In-process rheometry as a PAT tool for hot melt extrusion.

TL;DR: Shear viscosity and exit pressure measurements were found to be sensitive to API loading and suggest that this technique could be used as a simple tool to measure material attributes in-line to build better overall process understanding for hot melt extrusion.

Abstract: Real time measurement of melt rheology has been investigated as a Process Analytical Technology (PAT) to monitor hot melt extrusion of an Active Pharmaceutical Ingredient (API) in a polymer matrix. A developmental API was melt mixed with a commercial copolymer using a heated twin screw extruder at different API loadings and set temperatures. The extruder was equipped with an instrumented rheological slit die which incorporated three pressure transducers flush mounted to the die surface. Pressure drop measurements within the die at a range of extrusion throughputs were used to calculate rheological parameters, such as shear viscosity and exit pressure, related to shear and elastic melt flow properties, respectively. Results showed that the melt exhibited shear thinning behavior whereby viscosity decreased with increasing flow rate. Increase in drug loading and set extrusion temperature resulted in a reduction in melt viscosity. Shear viscosity and exit pressure measurements were found to be sensitive to API loading. These findings suggest that this technique could be used as a simple tool to measure material attributes in-line, to build better overall process understanding for hot melt extrusion.

Summary

Introduction

• Hot Melt Extrusion (HME) is a continuous manufacturing process which is increasingly being used to generate amorphous solid dispersions or solutions of poorly soluble Active Pharmaceutical Ingredients (APIs) in polymer matrices 1, 2 .
• There exists a drive within the pharmaceutical industry to adopt real-time measurements for continuous processes to enhance process understanding and product quality, as part of a wider Quality by Design (QbD) approach.
• These basic process measurements give little direct indication of the consistency or rheology of the extrudate.
• Measurement of the pressure drop across this die at a range of flow rates allows calculation of rheological properties such as viscosity.
• A range of in-line rheological techniques have been reported for polymer extrusion to enhance process control or process understanding.

Thermal Analysis

• Thermo-gravimetric analysis (TGA) was carried out using a Q500 TGA (TA Instruments, UK) to determine the moisture content and the decomposition temperature of the base materials.
• All measurements were carried out in duplicate and the data were analyzed using Universal Analysis 2000 v.4.3A software (TA Instruments, UK).
• Samples of the polymer, drug, polymer:drug physical mixtures and extrudates were enclosed in an aluminum pan and sealed with a pin-holed lid allowing evaporation of moisture.
• A heat/cool/heat cycle was carried out for all the samples at rates of 10°C/min.
• The melting point was recorded at the top of the peak during the first heating stage, while the glass transition temperature (Tg) was calculated at onset, inflection and endpoint of the transition during the reheating step.

Rheological Analysis

• Off-line rheological testing was carried out using a Physica MCR 501 rotational rheometer (Anton Paar, Austria) with parallel plate geometry of diameter 25mm.
• The gap between the two plates was set to 1 mm for all tests.
• Frequency sweeps were performed at a constant strain of 3%, this value having been determined to be within the linear viscoelastic range by preceding strain amplitude tests.

Hot Melt Extrusion

• Extrusion was performed using a co-rotating twin screw pharmaceutical grade extruder (Pharmalab, Thermo Scientific, UK) with screw diameter 16mm and a screw length to diameter ratio of 40:1.
• The extruder was fitted with a rheological slit die (in-house design, University of Bradford) consisting of a temperature controlled adaptor and slit-die block.
• At each set temperature, the three pressure transducers used in the rheological die were calibrated to minimize any temperature-related signal drift.
• The powder blend or the polymer alone was fed into the extruder at each specified feed rate using a gravimetric twin-screw feeder.
• A linear fit was then applied and pressure drop along the slit length (ΔP) and predicted pressure at the exit of the die (P exit ) were calculated.

Results and Discussion

• DSC thermograms of the pure API, polymer and physical mixtures are shown in Figure 2 .
• This plasticisation can affect the melt processing behaviour of the polymer during melt extrusion, resulting in a viscosity reduction.
• For each material, a shear thinning effect was observed, in agreement with the off-line rheometry results previously shown in Figure 3 .
• Shear and complex viscosities measured during extrusion and using oscillatory rheometry are compared at 140°C for 20% w/w API in Figure 8 .
• These measurements displayed a clear discrimination between drug loadings not only in magnitude of exit pressure drop but also in the rate of increase with shear rate.

Conclusions

• An instrumented slit die rheometer designed to fit a pharmaceutical grade twin screw extruder has been developed and used to monitor hot melt extrusion of a development API within a copolymer matrix.
• Results showed that the compound displayed shear thinning behavior in the mixtures tested and that shear viscosity decreased with increase in API loading, reflecting miscibility of the API within the polymer matrix.
• Viscosity and die exit pressure were found to be heavily dependent upon.

Figures

Table 1: Set temperature (°C) profiles along the extruder barrel from die face to zones decreasing in number towards the feed throat

Figure 8 Comparison of in-line shear viscosity and off-line complex viscosity; 20% w/w API at a set temperature of 140°C

Figure 9 Effect of drug loading on exit pressure during extrusion at 160°C

Figure 4 Effect of drug loading and temperature on complex viscosity at a constant angular frequency of 50s -1 ; as measured by oscillatory parallel plate rheometry

Figure 5 Measured in-line rheometer pressure drop; 20% API, 160°C

Figure 1 Rheological extruder die

Figure 6 Effect of drug loading on measured shear viscosity during extrusion at 140°C

Figure 2 DSC thermograms showing initial heating of pure API and polymer; and second heating of physical mixtures (exotherm up, dashed lines indicate glass transition)

Table 3 – Gradient and intercept of predicted exit pressure vs. shear strain rate at 140 and 160°C, from linear fits

Figure 7 Measured viscosity during extrusion; effect of drug loading at 140°C

Figure 3 Effect of API loading on complex viscosity at 150°C; measured by parallel plate oscillatory rheometry

Table 2: Range extruder throughputs (g/hr) achieved and related process constraints

Full text

In-process rheometry as a PAT tool for hot melt extrusion
Item Type Article
Authors Kelly, Adrian L.; Gough, Timothy D.; Isreb, Mohammad; Dhumal,
Ravindra S.; Jones, J.W.; Nicholson, S.; Dennis, A.B.; Paradkar,
Anant R.
Citation Kelly AL, Gough T, Isreb M et al (2018) In-process rheometry as a
PAT tool for hot melt extrusion. Drug Development and Industrial
Pharmacy. 44(4): 670-676.
Download date 09/08/2022 21:44:59
Link to Item http://hdl.handle.net/10454/14086

The University of Bradford Institutional
Repository
http://bradscholars.brad.ac.uk
This work is made available online in accordance with publisher policies. Please refer to the
repository record for this item and our Policy Document available from the repository home
page for further information.
To see the final version of this work please visit the publisher’s website. Access to the
published online version may require a subscription.
Link to publisher’s version: https://doi.org/10.1080/03639045.2017.1408641
Citation: Kelly AL, Gough T, Isreb M et al (2018) In-process rheometry as a PAT tool for hot
melt extrusion. Drug Development and Industrial Pharmacy. 44(4): 670-676.
Copyright statement: © 2017 Taylor & Francis. This is an Author's Original Manuscript of an
article published by Taylor & Francis in Drug Development and Industrial Pharmacy in December
2017 available online at http://www.tandfonline.com/10.1080/03639045.2017.1408641

In-process Rheometry as a PAT tool for Hot Melt Extrusion
A L Kelly
1*
, T Gough
1
, M Isreb
1
, R Dhumal
1
, J W Jones
2
, S Nicholson
2
, A B Dennis
2
,
A Paradkar
1
1
Centre for Pharmaceutical Engineering Science, University of Bradford, UK, BD7 1DP
2
Bristol-Myers Squibb Research & Development, Reeds Lane, Moreton, UK, CH46 1QW
*Corresponding Author:
Dr Adrian Kelly
Centre for Pharmaceutical Engineering Science,
University of Bradford, BD7 1DP, UK
Tel: 00 44 1274 234532
Email: A.L.Kelly@Bradford.ac.uk
Keywords:
Polymer
Rheology
Process analytical technology
Twin screw extrusion
Drug
In-line
Solid dispersion

2
Abstract
Real time measurement of melt rheology has been investigated as a Process Analytical Technology
(PAT) to monitor hot melt extrusion of an Active Pharmaceutical Ingredient (API) in a polymer
matrix. A developmental API was melt mixed with a commercial copolymer using a heated twin
screw extruder at different API loadings and set temperatures. The extruder was equipped with an
instrumented rheological slit die which incorporated three pressure transducers flush mounted to the
die surface. Pressure drop measurements within the die at a range of extrusion throughputs were used
to calculate rheological parameters such as shear viscosity and exit pressure, related to shear and
elastic melt flow properties respectively. Results showed that the melt exhibited shear thinning
behavior whereby viscosity decreased with increasing flow rate. Increase in drug loading and set
extrusion temperature resulted in a reduction in melt viscosity. Shear viscosity and exit pressure
measurements were found to be sensitive to API loading. These findings suggest that this technique
could be used as a simple tool to measure material attributes in-line, to build better overall process
understanding for hot melt extrusion.

3
Introduction
Hot Melt Extrusion (HME) is a continuous manufacturing process which is increasingly being used to
generate amorphous solid dispersions or solutions of poorly soluble Active Pharmaceutical
Ingredients (APIs) in polymer matrices
1,2
. Typically HME renders the drug amorphous, a state which
can significantly enhance both drug kinetic solubility and bioavailability. The application of HME for
manufacture of pharmaceuticals has been widely reported including pellets
3
, sustained release
tablets
4,5
implants
6
and transdermal films
7
. A number of comprehensive reviews of the pharmaceutical
HME process are available
1,9,10
.
In the hot melt extrusion process the API, polymer and other excipients are conveyed along a heated
barrel by two closely intermeshing screws. Temperature, residence time and mixing intensity of the
process can be varied by tailoring extruder screw configuration and by adjusting process parameters
such as throughput and screw rotation speed. Within the process the API and carriers experience
significantly high temperatures and levels of shear deformation, which serve to melt the polymer and
dissolve or disperse the API within the matrix.
There exists a drive within the pharmaceutical industry to adopt real-time measurements for
continuous processes to enhance process understanding and product quality, as part of a wider Quality
by Design (QbD) approach. This has been exemplified by publication of the US Food and Drug
Administration (FDA) code of practice for Process Analytical Technology
10
. Within the extrusion
process, primary process variables such as temperature and pressure in the die can be readily
monitored to provide an indication of process stability (i.e. homogeneity of throughput). Motor
torque and material throughput can also be recorded and used to give an indication of specific energy
input to the melt, which is related to the temperature, material properties and degree of filling in the
extruder screw channels. However, these basic process measurements give little direct indication of
the consistency or rheology of the extrudate. Thus there is a need to develop suitable real-time
characterization techniques capable of providing such information to shed light on the likely real-time
effects of torque, temperature, API loading and its interaction with the polymer matrix. Simulation
can be used to help to understand and predict the behavior of materials within the process although
due to the highly complex three dimensional nature of twin screw extrusion flow, no fully-resolved
first principle simulations have been reported. Recent progress in HME simulation has been made
using finite element method (FEM)
11
, finite volume method (FVM)
12
and smoothed particle
hydrodynamics (SPH)
13
.
Spectroscopic techniques such as Raman and near infra-red (NIR) have been applied to hot melt
extrusion to monitor drug concentration or specific drug-polymer molecular interactions
14-17
.

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "In-process rheometry as a pat tool for hot melt extrusion" ?

In this paper, the authors investigate the use of rheometry as a complimentary, low-cost real-time measurement technique for HME. 

Q2. What is the effect of temperature on the viscosity of polymer molecules?

Increasing temperature provides the polymer molecules with greater mobility allowing them to flow more freely whereas plasticizers act to reduce the internal resistance of the polymer melt by effectively lubricating the flow of polymeric chains. 

Q3. What can be used to give an indication of specific energy input to the melt?

Motor torque and material throughput can also be recorded and used to give an indication of specific energy input to the melt, which is related to the temperature, material properties and degree of filling in the extruder screw channels. 

Q4. How long was the rheological die allowed to stabilize?

At each set throughput, the process was allowed a 15 minute stabilization period before pressure measurements were recorded, for a representative period of around 10 minutes. 

Q5. What is the use of a slit die rheometer?

In-line rheological slit dies have also been used in twin screw extrusion, both for monitoring reactive extrusion processes such as cross-linking of polyethylene 29 and for incorporation of additives such as the flame retardant magnesium hydroxide into a polyethylene 30 . 

Q6. How many Hz were used to measure the pressure of the slit die?

Three pressure transducers (Dynisco PT435) with a full scale deflection of 10.3 MPa were flush mounted at the surface of the slit and monitored at a frequency of 1 

Q7. How can rheology be measured in a die?

Real-time assessment of rheology within the extrusion process can be achieved by measurement of pressure drop inside an instrumented extruder die. 

Q8. What is the effect of the API loading on the die?

Results showed that the compound displayed shear thinning behavior in the mixtures tested and that shear viscosity decreased with increase in API loading, reflecting miscibility of the API within the polymer matrix. 

Q9. How much shear strain was observed at 40 % w/w API?

The plasticization effect of the API was also clearly observed, with shear viscosity decreasing from 1150 Pa.s at 20 % w/w API to 233 Pa.s at 40 % w/w API at an apparent shear strain rate of 15 s -1 . 

Q10. What can be used as a quality control indicator?

Such measurements can be used as a quality control indicator, using statistical process control and trending analysis to detect deviations from the desired set point. 

Q11. How many studies have been reported on the use of rheology?

Rheology has been used to characterize pharmaceutical solid dispersions and solutions, although only a relatively small number of studies have been reported. 

Q12. What is the effect of high temperature and mixing on the flow properties of the polymer?

It appears likely that this exposure to high temperature and mixing had an effect on the consistency of the flow properties of the compound, increasing the level of plasticization and mixing. 

Q13. What was the result of the rheological analysis of the API?

This indicated that the API was readily miscible within the polymer matrix in the molten state, and that the API had a plasticising effect.