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: The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology where required.
Abstract: Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
1,201 citations
Cites background from "Pharmaceutical Applications of Hot-..."
...The mixture is subsequently forced through a die to produce an extrudate of uniform shape (Crowley et al., 2007)....
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...More recently, hot-melt extrusion (HME) has grown in popularity as it appears to address many of the limitations of simple fusion methods (Breitenbach, 2002; Crowley et al., 2007; Repka et al., 2007)....
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TL;DR: Critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products are reviewed.
510 citations
TL;DR: This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction.
494 citations
Cites methods from "Pharmaceutical Applications of Hot-..."
...Several research groups have demonstrated HME processes as a viable method to prepare a wide range of accepted pharmaceutical drug delivery systems, including granules, pellets, transdermal patches, transmucosal films systems and implants (Breitenbach, 2002; Crowley et al., 2007; Fonteyne et al., 2013)....
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TL;DR: This review will consider the literature that describes the manufacture and characterization of mucoadhesive buccal films and hot-melt extrusion has been explored as an alternative manufacturing process and has yielded promising results.
381 citations
Cites methods from "Pharmaceutical Applications of Hot-..."
...Hot-melt extrusion has been used for the manufacture of controlled-release matrix tablets, pellets, and granules [84], as well as orally disintegrating films [85]....
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TL;DR: The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.
Abstract: Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.
359 citations
References
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TL;DR: The purpose of this study was to investigate the influence of sodium bicarbonate on the physicochemical properties of controlled release hot-melt extruded (HME) tablets containing Eudragit RS PO and/or EUDragit E PO and the drug release properties and buoyancy in media for HME tablets and directly compressed (DC) tablets were investigated.
154 citations
TL;DR: It appears that rapid precipitation of ITZ occurs upon entrance into the more neutral pH environment of the small intestine resulting in a brief opportunity for absorption.
153 citations
TL;DR: The method of choice in this study, melt extrusion, proved to overcome many of the shortcomings of conventional methods and achieve a significant increase in dissolution rate when compared to the pure drug or to the physical mixtures.
152 citations
TL;DR: Force--deflection profiles obtained from these experiments indicate that the force of adhesion, elongation at adhesive failure and modulus ofAdhesion are a function of the polymer additive in the HPC extruded films.
152 citations
TL;DR: The addition of 1, 3, and 5% Vitamin E TPGS facilitated the processing of the HPC/PEO films by decreasing the barrel pressure, drive amps, and torque of the extruder equipment.
149 citations