Molecular spectroscopy is a widely recognized technique for the characterization of solid-state materials. Numerous advantages exist with molecular spectroscopy, namely qualitative and quantitative analysis, real-time monitoring of transient species, the ability to study API or drug product, and more recently, process analytical technology (PAT) application. Due to these advantages, SSCI utilizes molecular spectroscopy for standard compendial methodology, but also for high-end research applications. Because of the wide range of spectroscopic instrumentation at SSCI, we can apply the appropriate technology to our customers needs.
Infrared and Raman Spectroscopy
SSCI performs solid-state analyses with state-of-the-art infrared (IR), near IR (NIR) and Raman spectrometers. Each of these techniques can provide both qualitative characterization of different solid forms and a means to quantitate the solid form composition within the drug substance or product.
- Infrared Spectroscopy
Alkyl Halide Pellet
Mineral Oil Mull
Variable Temperature Diffuse Reflectance
Variable Humidity Diffuse Reflectance
Attenuated Total Reflectance
- NIR Spectroscopy Imaging
- Raman Spectroscopy
Dispersive and FT-Raman Spectrometers
As an industry standard, ultraviolet/visible absorption spectroscopy is used by SSCI in support of dissolution, stability, and solubility studies.
Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique that can be used on a wide variety of solid and liquid materials. Specific NMR active nuclei within a sample can be observed, which confers a unique level of selectivity for NMR spectroscopy. SSCI routinely uses both solid-state and liquid-state cGMP NMR spectroscopy to characterize a wide variety of materials from small inorganic compounds to large molecules. SSCI has the necessary NMR capabilities to analyze specific nuclei like 19F in both solids and liquids because it is present in about 20% of pharmaceutical drugs. SSCI also has NMR capabilities for analyzing large molecule biologics, which are the fastest growing type of molecules currently being developed as drugs.
SSCI provides an in-depth and broad experience with small molecule, synthetic polymer, and biologics NMR spectroscopy using these common NMR applications:
- 2D NMR analyses such as COSY, NOESY, TOCSY, HMQC, HSQC, and HMBC with peak assignments of specific resonances to provide detailed information on molecular structure and conformation in solution.
- Compendial NMR methods in accordance with the EP or USP/NF specifications
- Qualitative and quantitative NMR (qNMR) method development and validation for all available NMR techniques. Most of our validated methods are used for clinical or commercial lot release, or stability studies.
- Comparability and sameness studies of biologics due to the sensitive and accurate fingerprint of the molecular conformation extracted from the NMR data.
- Identification and quantitation of known and unknown impurities
- Characterization of polymorphs, solvates, salts, co-crystals, and amorphous solids
- Chemical structure identification (solids and liquids)
- Analysis of formulations (solids and liquids)
- Analysis of stereoisomers (solids and liquids)
- Determine the number of molecules in the asymmetric unit (solids)
- Chemical exchange analysis (solids and liquids)
- Molecular motion analysis (solids and liquids)
- Conformational/structural analysis (solids and liquids); 3D chemical structure determination of small molecules and biologics using NMR restrained molecular dynamics (MD) simulations
NMR Service Benefits at SSCI:
- Hands on experience with both small molecule and large molecule (polymers, unmodified and modified peptide, protein, DNA, RNA) NMR spectroscopy
- Higher resolution and sensitivity with modern solids NMR spectrometer and probes.
- Customer selected data interpretation levels (very basic to very detailed) for maximum value and flexibility.
- Higher quality 2D spectra through advanced pulse sequences and data processing methods.
- cGMP compliance with US and European regulations to ensure the highest quality data, interpretation, and experimental consistency.
- As little as 10 mg of sample required for solid-state NMR.
Our equipment consists of 300 − 500 MHz NMR spectrometers some of which capable of analyzing both solids and liquids.
Liquid-state NMR spectroscopy is a common technique for determining molecular structure and conformation or to analyze specific components in a mixture either qualitatively or quantitatively. Solution NMR spectroscopy provides a sensitive method to quantify impurities, reaction products, or residual solvents including water. A large variety of methods for NMR spectroscopy of liquid solutions are available at 400 MHz (1H). Variable temperature experiments are also available for liquids NMR analyses. Some of the most common analyses include 1D NMR of 1H, 13C, 19F, and 31P NMR. More advanced 2D NMR analyses such as COSY, NOESY, TOCSY, HMQC, HSQC, and HMBC are also routinely performed. These techniques can be used to determine the assignments of specific resonances for a molecule, which can provide the necessary information to obtain a molecular conformation in solution. Most liquid-state NMR experiments require only a few milligrams of material.
- 5 mm double resonance pulsed field gradient (PFG) probe for high sensitivity on the X and Y channels (useful for typical small organic molecules and biologics). Observe 1H (~400 MHz) or 19F (~376 MHz) on the high band channel and 15N (~40 MHz) to 31P (~162 MHz) on the low band channel.
- 5 mm inverse detection PFG probe (useful for biologics and typical small organic samples). Observe 1H (~400 MHz) or 19F (~376 MHz) on the high band channel and 15N (~40 MHz) to 31P (~162 MHz) on the low band channel.
- 5 mm dual broadband PFG probe (ideal for organic and inorganic materials to observe 13C, 15N, and other lower frequency nuclei or those nuclei with low natural abundance). Observe 1H (~400 MHz) or 19F (~376 MHz) on the high band channel and 15N (~40 MHz) to 31P (~162 MHz) on the low band channel.
- Z-axis gradient capabilities for performing many of the newest pulsed field gradient experiments.
- Wide range of 2D NMR spectroscopic techniques available for structural elucidation.
- Variable temperature capabilities from −80 °C to 130 °C.
- Sample quantities in ~0.5 mL solvent:
- 1H or 19F – 0.1-5 mg, 31P – 10-20 mg, 13C – 20-50 mg
Solid-state NMR spectroscopy is useful for analyzing polymorphs, solvates, salts, cocrystals, amorphous solids, and formulations. SSCI can perform high resolution solid-state NMR spectroscopy at 400 MHz (1H) for most of the NMR active nuclei on the periodic table. However, the most frequently observed nuclei in solid pharmaceutical compounds are 13C, 31P, 19F, and 15N. Variable temperature experiments can be performed from –75°C to 100°C. Available SSNMR techniques include standard direct excitation or enhancement via ramped amplitude cross polarization, modulated high power proton decoupling, very high speed spinning (up to 18 kHz), spectral editing, and spinning sideband suppression. Solid-state NMR experiments require approximately 50 mg of material with the potential to use as little as 10 mg.
- Agilent T3 narrow bore double and triple resonance 4 mm solid-state NMR probes.
- Doty Scientific 4 mm HF probe specifically designed for simultaneous 1H decoupling while detecting 19F or the reverse.
- Doty Scientific 4 mm HFX probe specifically designed for simultaneous 1H decoupling while detecting 19F or X nuclei or 19F decoupling while observing X.
- Low frequency: Observe any NMR active nucleus with a resonance frequency between 15N (~40 MHz) and 31P (~162 MHz).
- High Frequency: Observe or decouple 1H (~400 MHz) and 19F (~376 MHz) nuclei.
- MAS and CP/MAS available up to 18 kHz spinning speed (with modern phase modulated decoupling and/or TOSS spinning sideband suppression) to offer the highest data quality.
- Simultaneous 1H and 19F decoupling while observing on the X-channel or 1H decoupling while observing 19
- 2D correlation spectroscopy of common nuclei (1H, 13C, 15N, 19F, 29Si, 31P)
- 2D MQMAS or STMAS of quadrupolar nuclei.
- Variable temperature capabilities from −75 °C to 100 °C.
Sample quantities: 40-50 mg (optimal), 5-10 mg (possible)