1
Rheology in the
Pharmaceutical Industry
Kevin Barber
Thermo Fisher Scientific
UK Summer Symposium 2011
London - QEIICC - Tuesday 7th June
3
Contents
• Introduction
• Faster to the market
• Improve process stability and reliability
• Optimise pharmaceutical coatings
• Overview rheological tests
Introduction
5
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
6
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
7
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
9
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
10
Prediction of mechanical stability
• Indicators
• Amplitude sweep (LVR)
• Low shear stresses (e.g. Yield Stress)
• Low shear rates (CR)
11
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
12
Product development – Tooth gel instead of paste?
• Flow curves
at 23°C
• Amplitude
sweeps
at 23°C
G'
tan d
Gel
Paste
Paste
Gel
13
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
15
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
16
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
17
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)
18
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
19
Shear and extensional deformation
Coating roll
Material to which coating is applied
Coating material
20
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
21
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
23
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
24
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
25
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
26
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 :
27
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)
28
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
30
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)
31
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
32
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
33
Thank you for your attention
Any questions ?