Amorphous Drug Formulations: Progress, Challenges and Perspectives

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 11667

Special Issue Editor


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Guest Editor
UMET – Unité Matériaux et Transformations, Université de Lille, CNRS, INRAE, Centrale Lille, UMR 8207, F-59000 Lille, France
Interests: molecular glasses; bioavailability vs. physical stability; mesoporous silica; biopreservation; deep-eutectic solvents

Special Issue Information

Dear Colleagues,

We are pleased to announce a Special Issue of Pharmaceutics entitled “Amorphous Drug Formulations: Progress, Challenges and Perspectives”

The extensive academic research on amorphous drug formulations can be estimated by searching SCOPUS for two search terms, (amorphous) AND (drug). More than 3000 references were found for a 10-year period, and almost 2000 since 2017. Two main factors in increasing research in this area originate from (i) the poor solubility and bioavailability of newer APIs in the crystalline state, and (ii) the bioprotective effect of amorphous solids immobilizing labile therapeutic proteins. A large part of research in the design of innovative and smart drug delivery systems is based on stabilizing the amorphous state of APIs and/or excipients. Physical instability remains a key problem of amorphous pharmaceuticals and biopharmaceuticals, and their vulnerability to various stresses during preparation, manufacturing processes or storage limits their therapeutic use.

This Special Issue aims to focus on new strategies to make the use of amorphous drugs more common, combining advances in new formulations and methods for preparing formulations, supported by fundamental research on the amorphous solid-state.

Original research articles and review articles dealing with all aspects of amorphous drug formulations from the design of new types of formulations to the evolution in the amorphizing and manufacturing processes are welcome. Designing co-amorphous formulations, solid dispersions, and new types of excipients (e.g., DES); the use of drug carriers (e.g., mesoporous silica); and new developments in spray-drying, freeze-drying, hot-melt extrusion, and co-milling in relation with the selection of suitable excipients for amorphization and subsequently for stabilization will be considered. Analytical techniques providing information on the detection, quantification or prediction of subtle transformations (e.g., partial recrystallization, nanocrystallization) of amorphous solid states will also be considered.

Prof. Dr. Alain Hedoux
Guest Editor

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Keywords

  •  bioavailability
  •  physical stability
  •  co-amorphous drug formulations
  •  drug delivery systems
  •  polymeric carriers
  •  mesoporous silica carrier systems
  •  biopreservation

Published Papers (8 papers)

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Research

22 pages, 13242 KiB  
Article
Co-Amorphous Versus Deep Eutectic Solvents Formulations for Transdermal Administration
by Yannick Guinet, Laurent Paccou and Alain Hédoux
Pharmaceutics 2023, 15(6), 1710; https://doi.org/10.3390/pharmaceutics15061710 - 12 Jun 2023
Cited by 2 | Viewed by 972
Abstract
Transdermal administration can be considered as an interesting route to overcome the side-effects inherent to oral intake. Designing topical formulations with maximum drug efficiency requires the optimization of the permeation and the stability of the drug. The present study focuses on the physical [...] Read more.
Transdermal administration can be considered as an interesting route to overcome the side-effects inherent to oral intake. Designing topical formulations with maximum drug efficiency requires the optimization of the permeation and the stability of the drug. The present study focuses on the physical stability of amorphous drugs within the formulation. Ibuprofen is commonly used in topical formulations and then was selected as a model drug. Additionally, its low Tg allows easy, unexpected recrystallization at room temperature with negative consequence on skin penetration. In this study, the physical stability of amorphous ibuprofen was investigated in two types of formulations: (i) in terpenes-based deep eutectic solvents (DES) and (ii) in arginine-based co-amorphous blends. The phase diagram of ibuprofen:L-menthol was mainly analyzed by low-frequency Raman spectroscopy, leading to the evidence of ibuprofen recrystallization in a wide range of ibuprofen concentration. By contrast, it was shown that amorphous ibuprofen is stabilized when dissolved in thymol:menthol DES. Forming co-amorphous arginine–ibuprofen blends by melting is another route for stabilizing amorphous ibuprofen, while recrystallization was detected in the same co-amorphous mixtures obtained by cryo-milling. The mechanism of stabilization is discussed from determining Tg and analyzing H-bonding interactions by Raman investigations in the C=O and O–H stretching regions. It was found that recrystallization of ibuprofen was inhibited by the inability to form dimers inherent to the preferential formation of heteromolecular H-bonding, regardless of the glass transition temperatures of the various mixtures. This result should be important for predicting ibuprofen stability within other types of topical formulations. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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12 pages, 1705 KiB  
Article
Analysis of the Dissolution Mechanism of Drugs into Polymers: The Case of the PVP/Sulindac System
by Mansour Latreche and Jean-François Willart
Pharmaceutics 2023, 15(5), 1505; https://doi.org/10.3390/pharmaceutics15051505 - 15 May 2023
Viewed by 878
Abstract
This paper is dealing with the dissolution mechanism of crystalline sulindac into amorphous Polyvinylpyrrolidone (PVP) upon heating and annealing at high temperatures. Special attention is paid on the diffusion mechanism of drug molecules in the polymer which leads to a homogeneous amorphous solid [...] Read more.
This paper is dealing with the dissolution mechanism of crystalline sulindac into amorphous Polyvinylpyrrolidone (PVP) upon heating and annealing at high temperatures. Special attention is paid on the diffusion mechanism of drug molecules in the polymer which leads to a homogeneous amorphous solid dispersion of the two components. The results show that isothermal dissolution proceeds through the growth of polymer zones saturated by the drug, and not by a progressive increase in the uniform drug concentration in the whole polymer matrix. The investigations also show the exceptional ability of temperature Modulated Differential Scanning Calorimetry (MDSC) to identify the equilibrium and out of equilibrium stages of dissolution corresponding to the trajectory of the mixture into its state diagram. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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17 pages, 6017 KiB  
Article
Amorphization of Ethenzamide and Ethenzamide Cocrystals—A Case Study of Single and Binary Systems Forming Low-Melting Eutectic Phases Loaded on/in Silica Gel
by Katarzyna Trzeciak, Ewelina Wielgus, Sławomir Kaźmierski, Tomasz Pawlak and Marek J. Potrzebowski
Pharmaceutics 2023, 15(4), 1234; https://doi.org/10.3390/pharmaceutics15041234 - 13 Apr 2023
Cited by 1 | Viewed by 1150
Abstract
The applicability of different solvent-free approaches leading to the amorphization of active pharmaceutical ingredients (APIs) was tested. Ethenzamide (ET), an analgesic and anti-inflammatory drug, and two ethenzamide cocrystals with glutaric acid (GLU) and ethyl malonic acid (EMA) as coformers were used as pharmaceutical [...] Read more.
The applicability of different solvent-free approaches leading to the amorphization of active pharmaceutical ingredients (APIs) was tested. Ethenzamide (ET), an analgesic and anti-inflammatory drug, and two ethenzamide cocrystals with glutaric acid (GLU) and ethyl malonic acid (EMA) as coformers were used as pharmaceutical models. Calcinated and thermally untreated silica gel was applied as an amorphous reagent. Three methods were used to prepare the samples: manual physical mixing, melting, and grinding in a ball mill. The ET:GLU and ET:EMA cocrystals forming low-melting eutectic phases were selected as the best candidates for testing amorphization by thermal treatment. The progress and degree of amorphousness were determined using instrumental techniques: solid-state NMR spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. In each case, the API amorphization was complete and the process was irreversible. A comparative analysis of the dissolution profiles showed that the dissolution kinetics for each sample are significantly different. The nature and mechanism of this distinction are discussed. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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12 pages, 2289 KiB  
Article
Compaction Behavior of Co-Amorphous Systems
by Cecilie-Mathilde Sørensen, Jukka Rantanen and Holger Grohganz
Pharmaceutics 2023, 15(3), 858; https://doi.org/10.3390/pharmaceutics15030858 - 06 Mar 2023
Cited by 4 | Viewed by 1752
Abstract
Co-amorphous systems have been shown to be a promising strategy to address the poor water solubility of many drug candidates. However, little is known about the effect of downstream processing-induced stress on these systems. The aim of this study is to investigate the [...] Read more.
Co-amorphous systems have been shown to be a promising strategy to address the poor water solubility of many drug candidates. However, little is known about the effect of downstream processing-induced stress on these systems. The aim of this study is to investigate the compaction properties of co-amorphous materials and their solid-state stability upon compaction. Model systems of co-amorphous materials consisting of carvedilol and the two co-formers aspartic acid and tryptophan were produced via spray drying. The solid state of matter was characterized using XRPD, DSC, and SEM. Co-amorphous tablets were produced with a compaction simulator, using varying amounts of MCC in the range of 24 to 95.5% (w/w) as a filler, and showed high compressibility. Higher contents of co-amorphous material led to an increase in the disintegration time; however, the tensile strength remained rather constant at around 3.8 MPa. No indication of recrystallization of the co-amorphous systems was observed. This study found that co-amorphous systems are able to deform plastically under pressure and form mechanically stable tablets. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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19 pages, 10383 KiB  
Article
Prediction of Unwanted Crystallization of Freeze-Dried Protein Formulations Using α-Relaxation Measurements
by Sebastian Groël, Tim Menzen and Gerhard Winter
Pharmaceutics 2023, 15(2), 703; https://doi.org/10.3390/pharmaceutics15020703 - 20 Feb 2023
Cited by 2 | Viewed by 1418
Abstract
There is a lack of methods to predict the isothermal crystallization behavior of amorphous freeze-dried formulations stored below the glass transition temperature. This study applies isothermal microcalorimetry to predict long-term crystallization during product storage time. The relaxation curve of a fresh sample recorded [...] Read more.
There is a lack of methods to predict the isothermal crystallization behavior of amorphous freeze-dried formulations stored below the glass transition temperature. This study applies isothermal microcalorimetry to predict long-term crystallization during product storage time. The relaxation curve of a fresh sample recorded within 12 h after lyophilization is correlated with the long-term crystallization time at the same temperature. Storage conditions of 25 °C and 40 °C are examined and five model formulations containing either sucrose or trehalose with different concentrations of an IgG1 antibody are investigated. The amorphous formulations were created by different freeze-drying processes only differing in their freezing step (random nucleation; additional annealing step of 1.5 h and 3 h, controlled nucleation; quench cooling). Samples that crystallized during the study time of 12 months showed a promising correlation between their relaxation time and crystallization behavior upon storage. Furthermore, the study shows that polysorbate 20 strongly accelerates crystallization of sucrose and that the freezing step itself has a strong impact on the relaxation phenomena that is not levelled out by primary and secondary drying. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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20 pages, 4411 KiB  
Article
Ball-Milling Preparation of the Drug–Drug Solid Form of Pioglitazone-Rosuvastatin at Different Molar Ratios: Characterization and Intrinsic Dissolution Rates Evaluation
by M. Fernanda Muñoz Tecocoatzi, José C. Páez-Franco, Kenneth Rubio-Carrasco, Alejandra Núñez-Pineda, Alejandro Dorazco-González, Inés Fuentes-Noriega, Alfredo R. Vilchis-Néstor, Lilian I. Olvera, David Morales-Morales and Juan Manuel Germán-Acacio
Pharmaceutics 2023, 15(2), 630; https://doi.org/10.3390/pharmaceutics15020630 - 13 Feb 2023
Cited by 1 | Viewed by 1385
Abstract
Ball-milling using neat grinding (NG) or liquid-assisted grinding (LAG) by varying the polarity of the solvents allowed access to various drug–drug solid forms of pioglitazone hydrochloride (PGZ·HCl) and rosuvastatin calcium (RSV). Using NG, the coamorphous form was formed from the reaction of pioglitazone [...] Read more.
Ball-milling using neat grinding (NG) or liquid-assisted grinding (LAG) by varying the polarity of the solvents allowed access to various drug–drug solid forms of pioglitazone hydrochloride (PGZ·HCl) and rosuvastatin calcium (RSV). Using NG, the coamorphous form was formed from the reaction of pioglitazone hydrochloride (PGZ·HCl) and rosuvastatin calcium (RSV) in a 2:1 molar ratio. The formation of the expected coamorphous salt could not be corroborated by FT-IR, but DSC data showed that it was indeed a single-phase amorphous mixture. By varying the molar ratios of the reactants, either keeping PGZ·HCl constant and varying RSV or vice versa, another coamorphous form was obtained when a 1:1 molar ratio was employed. In the case of the other outcomes, it was observed that they were a mixture of solid forms coexisting simultaneously with the coamorphous forms (1:1 or 2:1) together with the drug that was in excess. When RSV was in excess, it was in an amorphous form. In the case of PGZ·HCl, it was found in a semicrystalline form. The intrinsic dissolution rates (IDRs) of the solid forms of PGZ·HCl-RSV in stoichiometric ratios (1:1, 2:1, 1:4, 6:1, and 1:10) were evaluated. Interestingly, a synchronized release of both drugs in the dissolution medium was observed. In the case of the release of RSV, there were no improvements in the dissolution profiles, because the acidic media caused the formation of degradation products, limiting any probable modification in the dissolution processes. However, the coamorphous 2:1 form exhibited an improvement of 1.03 times with respect to pure PGZ·HCl. It is proposed that the modification of the dissolution process of the coamorphous 2:1 form was limited by changes in the pH of the media as RSV consumes protons from the media due to degradation processes. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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14 pages, 2259 KiB  
Article
The Influence of Blonanserin Supersaturation in Liquid and Silica Stabilised Self-Nanoemulsifying Drug Delivery Systems on In Vitro Solubilisation
by Amalie Møller, Hayley B. Schultz, Tahlia R. Meola, Paul Joyce, Anette Müllertz and Clive A. Prestidge
Pharmaceutics 2023, 15(1), 284; https://doi.org/10.3390/pharmaceutics15010284 - 14 Jan 2023
Viewed by 1813
Abstract
Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study [...] Read more.
Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study aimed to understand the influence of supersaturated drug load on blonanserin solubilisation from liquid and silica solidified supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) during in vitro lipolysis. Stable liquid super-SNEDDS with varying drug loads (90–300% of the equilibrium solubility) were solidified by imbibition into porous silica microparticles (1:1 lipid: silica ratio). In vitro lipolysis revealed greater blonanserin solubilisation from liquid super-SNEDDS compared to solid at equivalent drug saturation levels, owing to strong silica-BLON/lipid interactions, evidenced by a significant decrease in blonanserin solubilisation upon addition of silica to a digesting liquid super-SNEDDS. An increase in solid super-SNEDDS drug loading led to increased solubilisation, owing to the increased drug:silica and drug:lipid ratios. Solidifying SNEDDS with silica enables the fabrication of powdered formulations with higher blonanserin loading and greater stability than liquid super-SNEDDS, however at the expense of drug solubilisation. These competing parameters need careful consideration in designing optimal super-SNEDDS for pre-clinical and clinical application. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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14 pages, 2111 KiB  
Article
Considerations on the Kinetic Processes in the Preparation of Ternary Co-Amorphous Systems by Milling
by Yixuan Wang, Thomas Rades and Holger Grohganz
Pharmaceutics 2023, 15(1), 172; https://doi.org/10.3390/pharmaceutics15010172 - 03 Jan 2023
Cited by 1 | Viewed by 1292
Abstract
In non-strongly interacting co-amorphous systems, addition of a polymer, to further stabilize the co-amorphous systems, may influence the phase behavior between the components. In this study, the evolution of the composition of the amorphous phase in the ternary system carvedilol (CAR)-tryptophan (TRP)-hydroxypropylmethyl cellulose [...] Read more.
In non-strongly interacting co-amorphous systems, addition of a polymer, to further stabilize the co-amorphous systems, may influence the phase behavior between the components. In this study, the evolution of the composition of the amorphous phase in the ternary system carvedilol (CAR)-tryptophan (TRP)-hydroxypropylmethyl cellulose (HPMC) was investigated, based upon previously formed and characterized binary systems to which the third component was added (CAR − TRP + HPMC, CAR − HPMC + TRP and TRP − HPMC + CAR). Ball milling was used as the preparation method for all binary and ternary systems. The influence of the milling time on the co-amorphous systems was monitored by DSC and XRPD. Addition of HPMC reduced the miscibility of CAR with TRP due to hydrogen bond formation between CAR and polymer. These bonds became dominant for the interaction pattern. In addition, when CAR or TRP exceeded the miscibility limit in HPMC, phase separation and eventually crystallization of CAR and TRP was observed. All ternary co-amorphous systems eventually reached the same composition, albeit following different paths depending on the initially used binary system. Full article
(This article belongs to the Special Issue Amorphous Drug Formulations: Progress, Challenges and Perspectives)
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