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The following message was posted to: PharmPK
Hi everyone,
Could you please give me some advice on the pH of
dosing solution for iv, ip, and PO admistration of
coumpounds in mice?
Thanks,
Xiaobing Qian
xiaobingqian.-at-.yahoo.com
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Hello.
we bring some of our compounds up in a pH of 7.4 for PO, IV, and IP.
To date, it hasn't been a problem.
We typically use Phosphate Buffered Saline, pH 7.4.
Hope this helps
Nicole Risher
Pharmacology-Profiling
PTC Therapeutics
100 Corporate Court
South Plainfield, NJ
nrisher.-a-.ptcbio.com
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The following message was posted to: PharmPK
Xiaobing Qian
Well following are some of the rules I follow
1. As far as possible give dose near physiological pH, provided
the dose to be administered is possible.
2. If extreme pH is must, then use it. Practically you can use any
pH. Orally it may not matter a lot.
IP will be painful. Give less quantity as much as possible.
In case of IV you can give a very small amount of volume (for mice
less than 0.1 ml, preferably 0.05 ml) and slow rate of injection/
infusion depending on difference over physiological pH. Use
infusion pump if required.
with regards
Prashant
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The following message was posted to: PharmPK
Hi,
there is no need to adjust the pH of dosing solutions if you dose PO
but you
should keep it in a reasonable range, let's say 4 to 9 to avoid any
gastrointestinal irritancy.
But if you consider IV or IP routes you should try and keep it as close
to
the physiological pH as possible. Doing this you avoid the risk of
precipitation that often occurs at the injection point. This
precipitation
should be of big impact in the pharmacokinetics of the drug. In this
manner
Nicole Risher's way to do is the good one.
Hope this helps,
Regards
Frederic
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The following message was posted to: PharmPK
Hi again,
just to reinforce the content of my message and to comment on
Prashant's one, I would once again point out the risk of precipitation
when you are using dosing solutions at pH far from the physiological
one. This leads to some mistakes in PK parameters determination.
So if you have to use this kind of solution do not hesitate to perform
some stability over pH studies with your dosing formulations.
Best regards,
Frederic Doc
Pfizer Global R&D
France
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The following message was posted to: PharmPK
Dear Frederic
Thanks for your addition. I believe you have experienced such
situations. Practically, IV dosing at extreme pH is going to be
risky as well due to precipitation, size of precipitate, etc.
With Best regards
Prashant
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The following message was posted to: PharmPK
For those folks discussing this pH of dosing solution a valuable source
would be handbook of injectables if one follows the pH that was used for
similar compounds it should solve the initial hesitation and doubts
regarding usage of a particular pH. If you are worried that drastic pH
changes causes precipitation.... Whenever drug salts out or
precipitates out
of the solution in a biological pH the precipitate in almost always is
in a
very fine form and this very fine particle size facilitates improved
absorption (classical biopharmaceutics books offer explanation to this
effect).
Hope this clarification adds value to the discussion.
Prasad Tata
Mallinckrodt, Inc.
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The following message was posted to: PharmPK
Hello Prasad,
let me add a few comments on your message.
I agree that generally the precipitate is made of fine amorphous
particles
because the rapid precipitation does not give the opportunity for active
molecules to re-organise as a crystal.
BUT
1- no solid particle can improve absorption as compared as molecules
in solution. And we are talking of solutions. It's common sense to say
that
absorption from a solution is always quicker than absorption from a
"precipitation - redissolution" system.
2- this kind of phenomenon (precipitation and redissolution) can
then modify the PK parameters by modifying the absorption rate.
3- imagine that your active is 100 fold more soluble in your dosing
solution than in the blood circulation. When you dose IV your active
will
precipitate massively (just 1% being kept in solution). This means that
you
need a blood volume at least 100-fold higher than the dosing volume to
hope
to redissolve your active. And I mention "at least" because the
dissolution
kinetics will be dependent on this rate. If your blood volume is
1000-fold
higher the dissolution is likely to be much more rapid than if it is
only
100-fold.
hope it does make sense.
Thanks for this interesting discussion.
Regards,
Frederic
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The following message was posted to: PharmPK
Dear Frederic
I fully agree with you. However the discussion had started - How
to manage a situation where it is not possible to use normal
physiological pH.Instead an extreme pH would be required to make
an administerable formulation. One has take into account what
could be consequences of this and you have penned them nicely.
With Regrds
Dr. Prashant
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