Delivery and Formulation                    Tablets Under Pressure By Michael Gamlen                           The hardnes... Figure 1:                                                            Hardness of 3mm and 6mm diameter Avicel...  Figure 3: The                                                        Tensile fracture stress for 3mm and 6m...                                                                       Figure 5: Compaction (top), ejection  ...
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’Tablets Under Pressure’


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Whilst hardness has traditionally been used as a measure of tablet quality,
tensile strength is in fact more appropriate when comparing tablets of
different composition, shape and size, and compressed on different
pieces of equipment.

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’Tablets Under Pressure’

  1. 1. Delivery and Formulation Tablets Under Pressure By Michael Gamlen The hardness of a tablet has traditionally been used as a measure of and Dipankar Dey at quality; however, tensile strength is more appropriate when comparing Gamlen Tableting Ltd tablets of different composition, shape and size, and compressed on different pieces of equipment. The modern tablet is a complex – preventing a priori prediction unable to measure compression drug delivery system in which of quality. force. It is a very important control the drug substance is combined parameter because compression with a number of excipients to aid This causes manufacturers affects every tablet property, formulation of the desired product; particular problems in developing including disintegration, dissolution these include bulking agents, and producing the ideal tablet and friability. In some cases stability binders, disintegrants and coatings, that fulfils its therapeutic purpose, is also affected. However, tablet all of which have some function and can be manufactured both hardness (or breaking force) to aid processing of the drug efficiently and economically. comparisons are applicable to substance into the end-product. The Even small variations in material one tablet size and shape only. If excipients and drug substance are properties or process parameters the size, shape or thickness of a processed through a number of unit can have profound effects on final tablet is materially changed, then operations such as mixing, blending, tablet quality. all tablet hardness comparisons granulation, tableting and often will become incorrect. It is obvious coating to form the final product. Measuring the Correct that it is more difficult for a small Tablet Properties tablet to withstand a given fracture The final tablet has to fulfil a load than a larger tablet. Simple number of characteristics, including To assess the impact of hardness measurements are thus the ability to deliver the correct starting material properties and not a valid basis for comparison in amount of drug substance into the manufacturing conditions on this situation. patient’s system at the required tablet properties, it is important rate, as well as physicochemical to ensure that the correct In fact, there are two factors at work properties that make it easy to characteristics are used when here. One is the area across which a handle, administer and store. For making comparisons between tablet breaking force is applied, as dispensable products, these include tablets comprising different clearly the strength of the tablet will a suitable size, hardness, texture and formulations or made on different be proportional to the area across stability, as well as taste and smell. pieces of equipment. In fact, it which the force is distributed. Innovations in Pharmaceutical Technology issue 42. © Samedan Ltd. 2012 is actually very difficult to make Process and formulation scientifically robust comparisons The second factor is that, if the development of the desired tablet between formulations and same compaction force is applied form is time- processes for a number of reasons. to (say) a 6mm circular tablet and Keywords consuming and a 3mm circular tablet, the force complex because Tablet hardness, or breaking per unit area on the small tablet knowledge of strength, is an important and will be four times that on the large Tableting excipient/drug widely used parameter to control tablet (because area is proportional Tablet hardness substance material the tablet manufacturing process. to the square of the diameter of a Compression force properties and In many cases, it is used as a circle). So the material in the 3mm Compaction pressure their relationship surrogate measure for compression tablet will experience a compaction to processing force during manufacture – often pressure four times that of the 6mm Tensile fracture stress parameters is limited because the tablet machine is tablet at the same load.
  2. 2. Figure 1: Hardness of 3mm and 6mm diameter Avicel PH-102 tablets thickness of the tablet and 200 Comparison of compression force must also a 3mm and 180 6mm tablets be taken into account so that a 6mm tablet 160 3mm tablets graph of TFS versus compaction 140 pressure can be prepared. Tablet hardness (N) 120 The differences in tablet thickness, diameter and compression 100 force for circular tablets can 80 then easily be accounted 60 for by calculating the tablet 40 tensile fracture strength 20 and tablet compaction 0 pressure. 0 1 2 3 4 Compression force (kN) Tablet Tensile Fracture Stress For cylindrical tablets, TFS can be It is essential that these factors (measured by breaking force); calculated from the breaking force are taken into account when making however, this takes no account of according to the following equation, comparisons between tablets. the differences in tablet thickness, first used by Fell and Newton in or the effect of differences in 1970 (1): Instead of comparing breaking compaction pressure (see Figure 2). loads (measured in Newtons or Only the applied compression force 2P kg), tablets should be compared is quoted, which does not take σt = — using breaking stress (‘pressure’), into account the punch diameter, Dt which in engineering terms is and hence the area over which the called the tensile fracture stress compaction force is applied. where σt is the tensile fracture (TFS) (1). Rather than comparing strength of the tablet, P is the compaction force, we should Making Valid Comparisons fracture force (N), D is the tablet compare fracture stress based on diameter and t is the overall the work of Newton et al (2). When Comparing formulations using thickness. The equation takes we do this, the results make much only compression force and account of the breaking load, more sense. hardness does not reveal all of the thickness and diameter of the information available in the data. tablet, and effectively divides the In Figure 1, 3mm and 6mm tablets To make the proper comparison, breaking load by the area of the appear to have a similar hardness the tablet punch diameter, fracture surface. Figure 2: Thickness and diameter need to be accounted for in any tablet hardness quote 6mm 3mm Thickness Thickness
  3. 3. Figure 3: The Tensile fracture stress for 3mm and 6mm diameter Avicel PH-102 tablets For tablets that are not flat-faced, tablet tensile 14 the cross-sectional area of the die strength 6mm tablets is still normally used. comparison for 12 a 3mm and 3mm tablets Tensile fracture stress (MPa) 6mm tablet 10 TFS/Compaction Pressure Comparisons 8 6 When TFS and compaction pressure are reviewed, the data reveals 4 its full value. By using the tensile strength for tablets and normalising 2 the applied force with the punch 0 diameter to give the compaction 0 100 200 300 400 500 600 pressure, we can see the impact of Compaction pressure (MPa) tablet size and compaction pressure on TFS, and the effect of tablet size appropriate formula must be used to on compressibility. calculate the TFS for the comparison to be valid. The effect of increasing compaction pressure on tablet tensile strength Compaction Pressure is shown in Figure 3. There is an For a flat-faced tablet, compaction area of overlap of around 150MPa pressure is calculated simply by of compaction pressure where dividing the force applied by the the tensile strength of a 6mm die area: tablet is similar to that of a 3mm tablet. Normalising the data in this P way provides an objective way toFigure 4: The Gamlen This formula is only correct for Cp = — measure tablet physical propertiesTablet Press GTP-1 flat-faced cylindrical tablets; for A over a wide range of compactionImages: Gamlen convex-faced round tablets, the pressures and using a small amountTableting Limited formula becomes: where Cp is the compaction of material. The data shows that the pressure and A is the area of the die. behaviour of Avicel PH-102, when compressed into a 30mg tablet 10P σt = As mentioned earlier, at the same of 3mm diameter, is completely t t W compression force, punch diameter scalable to the behaviour of a (2.84 — – 0.126 — + 3.15 — + 0.01) has an exponential effect on 100mg tablet of 6mm diameter. D W D compaction pressure. For example, Similar results have been obtained 400kg of compression force on a for other materials (2). where σt is the tensile strength, P 3mm punch produces four times the is the fracture load, D is the tablet pressure as 400kg on a 6mm punch. diameter, t is the overall thickness and W is the wall height of the tablet. Both of these equations are also listed in monograph 1217 of the United States Pharmacopeia. Similarly, an equation for a wide range of elongated tablets has been derived by Pitt et al (3). Hence if tablets of different shape are to be compared, the
  4. 4. Figure 5: Compaction (top), ejection purpose as it is both a tablet press (middle) and fracture (bottom) profiles and a tablet fracture tester. For the for an Avicel PH-102 tablet measurement of tablet breaking load, the press records both force TFS Measurement and displacement during both in Formulation compression and fracture, and also Development provides the ejection force profile associated with tablet ejection Tensile fracture stress (see Figure 5). measurement is an important material property In the scale-up of tablet independent of tablet size. production, the press can be used Any statement requiring a to determine the relationship specific hardness to pass between tablets developed at a friability test or survive the bench-top scale using a few a coating operation is not grams of material (often at the universally applicable as it early development stage) and the would apply to one specific final tablet manufactured on a size only. Normalising the rotary tablet press. The latter uses data would remove that hundreds of kilograms of material, barrier and help in comparing making process development formulations of different difficult because of practical tablet sizes and shapes, or difficulties in experimentation; compressed on different smaller and different shaped equipment. tablets can, however, be scaled to the final desired tablet Comparison of tablet TFS is design if TFS is used as the relatively straightforward basis for comparison. if tablets are made at a controlled compaction Conclusion pressure. At Gamlen, we have developed a bench-top, While tablet development computer-controlled tablet has traditionally used tablet press (the GTP-1, Figure 4) hardness as a measure of the that is well-suited for this physical attribute of a tablet, tensile strength is in fact more appropriate when comparing Michael Gamlen is Managing Director of Gamlen Tableting Limited (Nottingham, UK), a leading provider of expertise, equipment and services in the design, different formulations and tablets development and manufacturing of pharmaceutical tablet dosage forms. compressed on different pieces of Awarded a first class honours degree in pharmacy, specialising in pharmaceutical equipment and at different scales. engineering, he studied for a PhD at Nottingham University (UK). He was Head of Tablet Development at the The Wellcome Foundation for 15 years, and has since References worked for Vanguard Medica Limited and as a consultant. Michael has over 30 years’ experience 1. Fell JT and Newton JM, of tablet development and specialises in managing product development, formulation, tablet Determination of tablet and process development studies. He has been teaching professional tableting courses for strength by the diametral many years and his courses are highly rated, often exceeding the expectation of participants. compression test, J Pharm Sci Email: 59, pp688-691, 1970 2. Newton JM, Rowley G, Fell JT, Dipankar Dey is an Oxford-educated doctoral graduate with extensive senior et al, J Pharm Pharmacol 23 management experience in the pharmaceutical and medical diagnostics industries. Dipankar joined Gamlen Tableting Ltd from Oystar Manesty (Liverpool, UK) where Suppl 195S-201S, 1971 he was Head of Process Development. He has particular expertise in manufacturing 3. Pitt KG and Heasley MG, solid dose and biopharmaceuticals, and has worked in a number of different Determination of the tensile functions including technology transfer, new product development, training and strength of elongated tablets, manufacturing. He also has experience in film coating and the implementation of Process Analytical Powder Technol, in press, Technology (PAT). Email: powtec.2011.12.060