I have read some discussions for IV precipitation, but I have severalBack to the Top
questions.
What happen when one NCE precipitated in blood, what happen with Pk
parameters. How is eliminated this drug?.
How can I know if some drug could have been precipitated?
If I know the solubility at physiological pH. Can I say that I have
dosed a quantity of drug than divided for blood volume is greater than
solubility of the drug, the drug is going to precipitate, always?
thanks
Hello,Back to the Top
I am going to try and answer all of your questions about precipitation:
>What happen when one NCE precipitated in blood, what happen with Pk
parameters.
PK parameters are modified as the AUC per iv can be underestimated. In this
case drugs can show F (bioavailability per oral as compared to iv) larger
than 100% !!!
>How is eliminated this drug?.
In fact the precipitation acts as a reservoir of the drug that will
solubilize slowly with respect of the max plasma solubility of the drug.
Elimination will be dependent on the solubilization kinetics.
>How can I know if some drug could have been precipitated?
In general the precipitation occurs at the injection point causing an
inflammation or a tissue necrosis. This is a way to see this precipitation.
The F calculation showing a value upper than 100% must be a warning point.
>If I know the solubility at physiological pH. Can I say that I have
dosed a quantity of drug than divided for blood volume is greater than
solubility of the drug, the drug is going to precipitate, always?
I am not sure that I pretty well understand this question. But if your
dosage form is much more concentrated than the plasma solubility you may
have some precipitation. But it is not that easy because when you dose your
solution there is a dilution in the plasma compartment and hopefully this
dilution oftenly leads to a concentration that is finally lower than the
plasma solubility. Other events can interfere if your drug is complexed
with surfactants or highly bound to proteins.
I hope this gives you some answers to your questions.
Best regards,
Frederic Doc
ex-Pfizer
CEO and co-founder, ACRITER Consulting
This is interesting, and I am no expert on the subject, but I have someBack to the Top
questions:
Since mixing of the injected solution would occur locally at first, it
seems difficult to determine when/where precipitation would take place. The
concentration of the injected solution in its medium could be almost at
solubility, or it could be relatively low compared to the solubility in
that medium. And it seems that dosing as bolus or infusion could make a
significant difference.
For a bolus dose, if injected concentration is almost equal to the
solubility, then it seems that precipitation might occur close to the
injection point as the solution mixes with blood. If the injected
concentration is relatively low, then it might need to mix with more blood
before the solubility in the mixed medium would become supersaturated, and
precipitation might begin. Then precipitation might take place as a
distributed process in the circulatory system.
Does this make sense?
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
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
I have 4 articles on evaluating in vitro whether or not a drug willBack to the Top
precipitate when injected IV. If you wish them, please email me at
harold.at.arishel.com.
Harold Boxenbaum, Ph.D.
Arishel Inc. (Consulting)
Pharmacokinetic \0x2260 Pharmaceutical \0x2260 Medical \0x2260 Biotechnology \0x2260 Nutraceutical
14621 Settlers Landing Way
North Potomac, MD 20878-4305
Phone: (301) 424-2806
Fax: (301) 424-8563
E-Mail: harold.-a-.arishel.com
Dear all,Back to the Top
We had a interesting problem faced by our team.
Drug precipitates at pH 7.4, which is known to us. So
the formulation was made in a such a way that the
formulation solution is stable and it starts forming
colloidal precipitation at pH7.4 after 20minutes. So
we used this formulation for studying IV studies. But
still we are not able to detect any drug in plasma. I
am not able to understand what happened the drug
injected iv. The maximum aqueous solubility of this
NCE is 1microgrm/ml only at various pH ranges.
* The NCE is not detected in IV. The possibility is
only due to poor solubility. Is that so. I am not able
to detect the drug in plasma. The formulation which
does not precipitate did not improve the drug
availability in plasma.
Second interesting thing, when I added the drug in to
the blood as such, the blood and plasma was separated
was analysed separately. But we couldnot detect the
drug both in blood and plasma.Is there any possibility
of binding to RBC and hence, we are unable to measure
the drug in both plasma and blood, when drug is added
directly into blood. But, when add the drug directly
to the plasma as such, and we could detect the drug by
HPLC.
The property of the drug is very poor solubility and
precipitates at pH 7.4. Only formulation was made
which will make it stable at pH 7.4(colloidal
precipitation occurs after 30minutes).
I need to understand why we are not able to detect any
drug when administered intravenous.
regards
What are the pKas of the NCE? When you say it precipitates at pH 7.4,Back to the Top
that has to be at some concentration exceeding its solubility at pH 7.4.
If this is similar to the drug you mentioned in your previous post with
a logP of 5, it may be that binding to RBCs and plasma proteins is
almost complete.
As I noted in the previous posting, the drug has to go somewhere. What
do you recover in urine? If you can't find parent drug anywhere
(assuming you've looked everywhere), you'll have to look for
metabolites.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
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.-a-.simulations-plus.com
Dear Sivakuar,Back to the Top
When dealing with such kind of compounds with poor physiochemical
properties, one should follow a systematic approach.
1. Have a sensitive analytical method and validate it for the intended
purpose
2. Make sure you are able extract drug (% recovery ??) from the matrix
3. Then confirm the stability of your drug in blood and plasma
If your drug is stable and analytical method is sensitive then you can
try
and rule out other things (metabolism, efflux, solubility issues etc)
one by
one.
Hope this helps.
Kasiram.
Hi,Back to the Top
The recovery of the compound in plasma is above 90%
the stability in plasma is ok. but when we incubate
the drug in blood and analyse immediately we can
recover the drug from blood as well as plasma. it is
not so when we incubate the drug with blood for 30
mins. What could be the possiblities of absence of
drug on incubation with time? is there any drug having
this type of behaviour in blood.
regards
sivakumar
-
Hi,
The compound is neutral compound. log p is above 5
the formulation is stable as such but when you put in
to pH 7.4 it forms colloidal precipitation after 5 min
the solubility is poor but it was taken care in
formulation.(aqueous solubility of the drug is 1 micro
grams per ml) protein binding studies was done using 10 kd and found
to show 99 % protein bound.
but where as in IV sample drug was not recovered in
blood as well as plasma. Parent drug is not found in
urine.
can you suggest why we could not find the drug in IV
samples?
regards
sivakumar
Hi,Back to the Top
The following references might be interesting for you to solve the
problem regarding the recovery of drugs from blood.
J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Jan
5;766(1):99-105. Determination of topotecan in human whole blood
and unwashed erythrocytes by high-performance liquid
chromatography. Loos WJ, van Zomeren DM, Gelderblom H, Verweij J,
Nooter K, Stoter G, Sparreboom A.
Pharmacological Reviews Volume 49, Issue 3 , September 1997, Pages
279-295. Red blood cells: a neglected compartment in
pharmacokinetics and pharmacodynamics.Hinderling, P H.
Jai
Hi Sivakumar,Back to the Top
Did you run a control (drug spiked into pH7.4 phosphate buffer or
saline) with your blood/plasma samples. If not run a control exposing it to the
same conditions as this rules out the stability issues of your drug at those
conditions.
Also, after incubating the drug with blood/plasma, sonicate for some
time (10 sec) before proceeding to extraction as that will help lyse the RBC
and aid in extraction of drug (in case drug has partitioned into RBC).
I feel that your drug is getting degraded in the blood over time. This
is because, even if you consider that your drug is partitioning into RBC
you should be able to see some levels (if drug is stable). To confirm this,
you can check time dependent degradation by spiking blood in bulk and divide
into 5 aliquots and analyse for drug at 0, 5, 10, 20 and 30 min (If
degradation process is fast you may have to have close time points, say
0, 2, 5, 10, 15 min). Make sure you sonicate your blood sample before
extraction. This way you can confirm whether your drug is being lysed by
enzymes in blood/plamsa.
Also check for appearance of additional peaks in your hplc
chromatogram. If possible use PDA detector and have delayed run times.
Hope this helps.
Kasiram.
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