Salt Selection in Pharmaceutical

Product Development

By

Tanpula Dilip Kumar

M.S.(pharm.) Pharmaceutics

NIPER

Rae Bareli

6th dec,2014

Contents

• Introduction.

• The importance of salt formation.

• Criteria of salt selection.

• Salt selection strategies.

– Selection of chemical forms of salts.

– Selection of physical forms of salts.

• Salt selection timing.

• Salt selection team.

• Case study.

• Conclusion.

• References.

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Introduction

• During the past ten years the pharmaceutical industry has led

to an evolutionary change in the way it is discovering and

developing drugs.

• In the search of more potent and highly specific drug

molecules, more lipophilic and water insoluble compounds are

being selected.

• The salt formation is thus considered critical in solving this

problem.

• The suitable choice of the most desirable salt form is an

important step in the development process since it has an

impact on physico-chemical and biopharmaceutical properties.

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The Importance of salt formation

• Salt formation can improve solubility, permeability and

dissolution rate etc.

• Berge et al. (1977) reviewed various advantages of using salt

forms of drugs in pharmaceutical formulations which include

improved dissolution rate and bioavailability of poorly water-

soluble compounds.

• Salt forms of drugs have a large effect on the drugs quality,

safety, and performance.

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Criteria of salt selection

• The following parameters are often considered essential

criteria for the selection of a particular form:

Aqueous solubility measured at various pH values.

High degree of crystallinity.

Low hygroscopicity which gives consistent performance.

Optimal chemical and solid-state stability under accelerated

conditions.

Limited number of polymorphs.

Ease of synthesis, handling, or formulation development.

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Salt selection strategies

• Selection of Chemical form of salt selection.

• Selection of Physical form of salt selection.

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Salt

Selection

Strategy

Physical

form

Chemical

form

Selection of chemical form of salt

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Role of pH

The pH solubility profile and pHmax values are used to determine

the potential of the counter ion for the salt formation with a

particular drug.

The difference between the pKa of the base and the acid must be

typically 2 pH units

Selection of physical form of salt

Tier 1-Crystallinity (visual, microscopy)

~Crystallization from different solvents.

~Aqueous solubility including microscopic examination of

suspended solids.

Tier 2-Evaluation of crystalline form

(Powder X-ray diffraction, hot-stage microscopy)

~Thermal properties (DSC, TG).

~Hygroscopicity.

Tier 3-Humidity/temperature-dependent changes in crystal form

(Powder X-ray, DSC, TG, VT-XRD, etc.)

Tier 4-Bioavailability (optional)

~Stress stability.

~Scale-up considerations.

Final form.Multi tier approach of salt selection

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Salt selection timing

• Salt selection must be done at an early stage of drug

development.

• Ideally, the salt form should be chosen before long-term

toxicology studies are performed

• Changing the salt form at a later stage may force a repetition

of toxicological, formulation, and stability studies.

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Salt selection team

• The selection of optimal salt- multi disciplinary team

approach.

• The team -representative from pharmaceutics, chemical

process development, and analytical research.

• Inputs from drug safety and marketing are also considered.

• The team decides whether to form salt for a particular weak

acid/base or use them in free form.

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Case study

Case Study: RPR127963

• RPR 127963 -treatment of cardiovascular diseases.

• It is crystalline, very weak base with a pKa of 4.10.

• 5 salt forms hydrochloride, mesylate, citrate, tartrate, and

sulfate are produced.

• The properties of these salts and the free base were then

studied and compared.

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Case study contd..

• The citrate, tartrate, and hydrochloride salts were poorly

soluble and low melting point.

• Mesylate and sulfate were highly soluble and have high

melting point and no polymorphism.

• Sulfate salt was preferable over mesylate.

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Conclusion

• Proper strategies for salt selection is very important for the

process of drug development.

• The strategies selected should also balance and minimize

resources and risks.

• When the appropriate screening strategies are engaged, then

selection of salt form can be made with a minimum amount of

drug substance, and within a short period of time.

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References

1.Heinrich Stahl P., Wermuth C.G. (editors), Handbook of

Pharmaceutical Salts: properties selection and use, IUPAC,

WILEY-VCH, 2002.

2.Wei-Qin (Tony) Tong, Salt Screening and Selection: New

Challenges and Considerations in the Modern Pharmaceutical

Research and Development Paradigm. In: Developing Solid Oral

Dosage Forms, Eds: Yihong Qui, Yisheng Chan, Geoff.G.Z.Zang,

Academic Press,2009, 1st edition, pg no:75-86

3. Richard J. Bastin, Michael J. Bowker, and Bryan J. Slater. Salt

Selection and Optimisation Procedures for Pharmaceutical New

Chemical Entities. Organic Process Research & Development

2000, 4, 427-435.

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