Pharmaceutical Physical Chemistry Study Notes

Pharmaceutical Physical Chemistry Study Notes

• Solubility of Solids in Liquids (Continued):
  • Maintaining a homogenous solution requires optimizing pH for maximum therapeutic effect.
  • The relationship between drug solubility and pH is expressed by equations.
  • Acidic drugs: pH = pKa + log (S - So) / So.
    • S: overall drug solubility
    • So: solubility of unionized form
    • pKa: partition coefficient
  • Basic drugs: pH = pKb - log (S - So) / So
  • Knowing the pH allows for calculating the solubility of an acidic drug.

Example Calculation

• Phenobarbital Example:
  • Determine the pH required for phenobarbital separation from a solution with an initial concentration (S) of 0.039 mol/L and a molar solubility (So) of 0.005 at 25°C.
  • The pKa for phenobarbital is 7.41 at 25°C.
  • pH = pKa + log (S - So) / So = 7.41 + log (0.039 - 0.005) / 0.005 = 8.24

Influence of Solvents

• Cosolvency: Solutes are often more soluble in a mixture of solvents than in a single solvent.
• Example: 1g of phenobarbital is soluble in: 1000 ml of water, 10 ml of alcohol, 40 ml of chloroform, 15ml of ether. A combination of 22% alcohol, 40% glycerin, and 38% water can increase the solubility to 1.5% w/v.

Combined Effect of pH and Solvents

• Solvents affect weak electrolytes in buffered solutions in two ways:
  • Adding alcohol to aqueous solutions of weak electrolytes increases the solubility of the non-ionized species. This is due to alcohol's lower polarity compared to water, which decreases electrolyte dissociation, thus reducing drug solubility.

Effect of Molecular Structure of Solutes

• Minor changes in a compound's structure can significantly impact its solubility in a liquid.
  • Example: The introduction of a hydroxyl group can drastically improve the water solubility of a substance.
  • Conversion of a weak acid to its sodium salt leads to an increased degree of ionic dissociation and thus, better water solubility.

Crystal Characteristics and Solubility

• Polymorphism: Different crystalline forms of the same substance (polymorphs) affect the drug's properties, including solubility.
• Example: Steroids, barbiturates, and sulfonamides exhibit polymorphism.

Crystal Size and Solubility

• Smaller particles increase solubility due to changes at the interfacial free energy.

Complexes and Solubility of Drugs

• Adding a third substance, potentially forming an intermolecular complex with the solute, can either increase or decrease solubility.
• Example: Complexes between 3-aminobenzoic acid and carboxylic acids increase its water solubility. Similarly, complexes between mercuric iodide and potassium iodide can assist in solution preparation.

Surface Active Agents and Solubility

• Surface-active agents (amphiphilic agents) enhance solubility by allowing weakly acidic or basic drugs to dissolve.
• Example: Polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monolaurate (Span 20), and sorbitan monooleate (Span 80)
• Applications: Solubilization of weak electrolytic drugs in aqueous solutions of non-ionic surfactants, like polysorbate 80 (Tween 20 on peppermint oil).

Solubilizing Agents

• Enhancing the solubility of poorly soluble drugs through specific materials.
  • Example: PEG 400 increases hydrochlorthiazide solubility, while caffeine and nicotinamide increase halofantrine solubility.

Specifications for Selecting Solubilizing Agents

• Critical properties for solubilizing agents include:
  • Non-toxicity
  • Miscibility with the solvent (usually water)
  • Compatibility with the substance to be solubilized
  • Absence of objectionable odor and taste
  • Relatively low volatility
  • Appropriate amount (not an excess nor insufficient).

The Phase Rule

• Miscibility of Liquids: Defines the degrees of freedom in a system with varying temperature, pressure, and concentration. This concept involves components and phases.
• Solid Solubility in Liquids: Similar principles are applicable to solid-liquid systems, but pressure is typically fixed at 1 atm.

Summary of pages 1-8

• Notes concern physical chemistry concepts related to drug preparations and dosage forms.
• Topics covered include solvent effects on drug solubility, different structural and morphological factors affecting solubility, formation of complexes for improving solubility, and the use of solubilizing agents.

This quiz covers the solubility of solids in liquids, focusing on how pH influences the solubility of acidic and basic drugs. You will explore equations related to drug solubility and apply these concepts through example calculations, including the case of phenobarbital. Enhance your understanding of cosolvency and its effects in pharmaceutical applications.