Solid state properties Flashcards
Introduction- Why do we need to know about the properties of substances in the solid state e
-Practically all drug substances are handled in the powder form at some stage during the manufacturing of dosage forms
Solid states
- Solid drug substances can be in any of the following forms:
- Crystalline
- Amorphous
Crystalline solids Are:
- 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
Amorphous forms
-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
Crystals
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
Pharmaceutical examples
- 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
Improved oral bioavailability
- In-vivo solubility enhancement for oral drugs
- Complementary to particle size reduction and liquid filled capsules
Crystal properties
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
Crystal habit
-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
Crystal formation- occurs as a result fo 3 successive processes
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
1) supersaturations
-This can be achieved by A) Cooling B)Evaporation C) Solvent mixing or additive D) Chemical reaction
2) Crystal nuclei
- Formed by the collision of solute molecules/atoms
- This can be achieved by seeding i.e putting solid units into the system
3) Crystal grow
- 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
Factors affecting crystal form and or habit
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
Possible effects of changes in crystal habit
- Suspension stability
- Suspension syringe-ability
- Tableting properties
- Dissolution
- Powder flow properties
Crystal solvates
-When some compounds crystallise they may entrap the solvent in the crystal
Solvate
- 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
Hydrate
- 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
Crystal solvates
-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
Crystal solvates- dissolution related to solubility
-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)
Bioavailability
- 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
Polymorphism
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
Factors influencing polymorphism
- MPT
- Hardness
- Different habits
- Solubility
- Drug dissolution
- Bio-availability
Form A v B
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
Techniques for studying polymorphism
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
How to get a uniform API blend
- Have the same drug particles
- Granulation
