Pharmaceutical salts are important in the process of drug development. Using different chemical species to neutralise the parent drug can produce a diverse series of compounds, and this process is traditionally used to improve drug solubility and drug dissolution rates.

For negatively charged drugs which are paired with cationic counterions, there seems to be a general lack of variety in the counterion choice, which is usually a metal ion such as sodium. Other counterions such as ammonium cations (e.g choline and respective cations of benzathine, diethanolamine, diethylamine, meglumine, piperazine, procaine) or silver have not been used over the past 25 years.

On the other hand, there seem to be many more anionic counterions, most notably chloride, but also mesylate (e.g imatinib mesylate), besylate (amlodipine besylate), hydrocortisone succinate, and so on.

How can such a trend be explained in drug development process or chemistry of substances thereof? Could it simply be because there are fewer negatively charged drugs, or are there other explanations?

  • 2
    $\begingroup$ Lacking a background in medicinal chemistry, I cannot really give an answer. I would think that counterions are mostly governed by toxicity and solubility, in that aspect, $\ce{Na+}$ seems a reasonable choice. $\endgroup$
    – TAR86
    Jan 10 '18 at 21:05
  • $\begingroup$ Could this just generally be an availability issue? The only stable cations I can think of are metal cations, while there's a whole bunch of inorganic oxoanions (chlorate, chloride, perchlorate, chlorite, and hypochlorite are all "chlorine anions") and a lot more organic anions (e.g. conjugates to carboxylic acids) $\endgroup$
    – chipbuster
    Jan 11 '18 at 1:40
  • $\begingroup$ Why do you think they weren't used? For example salt of diclofenak and diethylamine is used. $\endgroup$
    – Mithoron
    Jan 11 '18 at 23:45

Here is what I managed to find:

In various researches, cationic counterions were associated with a high prevalence of unexpected incompatibilities in drug development processes. Owing to their low solubilities, (typically <0.1% ) cationic counterions are infrequently used in many pharmaceutical preparations, however may be preferred to provide prolonged slow absorption while achieving effective plasma concentrations for some therapeutic uses, which is the case for benzathine and procaine penicillin G intramuscular injections.1 Furthermore cationic counterions, to a greater extent are susceptible to salting. Salting out results when highly hydrated inorganic ions (e.g $\ce{K+}$, $\ce{Na+}$) deprive organic ions and molecules of adequate water molecules to remain dissolved.

In addition another important factor influencing pharmaceutical salt selection is compatibility with excipients (diluents, binders, disintergrants, glidants, preservatives etc). Most amine derived counterions are incompatible with excipients. For example, the counterion of tromethamine (a primary amine) should not be used with reducing sugars as excipients because of a possible Maillard reaction, consequently limiting the available entities in the cationic counterions' pool .2

The trend can also be explained as a consequence of the changes in research techniques employed by the pharmaceutical industry. It can also be attributed to small absolute numbers of approved drug products containing salts formed from acidic entities.3

Overally, anionic counterions are favoured in drug development due to the wide availability of weakly basic pharmaceutically active principles (approximately 75% of drugs are estimated to be weak bases) 4, consequently leading to correspondingly low availability of cationic counterions for acidic drugs which comprise only about 20%, with remaining percentage being neutral.


  1. Newton D, W. Drug Incompatibility chemistry (American Journal of Health-System Pharmacy) Available from: http://www.medscape.com/viewarticle/590261.

  2. Wu, Y., Levons, J., Narang, A. S., Raghavan, K., & Rao, V. M. (2011). Reactive impurities in excipients: Profiling, identification and mitigation of drug-excipient incompatibility. AAPS PharmSciTech, 12(4), 1248-1263.

  3. Paulekuhn, G. S., Dressman, J. B., & Saal, C. (2007). Trends in active pharmaceutical ingredient salt selection based on analysis of the orange book database. Journal of Medicinal Chemistry, 50(26), 6665-6672.

  4. Manallack, D. T. (2007). The pKa Distribution of Drugs: Application to Drug Discovery. Perspectives in Medicinal Chemistry 1( )25–38.


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