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Dear All,
Does anyone know if it is regular to have different dissolution
rates/time for
different strengths for a human pharmaceutical product. How much can
the dissolution rates/time
differs between different strength, for example the strength of 5 mg
and 10 mg and still be OK??
I will be very glad for all support that I can get in this matter.
Thank's in advance,
Yours sincerely,
Anna Karlsson
Associate Regulatory Affairs
Hi Anna,Back to the Top
Different dissolution profiles for diffrent strengths is not something
uncommon. A difference of 5mg shouldn't be a big deal unless the drug
and the
exipients are highly water soluble and have large particle size. This
aids
in forming interconnecting channels beteen drug particles embedded
within
the tables body (if we are talking solid dosage forms that is). A 10-30%
diffrence is acceptable (not FDA perspective here) if it matches the
drug
absorption profile in the gut or the progression of a disease state.
Hope this helps.
Murad
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Dear Anna,
While it is not uncommon to have different dissolution rates for
different strengths, the extent of difference is critical especially if
you are conducting Bioequivalence studies on one strength and taking
biowaiver on the other strength. In this case you have to proove that
the dissolution profile of both strengths are similar by F2 method or
some other statistical method accepted by FDA. Normally for a multiple
strength product, BE is conducted on highest strength and bio-waiver is
granted for lower strengths if all strengths are dose proportional.
Hope this helpls,
Sunil Vandse,
Able Labs
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Assuming particle size and excipients are the same for both doses, the
instantaneous dissolution rate will depend mostly on the difference
between the solubility of the drug and the current concentration. If
the solubility is low, you could be approaching saturation, which would
slow down the dissolution rate.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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Walt,
In case of low solubility drugs, the dissolution rate may be lower for
highest strength dosage form due to saturation. Don't you think in that
case, the dissolution media/apparatus will have to be selected such
that sink condition is maintained for the highest strength? Of course,
with the modifed dissolution media/method, the lower strength may still
show faster dissolution rate.
Sunil Vandse
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The following message was posted to: PharmPK At 05:32 AM 3/10/2004,
Sunil Vandse wrote:
"Walt,
In case of low solubility drugs, the dissolution rate may be lower for
highest strength dosage form due to saturation. Don't you think in that
case, the dissolution media/apparatus will have to be selected such
that sink condition is maintained for the highest strength? Of course,
with the modifed dissolution media/method, the lower strength may still
show faster dissolution rate.
"
First, I'm not a dissolution testing expert. But I will express an
opinion, which may be shot down by someone who knows more than I do.
True sink conditions can never be obtained in a closed vessel. Perhaps
a flow-through method would be better for compounds with such low
solubilities that saturation is approached.
My original response was based on thinking about how things behave in
vivo. In vivo, we typically think about dissolution in the stomach,
which will behave more like a closed vessel if we're dealing with short
dissolution times (e.g., 15-30 minutes). We usually take stomach volume
in fasted state human to be 50 mL plus the dose volume (200-250 mL) -
much less than a 900 mL dissolution test.
For an in vitro test, it goes back to the question of why a
dissolution test is performed. For example, is it for quality control,
for comparing a generic to innovator dosage form, or to predict the
likely in vivo dissolution rate? It seems to me that the goal should
define the method.
With respect to this, I have always had a problem with the original
BCS definition of rapid dissolution, because it dealt with the largest
dosage form rather than the largest dose. Suppose you have a compound
that has high permeability and you want to call it BCS Class I. The IQ
test was easy - if your dosage form doesn't dissolve fast enough, use
smaller tablets/capsules but require patients to take more of them at a
time (" . . . take 12 of these and call me in the morning").
I believe the FDA may have modified the definition, or is considering
it, to avoid this loophole.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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