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Michael A. Repka - One of the best experts on this subject based on the ideXlab platform.
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novel gastroretentive floating pulsatile drug delivery system produced via hot Melt Extrusion and fused deposition modeling 3d printing
Pharmaceutics, 2020Co-Authors: Nagireddy Dumpa, Suresh Bandari, Michael A. RepkaAbstract:This study was performed to develop novel core-shell gastroretentive floating pulsatile drug delivery systems using a hot-Melt Extrusion-paired fused deposition modeling (FDM) 3D printing and direct compression method. Hydroxypropyl cellulose (HPC) and ethyl cellulose (EC)-based filaments were fabricated using hot-Melt Extrusion technology and were utilized as feedstock material for printing shells in FDM 3D printing. The directly compressed theophylline tablet was used as the core. The tablet shell to form pulsatile floating dosage forms with different geometries (shell thickness: 0.8, 1.2, 1.6, and 2.0 mm; wall thickness: 0, 0.8, and 1.6 mm; and % infill density: 50, 75, and 100) were designed, printed, and evaluated. All core-shell tablets floated without any lag time and exhibited good floating behavior throughout the dissolution study. The lag time for the pulsatile release of the drug was 30 min to 6 h. The proportion of ethyl cellulose in the filament composition had a significant (p < 0.05) effect on the lag time. The formulation (2 mm shell thickness, 1.6 mm wall thickness, 100% infill density, 0.5% EC) with the desired lag time of 6 h was selected as an optimized formulation. Thus, FDM 3D printing is a potential technique for the development of complex customized drug delivery systems for personalized pharmacotherapy.
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development of poloxamer gel formulations via hot Melt Extrusion technology
International Journal of Pharmaceutics, 2018Co-Authors: Nicole S. Mendonsa, Feng Zhang, Narasimha S Murthy, Seyed Meysam Hashemnejad, Santanu Kundu, Michael A. RepkaAbstract:Abstract Poloxamer gels are conventionally prepared by the “hot” or the “cold” process. But these techniques have some disadvantages such as high energy consumption, requires expensive equipment and often have scale up issues. Therefore, the objective of this work was to develop poloxamer gels by hot-Melt Extrusion technology. The model drug selected was ketoprofen. The formulations developed were 30% and 40% poloxamer gels. Of these formulations, the 30% poloxamer gels were selected as ideal gels. DSC and XRD studies showed an amorphous nature of the drug after Extrusion. It was observed from the permeation studies that with increasing poloxamer concentration, a decrease in drug permeation was obtained. Other studies conducted for the formulations included in-vitro release studies, texture analysis, rheological studies and pH measurements. In conclusion, the hot-Melt Extrusion technology could be successfully employed to develop poloxamer gels by overcoming the drawbacks associated with the conventional techniques.
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Bioadhesive Drug Delivery System for Enhancing the Permeability of a BCS Class III Drug via Hot-Melt Extrusion Technology
AAPS PharmSciTech, 2017Co-Authors: Nicole S. Mendonsa, Priyanka Thipsay, Scott T. Martin, Michael A. RepkaAbstract:As the buccal route of administration has the ability to avoid the GI tract and first-pass effect by directing the absorption toward the cheek area, the bioavailability of BCS class III drugs can be increased through this route. Only a handful of studies have been conducted using oleic acid as a permeation enhancer in any transbuccal drug delivery system. Therefore, the objectives of this novel study were to develop a buccal tablet using two concentrations of oleic acid for a model BCS class III drug via hot-Melt Extrusion technology and to investigate the effects of oleic acid on the physicochemical properties of the tablet. The model drug selected was ondansetron hydrochloride. Formulations consisting of polymers (hydroxypropyl methylcellulose and polyethylene oxide) and two concentrations of oleic acid were prepared by hot-Melt Extrusion techniques. A Melting point depression of the drug was obtained in the extruded granules as seen by the DSC thermograms. The ex vivo permeation studies showed a greater permeation of the drug in the formulation containing 10% oleic acid (F2) as compared to the formulation containing 20% oleic acid (F1), although not statistically significant. The in vitro bioadhesion studies, swelling studies, and surface pH measurements of the tablets were also conducted. In conclusion, permeation studies exhibited the potential of oleic acid as a buccal permeation enhancer as a significant permeation of the drug was obtained in the formulations. Hot-Melt Extrusion technology was successfully employed to formulate buccal tablets of ondansetron hydrochloride.
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Dual-mechanism gastroretentive drug delivery system loaded with an amorphous solid dispersion prepared by hot-Melt Extrusion
European Journal of Pharmaceutical Sciences, 2017Co-Authors: Anh Q. Vo, Manjeet B. Pimparade, Xinyou Ye, Scott T. Martin, Xin Feng, Michael A. RepkaAbstract:Abstract In the present study, we aimed to prepare a gastroretentive drug delivery system that would be both highly resistant to gastric emptying via multiple mechanisms and would also potentially induce in situ supersaturation. The bioadhesive floating pellets, loaded with an amorphous solid dispersion, were prepared in a single step of hot-Melt Extrusion technology. Hydroxypropyl cellulose (Klucel™ MF) and hypromellose (Benecel™ K15M) were used as matrix-forming polymers, and felodipine was used as the model drug. The foam pellets were fabricated based on the expansion of CO2, which was generated from sodium bicarbonate during the Melt-Extrusion process. A 2n full factorial experimental design was utilized to investigate the effects of formulation compositions to the pellet properties. The Melt-Extrusion process transformed the crystalline felodipine into an amorphous state that was dispersed and “frozen” in the polymer matrix. All formulations showed high porosity and were able to float immediately, without lag time, on top of gastric fluid, and maintained their buoyancy over 12 h. The pellet-specific floating force, which could be as high as 4800 μN/g, increased significantly during the first hour, and was relatively stable until 9 h. The sodium bicarbonate percentage was found to be most significantly effect to the floating force. The ex vivo bioadhesion force of the pellets to porcine stomach mucosa was approximately 5 mN/pellet, which was more than five times higher than the gravitation force of the pellet saturated with water. Drug release was well controlled up to 12 h in the sink condition of 0.5% sodium lauryl sulphate in 0.1 N HCl. The dissolution at 1, 3, 5, and 8 h were 5–12%, 25–45%, 55–80%, and ≥ 75% respectively for all 11 formulations. In biorelevant dissolution medium, a supersaturated solution was formed, and the concentration was maintained at around 2 μg/mL, approximately 10-folds higher than that of the pure felodipine. All input factors significantly affected dissolution in the first 3 h, but afterwards, only drug load and hypromellose (HPMC) content had significant effects. The prepared drug delivery system has great potential in overcoming low and fluctuating bioavailability of poorly soluble drugs. Chemical Felodipine (PubChem CID: 3333); hypromellose (PubChem CID: 57503849), hydroxypropyl cellulose (PubChem CID: 71306830), sodium bicarbonate (PubChem CID: 516892); sodium carbonate (PubChem CID: 10340).
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the effects of polymer carrier hot Melt Extrusion process and downstream processing parameters on the moisture sorption properties of amorphous solid dispersions
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Xin Feng, Manjeet B. Pimparade, Abdullah S. Alshetaili, Roshan V. Tiwari, Hemlata Patil, Michael A. RepkaAbstract:Objective The aim of this study was to evaluate the effect of polymer carrier, hot Melt Extrusion and downstream processing parameters on the water uptake properties of amorphous solid dispersions. Methods Three polymers and a model drug were used to prepare amorphous solid dispersions utilizing the hot Melt Extrusion technology. The sorption–desorption isotherms of solid dispersions and their physical mixtures were measured by the dynamic vapour sorption system, and the effects of polymer hydrophobicity, hygroscopicity, molecular weight and the hot Melt Extrusion process were investigated. Fourier transform infrared (FTIR) imaging was performed to understand the phase separation driven by the moisture. Key findings Solid dispersions with polymeric carriers with lower hydrophilicity, hygroscopicity and higher molecular weight could sorb less moisture under the high relative humidity (RH) conditions. The water uptake ability of polymer–drug solid dispersion systems were decreased compared with the physical mixture after hot Melt Extrusion, which might be due to the decreased surface area and porosity. The FTIR imaging indicated that the homogeneity of the drug molecularly dispersed within the polymer matrix was changed after exposure to high RH. Conclusion Understanding the effect of formulation and processing on the moisture sorption properties of solid dispersions is essential for the development of drug products with desired physical and chemical stability.
James W. Mcginity - One of the best experts on this subject based on the ideXlab platform.
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hot Melt Extrusion versus spray drying hot Melt Extrusion degrades albendazole
Drug Development and Industrial Pharmacy, 2017Co-Authors: Soraya Hengsawas Surasarang, Siyuan Huang, Justin M Keen, James W. Mcginity, Feng Zhang, Robert O. WilliamsAbstract:AbstractThe purpose of this study was to enhance the dissolution properties of albendazole (ABZ) by the use of amorphous solid dispersions. Phase diagrams of ABZ–polymer binary mixtures generated from Flory–Huggins theory were used to assess miscibility and processability. Forced degradation studies showed that ABZ degraded upon exposure to hydrogen peroxide and 1 N NaOH at 80 °C for 5 min, and the degradants were albendazole sulfoxide (ABZSX), and ABZ impurity A, respectively. ABZ was chemically stable following exposure to 1 N HCl at 80 °C for one hour. Thermal degradation profiles show that ABZ, with and without Kollidon® VA 64, degraded at 180 °C and 140 °C, respectively, which indicated that ABZ could likely be processed by thermal processing. Following hot Melt Extrusion, ABZ degraded up to 97.4%, while the amorphous ABZ solid dispersion was successfully prepared by spray drying. Spray-dried ABZ formulations using various types of acids (methanesulfonic acid, sulfuric acid and hydrochloric acid) and...
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hot Melt Extrusion basic principles and pharmaceutical applications
Drug Development and Industrial Pharmacy, 2014Co-Authors: Bo Lang, James W. Mcginity, Robert O. WilliamsAbstract:AbstractOriginally adapted from the plastics industry, the use of hot-Melt Extrusion has gained favor in drug delivery applications both in academia and the pharmaceutical industry. Several commercial products made by hot-Melt Extrusion have been approved by the FDA, demonstrating its commercial feasibility for pharmaceutical processing. A significant number of research articles have reported on advances made regarding the pharmaceutical applications of the hot-Melt Extrusion processing; however, only limited articles have been focused on general principles regarding formulation and process development. This review provides an in-depth analysis and discussion of the formulation and processing aspects of hot-Melt Extrusion. The impact of physicochemical properties of drug substances and excipients on formulation development using a hot-Melt Extrusion process is discussed from a material science point of view. Hot-Melt Extrusion process development, scale-up, and the interplay of formulation and process att...
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fusion production of solid dispersions containing a heat sensitive active ingredient by hot Melt Extrusion and kinetisol dispersing
European Journal of Pharmaceutics and Biopharmaceutics, 2010Co-Authors: James Dinunzio, Robert O. Williams, Chris Brough, Justin R Hughey, Dave A Miller, James W. McginityAbstract:Abstract Many techniques for the production of solid dispersions rely on elevated temperatures and prolonged material residence times, which can result in decomposition of temperature-sensitive components. In this study, hydrocortisone was used as a model temperature-sensitive active ingredient to study the effect of formulation and processing techniques as well as to characterize the benefits of KinetiSol® Dispersing for the production of solid dispersions. Preformulation studies were conducted using differential scanning calorimetry and hot stage microscopy to identify optimum carriers for the production of amorphous solid dispersions. After identification, solid dispersions were prepared by hot Melt Extrusion and KinetiSol® Dispersing, with material characterized by X-ray diffraction, dissolution and potency testing to evaluate physicochemical properties. Results from the preformulation studies showed that vinylacetate:vinylpyrrolidone (PVPVA) copolymer allowed for hydrocortisone dissolution within the carrier at temperatures as low as 160 °C, while hydroxypropyl methylcellulose required temperatures upward of 180 °C to facilitate solubilization. Low substituted hydroxypropyl cellulose, a high glass transition temperature control, showed that the material was unable to solubilize hydrocortisone. Manufacturing process control studies using hot Melt extruded compositions of hydrocortisone and PVPVA showed that increased temperatures and residence times negatively impacted product potency due to decomposition. Using KinetiSol® Dispersing to reduce residence time and to facilitate lower temperature processing, it was possible to produce solid dispersions with improved product potency. This study clearly demonstrated the importance of carrier selection to facilitate lower temperature processing, as well as the effect of residence time on product potency. Furthermore, KinetiSol® Dispersing provided significant advantages over hot Melt Extrusion due to the reduced residence times and lower required processing temperatures. This allowed for the production of solid dispersions with enhanced product potency.
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pharmaceutical applications of hot Melt Extrusion part i
Drug Development and Industrial Pharmacy, 2007Co-Authors: Michael M Crowley, Michael A. Repka, James W. Mcginity, Feng Zhang, Sridhar Thumma, Sampada B Upadhye, Sunil Kumar Battu, Charles R MartinAbstract: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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influence of a lipophilic thermal lubricant on the processing conditions and drug release properties of chlorpheniramine maleate tablets prepared by hot Melt Extrusion
Journal of Drug Delivery Science and Technology, 2004Co-Authors: Y Zhu, Navnit Hargovindas Shah, A W Malick, Martin Howard Infeld, James W. McginityAbstract:The objective of this study was to investigate the influence of a lipophilic thermal lubricant on the processing conditions and properties of chlorpheniramine maleate (CPM) tablets prepared by hot-Melt Extrusion. CPM tablets containing Eudragit RS PO, triethyl citrate (TEC) and glyceryl monostearate (GMS) were prepared by hot-Melt Extrusion. An investigation of the thermal stability of CPM, Eudragit RS PO, TEC and GMS as determined by thermogravimetric analysis (TGA) showed that CPM and the excipient components of the extruded tablets were stable at the thermal processing temperatures. The incorporation of either TEC or GMS into the powder blend decreased the drive AMPS and the torque values during the hot-Melt Extrusion process. The glass transition temperature of Eudragit RS PO and the Melting point of GMS were determined using differential scanning calorimetry (DSC) from a physical mixture, and the results demonstrated that these two materials were not miscible in the molten state. These results were in agreement with findings from scanning electron microscopy (SEM) and X-ray diffraction studies. An increase in the thermal lubricant (GMS) level in the Eudragit RS PO system resulted in an increase in the rate of drug release from the tablets. Both TEC and GMS facilitated thermal processing. While TEC lowered both the glass transition temperature and the Melt viscosity of the acrylic polymer, GMS only decreased the Melt viscosity of the acrylic polymer and had no effect on the glass transition temperature.
Dennis Douroumis - One of the best experts on this subject based on the ideXlab platform.
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Development and optimization of ketoconazole oral strips by means of continuous hot-Melt Extrusion processing
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Mohammed Maniruzzaman, Smirna Farias, Arun Nair, Joshua S Boateng, Babur Z Chowdhry, Ian J. Slipper, Dennis DouroumisAbstract:Objectives The aim of this study was to develop mucoadhesive oral strips using hot-Melt Extrusion as a continuous manufacturing process. Methods Powder blends of ketoconazole, a water-insoluble drug – either hydroxypropyl methylcellulose (HPMC) or soluplus (SOL), sorbitol (SRB) and magnesium aluminometasilicate (MAS) were extruded to manufacture thin strips with 0.5-mm thickness. The presence of the inorganic metasilicate facilitated smooth processing of the extruded strips as it worked as an absorbent directly impacting on the extensive mixing of the drug/excipients inside the extruder barrel. Key findings The use of MAS also favoured the rapid hydration, swelling and eventual disintegration of the strips. Differential scanning calorimetry and transmission X-ray diffraction analysis revealed the existence of the amorphous drug within the extruded strips. Scanning electron microscopy and energy dispersive X-ray undertaken on the formulations showed a homogeneous drug distribution within the extruded strips. Conclusion The strips produced via continuous hot-Melt Extrusion processing showed significantly faster release of ketoconazole compared to the bulk drug substance.
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Novel Controlled Release Polymer-Lipid Formulations Processed by Hot Melt Extrusion
AAPS PharmSciTech, 2016Co-Authors: Mohammed Maniruzzaman, Muhammad T. Islam, Sheelagh Halsey, Devyani Amin, Dennis DouroumisAbstract:The aim of the study was to investigate the effect of novel polymer/lipid formulations on the dissolution rates of the water insoluble indomethacin (INM), co-processed by hot Melt Extrusion (HME). Formulations consisted of the hydrophilic hydroxypropyl methyl cellulose polymer (HPMCAS) and stearoyl macrogol-32 glycerides—Gelucire 50/13 (GLC) were processed with a twin screw extruder to produce solid dispersions. The extrudates characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and hot stage microscopy (HSM) indicated the presence of amorphous INM within the polymer/lipid matrices. In-line monitoring via near-infrared (NIR) spectroscopy revealed significant peak shifts indicating possible interactions and H-bonding formation between the drug and the polymer/lipid carriers. Furthermore, in vitro dissolution studies showed a synergistic effect of the polymer/lipid carrier with 2-h lag time in acidic media followed by enhanced INM dissolution rates at pH > 5.5.
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increased dissolution rates of carbamazepine gluconolactone binary blends processed by hot Melt Extrusion
Pharmaceutical Development and Technology, 2015Co-Authors: Hiren G. Moradiya, Ali Nokhodchi, M S A Bradley, R J Farnish, Dennis DouroumisAbstract:Carbamazepine (CBZ) shows a poor dissolution, therefore, it is important to enhance its dissolution in GI tract to improve its bioavailability. In the present study, a new hydrophilic carrier, d-gluconolactone (GNL), was extruded with CBZ at various molar ratios to produce granules by using hot Melt Extrusion (HME) processing. The granular extrudates were characterised by X-ray powder diffraction, differential scanning calorimetry and hot stage microscopy to determine the solid state of CBZ. It was found that bulk CBZ (Form-III) transformed to the polymorphic Form-I during the HME processing. GNL was proved to be an efficient carrier for CBZ to enhance the dissolution rate. The increase in the dissolution rate was observed for both physical mixtures and the extrudates of CBZ-GNL. However, the extrudates showed faster dissolution rates compared to physical mixtures in an ascending order of 2:1 < 1:1 < 1.5:1 (CBZ:GNL). The increase in the dissolution rates was attributed to the transformation of CBZ III to Form-I and also to the increased drug wettability/solubilisation in the presence of the carrier
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Continuous cocrystallisation of carbamazepine and trans-cinnamic acid via Melt Extrusion processing
CrystEngComm, 2014Co-Authors: Hiren G. Moradiya, Muhammad T. Islam, Sheelagh A. Halsey, Babur Z Chowdhry, Martin J Snowden, Mohammed Maniruzzaman, Dennis DouroumisAbstract:A solvent free process for the formation of carbamazepine (CBZ)–trans-cinnamic acid (TCA) cocrystals, in stoichiometric ratios, was developed using continuous hot Melt Extrusion processing. Physicochemical characterization of the CBZ–TCA extrudates included scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and hot stage microscopy to evaluate the shape, morphology, purity and crystallinity of the freshly made cocrystals. The obtained cocrystals were of high quality compared to the prototype produced by a solvent crystallization technique. Furthermore, an in-line NIR probe was used to investigate the gradual formation of cocrystals during Extrusion processing. The quality of the CBZ–TCA cocrystals was found to depend on the processing parameters such as temperature and the screw type. The extruded cocrystals showed faster dissolution rates compared to bulk CBZ and the prototype cocrystals.
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a review of hot Melt Extrusion process technology to pharmaceutical products
International Scholarly Research Notices, 2012Co-Authors: Mohammed Maniruzzaman, Joshua S Boateng, Martin J Snowden, Dennis DouroumisAbstract:Over the last three decades industrial adaptability has allowed hot-Melt Extrusion (HME) to gain wide acceptance and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. HME has already been demonstrated as a robust, novel technique to make solid dispersions in order to provide time controlled, modified, extended, and targeted drug delivery resulting in improved bioavailability as well as taste masking of bitter active pharmaceutical ingredients (APIs). This paper reviews the innumerable benefits of HME, based on a holistic perspective of the equipment, processing technologies to the materials, novel formulation design and developments, and its varied applications in oral drug delivery systems.
Mohammed Maniruzzaman - One of the best experts on this subject based on the ideXlab platform.
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advanced pharmaceutical applications of hot Melt Extrusion coupled with fused deposition modelling fdm 3d printing for personalised drug delivery
Pharmaceutics, 2018Co-Authors: Mohammed Maniruzzaman, Ali NokhodchiAbstract:Three-dimensional printing, also known as additive manufacturing, is a fabrication process whereby a 3D object is created layer-by-layer by depositing a feedstock material such as thermoplastic polymer. The 3D printing technology has been widely used for rapid prototyping and its interest as a fabrication method has grown significantly across many disciplines. The most common 3D printing technology is called the Fused Deposition Modelling (FDM) which utilises thermoplastic filaments as a starting material, then extrudes the material in sequential layers above its Melting temperature to create a 3D object. These filaments can be fabricated using the Hot-Melt Extrusion (HME) technology. The advantage of using HME to manufacture polymer filaments for FDM printing is that a homogenous solid dispersion of two or more pharmaceutical excipients i.e., polymers can be made and a thermostable drug can even be introduced in the filament composition, which is otherwise impractical with any other techniques. By introducing HME techniques for 3D printing filament development can improve the bioavailability and solubility of drugs as well as sustain the drug release for a prolonged period of time. The latter is of particular interest when medical implants are considered via 3D printing. In recent years, there has been increasing interest in implementing a continuous manufacturing method on pharmaceutical products development and manufacture, in order to ensure high quality and efficacy with less batch-to-batch variations of the pharmaceutical products. The HME and FDM technology can be combined into one integrated continuous processing platform. This article reviews the working principle of Hot Melt Extrusion and Fused Deposition Modelling, and how these two technologies can be combined for the use of advanced pharmaceutical applications.
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Development and optimization of ketoconazole oral strips by means of continuous hot-Melt Extrusion processing
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Mohammed Maniruzzaman, Smirna Farias, Arun Nair, Joshua S Boateng, Babur Z Chowdhry, Ian J. Slipper, Dennis DouroumisAbstract:Objectives The aim of this study was to develop mucoadhesive oral strips using hot-Melt Extrusion as a continuous manufacturing process. Methods Powder blends of ketoconazole, a water-insoluble drug – either hydroxypropyl methylcellulose (HPMC) or soluplus (SOL), sorbitol (SRB) and magnesium aluminometasilicate (MAS) were extruded to manufacture thin strips with 0.5-mm thickness. The presence of the inorganic metasilicate facilitated smooth processing of the extruded strips as it worked as an absorbent directly impacting on the extensive mixing of the drug/excipients inside the extruder barrel. Key findings The use of MAS also favoured the rapid hydration, swelling and eventual disintegration of the strips. Differential scanning calorimetry and transmission X-ray diffraction analysis revealed the existence of the amorphous drug within the extruded strips. Scanning electron microscopy and energy dispersive X-ray undertaken on the formulations showed a homogeneous drug distribution within the extruded strips. Conclusion The strips produced via continuous hot-Melt Extrusion processing showed significantly faster release of ketoconazole compared to the bulk drug substance.
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Novel Controlled Release Polymer-Lipid Formulations Processed by Hot Melt Extrusion
AAPS PharmSciTech, 2016Co-Authors: Mohammed Maniruzzaman, Muhammad T. Islam, Sheelagh Halsey, Devyani Amin, Dennis DouroumisAbstract:The aim of the study was to investigate the effect of novel polymer/lipid formulations on the dissolution rates of the water insoluble indomethacin (INM), co-processed by hot Melt Extrusion (HME). Formulations consisted of the hydrophilic hydroxypropyl methyl cellulose polymer (HPMCAS) and stearoyl macrogol-32 glycerides—Gelucire 50/13 (GLC) were processed with a twin screw extruder to produce solid dispersions. The extrudates characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and hot stage microscopy (HSM) indicated the presence of amorphous INM within the polymer/lipid matrices. In-line monitoring via near-infrared (NIR) spectroscopy revealed significant peak shifts indicating possible interactions and H-bonding formation between the drug and the polymer/lipid carriers. Furthermore, in vitro dissolution studies showed a synergistic effect of the polymer/lipid carrier with 2-h lag time in acidic media followed by enhanced INM dissolution rates at pH > 5.5.
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Continuous cocrystallisation of carbamazepine and trans-cinnamic acid via Melt Extrusion processing
CrystEngComm, 2014Co-Authors: Hiren G. Moradiya, Muhammad T. Islam, Sheelagh A. Halsey, Babur Z Chowdhry, Martin J Snowden, Mohammed Maniruzzaman, Dennis DouroumisAbstract:A solvent free process for the formation of carbamazepine (CBZ)–trans-cinnamic acid (TCA) cocrystals, in stoichiometric ratios, was developed using continuous hot Melt Extrusion processing. Physicochemical characterization of the CBZ–TCA extrudates included scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and hot stage microscopy to evaluate the shape, morphology, purity and crystallinity of the freshly made cocrystals. The obtained cocrystals were of high quality compared to the prototype produced by a solvent crystallization technique. Furthermore, an in-line NIR probe was used to investigate the gradual formation of cocrystals during Extrusion processing. The quality of the CBZ–TCA cocrystals was found to depend on the processing parameters such as temperature and the screw type. The extruded cocrystals showed faster dissolution rates compared to bulk CBZ and the prototype cocrystals.
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a review of hot Melt Extrusion process technology to pharmaceutical products
International Scholarly Research Notices, 2012Co-Authors: Mohammed Maniruzzaman, Joshua S Boateng, Martin J Snowden, Dennis DouroumisAbstract:Over the last three decades industrial adaptability has allowed hot-Melt Extrusion (HME) to gain wide acceptance and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. HME has already been demonstrated as a robust, novel technique to make solid dispersions in order to provide time controlled, modified, extended, and targeted drug delivery resulting in improved bioavailability as well as taste masking of bitter active pharmaceutical ingredients (APIs). This paper reviews the innumerable benefits of HME, based on a holistic perspective of the equipment, processing technologies to the materials, novel formulation design and developments, and its varied applications in oral drug delivery systems.
Robert O. Williams - One of the best experts on this subject based on the ideXlab platform.
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Processing thermally labile drugs by hot-Melt Extrusion: The lesson with gliclazide.
European Journal of Pharmaceutics and Biopharmaceutics, 2017Co-Authors: Siyuan Huang, Sophie M. Delpon De Vaux, John P. O'brien, John R. Stutzman, Kevin P. O’donnell, Robert O. WilliamsAbstract:Abstract The formation of molecularly dispersed amorphous solid dispersions by the hot-Melt Extrusion technique relies on the thermal and mechanical energy inputs, which can cause chemical degradation of drugs and polymeric carriers. Additionally, drug degradation may be exacerbated as drugs convert from a more stable crystalline form to a higher energy amorphous form. Therefore, it is imperative to study how drug degrades and evaluate methods to minimize drug degradation during the Extrusion process. In this work, gliclazide was used as a model thermally labile drug for the degradation kinetics and process optimization studies. Preformulation studies were conducted using thermal analyses, and liquid chromatography–mass spectroscopy to identify drug degradation pathways and to determine initial Extrusion conditions. Formulations containing 10% drug and 90% AFFINISOL™ HPMC HME 100LV were then extruded using a twin screw extruder, and the extrudates were characterized using X-ray powder diffraction, modulated dynamic scanning calorimetry, and potency testing to evaluate physicochemical properties. The energies of activation for both amorphous gliclazide, crystalline gliclazide, and gliclazide solution were calculated using the Arrhenius equation to further guide the Extrusion optimization process. Preformulation studies identify two hydrolysis degradation pathways of gliclazide at elevated temperatures. The activation energy study indicates a significantly higher degradation rate for the amorphous gliclazide compared to the crystalline form. After optimization of the hot-Melt Extrusion process, including improved screw designs, machine setup, and processing conditions, gliclazide amorphous solid dispersion with ∼95% drug recovery was achieved. The ability to process thermally labile drugs and polymers using hot-Melt Extrusion will significantly expand the possible applications of this manufacturing process.
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hot Melt Extrusion versus spray drying hot Melt Extrusion degrades albendazole
Drug Development and Industrial Pharmacy, 2017Co-Authors: Soraya Hengsawas Surasarang, Siyuan Huang, Justin M Keen, James W. Mcginity, Feng Zhang, Robert O. WilliamsAbstract:AbstractThe purpose of this study was to enhance the dissolution properties of albendazole (ABZ) by the use of amorphous solid dispersions. Phase diagrams of ABZ–polymer binary mixtures generated from Flory–Huggins theory were used to assess miscibility and processability. Forced degradation studies showed that ABZ degraded upon exposure to hydrogen peroxide and 1 N NaOH at 80 °C for 5 min, and the degradants were albendazole sulfoxide (ABZSX), and ABZ impurity A, respectively. ABZ was chemically stable following exposure to 1 N HCl at 80 °C for one hour. Thermal degradation profiles show that ABZ, with and without Kollidon® VA 64, degraded at 180 °C and 140 °C, respectively, which indicated that ABZ could likely be processed by thermal processing. Following hot Melt Extrusion, ABZ degraded up to 97.4%, while the amorphous ABZ solid dispersion was successfully prepared by spray drying. Spray-dried ABZ formulations using various types of acids (methanesulfonic acid, sulfuric acid and hydrochloric acid) and...
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hot Melt Extrusion basic principles and pharmaceutical applications
Drug Development and Industrial Pharmacy, 2014Co-Authors: Bo Lang, James W. Mcginity, Robert O. WilliamsAbstract:AbstractOriginally adapted from the plastics industry, the use of hot-Melt Extrusion has gained favor in drug delivery applications both in academia and the pharmaceutical industry. Several commercial products made by hot-Melt Extrusion have been approved by the FDA, demonstrating its commercial feasibility for pharmaceutical processing. A significant number of research articles have reported on advances made regarding the pharmaceutical applications of the hot-Melt Extrusion processing; however, only limited articles have been focused on general principles regarding formulation and process development. This review provides an in-depth analysis and discussion of the formulation and processing aspects of hot-Melt Extrusion. The impact of physicochemical properties of drug substances and excipients on formulation development using a hot-Melt Extrusion process is discussed from a material science point of view. Hot-Melt Extrusion process development, scale-up, and the interplay of formulation and process att...
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fusion production of solid dispersions containing a heat sensitive active ingredient by hot Melt Extrusion and kinetisol dispersing
European Journal of Pharmaceutics and Biopharmaceutics, 2010Co-Authors: James Dinunzio, Robert O. Williams, Chris Brough, Justin R Hughey, Dave A Miller, James W. McginityAbstract:Abstract Many techniques for the production of solid dispersions rely on elevated temperatures and prolonged material residence times, which can result in decomposition of temperature-sensitive components. In this study, hydrocortisone was used as a model temperature-sensitive active ingredient to study the effect of formulation and processing techniques as well as to characterize the benefits of KinetiSol® Dispersing for the production of solid dispersions. Preformulation studies were conducted using differential scanning calorimetry and hot stage microscopy to identify optimum carriers for the production of amorphous solid dispersions. After identification, solid dispersions were prepared by hot Melt Extrusion and KinetiSol® Dispersing, with material characterized by X-ray diffraction, dissolution and potency testing to evaluate physicochemical properties. Results from the preformulation studies showed that vinylacetate:vinylpyrrolidone (PVPVA) copolymer allowed for hydrocortisone dissolution within the carrier at temperatures as low as 160 °C, while hydroxypropyl methylcellulose required temperatures upward of 180 °C to facilitate solubilization. Low substituted hydroxypropyl cellulose, a high glass transition temperature control, showed that the material was unable to solubilize hydrocortisone. Manufacturing process control studies using hot Melt extruded compositions of hydrocortisone and PVPVA showed that increased temperatures and residence times negatively impacted product potency due to decomposition. Using KinetiSol® Dispersing to reduce residence time and to facilitate lower temperature processing, it was possible to produce solid dispersions with improved product potency. This study clearly demonstrated the importance of carrier selection to facilitate lower temperature processing, as well as the effect of residence time on product potency. Furthermore, KinetiSol® Dispersing provided significant advantages over hot Melt Extrusion due to the reduced residence times and lower required processing temperatures. This allowed for the production of solid dispersions with enhanced product potency.