Abstract
Drug substance particle size is a critical property affecting drug product performance. Smaller particles dissolve faster and may improve bioavailability of the drug as a result. Smaller particles are typically dispersed more uniformly, leading to lower inter-tablet potency variation. Unfortunately, smaller particles can also result in poor powder handling characteristics or other processing issues. For example, powders can fail to flow through hoppers or stick to tooling surfaces, leading to poor tablet weight uniformity or tablet appearance issues. During crystallization, smaller particles can also be difficult to filter from the crystallization media. This can lead to higher levels of residual solvents and other impurities. Particle design and size selection are therefore critical to achieving a balance between manufacturability, bioavailability, and content uniformity . In this chapter, the impact of particle size on bioavailability is introduced and the impact on content uniformity is considered in depth. Control of the variability of tablet potency is discussed in relation to the overall particle size distribution. The risk-based selection of a positive control such as a screen to limit the maximum allowable particle size is discussed in relation to the occurrence of rare, but highly super-potent tablets.
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Notes
- 1.
The language of the USP Chapter <905> indicates an L1 acceptance value of 15%, which when divided by the acceptability constant of 2.4 (associated with tier 1 testing of n = 10 dosage units) gives an effective Cv of 6.25%.
- 2.
The language of the USP Chapter <905> indicates an L2 acceptance value 25, which when applied to a batch with mean individual contents of 100% (M = 1) provides an acceptable range of 75–125%.
- 3.
The number fraction is not equivalent to the mass fraction in the ith bin. To convert from a number fraction to a volume (or mass) fraction: \( f_{i} = \frac{{n_{i} D_{i}^{3} }}{{\sum\nolimits_{i = 1}^{N} {n_{i} D_{i}^{3} } }} \).
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Acknowledgements
The authors would like to acknowledge Dale Greenwood, and Susan Reutzel-Edens for extensive editorial review as well as Tim Kramer, Rick Berglund, Chad Wolf, Rich Meury, Sal Garcia-Munoz, and Paul Stroud for excellent technical feedback and discussions.
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Appendix: Expected Frequencies of Super-Potent Tablets for Bi-Disperse PSD’s with Differing Weight Fractions of Large Particles
Appendix: Expected Frequencies of Super-Potent Tablets for Bi-Disperse PSD’s with Differing Weight Fractions of Large Particles
Expected frequencies of super-potent tablets given a bi-disperse PSD with 1% w/w of large particles
Expected frequencies of super-potent tablets given a bi-disperse PSD with 3% w/w of large particles
Expected frequencies of super-potent tablets given a bi-disperse PSD with 10% w/w of large particles
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Hilden, J., Burcham, C.L., Stamatis, S.D., Miesle, J., Coutant, C.A. (2018). Guidance on Drug Substance Particle Size Controls for Solid Oral Dose Forms. In: Merkus, H., Meesters, G., Oostra, W. (eds) Particles and Nanoparticles in Pharmaceutical Products. AAPS Advances in the Pharmaceutical Sciences Series, vol 29. Springer, Cham. https://doi.org/10.1007/978-3-319-94174-5_7
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