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Journal ArticleDOI

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 (2 min read)

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.

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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

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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
.

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Cites background from "In-process rheometry as a PAT tool ..."

  • ...Rheology regards the study of the material flow and deformation behaviour and may be measured by applying an external force (shear-induced deformation) to a sample [3]....

    [...]

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TL;DR: A review of specific mechanical energy (SME) use in the pharmaceutical processing of amorphous solid dispersion (ASD) can be found in this article, along with the relative importance of thermal and mechanical input on various nonsolvent ASD processing methods.

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References
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Journal ArticleDOI
TL;DR: The highest dissolution rate and supersaturation of poorly water soluble drugs could be attributed to drug-polymer interactions occurred during HME.

227 citations


"In-process rheometry as a PAT tool ..." refers methods in this paper

  • ...Other workers have also used oscillatory rheometry as a preformulation tool [23,24]....

    [...]

Journal ArticleDOI
TL;DR: In this paper, hot-melt screw extrusion was presented as an alternative method for producing polymer-based sustained release (SFL) pellets, which were produced with diltiazem hydrochloride as model drug.
Abstract: Hot-melt screw extrusion was presented as an alternative method for producing polymer-based sustained release pellets. Special care was paid to the case of highly dosed freely soluble drugs which often pose technological problems with the usual manufacturing processes. In a preformulation study, polymers, plasticizers and drugs were selected according to various criteria including thermal stability. During these preliminary tests, the optimum extrusion conditions were defined. Four polymers were considered for extrusion trials, namely ethylcellulose, cellulose acetate butyrate, poly(ethylene-co-vinyl acetate) and a polymethacrylate derivative (Eudragit® RSPM). Pellets were produced with diltiazem hydrochloride as model drug. The surface appearance of various formulations was examined and the porosity assessed by means of mercury porosimetry. A distinct structure was found for the EVAC-based pellets. The overall porosity was less than 10%. Lastly, in vitro release of the drug showed a biphasic prof...

204 citations


"In-process rheometry as a PAT tool ..." refers methods in this paper

  • ...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]....

    [...]

Journal ArticleDOI
TL;DR: The study has indicated that the dispersion of the drug in the polymer may be complex in terms of both physical form and spatial distribution, with potential ramifications for stability and dissolution kinetics.

149 citations


"In-process rheometry as a PAT tool ..." refers background in this paper

  • ...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]....

    [...]

Journal ArticleDOI
TL;DR: This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery, as well as trans-drug delivery, oral mucosal, dermal, ungual and intravaginal systems.
Abstract: Introduction: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues. Areas covered: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release,...

139 citations


"In-process rheometry as a PAT tool ..." refers background in this paper

  • ...A number of comprehensive reviews of the pharmaceutical HME process are available [1,8,9]....

    [...]

Journal ArticleDOI

132 citations


"In-process rheometry as a PAT tool ..." refers methods in this paper

  • ...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]....

    [...]

Frequently Asked Questions (13)
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. 

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. 

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. 

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. 

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 . 

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 

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

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 . 

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. 

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

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. 

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