Assessing the Detection Limit of a Minority Solid-State Form of a Pharmaceutical by 1H Double-Quantum Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy

Maruyoshi, Keisuke; Iuga, Dinu; Watts, Abigail E.; Hughes, Colan E.; Harris, Kenneth David Maclean; Brown, Steven P.

doi:10.1016/j.xphs.2017.07.014

Cited by 23 publications

(23 citation statements)

References 69 publications

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“…These high frequency 1 H NMR peaks typically arise from hydrogen atoms in amine, ammonium, and carboxylic acid functional groups. 33,37,[40][41][42] The high frequency 1 H NMR signals can be used to observe the 1 H SSNMR spectra of the APIs within formulations. Fast MAS 1 H SSNMR Spectra of Commercial Dramamine® Tablets.…”

Section: Resultsmentioning

confidence: 99%

“…High frequency acid or amine peaks from APIs are typically between 8 and 20 ppm 33,37,[40][41][42] and are minimally affected by SSPs targeting the excipient resonances (Figure S2 and S4). Note that most APIs are marketed as free acids, salts, or cocrystals; 59 therefore, APIs will usually possess amine, ammonium, or acid functional groups that give rise to high frequency 1 H chemical shifts.…”

Section: Resultsmentioning

confidence: 99%

“…Protons with high chemical shifts are often involved in hydrogen bonding and are diagnostic of the solid form. 33,37,[40][41][42]55 The chemical shift of the ammonium group is identical in the tablet and pure API, immediately suggesting that the same API phase is present in both samples.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…41 They also showed fast MAS DQ-SQ experiments can detect and resolve minor polymorphic forms within mixtures of pure APIs down to a loading of 1 wt.%. 42 Zhou and Rienstra have previously applied fast MAS and proton detection to obtain 2D 1 H- 13 C HETCOR spectra of an ibuprofen tablet with high API loading (ca. 65 wt.%).…”

Section: Introductionmentioning

confidence: 99%

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Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS ¹H Solid-State NMR Spectroscopy

et al. 2019

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Active pharmaceutical ingredients (APIs) can be prepared in many different solid forms and phases that affect their physicochemical properties and suitability for oral dosage forms. The development and commercialization of dosage forms require analytical techniques that can determine and quantify the API phase in the final drug product. 13 C solid-state NMR (SSNMR) spectroscopy is widely employed to characterize pure and formulated solid APIs; however, 13 C SSNMR experiments on dosage forms with low API loading are often challenging due to low sensitivity and interference from excipients. Here, fast MAS 1 H SSNMR experiments are shown to be applicable for the rapid characterization of low drug load formulations. Diagnostic 1 H SSNMR spectra of APIs within tablets are obtained by using combinations of frequency-selective saturation and excitation pulses, 2D experiments and 1 H spin diffusion periods. Selective saturation pulses efficiently suppress the broad 1 H SSNMR signals from the most commonly encountered excipients such as lactose and cellulose, allowing observation of high frequency API 1 H NMR signals. 1 H SSNMR provides a one to three orders of magnitude reduction in experiment time compared to standard 13 C SSNMR experiments, enabling diagnostic SSNMR spectra of dilute APIs within tablets to be obtained within a few minutes. The 1 H SSNMR spectra can be used for quantification provided calibrations are performed on a standard sample with known API loading.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS ¹H Solid-State NMR Spectroscopy

et al. 2019

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“…Terahertz pulsed spectroscopy has been reported to detect solid forms with a limit of detection of approximately 1 % [21]. Similarly, solid-state nuclear magnetic resonance (ss-NMR) has a detection limit of 1 % [22]. The approach presented here is based on detecting solid form impurities at a single particle level, which is a fundamentally different approach to these bulk methods.…”

Section: Raman Modelmentioning

confidence: 99%

Simultaneous automated image analysis and Raman spectroscopy of powders at an individual particle level

Sekulovic

Verrijk

Rades

et al. 2021

Journal of Pharmaceutical and Biomedical Analysis

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Solid form diversity of raw materials can be critical for the performance of the final drug product. In this study, Raman spectroscopy, image analysis and combined Raman and image analysis were utilized to characterize the solid form composition of a particulate raw material. Raman spectroscopy provides chemical information and is complementary to the physical information provided by image analysis. To demonstrate this approach, binary mixtures of two solid forms of carbamazepine with a distinct shape, an anhydrate (prism shaped) and a dihydrate (needle shaped), were characterized at an individual particle level. Partial least squares discriminant analysis classification models were developed and tested with known, gravimetrically mixed test samples, followed by analysis of unknown, commercially supplied carbamazepine raw material samples. Classification of several thousands of particles was performed, and it was observed that with the known binary mixtures, the minimum number of particles needed for the combined Raman spectroscopy -image analysis classification model was approximately 100 particles per solid form. The carbamazepine anhydrate and dihydrate particles were detected and classified with a classification error of 1 % using the combined model. Further, this approach allowed the identification of raw material solid form impurity in unknown raw material samples. Simultaneous automated image analysis and Raman spectroscopy of powders at an individual particle level has its potential in accurate detection of low amounts of unwanted solid forms in particulate raw material samples.

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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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Assessing the Detection Limit of a Minority Solid-State Form of a Pharmaceutical by 1H Double-Quantum Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy

Cited by 23 publications

References 69 publications

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS ¹H Solid-State NMR Spectroscopy

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS ¹H Solid-State NMR Spectroscopy

Simultaneous automated image analysis and Raman spectroscopy of powders at an individual particle level

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

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Assessing the Detection Limit of a Minority Solid-State Form of a Pharmaceutical by 1H Double-Quantum Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy

Cited by 23 publications

References 69 publications

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS 1H Solid-State NMR Spectroscopy

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS 1H Solid-State NMR Spectroscopy

Simultaneous automated image analysis and Raman spectroscopy of powders at an individual particle level

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

Contact Info

Product

Resources

About

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS ¹H Solid-State NMR Spectroscopy

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS ¹H Solid-State NMR Spectroscopy