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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 45753

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Special Issue Editors

Prof. Dr. Karl G. Wagner

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Guest Editor

Department of Pharmaceutical Technology and Biopharmaceutics, University of Bonn, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany
Interests: hot-melt extrusion; enabling formulations; in vivo predictive biopharmaceutical tools; modified release dosage forms; process simulation and understanding

Mr. Andreas Gryczke

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Assistant Guest Editor

Drug Product Development, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen am Rhein, Germany
Interests: hot-melt extrusion; in silico process development; amorphous solid dispersions; residence time distribution and therefrom derived process understanding

Special Issue Information

Dear Colleagues,

Hot–melt extrusion has evolved throughout the past 30 years from being a young, pioneering research area in pharmaceutical processing to a mature, broadly accepted, and commercially applied technology. This Special Issue will explore the different facets of how it started, how it evolved to reach today’s state, and what the future might bring. The authors will cover all relevant sections from upstream processing, the extrusion process itself, the corresponding downstream options, as well as special aspects of analytics. All of this will be provided by an expert panel from both industry and academia with a primary emphasis on addressing the needs and interests of both academic and industrial readers.

Prof. Dr. Karl G. Wagner
Mr. Andreas Gryczke
Guest Editors

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Keywords

hot-melt extrusion
process development
modeling and simulation
process analytical tools
process understanding
formulation design
solid state characterization
stability
enabling formulations
performance evaluation
modified release
downstream
dissolution

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Published Papers (9 papers)

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Research

16 pages, 4837 KiB

Open AccessArticle

Hot-Melt 3D Extrusion for the Fabrication of Customizable Modified-Release Solid Dosage Forms

by Jaemin Lee, Chanwoo Song, Inhwan Noh, Sangbyeong Song and Yun-Seok Rhee

Pharmaceutics 2020, 12(8), 738; https://doi.org/10.3390/pharmaceutics12080738 - 5 Aug 2020

Cited by 21 | Viewed by 4634

Abstract

In this work, modified-release solid dosage forms were fabricated by adjusting geometrical properties of solid dosage forms through hot-melt 3D extrusion (3D HME). Using a 3D printer with air pressure driving HME system, solid dosage forms containing ibuprofen (IBF), polyvinyl pyrrolidone (PVP), and polyethylene glycol (PEG) were printed by simultaneous HME and 3D deposition. Printed solid dosage forms were evaluated for their physicochemical properties, dissolution rates, and floatable behavior. Results revealed that IBF content in the solid dosage form could be individualized by adjusting the volume of solid dosage form. IBF was dispersed as amorphous state with enhanced solubility and dissolution rate in a polymer solid dosage form matrix. Due to absence of a disintegrant, sustained release of IBF from printed solid dosage forms was observed in phosphate buffer at pH 6.8. The dissolution rate of IBF was dependent on geometric properties of the solid dosage form. The dissolution rate of IBF could be modified by merging two different geometries into one solid dosage form. In this study, the 3D HME process showed high reproducibility and accuracy for preparing dosage forms. API dosage and release profile were found to be customizable by modifying or combining 3D modeling. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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16 pages, 4127 KiB

Open AccessArticle

Orodispersible Polymer Films with the Poorly Water-Soluble Drug, Olanzapine: Hot-Melt Pneumatic Extrusion for Single-Process 3D Printing

by Hui-Won Cho, Seung-Hoon Baek, Beom-Jin Lee and Hyo-Eon Jin

Pharmaceutics 2020, 12(8), 692; https://doi.org/10.3390/pharmaceutics12080692 - 22 Jul 2020

Cited by 62 | Viewed by 6289

Abstract

Amorphous solid dispersions (ASDs) improve the oral delivery of poorly water-soluble drugs. ASDs of olanzapine (OLZ), which have a high melting point and low solubility, are performed using a complicated process. Three-dimensional (3D) printing based on hot-melt pneumatic extrusion (HMPE) is a simplified method for producing ASDs. Unlike general 3D printing, printlet extrusion is possible without the preparation of drug-loaded filaments. By heating powder blends, direct fused deposition modeling (FDM) printing through a nozzle is possible, and this step produces ASDs of drugs. In this study, we developed orodispersible films (ODFs) loaded with OLZ as a poorly water-soluble drug. Various ratios of film-forming polymers and plasticizers were investigated to enhance the printability and optimize the printing temperature. Scanning electron microscopy (SEM) showed the surface morphology of the film for the optimization of the polymer carrier ratios. Differential scanning calorimetry (DSC) was used to evaluate thermal properties. Powder X-ray diffraction (PXRD) confirmed the physical form of the drug during printing. The 3D printed ODF formulations successfully loaded ASDs of OLZ using HMPE. Our ODFs showed fast disintegration patterns within 22 s, and rapidly dissolved and reached up to 88% dissolution within 5 min in the dissolution test. ODFs fabricated using HMPE in a single process of 3D printing increased the dissolution rates of the poorly water-soluble drug, which could be a suitable formulation for fast drug absorption. Moreover, this new technology showed prompt fabrication feasibility of various formulations and ASD formation of poorly water-soluble drugs as a single process. The immediate dissolution within a few minutes of ODFs with OLZ, an atypical antipsychotic, is preferred for drug compliance and administration convenience. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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21 pages, 3345 KiB

Open AccessArticle

Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion

by Martin Spoerk, Ioannis Koutsamanis, Josip Matić, Simone Eder, Carolina Patricia Alva Zúñiga, Johannes Poms, Jesús Alberto Afonso Urich, Raymar Andreína Lara García, Klaus Nickisch, Karin Eggenreich, Andreas Berghaus, Kathrin Reusch, Yorick Relle, Johannes Khinast and Amrit Paudel

Pharmaceutics 2020, 12(6), 588; https://doi.org/10.3390/pharmaceutics12060588 - 24 Jun 2020

Cited by 8 | Viewed by 4707

Abstract

To avoid any type of cross-contamination, residue-free production equipment is of utmost importance in the pharmaceutical industry. The equipment cleaning for continuous processes such as hot melt extrusion (HME), which has recently gained popularity in pharmaceutical applications, necessitates extensive manual labour and costs. The present work tackles the HME cleaning issue by investigating two cleaning strategies following the extrusion of polymeric formulations of a hormonal drug and for a sustained release formulation of a poorly soluble drug. First, an in-line quantification by means of UV–Vis spectroscopy was successfully implemented to assess very low active pharmaceutical ingredient (API) concentrations in the extrudates during a cleaning procedure for the first time. Secondly, a novel in-situ solvent-based cleaning approach was developed and its usability was evaluated and compared to a polymer-based cleaning sequence. Comparing the in-line data to typical swab and rinse tests of the process equipment indicated that inaccessible parts of the equipment were still contaminated after the polymer-based cleaning procedure, although no API was detected in the extrudate. Nevertheless, the novel solvent-based cleaning approach proved to be suitable for removing API residue from the majority of problematic equipment parts and can potentially enable a full API cleaning-in-place of a pharmaceutical extruder for the first time. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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21 pages, 7905 KiB

Open AccessArticle

Influence of Carbamazepine Dihydrate on the Preparation of Amorphous Solid Dispersions by Hot Melt Extrusion

by Xiangyu Ma, Felix Müller, Siyuan Huang, Michael Lowinger, Xu Liu, Rebecca Schooler and Robert O. Williams III

Pharmaceutics 2020, 12(4), 379; https://doi.org/10.3390/pharmaceutics12040379 - 20 Apr 2020

Cited by 22 | Viewed by 5879

Abstract

Amorphous solid dispersions (ASDs) are commonly used in the pharmaceutical industry to improve the dissolution and bioavailability of poorly water-soluble drugs. Hot melt extrusion (HME) has been employed to prepare ASD based products. However, due to the narrow processing window of HME, ASDs are normally obtained with high processing temperatures and mechanical stress. Interestingly, one-third of pharmaceutical compounds reportedly exist in hydrate forms. In this study, we selected carbamazepine (CBZ) dihydrate to investigate its solid-state changes during the dehydration process and the impact of the dehydration on the preparation of CBZ ASDs using a Leistritz micro-18 extruder. Various characterization techniques were used to study the dehydration kinetics of CBZ dihydrate under different conditions. We designed the extrusion runs and demonstrated that: 1) the dehydration of CBZ dihydrate resulted in a disordered state of the drug molecule; 2) the resulted higher energy state CBZ facilitated the drug solubilization and mixing with the polymer matrix during the HME process, which significantly decreased the required extrusion temperature from 140 to 60 °C for CBZ ASDs manufacturing compared to directly processing anhydrous crystalline CBZ. This work illustrated that the proper utilization of drug hydrates can significantly improve the processability of HME for preparing ASDs. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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16 pages, 7685 KiB

Open AccessArticle

Processing of Polyvinyl Acetate Phthalate in Hot-Melt Extrusion—Preparation of Amorphous Solid Dispersions

by Marius Monschke, Kevin Kayser and Karl G. Wagner

Pharmaceutics 2020, 12(4), 337; https://doi.org/10.3390/pharmaceutics12040337 - 9 Apr 2020

Cited by 26 | Viewed by 5950

Abstract

The preparation of amorphous solid dispersions (ASDs) is a suitable approach to overcome solubility-limited absorption of poorly soluble drugs. In particular, pH-dependent soluble polymers have proven to be an excellently suitable carrier material for ASDs. Polyvinyl acetate phthalate (PVAP) is a polymer with a pH-dependent solubility, which is as yet not thoroughly characterized regarding its suitability for a hot-melt extrusion process. The objective of this study was to assess the processability of PVAP within a hot-melt extrusion process with the aim of preparing an ASD. Therefore, the influence of different process parameters (temperature, feed-rate) on the degree of degradation, solid-state and dissolution time of the neat polymer was studied. Subsequently, drug-containing ASDs with indomethacin (IND) and dipyridamole (DPD) were prepared, respectively, and analyzed regarding drug content, solid-state, non-sink dissolution performance and storage stability. PVAP was extrudable in combination with 10% (w/w) PEG 3000 as plasticizer. The dissolution time of PVAP was only slightly influenced by different process parameters. For IND no degradation occurred in combination with PVAP and single phased ASDs could be generated. The dissolution performance of the IND-PVAP ASD at pH 5.5 was superior and at pH 6.8 equivalent compared to commonly used polymers hydroxypropylmethylcellulose acetate succinate (HPMCAS) and Eudragit L100-55. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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23 pages, 4408 KiB

Open AccessArticle

A Rational Design of a Biphasic Dissolution Setup—Modelling of Biorelevant Kinetics for a Ritonavir Hot-Melt Extruded Amorphous Solid Dispersion

by Alexander Denninger, Ulrich Westedt, Jörg Rosenberg and Karl G. Wagner

Pharmaceutics 2020, 12(3), 237; https://doi.org/10.3390/pharmaceutics12030237 - 6 Mar 2020

Cited by 40 | Viewed by 5035

Abstract

Biphasic dissolution systems achieved good predictability for the in vivo performance of several formulations of poorly water-soluble drugs by characterizing dissolution, precipitation, re-dissolution, and absorption. To achieve a high degree of predictive performance, acceptor media, aqueous phase composition, and the apparatus type have to be carefully selected. Hence, a combination of 1-decanol and an optimized buffer system are proposed as a new, one-vessel biphasic dissolution method (BiPHa+). The BiPHa+ was developed to combine the advantages of the well-described biorelevance of the United States Pharmacopeia (USP) apparatus II coupled with USP apparatus IV and a small-scale, one-vessel method. The BiPHa+ was designed for automated medium addition and pH control of the aqueous phase. In combination with the diode array UV-spectrophotometer, the system was able to determine the aqueous and the organic medium simultaneously, even if scattering or overlapping of spectra occurred. At controlled hydrodynamic conditions, the relative absorption area, the ratio between the organic and aqueous phase, and the selected drug concentrations were identified to be the discriminating factors. The performance of a hot-melt extruded ritonavir-containing amorphous solid dispersion (ritonavir-ASD) was compared in fasted-state dissolution media leading to different dissolution-partitioning profiles depending on the content of bile salts. An advanced kinetic model for ASD-based well described all phenomena from dispersing of the ASD to the partitioning of the dissolved ritonavir into the organic phase. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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23 pages, 4356 KiB

Open AccessArticle

Development and Validation of an in-line API Quantification Method Using AQbD Principles Based on UV-Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process

by Juan Almeida, Mariana Bezerra, Daniel Markl, Andreas Berghaus, Phil Borman and Walkiria Schlindwein

Pharmaceutics 2020, 12(2), 150; https://doi.org/10.3390/pharmaceutics12020150 - 12 Feb 2020

Cited by 22 | Viewed by 5097

Abstract

A key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in Kollidon^® VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in-line analytical procedure was developed using predictive models based on UV-Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters—in-process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% β-expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at ±5%. The method robustness was tested by evaluating the effects of screw speed (150–250 rpm) and feed rate (5–9 g/min) on piroxicam content around 15% w/w. In-line UV-Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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14 pages, 2159 KiB

Open AccessArticle

Exploring the Complexity of Processing-Induced Dehydration during Hot Melt Extrusion Using In-Line Raman Spectroscopy

by Lærke Arnfast, Jeroen van Renterghem, Johanna Aho, Johan Bøtker, Dhara Raijada, Stefania Baldursdóttir, Thomas De Beer and Jukka Rantanen

Pharmaceutics 2020, 12(2), 116; https://doi.org/10.3390/pharmaceutics12020116 - 1 Feb 2020

Cited by 6 | Viewed by 2825

Abstract

The specific aim in this study was to understand the effect of critical process parameters on the solid form composition of model drug compounds during hot melt extrusion using in-line Raman spectroscopy combined with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) modeling for semi-quantitative kinetic profiling. It was observed that the hydrate and anhydrate solid forms of two model drugs in the melts of nitrofurantoin (NF):polyethylene oxide (PEO) and piroxicam (PRX):PEO could be resolved from a MCR-ALS model without an external calibration dataset. Based on this model, the influence of two critical process parameters (shear and temperature) on the solid form composition could be evaluated in a real-time mode and the kinetics of complex transformation pathways could be explored. Additionally, the dehydration pathways of NF monohydrate and PRX monohydrate in molten PEO could be derived. It can be concluded that dehydration of both hydrates in PEO occurs via competing mechanisms—a solution-mediated transformation pathway and a solid–solid transformation, and that the balance between these mechanisms is determined by the combined effect of both temperature and shear. Another important observation was that the water released from these hydrate compounds has a detectable effect on the rheological characteristics of this mixture. Full article

(This article belongs to the Special Issue Hot-Melt Extrusion)

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23 pages, 6857 KiB

Open AccessArticle

Clay-Polymer Nanocomposites Prepared by Reactive Melt Extrusion for Sustained Drug Release

by Xu Liu, Xingyu Lu, Yongchao Su, Eucharist Kun and Feng Zhang

Pharmaceutics 2020, 12(1), 51; https://doi.org/10.3390/pharmaceutics12010051 - 7 Jan 2020

Cited by 31 | Viewed by 4384

Abstract

Clay–polymer nanocomposites have exhibited a great potential as carriers for controlled release drug delivery. This study aims to prepare exfoliated montmorillonite–Eudragit RS nanocomposites using reactive melt extrusion and investigate the influence of claying loading, clay types (sodium montmorillonite (Cloisite Na) vs. organomodified montmorillonite (Cloisite 20)) on clay–polymer interactions and drug release properties. The clays were used as the filler material at various levels in Eudragit RS and theophylline was used as the active pharmaceutical ingredient. The resulting structure of the nanocomposites was characterized using TEM (transmission electron microscopy) and XRPD (X-ray powder diffraction). The hygroscopicity of the nanocomposites was investigated using DVS (dynamic vapor sorption). The effect of the interfacial interaction between the polymer and clay sheet, the clay loading as well as the clay type on the drug release behavior were further studied by dissolution testing. TEM and XRPD data show that when the clay content is increased from 5% to 15% by weight, the nanocomposite’s structure switches from a fully exfoliated state to intercalated structures or partial exfoliation with stacked clay layers. FT-IR (fourier transform infrared spectroscopy) and ssNMR (solid-state NMR) results suggest that Cloisite Na and Cloisite 20 layers exhibit different interaction strengths with polymer networks by creating compacted complex structures. The addition of nanoclay in the formulation could robustly adjust drug release profiles, and the clay concentration and type are important factors that affect the crossing-linking density of the nanocomposites by adjusting the drug release properties. This study indicates that the clay–Eudragit RS nanocomposites provide an improved oral controlled drug delivery system that minimizes the drug dosing frequency, potentially leading to improved patient compliance. Full article

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