Melt Extrusion Technology Research Articles

TASTE MASKING BY HOT MELT EXTRUSION WITHOUT LOSS OF BIOAVAILABILITY FOR PEDIATRICS

Objective: The aim of present work was to develop a platform technology for the pediatric dosage form to mask the bitter taste of Furosemide (FUR) and prepare a flexible solid oral dosage form.
 Methods: Excipient compatibility study was carried out by using Fourier-transform infrared spectroscopy (FTIR). Taste masking was done by hot melt extrusion (HME) technology. Eudragit EPO and Soluplus were used as a taste masking and solubilizing polymers respectively. The prepared solid dispersion and tablets were evaluated for their physicochemical parameters such as hardness, friability, disintegration, in vitro drug release.
 Results: Experimental data revealed that physical integrity, brittleness of granules, conversion of a drug in amorphous form was improved by combining Eudragit EPO with Soluplus. Plasticizer helped to complete HME at 80 °C. Less than 10% drug release in pH 6.8 medium revealed that release would be extremely limited in the saliva and thus avoiding bitterness. Animal study data revealed that bioavailability has been increased by 30%. Differential scanning calorimetry (DSC) and x-ray diffraction (XRD) tests confirmed the existence of molecularly dispersed drug. Fourier-transform infrared spectroscopy (FTIR) confirmed the unchanged functional groups of FUR after HME processing.
 Conclusion: Proposed platform technology masked the bitter taste and enhanced the bioavailability of FUR in D: P ratio of 1:2.

Robust superhydrophobic epoxy composite coating prepared by dual interfacial enhancement

Superhydrophobic surfaces with special wettability have a promising potential for self-cleaning, anti-fouling, and anti-corrosion applications. However, the practical applications of superhydrophobic coatings are currently limited by their poor mechanical strength and hydrophobic durability. Here, we report a superhydrophobic epoxy (EP) composite coating with improved durability, achieved by a dual interfacial enhancement. First, melt extrusion technology was used to enhance the bonding force between EP and polytetrafluorethylene (PTFE). Then, combining dopamine self-polymerization and sol-gel approaches, the interfacial strength between graphene-polydopamine (GP) and SiO2 was enhanced by in-situ growth of SiO2 on the GP surface. After modification with 1H,1H,2H,2H-perfluorooctyltriethoxysilane (POTS), the superhydrophobic EP-PTFE/GP-SiO2-POTS coating (WCA = 156.3 ± 1.5°, WSA = 3.5 ± 0.5°) was successfully prepared on a steel surface by electrostatic spraying. With the enhanced interfacial strength, the prepared composite coating demonstrated excellent mechanical performance, and could withstand 105 abrasion cycles with only 54.4 mg weight loss. Moreover, due to the induction effect of graphene, a special multilayered nano-micro-nano structure was formed by the evenly distributed nano-SiO2 particles on the coating surface, which is beneficial to extend its superhydrophobic duration. The prepared coating can maintain its superhydrophobicity even after being scratched or immersed in 3.5 wt% NaCl solution for 60 days. Therefore, the prepared superhydrophobic coating demonstrates great potential for application in anti-fouling, drag reduction, and other fields.

Hot melt extrusion technology for improved dissolution, solubility and “spring-parachute” processes of amorphous self-micellizing solid dispersions containing BCS II drugs indomethacin and fenofibrate: Profiles and mechanisms

Many strategies have been employed to improve oral drug delivery. One such approach involves the use of supersaturable delivery systems such as amorphous self-micellizing solid dispersions (SmSDs). SmSDs have attracted more attention recently, but little is known regarding the impact of production methods on profiles and internal mechanisms of final SmSDs in spite of its importance. In this study, amorphous SmSDs containing self-micellizing Soluplus® and BCS II drug (either indomethacin (IND) or fenofibrate (FEN)) were generated using various methods: solvent evaporation (SOL), freeze-drying (FD), microwave radiation-quench cooling (MQC), and hot melt extrusion (HME). Microscopic morphology, amorphous state, thermal behavior, dissolution/solubility, and “spring-parachute” data were used to assemble physicochemical profiles for SmSD systems prepared using each method. Analysis of intermolecular interactions, solubilization, and crystallization inhibition further uncovered internal mechanisms explaining observed physicochemical properties. Generally, SmSD/IND and SmSD/FEN systems generated using HME exhibited superior dissolution, solubility, and spring-parachute profiles. The superior advantages of HME-generated SmSD/IND systems were attributed to relatively stronger intermolecular interactions than observed in SmSD/IND systems fabricated using other methods. Moreover, self-micellizing Soluplus® carrier was able to solubilize IND or FEN and suppress drug crystallization from a supersaturated state, which seemed to be an important mechanism for the properties enhancement caused by SmSD/FENHME. This knowledge should be useful for guiding further development of self-micellizing solid dispersions and for gaining deeper understanding of how HME technology can improve supersaturable drug delivery based on SmSDs strategy.

Effects of formulation composition on the characteristics of mucoadhesive films prepared by hot-melt extrusion technology.

To investigate the effects of formulation composition on the physico-chemical and drug release properties of mucoadhesive buccal films prepared by melt extrusion technology, using a response surface methodology. Salbutamol sulphate, an antiasthmatic drug was used for this study. Klucel hydroxypropylcellulose (HPC) EF (film-forming polymer), Benecel hydroxypropylmethylcellulose (HPMC) K-15M (drug release retardant) and polyethylene glycol (PEG) 4500 (plasticiser) were the three independent factors utilised for the study. The responses were fitted to a full quadratic model and P-values for each of the factors were used to determine their significance on the film characteristics. Films were successfully extruded using the corotating twin-screw extruder. The torque during extrusion was found to be significantly affected by all the three factors and no interaction between factors was observed. A significant interaction was observed between HPC and PEG 4500 for stiffness of films. For disintegration time and swelling index, a significant interaction was found between HPC and HPMC. The invitro % drug release was directly correlated with HPMC content and not with other factors and varied from 69-89% at 4h. The influence of extrusion process and formulation parameters on salbutamol sulphate films was elucidated, indicating the use of melt extrusion as a feasible method for film preparation.

Investigating a Novel Hot Melt Extrusion-Based Drying Technique to Solidify an Amorphous Nanosuspension Using Design of Experiment Methodology.

The hot melt extrusion (HME) technology was explored and optimized to solidify an amorphous nanosuspension using Quality by Design (QbD) methodology. A design of experiments (DoE) approach was used to perform a set of 15 experiments, varying independent variables (feed rate, input temperature, and screw speed) within a design space. Redispersibility index (RDI), moisture content, and process yield constituted the critical quality attributes (CQAs) of the experimental design. Regression analysis and ANOVA were employed to identify and estimate significant main effects and two-way interactions, and model the process of HME drying for predictive purposes. The optimized HME-dried end product was characterized for physicochemical properties using differential scanning calorimetry (DSC), X-ray powder diffractions (XRPD), polarized light microscopy (PLM), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution studies. The statistical analysis reveals feed rate and input temperature as significant independent variables, critically influencing RDI and moisture content of solidified end product. The model developed for process yield was insignificant at a p-value of 0.05. The API retained its amorphous nature after the extrusion process which was confirmed using DSC and XRPD techniques. PLM was unsuitable to differentiate and determine crystallinity of drug moiety in the presence of a semi-crystalline bulking agent, microcrystalline cellulose (MCC). In vitro dissolution study depicted solubility and dissolution enhancement for HME-dried amorphous nanosuspension in both the dissolution media which can be attributed to amorphous nature of nanosized drug particles. A well-designed study implemented by DoE aided in developing a robust and novel HME technique to dry aqueous nanosuspension.

Preparation of a crystalline salt of indomethacin and tromethamine by hot melt extrusion technology

Although salt formation is the most ubiquitous and effective method of increasing the solubility and dissolution rates of acidic and basic drugs, it consumes large quantities of organic solvents and is a batch process. Herein, we show that the dissolution rate of indomethacin (a poorly water-soluble drug) can be increased by using hot melt extrusion of a 1:1 (mol/mol) indomethacin:tromethamine mixture to form a highly crystalline salt, the physicochemical properties of which are investigated in detail. Specifically, pH–solubility studies demonstrated that this salt exhibited a maximal solubility of 19.34 mg/mL (>1000 times that of pure indomethacin) at pH 8.19. A solvent evaporation technique was also used for salt formation. Spectroscopic analyses (infrared, nuclear magnetic resonance) of both; demonstrated, in situ salt formation with proton transfer. Powder X-ray diffraction and differential scanning calorimetry confirmed the crystalline nature of salts formed by both methods. Even though a number of amorphous salts of acidic drugs have been reported, the formation of a crystalline salt of an acidic drug by hot melt extrusion is completely unprecedented, which makes this study an important benchmark for the pharmaceutical production industry.

Degradable Nanocomposites for Fused Filament Fabrication Applications

There has been a substantial increase in the use and development of plastics over the last century. However, due to ever-diminishing petroleum feedstocks and growing concern for the environment, there has been a rise in the use of eco-friendly polymers affording similar properties to that of their depleting counterparts. Poly(ε-caprolactone) is one such polymer. This present study investigates the possibility of developing a degradable nanocomposite, suitable for fused filament fabrication, utilizing hot melt extrusion technology to blend poly(ε-caprolactone), poly(ethylene) oxide and the nanoclay halloysite at loadings of two and six weight percent. The extruded blends were characterized using common polymer testing techniques. The addition of poly(ε-caprolactone) to the poly(ethylene) oxide matrix provided a plasticizing effect which was apparent with the melt flow index and melting point of the blends reducing with an increase in poly(ε-caprolactone) content. Upon reinforcing the matrix with halloysite, there was a significant improvement in mechanical properties. The addition of halloysite significantly increased Young’s modulus 11% and 25% when the loading was two and six percent respectively. Furthermore, it was also possible to produce a filament with the desired properties, diameter 1.75 mm, for fused filament fabrication, with subsequent studies required to evaluate their printability.

Pharmaceutical 3D printing: Design and qualification of a single step print and fill capsule

Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug-containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin-walled drug-free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule ‘shell’ and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension ‘.gcode’) were modified by creating discrete zones, so-called ‘zoning process’, with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X-ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work.

Hot-Melt Extrusion Technology in the Emerging Pharma Field

After the plastic industry, now in Pharmaceutical industry hot melt extrusion (HME) technology has emerged and has made its way for the easy development of the pharmaceutical products due to its severe advantages like free of solvents, faster processing technology, operation in simple and continuous process, and high degree of automation, are few among them over to the other conventional methods. Day by day the interest on HME technology has been increasing due to its promising approach towards the drug delivery systems. The gradual increase in the patents of HME technology will enlighten us the need of it in this field of medicines. This article mainly reviews the general design and construction of hot melt extruder along with the advantages, disadvantages and applications of the HME.

Melt Extrusion for a High Melting Point Compound with Improved Solubility and Sustained Release.

The objective of the current study was to develop an amorphous solid dispersion for a high melting point compound, griseofulvin (GRF), with an enhanced solubility and a controlled release pattern utilizing hot melt extrusion (HME) technology. Hypromellose acetate succinate (HPMCAS, Shin-Etsu AQOAT®, medium particle size) was explored as the polymeric carrier, while hypromellose (HPMC, Metolose® SR) was chosen as the release rate control agent. GRF presented an HPMCAS grade-dependent solubility: AS-HMP>AS-MMP>AS-LMP. At 10wt.% loading, the release of GRF was prolonged to 6h with the incorporation of 10% HPMC 90SH-100SR, while its solubility was enhanced up to sevenfold. Fourier transform infrared spectroscopy (FT-IR) identified the H-bonding between drug and polymers. Element analysis utilizing X-ray photoelectron spectroscopy (XPS) discovered that less GRF aggregated on the surface of binary powders compared with ternary powders containing HPMC, indicating the relatively poor wettability of the latter one. The morphology of extrudates was observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM), illustrating a much smoother and uniform surface of binary extrudates. Immediate release tablets including 10% super-disintegrant L-HPC were able to achieve identical dissolution profile as the powders of extrudates.

Advances in hot-melt extrusion technology toward pharmaceutical objectives

Hot Melt Extrusion (HME) technology is a widely used for manufacturing process in the plastic and pharmaceutical industries and is an efficient and simple for the production of a solid dispersion. This technique is an environmental friendly, continuous process that does not use solvents. It is time and cost efficient and can be easily scaled up. In addition, HME may be used in conjunction with other technologies to effectively increase the solubility and dissolution rate of poorly water-soluble drugs. Numerous research papers on the progress of HME technology in the pharmaceutical industry have been written, and products manufactured using HME have been approved by the FDA. However, there are some drawbacks to the products manufactured using through HME. These are related to the high energy input coming from the applied shear forces and high temperature, which could lead to drug or polymer degradation and thus significantly impact the product quality. Despite these disadvantages, HME has been employed in various advanced applications, such as taste masking and targeted drug delivery. This review article focuses on advances in HME technology, which include improvement in the weaknesses of HME, patient-centric formulations, and the outlook for uses such as formulation development.

Design and Evaluation of Topical Diclofenac Sodium Gel Using Hot Melt Extrusion Technology as a Continuous Manufacturing Process with Kolliphor® P407.

The aim of the present context was to develop and evaluate a Kolliphor® P407-based transdermal gel formulation of diclofenac sodium by hot melt extrusion (HME) technology; central composite design was used to optimize the formulation process. In this study, we have explored first time ever HME as an industrially feasible and continuous manufacturing technology for the manufacturing of gel formulation using Kolliphor® P407 and Kollisolv® PEG400 as a gel base. Diclofenac sodium was used as a model drug. The HME parameters such as feeding rate, screw speed, and barrel temperature were crucial for the semisolid product development, and were optimized after preliminary trials. For the processing of the gel formulation by HME, a modified screw design was used to obtain a uniform product. The obtained product was evaluated for physicochemical characterization such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), pH measurement, rheology, surface tension, and texture profile analysis. Moreover, it was analyzed for general appearance, spreadibility, surface morphology, and drug content. The optimized gel formulation showed homogeneity and transparent film when applied on a glass slide under microscope, pH was 7.02 and uniform drug content of 100.04 ± 2.74 (SD = 3). The DSC and XRD analysis of the HME gel formulation showed complete melting of crystalline API into an amorphous form. The Kolliphor® P407 and Kollisolv® PEG400 formed excellent gel formulation using HME with consistent viscoelastic properties of the product. An improved drug release was found for the HME gel, which showed a 100% drug release than that of a marketed product which showed only 88% of drug release at the end of 12h. The Flux value of the HME gel was 106 than that of a marketed formulation, which showed only about 60 value, inferring a significant difference (P < 0.05) at the end of 1h. This study demonstrates a novel application of the hot melt extrusion process for manufacturing of topical semisolid products.

Physicochemical characterization of olmesartan medoxomil: polymer solid dispersions by hot melt extrusion for dissolution rate enhancement

Aim The prime objective of this investigation was to improve solubility and dissolution rate of poorly water-soluble drug, olmesartan medoxomil, by preparation of stable solid dispersions (SDs) of low glass transition temperature employing hot-melt extrusion technique.Materials and methods Soluplus (SOL) was used as a primary solubilizing agent along with different solubility/absorption enhancers such as polyethylene glycol (PEG)-8000 and Kolliphor F127. After extrusion, the extrudates were pelletized, and physical state of the drug was assessed using powder X-ray diffraction and differential scanning calorimetry techniques.Results The SDs were found to be amorphous, thermodynamically and physicochemically stable. Scanning electron microscopy of the formulations revealed a surface, indicating absence of crystallinity. The drug content was found to be in the range of 98.16±1.3 to 99.98±1.1%. The dissolution performance of the extrudates was compared with that of the pure drug, and substantial improvement was observed in the order of SOL-PEG-8000>SOL-KF127>SOL only. In-vitro drug release rate was Higuchi matrix controlled, and the release rate mechanism was found to be non-Fickian. Stability studies over a period of 3 months indicated amorphous nature of drug in the formulation, and no significant deviations were observed in the drug content and in-vitro drug dissolution characteristics.Conclusion Hot melt extrusion technology promises an ideal platform for enhancing the solubility and dissolution of poorly water-soluble drugs. The results obtained suggest that olmesartan medoxomil in the form of SDs has potential for oral drug delivery and could be an efficacious approach for enhancing therapeutic potential.

Hot melt extrusion as an approach to improve solubility, permeability and oral absorption of a psychoactive natural product, piperine.

The aims of the current research project were to investigate the efficiency of various polymers to enhance the solubility and increase the systemic absorption of piperine using hot melt extrusion technology. Piperine 10-40% w/w and Eudragit(®) EPO/Kollidon(®) VA 64 or Soluplus(®) were mixed, and the resulting blends were extruded using a twin-screw extruder (Process 11, Thermo Fisher Scientific). Drug release profiles and piperine solubility studies of the extrudates were evaluated. A non-everted intestinal sac was employed for the most promising formulation, 10% w/w piperine/Soluplus(®) , and pure piperine to study the permeability characteristics. Dissolution studies demonstrated enhancement in piperine per cent release of 10% and 20% w/w piperine/Soluplus(®) extrudates up to 95% and 74%, respectively. The solubility of 10% and 20% piperine/Soluplus(®) increased more than 160- and 45-fold in water, respectively. Furthermore, permeability studies demonstrated the enhancement in piperine absorption of 10% w/w piperine/Soluplus(®) extrudates up to 158.9 μg/5 ml compared with pure piperine at 1.3 μg/5 ml within 20 min. These results demonstrated that increasing the bioavailability of piperine may be achieved as demonstrated by findings in this study.

Preparation and characterizations of stable amorphous solid solution of azithromycin by hot melt extrusion

In the present study aim was to prepare stable solid solution azithromycin dihydrate (AZI) by hot melt extrusion technology (HME). Soluplus and Kollidon® VA 64 were selected among polymers based on Hansen solubility parameter calculation in order to prepare amorphous of AZI. Further physicochemical properties of extrudates were characterized by DSC, FTIR, XRD, SEM and contact angle measurement. DSC revealed single broad endothermic peak in extrudates indicated miscibility of AZI into polymeric carriers, which formed monophasic solid system termed as solid solution. XRD confirmed amorphous nature of AZI in extrudates. DSC and XRD suggested molecular dispersion of AZI in polymeric carriers. Amorphous AZI exhibited statistically significant high solubility (P < 0.0001) in water in comparison with pure AZI. Solid solution batch AZI 03 showed significant enhancement in solubility (P = 0.0004) in pH 6. The dissolution in dissolution medium pH 6 and water resulted in statistically significant differences (P < 0.05) in the percentage amorphous AZI dissolved compared to the percentage AZI dissolved over the period of 60 min. Solid solution formulation showed better wettability than that of pure AZI. Amorphization and increased wettability attributed to solubility and dissolution rate enhancement. Assay and amorphous solid solution characteristics of AZI were found to be stable under accelerated storage condition as per ICH guideline for a period of six months. Therefore, hot melt extrusion technology was suitable method to prepare stable solid solution and dissolution rate enhancement for poorly soluble active like AZI.

Solid-state characterization of Felodipine–Soluplus amorphous solid dispersions

The aim of the current study is to develop amorphous solid dispersion (SD) via hot melt extrusion technology to improve the solubility of a water-insoluble compound, felodipine (FEL). The solubility was dramatically increased by preparation of amorphous SDs via hot-melt extrusion with an amphiphilic polymer, Soluplus® (SOL). FEL was found to be miscible with SOL by calculating the solubility parameters. The solubility of FEL within SOL was determined to be in the range of 6.2–9.9% (w/w). Various techniques were applied to characterize the solid-state properties of the amorphous SDs. These included Fourier Transform Infrared Spectrometry spectroscopy and Raman spectroscopy to detect the formation of hydrogen bonding between the drug and the polymer. Scanning electron microscopy was performed to study the morphology of the SDs. Among all the hot-melt extrudates, FEL was found to be molecularly dispersed within the polymer matrix for the extrudates containing 10% drug, while few small crystals were detected in the 30 and 50% extrudates. In conclusion, solubility of FEL was enhanced while a homogeneous SD was achieved for 10% drug loading.

Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro–in vivo evaluations

The objective of this study was to develop caffeine citrate orally disintegrating tablet (ODT) formulations utilizing hot-melt extrusion technology and evaluate the ability of the formulation composition to mask the unpleasant bitter taste of the drug using in vitro and in vivo methods. Ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to enhance drug release. A modified screw configuration was applied to improve the extrusion processability and to preserve the crystallinity of the API. The milled extrudates were subjected to dissolution testing in an artificial salivary fluid and investigations using e-tongue, to assess the extent of masking of bitter taste of the API. There was an insignificant amount of drug released from the formulation in the salivary medium while over 80% of drug released within 30min in 0.1N HCl. ODTs were also developed with the extrudate mixed with mannitol and crospovidone. The quality properties such as friability and disintegration time of the ODTs met the USP specifications. The lead extrudate formulations and the ODTs prepared using this formulation were subjected to human gustatory evaluation. The formulations were found to mask the unpleasant taste of caffeine citrate significantly.

Mefenamic acid taste-masked oral disintegrating tablets with enhanced solubility via molecular interaction produced by hot melt extrusion technology

The objective of this study was to enhance the solubility as well as to mask the intensely bitter taste of the poorly soluble drug, Mefenamic acid (MA). The taste masking and solubility of the drug was improved by using Eudragit® E PO in different ratios via hot melt extrusion (HME), solid dispersion technology. Differential scanning calorimetry (DSC) studies demonstrated that MA and E PO were completely miscible up to 40% drug loads. Powder X-ray diffraction analysis indicated that MA was converted to its amorphous phase in all of the formulations. Additionally, FT-IR analysis indicated hydrogen bonding between the drug and the carrier up to 25% of drug loading. SEM images indicated aggregation of MA at over 30% of drug loading. Based on the FT-IR, SEM and dissolution results for the extrudates, two optimized formulations (20% and 25% drug loads) were selected to formulate the orally disintegrating tablets (ODTs). ODTs were successfully prepared with excellent friability and rapid disintegration time in addition to having the desired taste-masking effect. All of the extruded formulations and the ODTs were found to be physically and chemically stable over a period of 6 months at 40 °C/75% RH and 12 months at 25 °C/60% RH, respectively.

Controlled porosity solubility modulated osmotic pump tablets of gliclazide.

A system that can deliver drug at a controlled rate is very important for the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Poorly water-soluble drug with pH-dependent solubility such as gliclazide (GLZ) offers challenges in the controlled-release formulation because of low dissolution rate and poor bioavailability. Solid dispersion (SD) of GLZ consisted of hydroxypropyl cellulose (HPC-SSL) as a polymeric solubilizer was manufactured by hot melt extrusion (HME) technology. Then, controlled porosity osmotic pump (CPOP) tablet of gliclazide was designed to deliver drug in a controlled manner up to 16h. The developed formulation was optimized for type and level of pore former and coating weight gain. The optimized formulation was found to exhibit zero order kinetics independent of pH and agitation speed but depends on osmotic pressure of dissolution media indicated that mechanism of drug release was osmotic pressure. The in vivo performance prediction of developed formulation using convolution approach revealed that the developed formulation was superior to the existing marketed extended-release formulation in terms of attaining steady state plasma levels and indicated adequate exposure in translating hypoglycemic response. The prototype solubilization method combined with controlled porosity osmotic pump based technique could provide a unique way to increase dissolution rate and bioavailability of many poorly water-soluble, narrow therapeutic index drugs used in diabetes, cardiovascular diseases, etc.

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. The developed novel platform demonstrated better process control and size reduction compared to the conventional process of hot homogenization (batch process). Varying the process parameters enabled the production of SLN below 200 nm (for 60 mg/ml lipid solution at a flow rate of 100ml/min). Among the several process parameters investigated, the lipid concentration, residence time and screw design played major roles in influencing the size of the SLN. This new process demonstrates the potential use of hot melt extrusion technology for continuous and large-scale production of SLN.