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I'd like to know if PK exposure in rodents is independent of drug
salt form for an oral liquid formulation (or parenteral). We are
evaluating several different salts of the same drug for optimal
scaling-up. If we keep dose level and pH constant with the different
salts, will the exposure in rodents be the same? Theoretically, it
would seem that there should be no difference, but we have two
examples where one time it is essentially the same, the other it is
different, but may be related to differing pHs. Any insights or
examples are much appreciated.
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Your buffer well may play a role here. Depending on composition,
concentration and pH, you may end up with a range of salts of your
substance in the mixture. It is useful to bear in mind that rodent
stomachs are not that acidic and that your buffer may have some
effects also after dosing.
We have seen a range of salt effects on the PK of different
substances. I have also heard of different tox profiles for salts.
Nailing it down will be long and complex however, as you have also
effects of crystal form etc that turn up later.
Best regards
Michael
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Dear David,
The PK exposures of a compound in different salt could be similar or
different and there is no universal generalization on the same.
There are two components to understand this situation. A compound
based upon its pKa and pHmax may form salt with counter ions of
differing pKa values. Pharmaceutical compounds however are weakly
basic or acidic and hence do not offer much scope to have multiple
options to form salts always. Wetting, solubility or even a micro-
environment pH (pH of the saturated solution of salt) may differ with
different counter ions (salts) and may derive differential flux for
absorption. Keeping a constant pH of the formulation may not help if
it always exceeds pH max of the compound. So there lies potential for
differential PK.
The second component is the in situ events like common ion effect
(suppression of ionization due to common ion contributed by salt and
species available in upper git); or disproportionartion dictated by
physiological conditions and again the different counter ions (or
salts) may behave differently. Disproportionation for an example, may
lead to a micro- or nano-precipiation and that will surely going to
influence the extent and/or rate of absorption. The cumulative effects
of one or more of these situations may lead to similar or different
profile.
To my opinion optimal salt selection for scale up (even for
preclinical studies) should not rest only on bio-pharmaceutics/PK, but
also on rank-ordering of potential salts with respect to solid-state
(propensity to polymorphism), bulk properties & hygroscopicity and
stability. Oversight of these features may fetch short term benefits
but lead to unwarrnated inconsistencies and heartburns in the longer
run.
Hope this will help.
--
Dr. Vaibhav Sihorkar
Head (Pharmaceutical Development)
Aurigene Discovery Technologies Ltd.
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Salt will impact solubility. Li salts of organics are the most soluble
but the Li has other baggage.
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Dear David,
As mentioned by other friends, making salt form of the water insoluble
drug (preferentially of BCS class II) is one of the most practised
approach of enhance aqeous solubility and hence bioavailability of
such drug.
So, extensive salt form screening, and eventually finalising optimal
salt form is penultimate preformulation step in preclinical
development. Hence most of Pharma giant spend a lot in this part of
discovery pharmaceutics. Of course, different alt forms always have
different physicochemical properties, physical and chemical stability,
degradation behavior, surface polarity hence hygroscopicity,
propensity of exisiting in different crystal forms-polymorphs
(possible numbers and types) and finally different solubility.
Different solubility definitely provides the differential saturation/
supersaturation/precipitation in the physiological condition that
directly impact on its absorption( Noyes-Whitney Equation) and indeed
the different PK profiles are expected withourt any surprise.
In discovery set up the counter ions selection is very crucial
experiment that affects the P'kinetics and tioxcokinetics of the
compounds. Counter ions are generally selected based on the
therapeutic area also, if the molecule is of antihypertensive
candidate, Na+ is never accepted. There are several other rationales
for the selection. The functional moeity (acid or base, generally
drugs are weakly acidic/basic), technological aspects, processibility,
and of course pKa of the compound is of prime importance. In situ salt
formation is commonly practised for a lot of compounds during the Tox
studies prior to their detalied salt form screening. Buffer
concentration, pH stability studies (rate of precipitation), and ionic
strength manipulation of the formulation are the pivotal aspects for
comparing their Pks.
You can get surplus lit on this:
Discovery Today Volume 12, Numbers 23/24 December 2007
Characterization of the solid state: quantitative issues, Advanced
Drug Delivery Reviews 48 (2001) 67-90
Preparation and evaluation of itraconazole dihydrochloride for the
solubility and dissolution rate enhancement, International Journal of
Pharmaceutics 367 (2009) 109-114
Salt formation to improve drug solubility, Advanced Drug Delivery
Reviews 59 (2007) 603-616
Solid form selection of zwitterionic 5-HT4 receptor agonist,
International Journal of Pharmaceutics 350 (2008) 35-42
Determination of p
Ka values of active pharmaceutical ingredients, Trends in Analytical
Chemistry, Vol. 26, No. 11, 2007
Amrit
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David,
It is fairly clear to me that you are talking about solutions, not
suspensions, so I can think of four reasons why you might see a
difference.
(A) the common ion effect if you have a chloride salt means that the
solubility in gastric fluid is lower than in buffer (oral only);
(B) 1 or more salt forms have less soluble crystal forms than the one
you dissolved in the first place (the dreaded polymorphism); the dose
solution is metastable and will at some point precipitate the less
soluble form, and this will depend on the counter-ion;
(C) your counter ion might affect the pH of urine if the dose is quite
large, and this would affect your parenteral route - eg chloride
(acidifies urine) versus citrate (metabolised).
I am sure there are other explanations, but some indication of dose size
would help.
Regards.
Ted
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