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Dear all,
I would like to ask a question regarding aqueous solubility of compound.
in a situation where aqueous solubility of compound is low,the people calculate aqueous solubility against compound dissolved in non aqueous solvents (as a standard) like methanol/DMSO (to ensure complete solubility ).
Is it appropriate to back calculate aqueous solubility against non aqueous solubility?
Waiting for your expert comment...........
Regards,
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Dear Rahul,
Irrespective of the solvent system used, you should have the compound in completely solubilised form as a standard reference. Dont think that solvent system is different. checking the solubility in a particular solvent system is the main objective whether it is aqueous or non aqueous.
With regards,
Vijay,
G7 Synergon Pvt Ltd.
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Dear all,
I am working on a series of highly lipophilic compound(s).
i would like to know the acceptable cut off (Minimum) aqueous solubility of my compounds.
Regards,
Rahul Vats
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The following message was posted to: PharmPK
Rahul,
You asked: "I am working on a series of highly lipophilic compound(s). I
would like to know the acceptable cut off (Minimum) aqueous solubility of my
compounds."
The simple answer is - it depends.
If the dose is small, you could get away with lower solubility than if the
dose is large. If the permeability is high, you can get away with lower
solubility than if the permeability is low. If the compound is acidic, you
could get away with lower water solubility than if the compound is neutral
or basic. If you micronize or use nanoparticles, you might get away with
lower solubility than if you use larger particles.
So it all depends on a number of factors.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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The following message was posted to: PharmPK
Dear Walt,
You have suggested very good pointers to look at solubility. Many
companies use solubility as a filter for hit selection. There is a
danger that we may miss some really potential molecules, just because
they have poor aqueous solubility.
What the group thinks in using solubility as a filter for hit selection?
Regards,
Vinayak
Vinayak Nadiger
Manager, Bioanalytical
Forma Therapeutics(Singapore)
11,Biopolis Way ,Helios # 08-05
Singapore 1386607
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The following message was posted to: PharmPK
Dear Vinayak,
The next question is - which solubility?
Aqueous solubility, solubility in some buffer(s), solubility in biorelevant
fluids? There can be a significant difference in solubilities in different
media. We have just completed a year-long study wherein we measured the
solubilities of 160 drugs and drug-like molecules in SGF, FaSSIF, and
FeSSIF. The results are quite surprising in some instances. We have just
announced that this database is available as a product.
Note that fosinopril has a solubility measured on the order of 100 ng/mL.
The dose is small, The permeability is not too bad. It is also an acid that
shows significant improvement in solubility at intestinal pH. If it had been
thrown out on the basis of this solubility, it would not have been an
approved drug.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Rahul,
In Discovery one of the real cut-off points that many people come up against is whether you can conduct early (e.g. zebra fish) and acute tox experiments with your compounds. If you can not get adequate aqueous solubility to conduct these screens, often the compounds are thrown out even at that stage. I would suggest to try formulating these compounds as early as possible to make sure you don't loose otherwise valuable highly potent candidates.
Best regards,
Gabor
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Dear Rahul,
The question is very broad indeed!. It is based on the dosage requirement. For some compounds MEC will be very low (Active at nanomolar), at the same time to establish MTD you may require/forced to have high concentration of solution. Normally you cant have solubility cut off for discovery molecules, perhaps you can improve the solubility of your molecules by several ways.
Hope it may be helpful
Regards
Devarajan
Formulation research.
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The following message was posted to: PharmPK
The early discovery needs of solubility have different perspective at different milestones and most of the times, it is not well discussed and understood.
You may need to have some aqueous solubility at early (hit screen) stage as you would like to perform an in vitro screen and an apparent solubility (final DMSO concentration <1 or2%v/v) is good enough information to have at this stage. In all probability this number will be an over-projection and kinetically driven due to super-saturation involved therein and may tend to vary from lab to lab. The cut off solubility number could be depending upon your assay set up.
As you move further, you would like to have a solubility information that offers you confidence (towards lead ID/Opt) on the scaffold you are working on and this is the place where most of the solubility concepts are mis-understood. An aqueous solubility or lack of it, should not be the SOLE basis of selection or rejection of any compound at this stage. If your compound is reasonably potent (say for an example, an IC 50 in submicron range) and if permeability is not the rate limiting, even a solubility of ~10-20 uM (~500 daltons mol wt compound) in any bio-relevant media should offer a window of opportunity to move on, DESPITE IF THE COMPOUND DOES NOT RECORD ANY AQUEOUS SOLUBILITY. Of course, you may need to think twice if your compound is not potent enough (say for an example as IC50>10uM) or have other liabilities like permeability or pre-systemic or systemic metabolism. The role of Pharmaceutical Development groups have increased considerably in early discovery and preclinical development that a low/poor s
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Dear all,
Thanks for your expert comments.
But still i am worried about my "Tox dose" which will be high.
Even in normal therapeutic dose (in pre-clinical studies ) people used to try different formulations in such a way that some times it (bio-enhancers, excepients ) exceeds acceptable limit to get good bio-availability & efficacy as well, for the compounds which are poorly soluble. I am sure that extrapolating this dose (pre-clinical therapeutic ) may (because of very less dose required as compare to pre-cliical animals) or may not (because of lesser affinity of compound in real sense (patient) leads to higher required dose or some other reasons ) soluble in targated patients.
But at the same time our drug formulations are also limited for humans.
Is it advisable to go for further development ?
Regards,
Rahul Vats
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The following message was posted to: PharmPK
Dear Rahul,
The compounds with poor solubility (unless they are very potent) do necessitates an oral bio-availability enhancement strategy and surely you will need pharmaceutical development experts to guide you develop a tox formulation with excipients within NOEL or NOAEL levels (for the highest dose).
Poor solubility comes most obviously in drug discovery, as a liability, by virtue of endless desire of getting more and more potent compounds and satisfying the lipophilic pockets of target site(s). So it is, more often than not, unavoidable. Surely given an opportunity, any discovery team would like to choose a relatively more soluble compound (in relevant bio-fluid, and not necessarily aqueous solubility) over a practically insoluble compound. Having said that, opportunities to address solubility issues does exist, but are challenging and need judicious and measured approach. It will be criminal in today's discovery set up to a compound with desired potency and efficacy, be dropped due to solubility issues.
It is doable and future developments depend upon how much risk appetite you have to move further based on the data you generate on the most relevant/sensitive tox species. Also make sure that the tox formulation conceptually can be translated to a potential clinical formulation/drug product so that you can avoid re-doing bridging studies in future.
regards
--
Vaibhav Sihorkar, Ph.D.
[Head, Pharmaceutical Development]
Aurigene Discovery Technologies Limited
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