Hot Melt Extrusion Formulations Research Articles

Preparation and Evaluation of Inhalable Microparticles with Improved Aerodynamic Performance and Dispersibility Using L-Leucine and Hot-Melt Extrusion.

Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility while simultaneously maintaining the high aerodynamic performance of inhalable microparticles. This study explored using LEU in HME to improve dispersibility and maintain the high aerodynamic performance of inhalable microparticles. Formulations with crystalline itraconazole (ITZ) and LEU were made via co-jet milling and HME followed by jet milling. The LEU ratio varied, comparing solubility, homogenization, and aerodynamic performance enhancements. In HME, ITZ solubility increased, and crystallinity decreased. Higher LEU ratios in HME formulations reduced the contact angle, enhancing mass median aerodynamic diameter (MMAD) size and aerodynamic performance synergistically. Achieving a maximum extra fine particle fraction of 33.68 ± 1.31% enabled stable deep lung delivery. This study shows that HME combined with LEU effectively produces inhalable particles, which is promising for improved drug dispersion and delivery.

Hot melt extrusion: An emerging manufacturing method for slow and sustained protein delivery.

With the rapid development of the biopharmaceutical industry, an increasing number of new therapeutic protein products (TPPs) have been approved by the FDA and many others are under pre-clinical and clinical evaluation. A major limitation of biopharmaceuticals is their limited half-life when administered systemically. A one-time, implantable, sustained protein delivery device would be advantageous in order to improve the quality of life of patients. Hot melt extrusion (HME) is a mature technology that has been extensively used for a broad spectrum of applications in the polymer and pharmaceutical industry and has achieved success as evidenced by a variety of FDA-approved commercial products. These commercial products are mostly for sustained delivery of small molecule therapeutics, leaving a significant gap for HME formulation of therapeutic proteins. With the increasing need of sustained TPP delivery, HME shows promise as a downstream processing method due to its high efficiency and economic value. Several challenges remain for the application of HME in protein delivery. Progress of HME for protein delivery, challenges encountered, and potential solutions will be detailed in this review article. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.

Vacuum Compression Molding as a Screening Tool to Investigate Carrier Suitability for Hot-Melt Extrusion Formulations.

Hot-melt extrusion (HME) is the most preferred and effective method for manufacturing amorphous solid dispersions at production scale, but it consumes large amounts of samples when used for formulation development. Herein, we show a novel approach to screen the polymers by overcoming the disadvantage of conventional HME screening by using a minimum quantity of active pharmaceutical ingredient (API). Vacuum Compression Molding (VCM) is a fusion-based method to form solid specimens starting from powders. This study aimed to investigate the processability of VCM for the creation of amorphous formulations and to compare its results with HME-processed formulations. Mixtures of indomethacin (IND) with drug carriers (Parteck® MXP, Soluplus®, Kollidon® VA 64, Eudragit® EPO) were processed using VCM and extrusion technology. Thermal characterization was performed using differential scanning calorimetry, and the solid-state was analyzed via X-ray powder diffraction. Dissolution studies in the simulated gastric fluid were performed to evaluate the drug release. Both technologies showed similar results proving the effectiveness of VCM as a screening tool for HME-based formulations.

An investigation into the formations of the internal microstructures of solid dispersions prepared by hot melt extrusion

Hot melt extrusion (HME) is a widely used manufacturing process for pharmaceutical solid dispersions. The complexity of the HME formulations and the number of excipients used in the process are increasing with the advancement of the relevant knowledge. However, one of the areas that is still significantly lacking understanding is the control of internal microstructure of extrudates. Internal microstructure, consisting of voids, in hot melt extruded amorphous solid dispersions is often observed without the causes having been systemically investigated in the literature. In this study, we investigated a range of factors that demonstrated their impacts on the formation of the voids. These include the effect of the types of the materials (i.e. drug, polymer and additive) used in the formulation, the quantity of the drug and the additives used, the key extrusion processing parameters, the type of extruder, and the drying of the raw materials prior to extrusion. The results indicate that the appropriate viscosity and the presence of phase-separated particulates are essential for the formation of the voids. The particulates act as nuclei for the entrapped gas bubbles and the viscosity of the mixture during extrusion governs the collapse/escape of the bubbles. To minimise void formation, the results of this study indicate that slow screw speed, low moisture content of the raw materials, fewer particulates and the addition of lubricants, such as low melting lipid excipients, could be beneficial. This study systematically examines the mechanism of void formation in HME extrudates and generates new strategies that can be used to manage such void formations.

NMR and Thermal Studies for the Characterization of Mass Transport and Phase Separation in Paracetamol/Copovidone Hot-Melt Extrusion Formulations.

The formulation of drug/polymer amorphous solid dispersions (ASDs) is one of the most successful strategies for improving the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Hot-melt extrusion (HME) is one method for preparing ASDs that is growing in importance in the pharmaceutical industry, but there are still substantial gaps in our understanding regarding the dynamics of drug dissolution and dispersion in viscous polymers and the physical stability of the final formulations. Furthermore, computational models have been built to predict optimal processing conditions, but they are limited by the lack of experimental data for key mass transport parameters, such as the diffusion coefficient. The work presented here reports direct measurements of API diffusion in pharmaceutical polymer melts, using high-temperature pulsed-field gradient NMR. The diffusion coefficient of a model drug/polymer system (paracetamol/copovidone) was determined for different drug loadings and at temperatures relevant to the HME process. The mechanisms of the diffusion process are also explored with the Stokes-Einstein and Arrhenius models. The results show that diffusivity is linked exponentially to temperature. Furthermore, this study includes rheological characterization, differential scanning calorimetry (DSC), and 1H ssNMR T1 and T1ρ measurements to give additional insights into the physical state, phase separation, and API/polymer interactions in paracetamol/copovidone ASD formulations.

Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies.

Amorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.

Hot Melt Extrusion as Solvent-Free Technique for a Continuous Manufacturing of Drug-Loaded Mesoporous Silica

The aim of this study is to explore hot melt extrusion (HME) as a solvent-free drug loading technique for preparation of stable amorphous solid dispersions using mesoporous silica (PSi). Ibuprofen and carvedilol were used as poorly soluble active pharmaceutical ingredients (APIs). Due to the high friction of an API:PSi mixture below the loading limit of the API, it was necessary to add the polymer Soluplus® (SOL) in order to enable the extrusion process. As a result, the APIs were distributed between the PSi and SOL phase after HME. Due to its higher affinity to PSi, ibuprofen was mainly adsorbed into the PSi, whereas carvedilol was mainly found in the SOL phase. Intrinsic dissolution rate was highest for HME formulations, containing PSi, compared to pure crystalline (amorphous) APIs and HME formulations without PSi. HME is a feasible solvent-free drug loading technique for preparation of PSi-based amorphous solid dispersions.

A novel hot-melt extrusion formulation of albendazole for increasing dissolution properties

The main aim of the research focused on the production of hot-melt extrusion (HME) formulations with increased dissolution properties of albendazole (ABZ). Therefore, HME was applied as a continuous manufacturing technique to produce amorphous solid dispersions of the poorly water soluble drug ABZ combined with the polymer matrix polyvinylpyrrolidone PVP K12. HME formulations of ABZ–PVP K12 comprised a drug content of 1%, 5% and 10% w/w. The main analytical characterisation techniques used were scanning electron microscopy (SEM), micro-computed tomography (μ-CT), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissolution profile studies. The application of SEM, XRPD and DSC evidenced drug physical transformation from crystalline to amorphous state and therefore, the achievement of an amorphous solid dispersion. The introduction of a novel technique, μ-CT, to characterise the internal structure of these materials revealed key information regarding materials distribution and void content. Dissolution profile studies evidenced a high increase in drug release profile compared to pure ABZ. These promising results can lead to a great enhancement of the oral bioavailability of ABZ dosage forms. Therefore, HME is a potential continuous manufacturing technique to overcome ABZ poor solubility properties and lead to a significant increase in the therapeutic effect.

An investigation into the influence of drug–polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations

While hot melt extrusion is now established within the pharmaceutical industry, the prediction of miscibility, processability and structural stability remains a pertinent issue, including the issue of whether molecular interaction is necessary for suitable performance. Here we integrate the use of theoretical and experimental drug–polymer interaction assessment with determination of processability and structure of dispersions in two polyvinylpyrrolidone-based polymers (PVP and PVP vinyl acetate, PVPVA). Caffeine and paracetamol were chosen as model drugs on the basis of their differing hydrogen bonding potential with PVP. Solubility parameter and interaction parameter calculations predicted a greater miscibility for paracetamol, while ATR-FTIR confirmed the hydrogen bonding propensity of the paracetamol with both polymers, with little interaction detected for caffeine. PVP was found to exhibit greater interaction and miscibility with paracetamol than did PVPVA. It was noted that lower processing temperatures (circa 40°C below the Tg of the polymer alone and Tm of the crystalline drug) and higher drug loadings with associated molecular dispersion up to 50% w/w were possible for the paracetamol dispersions, although molecular dispersion with the non-interactive caffeine was noted at loadings up to 20% w./w. A lower processing temperature was also noted for caffeine-loaded systems despite the absence of detectable interactions. The study has therefore indicated that theoretical and experimental detection of miscibility and drug–polymer interactions may lead to insights into product processing and extrudate structure, with direct molecular interaction representing a helpful but not essential aspect of drug–polymer combination prediction.

Taste Masking of Griseofulvin and Caffeine Anhydrous Using Kleptose Linecaps DE17 by Hot Melt Extrusion.

The objective of this project was to investigate the potential of Kleptose Linecaps DE17 (KLD) in masking the unpleasant/bitter taste of therapeutic agents by hot melt extrusion (HME). Griseofulvin (GRI) and caffeine anhydrous (CA) were used as a bitter active pharmaceutical ingredient (API) model drugs. Thermogravimetric studies confirmed the stability of GRI, CA, and KLD at the employed extrusion temperatures. The differential scanning calorimetry (DSC) studies revealed a characteristic melting endotherm of GRI at 218-220°C and CA at 230-232°C in the physical mixtures as well as in all extrudates over the period of study, indicating the crystalline nature of drug. HME of KLD was achieved only in the presence of plasticizer. Among the several plasticizers investigated, xylitol showed improved processability of KLD at 15% w/w concentration. Dissolution studies of HME extrudates using simulated salivary medium exhibited ∼threefold less release compared to physical mixture at the end of 5min (the lesser drug release, better the taste masking efficiency). Furthermore, the results from the sensory evaluation of products in human panel demonstrated strong bitter taste in the case of physical mixture compared to the HME formulation, suggesting the potential of Kleptose Linecaps DE17 as taste masking polymer in melt extruded form.

Novel supercritical carbon dioxide impregnation technique for the production of amorphous solid drug dispersions: a comparison to hot melt extrusion.

The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.

Analyzing the impact of different excipients on drug release behavior in hot-melt extrusion formulations using FTIR spectroscopic imaging

The drug release performance of hot-melt extrudate formulations is mainly affected by its composition and interactions between excipients, drug and the dissolution media. For targeted formulation development, it is crucial to understand the role of these interactions on the drug release performance of extrudate formulations. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging was used with an in-situ flow-cell device to analyze the impact of different excipients on drug release from extrudates. The compositions differed in the type of polymer (copovidone and Soluplus®), the salt or acid form of ibuprofen and the addition of sodium carbonate. For comparison, conventional USP (United States Pharmacopeia) Apparatus 2 dissolution studies were performed. FTIR imaging revealed that differences in the drug release rate were mainly due to drug–polymer interactions. Ibuprofen acid showed interactions with the matrix polymer and exhibited a slower drug release compared to non-interacting ibuprofen salt. Addition of sodium carbonate to the ibuprofen acid containing formulations enhanced the drug release rate of these systems by interfering with the drug–polymer interactions. In addition, drug release rates also depended on the polymer type, showing faster drug release rates for extrudate formulations containing copovidone compared to Soluplus®. FTIR imaging revealed that the stronger the drug–polymer interaction in the formulations, the slower the drug release. The addition of sodium carbonate improved release as it reduces drug–polymer interactions and allows for the formation of the more water-soluble ibuprofen salt.

A Fast and Reliable Empirical Approach for Estimating Solubility of Crystalline Drugs in Polymers for Hot Melt Extrusion Formulations

A novel empirical analytical approach for estimating solubility of crystalline drugs in polymers has been developed. The approach utilizes a combination of differential scanning calorimetry measurements and a reliable mathematical algorithm to construct complete solubility curve of a drug in polymer. Compared with existing methods, this novel approach reduces the required experimentation time and amount of material by approximately 80%. The predictive power and relevance of such solubility curves in development of amorphous solid dispersion (ASD) formulations are shown by applications to a number of hot-melt extrudate formulations of ibuprofen and naproxen in Soluplus. On the basis of the temperature-drug load diagrams using the solubility curves and the glass transition temperatures, physical stability of the extrudate formulations was predicted and checked by placing the formulations on real-time stability studies. An analysis of the stability samples with microscopy, thermal, and imaging techniques confirmed the predicted physical stability of the formulations. In conclusion, this study presents a fast and reliable approach for estimating solubility of crystalline drugs in polymer matrixes. This powerful approach can be applied by formulation scientists as an early and convenient tool in designing ASD formulations for maximum drug load and physical stability.

Dissolution and Bioavailability Enhancement of Efavirenz by Hot Melt Extrusion Technique

The aim of this study is to improve dissolution and bioavailability of poorly water soluble Efavirenz (Efv), a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Its effectiveness can be attributed to its long half-life (t1/2) of 52–76 h after single dose. Formulation of poorly water soluble drug for oral delivery is one of the biggest challenges. Amongst the available approaches, the novel solid dispersion (SD) technique known as hot melt extrusion (HME) has often proved to be the most widely used method in improving dissolution and bioavailability of the drugs because of its various advantages. Dissolution enhancement of Efv was done by HME technology where crystalline form of API is converted to amorphous form using hydrophilic polymer like Kollidon VA64. Surfactants like Polyethylene glycol (PEG 4000), polyoxy 35 castor oil (Chremophor EL) and Sorbiton monolaurate (Montane 20PHA) were used as plasticizer for process feasibility. Physical mixtures of drug, polymer and surfactant were prepared in ratio of 1:1:0.1. These physical mixtures were subjected to melt and the resultant formulations were subjected to physical characterization, dissolution, permeability and in vivo testing. Pharmacokinetics of Efv was studied in rats. Drug efflux pumps like P-glycoprotein (P-gp) were recognized to posses’ functional role in determining the pharmacokinetics of drugs. Inhibition of P-gp improves intestinal absorption and tissue distribution while reducing the substrate metabolism and its elimination. Drug release showed comparative similar release for all the HME formulations while the permeability studies showed improved permeability of formulations containing Sorbiton Monolaurate and PEG 4000. In comparison to the Non HME (NHME) formulation, the SD prepared with KollidonVA64 (drug: polymer 1:1) by HME process showed a significant enhancement in permeability with all the three surfactants. SD prepared by PEG 4000 resulted in 106.98% enhancement in extent of absorption. In conclusion, solid dispersion prepared using certain polymer could serve as a promising formulation approach to enhance the dissolution and bioavailability of Efv.

Improved Lysozyme Stability and Release Properties of Poly(lactide-co-glycolide) Implants Prepared by Hot-Melt Extrusion

To assess the feasibility of hot-melt extrusion (HME) for preparing implants based on protein/poly(lactide-co-glycolide) (PLGA) formulations with special emphasis on protein stability, burst release and release completeness. Model protein (lysozyme)-loaded PLGA implants were prepared with a screw extruder and a self-built syringe-die device as a rapid screening tool for HME formulation optimization. Lysozyme stability was determined using DSC, FTIR, HPLC and biological activity. The simultaneous effect of lysozyme and PEG loadings was investigated to obtain optimized formulations with high drug loading but low initial release. Lysozyme was recovered from implants with full biological activity after HME. The release from all implants reached the 100% value in 60-80 days with nearly complete enzymatic activity of the last fraction of released lysozyme. Pure PLGA implants with up to 20% lysozyme loading could be formulated without initial burst. The incorporation of PEG 400 reduced the initial burst at drug loadings in excess of 20%. A complete lysozyme recovery in active form with a burst-free and complete release from PLGA implants prepared by hot-melt extrusion was obtained. This is in contrast to many reported microparticulate lysozyme-PLGA systems and suggests the great potential of hot-melt extrusion for the preparation of protein-PLGA implants.

Stabilization of hot-melt extrusion formulations containing solid solutions using polymer blends.

This study was aimed at enhancing the physical stability of the drug clotrimazole (CT) and the polymer contained within hot-melt extrusion (HME) films using polymer blends of hydroxypropyl cellulose (HPC) and poly(ethylene oxide) (PEO). The HME films were investigated for solid-state characteristics, moisture sorption, bioadhesivity, mechanical properties, glass transition temperature, release characteristics, and physical and chemical stability of the drug and the polymer within the HME films. The solid-state characterization of the drug and the polymer was performed using differential scanning calorimetry, x-ray diffractometry, and dynamic mechanical analysis. A texture analyzer was used to study the bioadhesive and mechanical properties of the HME films. The physical and chemical stability of the films, stored at 25 degrees C/60% relative humidity or in a desiccator, was studied for up to 12 months. CT was found to be in solid solution within all of the formulations extruded. The physical stability of the drug and PEO in the HME films increased with increasing HPC concentration, but the bioadhesivity and flexibility of the PEO films decreased with increasing HPC concentration. Films containing HPC:PEO:CT in the ratio of 55:35:10 demonstrated optimum physical-mechanical, bioadhesive, and release properties. In conclusion, polymer blends of HPC and PEO were used successfully to tailor the drug release, mechanical and bioadhesive properties, and stability of the HME films.