week 3 solids

Physical Pharmacy:

Pharmaceutical Solids

Week 3

Learning Objectives:

  • Understand solid state properties:

    • Crystalline structure

    • Polymorphism

  • Understand the active pharmaceutical ingredient (API) and its role in medicine:

    • Pharmaceutical Salt

    • Salt formulation

    • Active drug moiety in pharmaceutical salt

  • Understand solid dispersion and phase diagram.

Active Pharmaceutical Ingredient (API):

Definition:

  • A relatively pure substance that exhibits pharmacological activities.

Properties:

  • Preferred to be in solid state due to:

    • Better physical and chemical stability.

    • Easiness in handling and manufacturing.

Example of an API:

  • Clopidogrel API and its drug product.

Properties of Solid API:

Key Properties:

  • Melting Point: The temperature at which a solid becomes a liquid.

  • Solubility: The ability of a substance to dissolve in a solvent.

  • Particle Size and Distribution: Refers to the dimensions of the particles and how they spread in a given volume.

  • Crystalline or Amorphous: Distinction between ordered (crystalline) and disordered (amorphous) solids.

  • Polymorphism: The ability of a substance to exist in more than one form or crystal structure.

  • Hygroscopic Property: The ability to absorb moisture from the air.

  • Flow Property: How easily the powder flows.

  • Wettability: The ability of a liquid to maintain contact with a solid surface.

Classification of Pharmaceutical Solids:

Amorphous vs. Crystalline Solids:

  • Amorphous Solids: Lacks a definitive structure, isotropic properties, and higher solubility but lower stability.

  • Crystalline Solids: Have a defined geometrical shape and structure.

Types of Crystalline Solids:

  • Polymorphs: Different crystalline forms of the same compound.

  • Solvates/Hydrates: Crystals that include solvent or water molecules.

Classification Terms:

  • Monotropic: Only one stable form exists.

  • Enantiotropic: Multiple forms can convert to one another under specific conditions.

  • Reversible vs. Non-reversible Polymorphism: Some polymorphs can revert while others cannot.

Crystal Habits:

Definition:

  • The macroscopic shape of a crystal characterized by its flat faces and specific orientations.

Impact Factors:

  • Morphology depends on:

    • Crystallization conditions, which can affect:

    • Bulk density

    • Flow properties

    • Compression behavior of API and products.

Microscopic Structure of Crystals:

Crystalline Structure:

  • At the microscopic level, crystals consist of a highly ordered arrangement of atoms, ions, or molecules forming a crystalline lattice or unit cell.

Unit Cell Types:

  • There are 7 basic unit cells (primitive cells):

    • Cubic

    • Hexagonal

    • Trigonal

    • Tetragonal

    • Orthorhombic

    • Monoclinic

    • Triclinic

Variation of Unit Cells:

  • End-centered, face-centered, body-centered variations.

Polymorphism:

Definition:

  • Different crystalline forms that a compound can adopt depending on crystallization conditions (solvent and temperature).

Example of Polymorphs:

  • Spironolactone demonstrates polymorphism.

Polymorph Relationships:

  • Different crystal habits may exhibit differing crystalline structures.

Stability of Polymorphs:

Key Points:

  • Only one thermodynamically stable polymorph exists for a compound, while other forms are metastable.

  • Metastable forms can convert into the stable form, impacting solubility and stability.

    • Example: Diamond vs. Graphite.

Implications of Polymorph Stability:

  • Conversion influences:

    • Solubility changes

    • Stability changes

    • Formulation aspects like cream appearance and caking in suspensions.

Hydrates and Anhydrates:

Definitions:

  • Hydrate: Crystals incorporating water molecules in the structure (e.g., Levofloxacin hemihydrate).

  • Anhydrate: Crystals lacking water molecules, generally less stable than hydrates.

Solvates:

Definition:

  • Crystals containing solvent molecules, either stoichiometric or non-stoichiometric.

Example:

  • Darunavir Ethanolate vs. Remogliflozin etabonate (not a solvate; an ethyl carbonate ester).

Amorphous Solids:

Characteristics:

  • Typically found in free acids or bases, lacking structured molecular packing.

  • Key traits include:

    • No fixed melting point (isotropic)

    • Higher solubility and thus better bioavailability, but less stability than crystalline forms.

Example:

  • Novobiocin as an example of an amorphous solid.

Crystalline Solids vs. Amorphous Solids:

Comparison:

  • Crystalline Solids:

    • Ordered structure

    • Fixed melting point

    • Generally good stability and solubility variations among polymorphs.

    • Anisotropic properties.

  • Amorphous Solids:

    • Disordered structure, no fixed melting point

    • Higher solubility, lower stability.

    • Isotropic properties.

Phase Diagrams:

Definition:

  • Graphical representation of states of matter at given temperatures and pressures (One component phase diagram).

Components:

  • X-Axis: Temperature

  • Y-Axis: Pressure

  • Critical Temperature: A temperature above which it is impossible to liquefy a gas regardless of pressure.

  • Triple Point: Conditions under which all three phases (gas, liquid, solid) coexist (e.g., for water: 273.16 K at 0.6117 kPa).

Phase Transitions:

Types:

  • Vaporization: Liquid to gas.

  • Condensation: Gas to liquid.

  • Freezing: Liquid to solid.

  • Melting: Solid to liquid.

  • Sublimation: Solid to gas (endothermic process).

Examples:

  • Dry ice (solid CO2) and ice (solid H2O).

Lyophilization (Freeze-Dry Process):

Definition:

  • A process employed to manufacture solid powders suitable for parenteral administration, improving drug stability.

Steps involved:

  1. Compounding: Dissolving API and excipients in a solution.

  2. Freezing: Converting the solution to ice at low temperatures.

  3. Drying: Removing water through sublimation of the ice.

Eutectic Mixtures:

Definition:

  • A mixture of two or more solid substances that forms a liquid at a temperature lower than the melting point of the individual components.

Example:

  • Lidocaine and prilocaine at a 1:1 molar ratio forming a eutectic mixture, creating a gel formulation for topical use.

Assigned Reading Material:

  • Chapter 2, pages 24-31

  • Chapter 2, pages 34-37