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Hi all
I want to know about the basic difference between the salt form of
a drug and its ester form. We generally involve propionate,
valerate as the salt forms but they also are ester in nature. So I
want to know the underlying point which decides whether to classify
the given form of a drug as a salt form or an ester form.
Thanks in advance
Lokesh Kumar
M.Pharm student
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Dear Lokesh,
Only a drug possessing a carboxylic acid (i.e. -COOH) group may be
converted into a salt or ester form. Typically, when one talks about
a salt form, we are talking about an inorganic salt such as sodium,
potassium, etc. One would do this in the event of the parent acid
possessing poor solubility properties. On the other hand, an ester
form is when the carboxylic acid group is converted chemically to a
neutral ester group (i.e. -COOCH3) such as a methyl group. In this
case, one is approaching the development in more of a pro-drug
fashion where the ester is converted in the body to the active
carboxylic acid.
One can do the same salt treatment for drugs that are basic in nature
by converting to the chloride or bromide salt. More exotic ones may
involve using organic counterions such as acetates.
Hope this helps.
Tai
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The following message was posted to: PharmPK
Salts can be prepared from drugs with acidic or basic functional
groups such
as carboxylic acids, imides, sulfonamides and amines. Salts are
prepared by
treating the amine with strong acid or the carboxylic acid with
strong base
resulting in a charged form. You could make a propionate salt but more
generally you see hydrochloride, sodium, or potassium salts. Esters
can be
prepared from drugs with either a carboxylic acid or alcohol functional
group. Either preparation of a salt or preparation of an ester
derivative
can enhance water solubility of a drug. An ester derivative would
have to be
hydrolyzed before it is active.
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I had always understood esters to be generally less water soluble
than the parent acid or alcohol, although usually more permeable as
they are more lipophilic and, via this mechanism, enhance absoprtion,
prior to metabolic activation by plasma esterases.
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The following message was posted to: PharmPK
Dear Lokesh,
Talking of a propionate ester of the drug gives one to understand that
there is a hydrolyle group (OH) on the drug's structure.
A propionate ester of a drug is a derivative of a drug in which the
propionyl moiety is covalently bound to the oxygen atom from a former
hydroxyle group (OH) of the drug.
Drug: R-OH --> n-propionate ester: R-O-CO-CH2-CH3
Therefore, the drug and its ester derivative are not the same molecule.
Talking of a propionate salt of a drug gives one to understand that
there is a basic group on the drug's structure such as an amine (NH3).
In a propionate salt of a drug, an ionic (not covalent) bond is formed
between the propionate anion CH3-CH2-COO(-) and the cation Drug-NH3(+)
which is the acidic form of the drug.
Compared to the non salified form (where the drug is not ionized), the
salt form of the drug often gives crystals, i.e., a powder form which is
easily handled and easily dissolved in water.
Hope I've made myself clear.
Frederic MASSIERE, Oroxcell.
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This is in response to the comment, "I had always understood esters
to be generally less water soluble than the parent acid or alcohol,
although usually more permeable as they are more lipophilic and, via
this mechanism, enhance absoprtion, prior to metabolic activation by
plasma esterases."
It depends on the drug and on the ester being formed. For example,
if the drug is an alcohol and the ester is formed with the carboxylic
acid of valine (an amino acid), the resulting ester will have a
protonatable (and therefore potentially charged) group, and may well
be more water soluble than the parent alcohol. Furthermore, valine
esters often show enhanced absorption because of active transport
prior to cleavage by plasma esterases.
Tom Tarnowski, Ph.D.
650 692-9296
ttarnowski1.-a-.aol.com
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The following message was posted to: PharmPK
I understand esters can be formed in many ways using functional groups
such as -OH, -NH2 and -COOH. Earlier we looked at the solubility and
pharmacokinetics of prodrugs of celecoxib which are both esters (acetyl,
propionyl or butyryl) and Na salts (see Ref below for details). Although
the enhancement in solubility was similar for all the three prodrugs
(possibly due to all being Na salts), increase in bioavailability was
observed only with propionyl and butyryl prodrugs (possibly being more
lipophilic) while no change is observed with acetyl prodrug on
comparison with celecoxib itself. This suggests ester prodrugs not only
exhibit improved aqueous solubility but also enhanced absorption.
Pharmacological and Pharmacokinetic Evaluation of Celecoxib Prodrugs in
Rats. Rao N.V.S. Mamidi, Ramesh Mullangi, Jagannath Kota, Ravikanth
Bhamidipati, Ansar A. Khan, Kasiram Katneni, Srinivasaraju Datla, Sunil
K. Singh, Koteswar Y. Rao, C. Seshagiri Rao, Nuggehally R. Srinivasa and
Ramanujam Rajagopalan. Biopharm. Drug Dispos. 23: 273-282 (2002)
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This is a formulator's perspective to differentiate between a salt
and an ester prodrug.
The prodrugs are means to overcome physical barrier to drug's
absorption (from oral delivery standpoint). They may increase
solubility of a hydrophobic moiety (Amprenavir versus phosphate
prodrug of amprenavir) or they may increase permeability of a very
hydrophilic drug (tenofovir versus tenofovir disoproxil fumarate
prodrug). However, they will represent themselves different from an
NCE from a regulatory perspective even though they chemically or
enzymatically destined to be cleaved prior to exerting their effect.
Salts on other hand, many not necessarily offer permeability
advantage and apart from ion pair mechanism in certain instances,
only offer increased wetting and aid on dissolution aspect of oral
absorption.
Any comments or remarks are welcome.
[Dr. Vaibhav Sihorkar]
Senior Scientist
Discovery Research
Dr. Reddy's laboratories Limited
Hyderabad, India
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The following message was posted to: PharmPK
"I understand esters can be formed in many ways using functional
groups such as -OH, -NH2 and -COOH" How do you form an ester from a
primary amine group - do you mean an amide?
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The following message was posted to: PharmPK
"I understand esters can be formed in many ways using functional groups
such as -OH, -NH2 and -COOH" How do you form an ester from a primary
amine group - do you mean an amide?
The definition of salt according to www.wordnet.princeton.edu is
a compound formed by replacing hydrogen in an acid by a metal (or a
radical that acts like a metal) " NaCl, BaSo4 etc. mostly inorganic in
nature and the key is transfer of electrons in Ionic bond formation
(12th grade inorganic chemistry).
Where as ester is formed by oppositely charged functional groups and
forming a new compound by fusion of functional groups, here the fusion
takes place predominantly by covalent bonds the esters are predominantly
organic compounds (Organic chemistry 101).
Now the confusion starts when we are dealing with compounds like
morphine sulphate, or diclofenac sodium etc. what do we call them
organic salts??? Or organic compounds (Real Life Lesson). Here the
organic portion and inorganic portion are connected by a loose bond
called coordinate covalent bond or held together by Vander wall forces
and each component (sometimes) referred as counter ions. These compounds
with a counter ion are synthesized to address some physico-chemical
issues such as solubility, stability etc but invariably the
pharmacological activity remains with the organic moiety called
pharmacophore.
I hope this clarification helps to clear the difference between salt and
ester (or perhaps add more confusion).
Regards,
Prasad Tata
Saint Louis, MO
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The following message was posted to: PharmPK
Dear Tata,
You are right, I meant an amide. In case of celecoxib, it's the
sulfonamide (-S02NH2) group which was used to make an ester (-SO2NHCOR)
followed by Na salt (-SO2NCOR(-).Na(+)).
Kasiram
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From a purely synthetic chemistry point of view, an ester is a
functional group that is treated as a derivative of a carboxylic acid
with the formula RC(=O)OR'. The partners that make up this
functionality are the carboxylic acid portion (RCOOH) and alcohol
(HOR') with the removal of a molecule of water during the reaction
process. Obviously, the portion of pharmaceutical interest can be
either the alcohol or the carboxylic acid. One can also do the
analogous transformation with amines (to give amides) and sulfonic
acids (to give sulfonates) or between amines and sulfonic acids (to
give sulfonamides). The molecules here are typically not the
biologically acitve compound but will break down in vivo to release
the biologically active compound, whether it be the alcohol,
carboxylic acid, amine, or sulfonic acid. Thus they are prodrugs.
Salts, on the other hand, is an ionic complex formed from an acid and
a base. Examples are alkali metal salts of carboxyiic or sulfonic
acids and halide salts of amines. In the former case, the source of
the alkali metal is a base like sodium hydroxide and the latter case
the source is the halide is an inorganic acid such as hydrochloric
acid. Of course, one is not restricted to using inorganic
counterions so the sodium hydroxide may be substituted by an amine
(triethylamine) while the hydrochloric acid may be substituted by an
organic acid (ie. acetic acid).
The take home message though is an ester, amides, and sulfonamides
are purely organic molecules held together entirely by covalent bonds
while salts are more like a complex between 2 opposing ions held
together by electrostatic attraction. Typical impetus for developing
the ester, amide, or sulfonamide derivative of the biologically
active molecule is due to the desire to attack the issue from a
prodrug perspective while the impetus for developing salts of the
bioactive molecule is due to the need to resolve some PK (i.e.
solubility) issues.
Hope this long winded blurb is helpful.
Tai
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)