Molecular Disorder of Bicalutamide—Amorphous Solid Dispersions Obtained by Solvent Methods

The effect of solvent removal techniques on phase transition, physical stability and dissolution of bicalutamide from solid dispersions containing polyvinylpyrrolidone (PVP) as a carrier was investigated. A spray dryer and a rotavapor were applied to obtain binary systems containing either 50% or 66% of the drug. Applied techniques led to the formation of amorphous solid dispersions as confirmed by X-ray powder diffractometry and differential scanning calorimetry. Moreover, solid–solid transition from polymorphic form I to form II was observed for bicalutamide spray dried without a carrier. The presence of intermolecular interactions between the drug and polymer molecules, which provides the stabilization of molecularly disordered bicalutamide, was analyzed using infrared spectroscopy. Spectral changes within the region characteristic for amide vibrations suggested that the amide form of crystalline bicalutamide was replaced by a less stable imidic one, characteristic of an amorphous drug. Applied processes also resulted in changes of particle geometry and size as confirmed by scanning electron microscopy and laser diffraction measurements, however they did not affect the dissolution significantly as confirmed by intrinsic dissolution study. The enhancement of apparent solubility and dissolution were assigned mostly to the loss of molecular arrangement by drug molecules. Performed statistical analysis indicated that the presence of PVP reduces the mean dissolution time and improve the dissolution efficiency. Although the dissolution was equally affected by both applied methods of solid dispersion manufacturing, spray drying provides better control of particle size and morphology as well as a lower tendency for recrystallization of amorphous solid dispersions.

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Spray-Dried Paracetamol/Polyvinylpyrrolidone Amorphous Solid Dispersions: Part I—Stability of Powders and Tablets

Pharmaceutics ◽

10.3390/pharmaceutics13111938 ◽

2021 ◽

Vol 13 (11) ◽

pp. 1938

Author(s):

Lena Ritters ◽

Yuanyuan Tian ◽

Stephan Reichl

Keyword(s):

Solid Dispersions ◽

Physical Stability ◽

Amorphous Solid ◽

Polymorphic Form ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

Pharmaceutical Ingredients ◽

Poorly Soluble ◽

The Stability ◽

Spray Dried

The formulation of active pharmaceutical ingredients (APIs) in amorphous solid dispersions (ASDs) is a promising approach to improve the bioavailability of poorly soluble compounds. However, problems often arise in the production of tablets from ASDs regarding the compressibility and recrystallization of the API. In the present study, the preparation of spray-dried ASDs of paracetamol (PCM) and four different types of polyvinylpyrrolidone (PVP) and their further processing into tablets were investigated. The influence of PVP type on the glass transition temperature (Tg) and the physical stability of ASD powders were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). ASD powders with 10 to 30% PCM were stable for at least 48 weeks. PCM contents of 40 to 50% led to recrystallization of the amorphous PCM within a few days or weeks. ASD with PVP/vinyl acetate (VA) copolymer (PVP/VA) was the most unstable and tended to recrystallize in PCM polymorphic form II. This formulation was therefore used for tablet studies. The influence of compression force on recrystallization, crushing strength, and drug release was investigated. Even high compression forces did not affect the stability of the ASD. However, the ASD tablets led to slow release of the API.

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Crystallization Tendency of Pharmaceutical Glasses: Relevance to Compound Properties, Impact of Formulation Process, and Implications for Design of Amorphous Solid Dispersions

Pharmaceutics ◽

10.3390/pharmaceutics11050202 ◽

2019 ◽

Vol 11 (5) ◽

pp. 202 ◽

Cited By ~ 7

Author(s):

Kohsaku Kawakami

Keyword(s):

Solid Dispersions ◽

Physical Stability ◽

Amorphous Solid ◽

Developmental Studies ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

Drug Molecules ◽

Candidate Drug ◽

Poorly Soluble ◽

Crystallization Tendency

Amorphous solid dispersions (ASDs) are important formulation strategies for improving the dissolution process and oral bioavailability of poorly soluble drugs. Physical stability of a candidate drug must be clearly understood to design ASDs with superior properties. The crystallization tendency of small organics is frequently estimated by applying rapid cooling or a cooling/reheating cycle to their melt using differential scanning calorimetry. The crystallization tendency determined in this way does not directly correlate with the physical stability during isothermal storage, which is of great interest to pharmaceutical researchers. Nevertheless, it provides important insights into strategy for the formulation design and the crystallization mechanism of the drug molecules. The initiation time for isothermal crystallization can be explained using the ratio of the glass transition and storage temperatures (Tg/T). Although some formulation processes such as milling and compaction can enhance nucleation, the Tg/T ratio still works for roughly predicting the crystallization behavior. Thus, design of accelerated physical stability test may be possible for ASDs. The crystallization tendency during the formulation process and the supersaturation ability of ASDs may also be related to the crystallization tendency determined by thermal analysis. In this review, the assessment of the crystallization tendency of pharmaceutical glasses and its relevance to developmental studies of ASDs are discussed.

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Rapid Assessment of the Physical Stability of Amorphous Solid Dispersions

Crystal Growth & Design ◽

10.1021/acs.cgd.6b01901 ◽

2017 ◽

Vol 17 (5) ◽

pp. 2478-2485 ◽

Cited By ~ 13

Author(s):

Pinal Mistry ◽

Kweku K. Amponsah-Efah ◽

Raj Suryanarayanan

Keyword(s):

Solid Dispersions ◽

Rapid Assessment ◽

Physical Stability ◽

Amorphous Solid ◽

Amorphous Solid Dispersions

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

Pharmaceutics ◽

10.3390/pharmaceutics11100529 ◽

2019 ◽

Vol 11 (10) ◽

pp. 529 ◽

Cited By ~ 4

Author(s):

Piyush Panini ◽

Massimiliano Rampazzo ◽

Abhishek Singh ◽

Filip Vanhoutte ◽

Guy Van den Mooter

Keyword(s):

Single Phase ◽

Solid Dispersions ◽

Amorphous Solid ◽

Glass Forming Ability ◽

Amorphous Solid Dispersion ◽

Class Iii ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

Modulated Differential Scanning Calorimetry ◽

Glass Forming

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.

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Unravelling the Miscibility of Poly(2-oxazoline)s: A Novel Polymer Class for the Formulation of Amorphous Solid Dispersions

Molecules ◽

10.3390/molecules25163587 ◽

2020 ◽

Vol 25 (16) ◽

pp. 3587

Author(s):

Melissa Everaerts ◽

Ali Tigrine ◽

Victor R. de la Rosa ◽

Richard Hoogenboom ◽

Peter Adriaensens ◽

...

Keyword(s):

Body Temperature ◽

Drug Release ◽

Solid Dispersions ◽

Amorphous Solid ◽

Water Soluble ◽

Resonance Spectroscopy ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

Soluble Polymer ◽

Water Soluble Polymer

Water-soluble polymers are still the most popular carrier for the preparation of amorphous solid dispersions (ASDs). The advantage of this type of carrier is the fast drug release upon dissolution of the water-soluble polymer and thus the initial high degree of supersaturation of the poorly soluble drug. Nevertheless, the risk for precipitation due to fast drug release is a phenomenon that is frequently observed. In this work, we present an alternative carrier system for ASDs where a water-soluble and water-insoluble carrier are combined to delay the drug release and thus prevent this onset of precipitation. Poly(2-alkyl-2-oxazoline)s were selected as a polymer platform since the solution properties of this polymer class depend on the length of the alkyl sidechain. Poly(2-ethyl-2-oxazoline) (PEtOx) behaves as a water-soluble polymer at body temperature, while poly(2-n-propyl-2-oxazoline) (PPrOx) and poly(2-sec-butyl-2-oxazoline) (PsecBuOx) are insoluble at body temperature. Since little was known about the polymer’s miscibility behaviour and especially on how the presence of a poorly-water soluble drug impacted their miscibility, a preformulation study was performed. Formulations were investigated with X-ray powder diffraction, differential scanning calorimetry (DSC) and solid-state nuclear magnetic resonance spectroscopy. PEtOx/PPrOx appeared to form an immiscible blend based on DSC and this was even more pronounced after heating. The six drugs that were tested in this work did not show any preference for one of the two phases. PEtOx/PsecBuOx on the other hand appeared to be miscible forming a homogeneous blend between the two polymers and the drugs.

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Prediction of the physical stability of amorphous solid dispersions: relationship of aging and phase separation with the thermodynamic and kinetic models along with characterization techniques

Expert Opinion on Drug Delivery ◽

10.1080/17425247.2021.1844181 ◽

2020 ◽

pp. 1-16

Author(s):

Zhaoyang Zhang ◽

Luning Dong ◽

Jueshuo Guo ◽

Li Li ◽

Bin Tian ◽

...

Keyword(s):

Phase Separation ◽

Kinetic Models ◽

Solid Dispersions ◽

Physical Stability ◽

Amorphous Solid ◽

Amorphous Solid Dispersions ◽

Characterization Techniques ◽

Relationship Of

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Compression-Induced Phase Transitions of Bicalutamide

Pharmaceutics ◽

10.3390/pharmaceutics12050438 ◽

2020 ◽

Vol 12 (5) ◽

pp. 438 ◽

Cited By ~ 1

Author(s):

Joanna Szafraniec-Szczęsny ◽

Agata Antosik-Rogóż ◽

Justyna Knapik-Kowalczuk ◽

Mateusz Kurek ◽

Ewa Szefer ◽

...

Keyword(s):

Solid Dispersions ◽

Amorphous Solid ◽

Active Pharmaceutical Ingredient ◽

X Ray Diffraction ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

X Ray ◽

High Propensity ◽

Poorly Soluble ◽

Amorphous Drug

The formation of solid dispersions with the amorphous drug dispersed in the polymeric matrix improves the dissolution characteristics of poorly soluble drugs. Although they provide an improved absorption after oral administration, the recrystallization, which can occur upon absorption of moisture or during solidification and other formulation stages, serves as a major challenge. This work aims at understanding the amorphization-recrystallization changes of bicalutamide. Amorphous solid dispersions with poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA) were obtained by either ball milling or spray drying. The applied processes led to drug amorphization as confirmed using X-ray diffraction and differential scanning calorimetry. Due to a high propensity towards mechanical activation, the changes of the crystal structure of physical blends of active pharmaceutical ingredient (API) and polymer upon pressure were also examined. The compression led to drug amorphization or transition from form I to form II polymorph, depending on the composition and applied force. The formation of hydrogen bonds confirmed using infrared spectroscopy and high miscibility of drug and polymer determined using non-isothermal dielectric measurements contributed to the high stability of amorphous solid dispersions. They exhibited improved wettability and dissolution enhanced by 2.5- to 11-fold in comparison with the crystalline drug. The drug remained amorphous upon compression when the content of PVP/VA in solid dispersions exceeded 20% or 33%, in the case of spray-dried and milled systems, respectively.

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