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Journal ArticleDOI

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

01 Apr 2018-Drug Development and Industrial Pharmacy (Taylor & Francis)-Vol. 44, Iss: 4, pp 670-676

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.
Topics: Melt flow index (58%), Extrusion (57%), Viscosity (54%), Plastics extrusion (54%), Shear thinning (54%)

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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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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
.

Citations
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Abstract: Introduction: Currently, hot melt extrusion (HME) is a promising technology in the pharmaceutical industry, as evidenced by its application to manufacture various FDA-approved commercial products i...

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Abstract: Interest in 3D printing for pharmaceutical applications has increased in recent years. Compared to other 3D printing techniques, hot melt extrusion (HME)-based fused deposition modeling (FDM) 3D printing has been the most extensively investigated for patient-focused dosage. HME technology can be coupled with FDM 3D printing as a continuous manufacturing process. However, the crucial pharmaceutical polymers, formulation and process parameters must be investigated to establish HME-coupled FDM 3D printing. These advancements will lead the way towards developing continuous drug delivery systems for personalized therapy. This brief overview classifies pharmaceutical additive manufacturing, Hot Melt Extrusion, and Fused Deposition Modeling 3D printing techniques with a focus on coupling HME and FDM 3D printing processes. It also provides insights on the critical material properties, process and equipment parameters and limitations of successful HME-coupled FDM systems.

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Journal ArticleDOI
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TL;DR: The proposed validation of the approach included the rheometer qualification, followed by the validation of numerous operational critical parameters regarding a rheology profile acquisition, which provided a standard framework for the development of a reliable and robust rheological profile acquisition.
Abstract: The increasing demand for product and process understanding as an active pursuit in the quality guideline Q8 and, more recently, on the draft guideline on quality and equivalence of topical products, has unveiled the tremendous potential of rheology methods as a tool for microstructure characterization of topical semisolid dosage forms. Accordingly, procedure standardization is a dire need. This work aimed at developing and validating a methodology tutorial for rheology analysis. A 1% hydrocortisone cream was used as model cream formulation. Through a risk assessment analysis, the impact of selected critical method variables (geometry, temperature and application mode) was estimated in a broad range of rheological critical analytical attributes-zero-shear viscosity, upper-shear thinning viscosity, lower-shear thinning viscosity, infinite-shear viscosity, rotational yield point, thixotropic relative area, linear viscoelastic region, oscillatory yield point, storage modulus, loss modulus, and loss tangent. The proposed validation of the approach included the rheometer qualification, followed by the validation of numerous operational critical parameters regarding a rheology profile acquisition. The thixotropic relative area, oscillatory yield point, flow point and viscosity related endpoints proved to be highly sensitive and discriminatory parameters. This rationale provided a standard framework for the development of a reliable and robust rheology profile acquisition.

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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]....

    [...]


Book ChapterDOI
01 Jan 2019-
Abstract: Hot-melt extrusion (HME) has emerged as a well-established industrial manufacturing technology in the pharmaceutical industry. There are a number of publications and patents on HME being used for the enhancement of solubility and bioavailability of poorly soluble drugs. The HME has been successfully used not only for solubility and dissolution rate enhancement but also for manufacturing various dosage forms such as granules, pellets, tablets, films, implants, suppositories, stents, depots, ophthalmic implants, and topical delivery systems. The processing parameters such as operating temperature, feed rate, screw speed, screw configuration, etc., has crucial role on the quality of final product. This chapter is focused on the application of quality by design (QbD) on the process optimization of HME to produce robust finished product. The knowledge of QbD and Process Analytical Technology (PAT) can be utilized to make HME as a continuous manufacturing process.

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Abstract: Specific mechanical energy (SME) is a frequently overlooked but essential parameter of hot-melt extrusion (HME). It can determine whether an amorphous solid dispersion (ASD) can be successfully processed. A minimum combination of thermal input and SME is required to convert a crystalline active pharmaceutical product (API) into its amorphous form. A maximum combination is allowed before it or the carrier polymer chemically degrades. This has important implications on design space. SME input during HME provides information on the totality of the effect of various independent processing parameters such as screw speed, feed rate, and complex viscosity. If only these independent processing parameters are considered separately instead of SME, then important information would be lost regarding the interaction of these parameters and their ability to affect ASD formulation. A complete understanding of the HME process requires an analysis of SME. This paper provides a review of SME use in the pharmaceutical processing of ASDs, the importance of SME in terms of a variety of formulation qualities, and novel future uses of SME. Theoretical background is discussed, along with the relative importance of thermal and mechanical input on various nonsolvent ASD processing methods.

3 citations


References
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Journal ArticleDOI
W. P. Cox1, E. H. Merz1Institutions (1)

1,608 citations


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

  • ...In polymer rheology, the Cox–Merz rule [33] is an empirical relationship which states that for many polymeric systems the steady state shear viscosity plotted against shear rate corresponds closely to the complex viscosity plotted against angular frequency, allowing pressure driven flow and oscillatory deformation to be compared directly....

    [...]


Journal ArticleDOI
TL;DR: The pharmaceutical applications of hot-melt extrusion, including equipment, principles of operation, and process technology, are reviewed and the physicochemical properties of the resultant dosage forms are described.
Abstract: Interest in hot-melt extrusion techniques for pharmaceutical applications is growing rapidly with well over 100 papers published in the pharmaceutical scientific literature in the last 12 years. Hot-melt extrusion (HME) has been a widely applied technique in the plastics industry and has been demonstrated recently to be a viable method to prepare several types of dosage forms and drug delivery systems. Hot-melt extruded dosage forms are complex mixtures of active medicaments, functional excipients, and processing aids. HME also offers several advantages over traditional pharmaceutical processing techniques including the absence of solvents, few processing steps, continuous operation, and the possibility of the formation of solid dispersions and improved bioavailability. This article, Part I, reviews the pharmaceutical applications of hot-melt extrusion, including equipment, principles of operation, and process technology. The raw materials processed using this technique are also detailed and the physicochemical properties of the resultant dosage forms are described. Part II of this review will focus on various applications of HME in drug delivery such as granules, pellets, immediate and modified release tablets, transmucosal and transdermal systems, and implants.

699 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]....

    [...]

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

    [...]


Journal ArticleDOI
T. De Beer1, A. Burggraeve1, Margot Fonteyne1, L. Saerens1  +2 moreInstitutions (1)
TL;DR: This paper aims at reviewing the use of Raman and NIR spectroscopy in the PAT setting, i.e., during processing, with special emphasis in pharmaceutics and dosage forms.
Abstract: Within the Process Analytical Technology (PAT) framework, it is of utmost importance to obtain critical process and formulation information during pharmaceutical processing. Process analyzers are the essential PAT tools for real-time process monitoring and control as they supply the data from which relevant process and product information and conclusions are to be extracted. Since the last decade, near infrared (NIR) and Raman spectroscopy have been increasingly used for real-time measurements of critical process and product attributes, as these techniques allow rapid and nondestructive measurements without sample preparations. Furthermore, both techniques provide chemical and physical information leading to increased process understanding. Probes coupled to the spectrometers by fiber optic cables can be implemented directly into the process streams allowing continuous in-process measurements. This paper aims at reviewing the use of Raman and NIR spectroscopy in the PAT setting, i.e., during processing, with special emphasis in pharmaceutics and dosage forms.

423 citations


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

  • ...Recent progress in HME simulation has been made using finite element method (FEM) [11], finite volume method...

    [...]

  • ...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]....

    [...]


Journal ArticleDOI
15 May 2007-Talanta
TL;DR: Recent developments in the pharmaceutical domain where NIR spectroscopy can be applied from raw material identification to final product release are reviewed.
Abstract: Near-infrared (NIR) spectroscopy is a fast and non-destructive analytical technique that offers many advantages for a broad range of industrial applications. In this work, we reviewed recent developments in the pharmaceutical domain where it can be applied from raw material identification to final product release. The characteristics of NIR allow the technique to be implemented as a process analytical technology (PAT). Moreover, recent instrumental developments open the perspectives of numerous applications in the NIR imaging area. After "Introduction", according to their subject, the applications are discussed in the parts "Identification", "Water content", "Assay" and "Other applications".

343 citations


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TL;DR: The Higuchi diffusion model, Percolation Theory and Polymer Free Volume Theory were applied to the dissolution data to explain the release properties of drug from the matrix systems and the release rate was shown to be dependent on the ethyl cellulose particle size, compaction force and extrusion temperature.
Abstract: The objective of this research project was to determine the physicochemical properties and investigate the drug release mechanism from ethyl cellulose (EC) matrix tablets prepared by either direct compression or hot-melt extrusion (HME) of binary mixtures of water soluble drug (guaifenesin) and the polymer. Ethyl cellulose was separated into "fine" or "coarse" particle size fractions corresponding to 325-80 and 80-30 mesh particles, respectively. Tablets containing 30% guaifenesin were prepared at 10, 30, or 50 kN compaction forces and extruded at processing temperatures of 80-90 and 90-110 degrees C. The drug dissolution and release kinetics were determined and the tablet pore characteristics, tortuosity, thermal properties and surface morphologies were studied using helium pycnometry, mercury porosimetry, differential scanning calorimetry and scanning electron microscopy. The tortuosity was measured directly by a novel technique that allows for the calculation of diffusion coefficients in three experiments. The Higuchi diffusion model, Percolation Theory and Polymer Free Volume Theory were applied to the dissolution data to explain the release properties of drug from the matrix systems. The release rate was shown to be dependent on the ethyl cellulose particle size, compaction force and extrusion temperature.

233 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]....

    [...]


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