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Is there a reason for why most medicines are in salt form?

Why not have them in conjugate base form?

Nickotine
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2 Answers2

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In general, salts are more soluble in water than organic acids or organic bases, because they are made of ions. It is a general trend. There are plenty of exceptions. So usually salts are quickly dissolved in the stomach and absorbed in the intestine later on.

Maurice
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  • thank you for your answer, but how does this work? they dissociate to the ions anyway, so does the conjugate base alone not dissociate @maurice ? – Nickotine Mar 27 '21 at 10:24
  • An organic base is a molecule made of covalent bonds. It will not dissociate. A good example is ammonia $\ce{NH3}$ (which is not organic) and amines obtained by replacing one H by $\ce{CH3}$ or $\ce{C2H5}$ or any other organic radical- These molecules are not polar, they cannot dissociate, and are not too much soluble in water. And all they can do is to accept a proton from an acid. In that case it becomes charged and soluble into water. – Maurice Mar 27 '21 at 21:29
  • thank you very much now I get it @maurice – Nickotine Mar 27 '21 at 22:52
  • actually I have another question if it’s a hcl salt for example it’s only the h and cl that ionise, the substance still exists in its pure form not an ion... perhaps it’s just a cost thing? @maurice – Nickotine Mar 28 '21 at 17:20
  • i think this only applies to sodium salts not hx salts @maurice – Nickotine Mar 28 '21 at 17:29
  • @Nickotine I don't understand your question. An $\ce{HCl}$ salt does not contain HCl any more. Let's consider $\ce{NH3}$ or $\ce{OH-}$ which both react with $\ce{HCl}$. A part from the ion $\ce{Cl-}$, the reaction produces $\ce{NH4+}$ or $\ce{H2O}$. which are much weaker acids than $\ce{HCl}$. So where is the problem ? – Maurice Mar 28 '21 at 18:51
  • I’m saying that in the case of Med-HCl, med remains unionised so what’s the point of having it attached to HCl when Med by itself is equivalent and more potent gram for gram as its molar mass is smaller, it remains in covalent form in both cases @maurice – Nickotine Mar 28 '21 at 20:43
  • I’m interested in this because how can the drug work while not being an ion? it would just be too unreactive right? does it work in an equilibrium then? @maurice – Nickotine Mar 29 '21 at 00:37
  • @ If a drug is a salt, it is part of an equilibrium. And the state of the equilibrium changes. In the stomach, the solutions are acidic. They get neutralized in the intestine. – Maurice Mar 29 '21 at 08:47
  • h and cl dissociate leaviing the covalent form of the drug, this is equivalent to taking the covalent form of the drug by itself you have still not explained this @maurice – Nickotine Mar 29 '21 at 09:25
  • @Nickotine. If an insoluble substance $\ce{B}$ is swallowed, it will stay in big grains or blocks on the bottom of the solution. If it is swallowed as an ion $\ce{BH+}$, it will be distributed in all the solution. If it now meets an acid solution, the insoluble $\ce{B}$ will be formed again. But it will make monomolecular particules which stay in suspension in the liquid. They may even form a colloid, which is able to cross the intestinal membrane and pass into the blood. This is the way insoluble substances like cholesterol stay in the blood. – Maurice Mar 29 '21 at 10:15
  • so the reason is because it won’t dissolve? would a work around be to take it as a powder in a capsule? also even thkugh it dissolves how does a covalent molecule react? @maurice – Nickotine Mar 29 '21 at 11:34
  • @Nickotine. I don't understand what you mean with "Would a work around be to take it as a powder ?". – Maurice Mar 29 '21 at 15:58
  • you said it will stay in big grains or blocks, so if it was a powder you wouldn't have that problem, and since in both cases the medicine is in its covalent state how does it react? @maurice – Nickotine Mar 29 '21 at 16:14
  • The thinnest powders are still made of aggregates containing at least billions of billions of molecules. If the same insoluble substances is made from a solution having reacted with something, the insoluble substances may be present in aggregates containing maybe one hundred or thousand molecules. This is much smaller that the grains of powder as explained above. – Maurice Mar 29 '21 at 19:13
  • and how does a covalent molecule react in the body? since only h and cl ionise @maurice – Nickotine Mar 29 '21 at 22:50
  • @Nickotine. Once a covalent molecule is "suspended" like a colloid in the blood, it may go to any part of the body, like cholesterol. The rest is a medical or a biological question. I don't know how it reacts. – Maurice Mar 30 '21 at 09:02
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Indeed, 50% of the US’s FDA approvals consists of compounds in the salt form, (Paulekuhn et al. 2007) but the choice depends on multiple factors beyond the acid/salt choice as Gupta et al. (2018) noted in their review:

The physicochemical and biological properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development.

References

Paulekuhn, G.S., Dressman, J.B., and Saal, C. (2007) “Trends in active pharmaceutical ingredient salt selection based on analysis of the orange book database.” J. Med. Chem. 50:6665. DOI: 10.1021/jm701032y

Gupta, D., Bhatia, D., Dave, V., Sutariya, V. and Gupta, S.V. (2018) “Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations.” Molecules 23:1719. DOI: 10.3390/molecules23071719

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