Solubility, Complexation, and Buffers in Pharmaceutical Science

Posted on Dec 16, 2024 in Chemistry

Solubility Expression

Solubility is defined as the concentration of a solute in a solvent when the solution becomes saturated at a specific temperature and pressure. It is expressed as:

  • Molarity (M): Moles of solute per liter of solution (mol/L).
  • Molality (m): Moles of solute per kilogram of solvent (mol/kg).
  • Parts per million (ppm): Milligrams of solute per liter of solution, often used for very low solubility levels.
  • Percentage concentration: Expressed as weight/volume (% w/v) or weight/weight (% w/w).

Example: The solubility of sodium chloride in water at 25°C is 36 g/100 mL, indicating that 36 g of NaCl can dissolve in 100 mL of water.

Factors Affecting Solubility of Drugs

  • Nature of Solute and Solvent:
    • Polar solutes dissolve in polar solvents (e.g., sugar in water).
    • Nonpolar solutes dissolve in nonpolar solvents (e.g., oil in benzene).
  • Temperature:
    • Solubility of solids typically increases with temperature (endothermic dissolution).
    • Gas solubility decreases as temperature increases (e.g., CO₂ escaping from soda).
  • Pressure:
    • Mainly affects gases. According to Henry’s Law, solubility of a gas increases with an increase in pressure.
  • Particle Size:
    • Smaller particles have larger surface areas, increasing dissolution rates.
  • pH of the Solution:
    • Affects ionizable drugs (weak acids and bases). For example, weak acids dissolve more in basic pH due to ionization.
  • Cosolvency:
    • The addition of cosolvents (e.g., ethanol, propylene glycol) enhances solubility.

Solubility of Liquid in Liquid

1. Completely Miscible: Liquids mix in all proportions (e.g., ethanol and water).

2. Partially Miscible: Some liquids form two layers when mixed beyond a limit (e.g., phenol and water).

3. Immiscible Liquids: Do not mix at all (e.g., oil and water).

Applications:

Understanding liquid-liquid solubility is crucial for emulsions and formulations.

Crystalline Solids vs. Amorphous Solids

Crystalline Solids:

  • Have an ordered structure.
  • Sharp melting points.
  • Exhibit anisotropy (different properties in different directions).
  • Example: Sodium chloride (NaCl).

Amorphous Solids:

  • Lack long-range order.
  • No distinct melting points.
  • Exhibit isotropy (same properties in all directions).
  • Example: Glass, amorphous silicon dioxide.

Aerosols and Their Applications

Aerosols are colloidal dispersions of small solid or liquid particles in a gas.

Applications:

  • Medical: Asthma inhalers (e.g., salbutamol).
  • Cosmetic: Hair sprays, deodorants.
  • Industrial: Spray paints and pesticides.

Eutectic Mixture

A eutectic mixture is a combination of two or more substances that melts at a single lower temperature than the individual components.

Examples in Pharmacy:

  • Camphor and menthol mixtures enhance drug solubility and absorption.

Relative Humidity

Relative humidity measures the moisture in air relative to the maximum amount the air can hold at that temperature.

Pharmaceutical Importance:

  • High humidity may cause hygroscopic drugs to absorb moisture, reducing stability.

Physicochemical Properties of Drugs

  • Optical Rotation: The ability of a chiral drug molecule to rotate plane-polarized light.
    • Positive rotation: Dextrorotatory (+).
    • Negative rotation: Levorotatory (-).

Example: D-glucose and L-glucose have identical formulas but rotate light differently.

Solubilization

Solubilization is the process by which poorly water-soluble drugs are made soluble in water through the addition of surfactants.

  • Mechanism:

    • Surfactants form micelles in water above the critical micelle concentration (CMC).
    • Hydrophobic drug molecules are entrapped in the core of the micelle, enhancing solubility.

  • Applications:

    • Solubilization of hydrophobic drugs like vitamin D using surfactants.
    • Development of clear, stable aqueous solutions for injections.

Detergency

Detergency refers to the cleaning action achieved by the reduction of surface and interfacial tension.

  • Mechanism:

    • Surfactants emulsify oil, grease, or dirt, enabling their removal with water.

  • Applications in Pharmacy:

    • Cleaning of pharmaceutical equipment.
    • Used in formulations like medicated soaps and shampoos.

Practical Applications in Pharmacy

  1. Suspensions:

    • Surfactants reduce surface tension, preventing particle aggregation.
    • Wettability improves dispersion of solid particles.

  2. Emulsions:

    • Surfactants stabilize emulsions by reducing interfacial tension.
    • HLB values guide the choice of surfactant for O/W or W/O emulsions.

  3. Aerosols:

    • Surface tension affects the formation and stability of aerosol droplets.
    • Surfactants enhance uniform dispersion in inhalation therapies.

  4. Tablet Coating:

    • Surface tension influences the uniformity of film coating.

  5. Drug Delivery Systems:

    • Solubilization through micelle formation enhances the bioavailability of poorly soluble drugs.

  6. Young-Laplace Equation (Surface Pressure):

    • ΔP=2γ/r
    • Where ΔP = pressure difference across the interface, γ = surface tension, and r = radius of the droplet.

  7. Critical Micelle Concentration (CMC):

    • The concentration of surfactant above which micelles form.

Classification of Complexation

Complexation involves the interaction between two or more molecules or ions to form a stable, non-covalent association. These complexes can modify the physical, chemical, and biological properties of drugs.

Types of Complexes:

  1. Inorganic Complexes:

    • These involve coordination bonds between metal ions and ligands.
    • Examples:
      • Hemoglobin, where iron forms a complex with the porphyrin ring.
      • Cisplatin (a platinum complex) used in cancer chemotherapy.

  2. Organic Complexes:

    • Formed through weak non-covalent interactions like hydrogen bonding, van der Waals forces, or hydrophobic interactions.
    • Examples:
      • Caffeine with salicylic acid: Caffeine forms complexes with acidic drugs, improving drug solubility and taste masking.
      • Cyclodextrin inclusion complexes: Cyclodextrins form a “host-guest” inclusion complex to encapsulate poorly water-soluble drugs, enhancing solubility and stability (e.g., beta-cyclodextrin with itraconazole).

  3. Biological Complexes:

    • These complexes occur naturally in biological systems and include drug-protein interactions.
    • Examples:
      • Enzyme-substrate complexes: A substrate binds to an enzyme’s active site for catalysis.
      • DNA-drug interactions: Anti-cancer drugs like doxorubicin bind to DNA and inhibit replication.

Buffers in Pharmaceutical and Biological Systems

Buffers are solutions that resist changes in pH upon addition of small amounts of acids or bases. They are essential in maintaining the stability and efficacy of pharmaceutical formulations and biological systems.

Components of Buffers:

  1. Weak acid and its conjugate base: E.g., acetic acid and sodium acetate.
  2. Weak base and its conjugate acid: E.g., ammonium hydroxide and ammonium chloride.

Pharmaceutical Buffers:

Buffers are used to stabilize the pH of drug formulations, as many drugs are stable only in a specific pH range.

  • Phosphate Buffer System (pH 7.4):

    • Used for parenteral formulations and eye drops.
    • Mimics the pH of body fluids.

  • Citrate Buffer System (pH 3-6):

    • Stabilizes acidic drugs and is used in injectables and syrups.

  • Tris Buffer System (pH 7-9):

    • Commonly used in biological studies and biopharmaceutical products.

Biological Buffers:

Buffers are critical for maintaining homeostasis in biological systems. For instance:

  • Bicarbonate Buffer System: Maintains blood pH at 7.4. Any deviation can cause acidosis or alkalosis.
  • Phosphate Buffer System: Operates in intracellular fluids and kidneys to regulate acid-base balance.

Critical Solution Temperature (CST)

The CST is the highest temperature at which two partially miscible liquids become completely miscible.

Example: Phenol and water have a CST of 68.4°C.

Distribution Law

This explains how a solute distributes between two immiscible solvents at equilibrium.

Example: In drug formulation, partition coefficient (oil/water) is critical for predicting drug absorption and bioavailability.

Surfactants and the HLB Scale

Surfactants are molecules that have both hydrophilic (water-attracting) and lipophilic (oil-attracting) parts. They lower the surface or interfacial tension and are widely used in pharmacy.

Classification of Surfactants:

  1. Anionic Surfactants: Negatively charged head group (e.g., sodium lauryl sulfate).
  2. Cationic Surfactants: Positively charged head group (e.g., benzalkonium chloride).
  3. Nonionic Surfactants: No charge; hydrophilicity due to polar groups (e.g., Tween, Span).
  4. Zwitterionic Surfactants: Both positive and negative charges (e.g., lecithin).

HLB Scale (Hydrophilic-Lipophilic Balance):

  • The HLB value determines the type of emulsion formed:
    • Low HLB (3–6): Suitable for water-in-oil (W/O) emulsions.
    • High HLB (8–18): Suitable for oil-in-water (O/W) emulsions.

Example:

  • Tween 80 (HLB ~15): Used for O/W emulsions.
  • Span 60 (HLB ~4.7): Used for W/O emulsions.

Protein Binding

Protein binding refers to the reversible interaction of a drug with plasma or tissue proteins. Only the free (unbound) drug is pharmacologically active.

Types of Binding:

  1. Albumin Binding:

    • Albumin is the most abundant plasma protein and binds acidic drugs like warfarin, phenytoin, and salicylates.

  2. Alpha-1 Acid Glycoprotein Binding:

    • It binds primarily to basic and neutral drugs like propranolol and lidocaine.

  3. Lipoprotein and Globulin Binding:

    • Lipoproteins bind lipophilic drugs.
    • Globulins often bind steroid hormones and vitamins.

Factors Influencing Protein Binding:

  • Drug concentration.
  • Protein concentration.
  • Binding affinity (determined by chemical structure).
  • Pathological conditions (e.g., hypoalbuminemia reduces binding sites).

Importance of Protein Binding:

  1. Pharmacokinetics: Bound drugs act as a reservoir, releasing free drug over time.
  2. Drug-Drug Interactions: Highly protein-bound drugs compete for binding sites (e.g., warfarin with NSAIDs, leading to enhanced anticoagulant effect).
  3. Drug Half-life: Protein binding prolongs the elimination half-life of a drug.

Isotonic Buffers

Isotonic solutions have an osmotic pressure equal to that of body fluids (e.g., blood, tears). This prevents osmotic stress on cells.

Examples:

  1. Sodium Chloride Solution (0.9% NaCl):

    • Used in IV fluids to prevent hemolysis or crenation of red blood cells.

  2. Dextrose Solution (5% D-glucose):

    • Commonly used as a source of energy in parenteral nutrition.

  3. Ringer’s Lactate:

    • Contains Na⁺, K⁺, Ca²⁺, and lactate, used for fluid replacement therapy.

Applications of Isotonic Buffers:

  1. Parenteral Formulations:

    • To avoid irritation at the site of injection (e.g., IV drugs like insulin, antibiotics).

  2. Ophthalmic Solutions:

    • Eye drops must be isotonic to avoid discomfort and irritation.

  3. Biological Systems:

    • Buffers are essential in maintaining isotonicity during blood transfusions and dialysis.

Key Calculations in Buffer and Isotonic Solutions:

  1. Henderson-Hasselbalch Equation:

    • Used to calculate the pH of a buffer system: pH=pKa+log⁡([A⁻][HA])

    Where:

    • [A⁻] = concentration of conjugate base.
    • [HA] = concentration of weak acid.

  2. Isotonicity Calculation:

    • Adjustments for osmotic pressure using NaCl Equivalent Method: E=MW of drug×idrugMW of NaCl×iNaCl