Pharmaceutical Applications of Hot-Melt Extrusion: Part I
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.
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Dissertation•
10 Dec 2015
TL;DR: In this paper, the dissolution performance of three solid dispersions model systems including felodipine, bicalutamide and indomethacin, all poorly soluble drugs, with copovidone, a water-soluble polymer.
Abstract: A high number of new chemical entities emerging from the drug development process show pharmacological activity, but at the same time are characterised by poor dissolution and solubility profiles. As a result, there is a strong push to develop innovative formulations for the delivery of such compounds so that the desired oral bioavailability and pharmacological effects are achieved. An increasingly popular class of formulations to improve the dissolution properties of poorly soluble drugs is represented by amorphous solid dispersions, whereby the drug is molecularly dispersed in a carrier matrix. One of the key challenges for developing amorphous solid dispersions in real-world formulations is the understanding of the dissolution performance. Although this is very important, due to the fact that the dissolution performance limits the in vivo efficacy, the dissolution mechanisms by which the amorphous solid dispersions dissolve is still not fully understood.
This thesis investigates the dissolution performance of three solid dispersions model systems including felodipine, bicalutamide and indomethacin, all poorly soluble drugs, with copovidone, a water-soluble polymer. The complexity of the model systems increases through the chapters, starting by testing the dissolution of a well-documented poorly soluble drug model, i.e. felodipine, as a function of the drug loading (5% and 50% w/w) (Chapter 3). In Chapters 4 and 5 the dissolution of bicalutamide, which is known to exist in at least two different polymorphic forms (form I and form II), is investigated as a function of three drug loadings (5%, 30% and 50% w/w). Finally, the dissolution of indomethacin, which presents a pH-variable solubility and dissolution rate due to its weakly acidic nature (pKa of 4.5), is probed as a function of both dissolution medium pH (pH 2 and 6.8) and drug loading (5%, 15%, 30%, 50%, 70% and 90% w/w) (Chapter 6).
The dissolution of amorphous solid dispersions and other oral dosage forms is commonly tested using the USP dissolution apparatuses (types I, II and IV). These methods present a significant limitation, i.e. they can not provide any directly spatially-resolved chemical information on potential changes occurring to the solid form (e.g. amorphous to crystalline, polymorphs or solvation-related transformations).
In this thesis Raman spectroscopy is employed as primary analytical technique in an attempt to fill the gaps related to the understanding of the dissolution mechanisms of amorphous solid dispersions and the limitations of the conventional USP apparatuses. The novelty of this approach derives from collecting Raman data directly from the dosage form in real time and in situ during the course of the dissolution test using a flow-through cell placed below the Raman microscope. Temporally- and spatially-resolved chemical Raman maps are generated using a novel mathematical approach which derives from the use of concatenated maps to explicitly probe the chemical and physical changes as a function of time as well as space. In-line ultraviolet spectroscopy is also integrated to the Raman system to directly relate changes in dissolution behaviour to physicochemical changes that occur to the solid form during the dissolution test.
A wide range of other state-of-the-art analytical techniques is also used to complement the Raman data to obtain a clear picture of drug release from amorphous solid dispersions. This includes a combined magnetic resonance imaging/ultraviolet flow cell system to allow, similarly to the Raman/ultraviolet method, changes in dissolution profile to be related to physical changes occurring in the solid material, and for the first time quantitative suppressed-water proton nuclear magnetic resonance spectroscopy was applied to amorphous solid dispersions. Proton nuclear magnetic resonance, due to the high chemical selectivity, provides quantitative data on both the drug and the polymer. Finally, the rotating disk dissolution rate test, i.e. a modified version of the conventional intrinsic dissolution rate test, is developed and employed for the first time to gain information, similarly to proton nuclear magnetic resonance spectroscopy, on the dissolution rates of both the drug and the polymer.
The dissolution performance of all amorphous solid dispersion model systems is shown to be strongly affected by the drug loading. At low drug loading the drug and the polymer dissolve with the same rate from the molecular dispersion, pointing to a drug release dependent on the high water solubility of copovidone. At high drug loading, the dissolution rates of both the drug and the polymer are significantly slower and this is shown to be ascribed to the formation of an amorphous drug-rich shell around the compact, followed by the drug re-crystallisation. For the high drug loaded amorphous solid dispersions, the dissolution performance is strongly dependent on the physicochemical properties of the drug, i.e. low aqueous solubility and high hydrophobicity. The dissolution behaviour of the amorphous indomethacin solid dispersions is also found to be affected by the dissolution medium pH. Indomethacin from the amorphous solid dispersions with 15% or higher drug loading is released only at pH 6.8 due to the significant increase in its aqueous solubility at this pH.
2 citations
Cites background or methods from "Pharmaceutical Applications of Hot-..."
...HME has been used to prepare ASDs in a number of previous studies, several of which used felodipine, bicalutamide and indomethacin as drug models.(6,45,52,126,127,133)...
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...2).(6,45) After the feeding stage, the material is moved through the extruder via one or two rotating screws which are located inside a cylindrical barrel....
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...In HME the material is melted/softened at elevated temperatures and continuously extruded to produce small fragments which are then milled and mixed with other formulation components.(45) The main advantages of HME are that it is a continuous and solvent-free process and that it can be scaled up to large-scale manufacturing....
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TL;DR: A systematic literature review of more than 150 high-impact related research articles on FDMed-polymer composite processing is presented in this paper , where the base and filler material used, and the process parameters including layer height, nozzle temperature, bed temperature, and screw type are discussed.
Abstract: Additive manufacturing (AM) highlights developing complex and efficient parts for various uses. Fused deposition modelling (FDM) is the most frequent fabrication procedure used to make polymer products. Although it is widely used, due to its low characteristics, such as weak mechanical properties and poor surface, the types of polymer material that may be produced are limited, affecting the structural applications of FDM. Therefore, the FDM process utilises the polymer composition to produce a better physical product. The review’s objective is to systematically document all critical information on FDMed-polymer composite processing, specifically for part fabrication. The review covers the published works on the FDMed-polymer composite from 2011 to 2021 based on our systematic literature review of more than 150 high-impact related research articles. The base and filler material used, and the process parameters including layer height, nozzle temperature, bed temperature, and screw type are also discussed in this review. FDM is utilised in various biomedical, automotive, and other manufacturing industries. This study is expected to be one of the essential pit-stops for future related works in the FDMed-polymeric composite study.
2 citations
Dissertation•
01 Jan 2015
TL;DR: In this paper, the authors evaluate the use of several non-conventional polymers as matrix excipients for hot melt extruded oral-release formulations, and emphasize the importance of the polymer rather than on the addition of a third component.
Abstract: The objective of this doctoral thesis was to evaluate the use of several non-conventional polymers as matrix excipients for hot melt extruded oral-release formulations. Expanding the range of polymers currently used for HME/IM could potentially solve the problems associated with the current formulations: pH dependent release profiles, stability issues, and low drug loaded dosage forms. Moreover, formulations containing 3 components (active pharmaceutical ingredient (API), polymer and other additional excipient) have been extensively described in literature. If the characteristics of an extrudate containing API and polymer does not meet the requirements, a third component (plasticizer, drug release modifier, swelling agent, etc.) is often added to improve the formulation its performance. This doctoral thesis has the intention to emphasize the importance of the polymer. Try to ‘keep it simple’. The focus should first be on the polymer rather than on the addition of a third component. To this end, the process of HME could be simplified as a combination of 2 components requires less quality control, process control and decreases the complexity of formulation characterization. Overall, this doctoral thesis accentuates the need for a more rational design of polymer matrix excipients for drug formulation via HME and IM.
2 citations
Cites methods from "Pharmaceutical Applications of Hot-..."
...Several downstream processing devices are available to transform the homogeneous extrudate into its final product form: (a) the extrudates can be cooled on conveying rolls [2]; (b) cutting the extrudates into small pellets can be done via a pelletizer (fast spinning short knives) immediately at the die exit (die-face pelletizing) or after cooling (strand pelletizing) [3]; (c) forcing the extrudates through chilled rolls (chill rolling) results in the continuous...
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TL;DR: In this article , the authors focus on the compaction behavior of polymeric excipients during compression in comparison to nonpolymeric materials and its consequences on commonly used Heckel analysis.
Abstract: The present study focuses on the compaction behavior of polymeric excipients during compression in comparison to nonpolymeric excipients and its consequences on commonly used Heckel analysis. Compression analysis at compaction pressures (CPs) from 50 to 500 MPa was performed using a compaction simulator. This study demonstrates that the particle density, measured via helium pycnometer (ρpar), of polymeric excipients (Kollidon®VA64, Soluplus®, AQOAT®AS-MMP, Starch1500®, Avicel®PH101) was already exceeded at low CPs (<200 MPa), whereas the ρpar was either never reached for brittle fillers such as DI-CAFOS®A60 and tricalcium citrate or exceeded at CPs above 350 MPa (FlowLac®100, Pearlitol®100SD). We hypothesized that the threshold for exceeding ρpar is linked with predominantly elastic deformation. This was confirmed by the start of linear increase in elastic recovery in-die (ERin-die) with exceeding particle density, and in addition, by the applicability in calculating the elastic modulus via the equation of the linear increase in ERin-die. Last, the evaluation of “density under pressure” as an alternative to the ρpar for Heckel analysis showed comparable conclusions for compression behavior based on the calculated yield pressures. However, the applicability of Heckel analysis for polymeric excipients was questioned in principle. In conclusion, the knowledge of the threshold provides guidance for the selection of suitable excipients in the formulation development to mitigate the risk of tablet defects related to stored elastic energy, such as capping and lamination.
2 citations
Dissertation•
01 Jan 2019
TL;DR: Using nanofiltration membranes for the recovery of phosphorous with a second type of technology for the separation of nitrogen and phosphorus is suggest to be a viable process.
Abstract: viii AIM AND OBJECTIVES x CHAPTER 1: PHYSICO-CHEMICAL PROPERTIES OF PHARMACEUTICAL ACTIVES
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References
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1,883 citations
Book•
01 Jan 1995
TL;DR: The authors provided the basic building blocks of polymer science and engineering by coverage of fundamental polymer chemistry and materials topics given in Chapters 1 through 7 and provided information on the exciting new materialsnow available and the emerging areas of technological growth that could motivate a new generation of scientists and engineers.
Abstract: From the Book:
PREFACE: At least dozens of good introductory textbooks on polymer science and engineering are now available. Why then has yet another book been written?
The decision was based on my belief that none of the available texts fully addresses the needs of students in chemical engineering. It is not that chemical engineers are a rare breed, but rather that they have special training in areas of thermodynamics and transport phenomena that is seldom challenged by texts designed primarily for students of chemistry or materials science. This has been a frustration of mine and of many of my students for the past 15 years during which I have taught an introductory course, Polymer Technology, to some 350 chemical engineering seniors. In response to this perceived need, I had written nine review articles that appeared in the SPE publication Plastics Engineering from 1982 to 1984. These served as hard copy for my students to supplement their classroom notes but fell short of a complete solution.
In writing this text, it was my objective to first provide the basic building blocks of polymer science and engineering by coverage of fundamental polymer chemistry and materials topics given in Chapters 1 through 7.
As a supplement to the traditional coverage of polymer thermodynamics, extensive discussion of phase equilibria, equation-of- state theories, and UNIFAC has been included in Chapter 3. Coverage of rheology, including the use of constitutive equations and the modeling of simple flow geometries, and the fundamentals of polymer processing operations are given in Chapter 11.
Finally, I wanted to provide information on the exciting new materialsnowavailable and the emerging areas of technological growth that could motivate a new generation of scientists and engineers. For this reason, engineering and specialty polymers are surveyed in Chapter 10 and important new applications for polymers in separations (membrane separations), electronics (conducting polymers), biotechnology (controlled drug release), and other specialized areas of engineering are given in Chapter 12. In all, this has been an ambitious undertaking and I hope that I have succeeded in at least some of these goals.
Although the intended audience for this text is advanced undergraduates and graduate students in chemical engineering, the coverage of polymer science fundamentals (Chapters 1 through 7) should be suitable for a semester course in a materials science or chemistry curriculum.
Chapters 8 through 10 intended as survey chapters of the principal categories of polymers commodity thermoplastics and fibers, network polymers (elastomers and thermosets), and engineering and specialty polymers may be included to supplement and reinforce the material presented in the chapters on fundamentals and should serve as a useful reference source for the practicing scientist or engineer in the plastics industry.
981 citations
TL;DR: A comparison of the carbonyl stretching region of γ indomethacin, known to form carboxylic acid dimers, with that of amorphous indometHacin indicated that the amorphously phase exists predominantly as dimers.
Abstract: Purpose. To study the molecular structure of indomethacin-PVP amorphous solid dispersions and identify any specific interactions between the components using vibrational spectroscopy.
904 citations
Book•
01 Jan 1988
TL;DR: In this article, the elastic properties of polymeric solids and their properties of rubber are discussed. But they focus on the structure of the molecule rather than the properties of the solids.
Abstract: Introduction. 1: Structure of the molecule. 2: Structure of polymeric solids. 3: The elastic properties of rubber. 4: Viscoelasticity. 5: Yield and fracture. 6: Reinforced polymers. 7: Forming. 8: Design. Further reading, Answers, Index
790 citations
TL;DR: Improved bioavailability was achieved again demonstrating the value of the technology as a drug delivery tool, with particular advantages over solvent processes like co-precipitation.
790 citations