The phase (trans)formation and physical state of a model drug in mesoscopic confinement

Ukmar, Tina; Godec, Aljaž; Planinšek, Odon; Kaučič, Venceslav; Mali, Gregor; Gaberšček, Miran

doi:10.1039/c1cp20874h

Cited by 29 publications

(34 citation statements)

References 30 publications

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“…The advanced solid-state NMR methods focused on detailed analysis of hydrogen bonding patterns and intramolecular distances and were supported by first principles calculations. 28,38,43,46,51 We report for the first time solid-state NMR spectra of IMC methanol solvate and form V. Due to the fact that IMC form V is formed via desolvation of the IMC methanol solvate, we focus on the changes in the peak positions and intensities for both forms and compare them to the previously assigned peaks of the spectrum of g-IMC (Fig. 2).…”

Section: Resultsmentioning

confidence: 98%

Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

Nartowski

Tedder

Braun

et al. 2015

Phys. Chem. Chem. Phys.

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The nanocrystallisation of complex molecules inside mesoporous hosts and control over the resulting structure is a significant challenge. To date the largest organic molecule crystallised inside the nano-pores is a known pharmaceutical intermediate - ROY (259.3 g mol(-1)). In this work we demonstrate smart manipulation of the phase of a larger confined pharmaceutical - indomethacin (IMC, 357.8 g mol(-1)), a substance with known conformational flexibility and complex polymorphic behaviour. We show the detailed structural analysis and the control of solid state transformations of encapsulated molecules inside the pores of mesoscopic cellular foam (MCF, pore size ca. 29 nm) and controlled pore glass (CPG, pore size ca. 55 nm). Starting from confined amorphous IMC we drive crystallisation into a confined methanol solvate, which upon vacuum drying leads to the stabilised rare form V of IMC inside the MCF host. In contrast to the pure form, encapsulated form V does not transform into a more stable polymorph upon heating. The size of the constraining pores and the drug concentration within the pores determine whether the amorphous state of the drug is stabilised or it recrystallises into confined nanocrystals. The work presents, in a critical manner, an application of complementary techniques (DSC, PXRD, solid-state NMR, N2 adsorption) to confirm unambiguously the phase transitions under confinement and offers a comprehensive strategy towards the formation and control of nano-crystalline encapsulated organic solids.

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Section: Resultsmentioning

confidence: 98%

Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

Nartowski

Tedder

Braun

et al. 2015

Phys. Chem. Chem. Phys.

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“…As the crystallization of the drug inside the pores requires high loading concentrations [31] and the solubility of IMC in conventional solvents is low, dimethyl sulfoxide (DMSO, purity ≥ 99.5 %, Merck) was used as a solvent. Other studied organic solvents were ethanol (Altia, purity > 99.5 %), acetone (Merck, purity > 99.8 %), and ethyl acetate (Merck, purity > 99.5 %).…”

Section: Chemicals and Measurementsmentioning

confidence: 99%

“…Crystallization inside the pores may occur only if the pore radius is wider than the d-layer. The dependence of crystallinity on pore size has been demonstrated experimentally [19][20]. It has, moreover, been shown that the phase transformations of confined API may differ from those of bulk API because of interactions between the API molecules and the pore walls [20][21].…”

Section: Introductionmentioning

confidence: 97%

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Insights into the Evaporation Kinetics of Indomethacin Solutions

et al. 2013

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Evaporation rates play a key role in evaporation crystallization and the drying of crystal products. Raman analysis was used to study the effect of the evaporation rate on the polymorphs of indomethacin at room temperature. The studied solvents were highly volatile ethanol, acetone, and ethyl acetate. The approach was based on a mass transfer model of evaporation, and experimental flux measurements were used for model evaluation. Evaporation rates from porous carriers were also investigated. The studied mesoporous silicon microparticles can be used in oral dosage forms of poorly soluble active pharmaceutical ingredients. Evaporation rates of dimethyl sulfoxide from a pure solvent, from indomethacin solutions, and from solutions containing microparticles were measured at 100°C. An evaporation rate model of porous particles was used and the predicted results were compared with the experimental results obtained.

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“…It should be noticed that in the standard calculations it is not possible to take into consideration the dynamics effects resulting from the thermal motions, therefore geometry optimization brings the structure closer to the DFT minimum at 0 K. The common approach is optimization of solely hydrogen atoms positions since in many cases it was found to provide the most accurate results . The calculations are usually performed using the Perdew–Burke–Ernzerhof (PBE) exchange–correlation functional, defined within the generalized gradient approximation (GGA) with the Tkatchenko and Scheffler method for the dispersion (DFT‐TS) correction …”

Section: Introductionmentioning

confidence: 99%

Does the choice of the crystal structure influence the results of the periodic DFT calculations? A case of glycine alpha polymorph GIPAW NMR parameters computations

2018

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Glycine is a common amino acid with relatively complex chemistry in solid state. Although several polymorphs (α, β, δ, γ, ε) of crystalline glycine are known, for NMR spectroscopy the most important is a polymorph, which is used as a standard for calibration of spectrometer performance and therefore it is intensively studied by both experimental methods and theoretical computation. The great scientific interest in a glycine results in a large number of crystallographic information files (CIFs) deposited in Cambridge Structural Database (CSD). The aim of this study was to evaluate the influence of the chosen crystal structure of α glycine obtained in different crystallographic experimental conditions (temperature, pressure and source of radiation of α glycine) on the results of periodic DFT calculation. For this purpose the total of 136 GIPAW calculations of α glycine NMR parameters were performed, preceded by the four approaches ("SP", "only H", "full", "full+cell") of structure preparation. The analysis of the results of those computations performed on the representative group of 34 structures obtained at various experimental conditions revealed that though the structures were generally characterized by good accuracy (R < 0.05 for most of them) the results of the periodic DFT calculations performed using the unoptimized structures differed significantly. The values of the standard deviations of the studied NMR parameters were in most cases decreasing with the number of optimized parameters. The most accurate results (of the calculations) were in most cases obtained using the structures with solely hydrogen atoms positions optimized. © 2018 Wiley Periodicals, Inc.

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The phase (trans)formation and physical state of a model drug in mesoscopic confinement

Cited by 29 publications

References 30 publications

Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

Insights into the Evaporation Kinetics of Indomethacin Solutions

Does the choice of the crystal structure influence the results of the periodic DFT calculations? A case of glycine alpha polymorph GIPAW NMR parameters computations

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