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I would expect an aqueous solution of ciprofloxacin to be basic for the following reasons:

  • The carboxyl group has pKa = 6.09 and the secondary amino group has pKa = 8.74. Because 8.74 is further from neutral pH than 6.09, I would expect the pH of an aqueous solution to be above 7.
  • The tertiary amino groups are connected to an aromatic ring, so they should be very weakly basic and not affecting pH much.

However, the PubChem Compound Summary says the following about ciprofloxacin: "pH range for the 1.0% aqueous concentrates in vials is 3.3 to 3.9; the pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6" (see https://pubchem.ncbi.nlm.nih.gov/compound/ciprofloxacin#section=pH)

Is an aqueous solution of ciprofloxacin solution really acidic and if it is, what is the reason?

I also found an article citing several estimates of the pKa:s and the consensus seems to be that the amino group is stronger than the carboxyl group. (Babić et al. Determination of pKa values of active pharmaceutical ingredients. Trends in Analytical Chemistry, Vol. 26, No. 11, 2007.)

Here is a picture of ciprofloxacin from Wikipedia:

ciprofloxacin

xavier_fakerat
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ttsc
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  • Here is a link to the article I mentioned. I cannot add the link to my question because I don't have enough reputation. https://bib.irb.hr/datoteka/305797.sandra.pdf – ttsc Apr 29 '16 at 17:21
  • If you have to ask, it's probably both. – Oscar Lanzi Nov 05 '23 at 22:37

2 Answers2

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Your predictions are right; the molecule has more basic character.

The drug itself is practically insoluble in water, because the big organic molecule is near it's isoelectric point at the pure water's pH. However by protonating or deprotonating it and thus making it charged it's solubility is greatly enchanced.

This is also the case with those medical ready-for-use infusions:

...CIPRO IV solutions are available as sterile 0.2% ready-for- use infusion solutions in 5% Dextrose Injection. CIPRO IV contains lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6.

Reference

Rok Narobe
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  • From the pKa values I calculate that even at neutral pH the carboxyl group should be charged 89,0% of the time and the amino group should be charged 98,2% of the time. That means that 99,8% of ciprofloxacin is charged at neutral pH. Why is this not enough for a good solubility? – ttsc Apr 30 '16 at 00:11
  • You're right in that near the isoelectric point that the amines are mostly protonated and the carboxylate groups are mostly deprotonated. However, this means that most of the molecules are actually NOT charged because they balance each other off. This results in the solubility dropping because the molecule as a whole has no charge. – IT Tsoi Apr 30 '16 at 04:36
  • You are right. The important thing is that it has no net charge. Charged molecules reppel (Columbian interaction) each other and therefore they can not aggregate. On the other hand neutral moleculs can stick together and participate. – Rok Narobe Apr 30 '16 at 09:13
  • That makes sense. I did not think that the net charge would matter. – ttsc Apr 30 '16 at 15:16
  • Btw, could it also be an important factor that the decreased pH makes the teartiary amino gropus more likely to be protonated? – ttsc Apr 30 '16 at 16:29
  • Sorry, I don't exactly understand what do you mean.

    Note that the tertiary amine groups are not the most basic group in the molecule because of the phenyl group as their substituent. In this case their predicted pKa values are negative (-0,2 and -1,5), so it is probably safe to assume that they don't get protonated at all. Secondary amine groups is the most basic in this molecule. In case of more complex molecules you may want to check pKa values using pKa predictor web tool (like this one: https://epoch.uky.edu/ace/public/pKa.jsp )

     – Rok Narobe May 01 '16 at 18:36
  • Ok. That explains it. I did not think that the pKa:s would be that low. I read that aryl amines have a pKa of around 4 or 5 and I thought that would be the case here as well. If the pKa:s are -0,2 and -1,5, it is clear to me that no protonation takes place. – ttsc May 05 '16 at 17:15
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The commercial active pharmaceutical ingredient (API) is ciprofloxacin hydrochloride. This may explain why you refer to the pH range as 3.3 to 3.9. It's not uncommon for non-literature references to mention API's without mentioning them as a salt.

Beerhunter
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