Use Of Hot Melt Extrusion Research Articles

Formulation and evaluation of inhaled Sildenafil-loaded PLGA microparticles for treatment of pulmonary arterial hypertension (PAH): A novel high drug loaded formulation and scalable process via hot melt extrusion technology (Part Ⅰ)

In recent years, several techniques were employed to develop a local sustained pulmonary delivery of sildenafil citrate (SC) as an alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). Most of these methods, however, need to be improved due to limitations of scalability, low yield production, low drug loading, and stability issues. In this study, we report the use of hot-melt extrusion (HME) as a scalable process for making Poly (lactic-co-glycolic acid) (PLGA) microparticles with high SC load. The prepared particles were tested in vitro for local drug delivery to the lungs by inhalation. Sodium bicarbonate was included as a porogen in the formulation to make the particles more brittle and to impart favorable aerodynamic properties. Six formulations were prepared with different formulation compositions. Laser diffraction analysis was used to estimate the geometric particle size distribution of the microparticles. In-vitro aerodynamic performance was evaluated by the next-generation cascade impactor (NGI). It was reported in terms of an emitted dose (ED), an emitted fraction (EF%), a respirable fraction (RF%), a fine particle fraction (FPF%), a mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). The formulations have also been characterized for surface morphology, entrapment efficiency, drug load, and in-vitro drug release. The results demonstrated that PLGA microparticles have a mean geometric particle size between 6 and 14 µm, entrapment efficiency of 77 to 89 %, and SC load between 17 and 33 % w/w. Fifteen percent of entrapped sildenafil was released over 24 h from the PLGA microparticles, and seventy percent over 7 days. The aerodynamic properties included fine particle fraction ranging between 19 and 33 % and an average mass median aerodynamic diameter of 6–13 µm.

The Use of Hot Melt Extrusion to Prepare a Solid Dispersion of Ibuprofen in a Polymer Matrix.

In this work, we report the use of the hot melt extrusion method in harsh extrusion conditions, i.e., screw rotation speed of 250 rpm, temperature above 100 °C, and two mixing zones, in order to obtain an amorphous dispersion of an active pharmaceutical ingredient (API) that is sparingly soluble in water. As a polymer matrix Eudragit EPO (E-EPO) and as an API ibuprofen (IBU) were used in the research. In addition, the plasticizer Compritol 888 ATO (COM) was tested as a factor potentially improving processing parameters and modifying the IBU release profile. In studies, 25% by weight of IBU, 10% of COM and various extrusion temperatures, i.e., 90, 100, 120, 130, and 140 °C, were used. Hot melt extrusion (HME) temperatures were selected based on the glass transition temperature of the polymer matrix (Tg = 42 °C) and the melting points of IBU (Tm = 76 °C) and COM (Tm = 73 °C), which were tested by differential scanning calorimetry (DSC). The thermal stability of the tested compounds, determined on the basis of measurements carried out by thermogravimetric analysis (TGA), was also taken into account. HME resulted in amorphous E-EPO/IBU solid dispersions and solid dispersions containing a partially crystalline plasticizer in the case of E-EPO/IBU/COM extrudates. Interactions between the components of the extrudate were also studied using infrared spectroscopy (FTIR-ATR). The occurrence of such interactions in the studied system, which improve the stability of the obtained solid polymer dispersions, was confirmed. On the basis of DSC thermograms and XRPD diffractograms, it was found that amorphous solid dispersions were obtained. In addition, their stability was confirmed in accelerated conditions (40 °C, 75% RH) for 28 days and 3 months. The release profiles of prepared tablets showed the release of 40% to 63% of IBU from the tablets within 180 min in artificial gastric juice solution, with the best results obtained for tablets with E-EPO/IBU extrudate prepared at a processing temperature of 140 °C.

Preparation of a ternary amorphous solid dispersion using hot-melt extrusion for obtaining a stable colloidal dispersion of amorphous probucol nanoparticles

In our previous reports, ternary amorphous solid dispersions (ASDs) of probucol (PBC)/polymer/surfactant were prepared by spray-drying and cryo-grinding, and colloidal dispersions of amorphous PBC nanoparticles were obtained by dispersing the ternary ASD into water. In this study, hot-melt extrusion, which is a practical method for preparing ASD formulations, was utilized to obtain ternary ASDs and colloidal dispersions of amorphous PBC nanoparticles. Polyvinylpyrrolidone K12 (PVP) with a relatively low Tg (below 100 °C) was used as a polymer, while poloxamer P407 (P407), which is chemically stable during the hot-melt extrusion process, was utilized as a surfactant. Ternary ASDs were successfully produced with high weight ratios of PVP and P407. A hydrogen bond between the PBC hydroxyl proton and PVP carbonyl oxygen in the ternary ASD was detected using solid-state NMR spectroscopy, suggesting that amorphous PBC was stabilized mainly by PVP. Stable colloidal dispersions of amorphous PBC nanoparticles were obtained from the PBC/PVP/P407 ASD at a weight ratio of 1:4:2. The mean particle size was below 200 nm and the amorphous state of PBC remained stable upon storage at 25 °C for 14 d. Solution-state 1H NMR and zeta-potential measurements suggested that P407 mainly stabilized the colloidal dispersion of amorphous PBC nanoparticles by steric hindrance at the solid/liquid interface. The findings of this study demonstrate that hot-melt extrusion can form practical ternary ASDs that provide colloidal dispersion of amorphous drug nanoparticles. Thus, this study advocates for the use of hot-melt extrusion in the design of an amorphous formulation for a variety of poorly water-soluble drugs.

Amorphous Drug-Polymer Salts: Maximizing Proton Transfer to Enhance Stability and Release.

An amorphous drug-polymer salt (ADPS) can be remarkably stable against crystallization at high temperature and humidity (e.g., 40°C/75% RH) and provide fast release. Here, we report that process conditions strongly influence the degree of proton transfer (salt formation) between a drug and a polymer and in turn the product's stability and release. For lumefantrine (LMF) formulated with poly(acrylic acid) (PAA), we first show that the amorphous materials prepared by slurry conversion and antisolvent precipitation produce a single trend in which the degree of drug protonation increases with PAA concentration from 0% for pure LMF to ∼100% above 70 wt % PAA, independent of PAA's molecular weight (1.8, 450, and 4000 kg/mol). This profile describes the equilibrium for salt formation and can be modeled as a chemical equilibrium in which the basic molecules compete for the acidic groups on the polymer chain. Relative to this equilibrium, the literature methods of hot-melt extrusion (HME) and rotary evaporation (RE) reached much lower degrees of salt formation. For example, at 40 wt % drug loading, HME reached 5% salt formation and RE 15%, both well below the equilibrium value of 85%. This is noteworthy given the common use of HME and RE in manufacturing amorphous formulations, indicating a need for careful control of process conditions to ensure the full interaction between the drug and the polymer. This need arises due to the low mobility of macromolecules and the mutual hindrance of adjacent reaction sites. We find that a high degree of salt formation enhances drug stability and release. For example, at 50% drug loading, an HME-like formulation with 19% salt formation crystallized faster and released only 20% of the drug relative to a slurry-prepared formulation with 70% salt formation. Based on this work, we recommend slurry conversion as the method for preparing ADPS for its ability to enhance salt formation and continuously adjust drug loading. While this work focused on salt formation, the impact of process conditions on the molecular-level interactions between a drug and a polymer is likely a general issue for amorphous solid dispersions, with consequences on product stability and drug release.

Hot-melt extrusion of photodynamic antimicrobial polymers for prevention of microbial contamination

Infectious disease outbreaks within healthcare facilities can exacerbate patient illness and, in some cases, can be fatal. Contaminated surfaces and medical devices can act as a reservoir for transmission of pathogens and have been linked to the rising incidence of healthcare-acquired infections. Antimicrobial surfaces can reduce microbial contamination and transmission and have emerged as a crucial component in healthcare infection control in recent years. The aim of this study was to manufacture antimicrobial polymer surfaces containing the photosensitiser, toluidine blue O (TBO), using hot-melt extrusion (HME). Several concentrations of TBO were combined with a range of medically relevant polymers via HME. TBO-polymer extrudates displayed no significant differences in thermal properties and surface wettability relative to non-loaded polymers. Minimal leaching of TBO from the surface was confirmed through in vitro release studies. Antibacterial activity was observed to vary according to the polymer and concentration of incorporated TBO, with PEBAX® polymers modified with 0.1% w/w TBO demonstrating promising reductions of >99.9% in viable bacterial adherence of a range of common nosocomial pathogens, including Staphylococcus aureus, Staphylococcus epidermidis, Acinetobacter baumannii and Escherichia coli. This study demonstrates the use of HME as a facile alternative method to common encapsulation strategies for the production of light-activated antimicrobial polymer surfaces. This method can be easily translated to large-scale manufacture and, in addition, the polymers constitute promising antimicrobial base materials for the rapidly growing additive manufacturing industries.

A Rapid Tool to Optimize Process Variables for Continuous Manufacturing of Metronidazole Ointment Using Melt Extrusion Technique.

The use of hot-melt extrusion (HME) technique in the preparation of semi-solid products offers several advantages over conventional processes. However, the optimization of the technique for preparation of semi-solid pharmaceuticals is challenging due to involvement of ingredients with different physical properties. Hence, a simple tool to optimize the mixing of ingredients that results in a target ratio and drug content uniformity is utmost important. In this study, a handheld colorimeter has been explored to optimize the process variables of twin screw processor for preparation of hydrophilic PEG-based ointment. The process parameters which were optimized with use of handheld colorimeter have been used for preparation of polyethylene glycol-based metronidazole ointment. The metronidazole ointment prepared by twin screw processor was compared with commercially available metronidazole gel for in vitro release testing and ex vivo permeation. The flux, ex vivo bioavailability, and Tmax of polyethylene glycol-based metronidazole ointment was found to be similar to that of marketed metronidazole gel.

Review on Hot Melt Extrusion Technology and it's Application

The use of hot-melt extrusion (HME) within the pharmaceutical industry is steadily increasing, due to proven its ability to efficiently manufacture novel products. With the use of HME we can increase solubility and bioavailability of the API. HME has proven to be a robust method of producing numerous drug delivery systems like modified, controlled and targeted drug delivery systems. resulting improved bioavailability as well as taste masking of bitter active pharmaceutical ingredients (APIs). Hot-melt extrusion techniques are pragmatic in the manufacture of a variety of dosage forms and formulations such as granules, pellets, tablets, suppositories, implants, stents, transdermal systems and ophthalmic inserts. In This paper we review about the types of Extruder, solid dispersion and Application of the HME to the pharmaceutical industries.

Effect of hot melt extrusion on physical and functional properties of insect based extruded products

The use of alternative protein sources is widely investigated nowadays to ensure a sufficient and nutritious diet for the society. Among different possibilities, insects are currently considered a sustainable and efficient alternative to study more in deep. To this purpose, the present work investigates the use of hot melt extrusion to produce pellets made of insect flour (Hermetia illucens) used alone or mixed in different ratios (1:1 to 1:3) with corn flour. The samples were analysed in terms of physical properties as moisture content, color, water activity, and functional properties as water absorption index, water solubility index, oil sorption and viscosity. The results of the physical properties showed that the color of the pellets was greatly influenced by the blends used: dark brown for insect flour and yellowish for corn flour. Pure insect flour pellets had the lowest water absorption index (2.1 ± 0.3%) and the highest water solubility index (16.8 ± 0.3). The viscoamilographic profiles showed that the addition of the insect flour affected the pasting properties of the formulations. Overall, the results indicate the possibility to include insect flour during the extrusion process as potential source of proteins.

Melt extrusion with poorly soluble drugs – An integrated review

Over the last few decades, hot melt extrusion (HME) has emerged as a successful technology for a broad spectrum of applications in the pharmaceutical industry. As indicated by multiple publications and patents, HME is mainly used for the enhancement of solubility and bioavailability of poorly soluble drugs. This review is focused on the recent reports on the solubility enhancement via HME and provides an update for the manufacturing/scaling up aspects of melt extrusion. In addition, drug characterization methods and dissolution studies are discussed. The application of process analytical technology (PAT) tools and use of HME as a continuous manufacturing process may shorten the drug development process; as a result, the latter is becoming the most widely utilized technique in the pharmaceutical industry. The advantages, disadvantages, and practical applications of various PAT tools such as near and mid-infrared, ultraviolet/visible, fluorescence, and Raman spectroscopies are summarized, and the characteristics of other techniques are briefly discussed. Overall, this review also provides an outline for the currently marketed products and analyzes the strengths, weaknesses, opportunities and threats of HME application in the pharmaceutical industry.

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterization.

Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.

Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug

Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1μg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life.

Hot Melt Extrusion Technique-A Review

Hot Melt Extrusion (HME) is well known process for the Plastic Industries but it is well accepted by the pharmaceutical industries for the last three decays. With the use of HME we can increase solubility and bio-availability of the API. HME has proven to be a robust method of producing numerous drug delivery systems like modified, controlled and targeted drug delivery systems. HME is a solvent free process that achieves solid molecular dispersions by a melt blending process, in which the API is dispersed and or dissolved into a polymeric matrix. HME is an excellent alternative to other conventionally available techniques such as roll spinning and spray drying. In This paper we review about the types of Extruder, solid dispersion and Application of the HME to the pharmaceutical industries.

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. A modified screw design was used in this process, and parameters such as feeding rate, barrel temperature, and screw speed were optimized to obtain a uniform product. The product characteristics were compared with an ointment of similar composition prepared by conventional fusion method. The rheological properties, drug release profile, and texture characteristics of the hot-melt extruded product were similar to the conventionally prepared product. This study demonstrates a novel application of the hot-melt extrusion process in the manufacturing of topical semi-solids.

Hot Melt Extruded and Injection Moulded Dosage Forms: Recent Research and Patents.

Hot Melt Extrusion (HME) and Injection Moulding (IM) are becoming more prevalent in the drug delivery field due to their continuous nature and advantages over current pharmaceutical manufacturing techniques. Hot melt extrusion (HME) is a process that involves the use of at least one reciprocating screw to force a thermoplastic resin along a heated barrel and through a die, while injection moulding is a forming process were molten polymer is forced at high pressure to enter a mould. HME offers a number of advantages over conventional pharmaceutical manufacturing techniques such as increased solubility and bioavailability of poorly water soluble drugs, a solvent free and continuous process, improved content uniformity and flexibility in manufacture. Injection moulding (IM) has been recognised as a rapid and versatile manufacturing technique, which has the advantages of being a continuous process, which is easily scaled up by the use of larger equipment and moulds. However, despite their advantages and the significant number of publications and patents on HME and IM drug delivery devices there are very few marketed formulations. These marketed products range from oral dosage forms which improve bioavailability and reduce pill burden to vaginal rings which provide long-term controlled release thus improving patient compliance. The patenting strategy for IM and HME seems to be focused towards patenting the finished product, more so than patenting the manufacturing process. This is probably due to the fact that the IM and HME processes have already been patented. HME is a process where raw materials (i.e. polymer, plasticizer, drug etc.) are mixed and pumped along by a rotating screw(s) at elevated temperatures through a die to produce a product of uniform shape. IM is similar to HME except that the raw materials are pushed into a mould which is set at lower temperatures. Interest in the use of HME and IM within the pharmaceutical industry is growing with as steady increase in the number of HME patents being issued and with more than 10 products, ranging from oral dosage forms to implantable devices, currently on the market. Therefore, this review of HME and IM is important to the scientific community to further understand and advance these novel and exciting manufacturing techniques.

Understanding Hot Melt Extrusion via near Infrared Spectroscopy

The use of hot melt extrusion (HME) to produce pharmaceutical solid dispersions utilises pharmaceutical grade polymer(s), potentially high temperatures and mechanical energy to convert a drug substance from a crystalline to an amorphous state. Process analytical technology (PAT), in general, provides numerous manufacturing advantages but those specific to HME will be highlighted. An in-line, transmission mode, Fourier transform near infrared spectroscopy (FT-NIR) and partial least squares (PLS) method was developed for real-time drug loading (% wt/wt) predictions during hot melt extrusion of a Merck product. The NIR/PLS method has been successfully used for process fault detection and real-time quality assurance via switch gate automation control; however, the focus herein will be the use of the method for process understanding with three specific examples provided.

Solid State Solubility of Miconazole in Poly[(ethylene glycol)-g-vinyl alcohol] Using Hot-Melt Extrusion

The use of hot-melt extrusion for preparing homogeneous API-excipient mixtures is studied for miconazole-PEG-g-PVA [poly(ethylene glycol)-poly(vinyl alcohol) graft copolymer] solid dispersions with a 5 cm(3) table-top, twin-screw corotating microcompounder (DSM Xplore). Phase behavior of PEG-g-PVA, miscibility of miconazole in PEG-g-PVA and the partitioning of miconazole between PEG and PVA amorphous phases are characterized using a combination of modulated DSC, XRPD, and solid-state (1)H and (13)C NMR methods. The (1)H NMR transverse magnetization relaxation (T(2) relaxation) method is used to analyze the phase composition and molecular mobility of the copolymer. The T(2) relaxation decay of pure PEG-g-PVA can be described by four T(2) relaxation components in the temperature range studied. PVA crystallinity is not largely affected by hot-melt extrusion and the presence of the drug. Miconazole preferably resides in the PEG amorphous phase, and its molecules are well dispersed in the PEG-g-PVA matrix using hot-melt extrusion mixing. Miconazole forms amorphous nanoclusters whose average size equals approximately 1.6 nm, indicating solid solution formation (molecular level dispersion) of the drug in the polymer.

Hot-melt Extrusion Technology and Pharmaceutical Application

The use of hot-melt extrusion (HME) within the pharmaceutical industry is steadily increasing, due to its proven ability to efficiently manufacture novel products. The process has been utilized readily in the plastics industry for over a century and has been used to manufacture medical devices for several decades. The development of novel drugs with poor solubility and bioavailability brought the application of HME into the realm of drug-delivery systems. This has specifically been shown in the development of drug-delivery systems of both solid dosage forms and transdermal patches. HME involves the application of heat, pressure and agitation through an extrusion channel to mix materials together, and subsequently forcing them out through a die. Twin-screw extruders are most popular in solid dosage form development as it imparts both dispersive and distributive mixing. It blends materials while also imparting high shear to break-up particles and disperse them. HME extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier, increasing dissolution rates and bioavailability. The most common difficulty encountered in producing such dispersions is stabilization of amorphous drugs, which prevents them from recrystallization during storage. Pharmaceutical industrial suppliers, of both materials and equipment, have increased their development of equipment and chemicals for specific use with HME. Clearly, HME has been identified as an important and significant process to further enhance drug solubility and solid-dispersion production.