selecting the salt form of a drug to improve the solubility of the drug is a very critical step

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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