POLYMORPHISM Flashcards
What approach is used to set acceptance criteria for polymorphism?
- Decision tree approach
What do trees 1 and 2 consider?
- Whether polymorphism is exhibited by the drug substance
- Whether the different polymorphic forms can affect performance of the drug product
What does tree 3 consider and when is it applied?
- Applied when polymorphism demonstrated for drug substance and shown to affect properties
- Considers potential for change in polymorphic forms in drug product
- Considers whether such a change has effect on product performance
Explain steps in tree 1.
- Conduct polymorphism screen on drug substance
- Can diff polymorphs be formed?
1) NO - no further action
2) YES - Characterise the forms
e.g Xray powder diffraction, microscopy, spectroscopy
GO TO TREE 2
Explain steps in tree 2
- Use this tree if diff polymorphic forms present
- Do the forms have differing properties e.g solubility, stability, melting point…
1) NO - no further action
2) YES… - Is drug product safety, performance or efficacy affected?
1) NO - no further action
2) YES… - Set acceptance criterion for polymorph content in drug substance
- GO TO TREE 3
Explain steps in tree 3
- Does drug product performance testing provide adequate control if polymorph ratio changes e.g dissolution
1) YES - establish acceptance criteria for relevant performance tests2
2) NO - Monitor polymorph form during stability of drug product… - Does a change occur which could affect safety or efficacy?
1) NO - No need to set acceptance criteria for polymorph change in drug product
2) YES - Establish acceptance criteria which are consistent with safety and/or efficacy
Why is production of Sulphathiazole an issue in terms of polymorphism?
- 4 diff polymorphic forms and more being discovered
- Form 1 has highest aq solubility
- Form 1 has lowest yield stress and therefore easiest to compress into tablets
- All polymorphs can be grown
- Different properties
Name 2 pieces of analytical equipment used regularly for evaluation of solid state crystal properties…
1) Powder x-ray diffraction
- Determine crystal structure and quantitative detection of polymorphs and crystallinity
2) Differential scanning calorimetry (DSC)
- Melting behaviour, quantitative detection of crystal forms (hydrates, solvates, polymorphs)
The higher the temperature the crystal polymorph melts at the ___ the stability
HIGHER
Why would you change a drug from its free base or acid to a particular salt form?
- Modifies chemical and biological properties of the drug without modifying its structure
- Improves sol, diss rate, abs and/or physiochem properties e.g stability, hygroscopicity
- Various salts of same active drug are distinct products with own properties which relate to diffs in clinical efficacy and safety e.g diff BA
A decision tree approach to salt selection can be used. Outline the decisions in the tree.
- CRYSTALLINITY
- can crystalline salts be prepared
HYGROSCOPICITY
- does the salt deliquesce at high humidity
SOLUBILITY
- Doe the salt have aqueous solubility
STABILITY
- Is the salt physically stable under accelerated conditions
POLYMORPHISM
- Are there multiple polymorphs of the salt
(IF NO THEN CANDIDATE)
CONTROL
- Can the process be controlled to produce desired form
(IF YES THEN CANDIDATE)
(IF NO THEN SECONDARY CANDIDATE)
_____ is the most commonly used salt for basic drugs as it has a ____ pKa
Hydrochloride
- LOW pKa
Why would you reformulate a salt form due to reduced stability?
-Give an example…
STABILITY
- Propoxyphene HCl salt
- Used with Aspirin
- Unstable when in close contact with each other!
- Reformulate propoxyphene HCl salt to napsylate salt
- Overcome instability issue
Why would you reformulate a salt form due to reduced toxicity?
-Give an example…
TOXICITY
- Some cations and anions are associated with toxic effects
- e.g Lithium kidney
- Change salt form to reduce toxic potential
- e.g to one which is slowly abs in GI tract as less toxic than those that are rapidly abs
Why would you reformulate a salt form due to stability (hygroscopicity) issues?
-Give an example…
STABILITY (HYDROSCOPICITY)
- Stability reduced if hygroscopic
- salts of mineral acids are polar
- ionised polar groups are hydrophilic and lead to hygroscopicity
- if drug susceptibly to hydrolytic degradation then can reduce stability
- Stability enhanced if introduce hydrophobic salt forming acid
e. g Xilobam tablets have high water sol sulphate salt of drug
- salt readily hydrolysed and dissolves in surface moisture
- introduce hydrophobic aryl sulphonic acid and barrier to dissolution so more stable in humid
