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Back to the forum  Query: 2017-08-24 01:13 CEST (UTC+2h)
 
Kiran
Junior

2017-06-24 18:25

Posting: # 17500
Views: 1,225
 

 Dissolution profie matching [Dissolution / BCS / IVIVC]

Hello everyone?
I am developing a generic formulation with drug containing high soluble polymorphic form than the reference product and having difficulty in matching end stage of drug release.

Reference product is showing around 52 % whereas test product is showing 96% release at 90 minutes ??

Any suggestions???
Helmut
Hero
Homepage
Vienna, Austria,
2017-06-24 19:30

@ Kiran
Posting: # 17501
Views: 1,046
 

 in vivo data before tweaking in vitro

Hi Kiran,

a generic product must demonstrate BE in the rate (Cmax) and extent of absorption (AUC), right?
If your dissolution method is not predictive (you can’t tell before you have in vivo data!) any difference might – or might not – be relevant.
Run a small pilot study to get an idea. IMHO, it is a waste of time to first tweak the dissolution which possibly was overdiscriminatory.

[image]All the best,
Helmut Schütz 
[image]

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Kiran
Junior

2017-06-24 20:19

@ Helmut
Posting: # 17502
Views: 1,047
 

 in vivo data before tweaking in vitro

Hello Mr.Helmut,

Firstly very thankful for your quick response.

Your input is valid but the thing is the dissolution method in which my generic product is faster is given in the FDA guidance and I am bound to meet f2 value w.r.t to that of the reference product.

One more thing is that the drug shows local action in the gut so invitro profile is more relevant to show comparison with that of the reference product.

The main reason I am presuming is the variation in the solubility of drugs in reference and test product to be the major reason for the variation in the dissolution profile due to polymorphic difference.The drug in the reference product has low solubility.

Regards,
Kiran.


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-06-25 12:48

@ Kiran
Posting: # 17503
Views: 1,003
 

 locally acting / diss. similarity mandatory

Hi Kiran,

» […] the thing is the dissolution method in which my generic product is faster is given in the FDA guidance and I am bound to meet f2 value w.r.t to that of the reference product.
»
» One more thing is that the drug shows local action in the gut so invitro profile is more relevant to show comparison with that of the reference product.

OK, if you are bound to one of the FDA’s guidance (e.g., mesalamine where additionally to fasting/fed BE dissolution similarity is mandatory), there is nothing you can do. Find another supplier of the API.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Kiran
Junior

2017-06-25 16:40

@ Helmut
Posting: # 17504
Views: 993
 

 locally acting / diss. similarity mandatory

» OK, if you are bound to one of the FDA’s guidance (e.g., mesalamine where additionally to fasting/fed BE dissolution similarity is mandatory), there is nothing you can do. Find another supplier of the API.

Hello Mr Helmut,

Thanks for the response.

Yes you are true.

We cannot change the intrinsic nature of API (Intrinsic dissolution or solubility) by making formulation changes, but my my current situation is I have to work out with present API source or quit.

I am trying to make premix with insoluble excipient may be it can retard the release (Cmax may be affected) have to do trial and error.:cool:

Thanks and regards,
Hari Kiran


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut]
ElMaestro
Hero

Denmark,
2017-06-25 20:21

@ Kiran
Posting: # 17505
Views: 988
 

 Dissolution profie matching

Hello Kiran,

I only ever heard of generic companies going for anther crystal morph when they had to work around an IP issue. Noone that I have ever met would ever accept it for any other reason.

» Any suggestions???

Try and look up, if you can, Potassium Chloride SR in EU. The API is othwerwise dissolving insanely fast. It's one of them resin-wax-oral-semi-solid-rubber-sponge thingies. I do apologise if that is not exactly what the formulation principle is actually called but I feel I am pretty close.
If I got it right the dissolution in that ...errrmmm... thing... is controlled simply by exposing some but very little API to the solvent at any and all times.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
Kiran
Junior

2017-06-26 05:11

@ ElMaestro
Posting: # 17506
Views: 961
 

 Dissolution profie matching

» I only ever heard of generic companies going for anther crystal morph when they had to work around an IP issue. Noone that I have ever met would ever accept it for any other reason.
»
» » Any suggestions???

Hello Mr.El maestro,

Thanks for your response.

You are right, I have to use alternate polymorphic form of API to circumvent the patent claim of the reference product.

The API in the generic product dissolves insanely fast due to highly soluble polymorphic form when it comes in contact with the solvent.

We should decrease the interaction with solvent, that's why I have mentioned in my above post about premix consisting of API and low soluble excipient.

Actually my core question is what are the excipient which can decrease solubility of API when it comes in contact with solvent, in order to match the dissolution profile with low soluble polymorphic form of drug in the reference product.

Can you suggest some excipients or any patent links which can solve the above situation to match dissolution profile with that of reference product.

Thanks and regards,
Hari Kiran.

» Try and look up, if you can, Potassium Chloride SR in EU. The API is othwerwise dissolving insanely fast. It's one of them resin-wax-oral-semi-solid-rubber-sponge thingies. I do apologise if that is not exactly what the formulation principle is actually called but I feel I am pretty close.
» If I got it right the dissolution in that ...errrmmm... thing... is controlled simply by exposing some but very little API to the solvent at any and all times.
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