L15 - Pre-formulation of solid dosage forms 2

• Physical form of a drug:(What are the Solid state forms of a drug?)

  - crystalline (polymorph, hydrates, solvates)- chiral,- habits,- amorphous

  
• Amorphous


  - drug easily forms intramolecular hydrogen bonds with water- more soluble

  
• Crystalline structure(features? how many types? what are they made of?

  - more stable (lower risk of solid state transformation)- low dissociation rate- well-defined edges and faces- sharp melting points- 7 types of crystal structures, all defined by lengths/angles between each side of the unit cell- made of unit cells

  
• Unit cells (of crystalline form)(what are the 7 primitive unit cells? what do drug molecules typically form?)

  - cubic- tetragonal- orthohombic- trigonal- monclinic- triclinic- hexagonaldrug molecules : orthohombic, monoclinic, triclinic

  
• Bravais Lattices


  14 configurations that crystal molecules can arrange themselves into

  
• What parameters are determined by nature of crystal structure?

  - solubility and dissolution rate- crystal hardness- chemical stability (enthalpy of solution, hygroscopicity, melting point etc)
• Crystal habit(What is is? what's it determined by? what does it influence?)

  The external shape of a crystal- determined by the way solute molecules orientate themselves whilst growing- slowest growing face dominates- influences solubility, stability, compaction, flow

  
• Crystal Form


  ordering of atoms to form a crystal structure - NOT habit!
• Miller Indices(what is it? what info does it give us?)

  - each crystal face has a designated index plane- gives info on molecular ordering of surface of a crystal face
• Pharmaceutical effects of habit(injectables? tableting? dry powder inhaler formulations?

  - plate-like crystals pass through needles bettwe than long needle-like crystals- tableting: plate-like crys
• Polymorphism


  when the same chemical compound exists in different crystal formspolymorphs are form 1 or form 2.

  
• Enantiomorphism

  chiral molecules crystallise as mirror images of each other

  
• Pseudopolymorphs (classes of polymorph)

  - salts (counterions)- hydrates (water molecules in crystal lattice)- solvates (solvent molecules in a crystal lattice)- co-crystals (solid excipient in crystal lattice)

  
• Enantiotropic


  solid phase transitions which transform reversibly without state change

  
• Monotropic


  if solid phase transitions are not achieved before a state changeany transition between polymorphs below melting point is irreversible

  
• Polymorphism: Form 1 vs Form 2

  Form 1:- lower density- lower lattice energy- lower melting point- faster dissolution rate- higher bioavailabilitythan form 2

  
• Why is polymorphism important?

  - want to form most thermodynamically stable polymorph in preformulation to make a more favourable productexternal conditions interconvert polymorphs - eg hygroscopicity- can obtain patents for desirable forms, eg form 1 or 2- assure regulators that no other crystallised forms of compound exist

  
• What properties can change with polymorphic form?

  - melting point- dissolution rate- compressibility- density- habit/crystal shape- hygroscopicity
• EXAMPLE: Chloramphenicol-3-Palmitate (CAPP)


  - three polymorphic forms- only form A marketed (most thermodynamically stable)- Form B has 8x higher bioavaliability- interconversion bc of alterations in storage can risk fatal doses if unwittingly administered