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Pharmaceutics
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Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process
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Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process

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 (20 September 2022) | Viewed by 20437

Special Issue Editors

Prof. Dr. Gabriele Sadowski

E-Mail Website
Guest Editor
Laboratory of Thermodynamics, Department of Biochemical and Chemical Engineering, TU Dortmund University, Emil-Figge-Str. 70, 44227 Dortmund, Germany
Interests: thermodynamic modeling; diffusion; polymer thermodynamics; thermodynamics of pharmaceutical systems; electrolyte systems; amorphous solid dispersions; reaction equilibria; solubility predictions; downstream processing; biological formulations
Dr. Christian Luebbert

E-Mail Website
Guest Editor
Amofor GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany
Interests: amorphous formulations; in-silico formulation development; process design; solubility predictions; long-term stability

Special Issue Information

Dear Colleagues,

Amorphous solid dispersions have become a preferred formulation technique to enhance the insufficient bioavailability of the increasing number of poorly-soluble molecules in drug development. The selection of the most appropriate manufacturing process depends on various material-related aspects, the intermolecular interplay among the substances or regulatory aspects and needs to be optimized individually for each formulation. The manufacturing process influences strongly the performance of the final formulation, e.g. stability or dissolution. High efforts have been made to understand and predict the role of the manufacturing process on the formulation performance, but many process decisions are still made based on trial-and-error basis or empirical knowledge. Experts and researchers are invited to contribute to this Special Issue on the rational selection of a manufacturing process for amorphous solid dispersion formulations to advance and exchange on this field of formulation development.

Prof. Dr. Gabriele Sadowski
Dr. Christian Luebbert
Guest Editors

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Keywords

  • amorphous solid dispersions
  • excipient selection
  • process design
  • critical quality attributes
  • enabling formulations
  • polymeric excipients
  • spray drying
  • hot melt extrusion

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Published Papers (5 papers)

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Research

25 pages, 4492 KiB  
Article
Nano-Dry-Melting: A Novel Technology for Manufacturing of Pharmaceutical Amorphous Solid Dispersions
by Malin Hermeling, Christoph Nueboldt, Roman Heumann, Werner Hoheisel and Joerg Breitkreutz
Pharmaceutics 2022, 14(10), 2145; https://doi.org/10.3390/pharmaceutics14102145 - 9 Oct 2022
Cited by 1 | Viewed by 2696
Abstract
Amorphous solid dispersions (ASD) are one of the most prominent formulation approaches to overcome bioavailability issues that are often presented by new poorly soluble drug candidates. State-of-the art manufacturing techniques include hot melt extrusion and solvent-based methods like spray drying. The high thermal [...] Read more.
Amorphous solid dispersions (ASD) are one of the most prominent formulation approaches to overcome bioavailability issues that are often presented by new poorly soluble drug candidates. State-of-the art manufacturing techniques include hot melt extrusion and solvent-based methods like spray drying. The high thermal and mechanical shear stress during hot melt extrusion, or the use of an organic solvent during solvent-based methods, are examples of clear drawbacks for those methods, limiting their applicability for certain systems. In this work a novel process technology is introduced, called Nano-Dry-Melting (NDM), which can provide an alternative option for ASD manufacturing. NDM consists of a comminution step in which the drug is ground to nanosize and a drying step provides a complete amorphization of the system at temperatures below the melting point. Two drug–polymer systems were prepared using NDM with a wet media mill and a spray dryer and analyzed regarding their degree of crystallinity using XRD analysis. Feasibility studies were performed with indomethacin and PVP. Furthermore, a “proof-of-concept” study was conducted with niclosamide. The experiments successfully led to amorphous samples at temperatures of about 50 K below the melting point within seconds of heat exposition. With this novel, solvent-free and therefore “green” production technology it is feasible to manufacture ASDs even with those drug candidates that cannot be processed by conventional process technologies. Full article
(This article belongs to the Special Issue Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process)
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19 pages, 91519 KiB  
Article
Downstream Processing of Itraconazole:HPMCAS Amorphous Solid Dispersion: From Hot-Melt Extrudate to Tablet Using a Quality by Design Approach
by Saurabh M Mishra, Margarethe Richter, Luis Mejia and Andreas Sauer
Pharmaceutics 2022, 14(7), 1429; https://doi.org/10.3390/pharmaceutics14071429 - 7 Jul 2022
Cited by 7 | Viewed by 4449
Abstract
The downstream processing of hot-melt extruded amorphous solid dispersions (ASDs) into tablets is challenging due to the low tabletability of milled ASDs. Typically, the extrudate strand is sized before milling, as the strand cannot be fed directly into the milling system. At the [...] Read more.
The downstream processing of hot-melt extruded amorphous solid dispersions (ASDs) into tablets is challenging due to the low tabletability of milled ASDs. Typically, the extrudate strand is sized before milling, as the strand cannot be fed directly into the milling system. At the lab scale, the strand can be sized by hand-cutting before milling. For scaling up, pelletizers or chill roll and flaker systems can be used to break strands. Due to the different techniques used, differences in milling and tablet compaction are to be expected. We present a systematic study of the milling and tableting of an extruded ASD of itraconazole with hypromellose acetate succinate (HPMCAS) as a carrier polymer. The strand was sized using different techniques at the end of the extruder barrel (hand-cutting, pelletizer, or chill roll and flaker) before being milled at varying milling speeds with varying screen sizes. The effects of these variables (sizing technology, milling speed, and screen size) on the critical quality attributes (CQAs) of the milled ASD, such as yield, mean particle size (D50), tablet compaction characteristics, and tablet dissolution, were established using response surface methodology. It was found that the CQAs varied according to sizing technology, with chill roll flakes showing the highest percentage yield, the lowest D50, and the highest tabletability and dissolution rate for itraconazole. Pearson correlation coefficient tests indicated D50 as the most important CQA related to tabletability and dissolution. For certain milling conditions, the milling of hand-cut filaments results in similar particle size distributions (PSDs) to the milling of pellets or chill roll flakes. Full article
(This article belongs to the Special Issue Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process)
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16 pages, 3926 KiB  
Article
A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development
by Samuel O. Kyeremateng, Kristin Voges, Stefanie Dohrn, Ekaterina Sobich, Ute Lander, Stefan Weber, David Gessner, Rachel C. Evans and Matthias Degenhardt
Pharmaceutics 2022, 14(5), 1044; https://doi.org/10.3390/pharmaceutics14051044 - 12 May 2022
Cited by 15 | Viewed by 4265
Abstract
Several literature publications have described the potential application of active pharmaceutical ingredient (API)–polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram [...] Read more.
Several literature publications have described the potential application of active pharmaceutical ingredient (API)–polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram as a risk assessment tool for HME are non-existent. Accordingly, within AbbVie, an HME risk classification system (HCS) based on API–polymer phase diagrams has been developed as a material-sparing tool for the early risk assessment of especially high melting temperature APIs, which are typically considered unsuitable for HME. The essence of the HCS is to provide an API risk categorization framework for the development of ASDs via the HME process. The proposed classification system is based on the recognition that the manufacture of crystal-free ASD using the HME process fundamentally depends on the ability of the melt temperature to reach the API’s thermodynamic solubility temperature or above. Furthermore, we explored the API–polymer phase diagram as a simple tool for process design space selection pertaining to API or polymer thermal degradation regions and glass transition temperature-related dissolution kinetics limitations. Application of the HCS was demonstrated via HME experiments with two high melting temperature APIs, sulfamerazine and telmisartan, with the polymers Copovidone and Soluplus. Analysis of the resulting ASDs in terms of the residual crystallinity and degradation showed excellent agreement with the preassigned HCS class. Within AbbVie, the HCS concept has been successfully applied to more than 60 different APIs over the last 8 years as a robust validated risk assessment and quality-by-design (QbD) tool for the development of HME ASDs. Full article
(This article belongs to the Special Issue Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process)
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17 pages, 47904 KiB  
Article
The Value of Bead Coating in the Manufacturing of Amorphous Solid Dispersions: A Comparative Evaluation with Spray Drying
by Eline Boel, Felien Reniers, Wim Dehaen and Guy Van den Mooter
Pharmaceutics 2022, 14(3), 613; https://doi.org/10.3390/pharmaceutics14030613 - 11 Mar 2022
Cited by 2 | Viewed by 4855
Abstract
Despite the fact that an amorphous solid dispersion (ASD)-coated pellet formulation offers potential advantages regarding the minimization of physical stability issues, there is still a lack of in-depth understanding of the bead coating process and its value in relation to spray drying. Therefore, [...] Read more.
Despite the fact that an amorphous solid dispersion (ASD)-coated pellet formulation offers potential advantages regarding the minimization of physical stability issues, there is still a lack of in-depth understanding of the bead coating process and its value in relation to spray drying. Therefore, bead coating and spray drying were both evaluated for their ability to manufacture high drug-loaded ASDs and for their ability to generate physically stable formulations. For this purpose, naproxen (NAP)–poly(vinyl-pyrrolidone-co-vinyl acetate) (PVP-VA) was selected as an interacting drug–polymer model system, whilst naproxen methyl ester (NAPME)–PVP-VA served as a non-interacting model system. The solvent employed in this study was methanol (MeOH). First, a crystallization tendency study revealed the rapid crystallization behavior of both model drugs. In the next step, ASDs were manufactured with bead coating as well as with spray drying and for each technique the highest possible drug load that still results in an amorphous system was defined via a drug loading screening approach. Bead coating showed greater ability to manufacture high drug-loaded ASDs as compared to spray drying, with a rather small difference for the interacting drug–polymer model system studied but with a remarkable difference for the non-interacting system. In addition, the importance of drug–polymer interactions in achieving high drug loadings is demonstrated. Finally, ASDs coated onto pellets were found to be more physically stable in comparison to the spray dried formulations, strengthening the value of bead coating for ASD manufacturing purposes. Full article
(This article belongs to the Special Issue Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process)
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15 pages, 6271 KiB  
Article
Superiority of Mesoporous Silica-Based Amorphous Formulations over Spray-Dried Solid Dispersions
by Hongwei Zhang, Minglu Li, Jianmin Li, Anjali Agrawal, Ho-Wah Hui and Demin Liu
Pharmaceutics 2022, 14(2), 428; https://doi.org/10.3390/pharmaceutics14020428 - 16 Feb 2022
Cited by 12 | Viewed by 2874
Abstract
The aim of this study was to compare the performance of two amorphous formulation strategies: mesoporous silica via solvent impregnation, and solid dispersions by spray drying. Poorly soluble fenofibrate was chosen as the model drug compound. A total of 30% Fenofibrate-loaded mesoporous silica [...] Read more.
The aim of this study was to compare the performance of two amorphous formulation strategies: mesoporous silica via solvent impregnation, and solid dispersions by spray drying. Poorly soluble fenofibrate was chosen as the model drug compound. A total of 30% Fenofibrate-loaded mesoporous silica and spray-dried solid dispersions (SDD) were prepared for head-to-head comparisons, including accelerated stability, manufacturability, and in vitro biorelevant dissolution. In the accelerated stability study under 40 °C/75% RH in open dish, mesoporous silica was able to maintain amorphous fenofibrate for up to 3 months based on solid-state characterizations by PXRD and DSC. This result was superior compared to SDD, as recrystallization was observed within 2 weeks. Under the same drug load, fenofibrate-loaded mesoporous silica showed much better flowability than fenofibrate-loaded SDD, which is beneficial for powder handling of the intermediate product during the downstream process. The in vitro 2-stage dissolution results indicated a well-controlled release of fenofibrate from mesoporous silica in the biorelevant media, rather than a burst release followed by fast precipitation due to the recrystallization in the early simulated gastric phase for SDD. The present study demonstrates that mesoporous silica is a promising formulation platform alternative to prevailing spray-dried solid dispersions for oral drug product development. Full article
(This article belongs to the Special Issue Amorphous Solid Dispersions: Rational Selection of a Manufacturing Process)
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