Tableting is a fundamental unit operation in the production of pharmaceutical oral solid dosage forms. Despite its long history of use and the development of innovations such as extended dwell times, unique technologies that independently and simultaneously measure and control both tablet weight and hardness, and a weight control system that provides increased sensitivity at lower forces, production problems still occur. Here, Dr Harald Stahl, Group Director, Application and Strategy Management, GEA, provides some troubleshooting tips from an unlikely source: the chess board
The board is set. Eight doughty pawns line up to battle with the opposition and, supported by a second row of rooks, knights and bishops, they’re prepared to give their all to attack the opposition, protect the king and release the queen. The playing field is level and, no matter whether the contenders are novices or grandmasters, the outcome is still to be decided.
The players begin to move the chess pieces, one after the other, based on the strategies they plan to employ to gain a better position in the game. The goal? To establish a position wherein their opponent’s king has no legal move to make: checkmate. The game’s afoot. Pawn to king four.
Elsewhere, in a pharmaceutical plant, a rotary tablet press is supposed to be operating at full capacity. Equipped with 25 stations and theoretically able to run at 120 revolutions per minute, the machine should be producing 180,000 tablets every hour … but something is amiss. Knight to bishop three.
Although seemingly unrelated, the movement of chess pieces can be used as a metaphor for the production of solid oral dosage forms. A position of checkmate will only be possible if the players fully comprehend the strategies and tactics they can use to trap the king.
Likewise, formulators and product developers need a deep and application-based understanding of all the factors that contribute to the creation of effective and easy-to-process medicines. Hence, every player is encouraged to study, learn and employ the tactics that have been used by grandmasters to beat their opponents, and plant managers are advised to look beyond they own specific piece of equipment or unit operation.
A trapped king — the production of out-of-specification tablets — is to be avoided at all costs!
Working from the top down and asserting its right to wear the crown, the tablet press is the king. The tablet press, ignoring tablet coating in this example, is the final stage of the tablet manufacturing process and plays a key role in successfully delivering tablets for distribution.
Yet, like the chess piece, this king is, perhaps, not as powerful as first meets the eye. Beyond a one-off castling exchange, a king can move in any direction on the board … but only one square at a time. Its manoeuvrability is limited and its options are often restricted.
To add some context, GEA’s compression experts are often asked how many punch stations a tablet press should have. It’s a good question, of course, and an important number; it helps to determine how many tablets per hour can be produced on a given piece of equipment.
But, there’s more to output rates than just the number of punches. The properties of the feed material are, in fact, more important and, for most pharmaceutical applications, actually determine the tablet production rate. Pawn to queen’s knight four. The king is starting to look vulnerable.
In an actual pharmaceutical manufacturing environment, the number of stations plays a somewhat less important role regarding the number of tablets that can be produced with a particular press.
The majority of pharmaceutical tablets are not produced at the press’s maximum compression speed because, often, it’s not actually possible to make tablets of acceptable quality at high rotation speeds. Defects such as capping, sticking and lamination may occur, and the tablets become subject to weight and content variations.
In many cases, reducing the rotation speed of the press makes it possible to avoid these problems. As such, the simple relationship between reduced rotation speed and fewer out-of-specification tablets will be observed. King to queen two. An endgame has been spotted. Queen to bishop six.
If a press is operated at a lower rotation speed to avoid problems such as capping, this can be equated to a reduction of the circumferential speed. In other words, capping, for instance, can be prevented if the press runs below a certain turret speed.
Thus, if a formulation has a strong tendency to cap, the number of tablets produced per hour cannot be improved by simply increasing the number of pressing stations. Only a reduction in the distance between the dies, which is offered by several manufacturers, can improve the output.
Furthermore, many tablet formulations are dwell-sensitive and require more time under compression to guarantee they come off the press without any faults. Needless to say, some granules are difficult to compress effectively; as such, an adequate dwell time under peak compression is required to achieve the required level of tablet hardness.
Slowing the tablet press down to achieve an increase in dwell time can eradicate these issues; but, this leads to a reduction in tablet production. Bishop to king seven. Checkmate.
If the sluggish king is the press, we can arbitrarily assign roles such as the quality of an individual raw material to each pawn; the knight could be the mode of elastic or plastic deformation (or brittle fraction) and the rook, as we’ll discover, is the fluid bed processor.
For the sake of argument, the bishop could be mixing or blending. And that leaves the queen. Arguably the most powerful piece on the board, the queen combines the power of a rook and bishop and can move any number of squares in any direction.
The queen in our analogy is the granulator. Granulation, which allows primary powder particles to adhere and form granules, is the single most important unit operation in drug manufacturing.
A number of different granulation and compression technologies are available to pharmaceutical manufacturers, all of which have individual strengths and weaknesses depending on the specific application; however, the theory of granulation is often poorly understood and the selection of a particular machine and granulation method is frequently done on the basis of tradition and personal experience, rather than by using strict scientific or cost-benefit criteria.
The basic techniques have changed dramatically in recent years and granulation for controlled release, extrusion, spheronisation, fluidisation techniques, spray drying, melt extrusion, oral dispersion technology and roller compaction are all technologies that are increasingly being used in modern pharmaceutical production and offer many advantages compared with previously available processes.
In essence, a granulator is a multipurpose processor that’s equally suitable for the high-speed dispersion of dry powders, aqueous or solvent granulations, effervescent products and wet and melt pelletisation.
For example, one of the most frequently used upstream processes is wet granulation with subsequent drying. How much drying is required is determined — in most instances — during the development stage when typical limits, such as a loss on drying (LOD) of <3%, is established.
The main selection criterion is chemical stability. During production, the success of the drying process is assessed by sampling and off-line testing. Of course, a value of 1% LOD is an acceptable result and will pass the test for chemical stability; but, for tableting, this is most often fatal.
Most products exhibit a greater level of tabletability with a higher moisture content. Yet, the optimal moisture content for tabletability has not necessarily been included in the development programme (R&D); usually, eccentric presses or small, rotary tablet presses operated at slow speeds are used when developing tablets. For this reason, the fluid bed processor and the inherent definition of the moisture content of the material that feeds the press can be thought of as the rook.
Granulation, which allows primary powder particles to adhere and form granules, is the single most important unit operation in drug manufacturing
The purpose of the wet granulation step is to improve both the tabletability as well as the flowability of the feed material. These material attributes are critical for the high speed operation of the press, which is why the granulator deserves its regal status as the queen.
To facilitate this very important task, a number of vital sub-operations need to be performed. First, the homogenous distribution of the binder liquid needs to be achieved. The slow addition of a low-to-medium viscosity liquid via a spray nozzle ensures optimal results — especially when compared with just pouring it in through an open lid or the use of starch paste.
Furthermore, the design of the processor — or, even more crucially, the impeller — is also of paramount importance. Appropriate impellers introduce both a tangential force component during rotation, which results in the horizontal distribution of the liquid, and a radial force component that ensures vertical dispersion.
Product sticking to the walls and the formation of big lumps, resulting in very long drying times, the excessive need for milling (which leads to a high percentage of fines, poor flowability and the use of limited press speeds to avoid weight variation) are typical indications of ineffective impeller design.
In chess, the goal is to checkmate the opponent’s king. To achieve that objective, however, the players take smaller, more manageable actions that work together to help them reach that endgame. Expert chess players consistently make purposeful moves that are focused on achieving their objectives.
And, whether it’s in the lab, in the facility or on the board, if you don’t keep your objectives in mind, you will waste a lot of time thinking aimlessly about moves that don’t serve a purpose. By contrast, when you know what to aim for, you will have the necessary motivation to search for the best way to implement your plans.
Going into battle without a carefully planned strategy is a recipe for disaster. If you want to overpower a strong enemy, you must know how to approach the battle. This means that you must know what your objectives are and understand how they will help you to achieve your goal. Whenever you reach a point when you feel that you don’t know what to do next, it’s a clear indication that you should’ve been thinking about your objectives.
Every move you make must be guided by your objectives. Moves that are based on vague ideas aren’t good enough. You should be clear about what you want to achieve. Although it might seem obvious, consistently making purposeful moves will make you a much stronger player and a worthy adversary.
When compression problems occur, it’s all too easy — and common — to focus on the press. The root cause of the issue, however, is more than likely a consequence of upstream processing. Poorly granulated materials will not compress well and most fine pharmaceutical compounds require granulation to improve their flowability and processing properties prior to tableting.
The king may have fallen to a triumphant cry of checkmate, but it was the moves of the lesser pieces that caused him to become exposed and unable to flee. Likewise, poor mixing, granulating and drying will lead to issues with tableting that cannot be rectified by adjusting the press.
To close with a Japanese proverb: we learn little from victory and much from defeat. In pharmaceutical terms, this means selecting the most appropriate technology, using the equipment to its maximum capacity and keeping a strong focus on the total cost of ownership. Many a grandmaster knows this to be true.