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`The Pharmaceutical Journal 10 MAR 2001
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`Home > PJ > Articles
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` The Pharmaceutical Journal Vol 266 No 7138 p322-323
`March 10, 2001
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`Articles
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`Changing the salt, changing the drug
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`By Glynis Davies, BSc, MRPharmS
`
`Changing the salt form of a drug affects its clinical efficacy and safety. This article discusses the potential
`issues related to the use of different salts of drugs
`
`Changing a drug from its free base or acid to a salt form is commonly done to improve its kinetics,
`absorption or physicochemical properties (eg, stability, hygroscopicity and flowability). Changing the salt
`form of a drug is a recognised means of modifying its chemical and biological properties without modifying
`its structure. Different salts of the same active drug are distinct products with their own chemical and
`biological profiles that underlie differences in their clinical efficacy and safety.
`There is, as yet, no reliable way of predicting exactly what effect changing the salt form of an active drug
`will have on its biological activity, and the supposition that the same salt form of two related parent
`compounds will behave in exactly the same way may not be correct. The literature contains many examples
`of salt forms that differ in the rate of absorption, toxicity and stability of the active drug.
`Salt formation
`Salts are formed by the reaction of an acid with a base. Any compound with the characteristics of either an
`acid or a base can, in theory, form a salt, but whether or not a salt is formed depends on the relative strength
`of the acid or base. When a drug is formulated as a salt, the particular salt form determines the
`physiochemical properties of the product: stability, solubility and dissolution rate. These properties influence
`how the drug is handled by the body: how it is absorbed, distributed, eliminated and excreted. The biological
`activity of a drug at its target site depends not only on its structure and effect at that site, but also on how
`readily it can reach the site and how readily it is removed from it.
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`Selecting an appropriate salt form for a drug is an important factor in the early stages of new drug
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`development. The monoprotic hydrochlorides are the most frequent choice of anionic salt-forming radicals,
`with hydrochloride salts outnumbering sulphates by nearly six to one and forming the largest percentage of
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`salts in use. A decision to change the salt form at a later stage introduces the need to repeat toxicological,
`formulation and stability tests, with obvious implications for the overall development and production time
`for the new pharmaceutical product.
`Once a drug has been marketed, there may be sound reasons for reformulating it in a different salt form to
`change its physicochemical properties. An example is provided by the analgesic propoxyphene, which was
`originally formulated as a hydrochloride salt. Propoxyphene was widely used in a fixed-dose combination
`with aspirin, but since aspirin proved to be unstable in close physical contact with propoxyphene
`hydrochloride, an additional step in the manufacturing process was needed to separate the two analgesics.
`When propoxyphene was reformulated as a napsylate salt, there was no problem of aspirin instability. The
`relative insolubility of the napsylate salt form compared with the hydrochloride was also an advantage, as it
`reduced the potential for parenteral abuse of propoxyphene.
`Substitution of one salt form of a drug for another can also change the rate of absorption and other
`pharmacokinetic variables, as well as toxic potential and stability, and all these properties can affect the
`biological activity of a drug and the clinical use of the formulation.
`Rate of absorption
`Salts differ in their solubility profiles and dissolution rates, which affect the rate of absorption of the drug
`2
`and, in turn, the onset, duration, and intensity of its effect. The bioavailability of a drug can therefore be
`modified by administering it in a different salt form. For example, a study of the relative bioavailability of
`the vasodilator naftidrofuryl in oxalate and citrate salt forms has shown that the relative rate of absorption is
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`higher for the citrate than for the clinically used oxalate form of the drug.
`An example of salt substitution changing the intensity of biological response to a drug is again provided by
`propoxyphene. This established analgesic was first marketed in the United States in the form of a
`hydrochloride salt more than 40 years ago. When it was reformulated, the new napsylate salt form was found
`to have greater potency and a longer duration of action than the hydrochloride, attributable to differences in
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`the rates of absorption of the two salt forms.
` Another example of the variation in biological activity with
`salt form is provided by calcium preparations. Brand-name preparations, each containing a different calcium
`salt with a different absorption rate, are reported to vary significantly in their ability to suppress secretion of
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`parathyroid hormone. This has implications for their clinical use as calcium supplementation in
`osteoporosis.
`Moving from clinical practice to veterinary medicine, a further example is provided by the anthelmintic
`pyrantel. The pamoate salt of pyrantel is reported to be three times as effective as the citrate against large
`bowel parasites, including resistant strains, because of its lower rate of absorption and consequently greater
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`retention in the gastrointestinal tract.
`Toxicity
`Some cations and anions are known to be associated with toxic effects and will contribute to the intrinsic
`toxicity of the salt form. For example, lithium cations have no toxic effect in small quantities but when
`ingested in large amounts can cause irreversible damage to the kidney. Similarly, tartrate anions, which are
`usually absorbed only minimally from the gastrointestinal tract, can cause renal damage if they reach the
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`circulation in high concentrations. In addition, pravadoline maleate caused renal tubular lesions in the dog,
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`as a result of maleic acid formed from the maleate anion.
`Changing the salt form of a drug can reduce its toxic potential. Typically, a salt that is slowly absorbed in
`the gastrointestinal tract is less toxic than one with a more rapid rate of absorption. For example,
`propoxyphene napsylate has an acute oral toxicity half that of propoxyphene hydrochloride when given to
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`rats or mice in equimolar doses; this is due to the more gradual absorption of the napsylate. Furthermore, in
`animal models, the napsylate appears to lack the convulsant properties of the hydrochloride.
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`Local irritancy Different salt forms can differ in their capacity to cause oesophageal irritation. For example,
`alprenolol in the form of the hydrochloride salt has an irritant effect on the oesophagus and can cause
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`oesophageal ulceration in humans, whereas alprenolol benzoate has no irritant effects.
` The difference in
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`Merck Exhibit 2195, Page 3
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`ulcerogenic potential has been related to the difference in solubility of the salts: alprenolol hydrochloride is
`highly water soluble and therefore may cause local damage due to local absorption, whereas alprenolol
`benzoate has low water solubility.
`Different salt forms can also differ in the level of irritancy to the gastrointestinal tract, which may result in
`ulceration or bleeding. Nitrate anions are known to cause local irritancy to the gastrointestinal tract leading
`2
`to nausea and gastric distress. Lithium salts irritate the gastrointestinal mucosa, an effect due predominantly
`to the anion moiety rather than the lithium cation. The effect is more marked, with greater discomfort to the
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`patient, the greater the amount of anion administered.
`Reaction products Different salt forms of a drug can differ in toxicity because of reaction products in their
`manufacture. Reaction between the cation or anion moiety of the salt and impurities associated either with
`the active drug or arising from the manufacturing process can result in the formation of toxic products. For
`example, formic acid has relatively low intrinsic toxicity, but its salts are often contaminated with highly
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`toxic methyl and ethyl formate esters, which are reaction-solvent side products.
`Stability
`The particular salt form of a drug can affect its stability. For example, the stability of a drug formulated for
`administration as tablets can be affected by the hygroscopicity of the salt form. Salts of mineral acids such
`as hydrochlorides, sulphates and methane sulphonates are highly polar. The polar ionised groups exposed on
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`crystal surfaces create a highly hydrophilic surface favouring wettability and leading to hygroscopicity.
` In
`turn, this can reduce stability, particularly if the drug is susceptible to hydrolytic degradation.
`Stability is also influenced by the hydrophobicity of the salt-forming acid. The formation of salts with low
`water solubility is a means of increasing the chemical stability of a drug that is sensitive to heat and
`moisture, such as xilobam. Stability is an issue for xilobam tablets containing the highly soluble sulphate salt
`of the drug, because the salt is readily hydrolysed and dissolves in surface moisture. However, when the
`salt-forming acid is aryl sulphonic acid, the hydophobic aryl group presents a barrier to dissolution and this
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`salt form of xilobam is more stable when exposed to high temperature and humidity.
`Thermal stability can vary from one salt form of a drug to another. For example, the hydrochloride salt of
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`lincomycin undergoes thermal degradation whereas the cyclamate is significantly more stable.
` Similarly,
`the procaine salt of penicillin G has good aqueous stability but poor thermal stability, unlike sodium or
`potassium salts of the antibiotic, which can withstand prolonged exposure (four days) to temperatures of
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`100C.
`Conclusion
`Different salt forms of a drug differ in ways that can impact on their clinical efficacy and safety. Changing
`the salt form varies the solubility and rate of dissolution of a drug, which in turn affects its bioavailability,
`pharmacokinetic profile, toxicity, and chemical stability. Early selection of an appropriate salt form in the
`development of a new drug will influence the timely completion of drug development and production, an
`important factor in accelerating the process of drug discovery.
`Substitution of one salt form for another can accelerate the onset and duration of biological activity of a drug
`and is a recognised means of reducing its toxic potential or improving its chemical stability. It is important to
`remember, however, that since changing the salt can dramatically change the properties of a drug, every salt
`form of a drug should be considered as a new medicinal product and tested appropriately before it is released
`for use in clinical practice.
`
`References
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`1.
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`2.
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`Tong W-Q, Whitesell G. In situ salt screening: a useful technique for discovery support and
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`Berge SM, Bighley LD, Monkhouse DC. Pharmaceutical salts. J Pharm Sci 1977;66:1-19.
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`4/5
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`Merck Exhibit 2195, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`3. Walmsley LM, Taylor T, Wilkinson PA, Brodie RR, Chasseaud LF, Alun-Jones V et al. Plasma
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`Sunshine A, Laska E, Slafta J, Fleischman E. A comparative analgesia study of propoxyphene
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`Deroisy R, Zartarian M, Meurmans L, Nelissenne N, Micheletti MC, Albert A et al. Acute changes in
`serum calcium and parathyroid hormone circulating levels induced by the oral intake of five currently
`available calcium salts in healthy male volunteers. Clin Rheumatol 1997;16:249-53.
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`Bjorn H, Hennessy DR, Friis C. The kinetic disposition of pyrantel citrate and pamoate and their
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`Everett RM, Descotes G, Rollin M, Greener Y, Bradford JC, Benziger DP et al. Nephrotoxicity of
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`10. Olovson S-G, Havu N, Regardh C-G, Sandberg A. Oesophageal ulcerations and plasma levels of
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`11. Altamura AC, Gomeni R, Sacchetti E, Smeraldi E. Plasma and intracellular kinetics of lithium after
`oral administration of various lithium salts. Eur J Clin Pharmacol 1977;12:59-63.
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`von Oettingen WF. The aliphatic acids and their esters: toxicity and potential dangers. AMA Arch Ind
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`13. Gould PL. Salt selection for basic drugs. Int J Pharm 1986; 33:201-17.
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`14. Walkling WD, Reynolds BE, Fegely BJ, Janicki CA. Xilobam: effect of salt form on pharmaceutical
`properties. Drug Dev Ind Pharm 1983;9:809-19.
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`15. Neville GA, Ethier JC. Characterization of some lincomycin and cyclamate salts by thermal analysis
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`16. Buckwalter FH. Antibiotic formulations. J Am Pharm Assoc Prac Ed 1954;15:694-700.
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`Glynis Davies is a pharmacist and medical writer. Correspondence to
`19 Llys Preswylfa, Mold, Clwyd CH7 1UP
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`©The Pharmaceutical Journal
`Citation: The Pharmaceutical Journal, March 2001, online | URI: 20004115
`
`5/5
`
`Merck Exhibit 2195, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`