My evil cat has a nasty infection in her gut, and for the past week my wife and I have been twice daily, in the famous Greco-Roman style, orally administering crushed-up Metronidazole HCl tablets to her. Luckily, our thoughtful vet figured a vile faux-cherry suspension would be most palatable for a feline, so we’ve had no serious problems. :dubious:
This morning, while nursing my various puncture wounds and researching in my Physicians’ Desk Reference whether the goo she’d just disgorged into my eye would cause permanent blindness, I got to thinking about the prevalence of HCl in pharmaceutical formulations. Happily, my eye will return to normal in a few hours, but the HCl question still persists. Here’s a brief overview.
My guess is that hydrochloride increases the digestibility of a medicine. Am I on the right track?
Keep in mind that your stomach already contains HCl and has a way of protecting itself from the acid it contains. The amount of HCl is also quite small, at least when compared to the amount already in the stomach. For example, a 500 mg tablet of metronidazole HCl contains 412 mg of metronidazole and 88 mg of HCl.
As the link above explains, many drugs are poorly soluble in water. Many drugs are also somewhat basic. When these drugs are reacted with just enough HCl so that there’s one molecule of HCl every molecule of the drug, a hydrochloride salt is formed that is more water-soluble than the original drug. (What actually happens is that the drug is protonated. The hydrogen atom from the HCl* is added at its most basic part, usually a nitrogen atom. Because this nitrogen atom now has more bonds than it normally has, it acquires a positive charge. Each molecule of the drug, which now has a positive charge, is associated with a negatively-charged chloride ion, Cl[sup]-[/sup]. These positive and negative charges make it much easier for water to be attracted to the drug molecule, because water has a partial negative charge at the oxygen and a partial positive charge at each hydrogen.)
(*: Not really from the HCl; it’s actually from the H[sub]3[/sub]O[sup]+[/sup] that forms when HCl – a gas at room temperature – is dissolved in water.)
Most orally-delivered drugs of the broad “organic base” class are poorly soluble in water, and not especially lipophillic either, as they are small and weakly polar. Very often these drugs are amines, and can be complexed relatively easily with H[sup]+[/sup] and Cl[sup]-[/sup] to produce a salt of higher solubility. However, increased solubility doesn’t always guarantee increased absorbtion, as the high concentraiton of Cl[sup]-[/sup] in the gastric juices makes it difficult, from an energetic standpoint, for the crystals of drug•HCl to dissociate (without getting into a longwinded discussion, this problem is related to LeChatelier’s Principle, and is called the “common ion effect”). Sometimes making other salts, like HBr salts, can hence be adventacious. Sometimes it’s even difficult to get the crystals to dissociate bith simple inorganic counterions such as these halides, so an organic counterion may be used instead, like a maleate or a mesylate. Such drugs, when water is evolved during formulation, can precipitate as amorphous solids rather than crystals, and these can have even better solubility and absorbtivity in the stomach and beyond, due to the lower energies of dissociation. But, more often than not, a simple HCl or HBr salt is fine, and hence these are much more common.
<hand-waving generality>
Another factor that should not be overlooked is the moderate protective effect of a “hydrogen chloride” variant on HCl attacks on nearby bonds, partly due to leChatelier effect, and also due to other more complex organic chemistry mechanisms, thereby altering preferred sites of opportunistic attack.
In lay terms: your stomach is full of HCl (hydrochloric acid), which can be highly destructive of many compounds (that’s its function). By deliberately complexing HCl (more likely: chlorinating and then buffering for storage) at a site chosen by you rather than allowing hydrochloric acid to choose its most preferred attack by its rapacious nature, you might gain some measure of protection. It’s a nasty fact of chemistry that the same energy factors that make a site of acid attack “preferred” often also make it the point where an attack will disrupt the electron structure of the compound the most.
It’s a lot like picking a spot to sit at a wedding reception. I tend to slide in between two lovely ladies, intead of inserting myself at a table that’s already guy-heavy. YMMV (and so may mine)
If you can reduce the gastric breakdown of a drug by 20% [a pittance in he often logarithmic world of reaction rates], you often boost its bioavailability [amount absorbed into the blood] by the same ratio – depending of course on the absorption characteristics of the drug. This can definitely be worth doing.
This is simplistic approach, of course, but simplicity often works! There are a fair number of drugs where the HBr formulation is preferred, because bromide i(heaver and less reactive than chloride) doesn’t break off as readily in the high HCl of the stomach, On these drugs, the Cl breaks off realively easily, leaving the "preferred (often more destructive) site of attack open. Putting an HCl or Cl at a site preemptively will tend to make nearby site less attractive for a second Cl attack
You can think of it as a very rapid series of exchanges between Drug-HCl (stable site) -> free drug -> drug+HCl (attacking more vulnerable site) In some cases, the heavier, but chemically similar HBr, will break off less readily, and protect a nearby more chemically vulnerable attack site for a bit longer than HCl would.
</hand-waving generality>
