Lecture 1 2024 Pharmaceutical Thermodynamics PDF

Aug 30 announcements Office hours on master contact sheet on Canvas – Begin next week after Labor Day Announcements on Canvas (and in class) No assessments on first two weeks of readings – week of Aug 26 and week of Sept 2 First two weeks – not responsible for calculation...

Aug 30 announcements Office hours on master contact sheet on Canvas – Begin next week after Labor Day Announcements on Canvas (and in class) No assessments on first two weeks of readings – week of Aug 26 and week of Sept 2 First two weeks – not responsible for calculations Reading for next week’s lectures will be uploaded Friday You can use UT Instapoll on Canvas for in poll responses today 1 Lecture+1+2024_class - August 30, 2024  PHM 387M Physical and Chemical Principles of Drugs Fall 2024 Introduction to Thermodynamics and Gibbs Free Energy 2 Lecture+1+2024_class - August 30, 2024  Learning Objectives Apply the basic laws of thermodynamics to understand pharmacy in practice Understand entropy and enthalpy with respect to pharmaceutical systems Learn about differential scanning calorimetry and its importance to drug-related processes involving enthalpy Understand how entropy explains the behavior of poorly water-soluble drugs and how to improve their solubility Understand the principle of Gibbs Free Energy and apply towards understanding pharmaceutical processes 3 Lecture+1+2024_class - August 30, 2024 Thermodynamics as a way to look at practice of pharmacy and dosage forms 4 Lecture+1+2024_class - August 30, 2024 In pharmacy practice: How do you know your drug is at the storage temperature? For those of you who have worked in a pharmacy, how many of you have measured the temperature of every tablet in every single container? 5 Lecture+1+2024_class - August 30, 2024  Zeroth Law of Thermodynamics (Thermal Equilibrium) If two bodies A and B are each in thermal equilibrium with a third body C, then they are in thermal equilibrium with each other (in other words, they share the same temperature) 6 Lecture+1+2024_class - August 30, 2024 Zeroth Law affects storage of medications https://www.kut.org/health/2023-08-04/austin-heat-prescription-drugs-effectiveness 7 Lecture+1+2024_class - August 30, 2024  Zeroth Law in Pharmacy Practice Someone at Merck accidentally left their MMR vaccine outside on their lab bench over the weekend before shipping it. You look at the storage label above. Would you recommend using it? What would you expect would happen? A. yes use it; vaccine is most likely still cold (~4°C—refrigerated temperature) B. don’t use it; vaccine is most likely still cold (~4°C—refrigerated temperature) C. yes use it; vaccine is most likely at room temperature D. do not use it; vaccine is most likely at room temperature 8 Lecture+1+2024_class - August 30, 2024 Someone unfortunately understood thermal equilibrium ☹ 9 Lecture+1+2024_class - August 30, 2024  Internal Energy, Work, and Heat The internal energy of the system is based on the microscale However, we can measure energies flow in and out of system macroscopically (via work/heat) Work: transfer of (mechanical) energy to/from a system from/to surroundings – We mainly think about pressure-volume work on a system Heat: thermal energy in transit 10 Lecture+1+2024_class - August 30, 2024  The First Law of Thermodynamics Although energy can be converted from one form to another, it cannot be created or destroyed. Esystem + Esurroundings = Euniverse = constant Or ∆Esystem + ∆Esurroundings = ∆Euniverse = 0 For a closed system, change in internal energy can be measured in terms of heat and work ∆E = E2 – E1 = q + w 11 Lecture+1+2024_class - August 30, 2024  Enthalpy enthalpy (H) Enthalpy, a state function, is the heat content associated with a process Heat given off or absorbed during a process at constant pressure is equal to the change in the enthalpy of the system. ΔΗ > 0 (+) Heat is absorbed by system Enthalpically hindered, endothermic ΔΗ < 0 (-) Heat is released from system Enthalpically favored, exothermic 12 Lecture+1+2024_class - August 30, 2024 Example of enthalpy in drug-related process: Enthalpy of binding of anti-HIV drugs to HIV protease You have this data of multiple anti-HIV drugs to the same target, HIV protease. 𝑎𝑛𝑡𝑖 − 𝐻𝐼𝑉 𝑑𝑟𝑢𝑔 + 𝐻𝐼𝑉 𝑝𝑟𝑜𝑡𝑒𝑎𝑠𝑒 ⇌ 𝑑𝑟𝑢𝑔 − 𝑝𝑟𝑜𝑡𝑒𝑎𝑠𝑒 𝑐𝑜𝑚𝑝𝑙𝑒𝑥 Q: Which drug is most (enthalpically) favorable for binding to the protease? * AHO Generic Name ΔH (kcal/mol) means its A. Nelfinavir 3.1 enthalpically favored * B. Indinavir 1.8 C. Saquinavir 1.2 D. Lopinavir -3.8 E. Ritonavir -4.3 13 Lecture+1+2024_class - August 30, 2024  On your own: enthalpy of binding of anti-HIV drugs to HIV protease 𝑎𝑛𝑡𝑖 − 𝐻𝐼𝑉 𝑑𝑟𝑢𝑔 + 𝐻𝐼𝑉 𝑝𝑟𝑜𝑡𝑒𝑎𝑠𝑒 ⇌ 𝑑𝑟𝑢𝑔 − 𝑝𝑟𝑜𝑡𝑒𝑎𝑠𝑒 𝑐𝑜𝑚𝑝𝑙𝑒𝑥 * AH O , Q: Which drug is least (enthalpically) favorable for it is the least binding to the protease? favorable /l " enthalpically hindered Generic Name ΔH (kcal/mol) A. Nelfinavir 3.1 B. Indinavir 1.8 C. Saquinavir 1.2 D. Lopinavir -3.8 E. Ritonavir -4.3 14 Lecture+1+2024_class - August 30, 2024  Exothermic reactions in drug dissolution: Heat Pads Sodium acetate (l) +H2O sodium acetate (s) Crystallization: sodium acetate (s) 15 Lecture+1+2024_class - August 30, 2024  Why do heat pads work? Sodium acetate (l) +H2O sodium acetate (s) A. feels warm, heat released from system, most likely due to exothermic reaction of stronger ionic bonds B. feels warm, heat absorbed into system, most likely due to exothermic reaction of forming stronger ionic bonds C. feels warm, heat released from system, most likely & due to endothermic reaction of forming stronger -- ionic bonds D. feels cold, heat absorbed into system due to breaking of strong bonds into weaker interaction with water 16 Lecture+1+2024_class - August 30, 2024  On your own: Why do ice packs work? Enthalpic changes in ‘drug’ dissolution Ammonium nitrate dissolution in water is overall an endothermic process NH4NO3 (s) + H2O  NH4+ (l) + NO3- (l) Exchange strong intramolecular ionic bonds for weaker polar bonds 17 Lecture+1+2024_class - August 30, 2024 In formulation sciences: Differential Scanning Calorimetry (DSC) as a technique to measure drug-related processes involving enthalpy A DSC measures the difference in heat flow rate (mW = mJ/sec) between a sample and inert reference as a function of time and temperature Courtesy of TA Instruments 18 Lecture+1+2024_class - August 30, 2024  Uses of DSC for enthalpic processes of drugs Measure ∆Hfus (melting) Measure ∆Hmix Measure ∆Hsoln Determine polymorphs (i.e., different structures) of a crystalline drug Determine moisture in preparation, post- formulation, oxidation Compatibility of excipients with drugs 19 Lecture+1+2024_class - August 30, 2024  Heat Flux DSC Cell Schematic 2900 Series DSC Reference Pan Sample Pan Dynamic Sample Chamber Lid Gas Purge Inlet Thermoelectric Disc (Constant) Chromel Chromel Disc Disc Heating Block Chromel Wire Thermocouple Alumel Wire Junction Courtesy of TA Instruments 20 Lecture+1+2024_class - August 30, 2024 DSC measures heat flow of samples laka. enthalpic change) -- temperature 21 Lecture+1+2024_class - August 30, 2024  Typical processes with drugs that can be determined by DSC Composite graph Oxidation exothermic process Or ↓ Decomposition Crystallization Heat Flow -> exothermic more endothermic ↓ Melting Glass Transition Cross-Linking (Cure) Pay attention to axes! This is a composite graphs of the enthalpies associated with the different processes Courtesy of TA Instruments 22 Lecture+1+2024_class - August 30, 2024 Can look at the compatibility of excipient with drug with DSC According to the DSC thermogram, is sodium laurel sulfate “compatible” with chlorpropamide drug? A. Yes B. No 23 Lecture+1+2024_class - August 30, 2024 Second Law of Thermodynamics: the connection between entropy and spontaneity of process The 2nd law refers to the probability that a process (e.g., reaction) will occur (i.e., direction a process follows). For an irreversible spontaneous process, the direction of the process proceeds towards a state of randomness Entropy is the natural tendency for a process to occur. According to 2nd law also states that when a system reaches equilibrium, the net entropy change between system and surroundings is 0. ∆Ssystem + ∆Ssurroundings = ∆Suniverse = 0 (equilibrium) 24 Lecture+1+2024_class - August 30, 2024 Example: albumin binding of poorly water-soluble drugs is partially entropy driven Paclitaxel is a poorly water soluble drug (