Solid state properties

Question 1

Introduction- Why do we need to know about the properties of substances in the solid state e

Answer 1

-Practically all drug substances are handled in the powder form at some stage during the manufacturing of dosage forms

Question 2

Solid states

Answer 2

• Solid drug substances can be in any of the following forms:
• Crystalline
• Amorphous

Question 3

Crystalline solids Are:

Answer 3

• Are arranged in fixed geometric patterns or lattices
• Have definitive shapes and an orderly arrangement of units
• Have defined, sharp mpt
• Most drugs (>96%) are crystalline solids
• The units that form the crystal structure can be atoms, molecules or ions (NaCl)
• long range order = specific and repeated

Question 4

Amorphous forms

Answer 4

-Structural units are arranged in random manner
-No short range order
-Don’t have a definite, sharp mpt
-These are usually more soluble and rapidly dissolving than the corresponding crystalline forms
+low glass transition= stability issue
+More hygroscopic= hydrolysis
-step change = glass transition= in amorphous material molecules are held together by glassy cage, the temp this breaks and frees up molecules
-continued heating can potentially recrystalise in a set arrangement

Question 5

Crystals

Answer 5

Crystalline compounds
-Solids with orientational and positional long-range order in 3 dimensions
Liquid crystalline compounds
-State of matter in which the molecules have long range orientational or positional order in some but not all dimensions
Amorphous compounds
-Solids with no orientational or positional long-range order

Question 6

Pharmaceutical examples

Answer 6

• Amorphous penicillin G: this is less stable than the crystalline salt- so preffered
• Amorphous Novobiocin (anti-biotics): this has improved GI bioavailability than crystalline salt

Question 7

Improved oral bioavailability

Answer 7

• In-vivo solubility enhancement for oral drugs

- Complementary to particle size reduction and liquid filled capsules

Question 8

Crystal properties

Answer 8

1) mpt: used as a test of purity and identity
2)Solubility: different crystal structures of the same drug have different solubility
3)Wettability: e.g. boric acid powder is not wetted as well as the crystals
4) Vapour pressure
5) Compressibility: e.g. aspirin crystals are easier to compress than the powder
6) Flow properties
NB- different polymorphs have different properties due to differences in shape

Question 9

Crystal habit

Answer 9

-This describes the overall shape of the crystal e.g. tabular; prismatic; acicular
This can influence:
-Compression
-Powder flow: plate-like crystals of tolbutamide can block hoppers
-Injectability through a syringe: e.g. tabular would be easier to inject than acicular

Question 10

Crystal formation- occurs as a result fo 3 successive processes

Answer 10

1) Supersaturation- more solute dissolved solution than the solvent can take 
\+Increase temp
\+add co-solvent  
2) Formation of crystal nuclei 
3) Crystal growth round the nuclei

Question 11

1) supersaturations

Answer 11

-This can be achieved by 
A) Cooling 
B)Evaporation 
C) Solvent mixing or additive 
D) Chemical reaction

Question 12

2) Crystal nuclei

Answer 12

• Formed by the collision of solute molecules/atoms

- This can be achieved by seeding i.e putting solid units into the system

Question 13

3) Crystal grow

Answer 13

• Can be considered as similar to the reverse of the dissolution process
• Involves transport of molecules/atoms to nuclei surface and arrangement in an ordered fashion in the lattice

Question 14

Factors affecting crystal form and or habit

Answer 14

1) Rate of precipitation and nucleation
- Influenced by conc and temp
- E.g. phenylsalicylate crystals
- Change from a tabular form to a more acicular form as rate of precipitation increases
2) Solvent: less viscous media favour the growth of equi-dimensional crystals
3) Surfactant present in solvent (as wetting agent) can alter crystal form: adsorb onto growth faces during crystal growth
4) presence of impurities

Question 15

Possible effects of changes in crystal habit

Answer 15

• Suspension stability
• Suspension syringe-ability
• Tableting properties
• Dissolution
• Powder flow properties

Question 16

Crystal solvates

Answer 16

-When some compounds crystallise they may entrap the solvent in the crystal

Question 17

Solvate

Answer 17

• This is where the crystallising solvent is included in the drug crystal lattice
  e. g. spironolactone
• Can form 4 solvates depending on whether it is crystallised from acetonitrile, ethanol, ethyl acetate or methanol
• This gives rise to different properties for the crystals

Question 18

Hydrate

Answer 18

• This is where water is included in the crystal structure
• E.g. CuSO4, mono, di and tri hydrate
• Different level of water trapped in crystal will influences its physical properties including solubility= bioavailability
• Hot stage microscopy can identify presence of solvate or hydrates- when the temperature reaches the boiling point of the solvate or hydrate, the formation of bubbles will occur

Question 19

Crystal solvates

Answer 19

-Hydrated and anhydrous form can have different mpt and solubility
e.g. Glutethimide mpt crystalline/anhydrous 83/68’C
Solubility (0.042%/0.026%)
-In terms of solubility anhydrides have greater solubility than hydrates= increased dissolution= increased bioavailability

Question 20

Crystal solvates- dissolution related to solubility

Answer 20

-Dissolution rate is related to solubility
e.g. dissolution behaviour of theophylline hydrates
LOOK at BB slides (but anhydrous is highest then mono, then dehydrate)

Question 21

Bioavailability

Answer 21

• Differences in solubility and disolution leads to differences in bio-availability
  e. g. ampicillin the serum levels and so bio-availability is far higher in anhydrase than trihydrate

Question 22

Polymorphism

Answer 22

Molecules can arrange themselves in 2 or more different ways in the crystal by either:
+Pakcing differently in the crystal lattice
+Or having differences in the orientation or conformation
-These different lattice configurations of the same molecule are called polymorphs
-Use DSC to identify polymorphs- step change= amorphous- identify different polymorphs by different MPT

Question 23

Factors influencing polymorphism

Answer 23

• MPT
• Hardness
• Different habits
• Solubility
• Drug dissolution
• Bio-availability

Question 24

Form A v B

Answer 24

Form A 
-Stable ;High MPT; Less soluble 
Form B 
-Metastable; lower MPT; more soluble 
-Form A dissolves so slowly and is hydrolysed so slowly that this polymorph is virtually without  biological action

Question 25

Techniques for studying polymorphism

Answer 25

1) X-ray diffraction
- When a specific marterial is exposed to X-rays- the angle at which the X-rays hit the powder will be different in polymorphs due to different crystal structures/ packing
2) Hot stage microscopy
- Use to visualise the crystals at different temps
- Observe changes in morphology of crystals
3) IR spectroscopy
- Different spectra is seen for most different polymorphs
4) MPT: lower for metastable than stable
5) Solubility: Higher for metastable than stable
6) Differential scanning calorimetry (DSC) or differential thermal analysis
- In both heat loss or gain resulting from physical or chemical changes occurring in the sample
- Differences in crystal packing leads to different thermal traces

Question 26

How to get a uniform API blend

Answer 26

• Have the same drug particles

- Granulation