Physical stability of amorphous pharmaceutical solids: Nucleation, crystal growth, phase separation and effects of the polymers

Shi, Qin; Li, Fang; Yeh, Stacy; Wang, Yanan; Xin, Junbo

doi:10.1016/j.ijpharm.2020.119925

Cited by 40 publications

(19 citation statements)

References 142 publications

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“…Polarized light microscope is one of the most widely used techniques in characterizing nucleation [21][22][23], crystal growth [24,25], polymorphic transition [26], and phase separation [27] of amorphous pharmaceutical solids. In recent studies, polarized light microscopy was often combined with a hot stage to extend its experimental temperature range and achieve the goal of precise temperature control.…”

Section: Combination Of Polarized Light Microscope and Hot Stagementioning

confidence: 99%

“…The high mobility of surface molecules originates from the special coordination environment, where molecules have fewer neighbors and a greater degree of freedom compared to the molecules in the interior [20,38,39]. For amorphous pharmaceutical solids, a high surface mobility causes the rapid nucleation and crystal growth at the free surface or interior interface, largely determining the physical stability [20,25,27,40]. Moreover, a high surface mobility could also allow the efficient equilibrium of newly deposited molecules in vapor deposition, facilitating the formation of highly stable glass with exceptionally low energy and high density [41,42].…”

Section: Surface Grating Decay and Surface Diffusionmentioning

confidence: 99%

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Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

Wang

Cheng

et al. 2021

Crystals

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The amorphous form of a drug usually exhibits higher solubility, faster dissolution rate, and improved oral bioavailability in comparison to its crystalline forms. However, the amorphous forms are thermodynamically unstable and tend to transform into a more stable crystalline form, thus losing their advantages. In order to investigate and suppress the crystallization, it is vital to closely monitor the drug solids during the preparation, storage, and application processes. A list of advanced techniques—including optical microscopy, surface grating decay, solid-state nuclear magnetic resonance, broadband dielectric spectroscopy—have been applied to characterize the physicochemical properties of amorphous pharmaceutical solids, to provide in-depth understanding on the crystallization mechanism. This review briefly summarizes these characterization techniques and highlights their recent advances, so as to provide an up-to-date reference to the available tools in the development of amorphous drugs.

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Section: Combination Of Polarized Light Microscope and Hot Stagementioning

confidence: 99%

Section: Surface Grating Decay and Surface Diffusionmentioning

confidence: 99%

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

Wang

Cheng

et al. 2021

Crystals

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“…In our proposed model, bubble-induced crystal growth is considered as a surface-facilitated process (Shi & Cai, 2016;Shi, Li et al, 2020;Shi, Tao et al, 2020). However, in the case of -IMC, the surface crystal growth and bubble-induced crystal growth respond differently to the high fluidity with increasing temperature.…”

Section: Bubble-induced Crystal Growthmentioning

confidence: 99%

“…Amorphization is one of the most effective pharmaceutical approaches to enhance the solubility and dissolution of poorly water soluble drugs by converting from the crystalline form to their long-range-disordered amorphous counterparts (Alam et al, 2012;Kalepu & Nekkanti, 2015;Shi, Li et al, 2020;Yu, 2001). Given their thermodynamically unstable nature, amorphous pharmaceutical solids can potentially undergo crystallization during processing and storage (Shi, Li et al, 2020;Bhugra & Pikal, 2008). In order to develop robust amorphous pharmaceutical formulations, it is important to understand the crystallization behaviors of amorphous solids.…”

Section: Introductionmentioning

confidence: 99%

Bubble-induced fast crystal growth of indomethacin polymorphs in a supercooled liquid

Shi¹,

Li²,

Xu³

et al. 2021

J Appl Cryst

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Physical stability is one of the main challenges when developing robust amorphous pharmaceutical formulations. This article reports fast crystal growth behaviors of the γ and α forms of indomethacin (IMC) initiated by bubbles in the interior of a supercooled liquid. Bubble-induced crystal growth of γ-IMC exhibits approximately the same kinetics as its surface crystal growth, supporting the view that bubble-induced crystal growth is a surface-facilitated process. In contrast, the rates of bubble-induced crystal growth of α-IMC are much faster than those of its surface crystal growth. These results indicate that the bubble-induced crystal growth not only depends on the interface created by the bubble but also strongly correlates with the true cavitation of the bubble. Moreover, bubble-induced fast crystal growth of γ- and α-IMC can be terminated at different temperatures by cooling. These outcomes are meaningful for the in-depth understanding of physical stability and pre-formulation study of amorphous pharmaceutical solids showing surface-facilitated crystal growth.

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“…Compared to solid crystal structures, the high-energy amorphous MCS-MM has a higher solubility. 40 The solubility product constant ( k sp ) of the salt species and the pH of the aqueous environment control the deposition of MDP-Ca salts. 14 The MCS-MM state on the dentin bonding interface needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Influence of Acidic Environment on Hydrolytic Stability of MDP-Ca Salts with Nanolayered and Amorphous Structures

Zhao¹,

Gao²,

Jin³

et al. 2022

IJN

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Purpose This study aimed to investigate the hydrolytic stability of 10-methacryloyloxydecyl dihydrogen phosphate calcium (MDP-Ca) salts with nanolayered and amorphous structures in different pH environments. Methods The MDP-Ca salts were synthesized from MDP and calcium chloride and characterized by X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and transmission electron microscopy (TEM). Inductively coupled plasma-mass spectrometry (ICP-MS) was used to quantify the release of calcium from the synthesized MDP-Ca salt, MDP-treated hydroxyapatite (MDP-HAp), and untreated HAp after soaking in acidic and neutral solutions for 1, 7, and 30 days. To study the hydrolytic process, we carried out molecular dynamics (MD) simulations of the nanolayered MCS-MD (monocalcium salt of the MDP dimer) and DCS-MD (dicalcium salt of the MDP dimer) structures, as well as of the amorphous-phase MCS-MM (monocalcium salt of the MDP monomer). Results The TEM images showed that the nanolayered structures were partially degraded by acid attack. Based on the ICP-MS results, the hydrolysis rate of the MDP-Ca salt in acidic and neutral environments followed the order HAp > MDP-HAp > MDP-Ca salt. The MD simulations showed that, in acidic environments, clusters of MDP remained aggregated and all Ca 2+ ions separated from the MDP monomer to interact with water molecules in aqueous solution. In neutral environments, Ca 2+ ions always interacted with phosphate groups, OH − ions, and water molecules to form clusters centered on Ca 2+ ions. Conclusion MDP-Ca presented higher hydrolysis rates in acidic than neutral environments. Nanolayered MCS-MD possessed the highest resistance to acidic hydrolysis, followed by amorphous MCS-MM and DCS-MD.

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Physical stability of amorphous pharmaceutical solids: Nucleation, crystal growth, phase separation and effects of the polymers

Cited by 40 publications

References 142 publications

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

Bubble-induced fast crystal growth of indomethacin polymorphs in a supercooled liquid

Influence of Acidic Environment on Hydrolytic Stability of MDP-Ca Salts with Nanolayered and Amorphous Structures

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