What Are "Salt Forms" Of Drugs And Why Are They Different?
In our latest question and answer, the pharmacist discusses what pharmaceutical salt forms are, their use, and how they can differ from one another.
Why do you often find names of elements or other compounds following a drug name? What do they do? Examples like Atorvastatin "Calcium", Diclofenac "Sodium/Potassium" or Amlodipine "Besylate".
There are many reasons why the name of your medication has another compound attached to it. Most likely, it is the "salt form" of the drug. A few examples you mentioned of drugs with salt forms include:
- Lipitor (Atorvastatin Calcium)
- Voltaren (Diclofenac Sodium)
- Norvasc (Amlodipine Besylate)
- Lopressor (Metoprolol Tartrate)
- Delsym (Dextromethorphan Hydrobromide)
In many cases, a drug substance (i.e. the parent compound) has certain characteristics that doesn't lend itself to being absorbed or utilized properly in our bodies. Fortunately, there are some chemical and biopharmaceutical tweaks that can be used to overcome this, often achieved by creating of a "salt form" of the drug in question.
What Are The Common Salt Forms?
Many drugs are only available in their "salt form", to improve the properties of the drug. In fact, more than 50% of drugs in the United States are actually a salt form, and not just the parent compound. The most commonly used salts are:
- Hydrochloride (HCl)
- Hydrobromide (HBr)
Why Create Drug Salt Forms?
As mentioned above, very often the properties of a parent drug compound aren't ideal for absorption and utilization in our bodies. A salt version of a drug, for example 'atorvastatin calcium', has better absorption and dissolution properties that simply 'atorvastatin', which enhances the effect of the medication after administration.
Absorption isn't the only reason why salt forms are created however. Below is a list of potential advantages of salt forms:
- Improved absorption (from improved solubility and dissolution)
- Altered release profile (i.e. extended release properties)
- Improved extreme temperature stability
- Improved photostability (i.e. less likely to break down with light exposure)
- Improved stability to moisture (i.e. improved hygroscopicity)
- Improved palatability (i.e. improved taste)
- Improved efficacy (some salt forms elicit different effects on the body - See Diphenhydramine Vs. Dimenhydrinate)
- Altered melting point (useful in drug manufacturing)
- Improved compatibility (useful in drug manufacturing)
Exactly which salt a drug manufacturer uses is based on several factors including:
- The pH of the parent drug compound (i.e. acidic or basic)
- The solubility of the compound
- The safety/tolerability of the salt form
- The dosage form being used (e.g. tablet, capsule)
- Indication the drug is used for (e.g. sodium salts aren't generally used for blood pressure medication)
So overall, salt forms of drugs have a significant effect on the properties of a given drug and can be a critical step in ensuring a drug works as intended. They are so important that without a salt form available, or if it isn't feasible to make one, a parent drug may not be worthwhile to manufacture or be made available.
Can A Drug Compound Have Different Salt Forms?
Things can get a little complicated when there is more than one salt form for a given drug compound and this is something that is often seen, for a variety of reasons. While the primary purpose of a salt form is to change the pharmacokinetic characteristics of a drug (e.g. solubility), these changes can significantly influence the overall effects of a medication, leading manufacturers to creating different salt forms of one parent drug.
So, while in most cases there is only one salt form of a drug (e.g. atorvastatin calcium), there may also be many different salt forms of a parent compound (e.g. calcium products, which includes calcium carbonate and calcium citrate).
In most cases, different salt forms of the same drug are not considered bioequivalent by the FDA, which means they cannot be substituted for one another. This makes sense since, as discussed above, different salt forms can significantly impact the properties of a drug.
In addition, most drugs that have multiple salt forms are unique drug products, each with their own brand name and patent protection.
Below is a list of common medications that have different salt forms, along with notes on each:
- Wellbutrin (bupropion hydrochloride)
- Aplenzin (bupropion hydrobromide)
There isn't much data to conclude a significant difference between these salt forms. It has been reported that bupropion hydrobromide may have a lower seizure risk, but this isn't confirmed.
- Calcium supplements
Different forms of calcium have different absorption and solubility properties. For example, calcium carbonate (i.e. Tums) needs to be taken with food as it is best absorbed in an acidic environment (food causes the release of gastric acid). Calcium citrate on the other hand, can be taken with or without food. Different salt forms of calcium also contain differing amounts of elemental calcium per dose.
- Khedezla (desvenlafaxine base)
- Pristiq (desvenlafaxine succinate)
There is no significant difference between these salt forms.
- Cambia (diclofenac potassium)
- Voltaren (diclofenac sodium)
The potassium salt may be absorbed faster and have a quicker onset of action. Also, the potassium salt may have higher water solubility, making it convenient for a powdered drug product intended to go into solution.
- Vibramycin (doxycycline hyclate)
- Monodox (doxycycline monohydrate)
Doxycycline hyclate is more acidic than doxycycline monohydrate. Therefore, the monohydrate salt form is sometimes considered to be better tolerated as it may cause less gastrointestinal side effects. However, the monohydrate version is more expensive and it may be not absorbed as well as the hyclate version depending on stomach pH. For these reasons, the hyclate version is often preferred.
- Toprol XL (metoprolol succinate extended release)
- Lopressor (metoprolol tartate)
Metoprolol succinate is available in an extended release formula while metoprolol tartrate is only available as an immediate release product. In addition, metoprolol succinate may be more effective in reducing mortality in heart failure patients than the tartrate salt and is therefore preferred over it in that population.
- Atarax (hydroxyzine hydrochloride)
- Vistaril (hydroxyzine pamoate)
It has been reported that hydroxyzine pamoate is more lipid soluble, and therefore has more sedative effects than hydroxyzine hydrochloride. This has led to hydroxyzine hydrochloride (Atarax) being used more often for allergic symptoms and itching (as it is an antihistamine), with hydroxyzine pamoate (Vistaril) being used more often for anxiety symptoms and insomnia. Whether these differing effects are clinically significant is not well known.
- Magnesium carbonate
- Magnesium chloride
- Magnesium citrate
Magnesium salts differ in many characteristics including elemental magnesium content per dose, absorption, tolerability and overall effects on the body.
How Are Drugs With Salts Listed On Your Prescription Label
Unfortunately, most pharmacies in the United States use different software and the consistency in listing drug names is not there. One pharmacy may dispense Lipitor as atorvastatin calcium, while another may simply list atorvastatin. This can create even more confusion if your pharmacy switches generic manufacturers of a drug on you.
For example, it isn't uncommon for a pharmacy to dispense 'amlodipine besylate' one month, but then switch the manufacturer of the product (as there are numerous) and dispense 'amlodipine' the next. They are the same drug compound (amlodipine besylate) but for whatever reason, the pharmacy software lists them differently.
If you ever have any questions regarding your prescription (especially if there is more than one salt form available!), be sure to speak with your pharmacist.