L15 - Pre-formulation Of Solid Dosage Forms 2 Flashcards
What does the functionaly of pharmaceutical products often depend upon? And their performance? (2)
- the physical form of the drug
- understanding the physical properties
What is the single biggest factor affecting the performance, development, patentability, manufacturing and profitability of a compound?
The physical form of a drug (solid state)
What are the different solid-state forms? (4)
- crystalline (polymorphs, hydrates, solvates)
- chiral
- habits
- amorphous
What are examples of amorphous and crystalline compounds?
- instant coffee, hailstones
- filter coffee, snow crystals
What can change with crystalline behaviours?
Highly important pharmaceutical parameters
What properties are determined primarily by the nature of the crystal structure? (4)
- solubility and dissolution rates
- crystal hardness (compressibility)
- chemical stability ( enthalpy of solution, transition, hygroscopicity, melting, sumblimation temp)
- colours, refractive index, heat capacity, conductivity, vol, density
What is the crystal habit?
The external shape of a crystal
What is the crystal habit associated with?
The way solute molecules orientate themselves when growing
What is the general shape of a crystal related to?
The growth of individual crystal faces
What face dominates?
The slowest growing one
What does crystal habit influence? (4)
- flow
- compaction
- stability
- solubility
What are the miller indices?
The designated index plane that each crystal face has
What does the miller index provide information about?
The molecular ordering of the surface of a crystal face
What are injectables?
Plate like crystal pass through needles better than long needle like crystals
What is tableting?
Plate like tolbutamol crystals do not flow and have poor compressibility
What does needle-shaped paracetamol crystal powder show?
Poorest compression properties
- shows greater capping and lamination than the plate or cube shaped crystals
What are dry powder inhaler (DPI) formulations?
Needle like crystals usually have better fine particle fraction
What unit cells?
The periodical aligned building blocks a crystal is composed of
What do unit cells reveal?
The crystal structure and symmetry specific for each substance
How many types od crystal structures are there and what are they defined by?
7
- lengths and angles between each side of the unit cell
What are the 7 primitive unit cells?
- cubic
- tetragonal
- orthorhombic
- trigonal
- monclinic
- triclinic
- hexagonal
What do drug molecules typically form?
Triclinic, monoclinic and orthorhombic unit cells
What are bravais lattices?
The 14 different configurations that molecules can arrange themselves into
What 2 polymorphic forms does paracetamol exist in?
- monoclinic (form 1)
- orthorhombic (form 2)
Why is form 1 commercially used? But what is it not suitable for?
- more thermodynamically stable at room temp
- direct compression, has to be mixed with binding agents before tableting
What is crystal form?
The ordering of atoms and molecules to form crystal structure
- doesn’t mean outer appearance (habit) of the crystals/particles
What is polymorphism?
When the same chemical compound exists in different crystal forms
What are polymorphs in special cases? (2)
Pseudopolymorphs
- solvates (solvent molecules in crystal lattice)
- hydrates (water molecules in crystal lattice)
What is enantiomorphism?
When the chiral molecules can crystalise as mirror images of each other
What are racemic mixture?
A mixture of D (dextro) and L (levo) crystal forms
What does the term enantiotropic mean?
When a solid phase transition which transform reversibly without passing through the liquid or gaseous phases
What does the term monotropic mean?
When the solid phase is not able to transition reversible before a phase change
What happens when a transition from one polymorph to another happens below melting point?
Then it is irreversible
What properties does form II have? (5)
- lower density
- lower lattice energy
- lower mp
- faster dissolution rate
- possible fracture line
What properties does form I have? (5)
- higher density
- higher lattice energy
- higher mp
- slower dissolution rate
- lower bioavailability
What properties may change with polymorphic form? (10)
- mp
- dissolution rate
- compressibility
- density
- flowability
- surface properties (surface energy and morphology)
- habit and crystal shape
- hygroscopicity
- hardness
- stability
Why is polymorphism essential during preformulation stage?
Important that the most thermodynamically stable polymorph is formed
- more favourable form may be obtained upon scailing up
What can occur during processing and storage?
Moisture mediated and solid state phase transformation from one polymorp to another
What is CAPP?
Chloramphenicol-3-palmitate
- broas spectrum antibiotic
How many forms can CAPP crystallise into? And which is most thermodynamically stable?
3 polymorphic forms
- form A is most stable
- but form B has eightfold higher bioactivity than A
What can CAPP create?
The danger of fatal dosages
- unwanted polymorph is unwittingly administered because of alterations in process or storage conditions
