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Salt selection in drug development, basic

concept in salt formation, salt selection

strategy, pharmaceutical and biologicaleffects of salt formation


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Salt selection in drug development Salt selection is a critical part of the drug

development process because selection of anappropriate salt can significantly reduce time to

market.

Salts are used to alter the physical or chemical

properties of a drug substance. If the correct saltis 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


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Now a days 50%drug used as a salt form.

A drug substance often has certain suboptimal

physicochemical or biopharmaceutical properties whichcan be overcome by salt formation.

The change in crystal structure that can be accomplishedby salt formation can lead to greatly improved properties.

In many cases, substances containing free acid or basegroups have poor aqueous solubility. Saltification of thesegroups often improves solubility, thus providing greaterbioavailability.

It is sometimes the case that a salt provides increasedchemical or physical stability compared to the parent drug

substance. Salts can also provide a means of purificationand/or a way to improve the handleability of a drugsubstance.

This fact indicates that the salt formation, of a drugsubstance is a critical step in drug development.

Salt formation is done by the pairingthe acid or base with


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Basic concept in salt formation

Salts are formed when a compound that isionized 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 andcounter ion are ionized according to the

dielectric constant of the liquid medium.

The charged groups in the drug's structureand the counterion are attracted by an

intermolecular coulombic force.

During favorable conditions, this force

crystallizes the salt form.


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Figure 1: Diagrammatic representation of salt formation


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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 latticeenergy 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 propertiesof solvent and solid such as the crystal packing

and presence of solvates.


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Principles of salt formation and salt

solubility

The aqueous solubility of an acidic or basic drug as afunction 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


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pHsolubility interrelationship of free base and its salt

This figure Illustrates that when the pH of the saturated solution of basic drug is lowere

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 satur

Raised above pH max


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pHsolubility interrelationship of free acid and its salt

This figure Illustrates that when the pH of the saturated solution of acidic drug is raised

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 saturat

Lowered below pH max


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The importance of salt formation

Salt forms of drugs have a large effect on thedrugs' quality, safety, and performance. The

properties of salt-forming species (i.e.,

counterions) significantly affect the

pharmaceutical properties of a drug (see TablesIa and Ib) and can greatly benefit chemists and

formulators in various facets of drug discovery

and development .


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Salt selection strategy Salt selection is viewed as apart of overall

objective of selecting the optimal form of adrug candidate.

Pharmaceutical companies previously

selected salts at various stages in drugdevelopment. however companies now tendto move the salt-selection process to theresearch phase to make the process more

foolproof. This timing is an important factor in the early

stages of new-drug development becausechanging the salt form at a later stage may

force a repetition of toxicological, formulation,


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A new salt form introduced at a late stage

must also be evaluated for potential impuritychanges, and its bioequivalence (bio-bridge),pharmacokinetic equivalence (PK-bridge), andtoxicity equivalence (tox-bridge) to theprevious salt form must be proven.

Salt formation can improve solubility anddissolutionrate of acids and basic drugs, thusincreasing their absorption rate andbioavailability.

However, not all salts will perform equallywell. For example, a crystalline, bioavailablesalt with few polymorphs is easier to purify,dry, mill, store, and manufacture into a drugproduct than a hygroscopic, amorphous salt.


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Delays in drug development due to improper salt

selection can be costly to the public health by

delaying drug availability. Unfortunately, rationalsalt 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.


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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


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When crystalline salts are obtained, samples are

placed under elevated humidity conditions and

monitored as solubility determinations are carriedout. 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 alsoprovide preliminary data related to hydrate

formation.

Concurrent with the hygroscopicity studies, the

equilibrium solubility of each salt in theappropriate 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


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Physical, and, if necessary, chemical stabilities

are determined under accelerated conditions.

Samples of each salt kept under appropriate

conditions are periodically analyzed to ensurethat 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 areconsidered "final salt candidates" as shown in

Figure 1.

As the development process proceeds and

additional drug substance becomes available,


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Based on above consideration ,salt selectionstrategy 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


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(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 saltformation appears to be feasible then should

be decide that which one of the available

counter ion would be most suitable for salt

formation.


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(a) feasibility assessment for salt formation:

There is no predictive procedure for

feasibility of a acidic or basic drug for saltformation

Anderson and flora reported that succesful

salt formation generally require that the Pkavalue 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, relativestronger acids like HBr, HCl, H2SO4

(pKa


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(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


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Consider a basic drug having pKa 3.7. From pH

solubility curve pH max of the compound was found tobe 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.


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(c) effect of counter ion on salt solubility:

It has been reported that aqueous solubilitys of

different salt forms of a compound may varydepending 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 bycounter ion because of common ion effect(

decrease in solubility) than the salt forms with

weaker counter ion(with weak acids and weak

bases).


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(2) Selection of physical forms of salts:

Many drugs can form multiple salts, and the

number of potential salts depends upon pKavalues. 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.

can be screened for optimal physical


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can be screened for optimal physicalform


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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 drugdevelopment otherwise any later changes in

salt form may require repeating many of the

development studies conducted prior to the

changes, with negative impacts of thedevelopment time and cost.


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Salt selection team

The salt selection is a team approaches either

representative of pharmaceutics, chemical

process development, and analyticalchemistry forming the core slat selection

team. Representative from drug discovery,

drug metabolism/kinetics in an expanded

team. Through such team work and withproper planning, the salt selection can be

removed from the critical development path,

thus accelerating drug development.


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Flow diagram for selecting the optimal

salt form of a drug.


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armaceu ca e ec o saform

The salt formation and selection include thecondition 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.


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Solubility and dissolution

Drug in saltform

Increase insolubility

So increase indissolution isalso observed


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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.


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(3) water vapour relationship:

The water level in a particular drug substances/

salt form greatly affect the shelf life andphysicochemical properties.

Hygroscopic deliquescence of a salt is a

indication of extremely high solubility in water.

As a rule ,the higher the solubility lower therelative 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.


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(4) Corrosiveness:

Saturated solution of API salt with pH values of2.5 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 anexpected extension of activity but simultaneously

improved bioavailability

when compared with hydrochloride salt, EX.

Laurate salt of propanolol


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Liquid dosage forms

High chemical stability in solution

Solubility sufficiently high to accommodate a

single dose in the appropriate volume.

In suspension drugssolid 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 liquiddosage form

Bi l i l ff f l f


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Biological effects of salt formsAbsorption:

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.


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Influence first pass metabolism:

The reduced bioavailability can also be causedby 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.


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Influence on preclinical safety (toxicity):

When developing pharmaceutical salts, one of theimportant 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, Irritationand sensitization testing studies should be done.

Route of administration:

In general routes of administration in safety studies


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Influence on pharmacodynamic properties

As a rule be assumed that, because of electrolyticdissociation in the aqueous media. Only the

active entity and not the complete salt reach the

therapeutic target.

Depending on the therapeutic use, salt formationcan 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.

N ll th id d b f i hi


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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 activeentity 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 neutralizeunwanted side effectsof active entity

(3) The counter ion is chosen to

pharmacologically act independentlyor

therapeutically in a synergistic manner.


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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

C l i


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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 aqueoussolubility, 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 propertiesshould be a ro riate to the rimar route of administration

Conclusion


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An understanding of the influence of drug andsalt 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 thoserequired 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.


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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


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