Preformulation - The Solid State

Question 1

Describe the solid state

Answer 1

• Physical state of matter
• Rigid structure
• Resistance to changes in shape and volume

Question 2

What is the importance of the solid state?

Answer 2

• Most medicines are solids
• Solid properties dictate physical characteristics e.g. solubility, mechanical properties - determines drug release profile
• Solid properties influence decisions and control over manufacturing processes

Question 3

Describe the structure of crystalline solids

Answer 3

• Atoms/molecules are arranged in a pattern that repeats periodically in 3 dimensions to an infinite extent
• Defined geometric shape with flat faces
• Sharp melting point
• Thermodynamically stable

Question 4

Describe the structure of salts and cocrystals.

Answer 4

Contain two or more components in the same lattice

Question 5

How can we differentiate between salts and cocrystals?

Answer 5

• Salts are composed of ions and cocrystals of neutral molecules
• If the proton resides on the base (proton transfer has occurred) and the crystalline acid-base complex is a salt
• If proton transfer has not occurred then it is a cocrystal

Question 6

How are cocrystals formed?

Answer 6

• By hydrogen bonds between drug and another molecule (conformer)
• Components are not ionised in the crystal

Question 7

Why use cocrystals?

Answer 7

• Improve drug physiochemical properties
• Are patentable
• Can be made for non-ionisable drugs
• Modulate drug solubility

Question 8

Why use salts?

Answer 8

• Improved physiochemical properties are possible
• Salts are more soluble than the free acid or free base
• Melting point of higher

Question 9

What are solvates/hydrates

Answer 9

Molecular adducts that incorporate solvents molecules in their crystal lattices
solvent is water = hydrates
solvent is other solvents = solvates

Question 10

why do organic compounds frequently form hydrates in presence of water?

Answer 10

Due to small molecular size of water
The multidirectional hydrogen bonding capability of water

Question 11

What is polymorphism?

Answer 11

Crystalline forms with the same chemical composition but different internal structures.

Question 12

Why are polymorphism and multiple crystal forms important?

Answer 12

• Different solids show different physical, chemical and mechanical properties
• Development will require identification of the most stable form; most stable=most desirable

Question 13

How are polymorphs analysed?

Answer 13

• x ray diffraction: crystal structure
• thermal behaviour: melting point and heat fusion
• thermodynamic stability: free energy, solubility (the more soluble polymorph = the less stable)

Question 14

Describe amorphous solids

Answer 14

• Amorphous solid does not posses the long-range order characteristic of a crystal
• Solubility is improved by disarranging its crystalline lattice to produce a higher energy state of amorphous form

Question 15

State the properties of amorphous solids.

Answer 15

• No long range order (have short range order).
• Exhibit a “halo” in X-ray powder diffraction patterns (compared to
  crystalline peaks).
• Have a glass transition temperature (Tg).
• Less physically and chemically
  stable than crystalline materials.
• Faster dissolution than crystalline
  materials

Question 16

What is glass transition?

Answer 16

Physical change from a glassy state to a rubbery state upon heating

Question 17

How can glass transition temp be determined?

Answer 17

Using differential scanning calorimetry.

Question 18

What is a key problem of amorphous drugs?

Answer 18

• physical instability leads to crystallisation due to the high free energy of the amorphous state relative to the crystalline state.

Question 19

Describe solid form transformations?

Answer 19

• One solid form spontaneously converts to another when thermodynamically favourable
• Depends on environmental conditions
• Generally solubility decreases as stability increases

Question 20

Why is Gibbs free energy used?

Answer 20

• Used to determine whether a reaction is favoured or disfavoured.
• If ΔG < 0, then products are favoured at equilibrium.
• If ΔG > 0  “thermodynamically disfavoured”.

Question 21

State the Gibbs free energy equation.

Answer 21

△G = △ H - T △S