Bioequivalence and Bioavailability Forum • Use of pro-drug instead of active

Ionsource
☆

Pakistan,
2012-08-04 15:07
(4681 d 16:26 ago)

Posting: # 9036
Views: 5,347

Use of pro-drug instead of active [Bioanalytics]

Hi everybody

Is it appropriate to use Candesartan cilexitil instead of candesartan (unesterified) to develop analytical method for candesartan. I personally believe it shouldn't be done but I got confused when I had read in FDA guidance the following text
"If possible, the reference standard should be identical to the analyte. When this is not possible, an established chemical form (free base or acid, salt or ester) of known purity can be used". how could an ester be used instead?

Please somebody let me know. thanks

Helmut
★★★

Vienna, Austria,
2012-08-05 03:26
(4681 d 04:07 ago)

@ Ionsource
Posting: # 9038
Views: 4,648

Use of pro-drug instead of active

Post reply

Hi Ionsource,

great nick!

❝ Is it appropriate to use Candesartan cilexitil instead of candesartan (unesterified) to develop analytical method for candesartan. I personally believe it shouldn't be done…

You are right. This would not work. Candesartan cilexetil is much more lipophilic and has no relationship to candesartan in extraction and chromatography.

❝ […] FDA guidance the following text

❝ "If possible, the reference standard should be identical to the analyte. When this is not possible, an established chemical form (free base or acid, salt or ester) of known purity can be used". how could an ester be used instead?

This is nonsense, forget it. FDA claims that the guidance is under revision for years. High times to sweep things like that out. You will not find such a crazy statement in the European guideline.

If you dont’t have candesartan, ask a friend in the organic chemistry lab to hydrolyze the ester. A little bit hydrochloric acid in methanol on the reflux should do the job pretty fast and complete. SCNR. :cool:

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Ionsource ☆ Pakistan, 2012-08-05 16:17 (4680 d 15:15 ago) @ Helmut Posting: # 9039 Views: 4,613	Use of pro-drug instead of active Post reply
	Hi Sir, Thanks for liking my nick and your prompt reply. I'll do it as you say. Regards

Helmut
★★★

Vienna, Austria,
2012-08-05 17:35
(4680 d 13:57 ago)

@ Ionsource
Posting: # 9040
Views: 4,694

Sources of reference standards

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Hi Ionsource!

❝ I'll do it as you say.

Caution: The last section in small print was meant as a joke! Get a candesartan reference standard. If you hydrolyze the ester (or even synthesize it – which is a 8-step procedure) you would have to show identity and purity. Of course that’s possible with the usual arsenal of physical chemistry (melting point, molecular mass, solubility, IR, UV ε, MS, NMR,…). That’s by far more expensive than buying a certified reference. If you are working with MS I would strongly suggest the one labeled on the core (²H₄ candesartan) rather than on the carboxylic radical (²H₅ candesartan).

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Ionsource ☆ Pakistan, 2012-08-06 08:27 (4679 d 23:05 ago) @ Helmut Posting: # 9041 Views: 4,610	Sources of reference standards Post reply
	Hi Sir What can I say but I'll do it as you say I have plan to do it on HPLC with Fluorescence detection. Thanks again for your advice. Regards

Ohlbe ★★★ France, 2012-08-09 01:53 (4677 d 05:40 ago) @ Helmut Posting: # 9051 Views: 4,585	FDA guidance Post reply
	Dear Helmut, ❝ FDA claims that the guidance is under revision for years. High times to sweep things like that out. According to FDA's web site the draft guidance is supposed to be published for consultation by the end of this year... We'll see what's inside ! Regards Ohlbe — Regards Ohlbe