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Tablet Manufacturing: Challenges & Problem Solving

Presentation · December 2019

DOI: 10.13140/RG.2.2.14667.62248

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 12/26/2020

TABLET MANUFACTURING
CHALLENGES & PROBLEM SOLVING
Nasser Nyamweya, Ph.D.

Tablet Development Training Workshop 2019 December 3rd, 2019 1

INTRODUCTION
• Review of the Tableting
Process
(filling, compression, ejection)
• Material Requirements
̶ Power Flow
̶ Powder Compaction
• Tablet Evaluation
• Tableting Issues

A turret with tooling on a rotary press: the turret positions & moves the dies and punches. The
rotatary speed of the turret determines the speed at which tablets are produced.

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POWDER FLOW
Cams – guide the
movement of the punches
(upwards or downwards)

Hopper –
contains &
feeds the
powder to be
compressed

Ref: https://www.saintytec.com/tablet-
Compression
compression-machine-parts/
rolls – force
punches to
Fill Cam –  lower punch allowing powder to enter the die compress
Feeder – improves powder filling into the die
Ref: https://pharmapathway.com/working-and-principle-of-tablet-compression-machine/

Tablet Development Training Workshop 2019 December 3rd, 2019 4

THE TABLETING PROCESS

• A powder flows into a die (based on volume)
and is compressed by 2 punches to form a
densified compact Upper Compression Roll
• Densification brings the powder particles
into close contact
• Powder particles that can no longer Upper Punches
accommodate the applied load (force)
Dies
deform (change in shape)
• The combination of particle deformation
and densification results in bond formation Lower Punches
between the powder particles forming a
tablet
• The shape & size of the tablet is determined Lower Compression Roll
by the shape & size of the die & punches

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POWDER FLOW
• Tablet weight (& 
the dose) is controlled
by the amount of
powder flowing into
the dies
• Poor flow will lead to:
1) difficulty of powder
exiting the hopper
2) tablet weight variation
Ref: Prescott, J.K. & Barnum, R.A.. (2000). On powder flowability.
Pharmaceutical Technology. 24. 60-84+236.

Tablet Development Training Workshop 2019 December 3rd, 2019 7

POWDER FLOW

Ref: Prescott, J.K. & Barnum, R.A.. (2000). On powder flowability.

Pharmaceutical Technology. 24. 60-84+236.
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POWDER FLOW

Ref: Lumay, Geoffroy et al. Powder Technology Volume 224, 2012, Pages 19-27(2012).

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POWDER FLOW
• Tablet size is determined based on the volume of the die

• Powder or material being tableted must flow rapidly and uniformly

into the dies to ensure reproducible tablet to tablet weights
(especially for high speed presses)

• The powder should not segregate easily (e.g., from the hopper to the
dies or as a result of machine vibration)

• Factors affecting flow: particle size, shape, density, surface

characteristics (e.g., roughness, moisture content), charge

Tablet Development Training Workshop 2019 December 3rd, 2019 10

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POWDER FLOW: Considerations

• Particle size
– The larger the particle size the better the flow
– Less inter-particulate surface interactions

• Particle shape
– The more spherical the particle, the better the flow
– Spheres, cubes will have the best flow
– Needles, fibrous particles will have the worst flow

• Granulation (agglomeration) is a common approach to addressing

powder flow issues in tableting

Tablet Development Training Workshop 2019 December 3rd, 2019 11

POWDER COMPACTION: Considerations

• Compression = reduction in volume; particles come into closer
contact (due to the pressure applied by the punches)
• Compaction = compression + increased mechanical strength (e.g.,
hardness) due to inter-particulate bonding
– Inter-particulate bonds are formed when particle are brought in close contact
by compression
– Some of these bonds are broken after compression {e.g., from elastic recovery
and the forces experienced by the tablet upon ejection from the die (e.g.,
friction) }
• Poor bonding between particles; too much elastic recovery; or high
friction at die wall during ejection can lead to either capping;
lamination, or poor tablet formation

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FORMULATION: Excipients
Raw Material Function
API (the drug) Therapeutic effect
Filler Provide bulk
Binder Hold the powder particles together
Lubricant To facilitate tablet ejection from the die
Disintegrant To facilitate rapid drug dissolution and
(immediate release tablets) absorption
Glidant Improve powder flow
Anti-adherent Prevent sticking onto the punches
Others e.g., wetting agents; coloring agents
Note: the levels of the excipients is an important consideration (esp. for binders, lubricants & disintegrants)

Tablet Development Training Workshop 2019 December 3rd, 2019 13

FORMULATION: 3 key excipients

Issue Solutions
Binder Increasing binder levels may:
1) Increase tablet hardness (to a certain level)
2) Decrease the rate of drug release
Lubricant Increasing lubricant levels may:
1) Decrease the rate of drug release
2) Decrease tablet hardness
Disintegrant Increasing disintegrant levels tends to increase
the rate of drug release

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TABLET PRESS: Process Variables

1) Compression Force (pressure)
̶ Increasing the pressure increases the mechanical strength (hardness) of the
tablets (and vice versa)
2) Press Speed
̶ The faster the press speed (RPMs), the shorter the dwell time (the time the
powder is under peak compression pressure)
3) Pre-compression
̶ The a smaller compression roll before the main compression roll that can
provide a small amount of powder densification prior to main compression
4) Tablet Thickness

• Tablet Weight (adjustable, but fixed by the dose of API)

Tablet Development Training Workshop 2019 December 3rd, 2019 15

TABLET PRESS: Compression Force

Ref: Anbalagan, P. et al. Journal of

Pharmaceutical Investigation 47 (2017): 173-181.

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TABLET PRESS: Forces experienced by…

Upper
punch

Die

Lower
punch

1) Powder flow into the 2) Beginning of 3) Peak of 4) Die wall &

die by gravity (no compression forces compression forces ejection forces
pressure on the powder) & die wall forces & die wall forces

Tablet Development Training Workshop 2019 December 3rd, 2019 17

TABLET PRESS: Ejection & Die-wall Forces

Ref: Takeuchi H. et al.

Int J PharmApr 15;274(1-2):131-8. . (2004)

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TABLET DEFECTS

Ref: https://www.researchgate.net/publication/317692120_Mechanics_and_Computational_Modeling_of_Pharmaceutical_Tabletting_Process

Tablet Development Training Workshop 2019 December 3rd, 2019 19

TABLET DEFECTS: Capping & Lamination

Possible Cause Solutions

Excessive fines • Remove fines
• Optimize granulation
Air entrapment • Use pre-compression
• Reduce upper punch penetration
• Reduce press speed
• Use of tapered dies
Poor bonding • Increase dwell time
• Optimize granulation (binder)
• Do not over-dry the granules
• Optimize lubrication
High ejection • Optimize lubrication
force
Ref: Mazel, V. et al. Int J Pharm. 2015 478(2):702-4. (2015)

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TABLET DEFECTS: Capping & Lamination

Damaged tablet punch land

Ref: https://www.tabletscapsules.com/enews_tc/2018/issues/tcnews_11_26_18question.html

Ref: https://natoli.com/maximizing-your-tooling-roi/

Tablet Development Training Workshop 2019 December 3rd, 2019 21

TABLET TOOLING: Considerations

Ref: Anbalagan, P.; Heng, P.W.S.; Liew, C.V. Int. J.
Pharm. 2017, 524, 373–381.
“tablets produced from the punches with
radius edge face geometry consistently
displayed better physical quality; higher tensile
strength and lower capping tendency”

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TABLET TOOLING: Considerations

Ref:https://www.manufacturingchemist.com/news/article_page/The_importance_of_FFRE_tab
let_design_in_encouraging_consumer_acceptance/155471

Tablet Development Training Workshop 2019 December 3rd, 2019 23

TABLET DEFECTS: Picking

Ref: Chattoraj, Sayantan et al. J Pharm Sci. 107(9):2267-2282. (2018)

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TABLET DEFECTS: Sticking

Ref: Chattoraj, Sayantan et al. J Pharm Sci. 107(9):2267-2282. (2018)

Tablet Development Training Workshop 2019 December 3rd, 2019 25

TABLET DEFECTS: Picking and Sticking

Ref: Osamura, Takashi et al.. Asian Journal of Pharmaceutical Sciences. Volume 12. (2017), Pages 412-417

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TABLET DEFECTS: Picking & Sticking

Possible Cause Solutions
High moisture levels in the • Optimize moisture levels
formulation • Environmental humidity control
Low melting point • Reduce press speed
components in the • High chrome steel punches
formulation • Coated punches [e.g., w/Hard Chrome (Cr) and Chromium Nitride (CrN)]
Punch surface (cleanliness, Clean and polish tooling; replace tooling if worn
roughness)
Tooling design Alternative punch design; logo/embossing design

Tablet Development Training Workshop 2019 December 3rd, 2019 27

TABLET EVALUATION & CHARACTERIZATION

Mechanical
Weight properties

Dimensions

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TABLET EVALUATION & CHARACTERIZATION

Test Rationale
Appearance, color General quality and aesthetics
Weight Dose
Thickness Drug release
Hardness Drug release
Friability Handling and transportation
Disintegration Drug release
Dissolution Drug release; in vivo bioavailability
Assay, related substances, H2O Stability

Tablet Development Training Workshop 2019 December 3rd, 2019 29

SUMMARY
1) Optimize the formulation composition (raw
materials and their amounts); powder flow; and
compactibility
2) Optimize tablet press variables
3) Proper selection of tablet tooling
4) Ensure proper maintenance of the tablet press
and the tooling (variation in tooling can lead to
variability of tablets within a given batch)
5) Control moisture

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Thank You for Your Attention

Dr. Nasser Nyamweya
email: [email protected]

Tablet Development Training Workshop 2019 December 3rd, 2019 31

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