The word PILL has become a sort of universal term for almost any solid medication that is taking by mouth. Newspaper accounts will often announce the discovery of some new drug with a story that starts Scientists have discovered a new pill that…. The word also makes frequent appearances in news accounts of the current furor over the price of pharmaceuticals and current efforts to provide seniors with insurance coverage for drugs. In a narrower sense The Pill has morphed into a shorthand term for oral contraceptives. A search on The Pill in Google will turn up close to a million hits, the preponderance of which refer to contraceptives.

Pharmaceutical professionals view this phenomenon with bemusement because there have been virtually no pills made for at least several decades. Instead, all currently used oral medications consist of tablets, capsules or their variants.

Pharmacists faced a real problem over a century ago when relatively pure new drugs became available since most of these were powders. Patients would complain that swallowing a dose of powder could be just plain difficult. As a result the pharmacist would combine the powder with some innocuous stuff that would cause the powder to stick together. He would then roll that into a little ball that could be easily swallowedthe first pill. The process for making those was of course too time consuming for making them in any quantity to say nothing of mass production. The properties of those doses also varied enormously. Some stuck together so well that they passed through the digestive system unchanged. This was reflected by original logo of a company that introduced pills that would disintegrate in the stomach: the Upjohn Company used a vignette of a thumb crushing a pill in all its early ads.

The development of the coating pan led to the birth of what is properly called a pill. In another bit of semantic deception this apparatus is actually not really what we usually visualize as a pan. It consists instead of a large drum closed at one end and with a slightly restricted opening at the other. The drum is tilted a bit from the horizontal and slowly rotates as a stream of warm air is allowed to flow through. Making pills started by loading the drum with small seeds that would form the centers of the dosage form. These often consisted of grains of sugar and were called nonpareils. The coating pan operator, usually a highly skilled professional, then carefully ladled a solution of drug in some relatively volatile liquid onto the seeds as they tumbled in the rotating drum. As the solvent evaporated this hopefully left a layer of drug spread evenly over the nonpareils. This procedure was then repeated to build up the drug layer by layer until the individual particles, pills, had the required weight. This process is obviously very labor intensive. It also requires very frequent assay to make sure that the pills contain the proper amount of drug. These drawbacks led the pharmaceutical industry to look for alternative methods for producing oral dosage.

Coating pans can however still be seen in many pharmaceutical manufacturing plants. There they are sometimes used to apply film coatings to tablets; they can also be used to remove dust from capsules by rolling them with salt.

The great mass of what are called pills actually consists of compressed tablets. These are made by a quite different process that can be readily scaled up to mass produce a very uniform product with minimal labor input. Most of the powders that make up drug substances will not readily stick together to form tablets. In addition, some are administered in such tiny amounts that they would form miniscule tablets. Consider for example the probable size of a 0.075 mg synthetic thyroid tablet… for reference, that is about 2 one-millionths of an ounce. The vast majority of drugs are, as a result, combined with a number of other compounds to provide bulk, to include substances that will form tablets under compression and finally ingredients that will help them go through the presses such as the lubricant magnesium stearate. These non-active parts of any tablet are itemized by FDA regulation under the Other Ingredient or Inactive Ingredients listing on every drug label.

The principle involved in making tablets is relatively simple: the presses are, on the other hand quite complex. Tablets are formed by filling a cavity within a die with powder. Two pistons, called punches, then enter the die from opposite directions and squeeze the powder. When sufficient force has been applied the powder will compact into a tablet. (Pharmaceutical scientists have been known to conduct quick and dirty trials of a new formulation by actually putting punches into a powder filled die and then simply hitting one of the punches with a hammer).

The operating center of a high speed rotary tablet press consists of a set of thick horizontally disposed facing round steel plates separated by narrow gaps. Starting from the top we have a plate equipped with a series of circumferentially disposed slides for punches. The central plate has anywhere from 16 to as many as 40 larger holes. These cavities called stations are disposed at regular intervals in positions that correspond to the slides in the facing plates. The lower plate is an exact replica of the top one. Set within each of the stations in the central plate is a die. These are polished steel cylinders bored with a hole that corresponds to the outer dimension of the tablet. A series of punches ride in special sleeves in both the upper and lower circles. The punch itself consists of a cylinder of tough steel whose shape brings to mind the valve of an internal combustion engine. At one end of the punch we find the face; this is a highly polished, often concave, steel surface that is engraved (de-bossed in the trade) with whatever pattern will appear on the face or on the bottom of the tablet. The thin part of the stem is the same diameter as the inner bore of the die in which it will operate. The heavier part of the punch will slide in the bearing surface of the rotating upper or lower plate. The flanged end of the punch, which looks something like the working part of a valve, is the rail follower. This will follow the contour of the circular rail that dictates the position of the punch as it travels around the circle.

Figure 1 shows a Tablet Press Punch

Figure 2 depicts a highly stylized version of the working parts of a tablet press. The rotating operation has been straightened out for the sake of clarity (the press would be moving from right to left). The operation starts at the extreme left with a heap of powder delivered by a special hopper. This is swept into available die by a structure called the feed frame. The position of the punch has been set by the bottom rail so that the die will accept just the right amount of powder for a tablet. The top punch is withdrawn all the way at this point. As the press continues to rotate the rails start to lower the upper punch and raise the bottom one. Compression starts when the top punch has dropped far enough to close off the top of the die. Directly after this each of the punches travel under the compression rolls. These are freely rotating heavy wheels that exert tons of pressure on the flat end faces of the punch rail follower. The force exerted by the rolls leads to the formation of the compressed tablet. It might be added that some of the more complex presses actually use two sets of rolls, the first set acting as a pre-compression station. As the press continues on its way the top punch is gradually withdrawn by a secondary rail that catches the bottom of the valve like structure. At just about this time, a sharp upward bend in the bottom rail causes the lower punch to quickly rise. This flips the finished tablet out of the die. A guide then directs the ejected tablet out of the press onto a chute that leads to a receiving container. In the time it has taken to read these two paragraphs, a modern high speed tablet press will have spat out several thousand finished tablets. A 40 station press is capable of turning out a stream of 4400 tablets per minute!

Figure 2: Depicts a Tablet Press

The dies and punches used to produce the garden variety round tablets with which we are most familiar are themselves circular in cross section. The punches are allowed to freely rotate with the slides, cutting wear. Going to specialized custom shapes generally involves the many additional complications required to keep the parts in constant alignment. The keyed punches used for those tablets are a good deal more expensive and require more maintenance. An increasing number of specialized shapes have nevertheless been recently introduced. Product tampering, for example, has led many manufacturers to replace over-the-counter drugs once sold as capsules with so-called caplets. These are simply capsule shaped tablets.

Hard gelatin capsules are the second most common dosage form; these too are quite often also called pills. These are even further removed from pills since they are usually filled with drug in loose powder form. These powders often do not, by the way, consist of pure drug substance. The high potency and resulting low dosage of many modern drugs means that only a small amount of pure drug substance needs to be put in any one capsule. Manufacturers will often dilute the drug with some inert ingredient so that they can more easily control filling. Capsules are, as a rule, more expensive to produce than tablets. Producing drugs in this form involves first the purchase of empty capsule shells from one of only half a dozen or so manufacturers. An additional reason for the higher expense comes from the fact that capsule shell production is intrinsically significantly slower than is tablet compression. A typical modern high speed capsule filling machine will deliver 40,000 capsules per hour, or only about one-sixth the amount of a tablet press.

Modern automatic capsule filling machines use the same rotary motions as tablet presses. The machine in this case however includes special feed mechanisms for empty capsule shells as well as one for drug fill. For the sake of simplicity Figure 3 shows only the filling step as used in one of the current high speed machines. The heart of the machine is a reservoir, called a bowl, that is supplied an accurately maintained level of fill. The bottom of this bowl consists of a plate in which there are drilled a circle of holes which when closed at one end define a volume that represents the volume of drug-excipient mix that is to be loaded into each capsule. As the machine rotates the tampers come down through the mix to first trap the right volume. They then go down further and slightly compress the powder against a blind plate below the perforated one. At the final station the tamped load will get to a hole in the blind plate. In the meantime a capsule will have arrived at the same orifice. A final move on the part of the tamper pushes the load of powder into the capsule. The upper half of the capsule then rejoins the filled bottom and is tapped into place. Many capsules are now sealed with a band of gelatin to avoid tampering.

Figure 3: Shows tamper resistant system

Next time you see or use the word pill recall that you probably mean tablet or capsule. Or better yet, reserve the term to describe an obnoxious person.