Anisotropy in Compacted Pharmaceutical Powders

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1 Anisotropy in Compacted Pharmaceutical Powders Matthew P. Mullarney Materials Science Oral Products Center of Emphasis Pfizer Global Research and Development, Groton, CT Forth Annual Garnet E. Peck Symposium Lafayette, Indiana September 21,

2 Pfizer Global R&D Pharmaceutical Sciences Oral Products Center of Emphasis Materials Science Materials Assessment Laboratory Groton, CT 2

3 Pfizer Materials Assessment Tools Microscopy Particle sizing Powder flow Compaction simulation Compact mechanical property testing 3

4 Powder compaction Pharmaceutical tablets are typically manufactured on a high-speed press by compressing a blend of powders/granules with two punches and a die. Powder compaction occurs uni-axially which induces variations in stress/strain distributions and porosity (Train, 1957). These variations may cause materials to behave differently depending on their orientation to testing. Therefore pharmaceutical compacts are anisotropic. Tablet lamination (in-die axial tablet failure) Hardness tester (radial crushing strength) 4

5 Anisotropy: A definition Wikipedia Anisotropy (the opposite of isotropy) is the property of being directionally dependent. Something which is anisotropic, may appear different, or have different characteristics in different directions. Typical anisotropic wood grain Splitting wood with the grain is much easier! Oriented plywood layers increase strength 5

6 Visualization of Compact Anisotropy X-ray microtomography X-ray Source 90% 80% 70% X-ray Detector High Density Low Transmission x-ray system for the nondestructive three-dimensional imaging of compact structural density converts the density distribution into a grayscale/color spectrum. (Busignies et al, 2006) 6

7 Density Anisotropy in Tablets Uniphyl 400mg Purdue Frederick Glucotrol XL 5mg Pfizer Inc. High Low 7

8 Identification of Overcompression Microtomography can identify anisotropic density distributions near tablet scores caused by different tooling bisect geometries. (Sinka et al, Int. J. Pharm, 2004) 8

9 Tablet Overdensification & Capping Capping of Lactose Tablets Microtomography cross-sectional image Compact fracture region High density/stress The overcompression of uni-axially compacted tablets leads to high levels of anisotropic interparticulate stresses contributing to tablet failure. (Wu et al., Powder Tech, 2005) 9

10 Anisotropy in Ribbons Too? Roller surface types Roller compacted ribbons (prior to milling) Visual difference in ribbons 10

11 Anisotropic structure of ribbons MIDDLE OF RIBBON Gerteis - smooth rolls, steel side seals Freund TF Mini - serrated rolls, teflon seals EDGE OF RIBBON H L Compacted ribbon samples exhibit different degrees of density anisotropy which are dependent on the equipment features. 11

12 Anisotropy and its Causes In powder compression, the following mechanisms are thought to induce anisotropy: Particle Slip-Plane Biases: Single crystal reorientation leading to the formation of cleavage planes (Duncan-Hewitt et al.) Primary Particle Shape: Non-spherical particles orienting preferentially upon consolidation (Li and Puri, 1996) Degree of Elastic Strain Recovery: Varying degrees of axial/radial strain recovery (Moe and Rippie, 1997) Compression Conditions: Particulate-die-punch interactions (Li and Puri, 1996) 12

13 Measuring Anisotropy Anisotropy can lead to compact failure e.g. capping, lamination, and edge erosion Anisotropy screening is beneficial to robust dosage form design Published work uses different testing methods for measuring anisotropy in compacts (not geometrically isotropic) Research objective More quantitative assessment of anisotropy Material sparing approach (<10 g) Determine extent of mechanical property anisotropy Explain material failure mechanisms during tablet manufacturing 13

14 Materials α-lactose monohydrate Microcrystalline cellulose Aspartame Hydroxypropyl cellulose Spray-dried Lactose Dibasic calcium phosphate anhydrous 14

15 Sample Preparation and Mechanical Testing Die Top Punches Side Bottom Axial Radial Tri-Axial Press Compact Preparation Pendulum Impact Device Indentation Hardness Tensile Tester Tensile Strength Upper Punch Load Cells Actuators Split Die Sample Fracture Plane Sample Platens Split Die Lower Punch Die Cavity (Hiestand and Smith, Powder Tech, 1984) 15

16 Tensile Strength Results 7 Tensile Strength (MPa) Radial Axial 1 0 HPC DCP Lactose SD Lactose MCC Aspartame Direct comparison of axial and radial tensile strength Axial tensile strength < Radial tensile strength Related to capping/lamination tendency (axial) Related to crushing strength measurements (radial) 16

17 Tensile strength anisotropy The ratio of tensile strength values was used to quantify anisotropy. σ T ( axial) α = = σ ( radial) T As α deviates from unity (1.00), the material behaves more anisotropically. α = 0 : Completely anisotropic α = 1 : Completely isotropic 17

18 Tensile strength anisotropy Alpha 1.00 Alpha Alpha HPC DCP Lactose SD Lactose MCC Aspartame HPC: highly plastic and isotropic Aspartame: highly brittle and anisotropic Consistent with published fracture toughness data (lactose < MCC) Although MCC is somewhat anisotropic, its very high strength compensates enabling its tableting robustness. 18

19 Indentation Hardness Results 800 Dynamic Indentation Hardness (MPa) Top Bottom Side HPC DCP Lactose SD Lactose MCC Aspartame Indentation Hardness: top bottom > side The top and bottom surfaces were measurably harder than the sides for most materials, suggesting that uni-axial compression produces compacts with inhomogeneous porosity and/or location specific material stress/strain history. 19

20 Indentation Hardness Discussion Tablet solid fraction distribution (Kandeil et al., Powder Tech, 1977) Uniaxially compressed powders Possess a density distribution in their bulk structure (Train, 1957) Surface in contact with moving punch is slightly less ductile (Aulton, 1981) Solid fraction decrease from top to bottom in single sided compaction (Zhou, Zhao et al., 2002; Michrafy, Kadiri et al., 2003) Exponential punch force decay from top to bottom (Unckel, 1945) 20

21 Indentation hardness anisotropy The ratio of indentation hardness values was used to quantify anisotropy. β = H H o o ( side) ( top) = As β deviates from unity (1.00), the material behaves more anisotropically. β = 0 : Completely anisotropic β = 1 : Completely isotropic 21

22 Indentation Hardness Anisotropy Beta Beta Beta HPC DCP Lactose SD Lactose MCC Aspartame Like α, β suggests HPC = isotropic and aspartame = anisotropic The observed anisotropy are likely due to the non-uniform stress distribution induced during uni-axial compaction 22

23 Compact Brittleness Determinations The brittleness of each compact was determined from the brittle fracture index (BFI). BFI σ T = σ T 0 BFI = 0 : not brittle BFI = 1: perfectly brittle The BFI is determined by measuring the regular tensile strength (σ T ) and compromised tensile strength (σ T0 ) of a compact. Regular Compromised Controlled defect 23

24 Anisotropy and Brittleness α β α, β Brittle Fracture Index BFI describes the strongest and weakest states of the compact Highly isotropic materials (e.g. HPC) were non-brittle Highly anisotropic materials (e.g. aspartame) were brittle Combination of compact properties must be evaluated to assess tablet manufacturing potential. 24

25 Summary Measurable degrees of mechanical property anisotropy were detected. Microtomography helps visualize the anisotropic density distribution. Increased anisotropy less likely to relieve interparticulate stresses through plastic deformation. The methods can help to predict capping and lamination potential. Attractive method for the formulation scientist because it is simple, broadly applicable and requires a small amount of material. Mullarney MP and Hancock BC, (2006). Mechanical property anisotropy of pharmaceutical excipient compacts. International Journal of Pharmaceutics, 314(1),

26 Acknowledgements Bruno Hancock Maureen Whitley Leya Behra Colleen Gendron Glenn Carlson Beth Langdon Dauda Ladipo Andrey Zinchuk Greg Amidon Cindy Oksanen Chris Sinko Keith Horspool Sheri Shamblin Garnet Peck Ken Morris Mary Ellen Hurt Manuscript reviewers 26

27 Thank you! Comments or questions? 27