Engineering pharmaceutical stability with amorphous solids

Roberts, Christopher J.; Debenedetti, Pablo G.

doi:10.1002/aic.690480602

Cited by 81 publications

(64 citation statements)

References 22 publications

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“…The transition from the glassy state to a semi-solid state (rubbery, gel-like or ultra-viscous liquid) is called glass transition and characterized by the glass transition temperature, T g Debenedetti and Stillinger, 2001;Roberts and Debenedetti, 2002;Zobrist et al, 2008). At the glass transition, discontinuous changes can be observed in thermodynamic properties such as molar volume, enthalpy or entropy, but dynamic properties such as viscosity and diffusivity change only gradually.…”

Section: Water Uptake By Amorphous Substancesmentioning

confidence: 99%

“…Amorphous substances have no long-range atomic order and are classified as solid glasses when their viscosity exceeds 10 12 Pa s Debenedetti and Stillinger, 2001). Semi-solid amorphous substances like rubbers and gels have lower viscosities but still tend to retain their envelope shape (Roberts and Debenedetti, 2002).…”

Section: Water Uptake By Amorphous Substancesmentioning

confidence: 99%

“…It applies to organic compounds with a wide range of molecular masses (e.g., mono-, di-and polysaccharides), and the amorphous state of spray-dried organic materials was confirmed by X-ray diffraction, differential scanning calorimetry and dynamic vapor sorption methods (Corrigan, 1984;Bhandari and Howes, 1999;Roberts and Debenedetti, 2002;Price and Young, 2003;Burnett et al, 2004;Langrish and Wang, 2006;and references therein).…”

Section: Introductionmentioning

confidence: 99%

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Amorphous and crystalline aerosol particles interacting with water vapor: conceptual framework and experimental evidence for restructuring, phase transitions and kinetic limitations

et al. 2009

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Abstract. Interactions with water are crucial for the properties, transformation and climate effects of atmospheric aerosols. Here we present a conceptual framework for the interaction of amorphous aerosol particles with water vapor, outlining characteristic features and differences in comparison to crystalline particles. We used a hygroscopicity tandem differential mobility analyzer (H-TDMA) to characterize the hydration and dehydration of crystalline ammonium sulfate, amorphous oxalic acid and amorphous levoglucosan particles (diameter ∼100 nm, relative humidity 5-95% at 298 K). The experimental data and accompanying Köhler model calculations provide new insights into particle microstructure, surface adsorption, bulk absorption, phase transitions and hygroscopic growth. The results of these and related investigations lead to the following conclusions:(1) Many organic substances, including carboxylic acids, carbohydrates and proteins, tend to form amorphous rather than crystalline phases upon drying of aqueous solution droplets. Depending on viscosity and microstructure, the amorphous phases can be classified as glasses, rubbers, gels or viscous liquids.(2) Amorphous organic substances tend to absorb water vapor and undergo gradual deliquescence and hygroscopic growth at lower relative humidity than their crystalline counterparts.(3) In the course of hydration and dehydration, certain organic substances can form rubber-or gel-like structures Correspondence to: U. Pöschl (u.poschl@mpic.de) (supramolecular networks) and undergo transitions between swollen and collapsed network structures.(4) Organic gels or (semi-)solid amorphous shells (glassy, rubbery, ultra-viscous) with low molecular diffusivity can kinetically limit the uptake and release of water and may influence the hygroscopic growth and activation of aerosol particles as cloud condensation nuclei (CCN) and ice nuclei (IN). Moreover, (semi-)solid amorphous phases may influence the uptake of gaseous photo-oxidants and the chemical transformation and aging of atmospheric aerosols.(5) The shape and porosity of amorphous and crystalline particles formed upon dehydration of aqueous solution droplets depend on chemical composition and drying conditions. The apparent volume void fractions of particles with highly porous structures can range up to ∼50% or more (xerogels, aerogels).(6) For efficient description of water uptake and phase transitions of aerosol particles, we propose not to limit the terms deliquescence and efflorescence to equilibrium phase transitions of crystalline substances. Instead we propose generalized definitions according to which amorphous and crystalline components can undergo gradual or prompt, partial or full deliquescence or efflorescence.We suggest that (semi-)solid amorphous phases may be important not only in the upper atmosphere as suggested in recent studies of glass formation at low temperatures. Depending on relative humidity, (semi-)solid phases and moisture-induced glass transitions may also play a role in gas-particle intera...

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Section: Water Uptake By Amorphous Substancesmentioning

confidence: 99%

Section: Water Uptake By Amorphous Substancesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amorphous and crystalline aerosol particles interacting with water vapor: conceptual framework and experimental evidence for restructuring, phase transitions and kinetic limitations

et al. 2009

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“…There is a common interest to stabilize unstable crystalline forms of pharmaceuticals since solubility and bioavailibility are usually improved. Even more interesting are amorphous drugs especially if they are stable for a long period of time [4,5]. However, this situation is hard to achieve in practice since pharmaceuticals show usually a strong tendency to crystallize.…”

Section: Introductionmentioning

confidence: 99%

Crystallization Behavior of Acetaminophen in Nanopores

Rengarajan¹,

Enke²,

Beiner³

2007

TOPCJ

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Abstract:The influence of nanoconfinement on the crystallization behavior of acetaminophen, a polymorphic drug occurring in three different crystalline forms, is investigated. Differential scanning calorimetry (DSC) and wide angle X-ray scattering (WAXS) data for a series of controlled porous glasses (CPGs) filled with acetaminophen are presented. The results show clearly that (i) the usually inaccessible crystalline form III of acetaminophen can be produced in pores with diameters between 22 and 103 nm and that (ii) the life time of amorphous acetaminophen is significantly increased in 10 nm pores. Bulk melting temperature and heat of melting of form III are estimated based on the Gibbs-Thomson equation. The experimental findings are confronted with the predictions of theoretical approaches aimed to describe thermodynamics and crystallization kinetics in nano-sized systems in order to understand the physical background of the observed changes.

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“…Freeze-tolerant organisms such as the Arctic char, for example, thrive in subfreezing habitats where cold denaturation can occur (6). Biopharmaceuticals are also exposed to cold conditions that can result in denaturation when they are lyophilized into freeze-dried solids to prolong their shelf life (7,8). Natural cryoprotectants such as sugars and polyols stabilize proteins against denaturation in cold-weather species (6), and similar compounds have been used to mitigate the damaging effects of freeze-drying in pharmaceutical formulations (7, 9).…”

mentioning

confidence: 99%

Computational investigation of cold denaturation in the Trp-cage miniprotein

Kim

Palmer

Debenedetti

2016

Proc. Natl. Acad. Sci. U.S.A.

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The functional native states of globular proteins become unstable at low temperatures, resulting in cold unfolding and impairment of normal biological function. Fundamental understanding of this phenomenon is essential to rationalizing the evolution of freeze-tolerant organisms and developing improved strategies for long-term preservation of biological materials. We present fully atomistic simulations of cold denaturation of an α-helical protein, the widely studied Trp-cage miniprotein. In contrast to the significant destabilization of the folded structure at high temperatures, Trp-cage cold denatures at 210 K into a compact, partially folded state; major elements of the secondary structure, including the α-helix, are conserved, but the salt bridge between aspartic acid and arginine is lost. The stability of Trp-cage's α-helix at low temperatures suggests a possible evolutionary explanation for the prevalence of such structures in antifreeze peptides produced by coldweather species, such as Arctic char. Although the 3 10 -helix is observed at cold conditions, its position is shifted toward Trp-cage's C-terminus. This shift is accompanied by intrusion of water into Trp-cage's interior and the hydration of buried hydrophobic residues. However, our calculations also show that the dominant contribution to the favorable energetics of low-temperature unfolding of Trp-cage comes from the hydration of hydrophilic residues.cold denaturation | Trp-cage miniprotein | protein folding T he functional native states of globular proteins that are stable near physiological conditions become labile when changes in temperature, pressure, and solvent composition alter their environment. The partial or complete unfolding of secondary and tertiary structure associated with this loss of stability can strongly affect protein behavior, leading to significantly impaired biological function (1, 2). Denaturation upon heating is a ubiquitous and well-studied phenomenon in which proteins gain configurational entropy and unfold as a result of increased kinetic energy. By contrast, the mechanisms responsible for pressure-induced unfolding, and for denaturation of globular proteins at low temperatures, remain incompletely understood (3-5).Fundamental understanding of cold denaturation is important due to its ecological implications and relevance to industrial processing of proteins and biological materials. Freeze-tolerant organisms such as the Arctic char, for example, thrive in subfreezing habitats where cold denaturation can occur (6). Biopharmaceuticals are also exposed to cold conditions that can result in denaturation when they are lyophilized into freeze-dried solids to prolong their shelf life (7,8). Natural cryoprotectants such as sugars and polyols stabilize proteins against denaturation in cold-weather species (6), and similar compounds have been used to mitigate the damaging effects of freeze-drying in pharmaceutical formulations (7, 9).Cold denaturation was first reported by Hopkins in 1930 (10). Brandts (11) subsequently observed ...

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Engineering pharmaceutical stability with amorphous solids

Abstract: P Pe er rs sp pe ec ct ti iv ve e

Cited by 81 publications

References 22 publications

Amorphous and crystalline aerosol particles interacting with water vapor: conceptual framework and experimental evidence for restructuring, phase transitions and kinetic limitations

Amorphous and crystalline aerosol particles interacting with water vapor: conceptual framework and experimental evidence for restructuring, phase transitions and kinetic limitations

Crystallization Behavior of Acetaminophen in Nanopores

Computational investigation of cold denaturation in the Trp-cage miniprotein

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