Lecture 15 - Pre-formulation of solid dosage forms II

Question 1

A drug can have different solid state forms. List some.

Answer 1

Crystalline (hydrates, solvates, polymorphs) chiral, habits and amorphous forms

Question 2

What is an amorphous form?

Answer 2

Solid phases which cannot be categorized by a repeating unit cell arrangement.

Question 3

Compare amorphous forms to crystalline solids.

Answer 3

• no lattice energy
• less stable
  -Higher solubilities and faster dissolution rates than crystalline equivalent and so can be used as an alternative to salt selection to increase bioavailability of poorly soluble compounds

Question 4

Define crystalline solids

Answer 4

have molecules which are packed in a defined and repeating order.

Question 5

Give examples of properties of a drug which are determined by the nature of the crystal structure

Answer 5

1. solubility and dissolution rates
2. crystal hardness
3. chemical stability(enthalpy of solution, enthalpy of transition, hygroscopicity, melting and sublimation temperatures)
4. heat capacity
5. conductivity
6. volume
7. density

Question 6

What is the crystal habit?

Answer 6

the external shape of a crystal.

Question 7

Give three examples of crystal habits.

Answer 7

tabular, prismatic, acicular.

Question 8

What determines the crystal habit?

Answer 8

• the way solute molecules orientate themselves when growing
• the growth of individual crystal faces affects the shape of the crystal- the slowest growing face will dominate.

Question 9

What do crystal habits influence in terms of drugs?

Answer 9

flow, compaction, stability, solubility

Question 10

How can a habit effect injectables?

Answer 10

Plate like crystals pass through needles better than long needle like crystals

Question 11

Give an example of why the habit is important when it comes to tableting.

Answer 11

Needle shaped paracetamol crystal powder show poorer compression properties than plate/tube shaped crystals.

Question 12

What crystals are better for DPI formulations?

Answer 12

needle like crystals- have better fine particle fractions.

Question 13

What makes up the crystal structure?

Answer 13

building blocks called unit cells.

Question 14

How are the 7 types of crystal structure defined? What are the 7 unit cells?

Answer 14

• defined by the lengths and angles between each side of the unit cell
• cubic, tetragonal, orthorhombic, trigonal, monoclinic, triclinic, hexagonal.

Question 15

The 14 different crystalline configurations are named…

Answer 15

bravais lattices.

Question 16

What is a polymorphic compound?

Answer 16

When a compound can crystallize to more than one unit cell/molecules in unit cells are arranged in different patterns, it is said to be polymorphic.

Question 17

What are two polymorphs of carbon?

Answer 17

graphite and diamond.

Question 18

Which polymorph is the most stable?

Answer 18

polymorph with the highest metling point.

Question 19

Different polymorphs have different…

Answer 19

physiochemical properties.

Question 20

Paracetamol has two polymorphic forms. Name them and describe the properties of form one.

Answer 20

• Two polymorphic forms – monoclinic and orthorhombic
• Form one/monoclinic is more thermodynamically stable at room temperature and is used commercially. But form one is not suitable for direct compression and has to be mixed with binding agents before tableting.

Question 21

How do hydrates and solvates form? What is the difference between the two?

Answer 21

• it is possible for materials to crystallize and in doing so trap individual molecules of the solvent within the lattice.
• A hydrate = solvent is water
• A solvate = solvent

Question 22

Are solvates desirable?

Answer 22

usually undesirable for pharmaceuticals because the solvent would be regarded as an unnecessary impurity UNLESS it was advantageous and was safe for use.

Question 23

Enantiomorphism

Answer 23

When chiral molecules crystallise as mirror images of each other.

Question 24

What is a pseudopolymorph?

Answer 24

special case of polymorph. The difference between hydrates/solvates and their anhydrous forms is described as pseudopolymorphism.

Question 25

Draw the family tree for different organic molecular solid forms.

Answer 25

Question 26

What is enantiotropic polymorphism?

Answer 26

under different conditions- temperature and pressure- the material can reversibly transform between alternative stable forms.

Question 27

What is monotropic polymorphism?

Answer 27

only one polymorphic form is stable and any other polymorph that is formed will eventually convert to this stable form. The true stable form has the highest melting point and all other forms are described as metastable- this means that the other forms exist for some period of time so appear stable but they will actually convert to the true stable form.

Question 28

Give examples of properties which can differ between polymorphic forms.

Answer 28

• Melting point
• Dissolution rate
• Compressibility
• Density
• Flowability
• Surface properties (surface energy and morphology)
• Habit and crystal shape
• Hygroscopicity
• Hardness
• Stability

Question 29

How do patents relate to polymorphs?

Answer 29

Patents can be taken out on certain polymorphic forms which are very effective.