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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Journal Article•
TL;DR: In this paper, the authors discuss the recent advances related on the area of solid dispersion technology and its manufacturing techniques at laboratory and industrial level, and highlight about various hydrophilic polymers used in this technique to enhance solubility of poorly soluble drugs.
Abstract: Poorly water soluble compounds have solubility and dissolution related bioavailability problems. The present review deals in detail about solid dispersion technology and its manufacturing techniques at laboratory and industrial level. This highlight about various hydrophilic polymers used in this technique to enhance solubility of poorly soluble drugs. It also discusses about modern characterization technique to characterize solid dispersion. In this review, it is intended to discuss the recent advances related on the area of solid dispersion technology. Keywords: Solid dispersion; Carriers; Solubility; Dissolution; Bioavailability.
57 citations
Cites background from "Pharmaceutical Applications of Hot-..."
...HME also offers several advantages over traditional pharmaceutical processing techniques including the absence of solvents, few processing steps, continuous operation, more possibility of the formation of solid dispersions and improved bioavailability [52]....
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TL;DR: 3DP coupled with HME, could be an effective blueprint to produce controlled-release GRFTs, providing the advantage of simplicity and versatility compared to the conventional methods.
Abstract: This work presents a novel approach for producing gastro-retentive floating tablets (GRFT) by coupling hot-melt extrusion (HME) and fused deposition three-dimensional printing (3DP). Filaments containing theophylline (THEO) within a hydroxypropyl cellulose (HPC) matrix were prepared using HME. 3DP tablets with different infill percentages and shell thickness were developed and evaluated to determine their drug content, floating behavior, dissolution, and physicochemical properties. The dissolution studies revealed a relationship between the infill percentage/shell thickness and the drug release behavior of the 3DP tablets. All the developed GRFTs possessed the ability to float for 10 h and exhibited zero-order release kinetics. The drug release could be described by the Peppas-Sahlin model, as a combination of Fickian diffusion and swelling mechanism. Drug crystallinity was found unaltered throughout the process. 3DP coupled with HME, could be an effective blueprint to produce controlled-release GRFTs, providing the advantage of simplicity and versatility compared to the conventional methods.
57 citations
Cites background from "Pharmaceutical Applications of Hot-..."
...Upon leaving the die, the polymer chains try to recover from the deformation applied by the co-rotating screw by “relaxing” and increasing their radius of gyration, resulting in the expansion of the filament diameter [27]....
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...2 mm) is commonly known as the “die swell,” corresponding to the effect of the heat and high shear stress generated during HME processing [27]....
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TL;DR: Assessment of the extrudability and performance of AFFINISOL™ HPMC HME (100LV and 4M) as compared to other widely used polymers in HME, which revealed that amorphous CBZ in the HME extrudates completely dissolved within 15 min, which was much more rapid than the time for complete dissolution of bulk CBZ and EUDRAGIT® E PO solid dispersion.
Abstract: Hypromellose is a hydrophilic polymer widely used in immediate- and modified-release oral pharmaceutical dosage forms However, currently available grades of hypromellose are difficult, if not impossible, to process by hot melt extrusion (HME) because of their high glass transition temperature, high melt viscosity, and low degradation temperature To overcome these challenges, a modified grade of hypromellose, AFFINISOL™ HPMC HME, was recently introduced It has a significantly lower glass transition temperature and melt viscosity as compared to other available grades of hypromellose The objective of this paper is to assess the extrudability and performance of AFFINISOL™ HPMC HME (100LV and 4M) as compared to other widely used polymers in HME, including HPMC 2910 100cP (the currently available hypromellose), Soluplus®, Kollidon® VA 64, and EUDRAGIT® E PO Formulations containing polymer and carbamazepine (CBZ) were extruded on a co-rotating 16-mm twin-screw extruder, and the effect of temperature, screw speed, and feed rate was investigated The performance of the solid dispersions was evaluated based on Flory–Huggins modeling and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Raman spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and dissolution All formulations extruded well except for HPMC 2910 100cP, which resulted in over-torqueing the extruder (machine overloading because the motor cannot provide efficient energy to rotate the shaft) Among the HME extrudates, only the EUDRAGIT® E PO formulation was crystalline as confirmed by DSC, XRD, and Raman, which agreed with predictions from Flory–Huggins modeling Dissolution testing was conducted under both sink and non-sink conditions Sink dissolution testing in neutral media revealed that amorphous CBZ in the HME extrudates completely dissolved within 15 min, which was much more rapid than the time for complete dissolution of bulk CBZ (60 min) and EUDRAGIT® E PO solid dispersion (more than 6 h) Non-sink dissolution in acidic media testing revealed that only CBZ contained in the AFFINISOL™ HPMC HME, and EUDRAGIT® E PO solid dispersions rapidly supersaturated after 15 min, reaching a twofold drug concentration compared to the CBZ equilibrium solubility In summary, AFFINISOL™ HPMC HME 100LV and AFFINISOL™ HPMC HME 4M are useful in the pharmaceutical HME process to increase wetting and dissolution properties of poorly water-soluble drugs like CBZ
57 citations
Cites background from "Pharmaceutical Applications of Hot-..."
..., Tg; the temperature at which the polymer starts to soften), the solubility of the drug in the softened or molten polymer, and the stability of the polymer are crucial to forming a homogeneous composition (11)....
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TL;DR: The developed statistical models identified suitable level of fillers and disintegrants for each studied HME polymer to achieve tablets with rapid DT (<15 min) and acceptable TS (≥1 MPa at 10–15% tablet porosity), and their predictivity was confirmed by conducting internal and external validation studies.
Abstract: The objective of the study was to identify the extragranular component requirements (level and type of excipients) to develop an immediate release tablet of solid dispersions prepared by hot melt extrusion (HME) process using commonly used HME polymers. Solid dispersions of compound X were prepared using polyvinyl pyrrolidone co-vinyl acetate 64 (PVP VA64), Soluplus, and hypromellose acetate succinate (HPMCAS-LF) polymers in 1:2 ratio by HME through 18 mm extruder. A mixture design was employed to study effect of type of polymer, filler (microcrystalline cellulose (MCC), lactose, and dicalcium phosphate anhydrous (DCPA)), and disintegrant (Crospovidone, croscarmellose sodium, and sodium starch glycolate (SSG)) as well as level of extrudates, filler, and disintegrant on tablet properties such as disintegration time (DT), tensile strength (TS), compactibility, and dissolution. Higher extrudate level resulted in longer DT and lower TS so 60–70% was the maximum amount of acceptable extrudate level in tablets. Fast disintegration was achieved with HPMCAS-containing tablets, whereas Soluplus- and PVP VA64-containing tablets had higher TS. Crospovidone and croscarmellose sodium were more suitable disintegrant than SSG to achieve short DT, and MCC was a suitable filler to prepare tablets with acceptable TS for each studied HME polymer. The influence of extragranular components on dissolution from tablets should be carefully evaluated while finalizing tablet composition, as it varies for each HME polymer. The developed statistical models identified suitable level of fillers and disintegrants for each studied HME polymer to achieve tablets with rapid DT (<15 min) and acceptable TS (≥1 MPa at 10–15% tablet porosity), and their predictivity was confirmed by conducting internal and external validation studies.
56 citations
Cites methods from "Pharmaceutical Applications of Hot-..."
...HME has been successfully applied to enhance solubility of poorly soluble drug substance through formation of an amorphous solid dispersion of drug substance in a polymeric (or lipid) carrier matrix (10,11)....
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TL;DR: The conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs, which was found to be highly stable after storage for 6 months.
Abstract: Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.
55 citations
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