Melt processing of pharmaceutical compounds: future developments & learnings

from the plastics industry Adrian Kelly

Centre for Pharmaceutical Engineering Science, University of Bradford

APS Amorphous by Design 2014,University of Bradford,

Tuesday 29th April 2014

Scope

• Introduction

• Polymer developments

• HME and downstream technologies

• Single screw extrusion

• PAT

• Extrusion of non-polymerics

• Injection moulding & micromoulding

• Molecular orientation to control drug release

• Screw-free melt processing

Centre for Pharmaceutical Engineering Science

• Interdisciplinary research centre

• Combines pharmaceutical science, polymer science and

process engineering

• Research themes:

– Pharmaceutical solid dispersions

– Processing & characterisation

– Cocrystallisation, polymorphic transformation

Hot melt extrusion ISO8 clean room

Pharmaceutical extruders

Thermo Fisher Pharmalab

16mm screw diameter, 15-40:1 L:D

(50g – 10kg)

Haake Minilab

Recirculating twin screw extruder

(5g - 250g)

Materials for healthcare grant

• EPSRC Capital for Great Technologies:

Advanced Materials for Healthcare EP/L027011/1

• Recent grant award (led by Prof Phil Coates

• £3.42M from EPSRC + £2M UoB support

• Equipment, PDRA and technician posts

• Includes processing and characterisation:

– AFM + integral confocal light microscopy + nanoindentation

– TEM, Micro CT scanner, SAXS-WAXS

– Raman mapping, FTIR, GPC, APC, DSC, TGA

– Hot melt extrusion, micromoulding, biaxial stretching, die drawing, 3D

printing, ultrasonic injection moulding

Pharmaceutical extrusion (hot melt extrusion)

• Twin screw extrusion mixing of API, polymer & excipients

– Surgical grade stainless steel

– Tight temperature control

– Complex feed (multi solid & liquid)

– Downstream cooling (no water)

• Becoming an accepted process (Norvir, Kaletra, Fenoglide etc.)

Courtesy: Particle Sciences Inc. USA

Developments in polymers

• Must be FDA approved

• Generally water soluble

• Low processing temperature

• Plasticisers may be required

• Generally not formulated for melt processing

Developments?

• New polymers / copolymers formulated for melt processing,

e.g. BASF Soluplus®, Dow Affinisol®

• Shin Etsu ‘cleaning compound’

• Pre-blended mixture (dry-blend) to simplify processing and minimise

segregation & feed problems

HME – downstream processing

• Current options: – Pelletisation

– Sheet extrusion and flaking

– Additional size reduction

steps required

• Downstream alternatives? – Calendering directly into tablet / caplet geometry

– Micro pelletisation or on-line spheronisation

(Young et al., 2002, Int. J. Pharm.)

– Die face pelletising (air-cooled)

Single screw extrusion

• This is an extra processing step, essentially a melt pump

• Example geometries include:

– Sheet or film (transdermal / transmucosal patches)

– Hollow tube (e.g. Stents)

– Fibres (sutures)

– More complex geometries/profiles

– Surface features (micro-channels or patterns)

• Co-extrusion

– Drug release control

– 2 or more drugs

• Foamed structures

– Floating or rapid release systems

– sCO2 a possibility

Terife et al., 2012, SPE ANTEC

HME Process monitoring of (PAT)

• In-line characterisation to measure/control product properties

• Highly relevant in pharmaceutical extrusion quality control (e.g. FDA

PAT Initiative, 2005)

• In-process monitoring techniques readily applied to HME; fits in well

with QbD approach

• Process monitoring capabilities at Bradford:

– Spectroscopy (NIR, Raman, UV-vis)

– Rheology

– Ultrasound

– Temperature field

– Energy consumption

– Flow visualisation (rheo-optics)

In-process NIR

• Thermo Fisher Antaris II with high temperature probe in

the die of a Thermo Pharmalab TSE

• Wavelength: 1000-2500nm (10,000-4,000cm-1)

• 32 scans taken every 30 seconds

NIR Spectra: Glipizide and PeO physical mixtures

• 2nd derivative used to more clearly highlight differences

GPZ

PeO

PM 1:2

PM 1:4

PM 1:6

NIR Spectra: In-line effect of drug loading (110°C)

• Drug loading can be detected during extrusion

GPZ

PeO

1:6 100°C

1:4 100°C

1:2 100°C

Transflectance NIR

• Systems which may be transparent or opaque in the melt state are

difficult to measure

• A transflectance method has been developed, using a reflectance

probe and highly polished opposing surface

• Attempt to measure Carbemazepine and PEG in a PVP-VA matrix;

transparent below ~15% API content

NIR probe

Polished surface

PEG

RMSEC: 0.633 Corr. Coeff.: 0.9864

RMSEP: 1.06 Corr. Coeff.: 0.9677

6 factors used

Calibration

Validation

Correction

Cross-correction

Ignore

5 20Actual

52

0C

alc

ula

ted

20% CBZ 5% PEG

20% CBZ 15% PEG

20% CBZ 7.5% PEG

20% CBZ 20% PEG

-0.0045

-0.0040

-0.0035

-0.0030

-0.0025

-0.0020

-0.0015

-0.0010

-0.0005

0.0000

0.0005

0.0010

0.0015

0.0020

0.0025

Ab

so

rba

nc

e

4800 5000 5200 5400 5600 5800 6000

Wav enumbers ( cm-1)

NIR calibration of CBZ and PEG in PVP-VA matrix

CBZ

PEG

CBZ

RMSEC: 0.788 Corr. Coeff.: 0.9936

RMSEP: 0.672 Corr. Coeff.: 0.9982

4 factors used

Calibration

Validation

Correction

Cross-correction

Ignore

3 31Actual

33

1C

alc

ula

ted

5% CBZ 10% PEG

10% CBZ 10% PEG

15% CBZ 10% PEG

20% CBZ 10% PEG

-0.0045

-0.0040

-0.0035

-0.0030

-0.0025

-0.0020

-0.0015

-0.0010

-0.0005

0.0000

0.0005

0.0010

0.0015

0.0020

0.0025

Ab

so

rba

nc

e

4800 5000 5200 5400 5600 5800 6000 6200

Wav enumbers ( cm-1)

5064 cm-1

NIR tracking a step change in API and plasticiser

Time

Load

ing

(wt

%)

22.5% CBZ >> 17.5% CBZ; 7.5% PEG >> 12.5% PEG

In-process rheometry using instrumented slit die

• Plasticising effect of API on shear viscosity

• Low cost, simple PAT tool

100

1000

10000

10 100

Wall Shear Rate (s-1)

Sh

ea

r V

isco

sity (

Pa

.s)

20% API

30% API

40% API

(API = Bristol Myers Squibb development drug)

Ultrasonic monitoring of HME

0.00E+00

8.00E+03

1.60E+04

2.40E+04

3.90E+11

3.91E+11

3.92E+11

3.93E+11

Peak h

eight (V

)

Tran

sit

tim

e (µ

s)

Transit time (µs)Peak height

10% MPT 20% MPT 30% MPT 40% MPT

Metoprolol tartrate (MPT) in Eudragit®

transmit receive

Raw voltage-time data

Non-polymeric HME applications

• Twin screw extrusion can be used as a continuous

method of providing shear and heat to materials

• Not necessarily melting the components

• Same advantages of HME – continuous, scalable

• Examples include:

– Granulation (wet, melt)

– Cocrystallisation

– Polymorphic transformation

Cocrystallisation by twin screw extrusion

Agglomerated co-crystals

Patent Application WO 2010/013035

Dhumal et al., 2010, Pharm. Res., 27, 2725

Co-former

Drug Co-crystal

SEM images of

agglomerated cocrystals

Polymorphic transformation by TSE (Chaitrali Kulkarni)

Patent application:

PCT/GB/1208489.3

Pure Drug A

Drug A’

Artemisinin

Piracetam

Chlorpropamide

Carbamazepine

Orthorhombic form Triclinic form

e.g. Artemisinin – stable triclinic form produced

140°C

0

20

40

60

80

100

0 5 10 15 20

Dru

g re

leas

e (

%)

Time in hours

Orthorhombic form Triclinic form

Injection moulding – a batch process

1. Injection - Screw acts as piston, rapidly forcing

melt into the mould cavity

2. Packing – Screw applies a fixed pressure as the

moulded polymer cools

3. Plasticisation + cooling – Screw rotates and moves backwards

to prepare next melt shot

4. Part ejection – Clamps move apart and part is ejected

or taken by robot

Injection moulding of pharmaceuticals

• Two cavity injection mould tool for Fanuc Roboshot

5 tonne injection moulding machine

• Feasibility of injection moulding solid dispersions / challenges

• Effect of processing conditions on structure and release rate

Injection moulding of HPMCAS based systems (Shivprasad Deshmukh)

Mechanical properties

DMA

Tensile properties

Spectroscopic

characterisation

Raman, FTIR, FT-NIR Surface properties

Contact angle

AFM

Thermal characterisation

TGA, DSC, MDSC

Biopharmaceutical

Evaluation

Drug release kinetics and

mechanism

HPMCAS and Ibuprofen

• Gradual change in surface appearance

• Ibuprofen crystal growth

40oC 75% RH

40oC 60% RH

25oC 60% RH

Post extrusion

0

10

20

30

40

50

60

70

0 10 20 30

Extruded system

40C 75 %RH

40C 60%RH

25C 60%RH

0

10

20

30

40

50

60

70

0 10 20 30

% C

ryst

allis

atio

n

Time (Days)

Injection moulded system

40C 75% B-07

25C 60% B-07

40C 60% B-07

Crystallisation of 33% Ibu, measured by MDSC

HPMCAS and Ibuprofen

• Size and amount of crystals are monitored

-0.6

-0.4

-0.2

0.0

0.2

He

at

Flo

w (

W/g

)

-20 0 20 40 60 80 100 120 140 160

Temperature (°C)

B-02 I 33 Bar 0 day––––––– B-02 I 33 Bar 1 day––––––– B-02 I 33 Bar 2 day––––––– B-02 I 33 Bar 3 day––––––– B-02 I 33 Bar 7 day––––––– B-02 I 33 Bar 21 day––––––– B-02 I 33 Bar 28 day–––––––

Exo Up Universal V4.5A TA Instruments

ambient 40°C, 75% RH

DSC NIR

Micromoulding – small scale injection moulding

Applications in healthcare, electronics, optics

Micromoulding medical examples

Moulded DRFP ProPoint core

(radio-opaque, rigid)

Moulded microneedles

Orientation & crystallinity to control drug release

•Capillary effect?

•Different permeation?

•Different function groups

available for drug – polymer

interaction?

• Can the morphology of the polymer matrix be tailored to

control drug release?

• Different crystal morphologies have different packing of

amorphous and crystalline regions of the polymer chains • Crystal density and size may vary

• Drug - polymer interaction

• Barrier properties/ water penetration

amorphous semi-crystalline semi-crystalline

+ oriented

• PeO (Mw 2x105) Injection moulded blends with different

additions of high Mw (2x106) PeO

PeO modified with small percentage of high Mw (Rohan Ambardekar)

0

20

40

60

80

100

120

0 50 100 150 200

Pe

rce

nta

ge c

um

ula

tive

re

leas

e

Time (minutes)

Injection moulded system at 1 bar

Blank

0.25%

0.50%

1.25%

• Retardation of drug release with small

amounts of higher molecular weight

component

• Negligible change in % crystallinity

• Release may be linked to orientation

and/or crystal size

Below C*

Near C*

Above C*

Cooling

Biaxial stretching of drug loaded films

Draw ratio 1 2 3 4

Orientation factor

0.006328 0.012091 0.034217 0.044984

WAXS view

0

100

200

300

400

500

600

700

1 7 14 21 28

Dru

g re

leas

ed

(µ

g/m

l)

Days

Day 1 burst release + individual release every week

Draw ratio 1

Draw ratio 2

Draw ratio 3

Draw ratio 4

0

100

200

300

400

500

600

700

800

900

0 10 20 30

Cu

mu

lati

vel D

rug

rele

ased

(µ

g/m

l)

Days

Cumulative drug release

Draw ratio 2

Draw ratio 1

Draw ratio 3

Draw ratio 4

Screw-less melt processing technologies

• Screw processing causes high shear and residence

times

• Alternative techniques include:

– Ultrasonic injection moulding (Ultrasion)

– Kinetisol process

(high friction & shear)

– High shear pan milling (UoB & Sichuan SKLPME, China)

Summary comments

• New pharmaceutical polymers can be expected

• Process analytics will become more widely used

• Moulding techniques and extruded products are likely to

generate more interest

• Morphology of the polymer matrix could be used to

control drug release

• Screw-free (low residence time) processing alternatives

are being explored

Acknowledgements

PhD Students:

Hrushikesh Karandikar, Shivprasad Deshmukh

Rohan Ambardekar, Prafulla Apshingekar, Sachin Korde,

Clive Wood, Abdolati Alwati

Colleagues:

Tim Gough, Elaine Brown, Ben Whiteside,

Anant Paradkar, Chaitrali Kulkarni, Suyog Aher

Fin Caton-Rose, Phil Coates

Industrial collaborators:

Shilpa Mistry (Shin Etsu)

Sheelagh Halsey, Rod Bottom (Thermo Fisher)

John Jones (BMS)