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Rheology in the

Pharmaceutical Industry

Kevin Barber

Thermo Fisher Scientific

UK Summer Symposium 2011

London - QEIICC - Tuesday 7th June

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Contents

• Introduction

• Faster to the market

• Improve process stability and reliability

• Optimise pharmaceutical coatings

• Overview rheological tests

Introduction

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Thermo Fisher Scientific Contribution Areas

Process Development & Manufacturing

Development

Stability Studies

ClinicalTrials

Assay Development Target Validation Packaging & Filling

QC & QA

Scale-up manufacturingchemical

Scale-up manufacturing drugs

Chromatography Products

Bioproduction

Cleanroom supplies

Analytical product testing & validation: HPLC, GC, Mass Spec, Rheology

Custom peptides

Biological Assay Systems

Drug Metabolism

Diagnostic Kits& Clinical Trial Supplies

Clinical trials support

Custom chemical synthesis

Extrusion- HME /continuous granulation

Rheology & Viscometry

Protein, DNA, siRNA & cell culture

DNA Sequencing

High purity solvents for DNA synthesis & sequencing

Organic chemicals & organic-synthesis products

Automated instrumentation

Liquid Handling

General Lab Supplies: pipettes, tips, vials, cold storage, centrifuges, incubators, biosafety cabinets, microplates, etc.

Combinatorial library services

Scale up toProduction

Instrument & Equipment Svcs

Asset Management Services

Lab Design & Start-up Services

Outsourcing Solutions Integrated Procurement Services

Chemical Services

Research

THERMO FISHER SCIENTIFIC PRODUCTS AND SERVICES

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Material Characterisation Scientific Capabilities

Viscometers

Rheometers

Lab Instruments Business Field Hand-held viscometer to absolute

Viscometer

Modular Rheometer line tailor-made to

application

RheoScope

Rheonaut

Micro compounders

Torque rheometers, extruders,

post-equipment

On-line viscometers

Micro compounding (5 g material only)

Modular torque rheometer for mixing

and extrusion with a comprehensive

post-ex accessory portfolio

On-line viscometer for large extrusion

lines

Process Instruments Business Field

Pharma Business Field

Customised extrusion lines for hot melt

extrusion / continuous granulation

Lab and production equipment

PAT solutions

Material characterisation

Micro compounders

Pharma extrusion and continuous

granulation solution

Material characterisation

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Comprehensive Solutions for Material Characterisation & Processing

Process Development & Manufacturing

Development

Process Optimization

QC & QAScale up toProduction

Formulation/ Development

Small Scale Micro Compounding

Hot melt extrusion solution

Continuous Granulation solution

Solid dosage forms Tablet coating development Mouth feeling Dosage form optimisation Development & optimisation of

packaging

Scale Up / Scale out production Hot melt extrusion solution Continuous granulation solution

Quality Control

QC for incoming materials

Routine QC measurement of end-products

Selected sample testing for shelf life testing

FormulationDevelopment

Top Coats/Liquids/etc.

Stability testing

Skin feeling

Dosage form optimisation

Development & optimisation of packaging

Process optimisation

Faster to the market

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Contents

Rheology as a tool to;

• Shorten the time for formulation development

• Optimise processing at its various stages

• Enhance the performance/quality of products

• Predict mechanical and thermal product stability (cyclic testing)

• Development of innovative products

• Gel instead of ointment

• Tooth gel instead of tooth paste

• Shaving gel instead of shaving foam

• Pressure sensitive adhesive

• Bioadhesive gel (sol/gel transition)

• Hot Melt Extrusion

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Prediction of mechanical stability

• Indicators

• Amplitude sweep (LVR)

• Low shear stresses (e.g. Yield Stress)

• Low shear rates (CR)

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Prediction of thermal stability (cyclic testing)

Source: Brummer et al; Beiersdorf

Issues

• Subjecting all developed formulations to

3 months stability testing at elevated

temperature

- Is time consuming

- Is Lab space and energy consuming

- Slows down the process of formulation

development

• Requirement of short term lab test to

predict stability and sort out those

formulations likely to fail in 3 months test

• Increase efficiency of formulation

development

• Decrease development costs

Goals

• Identify most promising formulations for

further development

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Product development – Tooth gel instead of paste?

• Flow curves

at 23°C

• Amplitude

sweeps

at 23°C

G'

tan d

Gel

Paste

Paste

Gel

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Product development – Tooth gel instead of paste?

• Frequency sweeps at 23°C reveal difference

in rheological behaviour of paste and gel

Toothpaste (sensitive)

G'

G"

|h*|

Tooth-gel

G'

G"

|h*|

"Paste" (cross-over frequency) "Gel" (elastic plateau)

G' = G"

Cross-over

frequency

Elastic plateau

G' >> G"

G' = 1.5e4 Pa

G' = 3e4 Pa

Improve process stability

and reliability

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Contents

• Training and support to generate efficient measuring jobs

providing reproducible, user-independent and meaningful results

• Guidance how to calculate relevant processing shear rates and frequencies

and to quantify and objectify processing steps by rheological measurements

(e.g. stirring, pumping, filling, flow in a pipeline, application)

• Services which contribute to process stability:

(e.g. loan units, service contracts or local back-up instruments/accessories)

• Assistance in setting up at-line measurements for most relevant processing

steps to secure correct composition and for trouble shooting

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Reproducible, user-independent and meaningful results

• Zero gap setting with lift element

• Eliminate sample history with pre-shear

• Sufficient equilibration time for structural and thermal equilibration

• Efficient and correct measurement

• Automated evaluation, QC and documentation

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Objectify processing steps by rheological measurements

• Pure shear deformation

(e.g. stirring, pumping, pipeline flow)

• Combination of

- shear deformation (brushing, application of ointment/gel)

- extensional deformation (inlet and outlet of die or nozzle)

(e.g. roll-coating, printing, spraying, spray-drying, filling, extrusion)

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Shear deformation - Shear rates and viscosities

• Examples for shear rates

Processing

Flow rate Inner diameter Shear rate

Pipeline 100 l/min = 1.7•10-3 m3/s 100 mm 2 1/s

Pipeline 6000 l/min = 0.1 m3/s 100 mm 100 1/s

Filling 2•10-4 m3/s 5 mm 2000 1/s

Application Velocity v Thickness y Shear rate

Painting 0.1 m/s 100 µm 1000 1/s

Painting 0.5 m/s 50 µm 10000 1/s

g =dv

dy

.

• High shear rates with thin layers

• Low shear rates with thick layers or large diameters

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Shear and extensional deformation

Coating roll

Material to which coating is applied

Coating material

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How services can improve process stability

• Installation (IQ/OQ, Part 11 Tool, documentation)

• Training

• Warranty Extension

• Maintenance and calibration

• Loan instrument for down time

• Back-up instrument/accessory (on-site) if production is dependant on

rheological measurement

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At-line measurements

• Identification of most relevant/critical processing steps

• Secure correct composition using efficient measuring jobs with

automated evaluation, QC and documentation

• Rheological result for trouble shooting and parameter adjustment

with processing machinery

Optimise pharmaceutical coatings

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Contents

• Issues and Goals

• Rotational measurements at different shear rates for determination of

flow behaviour and solid matter content-dependent viscosity

• Extensional measurements to study the influence of polymer and

pigment

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Optimisation of film coating process of tablets

• Issues

• Water soluble polymers: Long preparation time for instant release film coatings (powder in water) preparation quality affects surface quality of the coated cores

• Polymers insoluble in water: Emulsified in aqueous carrier, delivered as dispersion, susceptible to elevated temperatures and/or high shear rates, mainly for functional coatings (e.g. gastric resistant)

• Risk to spoil tables: Logo bridging, orange peel, spray drying

• Process time and manufacturing costs are directly linked to solid matter content of dispersion

• Goals

• High solid matter content

• Short preparation and processing time

• Selection of most economical formulation

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Flow properties of film coating dispersions

• Rotational measurements at different shear rates• Flow behaviour

• Newtonian: less critical

• Shear thinning: critical for re-start after stop of processing

• Solid matter content -dependent viscosity needs to be lower than maximum processable viscosity of the regarding coater (typically 40 - 100 mPas)

HPMC 6 mPas: Newtonian LustreClear: Shear thinning

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HAAKE CaBER (Capillary Break-up Extensional Rheometer)

The only commercially available extensional

rheometer for fluids

Determination of extensional behaviour

of fluids in R&D, production optimisation

and quality control

The thinning and breakup of a fluid filament

analysed with the HAAKE CaBER provides

valuable information about the material’s

extensional properties that rotational

rheometers cannot provide

• Cosmetic Emulsions,Pharmaceutical Solutions

• Filling processes• Strand formation/stringiness• Time to breakup• Processability• Spraying/Spray drying

Typical Applications :

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Extensional properties of film coating dispersions

• Optimal atomisation: within a certain range of extensional properties

depending on spraying nozzle type and spraying parameters

• Filament life time should be short and depends on the polymer type

(all samples shown here were adjusted to 50 mPas in shear)

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Extensional properties of film coating dispersions

• Polymer concentration has a strong impact on the filament life time

1.0E-02

1.0E-01

1.0E+00

1.0E+01

0.0E+00 4.0E-02 8.0E-02 1.2E-01 1.6E-01

Log. filament life-time [s]

Lo

g.

no

rmali

sed

fil

am

en

t d

iam

ete

r [-

] 5% HPMC 3mPas 5% HPMC 6mPas

10% HPMC 3mPas 10% HPMC 6mPas

15% HPMC 3mPas 15% HPMC 6mPas

20% HPMC 3mPas 20% HPMC 6mPas

• Best coating processes are achievable with a low viscous polymer solution

allowing for high solid matter contents and still yielding short filament life-

times.

• Pigments have a further impact on filament life time – at high concentrations

event the pigment type

Overview rheological tests

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Meaningful rheological tests – shear and/or extensional

• Shear testing modes

Controlled Rate (CR), Controlled Stress (CS), Controlled Deformation (CD)

• Oscillatory testing (CD, CS)

• Time sweep e.g. gelation (time), coalescence, UV-curing, cross-linking, degradation

• Amplitude sweep e.g. stability, Linear Viscoelastic Range (LVR), suitable amplitude

• Frequency sweep under which conditions is the sample liquid, paste-like, elastic or glassy

• Temperature sweep e.g. coagulation, curing, cross-linking, degradation, melting, glass trans.

• Cyclic testing temperature stability and shear stability

• Creep & recovery testing (CS)

• Rotational testing

• Flow Curve (CR) Newtonian and Non-Newtonian flow behavior

• Yield stress (CS, CD, CR) Recommended: CS-Ramp linear in time with log data distribution

• Thixotropy (CS, CR) Thixotropy loop and time sweep (dis- and re-aggregation)

• Extensional testing (e.g. shampoo filling)

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Overview Viscometers & Rheometers configurations

Area Instr. Configur. Measurements Application

QC

Production

Falling

Ball

Circulator Acc. to DIN 12058, one point measurement, high

accuracy for low viscose (water like) material

Test of Liquid Newtonian raw materials

QC

Production

VT

1/2 plus

Battery powered hand-held instrument,

transportable, easy to use, one point

measurement, no reading errors thanks to a

digital display

Test of raw material and end products,

e.g. cream, lotions

QC / R&D VT C/D/E CFR part 11 SW

Low viscosity and

small sample adapter

Acc. ISO 2555, by using adapters absolute

viscosity values and temperature controlled

using a circulator

from water-like products up to higher

viscous material: fragrances, emulsion,

suspensions

QC / R&D VT 550 Cylinder MV / SV ‘‘Standard‘‘ rotational testing methods, absolute

viscosity values, flow curves, thixotropy, yield

point determination,

modularity, with software or internal procedures

Standard measurements in R&D

(Development Shampoos, lotions) and

production control

QC

Production

RV1 TCP/P

TCL/Z with DG41

Absolute viscosity measurements, flow curves,

thixotropy tests, temperature depending effects

Pastes, ointments

Optimization of film coating process

QC / R&D CaBER 1 Extensional properties of liquids

(e.g. influence of M/W, concentration)

Optimization and simulation of processes like

filling, spraying

Influence of elastic additives like anti-

misting agents for optimized application

behaviour, adhesives, biopolymers,

Shampoo, Salves

QC / R&D RS 6000

MARS

UTCP/P

Pressure Cell

UV curing

CFR part 11 SW

Temperature curves (stability tests)

Behaviour under elevated pressure & temp.

Curing kinetics, simulation/optimization of

production process

Suspensions, Emulsions

Development of temp stable products

(e.g. sun products)

Contact lenses, dental materials

Sol/Gel transition, pharma polymers

R&D MARS RheoScope Module Structure property relations Stability of foams, particle distribution

(e.g. peelings), drug solubility in HME

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Portfolio Overview – Viscometers and Rheometers

HAAKE Falling ball HAAKE VT 1 plus

and 2 plusHAAKE VT C,D, E HAAKE VT 550

HAAKE RV 1/RS 1 HAAKE RS 6000 HAAKE MARS HAAKE CaBER

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Thank you for your attention

Any questions ?