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24 July/August 2021 Tablets & Capsules tion. Milling or recrystallizing an active pharmaceutical ingredient (API) may help to get its particle shape closer to a 1:1:1 aspect ratio and improve compaction. Strain rate sensitivity. Strain rate sensitivity is the percentage difference between the yield stress of a mate- rial measured at a high compression rate and at a low compression rate [5]. Fragmenting materials show low sensitivity while plastically deforming materials have high sensitivity. Higher production speeds are more obtainable by optimizing particle size above the brittle ductile transition. Permeability. The ability of air to escape during com- paction is related to the formulation's permeability, which is a function of particle size and void fraction. Larger particle sizes and void fractions increase permeability. Formulations with high bulk density tend to have lower void fractions and lower permeability. Use the Darcy equation to compare permeability for powders: Q = k A ∆P μ L Where Q is the airflow rate; k is the permeability; A is the tablet cross-sectional area; ∆P is the pressure difference; µ is the viscosity; and L is the cylinder height [3]. Moisture content. Adding moisture to a formulation often increases tablet strength. Flowability. To measure a formulation's flowability, use Carr's index: [(tapped density - bulk density)/tapped density] x 100. In many cases, a better flowability can lead to poorer compactibility, so striking a balance is desirable: Excellent = 5-10 Good = 12-16 Fair = 18-21 Poor = 23-28 Another common method to measure flowability is angle of repose, which is the angle in degrees from hori- zontal that a material forms when piled on a flat surface. The angle given is an approximate one. Excellent = 25-30 Good = 31-35 Fair = 36-40 Passable; may need help = 41-45 Poor; must agitate = 46-55 Very poor = 56-65 Not usable > 66 Factors that influence compactibility Understanding your formulation's characteristics is key to ensuring good tablet compaction. The following factors play an important role in a formulation's compactibility. Compressibility. Compressibility is a formulation's ability to undergo volume reduction under pressure. You can measure compressibility with a Heckel plot, using the equation: ln 1 = K P a + A 1 − ρ r Where ρ r is the compacted density relative to the bulk density; P a is the applied pressure; K is the slope—the yield pressure's reciprocal—with lower values indicating harder tablets; and A is the slope intercept. To conduct a Heckel plot, you must measure the formulation's true density, preferably with a helium pyc- nometer [1]. The area under the curve represents the volume reduction—compressibility—and the yield pres- sure is inversely related to the material's ability to deform plastically. You can use the results to compare excipients' properties and help optimize the formulation. For exam- ple, a high slope value (K) indicates that the formulation doesn't easily deform plastically and can benefit from adding a binder that does, such as povidone [2]. Particle size. Generally, small particles have better compressibility but poorer flowability [3]. Large particle sizes can improve compactibility [4], but a high percent- age of fines is detrimental. For most materials, an optimum particle size exists for the promotion of fragmentation. The size where frag- mentation begins to occur is called the brittle ductile transition. By first sieving the material, you can compare compactibility profiles using different particle sizes [5]. Fragmentation. Under compaction pressure, particles will deform or fragment; in many cases, both occur simul- taneously. While both mechanisms increase the surface area of mating surfaces for bonding, fragmentation gen- erally provides a stronger bond because it creates new surfaces untouched by the formulation's lubricant. Deformation can be plastic—irreversible—or elas- tic—returning to the previous shape after pressure release. Elastic deformation is always present to some degree, but minimizing elastic deformation is desirable for tablet strength. Some materials have different crystal-hydrate forms. These hydrates differ in their stability and ability to frag- ment. When sourcing excipients, be sure the hydrate form is suitable; for example, not all lactose is the same, and some types provide better compaction than others. Particle shape. For flowability, an ideal particle shape is a smooth sphere. Long and needle-like or flat disc- shaped particles exhibit poor flow. A rougher, slightly irregular particle shape is more advantageous for compac-

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