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TD-NMR to Quantify Components in Solid Mixtures

Applications for pharmaceutical formulation development

Characterizing the polymorphic forms of candidate pharmaceuticals is critical for success early in the drug development process. Newly proposed strategies using time-domain nuclear magnetic resonance (NMR) spectroscopy could help make this information quicker available and more accessible to researchers.

The need for knowledge

Active pharmaceutical ingredients (APIs) have a propensity to take on polymorphic forms and to form solvates and hydrates. This presents a challenge in drug development when samples being studied in early stages often contain a complex mixture of these solid-state forms. In the first six months of drug development, it is critical to characterize the different solid-state forms of the API to avoid unexpected consequences arising further down the line and to identify a stable and reproducible form of the drug. This includes knowing how the presence of these polymorphs is influenced by the production and storage of drugs, as well as interactions with excipients.

In particular, the presence of amorphous content can have a major impact on the properties of the drug, for example, affecting solubility and dosage. From a regulatory and patient safety viewpoint, it is therefore essential to be able to accurately quantify the amorphous content of APIs in mixtures.

Why use time-domain NMR?

Over recent years, solid-state NMR has emerged as major tool for analyzing API polymorphs. However, the method does have some drawbacks. For example, it can be both labor- and time-intensive.

Time-domain NMR is an alternative to classical NMR that offers a number of advantages over solid-state NMR. First, it can be performed on a benchtop instrument, requiring less space and capital outlay than performing high resolution solid-state NMR experiments. It works at low magnetic fields using permanent magnets, which do not require cryogenic cooling. Additionally, less time is needed to conduct the relaxation measurements. Sample preparation is especially straight forward: The solid powder is filled in a 10 mm glass tube.

Time-domain NMR is also able to analyze heterogeneous samples, and can be used on various drug formulations, including tablets, capsules, gels and pastes. These samples require minimal preparation and automation options are also available, making the method suitable for high throughput situations.

How we can use time-domain NMR

Researchers Dirk Stueber and Stefan Jehle recently proposed a method to use time-domain NMR to reveal the amorphous content in mixed drug samples. The strategy is not intended to replace high-resolution solid-state NMR in quality control, but the method is quicker and could help free up spectroscopists’ time for more challenging experiments.

In case of a two component mixture, it works by measuring T1 saturation recovery curves (SRC) of the pure components as reference curves that are subsequently used to quantify the components in a mixture of which a SRC has been measured. Both, 1H or 19F  relaxation curves can be used for quantification. So to study the amorphous content of a drug mixture, the method can be employed by measuring a sample of pure amorphous form of the drug (A), a sample of pure crystalline form of the drug (B) and the mixed sample that we want to determine the amorphous content of (C).

td-nmr relaxation curves

Researchers can then calculate the relative quantities of A and B in C by fitting linear combinations of the components to the SRC of the mixed sample using weighting coefficients, which provide the relative proportion of each component. The novelty of the approach is that a full relaxation time analysis which is often prone to errors is not required. Instead a linear combination of the reference SRCs is fitted to the SRC of the mixture and the result gives the relative amounts of the reference compounds in the mixture.

The team demonstrated their technique using mixed samples of the non-steroidal anti-inflammatory drugs ibuprofen and indomethacin. They created blends of the two drugs, containing a variety of relative amounts from 5-50 %. Applying their method, they were able to measure the SRCs in approximately 8 minutes each. Performing the fitting procedure, the researchers could then derive the coefficients of the linear combination of SRCs, which directly translate to the relative mass percentages of ibuprofen and indomethacin. Doing so, they found that the method was accurate to within half a percent.

To demonstrate the efficacy of the time-domain NMR technique, the team used a Bruker minispec mq20. Among the minispecs in the mq series, the mq20 offers the best possible performance-to-footprint ratio for common quality-control applications, ranging from the food industry, the chemical and polymer industry, as well as in the medical and pharmaceutical industry. The instruments are available at a range of 1H resonance frequencies, from 5 to 60 MHz. Furthermore, the minispec mq series can be upgraded using tool-free exchangeable probes, variable temperature NMR probes and pulsed field gradient systems, as well as the new minispec Sample Automation system, to maximize throughput and boost productivity.

References

Kawakami K. Current status of amorphous formulation and other special dosage forms as formulations for early clinical phases. Journal of Pharmaceutical Sciences 2009; 98: 2875-2885.

Shah B, Kumar Kakumanu V & Bansal AK. Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. Journal of Pharmaceutical Sciences 2006; 95: 1641-1665.

Stueber D & Jehle S. Quantitative Component Analysis of Solid Mixtures by Analyzing Time-Domain 1H and 19F T1 Saturation Recovery Curves. Presented at Experimental Nuclear Magnetic Resonance Conference; 10-15th April 2016; Pittsburgh, Pennsylvania.

Patent application No. US 62/294,375 is pending.

Contact Bruker to request more information about the minispec product line.