Crystalline Solids Flashcards
Name 4 pharmaceutical parameters that change with crystalline behaviour
1) Solubility and dissolution rates
2) Crystal hardness (compressibility)
3) Chemical stability (enthalpy of solution, enthalpy of transition, hygroscopicity, melting and sublimation temperatures)
4) Other (colour and refractive index, heat capacity, conductivity, volume, density)
Making order e.g making a crystal does what in terms of heat?
Gives out heat (as heat equals disorder)
The external shape of a crystal is termed the habit. The crystal habit is associated to the way solute molecules orientate themselves when _____
Growing
The slowest growing crystals have BIGGER or SMALLER faces?
Bigger faces - tend to dominate
Faster growing crystals tend to grow to a point
Different solvent molecules can ___ to crystal faces therefore different shape crystals can be formed while belonging to the same crystal system
adsorb
What 4 factors can crystal habit influence?
1) Compaction
2) Flow
3) Solubility
4) Stability
Pharmaceutical effects of habit:
Name issues associated with different types of crystal habit in relation to the following formulations…
1) Injectables
2) Tabletting
3) DPI formulations
1) Plate like crystals pass through needles better than long needle like crystals
2) Plate like Tolbutamol crystals do not flow and have poor compressibility but this doesn’t happen with Tolbutamol in other crystal habits
3) Needle like crystals usually have better fine particle fraction (are respirable)
What are repeating units that crystal lattices are constructed from?
Unit cells - all unit cells in a specific crystal are the same size and contain the same number of molecules or ions arranged in the same way
How can crystal structure be elucidated?
- Using X-ray diffraction
How many different types of crystal structure unit cells are there?
How many different braves lattices are there? Why is this number bigger?
What are the three common types of unit cell usually found in drugs?
- 7
- 14 - because Bravais lattices depend on the way crystalline material is arranged
- Monoclinic, Triclinic and Orthorhombic
Ibuprofen crystallises from hexane as elongated needle like crystals which have poor flow properties whereas crystallisation from ____ produces equidimensional crystals with better flow properties and ____ characteristics, making them more suitable for tableting.
- Methanol
- Compaction
What do we call the same chemical compound that exists in different crystal forms?
- Polymorphism
Chiral molecules can crystallise as mirror images of each other. This is called _______
Enantiomorphism
A mixture of D and L crystal forms are known as a ___ ___
Racemic Mixture - Companies usually take the therapeutic form and develop this
Name 4 different types of multicomponent crystal
1) Solvates (Solvent in crystal lattice)
2) Hydrates (Water molecules in crystal lattice)
3) Salts (Counter ions in crystal lattice)
4) Co-crystals (Solid excipients in crystal lattice)
List 7 factors influenced by crystal form NOT habit
1) Solubility and dissolution
2) True density, crystal shape
3) Compaction behaviour
4) Flow properties
5) Melting point, solid state stability
6) Rate of uptake in the body (diff polymorphs)
7) Diff enantiomers can be teratogenic
What is ‘crystal form’?
The crystalline structure
Why is polymorphism important in the preformulation stage of manufacturing?
- We must be sure that the most thermodynamically stable polymorph is formed in the preformulation stage as a more favourable form may be obtained upon scale up
Moisture mediated and solid state phase transformation from one polymorph to another can occur during processing and storage. Give an example of this.
- Phase transformations can cause changes in crystal size in suspensions and cause caking
- Crystal growth in creams as a result of phase transformation can cause the cream to become gritty
Give an example of a polymorphic drug form issue.
Ritanovir
- Wrong crystalline form produced
- Metastable form 1 crystals changed into more thermodynamically stable form 2 crystals
- Affected how the capsule dissolved (diff BA)
- Less BA so new formulation had to be developed
Give an example of issues with polymorphism with regard to CAPP.
- CAPP can crystallise in at least 3 polymorphic forms
- Form A is most thermodynamically stable and is marketed
- Form A has a low biological activity and is slowly hydrolysed in vivo
- BUT form B has an 8fold higher bioactivity than A
- Issues with fatal doses if unwanted form B polymorph is administered due to alterations in process or storage conditions
Give an example of issues with polymorphism with regard to Aripiprazole.
- Formulated as anhydrate
- Forms monohydrate when exposed to humidity
- Changes BA
- Packed in blister packs to prevent exposure and must not be opened until use
- Cannot be repackaged into dosage system e.g dosette box
Theophylline hydrate and anhydrate are examples of how hydrate forms can affect drug properties. Explain how.
- Sometimes solvents are important in holding together the crystal by H bonding
- This makes it difficult to desolvate
- In this example, the anhydrate is more soluble as there are no H bonds holding the crystal form together
- The monohydrate form is less soluble as the H bonds are holding the crystalline form together and there is already interactions with H2O
Amorphous solids have a ___ energy state than crystalline solids and are therefore ___ stable. This means they have a ___ rate of chemical degradation.
- Higher
- Less
- Faster
Amorphous forms of drugs often have a ___ solubility than if it were in a crystalline form
HIGHER
- Use of amorphous form may provide opportunity to enhance its BA in case of poorly water soluble drugs
Do stable or metastable polymorphs usually exhibit greater solubility?
- Metastable
- Metastable polymorphs tend to convert to the more stable polymorph over time
Are anhydrous polymorphs or hydrates more soluble?
Anhydrous polymorphs
Do amorphous forms of drugs have a crystalline lattice?
- What is a beneficial property of amorphous forms
NO
- More BA as less energy needed for dissolution
- More soluble
