(M1230-09-62) Detecting Low-Level Crystallinity in ASD-Like Samples Using SSNMR Techniques

Purpose: The physical form of a drug substance and the excipients in the drug product has a significant impact on its physical stability and bioavailability. Solid-State Nuclear Magnetic Resonance Spectroscopy (SSNMR) is a powerful and versatile technique for characterizing the physical form of a drug substance in a drug product of particular interest, relaxation times can be used to enhance or remove signals of different sample components such as polymorphs or excipients. This can simplify the quantification of each component by removing overlapping signals. This work showcasesa T1 rho filtering SSNMR technique capable of detecting low levels of crystalline API in amorphous dispersions based on the large difference in free-induction decay for amorphous and crystalline material.

Methods: A common issue with 13C SSNMR spectroscopy is the potential for excipient and API signal overlap in the spectrum, along with the overlap of the amorphous and crystalline API signals, for this reason, 19F SSNMR was chosen. Triamcinolone was chosen as an analyte since it contains a 19F atom in its structure and is known to be formulated in spray-dried dispersions with HPMC-AS. A 1H T1rho filtering 19F SSNMR NMR technique was used to quantify crystalline impurities with T1 relaxation times determined from pure samples of both triamcinolone polymorphs. As a benchmark, crystalline impurities were also examined by quantitative Powder X-Ray Diffraction (PXRD) using an alpha-quartz internal standard.

Results: In the SSNMR technique we investigated, the signal from amorphous material was able to be removed from the spectra allowing for the quantification of crystalline forms of triamcinolone. The 1H T1rho filtering shows that crystalline API signals can be extracted from the SDD spectra without time-intensive or specialized techniques such as spectral subtraction and deconvolution. 1H T1rho filtering is an experimental method accomplishes this goal by suppressing amorphous API signal directly. Low concentrations of crystalline impurities can be detected and quantified despite being undetectable by PXRD. Additionally, the SSNMR techniquepresented here are non-destructive, and does not require an internal standard.

Conclusion: 1H T1rho filtering SSNMR spectroscopy techniques have significant advantages for the detection of low levels of crystallized material in SDD samples over other techniques such as PXRD. This technique does not require specialized experimentation or an internal standard. As more APIs are formulated as SDD / ASDs and contain 19F nuclei on the molecule, 19F SSNMR spectroscopy can be used extensively to detect and quantify any crystalline impurities in the drug product sample.

References: Munson E. Solid-state NMR spectroscopy of drug substances and drug products: an overview. European Pharmaceutical Review [Internet]. 2020 Oct 14 [cited 2023 Jul 19];25:10–3

Detection of crystalline API in spray-dry dispersions by 19F SSNMR.

T1rho filtering to remove amorphous API 19F SSNMR signals

Crystalline impurities in spray-dry dispersions as detected by PXRD