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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Journal Article•
TL;DR: In this paper, the conditions for the processing of thermoplastics were determined and a correlation between the thermoplastic capacity to water and the drug release was found by means of selected examples.
Abstract: In connection with the preparation of solid sustained-release forms extrusion pellets were prepared. The conditions for the processing of the thermoplastics were determined. Lithium sulfate and caffeine served as model drugs. The drug release from the thermoplastics is insufficient. There was no evidence for a possible relation between the properties of the thermoplastics and the drug release. By means of selected examples a correlation between the thermoplastic capacity to water and the drug release could be found
28 citations
TL;DR: The current study demonstrated film-coating to be an efficient process for providing melt-extruded beads with pH-dependent drug release properties that were stable upon storage at accelerated conditions.
Abstract: The purpose of this study was to investigate the physicochemical properties of poly(ethylene oxide) (PEO) and guaifenesin containing beads prepared by a melt-extrusion process and film-coated with a methacrylic acid copolymer. Solubility parameter calculations, thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), modulated differential scanning calorimetry (MDSC), X-ray powder diffraction (XRPD) and high performance liquid chromatography (HPLC) were used to determine drug/polymer miscibility and/or the thermal processibility of the systems. Powder blends of guaifenesin, PEO and functional excipients were processed using a melt-extrusion and spheronization technique and then film-coated in a fluidized bed apparatus. Solubility parameter calculations were used to predict miscibility between PEO and guaifenesin, and miscibility was confirmed by SEM and observation of a single melting point for extruded drug/polymer blends during MDSC investigations. The drug was stable following melt-extrusion as determined by TGA and HPLC; however, drug release rate from pellets decreased upon storage in sealed HDPE containers with silica desiccants at 40 degrees C/75% RH. The weight loss on drying, porosity and tortuosity determinations were not influenced by storage. Recrystallization of guaifenesin and PEO was confirmed by SEM and XRPD. Additionally, the pellets exhibited a change in adhesion behaviour during dissolution testing. The addition of ethylcellulose to the extruded powder blend decreased and stabilized the drug release rate from the thermally processed pellets. The current study also demonstrated film-coating to be an efficient process for providing melt-extruded beads with pH-dependent drug release properties that were stable upon storage at accelerated conditions.
25 citations
"Pharmaceutical Applications of Hot-..." refers background in this paper
...L30 D-55 and designed a melt extruded pellet system with pHdependent drug release properties (Young et al., 2007)....
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TL;DR: The mean residence time was significantly influenced by the process variables screw speed and powder flow rate, and higher levels of these two factors reduced themean residence time.
Abstract: Anhydrous citric acid and sodium bicarbonate were granulated with ethanol in an extruder. A rough estimate of the dwell time was obtained by adding a small amount of colour in the inlet port and measuring the time until it reached the outlet. The mean residence time was calculated from results obtained when analyzing the colour content of the continuously sampled granulations after drying. There was a significant relationship between dwell time and mean residence time. After elimination of the abnormal values of three of the factor combinations, the degree of significance for the slope of the line increased from P=0.003(**) to P=0.0001(***). The mean residence time was significantly influenced by the process variables screw speed and powder flow rate. Higher levels of these two factors reduced the mean residence time.
25 citations
TL;DR: Theophylline release from the hot-melt extruded pellets was described using the Higuchi diffusion model, and drug release rates from wet-granulated and melt-extruded pellets did not change after post-processing thermal treatment.
Abstract: The objectives of this study were to investigate the particle size distribution, morphology and dissolution properties of spherical pellets produced by hot-melt extrusion and spheronization and to compare the properties of hot-melt extruded pellets with beads manufactured by a traditional wet-mass extrusion and spheronization method. Spherical pellets were produced by hot-melt extrusion without the use of water or other solvents. A powder blend of theophylline, Eudragit® Preparation 4135 F, microcrystalline cellulose and polyethylene glycol 8000 was hot melt-extruded and the resulting composite rod was cut into cylindrical pellets. The pellets were then spheronized in a traditional spheronizer at an elevated temperature. The same powder blend was processed using conventional wet-mass techniques. Unlike wet-mass extruded pellets, pellets prepared from hot-melt extrusion displayed both a narrow particle size distribution and controlled drug release in dissolution media less than pH 7.4. Scanning electron mi...
24 citations