Application of Hot-melt Extrusion in the Manufacturing of Amorphous Solid Dispersions Containing Thermally Labile Drugs
Application of Hot-melt Extrusion in the Manufacturing of Amorphous Solid Dispersions Containing Thermally Labile Drugs

Author: Siyuan Huang

Publisher:

Published: 2017

Total Pages: 654

ISBN-13:

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Hot-melt extrusion has gained favor over traditional pharmaceutical formulation techniques in bioavailability/solubility enhancement because it is a solvent-free and continuous operation process that does not require major downstream processing. However, the thermal and mechanical energy applied during the extrusion process can cause chemical degradation of drugs and polymeric carriers In Chapter 1, different methods of preparing amorphous solid dispersions were reviewed. The amorphous solid dispersions generated by different methodologies were compared in terms of physical stability, chemical stability, and the in vivo/in vitro performance. In Chapter 2, the solubility advantage of amorphous solid dispersions was investigated through the heterogeneous phase equilibria analysis. A thermodynamic model for the quantitative assessment of solubility advantage of amorphous solid dispersions was then presented. The thermodynamic model accounted for the chemical potential change as a result of (a) amorphization, (b) ASD formation, and (c) water partition. Experimental solubility advantages of amorphous solid dispersions containing indomethacin was studied by means of intrinsic dissolution measurement. The thermodynamic model allowed predicting the solubility advantage of amorphous solid dispersions. In Chapters 3 and 4, the strategies used in hot-melt extrusion to facilitate manufacture of amorphous solid dispersions containing thermally labile drugs were investigated. Formulation screening based on Flory-Huggins theory, and the utilization of polymer designed for the extrusion process was evaluated in Chapter 3. With the selection of proper formulations, amorphous solid dispersions containing 30% (w/w) carbamazepine were manufactured without any degradation. Improved dissolution properties were also revealed with the final formulations. In Chapter 4, gliclazide was identified as a thermally labile drug with severe degradation by hydrolysis at elevated temperatures, especially when it existed in amorphous or solution form. After optimization of the hot-melt extrusion process, including improved screw design, machine setup, and processing conditions, gliclazide amorphous solid dispersion with ~95% drug recovery was achieved. This study demonstrated the importance of the following factors on drug degradation: (a) changing screw design to facilitate shorter amorphous (melt) residence time, (b) lowering processing temperature to avoid excess thermal exposure, and (c) minimizing processing parameters to reduce unnecessary mechanical energy input.

Hot-Melt Extrusion
Hot-Melt Extrusion

Author: Dennis Douroumis

Publisher: John Wiley & Sons

Published: 2012-04-24

Total Pages: 404

ISBN-13: 1118307879

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Hot-melt extrusion (HME) - melting a substance and forcing it through an orifice under controlled conditions to form a new material - is an emerging processing technology in the pharmaceutical industry for the preparation of various dosage forms and drug delivery systems, for example granules and sustained release tablets. Hot-Melt Extrusion: Pharmaceutical Applications covers the main instrumentation, operation principles and theoretical background of HME. It then focuses on HME drug delivery systems, dosage forms and clinical studies (including pharmacokinetics and bioavailability) of HME products. Finally, the book includes some recent and novel HME applications, scale -up considerations and regulatory issues. Topics covered include: principles and die design of single screw extrusion twin screw extrusion techniques and practices in the laboratory and on production scale HME developments for the pharmaceutical industry solubility parameters for prediction of drug/polymer miscibility in HME formulations the influence of plasticizers in HME applications of polymethacrylate polymers in HME HME of ethylcellulose, hypromellose, and polyethylene oxide bioadhesion properties of polymeric films produced by HME taste masking using HME clinical studies, bioavailability and pharmacokinetics of HME products injection moulding and HME processing for pharmaceutical materials laminar dispersive & distributive mixing with dissolution and applications to HME technological considerations related to scale-up of HME processes devices and implant systems by HME an FDA perspective on HME product and process understanding improved process understanding and control of an HME process with near-infrared spectroscopy Hot-Melt Extrusion: Pharmaceutical Applications is an essential multidisciplinary guide to the emerging pharmaceutical uses of this processing technology for researchers in academia and industry working in drug formulation and delivery, pharmaceutical engineering and processing, and polymers and materials science. This is the first book from our brand new series Advances in Pharmaceutical Technology. Find out more about the series here.

Melt Extrusion
Melt Extrusion

Author: Michael A. Repka

Publisher: Springer Science & Business Media

Published: 2013-10-11

Total Pages: 472

ISBN-13: 1461484324

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This volume provides readers with the basic principles and fundamentals of extrusion technology and a detailed description of the practical applications of a variety of extrusion processes, including various pharma grade extruders. In addition, the downstream production of films, pellets and tablets, for example, for oral and other delivery routes, are presented and discussed utilizing melt extrusion. This book is the first of its kind that discusses extensively the well-developed science of extrusion technology as applied to pharmaceutical drug product development and manufacturing. By covering a wide range of relevant topics, the text brings together all technical information necessary to develop and market pharmaceutical dosage forms that meet current quality and regulatory requirements. As extrusion technology continues to be refined further, usage of extruder systems and the array of applications will continue to expand, but the core technologies will remain the same.

Amorphous Solid Dispersions
Amorphous Solid Dispersions

Author: Navnit Shah

Publisher: Springer

Published: 2014-11-21

Total Pages: 702

ISBN-13: 1493915983

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This volume offers a comprehensive guide on the theory and practice of amorphous solid dispersions (ASD) for handling challenges associated with poorly soluble drugs. In twenty-three inclusive chapters, the book examines thermodynamics and kinetics of the amorphous state and amorphous solid dispersions, ASD technologies, excipients for stabilizing amorphous solid dispersions such as polymers, and ASD manufacturing technologies, including spray drying, hot melt extrusion, fluid bed layering and solvent-controlled micro-precipitation technology (MBP). Each technology is illustrated by specific case studies. In addition, dedicated sections cover analytical tools and technologies for characterization of amorphous solid dispersions, the prediction of long-term stability, and the development of suitable dissolution methods and regulatory aspects. The book also highlights future technologies on the horizon, such as supercritical fluid processing, mesoporous silica, KinetiSol®, and the use of non-salt-forming organic acids and amino acids for the stabilization of amorphous systems. Amorphous Solid Dispersions: Theory and Practice is a valuable reference to pharmaceutical scientists interested in developing bioavailable and therapeutically effective formulations of poorly soluble molecules in order to advance these technologies and develop better medicines for the future.

Practical Guide to Hot-Melt Extrusion
Practical Guide to Hot-Melt Extrusion

Author: Mohammed Maniruzzaman

Publisher: Smithers Rapra

Published: 2015-07-22

Total Pages: 249

ISBN-13: 1910242128

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Over the past few decades, hot-melt extrusion (HME) techniques have been shown to exhibit remarkable potential for the manufacture of various pharmaceutical products. HME is an emerging processing technology used primarily for the manufacture of pharmaceutical solid dispersions, combining the advantages of a solvent-free process with fewer production steps making it suitable for easy to scale-up and continuous manufacturing applications. A single unit HME based operation, employing heat and mechanical shear, has displayed a significant potential to retain the stability even of thermo-labile therapeutics e.g., proteins. HME has now explicitly been established from a quality-by-design viewpoint for in-line data monitoring as per the recent guidelines issued by the US Food and Drugs Administration (FDA).This book will focus primarily on the foregoing subject areas and will be of significant interest to a broad/interdisciplinary readership across the industries and academia for, (but not limited to) the following reasons:- Emerging HME processes and applications for multiple drug delivery.- Solid-state engineering, solubility enhancement, controlled release, taste masking and sustained release case studies from a continuous manufacturing view-point.- Means to explore the potential of continuous manufacture of co-crystals for promoting solvent free production methods.- Scale-up case study and issue considerations and studies on the regulatory guidelines (FDA) for continuous manufacturing involving emerging HME techniques.

Pharmaceutical Amorphous Solid Dispersions
Pharmaceutical Amorphous Solid Dispersions

Author: Ann Newman

Publisher: John Wiley & Sons

Published: 2015-03-09

Total Pages: 502

ISBN-13: 1118455207

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Providing a roadmap from early to late stages of drug development, this book overviews amorphous solid dispersion technology – a leading platform to deliver poorly water soluble drugs, a major hurdle in today’s pharmaceutical industry. • Helps readers understand amorphous solid dispersions and apply techniques to particular pharmaceutical systems • Covers physical and chemical properties, screening, scale-up, formulation, drug product manufacture, intellectual property, and regulatory considerations • Has an appendix with structure and property information for polymers commonly used in drug development and with marketed drugs developed using the amorphous sold dispersion approach • Addresses global regulatory issues including USA regulations, ICH guidelines, and patent concerns around the world

Hot-melt extrusion with poorly soluble drugs
Hot-melt extrusion with poorly soluble drugs

Author: Jessica Albers

Publisher: Cuvillier Verlag

Published: 2008-08-22

Total Pages: 156

ISBN-13: 3736926979

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Hot-melt extrusion with poorly soluble drugs is a challenging method to enhance the solubility. The formation of solid dispersions, specifically of glassy solid solutions, wherein the drug is dispersed on a molecular basis in an inert carrier, leads to metastable systems that have advantageous dissolution behaviour but suffer from physical stability problems. To date, there is poor understanding of the solid state structure, the mechanism by which dissolution enhancement occurs, the stability on storage and in dissolution, and the processing to solid dosage forms. The hot-melt extrusion process is influenced by several parameters. The right coordination of these parameters is decisive for the production of solid dispersions and thus, the success in solubility enhancement. The solid state and the viscosity of the extrudates can be controlled by the temperature of the barrels. Besides the configuration of the screw and the temperature profile of the barrel, the design of the die plate represents the third important extrusion parameter. By keeping the dead storage capacity at a minimum, an early solidification and thus a blockage of the dies can be prevented. Due to shear forces evolving in the extruder barrel and the ability of the drug to dissolve in the molten carrier before reaching the melting temperature, the process temperature can be kept below the melting point of the substances. Basic butylated methacrylate copolymer is a suitable carrier to enhance the solubility of the poorly water-soluble drug celecoxib in a hot-melt extrusion process. The best solubility enhancement can be obtained by dispersing the drug in the molten carrier on a molecular basis and thus, to form glassy solid solutions. The solid state characteristics of the solid dispersion can be revealed by DSC analysis and interpretation of the corresponding glass transitions. Such systems may contain a drug load of up to 60% and are stable at increased temperature and humidity which is due to the very low water uptake of the components. Glassy solid solutions of celecoxib and basic butylated methacrylate copolymer have a fast dissolution rate and result in a 58 fold supersaturated solution. The mechanism of drug release from these glassy solid solutions is carrier-controlled and governed by dissolution. The enhancement of the dissolution rate is based on improved solubility and wettability. Basic butylated methacrylate copolymer interacts chemically with celecoxib in an acid-base reaction. The hot-melt extrusion process is highly dependent on the physicochemical properties of the compounds and their miscibility in the molten state. The use of basic butylated methacrylate copolymer as solubility enhancing carrier in hot-melt extrusion cannot be transferred easily to all drugs. Depending on the properties of the drug, specifically the melting point and the pKa, basic butylated methacrylate copolymer can be a useful carrier in glassy solid solution formation, but might be insufficient for solubility improvement. The formation of a glassy solid solution evolves from interactions between the drug and the carrier. Bonds can differ in their strength and can be advantageous or disadvantageous for a fast dissolution. Furthermore, decomposition processes can occur, when processing the drug at high temperatures. Thus, each formulation has to be analyzed separately. The interpretation of the chemical structure, the calculation of solubility parameters, the determination of melting temperatures and enthalpies, and the performance of molecular dynamics simulations are tools to predict the miscibility of drugs and carriers for the formulation of solid dispersions. A combined approach of tools predicting miscibility is highly appropriate, as no single technique may yield all the required information. Nevertheless, the evaluation of the melting behaviour via DSC has the highest impact. Hot-melt extruded glassy solid solutions can be processed into solid dosage forms. The mechanical energy input through milling and zabletting has no influence on the solid-state stability. The solution-state stability can be achieved by adding HPMC to the external phase. The filling of capsules with milled hot-melt extrudates is a promising technique to obtain solid dosage forms from glassy solid solutions. By the extensive analysis of the hot-melt extrusion process, the interactions of the compounds, the thermal characteristics, and the dissolution mechanism of the resulting systems, it is possible to predict the extrusion process in an early stage of development and to improve the dissolution of poorly soluble drugs.

Application of Reactive Melt Extrusion for Bioavailability Enhancement and Modified Drug Release
Application of Reactive Melt Extrusion for Bioavailability Enhancement and Modified Drug Release

Author: Xu Liu (Ph. D.)

Publisher:

Published: 2020

Total Pages: 528

ISBN-13:

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Hot melt extrusion (HME) has been widely applied to prepare amorphous solid dispersions (ASD) to improve the oral bioavailability of BCS Class II and Class IV compounds by increasing their kinetic solubility and dissolution rate. During the HME process, drug, polymer and other excipients are introduced into the barrel at different temperature setting and feed rates. The intermeshing screws mix and melt all materials using heat and an intense mechanical shearing force to achieve distributive and dispersive mixing and excellent homogeneity. The molecular level mixing allows close contact between API and excipients at high frequencies, which provide favorable environment to build drug-excipient intermolecular interactions to improve the physicochemical properties of ASD. Even though there are extensive reports about the pharmaceutical application of HME, most of the studies have been restricted to the manufacture of drug delivery systems where no clearly defined molecular level interaction are produced. Since the extrusion process is a high temperature and aggressive molecular level mixing process, lot of interactions would occur during the extrusion process, such as the ionic interaction, hydrogen bonding, pi-pi interaction, Van der Walls forces and lipophilic-lipophilic interactions. The rational design interactions between drug and excipients during the HME process would provide an inspiring strategy to overcome the drawback of HME, such as the thermal degradation of drug, poor physical stability of drug during the storage time or dissolution process. For ASD development, the polymer carriers play a critical role in stabilizing the drug amorphous state. Polymer selection to prepare the ASDs is largely empirical. There is a need for rational polymer selection, enabling design of stable amorphous solid dispersion. Drug-polymer interactions have been observed to improve the physical stability of ASDs. Supramolecular synthon approach has been applied to design cocrystal with adjusting physicochemical properties. What’s more, supramolecular synthon approach has been exploited to design ASD with exceptional physical stability. Based on all those non-covalent interactions, it is possible to achieve the in-situ modification of solid forms of active pharmaceutical ingredients by mechanochemistry using extrusion process, without changing the pharmacology of the API. The major goal of this research is to explore rational design interaction between drug and excipients during the HME process to prepare salt, polyelectronic complexes, nanocomposites, cocrystal and coamorphous to improve the oral bioavailability of poorly water-soluble drugs and adjusting drug release rate. In Chapter 1, we reviewed the most commonly used methods for characterization of ASDs both in solid state or in aqueous media. The advantage and disadvantage of each method is briefly summarized. All methods are divided into three different categories: microscopic and surface analysis methods, thermal analysis methods and spectroscopic methods. The latest characterization techniques are also introduced. Last, we discuss how these methods are applied at different stages in the ASDs product development life cycle. In Chapter 2, we investigate the reaction between naproxen and meglumine at elevated temperature with different molar ratio and study the impact of this reaction on the physical stabilities and in vitro drug-release properties of melt-extrudated naproxen amorphous solid dispersion. In Chapter 3, we use reactive melt extrusion to prepare sustained release lidocaine polyelectrolyte complex. In this study, the influence of the drug form (freebase vs. hydrochloride salt) on lidocaine-Eudragit L100-55 interactions, physical stability, and dissolution properties of extrudates was investigated. In Chapter 4, we prepare exfoliated montmorillonite-Eudragit RS nanocomposites using reactive melt extrusion and investigate the influence of clay loading, clay types on clay-polymer interactions and drug release properties. The clays are used as the filler material with Eudragit RS at different concentration and theophylline was the model compound. The resulting structure of the nanocomposites were characterized using TEM and XRPD. The hygroscopicity of the nanocomposites was investigated using DVS. The effect of the interfacial interaction between the polymer and the clay sheet, the clay loading as well as the clay type on the drug release behavior were further studied by the dissolution testing

Innovative Dosage Forms
Innovative Dosage Forms

Author: Yogeshwar Bachhav

Publisher: John Wiley & Sons

Published: 2019-08-20

Total Pages: 498

ISBN-13: 3527812180

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Teaches future and current drug developers the latest innovations in drug formulation design and optimization This highly accessible, practice-oriented book examines current approaches in the development of drug formulations for preclinical and clinical studies, including the use of functional excipients to enhance solubility and stability. It covers oral, intravenous, topical, and parenteral administration routes. The book also discusses safety aspects of drugs and excipients, as well as regulatory issues relevant to formulation. Innovative Dosage Forms: Design and Development at Early Stage starts with a look at the impact of the polymorphic form of drugs on the preformulation and formulation development. It then offers readers reliable strategies for the formulation development of poorly soluble drugs. The book also studies the role of reactive impurities from the excipients on the formulation shelf life; preclinical formulation assessment of new chemical entities; and regulatory aspects for formulation design. Other chapters cover innovative formulations for special indications, including oncology injectables, delayed release and depot formulations; accessing pharmacokinetics of various dosage forms; physical characterization techniques to assess amorphous nature; novel formulations for protein oral dosage; and more. -Provides information that is essential for the drug development effort -Presents the latest advances in the field and describes in detail innovative formulations, such as nanosuspensions, micelles, and cocrystals -Describes current approaches in early pre-formulation to achieve the best in vivo results -Addresses regulatory and safety aspects, which are key considerations for pharmaceutical companies -Includes case studies from recent drug development programs to illustrate the practical challenges of preformulation design Innovative Dosage Forms: Design and Development at Early Stage provides valuable benefits to interdisciplinary drug discovery teams working in industry and academia and will appeal to medicinal chemists, pharmaceutical chemists, and pharmacologists.

Hot-Melt Extrusion
Hot-Melt Extrusion

Author: Dennis Douroumis

Publisher: John Wiley & Sons

Published: 2012-06-25

Total Pages: 404

ISBN-13: 0470711183

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Hot-melt extrusion (HME) - melting a substance and forcing it through an orifice under controlled conditions to form a new material - is an emerging processing technology in the pharmaceutical industry for the preparation of various dosage forms and drug delivery systems, for example granules and sustained release tablets. Hot-Melt Extrusion: Pharmaceutical Applications covers the main instrumentation, operation principles and theoretical background of HME. It then focuses on HME drug delivery systems, dosage forms and clinical studies (including pharmacokinetics and bioavailability) of HME products. Finally, the book includes some recent and novel HME applications, scale -up considerations and regulatory issues. Topics covered include: principles and die design of single screw extrusion twin screw extrusion techniques and practices in the laboratory and on production scale HME developments for the pharmaceutical industry solubility parameters for prediction of drug/polymer miscibility in HME formulations the influence of plasticizers in HME applications of polymethacrylate polymers in HME HME of ethylcellulose, hypromellose, and polyethylene oxide bioadhesion properties of polymeric films produced by HME taste masking using HME clinical studies, bioavailability and pharmacokinetics of HME products injection moulding and HME processing for pharmaceutical materials laminar dispersive & distributive mixing with dissolution and applications to HME technological considerations related to scale-up of HME processes devices and implant systems by HME an FDA perspective on HME product and process understanding improved process understanding and control of an HME process with near-infrared spectroscopy Hot-Melt Extrusion: Pharmaceutical Applications is an essential multidisciplinary guide to the emerging pharmaceutical uses of this processing technology for researchers in academia and industry working in drug formulation and delivery, pharmaceutical engineering and processing, and polymers and materials science. This is the first book from our brand new series Advances in Pharmaceutical Technology. Find out more about the series here.