PRINCIPLES OF TABLET COMPRESSION -...

Petr ZámostnýUniversity of Chemistry and Technology Prague, Faculty of Chemical Technology, Department of Organic TechnologyLaboratory of Drug Manufacturing Processes

Workshop On Tablet Compression, 25.-26.1.2017, Department of Organic Technology, Faculty of Chemical Technology, UCT Prague 2/36

→Introduction

→Tablet compression basics

→Methods and tools to investigate compression process


FillingPre-compression

&compression

Ejection

Compression die

Upper punch

Lower punch


→Physico-technical properties of drugs and excipients (deformation behavior)

→moisture content,

→particle size and distribution,

→polymorphism, amorphism, and crystal habit,

→hydration state

→lubricant and binder level of the blend

→Choice of instrument settings - rate and magnitude of force transfer

→tableting speed

→pre/main compression force profile


→ Compressibility = ability to reduce volume

→ Compactibility = ability to form interparticular bonds

→ Requirements for direct compression of powder blend

→ high flowability

→ low segregation

→ high compactibility

→ Properties can be improved by pretreatment

→ granulation techniques

→ extrusion

→ spheronisation

→ co-processing

Mahmoodi F.: Compression properties of powders …, Uppsala 2012


→ Die filling

→ powder flow and/or possible segregation

→ Compressing and volume reduction

→ particle rearangement

→ particle deformation

→ particle fragmentation

→ bonding

→ tablet deformation

→ Decompression

→ axial deformation recovery

→ tablet transformation

→ Ejection

→ radial deformation recovery

courtesy of Jeff Dahl: https://commons.wikimedia.org/wiki/File:Tablet_press_animation.gif


→ The die must be filled without any cavities

→ The filling surface must be smooth

→ The material should not reduce volume due to vibrations

→ Good flow properties are key to eliminate those problems

→ Common methods

→ Angle of repose

→ Hausner ratio

→ They can be used to evaluate overall mixture performance

→ Advanced methods like POWDER RHEOMETRY can provide detailed info about

→ the properties of the components of the mixture

→ compare the effects of adhesion/cohesion

→ determine the flow properties at state most relevant to situation of die filling

→ examine the effects of previous blend treatment

→ examine flow patterns

YES NO

NO

NO


→ A formulation for direct tablet compression

→ API (5 %)

→ Microcrystalline cellulose (Avicel PH 101)

→ Milled lactose monohydrate (200 mesh)

→ Spray-dried lactose (FLOWLAC 100)

→ Sodium starch glycolate

→ Mg stearate

→ Aerosil

Process validation experience

Tablet uniformity is affected by the delay between mixing and tablet compression

Suspected causes

→ Mixture homogeneity is sensitive to flow conditions

→ Flow patterns change with mixture ageing

Objectives

→ Investigate causes

→ Develop evaluation methods

→ Suggest formulation improvement

API

MCC

SD LAC

200M LAC


BLEN

DIN

G D

RU

M

TABLETPRESS

Mass flow or funnel flow?

→ Mass flow behavior→ particles travel along parallel

trajectories

→ at similar velocities

→ less inter-particle shear

→ does not promote segregation

→ Funnel flow→ different particle trajectories and

velocities in different regions

→ significant inter-particle shear

→ promotes segregation


→ Conslusions→ Blend exhibits mass flow at normal conditions, but can switch to funnel flow if

aged

→ Prolonged delays between the mixing and tablet compression steps must be avoided

Nomograms adopted from Schulze, D. Powders and Bulk Solids: Behavior, Characterization, Storage and Flow; Springer, 2007

Mass flow Mass flow

Funnel flowFunnel flow

Fresh blend, φe = 30° Aged blend, φe = 40°


POWDER

REARRANGEMENT

DEFORMATION BONDINGFRAGMENTATION

PLASTICELASTIC


→Particles rearrange at low pressures

→small particle enter the voids among the coarse ones

→Factors affecting rearrangement

→particle size distribution

→shape

→particle friction

→Effects

→more contacts between particles

→the rearrangement produces a primary porous structure of the tablet

Easy rearrangement= dense packing= better bonding= narrow uniform pores= slower water intake

Difficult rearrangement= loose packing= worse bonding= broad pore distribution= faster water intake


→Elastic

→reversible

→E … (elastic) Young’s module

→Brittle fracture

→irreversible

→σF … fracture strength

→Plastic (ductile)

→irreversible

→σY … yield strength

Stress

Strain

ELASTIC

BRITTLE

PLASTIC

σF

σY

E


→Kelvin-Voigt’s model

→elastic component (spring) – Hooke’s body

→instantneous elastic deformation

→reversible

→plastic component („damper“)

→rate is proportional to stress

→irreversible

𝜎 = 𝐸𝜀

σ … stressε … strainE… elasticity modulusη … viscosity coefficient

𝜎 = 𝜂𝑑𝜀

𝑑𝑡

𝜎 = 𝐹𝜀 + 𝜂𝑑𝜀

𝑑𝑡


→Elastic deformation

→instantaneous

→strain is proportional to immediate stress

→Plastic deformation

→proceeds at rate proportional to immediate stress

→Brittle Fracture

→occurs if the stress exceeds the fracture strength

→Too fast compression may

→break the particles

→provide less plastic deformation

SLOWERCOMPRESSION

FASTERCOMPRESSION


→Mechanic interlocking of particles→result of particle shape and plasticity

→Attraction between solid particles (e.g. van der Waals forces)→result of increased contact

→Solid bridges →result of melting, crystallization, sintering,

chemical reaction

→Liquid film→result of capillary forces and surface tension

→Immobile liquid film→result of adsorbed liquids

+ -

+ -+ -

+ -

Pressure, friction


→ Free surface energy of solids – MEASURABLE & USABLE→ atoms or ions located at a surface have a different distribution of bonding forces than those

present within a particle

→ unsatisfied attractive molecular forces extend out to some small distance beyond the solid surface

→ Cohesion→ particulate attractive forces between like particles

→ Adhesion→ particulate attractive forces between un-like particles

→ The attractive forces resist the differential movement of constituent particles when subjected to an external force.

→ Other types of interaction depend on material state and processing→ electrostatic forces

→ adsorbed moisture

→ residual solvent


→ Contact area affects the number of interparticle interactions

→ Plastic deformation and brittle fracture may increase the contact area

→ Different materials may have bonds of different strength

→ Microstructure is essential for overall strength

→ Percolation threshold

→ small amount of component has crucial effect on strength

→ Positive: binder in granules

→ Negative: lubricant mixed for too long


Substance Radial strength (MPa)

MCC 4.00 ± 0.05

Pregelatinized starch 0.92 ± 0.06

Anhydrous lactose 0.76 ± 0.06

Sodium stearylfumarate 0.77 ± 0.01

Magnesium stearate 0.64 ± 0.01

Paracetamol 0.12 ± 0.01

MCC, anhydrous lactose, 0.5% lubricant: ∙∙∙∙∙∙ magnesium stearate, ――― sodium stearylfumarate

a)

b)

homogenization time, min


→ Pressure developed by upper punch FU, lowerpunch force FL is different

→ axial profile of strength

→ k … material constant

→ Force balance

→ FD … friction force

→ Mean compression force provides betterinformation than FU

D

Hk

UL eFF

UDL FFF

2

ULA

FFF


→ Radial force

→ λ … lateral stress ratio

→ Friction on die wall

→ Lubrication ratio R (R = 1 for zero friction)

→Important implications

→Wall friction affects

− top/bottom pressure difference

− degree of elastic recovery

− residual radial stress

→Lubrication affects wall friction

→ Many of the parameters can be measured by shear tests

UR FF

WRD tgFF

U

L

F

FR


→Releasing pressure by upper punch

→elastic recovery of the axial stress

→some residual radial stress persists

→Elastic particle relaxation

→FAST – accommodated by brittle fracture of surrounding material

→SLOW – accommodated by plastic deformation of surrounding material

→Cavity closure by residual radial stress

→may depend of lubrication

→may form secondary pore structure

Elastic particle (compressed)

Elastic particle (relaxed)

plastic particle(compacted)

Deco

mp

ression

FAST DECOMPRESSION SLOW DECOMPRESSION

Deco

mp

ression

elastic recovery andcavity formation

radial stress mayclose cavities


0,03

0,08

0,13

0,18

0 0,2 0,4 0,6 0,8 1

φ

ε

Elastic component content


→Tablet expands only axially duringdecompression

→There is still radial stress in the tablet whilecontained in the die

→Radial expansion after leaving die (2 – 10 %)

→Tablet may fracture

→lamination

→capping

σR = 0

σR > 0


→Capping

→Deep concave punches may expand radially, while the cylindrical part cannot

→Lamination

→Elastic expansion of some particles

→Expansion of entrained air

→Sticking

→Too much adhesion on the punch− intrinsic

− due to punch wear

σR = 0

σR > 0

Capping

Lamination

Sticking


→Laboratory and process-scale tablet presses

→Compaction analysers→basic mechanism,

→process variables,

→scale-up parameters,

→trouble shooting problem batches,

→creating compaction data bank,

→fingerprinting of new active pharmaceutical ingredients or excipients.

→Mathematical equations to describe→work of compaction,

→elasticity/plasticity

→time dependent deformation behavior of pharmaceuticals


→ Analysis of force required per displacement duringcompression and decompression

→ Work = force * length

→ Work = area under curve→ gross work of compression includes

− work of friction

− work of plastic deformation

− work of elastic deformation

− work of friction

→ work of elastic relaxation

→ Alternative explanation (empirical/inaccurate)→ EP = plastic deformation

→ EE = elastic deformation

→ EF = rearangement /friction

FORCE

DISPLACEMENT


→Joint effect of the machine speed andthe rate of plastic deformation

→More difficult to measure, but may be simulated by advanced compaction analyzer

→Compression→increasing displacement

→Dwell time→constant displacement (flat part of the

punch head under the roll)

→Relaxation→decreasing displacement

Schmidt PC, Leitritz M.: Eur J Pharm Biopharm. 1997;44:303–13.


→Various areas may be correlated to powder properties

→For example A6/A5 is a measure of plasticity

→decreasing force over time for plastic

→plateau for brittle

→Somewhat difficult to measure correctly

Schmidt PC, Leitritz M.: Eur J Pharm Biopharm. 1997;44:303–13.


→A measure of state of consolidation as a function of compaction pressure

→Kawakita

→Heckel

→Walker

→Cooper-Eaton

→Three-exponential

→All of the equations are semi-empirical and may provide compaction indices for the materials

→Example: Heckel equation


→Void fraction ε

→VB … bulk volume

→Vsolid … solid volume

→Can be expressed by relative density D

→Related to compressibility

DV

V

V

VV

solid

B

B

solid

B

solidB

11

B

solidB

V

VV


→ Heckel plot transforms the force-displacement data to linear relationship for plastic material

→ Matches the real systems in region II only

→ Heckel equation

→ possible for estimating yield pressure

Akp

1ln yp

k

1


→Tablet compression is a very complex process involving several phases

→Each phase is capable of making the whole process go wrong

→Further presentations will address the different aspects of compression

→What can be used to improve your tablets

→Experience

→Case studies

→Knowing what can be measured and how

→Understanding the compaction physics


→Thanks to all my students and my department colleagues for support

→… for supplying the results presented here namely to

→Jan Patera

→Martin Veselý

→Barbora Kreibichová

→Daniela Hofmanová

→Kateřina Langrová

→Hana Kletečková

→Petra Paličková

→Thanks to those bodies for helpingto equip the laboratory

PRINCIPLES OF TABLET COMPRESSION -...

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