Magnetic resonance in the characterization and quantification of polymorphs
Although Magnetic resonance is considered a well-established powerful technique to study polymorphs and amorphous forms, it has resided, so far, in the hands of few specialists. Recent technologic advances have enabled the deployment of the technique to a much wider scientific audience. We have overcome the price and complexity barriers, with the introduction of a benchtop spectrometer and greatly increase automation and sensitivity in our high-resolution floor standing instruments.
The minispec Form Check, a benchtop spectrometer for the quantification of components in solids mixtures such as a polymorph in the presence of another; amorphous form in the presence of polymorphs or polymorph/amorphous in the presence of excipients. The minispec Form Check approaches the quantification of solid forms from a completely different angle to that taken by other techniques (PXRD, Raman, IR). It is a time-domain (TD) instrument and therefore there is no fourier transform done, no frequency domain. The minispec Form Check pulls components apart based on their relaxation properties, T1 relaxation in this case. The T1 relaxation time of a drug's crystalline and amorphous form is generally very different, making this technique ideal, especially for the quantification of low level of amorphous (LOQ < 1%), which is challenging by PXRD and has a significant quantification error associated.
Improvements that have made open-access solid-state NMR a reality
The iProbe platform, that also includes probes for liquid state and high resolution magic angle spinning (HRMAS) applications, provides full automation capabilities so we can automate the tuning and matching steps, needed when changing from one sample to another. On top of that, since this is solid-state NMR, precise adjustment of the magic angle spinning position is also needed. The iProbe CPMAS has a motor which accurately and precisely chooses the correct orientation, using KBr as a reference compound.
The probe is currently offered at 400, 500 or 600 megahertz (MHz) base frequency for standard bore systems. It comes in a double channel set-up, meaning we have a proton channel which is also tunable to fluorine, and we have a broadband channel which goes from phosphorus down to nitrogen. Spinning speed, for four-millimeter samples, is up to 15-kHz magic-angle spinning.
CryoProbe for solids
The first ever cryogenically cooled probe for solid-state NMR (CPMAS CryoProbe) which is especially useful for the analysis of very low amount of compounds, as it is the case of polymorphs/amorphous in formulated material (drug product). Cooled electronics and a cooled probe set-up, while keeping the sample itself at the desired experimental temperature, are responsible of a sensitivity increase of a factor of three to four, which translates in at least 1 order of magnitude productivity increase.
The probe is currently available in an HCN (proton, carbon, nitrogen) configuration for 600 MHz magnets and provides magic angle speed of up to 20-kilohertz with 3.2 mm rotors. It also provides high power decoupling and cross-polarization (CP) set-up, so one can use double CP or traditional CP where there's no limitation compared to room temperature probes. On top of that, the probe includes automatic tuning and matching as well as an automated set-up for the adjustment of the magic angle.
Insights from Industry - Interview with Aptuit
Characterizing Polymorphs amd Amorphous Form
Solid-State NMR Spectroscopy of Drug Substances and Drug Products
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