Physical Pharmacy Week 6 Study Notes

Course Overview

  • Course Title: Pharmaceutics I
  • Subject: Physical Pharmacy
  • Week: 6

Learning Objectives

  • Be able to recognize acids and bases based on drug structures.
  • Understand and describe the equilibrium constant, Ka.
  • Predict the effect of ionic strength on pH.
  • Calculate the pH of drug solutions, focusing on weak acids or bases.

Classification of Acids and Bases

Strong Acids and Bases

  • Characteristics:
    • Strong electrolytes.
    • Examples:
    • Hydrochloric acid (HCl)
    • Sulfuric acid (H₂SO₄)
    • Sodium hydroxide (NaOH)
    • Behavior:
    • Complete ionization in water.

Weak Acids and Bases

  • Characteristics:
    • Weak electrolytes, often seen in drug molecules.
    • Examples:
    • Acetic acid (HOAc)
    • Ammonia (NH₃)
    • Behavior:
    • Partial ionization/dissociation in water.
    • Associated dissociation constants: pKa (for acids) and pKb (for bases).

Recognizing Acids and Bases in Drugs

Organic Acids

  • Typically contain a carboxyl (-COOH) group.
  • Examples of acids without the -COOH group:
    • Warfarin (pKa ~ 10.0)
    • Acetaminophen (pKa ~ 9.5)
    • Aspirin (pKa ~ 5.08)

Examples of Organic Acids and Bases:

Acids:
  • Acetic Acid:
    • Structure: COOH
  • Penicillin:
    • Structure: A complex with hydroxyl group and nitrogen.
  • Oxalic Acid:
    • Has two -COOH groups.
  • Trigonelline and Furosemide:
    • Contain different substituents affecting pKa.
Bases:
  • Organic Bases:
    • Typically contain an amine moiety.
  • Examples:
    • Tamoxifen
    • Propranolol
    • Epinephrine
    • Morphine
    • Diphenhydramine
    • Raloxifene

Compounds with Both Acidic and Basic Functional Groups:

  • Examples include amino acids, Levofloxacin, Risedronate, and Ceftazidime.

Dissociation Reactions

Weak Acids

  • Dissociation Reaction:
    • Conjugated base formation:
    • HA + H₂O ⇌ H₃O⁺ + A⁻
  • Where:
    • HA = weak acid
    • A⁻ = conjugate base
    • H₃O⁺ = hydronium ion

Definitions of pH and pOH

pH

  • Definition: Based on the concentration of hydronium ions (

    pH=−extlog[H+]pH = - ext{log}[H^+]
    )

pOH

  • Definition: Based on the concentration of hydroxide ions.
  • Relationship:
    pH+pOH=−extlog[H+][OH−]=−extlog(Kw)=14pH + pOH = - ext{log}[H^+][OH^-] = - ext{log}(K_w) = 14

Activity of Ions

  • pH can also be expressed based on the activity of ions: pH=−extlogext(Activity)pH = - ext{log} ext{(Activity)}
    • Activity coefficient $ ext{γ}$ can adjust pH calculations, especially at low concentrations.

Effect of Ionic Strength

  • Impact on hydronium ions' activity:
    • Higher ionic strength reduces the activity coefficient.
    • Normally $ ext{γ} < 1.0$.
    • Debye-Hückel theory applies, suggesting that ionic strength affects pH directly.
  • Example formula for activity coefficient:
    extlogextγ=−0.51heta1/2ext{log } ext{γ} = -0.51 heta^{1/2}
  • Increased ionic strength results in lower pH.

Calculation Examples

pH Calculations for Acids

  1. Example 0.05 M HCl:
    • pH with hydronium ion concentration:
      Initial Calculation:
      pH=−extlog(0.05)=1.30pH = - ext{log}(0.05) = 1.30
    • If activity coefficient adjusts to 0.83:
      pH=−extlog(0.83imes0.05)=1.38pH = - ext{log}(0.83 imes 0.05) = 1.38
    • With sodium chloride added, reducing activity coefficient to 0.77:
      pH=−extlog(0.77imes0.05)=1.41pH = - ext{log}(0.77 imes 0.05) = 1.41

Example of Penicillin V

  • Solubility: 24 mg/100 mL
  • pH of saturated solution in WFI: 3.3
  • Discussed: Will the pH change when prepared in 0.9% NaCl (normal saline)?

Concept of Dissociation Constants

KaK_a for Weak Acids

  • Dissociation constant KaK_a based on concentrations:
    • Ka=[H+][A−][HA]K_a = \frac{[H^+][A^-]}{[HA]}
    • pKa relationship:
    • pKa=−extlogKapKa = - ext{log} K_a

Trends in KaK_a and pKa

  • Higher pKa values indicate weaker acids:
    • Trifluoroacetic acid: pKa ~ 0.23
    • Acetic acid: pKa ~ 4.76
    • Phenobarbital: pKa ~ 7.4
    • Phenytoin: pKa ~ 8.3

Multiple Protic Acids

Diprotic Acids

  • Example Reaction:
    • Carbonic acid: H<em>2CO</em>3{H<em>2CO</em>3}
    • Steps of dissociation:
      1. H2CO3
        ightleftharpoons HCO_3^- + H^+
      2. HCO3^- ightleftharpoons CO3^{2-} + H^+
    • Condition: If K<em>a2>>K</em>a1K<em>{a2} >> K</em>{a1}, ignore the second dissociation step.

Triprotic Acids Example

  • Phosphoric Acid, H₃PO₄:
    1. First dissociation: 7.1imes10−37.1 imes 10^{-3} → pKa = 2.15
    2. Second dissociation: 6.3imes10−86.3 imes 10^{-8} → pKa = 7.20
    3. Third dissociation: 4.5imes10−134.5 imes 10^{-13} → pKa = 12.35

Weak Bases

KbK_b Values for Weak Bases

  • Definition of dissociation constant for weak bases:
    • B + H_2O
      ightleftharpoons BH^+ + OH^-
    • Kb=[BH+][OH−][B]K_b = \frac{[BH^+][OH^-]}{[B]}
  • Routine report of pKa for the conjugated acid instead of pKb.
  • Relationship:
    K<em>w=K</em>aimesK<em>bK<em>w = K</em>a imes K<em>bpK</em>w=pK<em>a+pK</em>b=14pK</em>w = pK<em>a + pK</em>b = 14

Example Calculations for Weaks

  1. Calculate pH for two different weak bases based on concentration and pKapK_a values.
  2. Consider scenarios where concentration determines solubility and pH shifts based on dissociation.

Assignment and Further Reading

  • Reading material: Refer specifically to Chapter 4, pages 61-71 for detailed explanations and references on the discussed topics.