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Salt selection in drug development, basic

concept in salt formation, salt selection


strategy, pharmaceutical and biological
effects of salt formation
Salt selection in drug development
Salt selection is a critical part of the drug
development process because selection of an
appropriate salt can significantly reduce time to
market.
Salts are used to alter the physical or chemical
properties of a drug substance. If the correct salt
is selected, subsequent development will be
facilitated.
In addition, salts that exhibit advantageous
properties are usually patentable as new
chemical compounds.
The selection of an appropriate salt form for a
potential drug candidate is an opportunity to
modulate its characteristics to improve
bioavailability, stability, manufacturability, and
patient compliance.


Now a days 50%drug used as a salt form.
A drug substance often has certain suboptimal
physicochemical or biopharmaceutical properties which
can be overcome by salt formation.
The change in crystal structure that can be accomplished
by salt formation can lead to greatly improved properties.
In many cases, substances containing free acid or base
groups have poor aqueous solubility. Saltification of these
groups often improves solubility, thus providing greater
bioavailability.
It is sometimes the case that a salt provides increased
chemical or physical stability compared to the parent drug
substance. Salts can also provide a means of purification
and/or a way to improve the handleability of a drug
substance.
This fact indicates that the salt formation, of a drug
substance is a critical step in drug development.
Salt formation is done by the pairing the acid or base with
its appropriate counter ion.

Basic concept in salt formation
Salts are formed when a compound that is
ionized in solution forms a strong ionic
interaction with an oppositely charged counter
ion, leading to crystallization of the salt form.
In the aqueous or organic phase, the drug and
counter ion are ionized according to the
dielectric constant of the liquid medium.
The charged groups in the drug's structure
and the counterion are attracted by an
intermolecular coulombic force.
During favorable conditions, this force
crystallizes the salt form.
Figure 1: Diagrammatic representation of salt formation

The salt form is separated into individual entities
(i.e., the ionized drug and the counter ion) in
liquid medium, and its solubility depends upon the
solvation energy in the solvent.
The solvent must overcome the crystal lattice
energy of the solid salt and create space for the
solute. Thus, the solubility of a salt depends on its
polarity, lipophilicity, ionization potential, and size.
A salt's solubility also depends on the properties
of solvent and solid such as the crystal packing
and presence of solvates.

Principles of salt formation and salt
solubility
The aqueous solubility of an acidic or basic drug as a
function of pH dictates whether the compound will form
suitable salts or not and, if salts are formed, what
some of their physicochemical
properties might be.
pHsolubility interrelationships also dictate what
counterions would be necessary to form salts, how
easily the salts may dissociate into their free acid or
base forms, what their dissolution behavior would be
under different GI pH conditions, and whether solubility
and dissolution rate of salts would be influenced by
common ions
pHsolubility interrelationship of free base and its salt
This figure Illustrates that when the pH of the saturated solution of basic drug is lowered below pH max
by using suitable counter ions then Salt form is formed.
Similarly any salt formed would be reconverted to its free base form if the pH of a saturated salt solution is
Raised above pH max

pHsolubility interrelationship of free acid and its salt
This figure Illustrates that when the pH of the saturated solution of acidic drug is raised above pH max
by using suitable counter ions then Salt form is formed.
Similarly any salt formed would be reconverted to its free acid form if the pH of a saturated salt solution is
Lowered below pH max

The importance of salt formation

Salt forms of drugs have a large effect on the
drugs' quality, safety, and performance. The
properties of salt-forming species (i.e.,
counterions) significantly affect the
pharmaceutical properties of a drug (see Tables
Ia and Ib) and can greatly benefit chemists and
formulators in various facets of drug discovery
and development .


Salt selection strategy
Salt selection is viewed as apart of overall
objective of selecting the optimal form of a
drug candidate.
Pharmaceutical companies previously
selected salts at various stages in drug
development. however companies now tend
to move the salt-selection process to the
research phase to make the process more
foolproof.
This timing is an important factor in the early
stages of new-drug development because
changing the salt form at a later stage may
force a repetition of toxicological, formulation,
and stability studies, thus increasing
development time and cost.

A new salt form introduced at a late stage
must also be evaluated for potential impurity
changes, and its bioequivalence (bio-bridge),
pharmacokinetic equivalence (PK-bridge), and
toxicity equivalence (tox-bridge) to the
previous salt form must be proven.
Salt formation can improve solubility and
dissolution rate of acids and basic drugs, thus
increasing their absorption rate and
bioavailability.
However, not all salts will perform equally
well. For example, a crystalline, bioavailable
salt with few polymorphs is easier to purify,
dry, mill, store, and manufacture into a drug
product than a hygroscopic, amorphous salt.

Delays in drug development due to improper salt
selection can be costly to the public health by
delaying drug availability. Unfortunately, rational
salt selection is not always practiced. Often the
first salt produced at laboratory scale is used for
development without further consideration.
In other cases, rather than initiating an orderly,
sequenced investigation based on the material
properties of the drug substance, drug developers
may re-use trial-and-error methods based on past
experience.
Therefor a decision tree approach to salt
selection is always necessary.
In the first step, salts are generated which contain
pharmaceutically-acceptable counterions. Target salts
are chosen by considering such factors as:
structure of the drug substance
pKa of the drug substance
chemical stability of the drug substance
available literature on structurally-related compounds
ease of large-scale preparation of the salt
type of drug product
anticipated loading of the drug substance in the drug
product
Salt Products are analyzed for crystallinity and melting
point. Low-melting salts may be relegated to lower
priority status at this point. Salts that were originally
obtained in an amorphous state may be subjected to
additional crystallization procedures (such as slurry
ripening, vapor diffusion, or trituration) and reanalyzed.

When crystalline salts are obtained, samples are
placed under elevated humidity conditions and
monitored as solubility determinations are carried
out. Salts that deliquesce or absorb excessive
amounts of water are considered of lower priority
than those that do not. Analyses of these
materials after several days of exposure also
provide preliminary data related to hydrate
formation.
Concurrent with the hygroscopicity studies, the
equilibrium solubility of each salt in the
appropriate aqueous media is estimated. The pH
values of solutions made in water are usually
determined and the information retained for later
use. Salts exhibiting appropriate solubilities are
taken to the next step.
Physical, and, if necessary, chemical stabilities
are determined under accelerated conditions.
Samples of each salt kept under appropriate
conditions are periodically analyzed to ensure
that their crystal forms are sufficiently stable. The
observance of new crystal forms at this stage
may require additional hygroscopicity and
solubility studies.
Salts that pass to the final stage are tested for
their propensity to exist in polymorphic forms
using an abbreviated screen. Salts that appear to
exist in one stable, crystalline polymorph are
considered "final salt candidates" as shown in
Figure 1.
As the development process proceeds and
additional drug substance becomes available,
these salt candidates can be prepared in larger
quantities for comparison of other properties such
as dissolution rate and excipient compatibility.
Based on above consideration ,salt selection
strategy for new drug candidates may have
the following components.

(1) Selection of chemical forms of salts
(2) Selection of physical forms of salts
(3) salt-selection timing
(4) Composition of salt-selection team

(1) Selection of chemical forms of salts:
At the outset of any salt-selection program, it
is important to determine whether a acid or
bases is amenable to salt formation. if the salt
formation appears to be feasible then should
be decide that which one of the available
counter ion would be most suitable for salt
formation.

(a) feasibility assessment for salt formation:
There is no predictive procedure for
feasibility of a acidic or basic drug for salt
formation
Anderson and flora reported that succesful
salt formation generally require that the Pka
value of a conjugate acid should be smaller
than the Pka of conjugate base to ensure the
proton transfer from acid to base
species.Thus according to them, relative
stronger acids like HBr, HCl, H2SO4
(pKa<2.0) would be suitable for preperation of
salts of weakly basic amines having pKa<4.0.
Wells recommended that, for the preparation
of salt forms of basic drug, the pka value of
acid used should be at least 2 pH unit lower
than the pka of the drug.


(b) Application of PH-solubility relationship:
Then pHmax value of a drug can be
determined experimentally by PH-solubility
study. it can be estimated theoretically from a
knowledge of pka, solubility of free and salt
forms of the compound.
To form a salt, the pH of solution of acidic
drug must be adjusted above its pHmax
value, and for basic drug, the pH of solution
must below the pHmax value.
The application of pH solubility relationship in
determining the feasibility for salt formation

Consider a basic drug having pKa 3.7. From pH
solubility curve pH max of the compound was found to
be pH 1. Therefore only two salts, a hydrochloride
and a sulphate salt could be prepared for this basic
drug, since only strong acids like HCl, H2SO4 can
only lower the pH below pH max-1
For a acidic drug like Phenytoin pH max is at pH-
11, therefore salt formation of Phenytoin is only
possible with strong alkali like NaOH weak bases
like Mg(OH)2, Ca(OH)2 not feasible.
(c) effect of counter ion on salt solubility:
It has been reported that aqueous solubilitys of
different salt forms of a compound may vary
depending on counter-ion used.
In selecting counter ion for salts, the fact should
be considered that certain counter ion can exerts
more pronounced common ion effect and can
reduce aqueous solubility than others.
Salt formed with relatively stronger counter ion
(HCL salt, Na salt) are relatively more affected by
counter ion because of common ion effect(
decrease in solubility) than the salt forms with
weaker counter ion(with weak acids and weak
bases).

(2) Selection of physical forms of salts:

Many drugs can form multiple salts, and the
number of potential salts depends upon pKa
values. When the synthesis of multiple salts
are feasible, it is important to narrow down the
number of salts based on its physicochemical
characterization of the salt.

A multi-tier approach whereby salts
can be screened for optimal physical
form
Salt selection timing

Morris pointed out that the selection of
suitable chemical form of a drug candidate
should be done at a early stage of drug
development otherwise any later changes in
salt form may require repeating many of the
development studies conducted prior to the
changes, with negative impacts of the
development time and cost.

Salt selection team

The salt selection is a team approaches either
representative of pharmaceutics, chemical
process development, and analytical
chemistry forming the core slat selection
team. Representative from drug discovery,
drug metabolism/kinetics in an expanded
team. Through such team work and with
proper planning, the salt selection can be
removed from the critical development path,
thus accelerating drug development.

Flow diagram for selecting the optimal
salt form of a drug.
Pharmaceutical effect of salt
form
The salt formation and selection include the
condition regarding the development, production
and storage of a dosage form up to the time of its
use for pharmaceutical aspect .
The physiological nature of each of the various
routes of administration Puts certain
requirements and limitation to properties of drugs
substances and amount to deal with.


Solubility and dissolution
Drug in salt
form
Increase in
solubility
So increase in
dissolution is
also observed
Solid dosage forms
(1) melting point:
Salt formation has been employed to increase
Melting point (in particular, for converting low
molecule weight acid or bases into solid)

(2) Tableting:
salt formation and the type of salt greatly affects
compressional behaviour of a drug substance.



(3) water vapour relationship:
The water level in a particular drug substances/
salt form greatly affect the shelf life and
physicochemical properties.
Hygroscopic deliquescence of a salt is a
indication of extremely high solubility in water.
As a rule ,the higher the solubility lower the
relative humidity at which the salt deliquescence.
At the critical humidity, a substance forms a
saturated solutions in the water adsorbed from
atmospheric humidity.
EX. Choline chloride (highly deliquescence salt).
Critical humidity of sodium valproate is 43%
r.h. at 23C.
So handling of such salts is difficult and require
extensive precautions.

(4) Corrosiveness:
Saturated solution of API salt with pH values of
2.5 or lower are definitely corrosive.
On the safe side, it is recommended to subject
salts with pH value of an unbuffered saturated
solution 4. to a test on corrosiveness.
(5) Controlled release dosage forms:
It can be done by choosing an appropriate
selection of salt form which not only produced an
expected extension of activity but simultaneously
improved bioavailability
when compared with hydrochloride salt, EX.
Laurate salt of propanolol


Liquid dosage forms

High chemical stability in solution
Solubility sufficiently high to accommodate a
single dose in the appropriate volume.
In suspension drugs solid state properties has to
remain unchanged.
The taste of salt must be acceptable, otherwise
masking a less acceptable taste must be
manageable.
For taste improvement, literature suggest to form
salts.


Requirements for a substance indented for liquid
dosage form
Biological effects of salt forms
Absorption:
It plays a crucial role in the selection of the salt forms.
Adsorption which depends on the in vivo dissolution of
the drug substance or salt.
Solubility and dissolution rate:
In a medium of fixed pH and buffer capacity, a drug will
have the same equilibrium solubility, whether it is a free
form or in the salt form. But the different salt can affect
the dissolution rate.
This is change in dissolution rate is due to
different pH of the diffusion layer at the surface of
the API salt.

Influence first pass metabolism:
The reduced bioavailability can also be caused
by a salt with lower solubility or smaller in vivo
dissolution rate.
Lower solubility causes low absorption which
can cause large first pass effect.

Distribution, metabolism and elimination can
increase by the salt formation.

Influence on preclinical safety (toxicity):
When developing pharmaceutical salts, one of the
important objectives is to demonstrate the safety of
the developed salt.

Preclinical safety studies:
Safety pharmacology, pharmacokinetics and
acute toxicity (single dose), repeated dose toxicity,
reproductive , genotoxicity, Oncogenecity, Irritation
and sensitization testing studies should be done.
Route of administration:
In general routes of administration in safety studies
should be similar to one used clinically.


Influence on pharmacodynamic properties
As a rule be assumed that, because of electrolytic
dissociation in the aqueous media. Only the
active entity and not the complete salt reach the
therapeutic target.
Depending on the therapeutic use, salt formation
can be used to prolong the release of the active
compound and to eliminate the undesirable drug
properties.

Salt of N-cyclohexylsulfamic acid can make bitter-
tasting drug acceptable because of their sweet
taste.

Normally, the acid and base furnishing
counter ion is selected with no intention of
changing the pharmacodynamics of the drug.
Each component of the API salt i.e. the active
entity and counter ion can exerts its own
biological effects on a living organism. The
following cases are possible:
(1) The counter ion is chosen to
synergistically enhance the desires effects of
the active entity.
(2) The counter ion is chosen to neutralize
unwanted side effects of active entity
(3) The counter ion is chosen to
pharmacologically act independently or
therapeutically in a synergistic manner.

Changing the salt form during or after product
development:
The final salt form of drug substances should be
identify as early as possible otherwise later
change may lead to repetitive development
process.
The selection of the salt form that desired
pharmacological, toxicological properties is a
complex multidisciplinary task.
Pharmacologists involvement is essential
because the in vivo efficacy and safety of the
salts form should be established properly thus
minimize the risk of repeating
pharmacological/toxicological studies.

Selection of an appropriate salt form for a new chemical
entity provides the pharmaceutical chemist and formulation
scientist with the opportunity to modify the characteristics of
the potential drug substance and to permit the development
of dosage forms with good bioavailability, stability,
manufacturability, and patient compliance.
Salts are most commonly employed for modifying aqueous
solubility, however the salt form selected will influence a
range of other properties such as melting point,
hygroscopicity, chemical stability, dissolution rate, solution
pH, crystal form, and mechanical properties.
Where possible, a range of salts should be prepared for
each new substance and their properties compared during a
suitable preformulation program. Since it is normally
possible to fully develop only one salt form, its properties
should be appropriate to the primary route of administration
and dosage form.
Conclusion
An understanding of the influence of drug and
salt properties on the finished product is
essential to ensure selection of the best salt.
The drug properties required for one dosage
form may be quite different from those
required for another. A well designed salt
selection and optimization study provides a
sound base on which to build a rapid and
economic product development programme.

REFERENCES
(1)C.G. Wermuth and P.H. Stahl, "Introduction,"
in Handbook of Pharmaceutical Salts: Properties,
Selection and Use, P.H. Stahl and C.G. Wermuth,
Eds. (WileyVCH, Weinheim, Germany, 2002)
(2)S.M. Berge, L.M. Bighley, and D.C. Monkhouse,
"Pharmaceutical Salts," J. Pharm. Sci.
(3)Tessella Scientific Software Solutions,
"Automated Salts and
PolymorphScreening,"www.tessella.com/Services/
CaseStudies/pdfs/_GSK_ASAP.pdf, accessed
Dec. 15, 2006.
(4)B.D. Anderson and R.A. Conradi, "Predictive
Relationships in the Water Solubility of Salts of a
Nonsteroidal Anti-inflammatory Drug," J. Pharm.
Sci. 74 (8), 815820 (1985).

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