by Michael Gamlen at Gamlen Tableting Limited
Characterisation of the compaction process is an important element of tablet development. Better understanding of tablet compression and ejection behaviour is essential for generation of data needed to support requirements of Quality by Design. It will help establish a more robust and reliable process, save time and money, and result in real patient benefits. We recommend widespread adoption in the industry.
Quality by Design (QbD) is a new pharmaceutical development paradigm in which products are designed to take account of the disease and its impact on the patient; the patient population; the drug properties; the preferred route of administration (from a clinical and a marketing perspective); and the requirements of the organisation manufacturing the product. In many cases the preferred dosage form will be an oral solid dosage form (OSD), usually tablets which are relatively cheap to manufacture and administer, and can be produced with a wide range of properties.
The basis of good science is the making of relevant and accurate measurements. This is particularly true in the case of tablet formulation developments. Tablets are complex products. Successful tablet development requires a good understanding of a number of key drug substance properties, as well as generating relevant and useful data on the formulation properties. Careful evaluation of the properties of the drug substance at the early stages is used to assist with the selection of both the salt of a new drug, and its polymorph form, as both of these can dramatically affect tablet properties and process selection.
Measuring drug substance properties relevant to compressibility requires the use of instrumented compaction systems such as a compaction simulator or a Gamlen Tablet Press. Comparison of different salts to select the most suited to manufacture is an important step in the development process. Preclinical studies on new materials have to be performed on the salt to be marketed, otherwise the work may have to be repeated. However at this early stage the drug substance is in short supply. Techniques able to work with small amounts of material are essential for success.
Drug substance properties must also be taken into account when developing the product formulation and manufacturing process. Selection of a sub-optimal process or formula may result in considerable extra costs and delays, and even failure. The principal manufacturing methods for tablets are summarised in Table 1.
|Direct compression||Low and intermediate drug contents
|Not suitable for very low or high drug contents. Susceptible to variations in drug substance properties.|
|Dry granulation||Low to high drug content depending on drug substance properties||Avoids the use of water.
Some limitations on utility dependent on the properties of the drug substance.
|Wet granulation||All drug contents
(from very low to very high)
|Flexible but resource intensive process which is hard to automate. Usually uses water in the manufacturing process so may not be suitable for moisture sensitive products|
Table 1 Key tablet process manufacturing processes
Using the ICH (ICH Q8 (R2)) terminology, each process has its own Critical Process Parameters (CPPs), and is affected by the Critical Quality Attributes (CQAs) of the drug substance. These are used to identify the Product Control Strategy (PCS), which should be based on understanding of the links between the formula and process, and the CPPs and CQAs. The data generated are used support the PCS, and are key to meeting the regulatory expectations of Quality by Design. The development of the formulation and process is usually an iterative one in which the formulation or process is adjusted based on evaluation of intermediates and products. The manufacturing scale used during formulation development depends on the amount of drug substance, and the equipment, available. As with the drug substance, the amount of material available is limited and instrumented, small scale systems are needed to evaluate the products in development in a cost effective manner.
Understanding tablet compaction
The study of tablet compaction, sometimes known as the physics of compaction, started with the development of instrumented single punch tablet presses in the 1950s (Higuchi, 1950). Instrumentation of rotary tablet presses in academia during the 1960s (Ridgway; Upjohn), was followed by the development of the compaction simulator in the 1970/80s (ICI). Compaction simulators imitate the movement of the punches of a rotary tablet press using multi-stage hydraulic systems. The tablet compression cycle is shown in Figure 1, and the key parameters which can be measured during compaction are listed in Table 2.
Figure 1 Tablet compaction cycle
Table 2 Tablet compaction parameters
The first measurements made were the upper and lower punch forces, which are readily converted to compaction pressures, an important step (see below). Compaction pressure determines all tablet properties including hardness, friability, disintegration and dissolution.
Measurements of punch position and die wall pressure are made to understand the process of compaction itself. This is done to try to understand which materials or formulations will make good tablets, and when a better understanding of material properties is needed. It is possible, but not easy, on a single punch tablet machine (and extremely difficult on a rotary tablet machine) so most studies of displacement have been done on compaction simulators.
Study of ejection force measurements is done to improve understanding of lubrication and ejection behaviour. Lubricants are a “necessary evil” in a tablet; they are essential for running of the tablet press but often have adverse effects on dissolution and compressibility. Measurement on rotary presses is problematic because the ejection cam is usually in contact with several ejection events at the same time, so ejection is also most easily studied on simulation system.
Tablet detachment stress can at present only be studied on the Gamlen Tablet Press (GTP). Taking advantage of its mode of operation, the GTP measure tablet detachment force quickly and easily, generating a unique insight into the lubrication process.
More about tablet compaction
Tablet hardness, or breaking strength, is an important and widely used parameter to control the tablet manufacturing process. In many cases it is used as a surrogate measure for compression force during manufacture, often because the tablet machine is unable to measure compression force. It is a very important control parameter because compression affects every tablet property including disintegration, dissolution and friability. In some cases stability is also affected. However, tablet hardness (or breaking force) comparisons are applicable to one tablet size and shape only. If the size, shape or thickness of a tablet is changed then tablet hardness comparisons become incorrect. It is intuitively obvious that it is more difficult for a small tablet to withstand a given fracture load than a larger tablet to do so.
Using measurements of compaction force and tablet thickness during the compaction event, it is possible to get a good understanding of material properties. To take account of the impact of tablet size on tablet hardness, it necessary to calculate the tensile fracture stress of the tablet, using a technique published by Fell and Newton in 1970 (Newton):
σt is the tensile fracture strength of the tablet, P is the fracture force (N), D is the tablet diameter, t is the overall thickness
The equation takes account of the breaking load, thickness and diameter of the tablet and effectively divides the breaking load by the area of the fracture surface. Other equations are available for other tablet shapes.
Using the tensile fracture stress, compaction pressure (the compaction force divided by the area of the tablet), and tablet thickness (together with the measured or calculated absolute density of the tablet), then three key compression properties (FIND) can be assessed – tabletability, compressibility and compactibility. Although these words sound very similar, they are being used to assess very different things – see Figure 2. Tabletability is defined as the relationship between compaction pressure and tensile fracture stress. Compressibility is the relationship between compaction pressure and solid fraction. Compactibility is the relationship between tensile fractures stress and solid fraction. These parameters can be set out in a 3d-plot to enable comparison of materials (Amidon), but are shown in 2d in Figure 3 to Figure 5 (al) for clarity. These data are used to select formulations and processes, and assist in the development of the Product Control Strategy.
Figure 2 The compaction triangle – tabletability, compressibility and compactibility
Figure 3 Compactibilty measurements on the GTP and Fette 2090
Figure 4 Tabletability measurements on the GTP and Fette 2090
Figure 5 Compressibility measurements on the GTP and the Fette 2090
Ejection and displacement force
Measurement of single tablet ejection and detachment force is not possible on a conventional tablet press because of mechanical and measurement limitations. We have recently reported (Gamlen, 2013) measurements of detachment and ejection stresses using the Gamlen Tablet Press – see Figure 6.
Figure 6 Operation of the Gamlen Tablet Press
Tablet detachment force is measured using a McMesin CFG 500N force gauge1. The ejection profile (force and displacement) of each tablet is recorded from which both the ejection stress and the work of ejection can be calculated. A typical ejection profile is seen in Figure 6. This is very useful for selecting well lubricated formulations and processes. The range of ejection and detachment forces for different direct compression agents is substantial.
Figure 7 Ejection and detachment forces for Galen IQ720
Figure 8 Ejection and detachment forces for Perlitol 500DC
In Figure 7 and Figure 8 above the contrasting behaviours of Galen IQ720 and Perlitol 500DC are seen. Sodium Stearyl Fumarate (SSF) is seen to be much more effective in Perlitol than it is in Galen IQ 720 – a completely unpredictable result.
Why use a Gamlen Tablet Press?
It can save you time, money and materials. People need help to study tablets under properly controlled conditions in a laboratory.
Michael Gamlen invented the Gamlen Tablet Press (GTP) to help you understand the relationship between the properties of your drug, formulation, and manufacturing process. When you do this you can develop better products more quickly, and improve productivity of your tablet manufacturing operations.
The GTP is the first machine designed to make tablets on a small scale at a user-specified compaction force. This force determines both the physical strength and the dissolution behaviour of the tablet. These are the key properties which ensure the tablet reaches the patient and delivers the drug.
The machine works by monitoring the force in real time using a PLC. The punch force and punch position are displayed in real time on a computer which is also used to input the compaction conditions. Using the GTP we make tablets of extraordinary reproducibility and consistency, within 1-2% force, and with no wastage. Batch yields are >99%.
For the measurement of tablet breaking load, the press records both force and displacement during both compression and fracture, and also provides the ejection force profile associated with tablet ejection
In the scale-up of tablet production, the press can be used to determine the relationship between tablets developed at the bench-top scale using a few grams of material (often at the early development stage) and the final tablet manufactured on a rotary tablet press. The latter uses hundreds of kilograms of material, making process development difficult because of practical difficulties in experimentation; smaller and different shaped tablets can, however, be scaled to the final desired tablet design if TFS is used as the basis for comparison.
If you want better tablet products and processes you need the Gamlen Tablet Press.
Characterisation of the compaction process is an important element of the tablet development process. Better understanding of tablet compression and ejection behaviour is essential for generation of the large volume of data needed to support the new requirements of Quality by Design. It will lead to more robust and reliable process, save time and money, and result in real patient benefits. We recommend more widespread adoption in the industry.
About the author
Michael Gamlen is managing director of Gamlen Tableting Limited, who provide a specialist small scale product development service including a free tabletability testing service for customer samples.
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