“My child is unable to swallow these pills… Can I crush them?”

“My grandmother is having trouble swallowing these capsules. Is there anything I can do?”

“The patient has an NG tube, and we can’t administer anything orally. What do you suggest?”

You’ve likely encountered these questions before - or are likely to in the future. And you probably remember the simple answers:

Immediate release can be crushed. Sustained/delayed/extended release cannot.

Of course, we can’t really stop there and still call ourselves pharmacists, can we? The answer is much more nuanced and complex. Are there exceptions to the above mantra? Yes. Are there blanket rules of thumb? Also, yes.

So let’s dive in and explore further…

Immediate vs. Delayed vs. Extended Release Formulations

Finding the answers to formulation questions isn’t easy. If you’re like most of us, you start by fumbling through the package insert to see if there are any instructions on crushing the tablet or opening the capsule in the “Dosage and Administration” section. I mean, if anyone has that knowledge, it should be the manufacturer, right?!

Or maybe you do a quick Google search to see if anything relevant comes up. But can you trust Dr. Google?

And what about the “exceptions?” What makes one ER tablet okay to crush when it’s a huge no-no for another?

Ready to have your mind blown?

You already know the answer to this question… (Image)

You’ve most likely been taught the answer to this riddle already. If only you paid attention during that one pharmaceutics class in pharmacy school, when we learned about coatings and additives for making a drug delayed or extended…

But, let’s be honest, most of us sat in the back row and alternated ‘studying’ Facebook with staring out the window. The pharmaceutical difference between ER vs DR vs IR is the ghost of a memory…something you (barely) retained for an exam and then promptly forgot it.

This post will (hopefully) help to dust the cobwebs off of those dark, dank corners of your brain.

Before we go any further, lets clarify something. According to the United States Pharmacopeia (USP) nomenclature guidelines, there are two terms for ‘modified release’:

Delayed Release (aka a drug modified to release later than typical)
Extended Release (aka a drug releases slowly over time)

The USP also includes examples of when to call your drug Delayed versus Extended.

Whoop dee do, right? Doesn’t exactly seem sufficient to cover all the bases.

In addition, USP also recommends terms for dosage forms when it comes to describing products, which is handy particularly now considering all the chat surrounding aerosolized medications.

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Fun fact: “retarded release” is also a term used to describe controlled-release medications, usually by our neighbors across the pond.
- Follow up fun fact #2: This terminology may get you proverbially (or literally) smacked here in the US.

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Anyways, for the remainder of this post, I’ll be using the terms Delayed or Extended. Those are the only 2 terms that the USP uses to describe a tablet or capsule with a mechanism of modified release.

No more getting lost in the diltiazem aisle because of the CC, CD, CR, DR, EC, ER, LA, SA, SR, TR, XL, XT, XR. Those are marketing terms, not pharmaceutical terms.

We won’t let you be confused by some marketing genius trying to put a clever (and profitable) spin on what amounts to either Delayed or Extended Release.

Especially since these letters can lead to some unfortunate issues.

Nonetheless, even if we’re boycotting the alphabet soup, the market will continue to use it. So you’ll need the ability to decipher which letters mean what kind of release system.

“But how? There are like 5 million denotations of release systems!”

The easy answer is to use your pharmacy database system to find AB-rated equivalents and trust that your coders did a good job. But that’s not really a satisfying answer for the NAPLEX, is it?

Alternatively, you can:

Look at the FDA Orange Book for the equivalents, although that website is still terribly unintuitive
Use Micromedex or some other drug information resource
Use RxNav (if you’re comfortable with crazy interfaces…)
Or if you want to dabble with creating your own tool, you can get the FDA Orange Book in separate files.

Alright, now that we have a better handle on that, let’s move on to the magic that makes these formulations possible.

Pharmaceutical Additives and Their Purpose

When you peruse the inactive ingredients in the package insert, you’ll find a word salad of ingredients (they’re the complex, “chemical-y” sounding names). Some of these same ingredients are also in cosmetics and other products, but you’ve probably glossed over them because we’re sorta “wired” to look at the active ingredient.

And who can pronounce 99% of them anyway?

But those inactive ingredients often have a purpose. They’re a lot less ‘inactive’ than you would think. Although a few of them are just fillers, many have a specific role in making the drug release in a certain way. This then goes on to impact the pharmacokinetics and possibly even pharmacodynamics of the drug

So let’s break them down by function with a few examples.

Sealing Coats

For tablets that have ingredients that might be affected by water (kind of like the aliens in Signs or the Wicked Witch of the West), a sealing coat is applied that is either shellac or polymer based.

For this, you’ll see either shellac or something like zein in the inactive ingredients.

Sweeteners

Mary Poppins knew her stuff with her patented spoonful remedy. And it’s not just plain glucose, it’s also our good friend sucrose.

Sugar syrups are used in coating tablets to mask or improve the flavor. Some powdering happens between coats with powdered sugar, starch, talc, acacia, or others to help dry between layers.

Some syrups also have some gelatin, acacia, or polyvinylpyrrolidone or other additives to enhance the coating. (Did someone yell caution with that alpha gal allergy and gelatin?)

In addition, sugar spheres are used for the core of micropellet formulations. One of the brand names for these sugar spheres is too great not to include here: Suglets! These balls are coated with the active ingredient and then coated multiple times with other substances before being packed into a capsule.

You might also see artificial sweeteners like aspartame, saccharin, or flavors like vanillin, grape, lime to improve the taste.

Colors

This should be #lifegoals for your tablet. (Image)

Artificial colors, like the ones found in our foods, are used to make tablets “stand out.”

There are a number of coloring agents out there, but a few are titanium dioxide, iron oxide, D&C, and FD&C colors.

Alloying Substances

These are agents that help with making the coating soluble or permeable to water. Polyethylene glycol (our good friend PEG) is a common example.

The Plastics…so fetch, Gretchen! (Image)

Plasticizers

No, these won’t help you in the Mean Girls universe.

These are for flexibility and elasticity of the coating (just like when we use plastic elsewhere in life). Diethyl phthalate, castor oil, or triacetin are some examples.

Surfactants

Not the stuff in your lungs. This is to help the film coating spread evenly.

So okay, maybe like the surfactant in your lungs. At least in terms of function.

You’ll see the term sorbitan in the name of some of these - better known as tween or span with a number after it.

Glossants

Nothing says “Take me!” like a shiny, beautiful coating. So get some wax and polish the tablet away, right? Our “go-tos” here are beeswax and shellac (you might remember shellac as an option for the Sealing Coat from above).

Solvents

There is nothing worse than a pile of wet tablets that won’t dry. The pharmaceutical way to fix this is to throw some volatile solvents into your coating that evaporate quickly. Acetone or alcohols are your BFFs here.

Film-Forming Agents

Depending on whether you want an enteric or non-enteric film coat, you’ll select different film-forming agents. For the enteric coatings, look for phthalate or shellac (yes, shellac again). In particular, you’ll run into Hydroxypropyl methylcellulose (aka hypromellose) phthalate, polyvinyl acetate (aka PVA) phthalate, diethyl phthalate, or cellulose acetate phthalate.

For non-enteric coatings, you might see methylcellulose, hydroxypropyl methylcellulose (again, hypromellose) without the phthalate, polyvinyl pyrrolidone, sodium carboxymethylcellulose, high molecular weight PEG, or ethyl cellulose pseudolatex.

These are just some examples of inactive ingredients used in pharmaceuticals. You can find many more on the interwebs, but here are some of our faves:

So much info… What does it all mean?!?!!

So you can describe the release…

You know the additives…

Now what?

Well, you take everything, throw it into a blender, and voila! New drugs!

Right?!?

Not quite, but there are definitely ways to get creative combinations when preparing the tablet coating.

And depending on how and what is used (and when), you can get different types of release forms.

Common Pharmaceutical Release Formulations

Microspheres or Beads

Microspheres are pretty much exactly what they sound like — Small spheres with a core (Suglets!) coated with active ingredient followed by multiple layers of coating with inactive ingredients.

They’re typically described as “pellets” or “sprinkles,” usually come in a capsule, and can often be opened up, sprinkled in applesauce or similar, and taken right away.

The spheres themselves, rather than the capsule container, have the coatings to slow down the drug release.

Examples include medications like Verelan SR, Depakote Sprinkle, Cardizem CD, Cardizem SR, Creon, Pancrease, Pancrease MT, Minocin, Drizalma Sprinkle, and many others (again, remember the SR, MT, CD, and all of those other abbreviations are marketing terms, not pharmaceutical terms).

By the way, does anyone eat applesauce regularly enough for this to be a common counseling point? (Maybe pharmaceutical companies have a deal with Mott’s. I dunno.)

We need to know about microspheres because we can sometimes use these formulations when patients can’t take oral meds.

Check this out for some tips about how pharmacists #makeitwork.

You’ll also see some products described as having “beads” or “microparticles,” which is basically the same concept.

Examples are things like Verelan PM, which is in capsule form, but also Naprelan, which is strangely in tablet form.

Osmotic Pump Systems

Osmotic pump systems (particularly OROS (Osmotic-controlled Release Oral delivery System) as it’s the only one at the time of this writing), are designed with a laser-drilled hole in the coating. Water gets through the coating via this hole and goes into an expanding agent, which then squeezes the drug out of that tiny hole.

Think of squeezing a tube of toothpaste - but in tablet form.

There is a fun, and memorable side effect of OROS tablet…

Once the drug is dissolved out of the membrane, you may be left with a hollow membrane or shell that can pass through the GI system. This has been described as ghost pills (Bill Murray to the rescue!). FYI, these hollow ghost pills are not the same as these ghost pills.

If you look closely enough at the OROS tablet, you’ll notice a small hole in the coating. Tegretol XR is one example:

See the tiny hole in the center of the pill on the right? That’s where the magic happens. (Image)

NAPLEX Tip: nifedipine (calcium channel blocker cousin to amlodipine) is available as 2 different once daily formulations. Procardia XL and Adalat CC. These are not AB-rated and therefore are not considered interchangeable. But why? They’re both the same active ingredient and both once a day…

It’s because of differing kinetics…resulting from differing formulations. Procardia XL is an osmotic release system (aka a “push-pull” delivery or some call it the “GITS” or Gastrointestinal Therapeutic System), which is similar to the OROS described above. On the other hand, Adalat CC is the Coat-Core system, meaning each tablet has 2 layers: a coat (in this case, slow release nifedipine) and a core (of fast release nifedipine).

By the way, the OROS release form leads to some interesting stories, and if you’re pumped to learn more about…drug pumps…(okay, sorry, that was a horrible pun), check out here and here for some pretty cool research.

Delayed AND Extended Release?

COVERA-HS (yet another formulation of verapamil) has a proprietary release system called COER-24, which combines a laser-drilled coating with an osmotic layer, which basically delays the onset and also extends the release of the active ingredient.

Other emerging technologies are described in this article, which is worth the read if you’re curious. It’s not recent (published in 2011), but it covers quite a bit.

Take Aways

So back to that patient that can’t swallow her pills…

If the tablet has some type of special coating, you probably can’t split or cut it.

But if the coating is simply a sugar coating, or if there are microspheres inside the capsule doing the delayed or extended release work, you might have a shot at still using the drug!

And if you’re not sure, there’s still always those external brains to lean on:

Handbook of Drug Administration via Enteral Feeding Tubes
ISMP’s Do Not Crush List (Free if you register an account, so do that. Don’t buy the wall chart unless you want it!)

So now that you know a little more about additives and release technologies, you should be able to translate those magnificent package inserts. Or, at least you know why there are some strange little ingredients listed.

tl;dr - If you don’t know whether something can be crushed or opened, check the package insert. If it’s still not clear, look it up elsewhere. Or at least know what the ingredients do to make an educated guess.

A Pharmaceutics Primer on Slow Release Drugs