Posting: # 7700
Polymorphism BE [Dissolution / BCS/IVIVC]
this is the case:
The oral tablet used in a succesfull bioequivalence study (companion animals) contained an active substance which was a mixture of 2 polymorphs: polymorph B for approximately 80% and polymorph A for approximately 20%. It is furter demonstrated for the active substance that in time the polymorph A converts into polymorph B (after 3 years 60-70% conversion). Further, it seems that polymorph A is more soluble than polymorph B:
Polymorph A: 1gm soluble in 30 ml water
Polymorph B: 1gm soluble in 50 ml water
Relevance of this solubility difference with regard to bioavailability in companion animals ??
We need to demonstrate that each future batch of tablets will still be within the bioequivalence range of earlier demonstrated results and therefore it is asked to demonstrate that the bioavailability of both polymorphs is the same (not depending on the ratio of polymorphs).
Is the following approach valid and relevant ?
We are able to obtain the polymorphic form B in pure form. We can perform comparative in-vitro dissolution studies (3 media with different pH) between active substance polymorph B and active substance wich is mixture of polymorph B/A (80:20). If dissolution profiles are identical we have demonstrated equal bioavailability for the possible range of polymorph ratios (going from 80% polymorph B to 100% polymorph B).
Sounds valid, or other ideas?
Posting: # 7711
IMHO your idea sounds reasonable. But please be advised: First of all you need to know if the originator product shows the same polymorphism. If the originator product is also a mixture of polymorph B with approximately 80% and polymorph A with approximately 20% and if you can demonstrate for the originator product that the polymorph A converts into polymorph B in the same way then you have some strong arguments. If the originator product is a different mixture of polymorph B and polymorph A you need to show if the polymorphs are effective in the same way. Otherwise you have a problem.
I hope this helps