The Use of 13C Labeling to Enhance the Sensitivity of 13C Solid-State CPMAS NMR to Study Polymorphism in Low Dose Solid Formulations

Booy, Kees-Jan; Wiegerinck, Peter; Vader, J.; Kaspersen, Frans M.; Lambregts, Dorette; Vromans, Herman; Kellenbach, Edwin

doi:10.1002/jps.20236

Cited by 22 publications

(10 citation statements)

References 12 publications

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“…Broader peaks observed in the EE-13 C2 spectrum ( Figure 4F), particularly for the labelled ethynyl groups at 75 and 85 ppm, are due to strong interactions between the two neighbouring 13 C atoms. 27 As previously observed with the solution-state spectra, the 13 C-ssNMR reference spectrum for the cured DDU-4331 elastomer displayed a single large (Si-CH3) signal at 1.3 ppm ( Figure 4D).…”

Section: Solid-state Nmr (Ssnmr) Reference Spectrasupporting

confidence: 79%

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system

McCoy

Apperley

Variano

et al. 2018

International Journal of Pharmaceutics

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Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) - an estrogenic steroid molecule also containing an ethynyl functional group - to an addition cure silicone elastomer. By preparing silicone elastomer samples containingC-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology applications.

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Section: Solid-state Nmr (Ssnmr) Reference Spectrasupporting

confidence: 79%

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system

McCoy

Apperley

Variano

et al. 2018

International Journal of Pharmaceutics

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“…One way to overcome these limitations is to use 13 C isotopically labeled APIs. For example, 13 C‐labeled steroid molecules could be detected at loadings as low as 0.5 wt.% in model formulations . However, this approach requires synthesis of isotopically labeled materials and cannot be applied to analyze commercial products.…”

Section: Applications Of Dnp‐enhanced Solid‐state Nmr Spectroscopy Tomentioning

confidence: 99%

DNP‐enhanced solid‐state NMR spectroscopy of active pharmaceutical ingredients

Zhao

Pinon

Emsley

et al. 2018

Magnetic Reson in Chemistry

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Solid-state NMR spectroscopy has become a valuable tool for the characterization of both pure and formulated active pharmaceutical ingredients (APIs). However, NMR generally suffers from poor sensitivity that often restricts NMR experiments to nuclei with favorable properties, concentrated samples, and acquisition of one-dimensional (1D) NMR spectra. Here, we review how dynamic nuclear polarization (DNP) can be applied to routinely enhance the sensitivity of solid-state NMR experiments by one to two orders of magnitude for both pure and formulated APIs. Sample preparation protocols for relayed DNP experiments and experiments on directly doped APIs are detailed. Numerical spin diffusion models illustrate the dependence of relayed DNP enhancements on the relaxation properties and particle size of the solids and can be used for particle size determination when the other factors are known. We then describe the advanced solid-state NMR experiments that have been enabled by DNP and how they provide unique insight into the molecular and macroscopic structure of APIs. For example, with large sensitivity gains provided by DNP, natural isotopic abundance, C- C double-quantum single-quantum homonuclear correlation NMR spectra of pure APIs can be routinely acquired. DNP also enables solid-state NMR experiments with unreceptive quadrupolar nuclei such as H, N, and Cl that are commonly found in APIs. Applications of DNP-enhanced solid-state NMR spectroscopy for the molecular level characterization of low API load formulations such as commercial tablets and amorphous solid dispersions are described. Future perspectives for DNP-enhanced solid-state NMR experiments on APIs are briefly discussed.

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“…13 C labeling was used to enhance the sensitivity of 13 C solid‐state nuclear magnetic resonance as a means of studying the effects of compaction on the polymorphism of a steroidal drug substance 168. The compound was labeled and then formulated into tablets at levels of 0.5–2.5% in active ingredient, and the tablets were then studied using solid‐state 13 C‐NMR.…”

Section: Effects Associated With Secondary Processing Of Crystal Formsmentioning

confidence: 99%

Polymorphism and Solvatomorphism 2005

Brittain¹

2007

Journal of Pharmaceutical Sciences

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The Use of 13C Labeling to Enhance the Sensitivity of 13C Solid-State CPMAS NMR to Study Polymorphism in Low Dose Solid Formulations

Cited by 22 publications

References 12 publications

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system

DNP‐enhanced solid‐state NMR spectroscopy of active pharmaceutical ingredients

Polymorphism and Solvatomorphism 2005

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