Physical Stability & Two-Phase Systems

Physical Stability and Two-Phase Systems

• Focuses on solid-liquid systems.
• Addresses crystalline and amorphous states, solid-state importance in formulations, crystallization methods, and supercritical fluid technology.

Physical Properties

• Includes particle size, surface area, solubility, dissolution, crystal properties (polymorphism), stability, and organoleptic properties.
• Organoleptic properties include taste, odour, and colour.

Physical Stability

• Primarily refers to visual and organoleptic appearances.
• Excessive temperatures, pH, moisture, and oxidation pose the greatest threats to chemical and physical drug lives.
• Changes in physical stability often stem from an indirect effect of chemical stability

Crystalline vs. Amorphous State

• Crystal are chemically defined with ordered atoms/molecules
• Ideal crystals feature building blocks arranged symmetrically in unit cells that repeat in three dimensions
• Ideal solid body is crystalline
• Amorphous material has atoms/molecules in random order, disordered like glass.
• Crystallization transitions a chemical from a liquid solution to a solid crystalline state, and is affected by solute concentration, pressure, and temperature
• Solute: A chemical in the liquid solution
• Solvent: A liquid dissolving the solute
• Anti-solvent: A liquid in which the solute cannot dissolve

Basic Crystallization Processes

• Supersaturation induces the solutions:
  • Cooling
  • Evaporation
  • Anti-solvent addition
  • Addition of a precipitant
• Nucleation is the formation of crystal nuclei.
• Homogeneous nucleation involves crystallization of pure solute molecules.
• Heterogeneous nucleation uses an impurity to starts crystallization
• Crystal growth involves adding solvated molecules to start nuclei

Saturation Solubility Curve

• Illustrates the relationship between solute concentration and temperature
• Solid state impacts:
  • Shape
  • Particle size
  • Polymorphism
  • Hydration
  • Solvation
• Also affects flowability, tableting, dissolution, bioavailability, disintegration, and routes of drug administration

Crystallization Methods

• Crystallization can be achieved via cooling, evaporation, anti-solvent addition, or precipitation

Supercritical Fluid Technology

• Supercritical fluids are above their critical temperature and pressure
• Supercritical fluids exhibit both gas and liquid properties
  • Viscosity
  • Dispersion (gas)
  • Density (liquid)
• Benefits:
  • High dissolution capacity due to high density
  • Rapid mass transfer due to low viscosity
• Super critical CO2 (scCO2)
  • Environmentally friendly solvent alternative ("Clean Technology")
  • Enables reactions not feasible in conventional solvents
    • Critical Temperature (Tc): 31.1 °C
    • Critical Pressure (Pc): 73.8 bar

Supercritical Fluids (SCFs)

• Definition: compressed gases with gas/liquid properties
• Examples: xenon, ethane, and carbon dioxide (CO₂)
• Importance: synthetic and analytical chemistry for unique processes

Supercritical CO₂ (scCO₂)

• Significance: environmentally friendly solvent
• Enables reactions unfeasible in conventional solvents
• Critical Points
  • Temperature: 31.1 °C
  • Pressure: 73.8 bar
• Solvent properties are similar to light hydrocarbons; fluorinated compounds dissolve better in scCO2 than hydrocarbons
• Density & Solubility: High-density SCFs increase solubility and precipitate fine solids in flow reactors

Applications of SCFs

• Enhanced solubility of fluorinated compounds in scCO₂ is utilized in polymerization
• Rapid expansion of supercritical solutions precipitates fine solids in flow reactors
• Higher concentrations of dissolved gases (N₂, H₂) in scCO₂ enhance organometallic reactions
• Hydrogenation: Effective use of gas miscibility

Unique Features of SCFs

• Miscible with gases like nitrogen (N₂) or hydrogen (H₂)
• SCFs achieve higher gas concentrations than conventional solvents

Rapid Expansion of Supercritical Solutions (RESS)

• It involves precipitating a solute from a supercritical fluid by reducing solvent density via rapid expansion

Supercritical Anti-Solvent (SAS)

• A solution sprays into a supercritical fluid for drug precipitation; drug particles precipitate and solvent extracts into supercritical fluid

Polymorphic Forms

• Overview: Explores crystallographic properties, unit cells, crystal lattice systems, crystal habit, polymorphism, solvates/hydrates, and defects

Properties of Crystalline Solids

• Atoms and molecules have ordered packing
• Crystals: Heat results into sharp transition from solid to liquid state (melting)
• Examples: sodium chloride, ibuprofen

Properties of Amorphous Materials

• Atoms and molecules arrange randomly
• Heat transitions amorphous substances into viscous liquids
• Examples: glass and spray-dried lactose monohydrate

Unit Cell as Geometric Descriptor

• Crystallographic structure: Periodic atomic/molecular reoccurrence in three dimensions
• Unit cell forms a repeating unit in three dimensions and the building block of the crystal.
• Description depends on geometry: three dimensions define length and three angles between axes

Dimensions and Angles Describing a Unit Cell

• a, b, and c are lengths of axes
• α, β, and γ are angles between axes

Crystal Lattice Systems

• Classification of crystal systems amounts to 7 possibilies
• These can give all degrees of atomic/molecular order, only at each unit cell corner
• Advanced crystallography classifies crystal systems into 14 Bravais lattices
• Bravais lattices factor in presence of central atoms or centre atoms edges in unit cell

Crystal Habit

• Describes overall crystal shape based on growth rates in each dimension
• Two orthorhombic crystals may have different elemental face combinations
• Crystal habit is modifiable by adding impurities
• Examples: surfactants modify crystal deposition

Polymorphism

• Substance forms crystals with different molecular or atomic order
• Polymorphs have same crystal lattice type (i.e., triclinic) but varying axis/angle proportions
• Variable attraction forces join molecules and polymorphs will have:
  • Varying thermodynamic stability
  • Varying free energies
  • Varying melting point, vapor pressure, and solubility
• It can effect manufacture, pharmacological activity, and drug bioavailability

Transition between Polymorphic Forms

• It is dictated by heat or pressure
• Enantiotropic transition: transitions between all forms
• Monotropic transition: unidirectional transition (metastable to stable)
• Stable polymorphic form has: lowest free energy, highest melting point, typically lowest solubility
• Polymorphic forms are named with Roman numerals by melting point from highest to lowest
  • E.g., testosterone (Form I = 155°C)
• Metastable forms have better solubility and bioavailability, as seen in previous figure

Crystal Solvates and Hydrates

• Crystallization sometimes leads to trapped solvent the crystal
  • Crystal solvates contain all solvents the crystallization process
  • Crystal hydrates' water presence
  • Anhydrates have no water
• Polymorphic solvate: solvent-structure interplay changes from crystal loosing solvent the results are a new crystal form
• Pseudo-polymorphic solvate is structure independant solvates
• Anhydrates & crystal hydrates vary by melting point/solubility, affecting pharmaceutics
• In general hydrates are less soluble, and may be thermodynamically more stable

Crystal Defects

• Can be due to:
  • missing atoms
  • substituting atoms
• These can effect properties

Summaries

• Understanding the meaning of unit cell and crystal lattice
• Knowledge about crystal habit and polymorphism
• Ability to differentiate between crystal hydrates and solvates