law of thermodynamics: entropy, free energy HM Free energy and equilibrium HM Chemical potential, the phase rule HM Phase diagrams, triple and critical points HM Systems of one, two, three components, eutectic points, , triangular phase HM diagrams Systems with multiple solid phases; polymorphs and solvates HM Acids & bases; pH, pKa; Henderson-Hasselbalch equations HM Activity and ionic strength HM i.e. thermodynamics (study of the energy of physical and chemical systems) Thermodynamics and pharmaceuticals A dosage formulation (medicine) is a system of multiple phases and components governed by thermodynamics and process equilibria System: part of the physical world defined for study Phase: homogenous portion of physical material bounded by interfaces Component: chemical ‘ingredient’ of the system [Pharmaceuticals: chemical components of medicines] Thermodynamics and pharmaceuticals A dosage formulation (medicine) is a system of multiple phases and components governed by thermodynamics and process equilibria Examples of equilibrium processes: – Binding of drugs to receptors or enzymes – Biochemical reactions in body metabolism – Processes for manufacturing Active Pharmaceutical Ingredients (APIs) – Many formulation processes – Most measures of pharmacological activity are, effectively, equilibrium constants Thermodynamics and pharmaceuticals A dosage formulation (medicine) is a system of multiple phases and components governed by thermodynamics and process equilibria Pharmaceutical analysis relies on quantitative measurement of partitioning between phases – chromatography, e.g., gas chromatography, TLC, HPLC or enthalpy (heat) transfers – Thermal Analysis or other quantitative physical effects  System and Surroundings System: defined part of the physical world under study Surroundings: rest of the physical world (or at least that part affected by changes to the system) Examples: a dosage form (tablet, suspension), a reaction in a vessel, a biochemical system  Equilibrium Pharmaceutical systems may consists of many components and phases, e.g. Components: API, excipients Phases: solid phase, immiscible liquids, gaseous phases Components may be partitioned between various phases System (phases & components) exist in dynamic equilibrium  Law of mass action & equilibrium constants E.g., say substances A and B react to form substances C and D Say the process requires a ratio of A to B of a:b and gives a ratio of C to D of c:d (a, b, c and d are known as the reaction stoichiometries) Can summarise the process as follows: The symbol means that the process occurs in both directions  Law of mass action & equilibrium constants React a of A with b of B C and D start forming (in a ratio c:d) C and D can also react to form A and B Eventually, the process ‘settles down’ to give constant amounts of A, B, C and D The process is then at equilibrium Is a dynamic equilibrium i.e., although the overall amounts of A, B, C and D stay the same, the process is still on-going in both directions  Law of mass action & equilibrium constants Equilibrium processes subject to the law of mass action E.g., for Can define the equilibrium constant (Keq) for the process as follows E.g., [C] stands for the concentration of component C Note the role played by the stoichiometries a, b, c and d in the equilibrium constant (Will offer a justification for this equation later) Examples of pharmaceutical processes and equilibria Drug partitioned between an aqueous medium (e.g. cell interior) and a lipid medium (e.g. cell membrane) Define drug concentration in both: [drug]aq, [drug]lipid The following equilibrium and equilibrium constant exist: 𝑑𝑟𝑢𝑔 𝑙𝑖𝑝𝑖𝑑 𝐾𝑒𝑞 =𝑃= 𝑑𝑟𝑢𝑔 𝑎𝑞. [known as a partition coefficient (P); generally use log P]  Reaction equilibria 𝑅𝑆𝑆𝑅 [𝐻2ሿ 𝐾𝑒𝑞 = 𝑅𝑆𝐻 2 Note: for reverse process 1 Equilibrium constant is inverted 𝐾𝑒𝑞 𝑙𝑒𝑓𝑡 → 𝑟𝑖𝑔ℎ𝑡 = 𝐾𝑒𝑞 𝑟𝑖𝑔ℎ𝑡 → 𝑙𝑒𝑓𝑡  Biochemical equilibrium: worked problem The concentration of a solution of G3P was initially 0.05 M. Isomerase was added. After the mixture came to equilibrium at 25 °C, the concentration of G3P was 0.002 M. Calculate Keq for the reaction at 25 °C. ‘M’ is short for moles per litre (mol L−1) Moles quantify the amount of a substance, will explain later. Define the equilibrium and the equilibrium constant [DHAP] Keq = [G3P] [G3P] = 0.002 M [DHAP] = 0.05 M − 0.002 M = 0.048 M 0.048 M Keq (at 25 ◦C) = = 24 0.002 M  Tutorial. Equilibrium Constants Keq (at 25 ◦C) for isomerisation of glucose-6- phosphate (G6P) to fructose-6-phosphate (F6P) is 0.428. Define the equilibrium constant Calculate [F6P] at equilibrium at 25 ◦C if the initial [G6P] is 0.1 M  Structure and stability of pharmaceutical systems Pharmaceutical systems: – E.g: medicines (dosage formulations of APIs and excipients) – Ligands & receptors, enzymes & substrates/inhibitors, others Chemical components: APIs, excipients, biomolecules Phases: solids, liquids, gases, other? Key issue: structure and stability