This document discusses salt selection strategies in pharmaceutical product development. It begins by explaining the importance of salt formation in improving drug solubility, permeability, and dissolution. The key criteria for salt selection are discussed, including aqueous solubility, crystallinity, hygroscopicity, stability, and ease of synthesis. A multi-tiered approach is described for selecting the chemical form and physical form of the salt. A case study demonstrates evaluating different salt forms of a drug and selecting the optimal sulfate salt. The conclusion emphasizes that a multidisciplinary team approach and proper screening strategies are important for efficiently selecting the best salt form early in development.

1. Salt Selection in Pharmaceutical
Product Development
By
Tanpula Dilip Kumar
M.S.(pharm.) Pharmaceutics
NIPER
Rae Bareli
6th dec,2014

2. 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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3. 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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4. 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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5. 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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6. 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

7. 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

8. 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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9. 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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10. 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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11. 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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13. 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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14. 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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15. 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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