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Hi,
For highly insoluble acids, bases and neutral compounds to be used in
pre-clinical studies, does anyone have an algorithm (perhaps
oversimplied if this works most of the time) for solubilizing these
compounds. For example, is it best to begin with organic solvents,
emuslsions, etc., or go directly to cyclodextrins, etc. I'm assuming
all the salt forms are also insoluble. Something simple, but
reasonable, would be much appreciated if this is possible. Please be
specific as to solvents, forms of cyclodextrins, etc. Thanks. Harold.
Harold Boxenbaum, Ph.D.
Pharmacokinetics Consultant
Arishel Inc.
14621 Settlers Landing Way
North Potomac, MD 20878-4305
(F) 301-424-8563
harold.at.arishel.com
www.arishel.com
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Hi,
Firstly there is fixed algorithm which will work most of the
times...!!. Generaly I prefer the following route.
1. Try different salts
2. use solvents (not organic) and cosolvents (PEG, propylene glycol,
Glycerin etc)
3. Try different surfactants (Tweens, Cremophors )
4. Combination of surfactants +Solvents+ Co solvents - to get
micro-emulsions - very tedious and requires series of experiments to
get the combination right.
5. Cyclodextrins
6. Exotic solvents
7. When all the above fails- Battle it out with chemistry section
pointing out the lack of developability of the molecule. Interestingly
you may have problems even with highly soluble drugs with low lipid
solubility where permeability becomes an issue.
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Harold,
We have extensive experience with insoluble compounds, and have found
that there is not a good agorithm even within a class. It also depends
on what is being done with the formulation (PK studies, in vitro
experiments, etc.). Among the beta-cyclodextrins, we found our compound
to be soluble and stable in only two of five tested, despite them being
the same beta-cyclodextrin derivative (2-OH propyl beta-cyclodextrin).
The organic usually works well to start as most insoluble compounds will
dissolve in combinations of ethanol:PEG or DMSO:PEG. However, after
acute exposure PK or tox experiments we typically try to move away from
the organic due to obvious reasons.
BR/ Karen
Karen Veverka, Ph.D.
GTx, Inc.
(901)523-9700 X104
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Dear Karen,
I am also interested in this topic. Could you elaborate more in terms
of
stability of your compounds in b-cyclodextrins? What are your
analytical
methods in determining the stability?
regards,
Megan
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Harold,
Continuing on the above subject, there are some solvents which are very
usefull. 2-Pyrol from ISP and Transcutol from Gattefosse are good
solvents. Transcutol in combination with PEG 400, Propylene glycol and
surfactant such as Cremophor RH 40 normally results in excellent
fomulations. Its very important to arrive at right ratio of surfactant
to Co-solvent. Solutol from BASF is another choice. However when you
use this approach, be sure that drug does not precipitate on dilution.
Regarding stability of the formulation, i feel its not necessary that
the drug be stable for extended period of time for pre-clinical
studies. I normally do a stability study of 1 week (at room temperature
as well as at refrigerated condition). If the pre-clinical study is for
longer duration then I make the formulation every week.
Hope this helps,
Sunil Vandse
Able Labs
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Hi Clerk
have a look on this review:
Strickley RG pharm res 2004(21) 201-30
hope this helps
marival
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