Active Ingredient Salts

Structure and properties

Many active pharmaceutical ingredients are present in the drug as organic salts. This means that the active ingredient is ionized and its charge is neutralized by a counterion (English ). For example, naproxen is present in the over-the-counter pain reliever as a sodium salt. In this form, it is referred to as naproxen sodium. Naproxen is negatively charged due to the deprotonated carboxylic acid and the sodium ion, the counterion, is positively charged. The charges may also be distributed inversely. Morphine hydrochloride consists of a positively charged (protonated) morphine molecule and a negatively charged chloride ion. The two components of the salts are organic and/or inorganic. For example, the Epsom salt magnesium sulfate is a purely inorganic compound. As a rule, the counterion (i.e., the sodium or chloride ion, for example) is pharmacologically inactive – in relation to the area of application. However, there are exceptions, such as silver sulfadiazine or dimenhydrinate. A salt is formed, for example, when an acid reacts with a basic active ingredient or a base reacts with an acidic active ingredient. Hydrochlorides, for example, are produced with hydrochloric acid (HCl). This is possible because many active ingredients have either acidic or basic properties, for example, they carry a carboxylic acid or an amino group.

Differences between the active ingredient and its salt

An active ingredient is not the same substance as its salt. The salt has a higher molecular mass, a different charge, and a different name. It may differ in terms of stability, processability, hygroscopicity, taste, flow properties, pharmacokinetics, pharmacodynamics, and toxicity. One important difference concerns water solubility. The salts are generally more water soluble than the unionized active ingredients and are dissolved more rapidly in the stomach and intestines after ingestion. As a result, they can be absorbed more quickly and may reach the site of action earlier. According to the expert information, the maximum plasma concentration is reached one to three hours earlier when naproxen sodium is administered than with naproxen (!) A significantly faster onset of action has also been documented for the ibuprofen salts (ibuprofen lysinate, ibuprofen arginate and ibuprofen sodium). Water solubility is also a prerequisite for parenteral administration. Therefore, for example, injection or infusion solutions contain an active ingredient salt if the active ingredient itself is not soluble. Here, too, the differences mentioned exist.

Selected examples

In generic

For legal or manufacturing reasons, generic drugs sometimes contain a different salt than the originator drug. Manufacturers of the originator products try to exploit these differences for argumentative purposes (see under amlodipine, perindopril, and clopidogrel).

Steroids pitfall

Caution: steroids are often referred to similarly to salts, for example, “hydrocortisone acetate.” However, the corresponding and not salts are meant. Glycerol trinitrate is also not a salt, but also an ester. Prodrugs such as olmesartan medoxomil and hydrates should not be confused with salts.

Lower amount of active ingredient

The active ingredient amounts and concentrations of drugs are often, although not always, referred to the salt. If the active ingredient is included as a salt, the actual amount of active ingredient will be less. In morphine retard tablets of 100 mg, for example, only 75 mg of morphine base is contained (!) This is due to the higher molecular mass of the salt morphine sulfate pentahydrate. The difference can be calculated with the ratio of the two molecular masses. Numerous comparable examples can be cited, for example, perindopril 5 and 10 mg.