Solid-State NMR Pharma Solutions

Magnetic resonance in the characterization and quantification of polymorphs

Although magnetic resonance is considered a well-established powerful technique for studying polymorphs and amorphous forms, thus far it has resided in the hands of few specialists. Recent technological advances, however, 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 have greatly increased automation and sensitivity with our high-resolution floor standing instruments.

New benchtop NMR solutions

The minispec Form Check, is a benchtop spectrometer for the quantification of components in solids mixtures; such as a polymorph in the presence of another form; amorphous form in the presence of a polymorphs or a polymorph/amorphous forms in the presence of excipients. The minispec Form Check approaches the quantification of solid forms from a completely different angle to that of other techniques (PXRD, Raman, IR). It is a time-domain (TD) instrument, which means there is no fourier transform to carry out, and 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 levels of amorphous form (LOQ < 1%), which is challenging by PXRD and is associated with a significant quantification error.

Improvements that have made open-access solid-state NMR a reality

Although traditionally in the hands of few specialists, recent advances have enabled the deployment of the technique to the walk-up lab. Instruments are now equipped with the new iProbe, enabling automatic tuning and matching and magic angle adjustment; and sample changers driven by the same automation software used in liquid-state NMR.

The iProbe platform, which also includes probes for liquid state and high resolution magic angle spinning (HRMAS) applications, provides full automation capabilities to enable automation of the tuning and matching steps, necessary when changing from one sample to another. In addition, 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 a broadband channel which goes from phosphorus down to nitrogen. Spinning speed, for four-millimeter samples, is up to 15-kHz magic-angle spinning.

The new "shuttle technology" enables the same sample changer to be used for both liquids and solids NMR, facilitating a simple upgrade from liquids to solids for half the price of a Powder X-ray Diffraction (PXRD) instrument!

User benefits:

• Identification and quantification of crystalline and amorphous content in APIs and formulated products
• Quantification of the amount of each form without the need for a standard
  
• Multiple attribute: multiple nuclei can be analyzed, providing several unique spectra for each form
• Unique to NMR, relaxation times:
  

1. identify peaks for different crystalline forms, as each form’s relaxation time is usually unique
2. selectively enhance or remove different forms in a mixture of components, which can be useful for form identification and showing intellectual property infringement
3. predict both particle size and chemical degradation rates, especially in formulated products.

• Selectivity: labelling of nuclei such as ¹³C and ¹⁵N can be used to enhance certain signals when sensitivity is a challenge, and avoids peak overlap
   

CryoProbe for solids

The first ever cryogenically cooled probe for solid-state NMR (CPMAS CryoProbe) is especially useful for analyzing very small amounts of compounds, as is often the case for polymorphs/amorphous forms in formulated material (drug product). Cooled electronics and a cooled probe set-up, while keeping the sample itself at the desired experimental temperature, create a sensitivity increase of a factor of three to four, which translates to at least one 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 speeds of up to 20-KHz with 3.2 mm rotors. It also provides high power decoupling and a cross- (CP) set-up, giving operators flexibility to use double CP or traditional CP with no limitation compared to room temperature probes. In addition, the probe includes automatic tuning and matching as well as an automated set-up to adjust the magic angle.

MAS Shuttle for fully automated solid-state NMR applications

The MAS Shuttle for CPMAS and HRMAS provides fully automated solutions reducing hands-on time and increasing throughput.

Equipment needed:

• iProbe
• Avance NEO console
• MAS3 pneumatic control unit
• SampleCase Automation system

The software, IconNMR, takes full control of running your experiment; from selecting the sample to co-ordinating the insertion, getting the rotor up to spin speed, and returning it safely back to its original position.

Once you’ve filled the SampleCase, your experiments can run unattended, increasing your instrument efficiency with automated operation. Samples can be run overnight or over weekends.

Solid State Analysis of Medicines Flyer: