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I wish someone to clarify :
1. The role of crystal structure in drug absorption process.
2. If one makes a solution of say amorphous powder and crystalline
material, would the absorption still be different.
Thanks : Yati Chugh
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[Two replies -db]
From: "Melethil, Srikumaran K."
To: "'PharmPK.-at-.boomer.org'"
Subject: RE: PharmPK (No subject)
Date: Mon, 14 Jun 1999 09:27:11 -0500
MIME-Version: 1.0
Once in solution, it should not matter.
---
From: "Ralph Quadflieg"
To: PharmPK.-at-.boomer.org
Date: Mon, 14 Jun 1999 09:03:50 +0000
MIME-Version: 1.0
Subject: Re: PharmPK (No subject)
Reply-to: quadflieg.-a-.uni-bonn.de
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Dear Yati,
as far as I know absorption is normally only be possible for
molecularly dissolved (real solution) substances. For the
absorption process the structure of crystal structure is not
important.
But:
The kineticts of dissolution (liberation) are highly dependent on the
crystal structure and if dissolution of drug substance is the rate
limiting step of invasion (dissolution + absorption) into the body
crystal structure will be important for the whole pharmacokinetics of
the drug.
If the formulation is a solution, and not a suspension (as you
indicated) crystal structure will have no impact on absorption.
Ralph
Ralph Quadflieg
Pharmaceutical Technology & Biopharmacy
University of Bonn
An der Immenburg 4
D-53121 Bonn
Germany
Tel.: ++49 228 73-5117
Fax.: ++49 228 73-5268
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>The kineticts of dissolution (liberation) are highly dependent on the
>crystal structure and if dissolution of drug substance is the rate
>limiting step of invasion (dissolution + absorption) into the body
>crystal structure will be important for the whole pharmacokinetics of
>the drug.
Agreed.
>If the formulation is a solution, and not a suspension (as you
>indicated) crystal structure will have no impact on absorption.
Not always true. In the case of a low solubility drug whose solubility is
pH-dependent, there may be situations where the drug is entirely in
solution in one region at its local pH, but in a more distal region at a
different pH where the solubility is lower, precipitation could occur.
For example, suppose the drug had a base pKa of about 4. The drug might be
in solution in the stomach (pH ~ 1.7), but the possibility of precipitation
in duodenum (pH ~ 6) would exist. Or suppose the drug had an acid pKa of
about 6. Then it might be completely in solution in the ileum (pH ~ 7.5),
but might precipitate in cecum (pH ~ 5).
So even if the drug was administered in solution, the possibility of
precipitation remains. The form of precipitation (crystal structure,
particle size and shape) may not be easy to predict, so that any subsequent
dissolution may also be difficult to predict, but the possibility
nonetheless remains. And, as you pointed out, the pharmacokinetics interact
strongly with the absorption (and hence dissolution/solubility) behavior of
the drug.
Walt Woltosz Phone: (661) 723-7723
Chairman & CEO FAX: (661) 723-5524
Simulations Plus, Inc. (NASDAQ:SIMU)
1220 West Avenue J
Lancaster, CA 93534-2902
U.S.A.
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walt.aaa.simulations-plus.com
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