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: Results suggest that HLE is an effective method to increase the solubility of poorly water-soluble drugs.
Abstract: In this study, drug-cyclodextrin (CD) complexes were prepared using hot liquid extrusion (HLE) process with an aim to improve solubility and bioavailability of carbamazepine. Saturation solubility studies of CBZ in water and different pH media showed a pH-independent solubility. Phase solubility studies of CBZ at different molar concentrations of beta-cyclodextrin (β-CD) and hydroxypropyl beta-cyclodextrin (HP-β-CD) indicated AL-type solubility profile with stability constants of 574 M−1 and 899 M−1 for β-CD and HP-β-CD. Drug-β-CD and drug-HP-β-CD complexes were prepared using HLE process and conventional methods (such as physical mixture, kneading method, and solvent evaporation) as well. Optimized complexes prepared using HLE viz. CBP-4 and CHP-2 showed a solubility of 4.27 ± 0.09 mg/mL and 6.39 ± 0.09 mg/mL as compared to plain CBZ (0.140 ± 0.007 mg/mL). Formation of drug-CD inclusion complexes was confirmed using DSC, FTIR, and XRD studies. Drug release studies indicated highest release of CBZ from CHP-2 (98.69 ± 2.96%) compared to CBP-4 (82.64 ± 2.45%) and plain drug (13.47 ± 0.54%). Complexes prepared using kneading showed significantly lesser drug release (KMB 75.52 ± 2.68% and KMH 85.59 ± 2.80%) as that of CHP-2 and CBP-4. Pre-clinical pharmacokinetic studies in Wistar rats indicated a significant increase in Cmax, Tmax, AUC, and mean residence time for CHP-2 compared to KMH and plain CBZ. All these results suggest that HLE is an effective method to increase the solubility of poorly water-soluble drugs.
11 citations
TL;DR: In this paper, the authors formulated taste-masked pellets of Efavirenz (EFZ) with Eudragit E PO as the matrix polymer utilizing hot melt extrusion (HME) technology.
11 citations
TL;DR: In this article, a flexible dosing platform of Zolpidem hemitartrate (ZHT) was developed to facilitate withdrawal therapy by extruding and 3D printing of ZHT.
Abstract: The long-term use of benzodiazepine receptor agonists (BZRAs) is associated with multiple side effects, such as increased sedation, hangover or an elevated risk of dependency and abuse. Unfortunately, the long-term use of BZRAs is reaching worrying intake rates, and therefore, the need for action is high. It was demonstrated already that the overall willingness of patients for deprescription increased when a slow dose reduction scheme with the possibility for dose increase, if needed, is employed. The current study aims to develop a flexible dosing platform of zolpidem hemitartrate (ZHT) to facilitate such withdrawal therapy. As this is the first report on the extrusion and 3D printing of ZHT, its thermal behaviour and sensitivity towards photolytic degradation was characterised. It was shown that ZHT possesses multiple polymorphs and was especially prone to oxidative photolysis. Next, a variety of immediate release polymers (Eudragit EPO, Kollidon VA64, Kollidon 12PF and Soluplus) were blended and extruded with Polyox WSR N10 to investigate their feedability and printability by mechanical and rheological analysis. The addition of PEO was shown to enable printing of these brittle pharmaceutical polymers, although the processing temperature was deemed critical to avoid surface defects on the resulting filaments. An EPO(70)PEO(30) system was selected based on its suitable mechanical properties and low hygroscopicity favoring ZHT stability. The matrix was blended with 1% or 10% API. The effect of certain printing parameters (caplet size, nozzle diameter, % overlap) on dissolution behaviour and caplet weight/dimensions/quality was assessed. A flexible dosing platform capable of delivering <1 mg and up to 10 mg of ZHT was created. Either caplet modification (incorporation of channels) or disintegrant addition (Primojel, Explotab, Ac-Di-Sol, Primellose and Polyplasdone-XL) failed to achieve an immediate release profile. This study provides the first report of a 3D-printed flexible dosing platform containing ZHT to aid in withdrawal therapy.
11 citations
TL;DR: KinetiSol® dispersing was used to thermally process hypromellose acetate succinate-based compositions containing the drug substance nifedipine and a highly compressible grade of low-substituted hydroxypropyl cellulose to evaluate the dissolution performance of amorphous solid dispersions containing a dispersed superdisintegrant with binding properties.
Abstract: While the use of amorphous solid dispersions to improve aqueous solubility is well documented, little consideration has traditionally been given to the finished dosage form. The objective of this study was to evaluate the dissolution performance of amorphous solid dispersions containing a dispersed superdisintegrant with binding properties. KinetiSol® dispersing was used to thermally process hypromellose acetate succinate-based compositions containing the drug substance nifedipine (NIF) and a highly compressible grade of low-substituted hydroxypropyl cellulose (New Binder Disintegrants; NBD-grade). Solid-state analysis demonstrated that compositions were rendered amorphous during processing. Tablets containing intra-dispersion NBD were found to exhibit non-sink dissolution performance similar to milled intermediate, demonstrating excellent disintegration characteristics. Conversely, tablets without intra-dispersion NBD were found to release significantly less NIF during dissolution analysis due to particle agglomeration. It was determined that compressibility and particle wetting increased as the level of intra-dispersion NBD increased.
11 citations
TL;DR: It is concluded that the HPMC polymer could be used as a novel excipient to develop nanocomposite via HME, in order to improve the functionality of soybean food products.
Abstract: The poor bioaccessibility of the phenolic compounds of soybeans is a key challenge to developing functional food products. Therefore, a novel hydrophilic food-grade hydroxypropyl methylcellulose (HPMC) polymer was added to soybean to prepare a soybean food composite (SFC), in order to improve the soybean’s functionality. The SFC was prepared with soybean (95%) plus HPMC (5%) (w/w) mixes (HSE), as well as 100% soybean extrudate (SE), at 80 °C and 130 °C by a hot melt extrusion (HME) process. A non-extrudate 100% soybean material was considered as a control. It is observed that water solubility was significantly increased (35.18%), and particle size reached to nano-size (171.5 nm) in HSE at 130 °C compared to the control (7.14% and 1166 nm, respectively). The total phenolic, flavonoid, and single isoflavones content, including daidzin, daidzein, glycitein, genistein, and genistin was significantly increased in HSE at 130 °C compared to the control. The antioxidant properties were also significantly increased in HSE at 130 °C compared to the control, measured by 2,2-diphenyl-1 picryl hydrazyl (DPPH), a ferric reducing antioxidant power assay (FRAP), and the phosphomolybdenum method (PPMD). Finally, it is concluded that the HPMC polymer could be used as a novel excipient to develop nanocomposite via HME, in order to improve the functionality of soybean food products.
11 citations
Cites background from "Pharmaceutical Applications of Hot-..."
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...[16] stated that polymers facilitate the agglomeration of compounds into granules by steric hindrance and non-covalent bonding with the polymeric chain in aqueous media....
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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