Pharmaceutical Manufacturing - Tablet Granulation Basics

By Neal Collier on Nov 04, 2010

So you always wanted to know the ins-and-outs of Tablet Manufacturing, but were too busy to do the research?  Have you found yourself sharing war stories at that ISPE get-together and then suddenly feeling left out when they start talking about that spiffy article in this month’s Tablets & Capsules on Granulation Methods in Bovine Oral Contraception?  Well fear not, weary Automation Warrior!  We at the Avanceon Institute for Making Stuff Simple are here to help!  Today we will take the complex world of Tablet Manufacturing and, in a few simple steps, clear the air once and for all on how tablets are made. ¹

First, let’s get something straight.  They are not pills.  Do NOT call them pills.  Ever!    If you remember nothing else, remember this one thing!  If you are trying to be cool and ‘Tablet-Savvy’ and all that, and the word ‘pills’ is in any sentence you utter, people will know you for the poseur that you are! OK, let’s get started.

Raw Materials

When a drug is made, and you don’t have the ingredients already in a powder form, a mixing tank is used.  Water is added to the mixing tank and then (usually) heated on the previous shift by Ray.  Your raw materials are then thrown into the tank by the Day Shift workers (these folks are identifiable by white coveralls, hairnets, facemasks, and blue booties – and bear a striking resemblance to the older and taller versions of Oompa-Loompas from Willy Wonka’s Chocolate Factory).  The raw materials are made up of the active ingredients and some other secret stuff.  ‘What are the active ingredients?’ you ask… …sorry, but that info is also secret. 

Then a not-so-secret process of heating, mixing, blending, drying, and general merriment ensues.  Once that is done you have the raw materials in some kind of a powder form.  The raw materials are then mixed in with filler material.  The filler material is composed of inert materials that help the active ingredients (still secret) get where they’re going (hey, stomach and intestinal tract, do I need to paint a picture?  I thought not).  Typically the filler is two-parts refried banana peels mixed with one-part leftover Chia Pet food.

When making tablets, the trick at this point is to make sure that the active ingredients (No! And stop asking!) are mixed evenly with everything else.  Mixed evenly?  That’s great!  Go directly to the Tablet Press, do not pass GO, do not collect $2,031,042.00. ² If you cannot mix the ingredients evenly, then you need to get fancy - which means that the ingredients need to be granulated.  There are literally thousands of granulation methods.  OK I lied; there are only two main ones: wet granulation and dry granulation. 

Wet Granulation

In the Wet Granulation process a liquid ‘binder’ is used to lightly agglomerate the powder mixture. The binder is some kind of wet material used to bind the mixture of ingredients together into a homogeneous ³ mass… like syrup left on the table at a diner by the last patrons at the $5 breakfast buffet.  When the wet binding material (WBM) is used care is taken to not add too much, or you are left with a mess of hard granules bunched together.  If not enough wet binding material is used, the granules are a gloppy mushy mess.  The wet binding material can be water-based or solvent-based⁴.  There are lots of wet binding materials in use today.  Some examples are cornstarch, gum, gelatin (Yes! Just like Jell-O!), Dippity-Doo, Wild Root Hair Oil, and melted Swedish Fish.

Here are the basic wet granulation process steps:

1. The active ingredient, excipients, and other stuff are weighed and mixed (remember Ray and the Oompa-Loompas?) to create the start of the granulate.
2. The WBM is then added to the whole mess and the wet granulate is mixed. 
3. Mixing happens.  It can be sl-o-o-ow or it can be fast, and it all depends on your ingredients, product, budget, biorhythms and the DOW cap gains index… regardless, there is a whole ‘lotta mixin’ goin’ on!
4. At this point the whole thing looks like something from a giant E-Z Bake Oven recipe.5  
5. The gloppy mass is then forced through a large mesh apparatus, forming it into granules or pellets.  (For those of you with rabbits, hamsters or gerbils, I know what you are thinking and the answer is “yes”.)
6.  The granules or pellets are dried, either in a tray-dryer or a fluid-bed dryer.  A tray-dryer is exactly what you think it is.  A fluid-bed dryer is very strange, and we’ll take a side detour to talk about that in a bit. 
7. After drying, the granules or pellets are passed through another screen to create granules of uniform size. 

What the Heck is a Fluid Bed Dryer, Anyway?

The substance to be processed (we can call it bulk solid material if you like) is placed on some kind of screen or other surface that is chock full o’ holes.  Air is then blown in a column up through the holey surface and across the solid/blobby matter in a continuous and uniform manner.  If you picture Marilyn Monroe in that white dress standing over the subway ventilation grate, you get the idea (full disclaimer: I am a guy and that is the image that popped into my head.  I cannot think of a comparable image for the ladies out there.  If a female engineer can think of one, I’ll be sure to pass it on and alert Netflix so they can stock up).

The cool thing about the fluid bed drying process is that the air that is blown up through the bulk solid material can be used to moisturize, dry, heat or cool!  The amount of air flow coupled with the size, number, placement and arrangement of the perforations can also help control the rate of moisturizing, drying, heating or cooling; all of which make the fluid bed dryer a pretty versatile piece of equipment.  It can also make julienne fries and cut a tin can in half!

Dry Granulation

Sometimes the substance you want to make into a tablet is sensitive to heat or moisture.  When that happens, you’ll have to make do with dry granulation.  The good news is that dry granulation is done with simple crushers, rollers and die presses under light pressure that produce little ‘compacts’ which are then carefully and gently broken up to produce the granules.  There are a lot of different ways and means to get dry compaction with the right density and granule formation (read: cheap).  The bad news is that you end up with a lot of tiny little granules that do NOT have the active ingredient in them, which can be bad if you are taking a drug for a specific purpose and all you get are excipients.  (See?  I just used that word in a sentence and you did not even blink!  Nice!)  For this reason dry granulation needs excipients with cohesive properties.  You may even need to add some more molten Swedish Fish to get the granules you need. 

Granule Lubrication

Remember making waffles on a Saturday morning?  Remember what happens when the waffles stick to the waffle iron?  Not good, right?  We have a similar issue when getting ready to make tablets.  We have spent all of this time making these granules with ingredients so that they stick together, but when we put them in the tablet press we darn sure don’t want them sticking to that, now do we? For this reason one last lubrication blending step is performed on the granules - they are evenly coated with a lubricant (typically in a low speed blender).  Once this is done, you are ready for the tablet press!

Summary

We just went through the basics of getting ready for making tablets.  We learned about raw material mixing and granulation methods.  Stay tuned for the next chapter, where we will tackle the Tablet Press and tablet coating!

GLOSSARY

ISPE: Commonly known as the International Society of Pharmaceutical Engineers, but actually a bunch of know-it-all Pharma Geeks.

Granulated: When something is granulated it is mixed.  Granulation is a mixing process and NOT how happy you are when Grandma puts a five-spot in your birthday card!

Agglomerate: OK, I looked this one up.  You are NOT going to believe this.  If this word is used as a verb it means “to form or collect into a rounded mass”; if it is used as an adjective then it means “gathered into a rounded mass”; BUT, if it is used as a noun, it means either “a confused or jumbled mass; a heap” or “a volcanic rock consisting of rounded and angular fragments fused together.”  What?? Volcanic rock? 

Me: “Honey, this meatloaf tastes like agglomerate!”
Wife: “Why thank you, dear!  What a sweet thing to say!”

Excipient: An inert substance that, when added to a drug, gives suitable consistency or form to the drug.  When excipients are mixed with the drug, they become the ‘vehicle’ to deliver the drug.  If you look these up, you will find that excipients are usually termed “more or less” inert.  That’s fancy Pharma talk for “Side effects?  No way, man! Well, we’re pretty sure… maybe…”

Footnotes
1. OK, not really. You *will* actually have to do some studying on your own. But hey, look on the bright side: this will keep you from having to watch re-runs of The Real Housewives of Automation Engineers. And you know nobody wants that. I mean, did you SEE the second episode? What was up with Francine? OMG!
2. Monopoly was invented in 1934, so accounting for inflation that $200.00 amounts to about $2,031,042.00 in 2010.
3. Oh, I am SO disappointed in you! Looking for the cheap joke! For shame!
4. “Solvents?” I can hear you say. “Like that coffee can in the garage with the paintbrush in it from when we did the bathroom?” In a word: yes. But why does this worry you? Aren’t you the same person who sneaks a Tastykake, candy bar or a Twinkie every now and then? Puh-lease! The chemicals in those babies make the contents of that paint can seem like a wheat germ soda from a vegan foods store, so stop your whining.
5. My older sister had one of these evil torturous ‘toys’ from back in the day and I still wake up in a cold sweat thinking about how sick I got eating a ‘Pumpkin Worm Surprise’ cake when I was 8.