Acid-Base Chemistry and pH Relationships

Topic 1: Solving pH and pKa Problems

• Junmei Wang, Associate Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh
• Contact information included for the professor and course website

Why Do We Learn Principles of Medicinal Chemistry?

• Ibuprofen and Naproxen are structurally similar but have different durations of action.
• Naproxen is a longer-acting agent.
• Ibuprofen has 98% plasma protein binding, while naproxen has 99%.
• Ibuprofen pKa is 4.5, and Naproxen's is 4.15.

Reference Book for Medicinal Chemistry Section

• Basic Concepts in Medicinal Chemistry by Marc W. Harrold and Robin M. Zavod
• Textbook is available online through the university library database.

Learning Objectives

• Explain the similarities, differences, and interrelationships between pKa of a functional group and pH of an environment.
• Explain how the Henderson-Hasselbalch equation was constructed and how it can calculate pH values, pKa values, and the ratio of ionized to unionized functional groups.
• Solve both qualitative and quantitative pH/pKa problems.

Basic Concepts

• pH = -log[H+]
• pOH = -log[OH−]
• pH + pOH = 14
• Includes an example table relating hydrogen ion concentration to pH and pOH.

Calculating pKa

• HA + H₂O ⇌ H₃O⁺ + A⁻ (Actual equation)
• HA ⇌ H⁺ + A⁻ (Simplified form)
• Kₐ = [H⁺][A⁻]/[HA] (Dissociation constant)
• pKa = -log([H⁺][A⁻]/[HA])

Basic Concepts (Basic Functional Groups)

• pKa for basic functional groups: B: + H⁺ ⇌ B:H⁺
• Kₐ = ([H⁺][B:])/[B:H⁺]
• pKa = -log([H⁺][B:])/[B:H⁺]

Key Summary Points for pH and pKa

• pH value is a property of the environment.
• Low pH values indicate acidic environments, high pH values indicate basic environments, and pH 7.0 is neutral.
• Key pH values include Saliva (6.4), Stomach (2.0), Duodenum (5.4), Plasma (7.4), Urine (5.7).
• pKa value is a property of a specific acidic/basic functional group; generally constant.
• Low pKa values indicate strong acids or weak bases.
• High pKa values indicate weak acids or strong bases.

Henderson-Hasselbalch Equation

• Includes the equation pH = pKa + log ([A⁻]/[HA]) and related variations for acidic and basic functional groups.

Equilibria for Acids and Bases

• Includes representations of mono and diprotic acids and bases.

Application of Henderson-Hasselbalch Equation

• Example question and answer regarding the ionization of a functional group in urine.
• pKa of 4.5; urine pH of 5.9; primarily unionized.

Three Scenarios on the Relationship of pH and pKa

• Three scenarios representing relationships between pH and pKa for acids and bases
• Indicates the relative importance of differences in pH and pKa rather than exact values.

Solving Qualitative pH and pKa Problem

• Example problem with Amoxicillin showing predominant forms of two functional groups.

Key Summary Points on Solving Qualitative Problems

• Identification of acidic and basic functional groups and pka values is first.
• Solutions are possible when comparing pH and pKa values; the Henderson Hasselbalch Equation is not always required.
• Explains quantitative situations when pH=pKa; pH>pKa; pH<pKa.

Solving Quantitative pH and pKa Problem

• Example problem determining the % of ionized drug at a given pH.

Calculating the pH of an Environment

• Example problem to calculate the pH needed for specific ionization of a drug.

Calculating pKa of A Function Group

• Example problem to calculate the pKa of a functional group given its ionization percentage in a specific pH.

The Rule of Nines

• Table and example demonstrating how pH-pKa difference correlates with ratio.

Key Summary Points on Solving Quantitative Problems

• The Henderson-Hasselbalch equation relates pH, pKa and ratio.
• Initial steps for the solution include identifying the acid/base character and analyzing the relationship between pH/pKa.
• Calculating percentage ionization using the Henderson Hasselbalch equation and related concepts.

The Importance of pH and pKa in Drug Therapy

• Aqueous Solubility: High-dose methotrexate used for tumors; it can precipitate in the renal tubules if urine pH is not raised. Crucial to maintain high ionization as increased solubility; alkaline urine required.
• Duration of Action: Phenobarbital renal elimination is pH-dependent. Decreassed urine pH will lead to reabsorption decreased renal elimination.
• Influence on Drug Binding Interactions: Ionic bonds are formed between drugs and biological targets over a significant distance; can be the first step in attraction.

Key Summary Points Involving the Importance of pH and pKa Drug Therapy

• Urinary and gastric pH are variable, while blood and tissue pH remains constant.
• Alterations of functional groups alter drug properties, affecting solubility, bioavailability, adverse reactions, duration, and binding interactions.

In Class Practice Problems

• Series of application problems for students' practice. Illustrative questions and scenarios are presented along with the appropriate equations and examples.

Homework

• Questions with several real-world drug molecule examples in solution, allowing students to apply concepts learned in the lecture.

Homework - Continued

• Table with various pH environments and their corresponding ionization outcomes.
• Application exercise for naproxen and dyclonine.

L1: Homework - Continued

• Further homework exercises employing Henderson-Hasselbalch equations and the "Rule of Nines."
• Illustrative cases focused on naproxen and dyclonine.