Why formulate drugs as HCl salts when HCl is in stomach acid?

Question

I know there are issues of formulation and industrial processing that make it advantageous to produce many amine containing drugs as their salts rather than as freebases. And if giving the drug intravenously, the increased water solubility is clearly an advantage. But if giving orally, is there not sufficient HCl in the stomach to have this occur in vivo? Is it just that some of these drugs are too non polar to even go into solution in the stomach acid? Or do we just need to avoid neutralizing too much of the stomach acid with a drug not intended for that purpose?

Answer 1

Another reason is that many drugs which are conjugated to hydrochloride salts is they are amines, and amines by themselves often stink. So people might be turned off from taking drugs that smell terrible (fishy).

Now, note that even though a label might say something such as "fexofenadine HCl" that doesn't mean there is HCl in the drug. Fexofenadine is an amine, and amines are somewhat basic - and more than basic enough for a strong acid such as HCl to completely protonate.

So if this is what you had in mind for the structure of fexofenadine, it isn't the most correct structure:

This would be a much better structure. The nitrogen in the ring has been protonated and it now bears a positive formal charge. Chloride ion is the counter ion.

Answer 2

Typically, a neutral drug species containing an amine nitrogen will have a higher melting hydrochloride salt that may be better than the "free base" in that it is easier to crystallize (and hence purify) for use in a drug formulation. But many types of salts are used besides the hydrochloride - it all depends on which salt gives good crystals and also works well from a physiological standpoint. For oral administration in the typical quantities used for drug doses, the counterion used probably will not make much if any difference, as it will be outnumbered by chloride and other species present in digestive juices.