Best Practices for Effective Tablet Lubrication Tony Carpanzano, B.S., R. Ph.

Director R&D, JRS Pharma, LP Agenda

1 Introduction

2 Manufacturing Challenges

3 Lubrication 101

4 Choosing a Lubricant

5 Summary Production Concerns

Achieving efficient lubrication for a trouble-free tablet manufacturing process is a search for the middle-ground between picking and sticking, and over-lubrication. Finding that balance can be difficult. Manufacturing Challenges Manufacturing Concerns

Less Lubricant Level More

Lubricant Effect

Picking Defect-free Okay looking Soft tablets Sticking tablets of tablets with with high Capping specified poor friability Laminating hardness disintegration & dissolution Manufacturing Concerns

Less Lubricant Level More

Lubricant Effect

Picking Defect-free Okay looking Soft tablets Sticking tablets of tablets with with high Capping specified poor friability Laminating hardness disintegration & dissolution

Unacceptable Acceptable Unacceptable

Quality Concerns Manufacturing Concerns

Less Lubricant Level More

Lubricant Effect

Picking Defect-free Okay looking Soft tablets Sticking tablets of tablets with with high Capping specified poor friability Laminating hardness disintegration & dissolution

Unacceptable Acceptable Unacceptable

Quality Concerns Lubrication Level and Blending Time

Continuum Lubricant Level Lubricant

Lubricant Blending Time Lubrication Level and Blending Time

Continuum Lubricant Level Lubricant

Lubricant Blending Time Tablet Lubrication Challenge

Issues with API Issues with Lubricant • API may be high dose or low • Lubricant level is dictated dose by need • API may be poorly or freely • Lubricant may not be soluble, but must dissolve to soluble, but must not affect provide therapy API solubility • API must be blended • Lubricant usually not well thoroughly to achieve blended, is expected to have uniformity a uniform effect • API may be very sticky and • Lubricant cannot affect cohesive disintegration/dissolution Lubrication 101 Lubricants

• In general, lubrication is poorly understood • Many formulators don’t take the time to understand lubricant effects • On their process • On their product’s physical integrity • On their product’s performance • QbD and Quality Risk Management now require this level of understanding Why lubricate?

Die wall lubrication:

• Tablet production • Tablet ejection from die Why lubricate?

Die wall lubrication:

• Tablet production • Tablet ejection from die Why Lubricate?

Die wall lubrication:

• Tablet production • Tablet ejection from die Why Lubricate?

Anti-adherence:

• Sticking on punch faces • Better to use an anti-adherent Why lubricate?

Reduce interparticulate friction & cohesion:

• During compaction o Reduces heat generated during tableting Why lubricate?

Improve flowability:

• From hopper, through feed frame, and into die • Better to use a flow aid or glidant What are the basic lubricant types?

There are two basic lubricant types/mechanisms:

1. Liquid film 2. Boundary • Stearic acid • Magnesium stearate • Hydrogenated oils o Other stearic acids • Sodium stearyl fumarate What are the basic lubricant types?

Boundary Liquid Film • Lubricant particles “sheared” • Partial to full melting during during blending process compaction process o Shear increased with mass • Lubricant “squeezed” to outer • Particles “coat” other formulation tablet surface ingredients o Creates “film” interface between o Particles become “slippery” tablet edge and die wall – Tablet edge becomes • Coated particles at die wall reduce “slippery” friction between tablet edge and » Punch faces also affected die wall • Use levels: 2% - 4% • Use levels: 0.25% - 2% o Offers auxilary binding properties o Adversely affects compaction o Typically requires anti-adherent o Adversely affects disintegration o Can affect disintegration and o Adversely affects dissolution dissolution What are the critical parameters?

• Blender size and geometry • Particle morphology • Formulation components Mass Shear • Surface area • Blending Time

• Tablet shape Die wall contact • Tablet size area Hydrophobicity/ • Dissolution targets hydrophilicity How is it best to determine the optimal level?

• Ejection force measurements o Literature suggests 100-300 N – Varies with respect to several parameters » Applied forces » Die wall contact area » Radial die wall pressure » Formulation composition • Tablet hardness / friability • Disintegration / Dissolution results When should lubrication occur?

It is generally left up to the formulator. When should lubrication occur?

• Lubricant added to blend • Usually final blending step

Internal Internal • Short blending times Lubrication

• Powder applied to die wall mechanically by press

• Several press manufacturers offer die External External

Lubrication lubrication systems Choosing a Lubricant Lubricants Used Today

Hydrophobic Lubricants Magnesium stearate 0.25% - 2.0% Calcium stearate 0.25% - 2.0% Insoluble Stearic acid 1% - 4% Hydrogenated Oils 1% - 4% Hydrophilic Lubricants Glyceryl behenate 2% - 5% Partially soluble Sodium stearyl fumarate 0.25% - 2.0% PEG 4000/6000 2% - 5% Sodium lauryl fumarate 2% - 4% Soluble Isoleucine 2% - 5% Sodium benzoate 1% - 4% Inorganic Materials 0.05% - 0.25% Glidant Fumed silica 0.25% - 2.0% Anti-adherent Talc 1% - 4% Anti-adherent Lubricants Used Today

Hydrophobic Lubricants Magnesium stearate 0.25% - 2.0% Calcium stearate 0.25% - 2.0% Insoluble Stearic acid 1% - 4% Hydrogenated Oils 1% - 4% Hydrophilic Lubricants Glyceryl behenate 2% - 5% Partially soluble Sodium stearyl fumarate 0.25% - 2.0% PEG 4000/6000 2% - 5% Sodium lauryl fumarate 2% - 4% Soluble Isoleucine 2% - 5% Sodium benzoate 1% - 4% Inorganic Materials 0.05% - 0.25% Glidant Fumed silica 0.25% - 2.0% Anti-adherent Talc 1% - 4% Anti-adherent Magnesium Stearate

The most widely used tablet (and capsule) lubricant

Advantages Disadvantages • Effectiveness (typical usage 0.5- • Reactivity with some APIs 1%) • Hydrophobicity • Good combination of the main • Effects of disintegration and lubricant actions dissolution • Forms film in effervescents • Effects on tablet tensile strength • Variability of key parameters both between manufacturers and from the same manufacturer • BSE/TSE risk Magnesium Stearate Sodium Stearyl Fumarate

• Also a boundary lubricant • Typical usage levels 0.5 – 1% • Good combination of the main lubricant actions • Somewhat hydrophilic as compared to magnesium stearate • Does not affect dissolution on over-blending • Does not reduce tablet strength to the same extent as magnesium stearate • Closest to magnesium stearate of all the alternative lubricants in terms of lubricating performance • Vegetable source – no BSE/TSE risk Physical Appearance

Magnesium Stearate Sodium Stearyl Fumarate

Sodium stearyl fumarate is closest to magnesium stearate out of all lubricants in appearance and lubricating functionality. Sodium Stearyl Fumarate Advantage

• Easier scale-up (“no scale-up surprise”) • Much lower impact on tablet strength vs. magnesium stearate • No incompatibility with APIs, unlike magnesium stearate • No metallic taste • Prevent or reduce film forming in effervescent applications Tablet Hardness as a Function of Lubrication Level & Blend TimeTablet Lubricated Hardness as a Function with Sodiumof Lubrication Stearyl Level andFumarate Blend Time Lubricated with PRUV Compaction force = 12 kN

12 11.5-12 11-11.5 11.5 10.5-11 11 10-10.5 9.5-10 10.5 9-9.5 10 8.5-9 9.5 8-8.5 9

Tablet hardness [kp] 8.5 8 0.25% 50 0.50% 25 Level 10 5 1.00% [%] Blend time [min] 2

Schindler, Zeleznik, & Renak – 2005 Tablet Hardness as a Function of Lubrication Level & Blend TabletTime Hardness Lubricated as a Function with of LubricationMagnesium Level and Stearate Blend Time Lubricated with Magnesium Stearate Compaction force = 12 kN

12 11.5-12 11-11.5 11.5 10.5-11 11 10-10.5 9.5-10 10.5 9-9.5 10 8.5-9 9.5 8-8.5 9

Tablet hardness [kp] 8.5 8 0.25% 50 0.50% 25 Level 10 5 1.00% [%] Blend time [min] 2

Schindler, Zeleznik, & Renak – 2005 Tablet Hardness as a Function of Blend Time and Lubricant Level

TabletSodium Hardness as Stearyla Function of FumarateLubrication Level and Blend Time Tablet HardnessMagnesium as a Function ofStearate Lubrication Level and Blend Time Lubricated with PRUV Lubricated with Magnesium Stearate Compaction force = 12 kN Compaction force = 12 kN 12 11.5-12 12 11.5-12 11-11.5 11-11.5 11.5 11.5 10.5-11 10.5-11 10-10.5 11 10-10.5 11 9.5-10 9.5-10 10.5 10.5 9-9.5 9-9.5 10 10 8.5-9 8.5-9 8-8.5 9.5 8-8.5 9.5

9 9 Tablet hardness [kp]

Tablet hardness [kp] 8.5 8.5 8 0.25% 8 0.25% 50 50 0.50% 0.50% 25 Level 25 Level 10 10 [%] 5 1.00% [%] 5 1.00% Blend time [min] 2 Blend time [min] 2

Schindler, Zeleznik, & Renak – 2005 2% Lubricant Level, Mixing Time Effect on Felodipine Dissolution Rate

120 100 80 60 40

% Dissolved % 20 0 0 20 40 60 80

Time2M SSF(Min.) 20M SSF 2% Lubricant Level, Mixing Time Effect on Felodipine Dissolution Rate

120 100 80 60 40

% Dissolved % 20 0 0 20 40 60 80 2M SSF Time20M SSF (Min.) 2M MgSt 20M MgSt Summary Summary

• Reduce adverse lubricant effects o Use less (particularly boundary lubricants) – A little lubricant goes a long way o Blend longer – Use the little that is added to its maximum potential • Conduct lubricant level / blending time studies at scale o Scale up related shear effects - beware Thank you for your attention!

Tony Carpanzano, B.S., R. Ph. Director, R&D JRS Pharma, LP Patterson, NY