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Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (10 June 2021) | Viewed by 23886

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Special Issue Editors

Prof. Dr. Rajesh N. Dave

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Guest Editor

Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
Interests: particle engineering; drug nano-particles and composites including thin films; amorphous solid dispersions; 3D printing; novel techniques for dry particle coating; film-coated particles; taste-masking and controlled release; nano-mixing; cohesive powder fluidization; discrete element modeling
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Ecevit Bilgili

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Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
Interests: particle engineering; pharmaceutical nanotechnology; drug nanosuspensions and nanocomposites; amorphous solid dispersions; multi-scale process modeling; pharmaceutical unit operations; milling; granulation; spray drying; extrusion
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Mohammad A. Azad

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Guest Editor

Department of Chemical, Biological and Bioengineering, North Carolina A&T State University, Greensboro, NC 27411, USA
Interests: advanced manufacturing (3D printing); materials science; polymer-based actives delivery; amorphous drug composites; process engineering; nanotechnology

Special Issue Information

Dear Colleagues,

An increasing number of poorly water-soluble small molecules in the pharmaceutical industry pipeline exhibit slow dissolution–absorption and thus poor bioavailability, presenting a major challenge in developing such molecules into medicines. To enhance the solubility and dissolution rate, amorphous solid dispersions (ASDs) have been commonly used as a platform approach. However, various challenges arise from drug–excipient miscibility, residual crystallinity, physical stability during storage, drug precipitation during dissolution, and the need for excessive amounts of excipients that limit drug loading. Moreover, downstream processing of ASD powders poses challenges potentially due to low bulk density and/or poor flowability of such powders.

Within the context of “Materials Science and Engineering”, this Special Issue aims to bring academics and industry practitioners in pharmaceutical science and engineering to disseminate knowledge and information about ASDs, physical stability, formulations and processes, dissolution, solid-state characterization, novel manufacturing methods, modeling, regulatory aspects, etc. Papers providing fundamental insights into ASD formation, a fresh perspective and analysis of existing formulation–processing approaches, and thermodynamic–kinetic aspects of physical stability, as well as those exploring supersaturation, the glass-forming ability of drugs, solution-mediated precipitation, and drug–excipient molecular interactions, are especially welcome. While the thematic emphasis is on “Materials Science and Engineering” with clear relevance to the dissolution enhancement of poorly soluble drugs, papers that aim to establish in vivo relevance and the impact of ASDs via in vitro permeability tests, in vivo resorption assessments, animal studies, and/or PKPD models are also welcome.

We look forward to receiving your submissions for this Special Issue.

Prof. Dr. Rajesh N. Dave
Prof. Dr. Ecevit Bilgili
Prof. Dr. Mohammad A. Azad
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

amorphous solid dispersions
poorly water-soluble drugs
bioavailability enhancement
drug loading
supersaturation and precipitation
physical stability
solid-state characterization
molecular interactions
flow, packing density, and compaction
formulation and process development

Published Papers (6 papers)

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Research

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19 pages, 2966 KiB

Open AccessArticle

Enhanced Supersaturation via Fusion-Assisted Amorphization during FDM 3D Printing of Crystalline Poorly Soluble Drug Loaded Filaments

by Guluzar Gorkem Buyukgoz, Christopher Gordon Kossor and Rajesh N. Davé

Pharmaceutics 2021, 13(11), 1857; https://doi.org/10.3390/pharmaceutics13111857 - 04 Nov 2021

Cited by 10 | Viewed by 2514

Abstract

Filaments loaded with griseofulvin (GF), a model poorly water-soluble drug, were prepared and used for 3D printing via fused deposition modeling (FDM). GF was selected due to its high melting temperature, enabling lower temperature hot-melt extrusion (HME) keeping GF largely crystalline in the filaments, which could help mitigate the disadvantages of high HME processing temperatures such as filament quality, important for printability and the adverse effects of GF recrystallization on tablet properties. Novel aspects include single-step fusion-assisted ASDs generation during FDM 3D printing and examining the impact of tablet surface areas (SA) through printing multi-mini and square-pattern perforated tablets to further enhance drug supersaturation during dissolution. Kollicoat protect and hydroxypropyl cellulose were selected due to their low miscibility with GF, necessary to produce crystalline filaments. The drug solid-state was assessed via XRPD, DSC and FT-IR. At 165 °C HME processing temperature, the filaments containing ~80% crystalline GF were printable. Fusion-assisted 3D printing led to GF supersaturation of ~153% for cylindrical tablets and ~293% with the square-pattern perforated tablets, indicating strong monotonous impact of tablet SA. Dissolution kinetics of drug release profiles indicated Fickian transport for tablets with higher SA, demonstrating greater SA-induced drug supersaturation for well-designed 3D printed tablets. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective)

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41 pages, 6147 KiB

Open AccessArticle

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

by Raman Iyer, Vesna Petrovska Jovanovska, Katja Berginc, Miha Jaklič, Flavio Fabiani, Cornelius Harlacher, Tilen Huzjak and Manuel Vicente Sanchez-Felix

Pharmaceutics 2021, 13(10), 1682; https://doi.org/10.3390/pharmaceutics13101682 - 14 Oct 2021

Cited by 31 | Viewed by 6758

Abstract

Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective)

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10 pages, 2305 KiB

Open AccessArticle

Processing Impact on In Vitro and In Vivo Performance of Solid Dispersions—A Comparison between Hot-Melt Extrusion and Spray Drying

by Yongjun Li, Amanda K. P. Mann, Dan Zhang and Zhen Yang

Pharmaceutics 2021, 13(8), 1307; https://doi.org/10.3390/pharmaceutics13081307 - 21 Aug 2021

Cited by 12 | Viewed by 3412

Abstract

Presently, a large number of drug molecules in development are BCS class II or IV compounds with poor aqueous solubility. Various novel solubilization techniques have been used to enhance drug solubility. Among them, amorphous solid dispersions (ASD), which convert a crystalline drug into an amorphous mixture of drug and polymer, have been demonstrated to be an effective tool in enhancing drug solubility and bioavailability. There are multiple ways to produce amorphous solid dispersions. The goal of the present study is to investigate two commonly used processing methods, hot-melt extrusion (HME) and spray drying, and their impact on drug bioperformance. The amorphous solid dispersions of a model compound, posaconazole (25% drug loading) in HPMCAS-MF, were successfully manufactured via the two processing routes, and the physicochemical properties, in vitro and in vivo performance of the resulting ASDs were characterized and compared. It was found that in vitro drug release of the ASDs from two-stage dissolution was significantly different. However, the two ASDs showed similar in vivo performance based on cynomolgus monkey PK studies. A mechanistic understanding of the in vitro and in vivo behaviors of the solid dispersions was discussed. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective)

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19 pages, 4803 KiB

Open AccessArticle

Impact of Laser Speed and Drug Particle Size on Selective Laser Sintering 3D Printing of Amorphous Solid Dispersions

by Rishi Thakkar, Miguel O. Jara, Steve Swinnea, Amit R. Pillai and Mohammed Maniruzzaman

Pharmaceutics 2021, 13(8), 1149; https://doi.org/10.3390/pharmaceutics13081149 - 27 Jul 2021

Cited by 19 | Viewed by 3887

Abstract

This research demonstrates the influence of laser speed and the drug particle size on the manufacturing of amorphous solid dispersions (ASD) and dosage forms thereof using selective laser sintering 3-dimensional (3D) printing. One-step manufacturing of ASD is possible using selective laser sintering 3D printing processes, however, the mechanism of ASD formation by this process is not completely understood and it requires further investigation. We hypothesize that the mechanism of ASD formation is the diffusion and dissolution of the drug in the polymeric carrier during the selective laser sintering (SLS) process and the drug particle size plays a critical role in the formation of said ASDs as there is no mixing involved in the sintering process. Herein, indomethacin was used as a model drug and introduced into the feedstock (Kollidon^® VA64 and Candurin^® blend) as either unprocessed drug crystals (particle size > 50 µm) or processed hot-melt extruded granules (DosePlus) with reduced drug particle size (<5 µm). These feedstocks were processed at 50, 75, and 100 mm/s scan speed using SLS 3D printing process. Characterization and performance testing were conducted on these tablets which revealed the amorphous conversion of the drug. Both MANOVA and ANOVA analyses depicted that the laser speed and drug particle size significantly impact the drug’s apparent solubility and drug release. This significant difference in performance between formulations is attributed to the difference in the extent of dissolution of the drug in the polymeric matrix, leading to residual crystallinity, which is detrimental to ASD’s performance. These results demonstrate the influence of drug particle size on solid-state and performance of 3D printed solid dispersions, and, hence, provide a better understanding of the mechanism and limitations of SLS 3D printing of ASDs and its dosage forms. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective)

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28 pages, 3651 KiB

Open AccessArticle

Impact of Matrix Surface Area on Griseofulvin Release from Extrudates Prepared via Nanoextrusion

by Meng Li, Casey Furey, Jeffrey Skros, Olivia Xu, Mahbubur Rahman, Mohammad Azad, Rajesh Dave and Ecevit Bilgili

Pharmaceutics 2021, 13(7), 1036; https://doi.org/10.3390/pharmaceutics13071036 - 07 Jul 2021

Cited by 7 | Viewed by 2910

Abstract

We aimed to examine the impact of milling of extrudates prepared via nanoextrusion and the resulting matrix surface area of the particles on griseofulvin (GF, a model poorly soluble drug) release during in vitro dissolution. Wet-milled GF nanosuspensions containing a polymer (Sol: Soluplus^®, Kol: Kolliphor^® P407, or HPC: Hydroxypropyl cellulose) and sodium dodecyl sulfate were mixed with additional polymer and dried in an extruder. The extrudates with 2% and 10% GF loading were milled–sieved into three size fractions. XRPD–SEM results show that nanoextrusion produced GF nanocomposites with Kol/HPC and an amorphous solid dispersion (ASD) with Sol. For 8.9 mg GF dose (non-supersaturating condition), the dissolution rate parameter was higher for extrudates with higher external specific surface area and those with 10% drug loading. It exhibited a monotonic increase with surface area of the ASD, whereas its increase tended to saturate above ~30 × 10⁻³ m²/cm³ for the nanocomposites. In general, the nanocomposites released GF faster than the ASD due to greater wettability and faster erosion imparted by Kol/HPC than by Sol. For 100 mg GF dose, the ASD outperformed the nanocomposites due to supersaturation and only 10% GF ASD with 190 × 10⁻³ m²/cm³ surface area achieved immediate release (80% release within 30 min). Hence, this study suggests that ASD extrudates entail fine milling yielding > ~200 × 10⁻³ m²/cm³ for rapid drug release, whereas only a coarse milling yielding ~30 × 10⁻³ m²/cm³ may enable nanocomposites to release low-dose drugs rapidly. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective)

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Other

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13 pages, 2175 KiB

Open AccessPerspective

Amorphous Drug-Polymer Salts

by Xin Yao, Amy Lan Neusaenger and Lian Yu

Pharmaceutics 2021, 13(8), 1271; https://doi.org/10.3390/pharmaceutics13081271 - 17 Aug 2021

Cited by 12 | Viewed by 3111

Abstract

Amorphous formulations provide a general approach to improving the solubility and bioavailability of drugs. Amorphous medicines for global health should resist crystallization under the stressful tropical conditions (high temperature and humidity) and often require high drug loading. We discuss the recent progress in employing drug–polymer salts to meet these goals. Through local salt formation, an ultra-thin polyelectrolyte coating can form on the surface of amorphous drugs, immobilizing interfacial molecules and inhibiting fast crystal growth at the surface. The coated particles show improved wetting and dissolution. By forming an amorphous drug–polymer salt throughout the bulk, stability can be vastly enhanced against crystallization under tropical conditions without sacrificing the dissolution rate. Examples of these approaches are given, along with suggestions for future work. Full article

(This article belongs to the Special Issue Amorphous Solid Dispersions of Poorly Soluble Drugs: Materials Science and Engineering Perspective)

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