Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation-Where Are We Now?

Hot-melt extrusion (HME) is a globally recognized, robust, effective technology that enhances the bioavailability of poorly soluble active pharmaceutical ingredients and offers an efficient continuous manufacturing process. The twin-screw extruder (TSE) offers an extremely resourceful customizable mixer that is used for continuous compounding and granulation by using different combinations of conveying elements, kneading elements (forward and reverse configuration), and distributive mixing elements. TSE is thus efficiently utilized for dry, wet, or melt granulation not only to manufacture dosage forms such as tablets, capsules, or granule-filled sachets, but also for designing novel formulations such as dry powder inhalers, drying units for granules, nanoextrusion, 3D printing, complexation, and amorphous solid dispersions.

An update on the contribution of hot-melt extrusion technology to novel drug delivery in the twenty-first century: part II.

Introduction: Interest in hot-melt extrusion (HME) technology for novel applications is growing day by day, which is evident from several hundred publications within the last 5 years. HME is a cost-effective, solvent free, 'green' technology utilized for various formulations with low investment costs compared to conventional technologies. HME has also earned the attention of the pharmaceutical industry by the transformation of this technology for application in continuous manufacturing.

An update on the contribution of hot-melt extrusion technology to novel drug delivery in the twenty-first century: part I.

Introduction: Currently, hot melt extrusion (HME) is a promising technology in the pharmaceutical industry, as evidenced by its application to manufacture various FDA-approved commercial products in the market. HME is extensively researched for enhancing the solubility and bioavailability of poor water-soluble drugs, taste masking, and modifying release in drug delivery systems. Additionally, its other novel opportunities or pharmaceutical applications, and capability for continuous manufacturing are being investigated.

Effects of Processing on a Sustained Release Formulation Prepared by Twin-Screw Dry Granulation.

Dry granulation is an indispensable process used to improve the flow property of moisture-sensitive materials. Considering the limitations of currently available dry granulation techniques, it is necessary to develop a novel technique. In this study, a twin-screw dry granulation (TSDG) technology was successfully applied to produce a sustained-release dry granule formulation, which was subsequently compressed into sustained-release tablets.

Exploratory studies in heat-assisted continuous twin-screw dry granulation: A novel alternative technique to conventional dry granulation.

Dry granulation is the preferred technique for solvent-sensitive products, especially drugs with stability problems such as hydrolysis. Twin-screw granulation is a continuous granulation technique, offering a potential alternative to conventional dry granulation techniques such as roller compaction. The major advantage of twin-screw granulation is the ability to adjust process parameters of dry granulation without compromising the compression properties.

Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets.

The main objective of this work was to explore the potential of coupling fused deposition modeling in three-dimensional (3D) printing with hot-melt extrusion (HME) technology to facilitate additive manufacturing, in order to fabricate tablets with enhanced extended release properties. Acetaminophen was used as the model drug and different grades and ratios of polymers were used to formulate tablets. Three-point bending and hardness tests were performed to determine the mechanical properties of the filaments and tablets.

Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide.

The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3(2) factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM).

Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century.

Introduction: Hot-melt extrusion (HME) technology is applied successfully in the plastic, rubber and food industry. HME has also emerged as an important technology for drug delivery applications in pharmaceutical research and manufacturing because of its process automation and low-cost scale-up properties, which reduce labor costs and capital investment. There are a number of commercial FDA-approved HME-derived products, signifying the commercial feasibility of this novel technique in drug delivery applications.

Development of a fast dissolving film of epinephrine hydrochloride as a potential anaphylactic treatment for pediatrics.

Objective: To develop a fast dissolving film strip containing epinephrine HCl for the potential treatment of pediatric anaphylaxis.

Methods: Four different films have been prepared by solvent casting technique where the percentages of the polymer (Lycoat RS720) were optimized. The polymer percentages were (20%, 25%, 27% and 30%) of the total formulation weighs.

Significant Improvement of Optoelectronic and Photovoltaic Properties by Incorporating Thiophene in a Solution-Processable D-A-D Modular Chromophore.

Through the incorporation of a thiophene functionality, a novel solution-processable small organic chromophore was designed, synthesized and characterized for application in bulk-heterojunction solar cells. The new chromophore, (2Z,2'Z)-2,2'-(1,4-phenylene)bis(3-(5-(4-(diphenylamino)phenyl)thiophen-2-yl)acrylonitrile) (coded as AS2), was based on a donor-acceptor-donor (D-A-D) module where a simple triphenylamine unit served as an electron donor, 1,4-phenylenediacetonitrile as an electron acceptor, and a thiophene ring as the π-bridge embedded between the donor and acceptor functionalities. AS2 was isolated as brick-red, needle-shaped crystals, and was fully characterized by ¹H- and (13)C-NMR, IR, mass spectrometry and single crystal X-ray diffraction.

Development of an Ointment Formulation Using Hot-Melt Extrusion Technology.

Ointments are generally prepared either by fusion or by levigation methods. The current study proposes the use of hot-melt extrusion (HME) processing for the preparation of a polyethylene glycol base ointment. Lidocaine was used as a model drug.

The effects of polymer carrier, hot melt extrusion process and downstream processing parameters on the moisture sorption properties of amorphous solid dispersions.

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.

Rat Palatability Study for Taste Assessment of Caffeine Citrate Formulation Prepared via Hot-Melt Extrusion Technology.

Developing a pediatric oral formulation with an age-appropriate dosage form and taste masking of naturally bitter active pharmaceutical ingredients (APIs) are key challenges for formulation scientists. Several techniques are used for taste masking of bitter APIs to improve formulation palatability; however, not all the techniques are applicable to pediatric dosage forms because of the limitations on the kind and concentration of the excipients that can be used. Hot-melt extrusion (HME) technology is used successfully for taste masking of bitter APIs and overcomes some of the limitations of the existing taste-masking techniques.

Formulation and development of orodispersible sustained release tablet of domperidone.

Commercially available domperidone orodispersible tablets (ODT) are intended for immediate release of the drug, but none of them have been formulated for sustained action. The aim of the present research work was to develop and evaluate orodispersible sustained release tablet (ODT-SR) of domperidone, which has the convenience of ODT and benefits of controlled release product combined in one. The technology comprised of developing sustained release microspheres (MS) of domperidone, followed by direct compression of MS along with suitable excipients to yield ODT-SR which rapidly disperses within 30 seconds and yet the dispersed MS maintain their integrity to have a sustained drug release.

Isoindigo-Based Small Molecules with Varied Donor Components for Solution-Processable Organic Field Effect Transistor Devices.

Two solution-processable small organic molecules, (E)-6,6'-bis(4-(diphenylamino)phenyl)-1,1'-bis(2-ethylhexyl)-(3,3'-biindolinylidene)-2,2'-dione (coded as S10) and (E)-6,6'-di(9H-carbazol-9-yl)-1,1'-bis(2-ethylhexyl)-(3,3'-biindolinylidene)-2,2'-dione (coded as S11) were successfully designed, synthesized and fully characterized. S10 and S11 are based on a donor-acceptor-donor structural motif and contain a common electron accepting moiety, isoindigo, along with different electron donating functionalities, triphenylamine and carbazole, respectively. Ultraviolet-visible absorption spectra revealed that the use of triphenylamine donor functionality resulted in an enhanced intramolecular charge transfer transition and reduction of optical band gap, when compared with its carbazole analogue.

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions.

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary.

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation.

Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds.

Formulation and development of pH-independent/dependent sustained release matrix tablets of ondansetron HCl by a continuous twin-screw melt granulation process.

The objective of the present study was to develop pH-independent/dependent sustained release (SR) tablets of ondansetron HCl dihydrate (OND), a selective 5-HT3 receptor antagonist that is used for prevention of nausea and vomiting caused by chemotherapy, radiotherapy and postoperative treatment. The challenge with the OND API is its pH-dependent solubility and relatively short elimination half-life. Therefore, investigations were made to solve these problems in the current study.

Tetraphenylethene-based star shaped porphyrins: synthesis, self-assembly, and optical and photophysical study.

Supramolecular self-assembly and self-organization are simple and convenient ways to design and create controlled assemblies with organic molecules, and they have provoked great interest due to their potential applications in various fields, such as electronics, photonics, and light-energy conversion. Herein, we describe the synthesis of two π-conjugated porphyrin molecules bearing tetraphenylethene moieties with high fluorescence quantum yield. Photophysical and electrochemical studies were conducted to understand the physical and redox properties of these new materials, respectively.

Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach.

This contribution describes a continuous process for the production of solid lipid nanoparticles (SLN) as drug-carrier systems via hot-melt extrusion (HME). Presently, HME technology has not been used for the manufacturing of SLN. Generally, SLN are prepared as a batch process, which is time consuming and may result in variability of end-product quality attributes.

A non-fullerene electron acceptor based on fluorene and diketopyrrolopyrrole building blocks for solution-processable organic solar cells with an impressive open-circuit voltage.

A novel solution-processable non-fullerene electron acceptor 6,6'-(5,5'-(9,9-dioctyl-9H-fluorene-2,7-diyl)bis(thiophene-5,2-diyl))bis(2,5-bis(2-ethylhexyl)-3-(thiophen-2-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione) (DPP1) based on fluorene and diketopyrrolopyrrole conjugated moieties was designed, synthesized and fully characterized. DPP1 exhibited excellent solubility and high thermal stability which are essential for easy processing. Upon using DPP1 as an acceptor with the classical electron donor poly(3-hexylthiophene), solution processable bulk-heterojunction solar cells afforded a power conversion efficiency of 1.

Continuous manufacturing of solid lipid nanoparticles by hot melt extrusion.

Solid lipid nanoparticles (SLN) can either be produced by hot homogenization of melted lipids at higher temperatures or by a cold homogenization process. This paper proposes and demonstrates the formulation of SLN for pharmaceutical applications by combining two processes: hot melt extrusion (HME) technology for melt-emulsification and high-pressure homogenization (HPH) for size reduction. This work aimed at developing continuous and scalable processes for SLN by mixing a lipid and aqueous phase containing an emulsifier in the extruder barrel at temperatures above the melting point of the lipid and further reducing the particle size of emulsion by HPH linked to HME in a sequence.