Crystalline Solids

Question 1

Name 4 pharmaceutical parameters that change with crystalline behaviour

Answer 1

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)

Question 2

Making order e.g making a crystal does what in terms of heat?

Answer 2

Gives out heat (as heat equals disorder)

Question 3

The external shape of a crystal is termed the habit. The crystal habit is associated to the way solute molecules orientate themselves when _____

Answer 3

Growing

Question 4

The slowest growing crystals have BIGGER or SMALLER faces?

Answer 4

Bigger faces - tend to dominate

Faster growing crystals tend to grow to a point

Question 5

Different solvent molecules can ___ to crystal faces therefore different shape crystals can be formed while belonging to the same crystal system

Answer 5

adsorb

Question 6

What 4 factors can crystal habit influence?

Answer 6

1) Compaction
2) Flow
3) Solubility
4) Stability

Question 7

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

Answer 7

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)

Question 8

What are repeating units that crystal lattices are constructed from?

Answer 8

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

Question 9

How can crystal structure be elucidated?

Answer 9

• Using X-ray diffraction

Question 10

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?

Answer 10

• 7
• 14 - because Bravais lattices depend on the way crystalline material is arranged
• Monoclinic, Triclinic and Orthorhombic

Question 11

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.

Answer 11

• Methanol

- Compaction

Question 12

What do we call the same chemical compound that exists in different crystal forms?

Answer 12

• Polymorphism

Question 13

Chiral molecules can crystallise as mirror images of each other. This is called _______

Answer 13

Enantiomorphism

Question 14

A mixture of D and L crystal forms are known as a ___ ___

Answer 14

Racemic Mixture - Companies usually take the therapeutic form and develop this

Question 15

Name 4 different types of multicomponent crystal

Answer 15

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)

Question 16

List 7 factors influenced by crystal form NOT habit

Answer 16

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

Question 17

What is ‘crystal form’?

Answer 17

The crystalline structure

Question 18

Why is polymorphism important in the preformulation stage of manufacturing?

Answer 18

• 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

Question 19

Moisture mediated and solid state phase transformation from one polymorph to another can occur during processing and storage. Give an example of this.

Answer 19

• 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

Question 20

Give an example of a polymorphic drug form issue.

Answer 20

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

Question 21

Give an example of issues with polymorphism with regard to CAPP.

Answer 21

• 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

Question 22

Give an example of issues with polymorphism with regard to Aripiprazole.

Answer 22

• 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

Question 23

Theophylline hydrate and anhydrate are examples of how hydrate forms can affect drug properties. Explain how.

Answer 23

• 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

Question 24

Amorphous solids have a ___ energy state than crystalline solids and are therefore ___ stable. This means they have a ___ rate of chemical degradation.

Answer 24

• Higher
• Less
• Faster

Question 25

Amorphous forms of drugs often have a ___ solubility than if it were in a crystalline form

Answer 25

HIGHER

- Use of amorphous form may provide opportunity to enhance its BA in case of poorly water soluble drugs

Question 26

Do stable or metastable polymorphs usually exhibit greater solubility?

Answer 26

• Metastable

- Metastable polymorphs tend to convert to the more stable polymorph over time

Question 27

Are anhydrous polymorphs or hydrates more soluble?

Answer 27

Anhydrous polymorphs

Question 28

Do amorphous forms of drugs have a crystalline lattice?

- What is a beneficial property of amorphous forms

Answer 28

NO

• More BA as less energy needed for dissolution
• More soluble