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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TL;DR: X-ray diffraction, differential scanning calorimetry and SEM studies permit us to conclude that in 10% prednisolone extrudate, the drug is mainly dispersed within the carrier, whereas in those containing 20% an important fraction of the drug remains in a crystalline state and is accumulated on the surface of the extrudates.
Abstract: The objective of this study is to evaluate the dissolution of a poorly soluble drug (prednisolone) from different sized matricial particles (from 1500 µm) with two drug contents (10% or 20%) obtained by hot melt extrusion using the hyperbranched polyesteramide Hybrane S1200 (water-soluble and with a Tg of 45 °C) as the carrier. X-ray diffraction, differential scanning calorimetry and SEM studies permit us to conclude that in 10% prednisolone extrudate, the drug is mainly dispersed within the carrier, whereas in those containing 20% an important fraction of the drug remains in a crystalline state and is accumulated on the surface of the extrudates. On particles proceeding from 10% drug extrudate, the drug dissolution rate is very high and slightly dependant on particle size and in all cases, higher than the pure micronized drug. However, on particles proceeding from 20% prednisolone extrudate particle size have a major effect on drug dissolution rate, attributable to higher proportions of crystalline drug accumulated on the surface, hindering polymer dissolution. Thus, the reduction of the particle size after extrudate grinding creates new surfaces from inside, that leads to strong increments on prednisolone dissolution rate, and becomes higher than the pure micronized drug one when the particle size is <250 µm.
2 citations
Dissertation•
28 Sep 2015
TL;DR: This thesis investigates the mechanism of detection and correlation of taste assessment between an untrained human taste panel and the electronic tongue and focuses on generating solid dispersion of Eudragit®EPO and quinine hydrochloride dihydrate.
Abstract: The publication of the European Paediatric Regulation (EC No. 1901/2006) in January 2007 brought the issue of taste assessment of medicines to the forefront. This regulation requires the early submission of a paediatric investigation plan (PIP).In most cases the applicant is required to provide an overview of planned measures / performed studies of which taste masking and assessment are of particular relevance. Therefore, there has been an increased interest in the development of objective taste assessment methods. The first area in this thesis focused on investigating and understanding the mechanism of detection of the Insent® electronic tongue TS 5000Z. Within this area, sensor responses to molecules possessing similar structures were analysed. In addition, metformin hydrochloride, paracetamol and ibuprofen were also analysed. In the development of objective taste assessment methods, such methods have to correlate with human taste perception. To this end, the second area investigated the correlation of taste assessment between an untrained human taste panel (n=24) and the electronic tongue. The human taste panel were presented with extemporaneously prepared amlodipine suspension which they graded in a visual analogue scale (VAS). These scores were compared to those obtained from the electronic tongue. It is widely accepted that hot melt extrusion is useful for generating solid dispersions that have taste masking capability. However there are limited reports in the literature that assess taste masking efficacy using electronic tongues. The third area of this thesis focuses on generating solid dispersion of Eudragit®EPO and quinine hydrochloride dihydrate. Overall, three key messages are concluded from the work detailed in this thesis. Firstly, the detection mechanism is dependent on the ionic / ionisation of the molecule under investigation. Secondly, strong correlation is shown between taste scores from the human panel and those obtained from the electronic tongue. Lastly, melt extrudates with 30% and 50% of quinine hydrochloride released less than 10% of drug in the first three minutes of dissolution therefore showing taste masking via both UV spectrophotochemical and electronic tongue analysis.
2 citations
TL;DR: In order to improve the water solubility of AZL and its bioavailability, an AZL-nicotinamide (NA) cocrystal was prepared by mechanical ball milling, and the effect of ball-milling conditions on cocrystals preparation were studied as mentioned in this paper .
2 citations
Dissertation•
01 Nov 2012
TL;DR: In this paper, the authors investigated the efficiency of hydrophilic polymers to enhance the dissolution rate of poorly water-soluble APIs processed by hot-melt extrusion (HME).
Abstract: Hot-melt extrusion (HME) is one of the most widely used technologies in the plastic, rubber and food industries and it has also been extensively explored and used in academia and the pharmaceutical industry over the last decade. This project aims to investigate the efficiency of hydrophilic polymers to enhance the dissolution rate of poorly water-soluble APIs processed by HME. Indomethacin (INM) and famotidine (FMT) were selected as model active substances while polyvinyl caprolactam graft copolymer, Soluplus® (SOL) and vinylpyrrolidone-vinyl acetate copolymer grades Kollidon® VA64 (VA64) and Plasdone® S630 (S630) were used as hydrophilic polymeric carriers. For the purpose of the study, all drug-polymer binary blends at various ratios were processed by a Randcastle single screw extruder. The physico-chemical properties and the morphology of the extrudates were evaluated via x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). INM and FMT exhibited strong plasticization effects at specific concentrations and were found to be molecularly dispersed within the polymer blends. The in vitro dissolution studies showed increased INM/FMT release rates for all formulations compared to that of pure APIs alone. Ibuprofen was also embedded in a methacrylate copolymer (Eudragit® EPO) matrix to produce solid dispersions by hot-melt extrusion processing. The obtained granules were incorporated into orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and cross-linked polyvinylpyrrolidone while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, and friability and dissolution profiles were further evaluated and compared with commercially available Nurofen® Meltlet ODTs. In vitro dissolution of the extruded ODTs showed rapid release of ibuprofen compared to that of Nurofen® Meltlets. The in vitro and in vivo evaluation of the masking efficiency of hot melt extruded paracetamol (PMOL) formulations was examined. Extruded granules containing high PMOL loadings in Eudragit EPO® (EPO) or Kollidon® VA64 (VA64) were prepared by HME. Similarly propranolol HCl (PRP), diphenhydramine HCl (DPD), cetirizine HCl (CTZ) and verapamil HCl (VRP) were used as model cationic active substances while pH sensitive anionic methacrylic acid based methyl methacrylate coplolymers Eudragit® L100 (L100) and ethyl acrylate copolymer Eudragit® L100-55 (Acryl-EZE®) (L100-55) were used as polymeric carriers in order to produce taste masked extruded formulations determining drug-polymers intermolecular interactions. The taste masking effect of the processed formulation was evaluated in vivo by a panel of six healthy human volunteers. In addition, in vitro evaluation was carried out by an Astree e-tongue (Alpha MOS) equipped with seven sensors and Taste Sensing System TS5000Z (INSENT), respectively.
The taste and sensory evaluation in human volunteers demonstrated that the formulation masked the bitter taste of the APIs and improved tablet palatability. In addition to that the taste sensing technology demonstrated taste improvement for all polymers by correlating the data obtained for the placebo polymers and the pure APIs alone. The e-tongue results were in good agreement with the in vivo evaluation. Molecular modelling (Gaussian 09) predicted the existence of two possible H-bonding types while Fourier Transform Infra-Red (FT-IR) and NMR studies confirmed drug-polymer interactions between the functional groups of both components (cationic drugs–anionic polymers). Furthermore, the intermolecular interactions evaluated by Flory-Huggins interaction parameters theory and X-ray photoelectron spectroscopy (XPS) showed stronger interactions between drug-polymer in L100 systems compared to that of L100-55 systems. The mechanism of the intermolecular interactions derived from this research showed the presence of H bonding between the amine group of the active substances and the carboxylic groups in the polymer.
Hydrocortisone (HCS) was also embedded and extruded with ethyl cellulose N10 (EC N10) or ethyl cellulose Premium 7 (EC P7) in order to develop sustained release tablets processed by HME. The compressed tablets were subsequently coated with an enteric coating polymer, Eudragit® S100 (15-20%), which showed sustained release over 12 hrs with a lag time of 2 hrs. Further analysis of the release mechanism of HCS from tablets was performed by implementing five different kinetic release models which confirmed that the release of HCS from both coated and uncoated tablets followed a first order kinetic model.
2 citations
Cites background from "Pharmaceutical Applications of Hot-..."
...1 Hot-melt extrusion (HME): Process technology Joseph Brama first invented the extrusion process for the manufacturing of lead pipes at the end of the eighteenth century [7] ....
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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