PHRM 6201: Physical Pharmacy - Week 7 Study Notes

PHRM 6201: Physical Pharmacy - Week 7 Study Notes

Understanding Pharmaceutical Salts

  • Key Learning Objectives:

    • Ability to understand salt formation from the perspective of intermolecular forces.

    • Understanding clinical implications of pharmaceutical salts.

    • Predicting the effect of ionic strength on pH.

    • Calculation of the pH of drug solutions, focusing on weak acids or weak bases.

Formation of Salts

  • Definition of Salts:

    • Salts are formed from cations (positively charged ions) and anions (negatively charged ions) through ionic forces (ionic bonds).

    • Salts function as strong electrolytes.

    • Types of Salts:

    • Inorganic Salts: e.g., Sodium Chloride (NaCl).

    • Organic Salts:

      • Involves organic components either as cations or anions.

      • Examples include sodium lactate and ammonium acetate.

    • Pharmaceutical Salts:

      • Formed specifically from drug molecules and counterions through ionic forces.

      • Drug molecules can exist as cations or anions, paired with inactive counterions (e.g., H(^+) and Cl(^-)).

Characteristics of Pharmaceutical Salts

  • Formation:

    • A pharmaceutical salt is created when a weak acid (anion) or a weak base (cation) drug is paired with an appropriate counterion through ionic interactions.

    • For weak acids: Use strong acids or bases such as:

    • Sodium (Na(^+)), Potassium (K(^+)), Calcium (Ca(2+)), Magnesium (Mg(2+)), Tromethamine, and Choline.

    • For weak bases: Use strong acids such as:

    • Hydrochloric (HCl), Hydrobromic (HBr), Sulfate, Tartrate, Besylate, Maleate, and Citrate.

Examples of Pharmaceutical Salts:

  • Weak Acids: Atorvastatin calcium, Clopidogrel bisulfate, Esomeprazole magnesium, Metoprolol tartrate, Warfarin sodium, Metformin HCl, Penicillin V potassium, Amlodipine besylate, Sildenafil citrate, Enalapril maleate, Citalopram HBr.

Purpose and Variations of Pharmaceutical Salts

  • Purpose:

    • To establish a stable crystalline structure.

    • To improve solubility and enhance bioavailability.

    • To enhance chemical and physical stability.

    • To facilitate better manufacturability.

  • Variations in Pharmaceutical Salts:

    • Crystalline Salts with polymorphs.

    • Solvates and Hydrates that can influence stability and solubility.

Clinical Implications of Different Salt Forms

  • Different Salt Forms of Drugs:

    • Example of Clopidogrel in Europe:

    • Available as Bisulfate (Plavix) and Besylate (bioequivalent to Plavix).

    • Resinate (Pregrel) which is a polymeric salt.

    • Dosage Forms Variability:

    • Metoprolol tartrate is intended solely for immediate-release tablets, while Metoprolol succinate is for extended-release tablets.

  • Pharmacokinetic (PK) Properties Changes:

    • Different salts may affect absorption, distribution, metabolism, and elimination.

    • Example: Diclofenac sodium vs. potassium, where potassium salt potentially offers a quicker absorption and onset of action.

    • Safety Profiles: Doxycycline hyclate leads to more gastrointestinal upset than doxycycline monohydrate due to acidity levels.

Drug Labeling and Regulatory Guidelines

  • Salts in Drug Labeling:

    • Survey of top 200 drugs revealed 59 unique salts.

    • 32 drugs express strength as salts, and 27 express strength as free acids/bases.

  • FDA Guidance (June 2015):

    • Focused on the naming of drug products with salt drug substances.

    • Recommended using the active moiety in drug names.

    • Strength indication based on the active moiety, with exceptions allowable under specific guidance.

Drug Strength Expressions for Salts of Acidic and Basic Drugs

  • Table 1: Drug strength expressions for salts of acidic drugs from the top 200 list, showcasing differences in how strengths are expressed across drugs, such as Atorvastatin calcium, Levothyroxine sodium, Esomeprazole magnesium, and several others.

  • Table 2: Drug strength expressions for salts of basic drugs from the top 200 list, showing various examples including Hydrocodone/APAP, Sildenafil citrate, and Metoprolol tartrate.

Calculation of pH of Salt Solutions

  • A salt is formed from an acid (anion) and a base (cation) through ionic interactions.

  • Types of Salts:

    • Salt of strong acid and strong base (e.g., NaCl) results in neutral pH.

    • Salt of strong acid and weak base (e.g., NH4Cl) is weakly acidic, similar to a weak acid solution.

    • Salt of weak acid and strong base (e.g., NaOAc) is weakly basic, akin to weak base solutions.

    • Salt of weak acid and weak base (e.g., NH4OAc) pH calculation is based on the acid and base strength (pKa and pKb) but independent of salt concentration.

Example Calculations

  • If you dissolve 201.5 mg of ephedrine HCl in 100 mL water:

    • Molecular Weight (MW) of Ephedrine: 165.2.

    • pKa of Ephedrine: 9.6.

    • Calculation of Concentration:

    • Concentration=rac201.5extmg(165.2ext+36.5)extg/mol/0.1extL=0.01extMConcentration = rac{201.5 ext{ mg}}{(165.2 ext{ + } 36.5) ext{ g/mol}}/0.1 ext{ L} = 0.01 ext{ M}

    • Resulting pH Calculation:

    • pH=pKa−extlogc=9.6−extlog(0.01)=5.8pH = pK_a - ext{ log } c = 9.6 - ext{ log }(0.01) = 5.8

  • **Ammonium Acetate Example:

    • Calculate pH of a 0.01 M solution:**

    • Ka=1.75imes10−5K_a = 1.75 imes 10^{-5}

    • Kb=1.74imes10−5K_b = 1.74 imes 10^{-5}

    • Use these constants in pH calculations which generally results in near neutral conditions around pH=7pH = 7.

Buffer Solutions

  • Definition:

    • An aqueous solution containing a weak acid and its conjugate base or weak base and its conjugate acid.

    • Buffer pH Ranges:

    • Acidic buffers (pH < 7) use weak acids.

    • Basic buffers (pH > 7) utilize weak bases.

  • Buffer Capacity (β):

    • Influenced by type of buffer (pKa), buffer pH ([H(^+)]), and buffer concentration (Ct).

    • Important for maintaining stable pH in various preparations.

Examples of Calculation

  • At a pH of 5.25, selecting appropriate acids or bases requires the target pKa values to be within 1 unit of the desired pH.

  • Example: 0.050 mol of citric acid and 0.100 mol of monosodium citrate in 500 mL yields a calculated pH apropos to the known properties of citric acid with associated pKa values.

Hydrolysis of Ampholytes

  • Definitions include molecules with both acidic and basic functional groups, such as amino acids and certain pharmaceuticals (e.g., Levofloxacin, Risedronate).

  • Relevant calculations involve using pKa values to derive pH for solutions containing ampholytes which tend to show independent behavior from ionic characteristics.

Problem Solving Examples

  • A solution of citric acid and sodium citrate with a given pKa to determine the resultant pH based on respective concentrations.

  • Similar analysis for sodium bicarbonate with adjustments for added compounds such as sodium carbonate, using respective pKa values in the calculations.

Conclusion

  • Final Review:

    • Understanding the multifaceted nature of pharmaceutical salts and their impact on drug behavior, focusing on practical applications in pH calculation and the importance of correct buffer selection for pharmaceutical formulations.

Assignments

  • Readings Assigned:

    • Chapter 4, pages 61-71.

    • Complete related calculation exercises leveraging provided data and theory principles discussed in class throughout this week.