W29N Physical Stability

Physical Stability and Two-Phase Systems

• Physical stability and two-phase systems involve solid-liquid interactions

Crystalline vs. Amorphous States

• Crystalline states are chemically well-defined with high degrees of atomic and molecular order, observable via polarized microscopy
• Ideal crystals have perfect arrays with defined symmetries repeating in three dimensions within unit cells
• Amorphous materials feature atoms and molecules in a disordered, random arrangement
• Crystals are thermodynamically more stable than amorphous materials

Crystallization from Solution

• Crystallization is the transition from a liquid solution to a solid crystalline state, influenced by solute concentration, pressure, and temperature
• A solute is a chemical in the liquid solution
• A solvent is the liquid dissolving the solute
• An anti-solvent is a liquid where the solute is insoluble
• Amorphous forms offer good solubility but poor stability
• Crystals are ordered molecules, making them a stable state for industry targets

Basic Crystallization Processes

• Supersaturation involves converting a liquid into a solution
• Colling
• Evaporation
• Addition of anti-solvent
• Addition of a precipitant drug to be precipitated is a solid form of supersaturation
• Nucleation is the formation of small crystal nuclei
• Homogeneous nucleation involves pure solute molecules crystallizing
• Heterogeneous nucleation involves catalytic crystal formation around impurities like seed crystals
• Crystal growth occurs as more solute molecules add to formed nuclei

Importance of Solid State in Formulations

• Solid state affects shape, particle size, polymorphism, hydration, and solvation
• Affects flowability, tableting, dissolution, bioavailability, disintegration, route of drug administration

Crystallization Methods

• Cooling crystallization involves reducing temperature to precipitate crystals
• Evaporation crystallization involves removing solvent to precipitate the drug

Crystallization by Anti-Solvent Addition

• This method relies on solubility equaling drug concentration
• A solvent dissolves the drug, while an anti-solvent reduces the drug's solubility
• The solvent and anti-solvent are miscible
• The drug should be sparingly soluble or insoluble in the solvent/anti-solvent mixture for effective crystallization

Crystallization by Precipitation

• Changing pH or adding a precipitating agent causes the drug to leave the solvent and precipitate as a crystal

Supercritical Fluid Technology

• Supercritical fluids (SCFs) possess characteristics of both gases and liquids when above their critical temperature and pressure
• SCFs combine gas-like viscosity and dispersion with liquid-like density
• SCFs have high dissolution capacity due to high density and enable rapid mass transfer because of low viscosity

Supercritical CO2 (scCO2)

• It's an environmentally friendly solvent alternative, enabling reactions not feasible in conventional solvents
• Critical temperature (Tc) is 31.1°C
• Critical pressure (Pc) is 73.8 bar

Solvent Properties of SCFs

• They have a solvent power similar to light hydrocarbons for most solutes
• Fluorinated compounds dissolve better in scCO2 than in hydrocarbons
• Solubility increases with higher density that is, with increased pressure
• This is exploited for precipitation of fine solids

SCF Applications

• Enhanced fluorinated compound solubility in scCO2 is applicable
• Rapid expansion of supercritical solutions leads to precipitation of fine solids in flow reactors
• Organometallic reactions are done because higher concentrations are dissolved
• This is efficient for hydrogenation

SCF Unique Features

• They are fully miscible with permanent gases
• They achieve higher gas concentrations than conventional solvents

Rapid Expansion of Supercritical Solutions (RESS)

• It involves precipitating a solute from a supercritical fluid by rapidly reducing solvent density

Supercritical Anti-Solvent (SAS) Technique

• A solution is sprayed into a supercritical fluid, acting as an anti-solvent
• Drug particles precipitate, and the solution's solvent is extracted into the supercritical fluid

Physical Stability and Polymorphism

• Understanding the physical principles and processes of crystallization, methods used in crystallization and procedures used in the supercritical fluid technology is important

Material Properties

• The crystallographic properties are of crystalline and non-crystalline materials

Crystals Properties

• Atoms/molecules are packed with order
• Crystals sharp transition from solid to liquid at melting point ex: NaCl, Ibuprofen

Amorphous Properties

• Atom/Molecules are arranged at random
• Amorphous soften and then have highly viscous liquids

Crystallographic Structure

• High degrees of order in crystals occur periodically take space in 3D
• Crystallographic structures are described in 3D lattice and unit cell is the repeating unit

Understanding Unit Cells

• They block from the crystal
• Many blocks fill crystal space
• Descriptions are dependent on geometry
• They are described by dimensions, lengths of axes, angles = Named from geometry

Crystal Lattice Systems

• 7 possible cells ( basic crystal systems) allow molecules exist at the corner of unit cell
• Advanced crystallography Classifies to 14 Bravais -lattices consider center molecules at edges

Crystal Habit

• Crystal morphology (external shape)
• Describes shape
• Results in growth dimension
• Crystals can do combinations with habit, may combine faces
• Same combination of crystallographic firms, habit can changed as a prismatic, isometric,tabular

Crystal Modification

• Habits can be modified with impurities
• Surfactancts in crystallization can change crystal shape
• Polymorphism (internal structure)

Polymorphism Properties

• Polymorphic can form with molecules atoms which give inner order and crystal shape
• The forms can have same type of crystal lattice and are diff proportions
• Polymorphic forms different order of elements, attraction force must join

Polymorphs

• Different stablity / free energies
• Have different fundamental properties ex: highest melting point = ^ stability, ^ vapour
• Effects manufacturer effects pharmacological/bioavailability activity

Chloramphenicol Stability

• Solid polymorph, or changing, improves internal structure stablity
• Heat or pressure converts unstable into stable

Transitioning

• Is enantiotropic from all
• Or, Montotropic is not from one form and vice versa
• Transitions are metastable from stable form
• Metastable forms are high energy

Stable Polymorphic Properties

• Has lowest free energy
• Highest melting point
• Lowest solubility
• Roman #'s Nomenclature form (I ,II ect) MP order
• Delivery better has stable forms for better sol/bioavailability

Paracetamol Properties

• Conditions for I and II depend on the storage
• Crystal solvates and crystal hydrates = water inside
• Crystallization materials entrap at the crystal

Solvate Properties

• solvated -Crystal solvent
• hydrates -Crystal water
• anhydrates -Crystal solvent
• solvate polymorphic. Solvant and Interact structure for crystalline loses form

Molecular Properties

• solvate - No solvent, crystal bond, will lattice and destroy
• Molecular Water, inside in crystal inside, no water, dissolves and properties
• Hydrates are less stablizing

Crystal Defects

• point defects exist
• Missing an atom
• And Impurity replacing with atomotropic?
• Defect influence crystals effects

Physical Properties

• Understanding, unit cell w lattie
• Knowledge, Polymorphism and habit
• Ability recognize hydrate/solvate