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19 pages, 4176 KiB

Open AccessArticle

Co-Amorphization of Kanamycin with Amino Acids Improves Aerosolization

by Bishal Raj Adhikari, Kārlis Bērziņš, Sara J. Fraser-Miller, Keith C. Gordon and Shyamal C. Das

Pharmaceutics 2020, 12(8), 715; https://doi.org/10.3390/pharmaceutics12080715 - 30 Jul 2020

Cited by 13 | Viewed by 3833

Different formulation techniques have been investigated to prepare highly aerosolizable dry powders to deliver a high dose of antibiotics to the lung for treating local infections. In this study, we investigated the influence of the co-amorphization of a model drug, kanamycin, with selected [...] Read more.

Different formulation techniques have been investigated to prepare highly aerosolizable dry powders to deliver a high dose of antibiotics to the lung for treating local infections. In this study, we investigated the influence of the co-amorphization of a model drug, kanamycin, with selected amino acids (valine, methionine, phenylalanine, and tryptophan) by co-spray drying on its aerosolization. The co-amorphicity was confirmed by thermal technique. The physical stability was monitored using low-frequency Raman spectroscopy coupled with principal component analysis. Except for the kanamycin-valine formulation, all the formulations offered improved fine particle fraction (FPF) with the highest FPF of 84% achieved for the kanamycin-methionine formulation. All the co-amorphous formulations were physically stable for 28 days at low relative humidity (25 °C/<15% RH) and exhibited stable aerosolization. At higher RH (53%), even though methionine transformed into its crystalline counterpart, the kanamycin-methionine formulation offered the best aerosolization stability without any decrease in FPF. While further studies are warranted to reveal the underlying mechanism, this study reports that the co-amorphization of kanamycin with amino acids, especially with methionine, has the potential to be developed as a high dose kanamycin dry powder formulation. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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6 pages, 1704 KiB

Open AccessCommunication

Influence of the Polymer Glass Transition Temperature and Molecular Weight on Drug Amorphization Kinetics Using Ball Milling

by Camilla Asgreen, Matthias Manne Knopp, Jeppe Skytte and Korbinian Löbmann

Pharmaceutics 2020, 12(6), 483; https://doi.org/10.3390/pharmaceutics12060483 - 27 May 2020

Cited by 8 | Viewed by 2791

Abstract

In this study, the putative correlation between the molecular mobility of a polymer and the ball milling drug amorphization kinetics (i.e., time to reach full drug amorphization, t_a) was studied using different grades of dextran (Dex) and polyvinylpyrrolidone (PVP) and the [...] Read more.

In this study, the putative correlation between the molecular mobility of a polymer and the ball milling drug amorphization kinetics (i.e., time to reach full drug amorphization, t_a) was studied using different grades of dextran (Dex) and polyvinylpyrrolidone (PVP) and the two model drugs indomethacin (IND) and chloramphenicol (CAP). In general, IND had lower t_a values than CAP, indicating that IND amorphized faster than CAP in the presence of the polymers. In addition, an increase in polymer molecular weight (M_w) also led to an increase in t_a for all systems investigated up to a critical M_w for each polymer, which was in line with an increase of the glass transition temperature (T_g) up to the critical M_w of each polymer. Hence, the increase in t_a seemed to correlate well with the T_g/M_w of the polymers, which indicates that the polymers’ molecular mobility had an influence on the drug amorphization kinetics during ball milling. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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23 pages, 4264 KiB

Open AccessArticle

Physicochemical Properties of Poly-vinyl Polymers and Their Influence on Ketoprofen Amorphous Solid Dispersion Performance: A Polymer Selection Case Study

by Emer Browne, Zelalem A. Worku and Anne Marie Healy

Pharmaceutics 2020, 12(5), 433; https://doi.org/10.3390/pharmaceutics12050433 - 08 May 2020

Cited by 33 | Viewed by 4510

Abstract

When developing an amorphous solid dispersion (ASD), a prudent choice of polymer is critical to several aspects of ASD performance including: processability, solid state stability and dissolution rate. However, there is little guidance available to formulators to aid judicious polymer selection and a [...] Read more.

When developing an amorphous solid dispersion (ASD), a prudent choice of polymer is critical to several aspects of ASD performance including: processability, solid state stability and dissolution rate. However, there is little guidance available to formulators to aid judicious polymer selection and a “trial and error” approach is often taken. This study aims to facilitate rational polymer selection and formulation design by generating ASDs using a range of poly-vinyl polymers and ketoprofen as a model active pharmaceutical ingredient (API) and evaluating several aspects of their performance. The molecular weight of the polymer and the ratio of vinyl pyrrolidone to vinyl acetate in the polymer were found to influence the relative humidity at which the relative humidity induced glass transition occurred, as well as the extent of ketoprofen supersaturation achieved during dynamic solubility testing. Interestingly, ASD tablets containing polymers with the vinyl pyrrolidone functional group exhibited higher tensile strengths than those without. This points towards the binder functionality of vinyl pyrrolidone. In conclusion, the physicochemical properties of poly-vinyl polymers greatly influence ketoprofen ASD performance and due regard should be paid to these properties in order to develop an ASD with the desired attributes. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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21 pages, 7611 KiB

Open AccessArticle

Importance of Mesoporous Silica Particle Size in the Stabilization of Amorphous Pharmaceuticals—The Case of Simvastatin

by Justyna Knapik-Kowalczuk, Daniel Kramarczyk, Krzysztof Chmiel, Jana Romanova, Kohsaku Kawakami and Marian Paluch

Pharmaceutics 2020, 12(4), 384; https://doi.org/10.3390/pharmaceutics12040384 - 22 Apr 2020

Cited by 14 | Viewed by 3588

Abstract

In this paper, the role of mesoporous silica (MS) particle size in the stabilization of amorphous simvastatin (SVT) is revealed. For inhibiting recrystallization of the supercooled drug, the two MS materials (Syloid^® XDP 3050 and Syloid^® 244 FP) were employed. The [...] Read more.

In this paper, the role of mesoporous silica (MS) particle size in the stabilization of amorphous simvastatin (SVT) is revealed. For inhibiting recrystallization of the supercooled drug, the two MS materials (Syloid^® XDP 3050 and Syloid^® 244 FP) were employed. The crystallization tendency of SVT alone and in mixture with the MS materials was investigated by Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS). Neither confinement of the SVT molecules inside the MS pores nor molecular interactions between functional groups of the SVT molecules and the surface of the stabilizing excipient could explain the observed stabilization effect. The stabilization effect might be correlated with diffusion length of the SVT molecules in the MS materials that depended on the particle size. Moreover, MS materials possessing different particle sizes could offer free spaces with different sizes, which might influence crystal growth of SVT. All of these factors must be considered when mesoporous materials are used for stabilizing pharmaceutical glasses. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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11 pages, 1144 KiB

Open AccessArticle

Theory of Structural and Secondary Relaxation in Amorphous Drugs under Compression

by Anh D. Phan and Katsunori Wakabayashi

Pharmaceutics 2020, 12(2), 177; https://doi.org/10.3390/pharmaceutics12020177 - 19 Feb 2020

Cited by 9 | Viewed by 3004

Abstract

Compression effects on alpha and beta relaxation process of amorphous drugs are theoretically investigated by developing the elastically collective nonlinear Langevin equation theory. We describe the structural relaxation as a coupling between local and nonlocal activated process. Meanwhile, the secondary beta process is [...] Read more.

Compression effects on alpha and beta relaxation process of amorphous drugs are theoretically investigated by developing the elastically collective nonlinear Langevin equation theory. We describe the structural relaxation as a coupling between local and nonlocal activated process. Meanwhile, the secondary beta process is mainly governed by the nearest-neighbor interactions of a molecule. This assumption implies the beta relaxation acts as a precursor of the alpha relaxation. When external pressure is applied, a small displacement of a molecule is additionally exerted by a pressure-induced mechanical work in the dynamic free energy, which quantifies interactions between a molecule with its nearest neighbors. The local dynamics has more restriction and it induces stronger effects of collective motions on single-molecule dynamics. Thus, the alpha and beta relaxation times are significantly slowed down with increasing compression. We apply this approach to determine the temperature and pressure dependence of the alpha and beta relaxation time for curcumin, glibenclamide, and indomethacin, and compare numerical results with prior experimental studies. Both qualitative and quantitative agreement between theoretical calculations and experiments validate our assumptions and reveal their limitations. Our approach would pave the way for the development of the drug formulation process. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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19 pages, 4117 KiB

Open AccessArticle

Evaluation of the Solid Dispersion System Engineered from Mesoporous Silica and Polymers for the Poorly Water Soluble Drug Indomethacin: In Vitro and In Vivo

by Ziyue Xi, Wei Zhang, Yali Fei, Mingshu Cui, Luyao Xie, Lu Chen and Lu Xu

Pharmaceutics 2020, 12(2), 144; https://doi.org/10.3390/pharmaceutics12020144 - 10 Feb 2020

Cited by 13 | Viewed by 3742

Abstract

This work explored absorption efficacy via an in vivo imaging system and parallel artificial membrane penetration in indomethacin (IMC) solid dispersion (SD) systems. Two different polymer excipients—hydroxypropyl methylcellulose (HPMC) and Kollicoat IR as precipitation inhibitors (PIs)—combined with mesoporous silica nanoparticles (MSNs) as carriers [...] Read more.

This work explored absorption efficacy via an in vivo imaging system and parallel artificial membrane penetration in indomethacin (IMC) solid dispersion (SD) systems. Two different polymer excipients—hydroxypropyl methylcellulose (HPMC) and Kollicoat IR as precipitation inhibitors (PIs)—combined with mesoporous silica nanoparticles (MSNs) as carriers were investigated. The IMC–SDs were prepared using the solvent evaporation method and characterized by solubility analysis, infrared (IR) spectroscopy, powder X-ray diffraction (PXRD), field emission scanning electron microscopy (FESEM), and differential scanning calorimetry (DSC). It was confirmed that IMC successfully changed into an amorphous state after loading into the designed carriers. The in vitro release and stability experiments were conducted to examine the in vitro dissolution rates of IMC–SDs combined with HPMC and Kollicoat IR as PIs which both improved approximately three-fold to that of the pure drug. Finally, in vivo studies and in vitro parallel artificial membrane penetration (PAMPA) experiments ensured the greater ability of enhancing the dissolution rates of pure IMC in the gastrointestinal tract by oral delivery. In brief, this study highlights the prominent role of HPMC and Kollicoat IR as PIs in MSN SD systems in improving the bioavailability and gastrointestinal oral absorption efficiency of indomethacin. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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7 pages, 799 KiB

Open AccessCommunication

Determining Thermal Conductivity of Small Molecule Amorphous Drugs with Modulated Differential Scanning Calorimetry and Vacuum Molding Sample Preparation

by Maximilian Karl, Jukka Rantanen and Thomas Rades

Pharmaceutics 2019, 11(12), 670; https://doi.org/10.3390/pharmaceutics11120670 - 10 Dec 2019

Cited by 3 | Viewed by 4250

Abstract

Thermal conductivity is a material specific property, which influences many aspects of pharmaceutical development, such as processing, modelling, analysis, and the development of novel formulation approaches. We have presented a method to measure thermal conductivity of small molecule organic glasses, based on a [...] Read more.

Thermal conductivity is a material specific property, which influences many aspects of pharmaceutical development, such as processing, modelling, analysis, and the development of novel formulation approaches. We have presented a method to measure thermal conductivity of small molecule organic glasses, based on a vacuum molding sample preparation technique combined with modulated differential scanning calorimetry. The method is applied to the two amorphous model compounds indomethacin and celecoxib. The measured values of below 0.2 W/m °C indicate very low thermal conductivity of the amorphous compounds, within the range of organic liquids and low conducting polymers. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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11 pages, 2990 KiB

Open AccessArticle

Determination of Stable Co-Amorphous Drug–Drug Ratios from the Eutectic Behavior of Crystalline Physical Mixtures

by Eric Ofosu Kissi, Keyoomars Khorami and Thomas Rades

Pharmaceutics 2019, 11(12), 628; https://doi.org/10.3390/pharmaceutics11120628 - 24 Nov 2019

Cited by 23 | Viewed by 7865

Abstract

Co-amorphous drug–drug systems have been developed with the overall aim of improving the physical stability of two or more amorphous drugs. Co-amorphous systems often show good physical stability, and higher solubility and dissolution rates compared to their crystalline counterparts. The aim of this [...] Read more.

Co-amorphous drug–drug systems have been developed with the overall aim of improving the physical stability of two or more amorphous drugs. Co-amorphous systems often show good physical stability, and higher solubility and dissolution rates compared to their crystalline counterparts. The aim of this study is to determine if eutectic mixtures of two drugs can form stable co-amorphous systems. Three drug–drug mixtures, indomethacin–naproxen (IND−NAP), nifedipine–paracetamol (NIF−PAR), and paracetamol–celecoxib (PAR−CCX), were investigated for their eutectic and co-amorphization behavior as well as their physical stability in the co-amorphous form. The phase diagrams of the crystalline mixtures and the thermal behavior of the co-amorphous systems were analyzed by differential scanning calorimetry. The solid-state form and physical stability of the co-amorphous systems were analyzed using X-ray powder diffractometry during storage at room temperature at dry conditions. Initial eutectic screening using nifedipine (NIF), paracetamol (PAR), and celecoxib (CCX) indicated that IND−NAP, NIF−PAR, and PAR−CCX can form eutectic mixtures. Phase diagrams were then constructed using theoretical and experimental values. These systems, at different drug-to-drug ratios, were melted and cooled to form binary mixtures. Most mixtures were found to be co-amorphous systems, as they were amorphous and exhibited a single glass transition temperature. The stability study of the co-amorphous systems indicated differences in their physical stability. Comparing the phase diagrams with the physical stability of the co-amorphous mixtures, it was evident that the respective drug–drug ratio that forms the eutectic point also forms the most stable co-amorphous system. The eutectic behavior of drug–drug systems can thus be used to predict drug ratios that form the most stable co-amorphous systems. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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15 pages, 4303 KiB

Open AccessArticle

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

by Felix Ditzinger, Daniel J. Price, Anita Nair, Johanna Becker-Baldus, Clemens Glaubitz, Jennifer B. Dressman, Christoph Saal and Martin Kuentz

Pharmaceutics 2019, 11(11), 577; https://doi.org/10.3390/pharmaceutics11110577 - 04 Nov 2019

Cited by 11 | Viewed by 4266

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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17 pages, 3322 KiB

Open AccessArticle

Myth or Truth: The Glass Forming Ability Class III Drugs Will Always Form Single-Phase Homogenous Amorphous Solid Dispersion Formulations

by Piyush Panini, Massimiliano Rampazzo, Abhishek Singh, Filip Vanhoutte and Guy Van den Mooter

Pharmaceutics 2019, 11(10), 529; https://doi.org/10.3390/pharmaceutics11100529 - 14 Oct 2019

Cited by 14 | Viewed by 3800

Abstract

The physical stability of amorphous solid dispersions (ASD) of active pharmaceutical ingredients (APIs) of high glass forming ability (GFA class III) is generally expected to be high among the scientific community. In this study, the ASD of ten-selected class III APIs with the [...] Read more.

The physical stability of amorphous solid dispersions (ASD) of active pharmaceutical ingredients (APIs) of high glass forming ability (GFA class III) is generally expected to be high among the scientific community. In this study, the ASD of ten-selected class III APIs with the two polymers, PVPVA 64 and HPMC-E5, have been prepared by spray-drying, film-casting, and their amorphicity at T0 was investigated by modulated differential scanning calorimetry and powder X-ray diffraction. It was witnessed that only five out of ten APIs form good quality amorphous solid dispersions with no phase separation and zero crystalline content, immediately after the preparation and drying process. Hence, it was further established that the classification of an API as GFA class III does not guarantee the formulation of single phase amorphous solid dispersions. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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Review

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19 pages, 1825 KiB

Open AccessReview

Microwave-Induced In Situ Amorphization: A New Strategy for Tackling the Stability Issue of Amorphous Solid Dispersions

by Wei Qiang, Korbinian Löbmann, Colin P. McCoy, Gavin P. Andrews and Min Zhao

Pharmaceutics 2020, 12(7), 655; https://doi.org/10.3390/pharmaceutics12070655 - 11 Jul 2020

Cited by 24 | Viewed by 3706

Abstract

The thermodynamically unstable nature of amorphous drugs has led to a persistent stability issue of amorphous solid dispersions (ASDs). Lately, microwave-induced in situ amorphization has been proposed as a promising solution to this problem, where the originally loaded crystalline drug is in situ [...] Read more.

The thermodynamically unstable nature of amorphous drugs has led to a persistent stability issue of amorphous solid dispersions (ASDs). Lately, microwave-induced in situ amorphization has been proposed as a promising solution to this problem, where the originally loaded crystalline drug is in situ amorphized within the final dosage form using a household microwave oven prior to oral administration. In addition to circumventing issues with physical stability, it can also simplify the problematic downstream processing of ASDs. In this review paper, we address the significance of exploring and developing this novel technology with an emphasis on systemically reviewing the currently available literature in this pharmaceutical arena and highlighting the underlying mechanisms involved in inducing in situ amorphization. Specifically, in order to achieve a high drug amorphicity, formulations should be composed of drugs with high solubility in polymers, as well as polymers with high hygroscopicity and good post-plasticized flexibility of chains. Furthermore, high microwave energy input is considered to be a desirable factor. Lastly, this review discusses challenges in the development of this technology including chemical stability, selection criteria for excipients and the dissolution performance of the microwave-induced ASDs. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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23 pages, 2673 KiB

Open AccessReview

Continuous Formulation Approaches of Amorphous Solid Dispersions: Significance of Powder Flow Properties and Feeding Performance

by Edina Szabó, Balázs Démuth, Dorián László Galata, Panna Vass, Edit Hirsch, István Csontos, György Marosi and Zsombor K. Nagy

Pharmaceutics 2019, 11(12), 654; https://doi.org/10.3390/pharmaceutics11120654 - 05 Dec 2019

Cited by 19 | Viewed by 4548

Abstract

Preparation and formulation of amorphous solid dispersions (ASDs) are becoming more and more popular in the pharmaceutical field because the dissolution of poorly water-soluble drugs can be effectively improved this way, which can lead to increased bioavailability in many cases. During downstream processing [...] Read more.

Preparation and formulation of amorphous solid dispersions (ASDs) are becoming more and more popular in the pharmaceutical field because the dissolution of poorly water-soluble drugs can be effectively improved this way, which can lead to increased bioavailability in many cases. During downstream processing of ASDs, technologists need to keep in mind both traditional challenges and the newest trends. In the last decade, the pharmaceutical industry began to display considerable interest in continuous processing, which can be explained with their potential advantages such as smaller footprint, easier scale-up, and more consistent product, better quality and quality assurance. Continuous downstream processing of drug-loaded ASDs opens new ways for automatic operation. Therefore, the formulation of poorly water-soluble drugs may be more effective and safe. However, developments can be challenging due to the poor flowability and feeding properties of ASDs. Consequently, this review pays special attention to these characteristics since the feeding of the components greatly influences the content uniformity in the final dosage form. The main purpose of this paper is to summarize the most important steps of the possible ASD-based continuous downstream processes in order to give a clear overview of current course lines and future perspectives. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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