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

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

Pharmaceutics ◽

10.3390/pharmaceutics10040194 ◽

2018 ◽

Vol 10 (4) ◽

pp. 194 ◽

Cited By ~ 8

Author(s):

Joanna Szafraniec ◽

Agata Antosik ◽

Justyna Knapik-Kowalczuk ◽

Karolina Gawlak ◽

Mateusz Kurek ◽

...

Keyword(s):

Binary Systems ◽

Solid Dispersions ◽

Physical Stability ◽

Amorphous Solid ◽

Polymorphic Form ◽

Dissolution Time ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

Intrinsic Dissolution ◽

Molecular Arrangement

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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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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Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component

Pharmaceutics ◽

10.3390/pharmaceutics12030197 ◽

2020 ◽

Vol 12 (3) ◽

pp. 197 ◽

Cited By ~ 6

Author(s):

Mahbubur Rahman ◽

Stephanie Ahmad ◽

James Tarabokija ◽

Nathaniel Parker ◽

Ecevit Bilgili

Keyword(s):

Solid Dispersions ◽

Sodium Dodecyl ◽

Minor Component ◽

Amorphous Solid ◽

Amorphous Solid Dispersions ◽

Acetone Water ◽

Poorly Soluble ◽

A Minor ◽

The Impact ◽

Spray Dried

This study aimed to elucidate the impact of a common anionic surfactant, sodium dodecyl sulfate (SDS), along with hydroxypropyl cellulose (HPC) and Soluplus (Sol) on the release of griseofulvin (GF), a poorly soluble drug, from amorphous solid dispersions (ASDs). Solutions of 2.5% GF and 2.5%–12.5% HPC/Sol with 0.125% SDS/without SDS were prepared in acetone–water and spray-dried. The solid-state characterization of the ASDs suggests that GF–Sol had better miscibility and stronger interactions than GF–HPC and formed XRPD-amorphous GF, whereas HPC-based ASDs, especially the ones with a lower HPC loading, had crystalline GF. The dissolution tests show that without SDS, ASDs provided limited GF supersaturation (max. 250%) due to poor wettability of Sol-based ASDs and extensive GF recrystallization in HPC-based ASDs (max. 50%). Sol-based ASDs with SDS exhibited a dramatic increase in supersaturation (max. 570%), especially at a higher Sol loading, whereas HPC-based ASDs with SDS did not. SDS did not interfere with Sol’s ability to inhibit GF recrystallization, as confirmed by the precipitation from the supersaturated state and PLM imaging. The favorable use of SDS in a ternary ASD was attributed to both the wettability enhancement and its inability to promote GF recrystallization when used as a minor component along with Sol.

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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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Impact of HPMCAS on the Dissolution Performance of Polyvinyl Alcohol Celecoxib Amorphous Solid Dispersions

Pharmaceutics ◽

10.3390/pharmaceutics12060541 ◽

2020 ◽

Vol 12 (6) ◽

pp. 541 ◽

Cited By ~ 3

Author(s):

Marius Monschke ◽

Karl G. Wagner

Keyword(s):

Polyvinyl Alcohol ◽

Dissolution Rate ◽

Solid Dispersions ◽

Amorphous Solid ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

Dissolution Studies ◽

Rapid Dissolution ◽

Poorly Soluble ◽

Inhibitory Potential

Amorphous solid dispersions (ASDs) have been proven to increase the bioavailability of poorly soluble drugs. It is desirable that the ASD provide a rapid dissolution rate and a sufficient stabilization of the generated supersaturation. In many cases, one polymer alone is not able to provide both features, which raises a need for reasonable polymer combinations. In this study we aimed to generate a rapidly dissolving ASD using the hydrophilic polymer polyvinyl alcohol (PVA) combined with a suitable precipitation inhibitor. Initially, PVA and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were screened for their precipitation inhibitory potential for celecoxib in solution. The generated supersaturation in presence of PVA or HPMCAS was further characterized using dynamic light scattering. Binary ASDs of either PVA or HPMCAS (at 10% and 20% drug load) were prepared by hot-melt extrusion and solid-state analytics were conducted using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and fourier-transformed infrared spectroscopy (FT-IR). The non-sink dissolution studies of the binary ASDs revealed a high dissolution rate for the PVA ASDs with subsequent precipitation and for the HPMCAS ASDs a suppressed dissolution. In order to utilize the unexploited potential of the binary ASDs, the PVA ASDs were combined with HPMCAS either predissolved or added as powder and also formulated as ternary ASD. We successfully generated a solid formulation consisting of the powdered PVA ASD and HPMCAS powder, which was superior in monophasic non-sink dissolution and biorelevant biphasic dissolution studies compared to the binary and ternary ASDs.

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Enhanced Dissolution Efficiency of Tamoxifen Combined with Methacrylate Copolymers in Amorphous Solid Dispersions

Crystals ◽

10.3390/cryst10111046 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1046

Author(s):

Dayanne T. C. da Silva ◽

Daniela Nadvorny ◽

Lucas J. de A. Danda ◽

Amanda C. Q. de M. Vieira ◽

Patricia Severino ◽

...

Keyword(s):

Drug Loading ◽

Solid Dispersions ◽

Amorphous State ◽

Amorphous Solid ◽

Physical Mixture ◽

Polymer Mixture ◽

Scanning Calorimetry ◽

Amorphous Solid Dispersions ◽

Acrylate Copolymer ◽

Poorly Soluble

Amorphous solid dispersions (SDs) containing poorly soluble tamoxifen dispersed in a meth(acrylate) copolymer combination were proposed as a controlled release system. The objective of this work was to investigate the characteristics and performance of the tamoxifen–polymer mixture and evaluate the changes in functionality through a supersaturating dissolution study condition while comparing it to a physical mixture at a fixed drug-loading proportion. Two polymers, Eudragit® L 100 and Eudragit® RL 100, were used to prepare SDs with a 1:1 polymer ratio, containing 10%, 20%, or 30% (wt/wt%) of tamoxifen, by the solvent evaporation method. A physical mixture containing 30% of tamoxifen was also prepared for comparison. SDs were characterized by X-ray diffraction, Fourier-transform infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Dissolution tests were conducted under non-sink conditions to verify the occurrence of drug recrystallization upon its release. Solid-state characterizations confirmed that the drug was in the amorphous state within the polymeric matrix. Tamoxifen release in an acidic medium was mainly affected by the increase in drug concentration caused by the possible loss of interactions that characterize the main polymer functionalities. At pH 7.4, supersaturation was slowly achieved while also contributing to the increase in the kinetic solubility of the drug. The physical mixture demonstrated the best overall performance, suggesting that the polymeric interactions may have negatively affected the drug release. The combination of polymers in the composing SD proved to be a promising strategy to tailor the delivery of poorly soluble drugs. Our study highlights important information on the behavior of tamoxifen as a poorly soluble drug in supersaturating dissolution conditions while released from SD systems.

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Effect of Storage Humidity on Physical Stability of Spray-Dried Naproxen Amorphous Solid Dispersions with Polyvinylpyrrolidone: Two Fluid Nozzle vs. Three Fluid Nozzle

Pharmaceutics ◽

10.3390/pharmaceutics13071074 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1074

Author(s):

Sonal V. Bhujbal ◽

Yongchao Su ◽

Vaibhav Pathak ◽

Dmitry Y. Zemlyanov ◽

Alex-Anthony Cavallaro ◽

...

Keyword(s):

Spray Drying ◽

Single Channel ◽

Solid Dispersions ◽

Physical Stability ◽

Volume Ratio ◽

Amorphous Solid ◽

Drug Dissolution ◽

Amorphous Solid Dispersions ◽

Two Fluid ◽

Spray Dried

In a spray drying operation, a two-fluid nozzle (2FN) with a single channel is commonly used for atomizing the feed solution. However, the less commonly used three-fluid nozzle (3FN) has two separate channels, which allow spray drying of materials in two incompatible solution systems. Although amorphous solid dispersions (ASDs) prepared using a 3FN have been reported to deliver comparable drug dissolution performance relative to those prepared using a 2FN, few studies have systematically examined the effect of 3FN on the physical stability. Therefore, the goal of this work is to systematically study the physical stability of ASDs that are spray-dried using a 3FN compared to those prepared using the traditional 2FN. For the 2FN, a single solution of naproxen and polyvinylpyrrolidone (PVP) was prepared in a mixture of acetone and water at a 1:1 volume ratio because 2FN allows for only one solution inlet. For the 3FN, naproxen and PVP were dissolved individually in acetone and water, respectively, because 3FN allows simultaneous entry of two solutions. Upon storage of the formulated ASDs at different humidity levels (25%, 55% and 75% RH), naproxen crystallized more quickly from the 3FN ASDs as compared with the 2FN ASDs. 3FN ASDs crystallized after 5 days of storage at all conditions, whereas 2FN ASDs did not crystallize even at 55% RH for two months. This relatively higher crystallization tendency of 3FN ASDs was attributed to the inhomogeneity of drug and polymers as identified by the solid-state Nuclear Magnetic Resonance findings, specifically due to poor mixing of water- and acetone-based solutions at the 3FN nozzle. When only acetone was used as a solvent to prepare drug-polymer solutions for 3FN, the formulated ASD was found to be stable for >3 months of storage (at 75% RH), which suggests that instability of the 3FN ASD was due to the insufficient mixing of water and acetone solutions. This study provides insights into the effects of solvent and nozzle choices on the physical stability of spray-dried ASDs.

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Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study

Pharmaceutics ◽

10.3390/pharmaceutics10030101 ◽

2018 ◽

Vol 10 (3) ◽

pp. 101 ◽

Cited By ~ 7

Author(s):

Michael Brunsteiner ◽

Johannes Khinast ◽

Amrit Paudel

Keyword(s):

Molecular Dynamics ◽

Oral Delivery ◽

Solid Dispersions ◽

Amorphous Solid ◽

Dynamics Simulation ◽

Limiting Factor ◽

Poorly Soluble Drugs ◽

Formulation Development ◽

Amorphous Solid Dispersions ◽

Poorly Soluble

Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here, we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer–small molecule drug combinations for which stability data are available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development.

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