Search

The CMAC workflow approach Since the development of the seminal workflow for seeded continuous cooling crystallisations, a number of workflows have been developed within CMAC that cover various processes including early stage crystallisation development, impurity rejection, and isolation.

Benchtop NMR spectrometers operating with magnetic fields of 1–2 T at sub-ppm resolution coupled with SABRE hyperpolarization show great promise as analytical platforms that can be used outside the traditional laboratory environment., Benchtop NMR spectrometers operating with low magnetic fields of 1–2 T at sub-ppm resolution show great promise as analytical platforms that can be used outside the traditional laboratory environment for industrial process monitoring. One current limitation that reduces the uptake of benchtop NMR is associated with the detection fields’ reduced sensitivity. Here we demonstrate how para-hydrogen (p-H2) based signal amplification by reversible exchange (SABRE), a simple to achieve hyperpolarization technique, enhances agent detectability within the environment of a benchtop (1 T) NMR spectrometer so that informative 1H and 13C NMR spectra can be readily recorded for low-concentration analytes. SABRE-derived 1H NMR signal enhancements of up to 17 000-fold, corresponding to 1H polarization levels of P = 5.9%, were achieved for 26 mM pyridine in d4-methanol in a matter of seconds. Comparable enhancement levels can be achieved in both deuterated and protio solvents but now the SABRE-enhanced analyte signals dominate due to the comparatively weak thermally-polarized solvent response. The SABRE approach also enables the acquisition of 13C NMR spectra of analytes at natural isotopic abundance in a single scan as evidenced by hyperpolarized 13C NMR spectra of tens of millimolar concentrations of 4-methylpyridine. Now the associated signal enhancement factors are up to 45 500 fold (P = 4.0%) and achieved in just 15 s. Integration of an automated SABRE polarization system with the benchtop NMR spectrometer framework produces renewable and reproducible NMR signal enhancements that can be exploited for the collection of multi-dimensional NMR spectra, exemplified here by a SABRE-enhanced 2D COSY NMR spectrum.

The conversion of [IrCl(COD)(IMes)] (COD = cis,cis-1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene) in the presence of an excess of p-H2 and a substrate (4-aminopyridine (4-AP) or 4-methylpyridine (4-MP)) into [Ir(H)2(IMes)(substrate)3]Cl is monitored by 1H NMR spectroscopy using a benchtop (1 T) spectrometer in conjunction with the parahydrogen (p-H2) based hyperpolarization technique signal amplification by reversible exchange (SABRE). A series of single-shot 1H NMR measurements are used to monitor the chemical changes that take place in solution through the lifetime of the hyperpolarized response. Non-hyperpolarized high-field 1H NMR control measurements were also undertaken to confirm that the observed time dependent changes relate directly to the underlying chemical evolution. The formation of [Ir(H)2(IMes)(substrate)3]Cl is further linked to the hydrogen isotope exchange reaction (HIE) which leads to the incorporation of deuterium into the ortho positions of 4-AP, where the source of deuterium is the solvent, methanol-d4. Comparable reaction monitoring results are achieved at both high-field (9.4 T) and low-field (1 T). It is notable, that the low sensitivity of the benchtop (1 T) NMR enables the use of protio solvents, which is harnessed here to separate the effects of catalyst formation and substrate deuteration. Collectively, these methods illustrate how low-cost low-field NMR measurements provide unique insight into a complex catalytic process through a combination of hyperpolarization and relaxation data.

para-Hydrogen (p-H 2) induced polarisation (PHIP) is an increasingly popular method for sensitivity enhancement in NMR spectroscopy. Its growing popularity is due in part to the introduction of the signal amplification by reversible exchange (SABRE) method that generates renewable hyperpolarisation in target analytes in seconds. A key benefit of PHIP and SABRE is that p-H 2 can be relatively easily and cheaply produced, with costs increasing with the desired level of p-H 2 purity. In this work, the efficiency of the SABRE polarisation transfer is explored by measuring the level of analyte hyperpolarisation as a function of the level of p-H 2 enrichment. A linear relationship was found between p-H 2 enrichment and analyte 1H hyperpolarisation for a range of molecules, polarisation transfer catalysts, NMR detection fields and for both the SABRE and SABRE-Relay transfer mechanisms over the range 29-99% p-H 2 purity. The gradient of these linear relationships were related to a simple theoretical model to define an overall efficiency parameter, E, that quantifies the net fraction of the available p-H 2 polarisation that is transferred to the target analyte. We find that the efficiency of SABRE is independent of the NMR detection field and exceeds E = 20% for methyl-4,6-d 2-nicotinate when using a previously optimised catalyst system. For the SABRE-Relay transfer mechanism, efficiencies of up to E = 1% were found for 1H polarisation of 1-propanol, when ammonia was used as the polarisation carrier.

Para-hydrogen (p-H2) induced polarisation (PHIP) is an increasingly popular method for sensitivity enhancement in NMR spectroscopy. Its growing popularity is due in part to the introduction of the signal amplification by reversible exchange (SABRE) method that generates renewable hyperpolarisation in target analytes in seconds. A key benefit of PHIP and SABRE is that p-H2 can be relatively easily and cheaply produced, with costs increasing with the desired level of p-H2 purity. In this work, the efficiency of the SABRE polarisation transfer is explored by measuring the level of analyte hyperpolarisation as a function of the level of p-H2 enrichment. A linear relationship was found between p-H2 enrichment and analyte 1H hyperpolarisation for a range of molecules, polarisation transfer catalysts, NMR detection fields and for both the SABRE and SABRE-Relay transfer mechanisms over the range 29 - 99% p-H2 purity. The gradient of these linear relationships were related to a simple theoretical model to define an overall efficiency parameter, E, that quantifies the net fraction of the available p-H2 polarisation that is transferred to the target analyte. We find that the efficiency of SABRE is independent of the NMR detection field and exceeds E = 20% for methyl-4,6-d2-nicotinate when using a previously optimised catalyst system. For the SABRE-Relay transfer mechnism, efficiencies of up to E = 1% were found for 1H polarisation of 1-propanol, when ammonia was used as the polarisation carrier.

Raman spectroscopy has been used to provide a rapid, noninvasive, and nondestructive quantification method for determining the parahydrogen fraction of hydrogen gas. The basis of the method is the measurement of the ratio of the first two rotational bands of hydrogen at 355 cm −1 and 586 cm −1 corresponding to parahydrogen and orthohydrogen, respectively. The method has been used to determine the parahydrogen content during a production process and a reaction. In the first example, the performance of an in-house liquid nitrogen cooled parahydrogen generator was monitored both at-line and on-line. The Raman measurements showed that it took several hours for the generator to reach steady state and, hence, for maximum parahydrogen production (50%) to be reached. The results obtained using Raman spectroscopy were compared to those obtained by at-line low-field nuclear magnetic resonance (NMR) spectroscopy. While the results were in good agreement, Raman analysis has several advantages over NMR for this application. The Raman method does not require a reference sample, as both spin isomers (ortho and para) of hydrogen can be directly detected, which simplifies the procedure and eliminates some sources of error. In the second example, the method was used to monitor the fast conversion of parahydrogen to orthohydrogen in situ. Here the ability to acquire Raman spectra every 30 s enabled a conversion process with a rate constant of 27:4 * 10 -4 s −1 to be monitored. The Raman method described here represents an improvement on previously reported work, in that it can be easily applied on-line and is approximately 500 times faster. This offers the potential of an industrially compatible method for determining parahydrogen content in applications that require the storage and usage of hydrogen.

Signal amplification by reversible exchange (SABRE) is a hyperpolarisation technique that catalytically transfers nuclear polarisation from parahydrogen, the singlet nuclear isomer of H2, to a substrate in solution. The SABRE exchange reaction is carried out in a polarisation transfer field (PTF) of tens of gauss before transfer to a stronger magnetic field for nuclear magnetic resonance (NMR) detection. In the simplest implementation, polarisation transfer is achieved by shaking the sample in the stray field of a superconducting NMR magnet. Although convenient, this method suffers from limited reproducibility and cannot be used with NMR spectrometers that do not have appreciable stray fields, such as benchtop instruments. Here, we use a simple hand-held permanent magnet array to provide the necessary PTF during sample shaking. We find that the use of this array provides a 25% increase in SABRE enhancement over the stray field approach, while also providing improved reproducibility. Arrays with a range of PTFs were tested, and the PTF-dependent SABRE enhancements were found to be in excellent agreement with comparable experiments carried out using an automated flow system where an electromagnet is used to generate the PTF. We anticipate that this approach will improve the efficiency and reproducibility of SABRE experiments carried out using manual shaking and will be particularly useful for benchtop NMR, where a suitable stray field is not readily accessible. The ability to construct arrays with a range of PTFs will also enable the rapid optimisation of SABRE enhancement as function of PTF for new substrate and catalyst systems.

This study investigates the effects of key process parameters of continuous mixing-induced supersaturation on the antisolvent crystallization of lactose using D-optimal Design of Experiments (DoE). Aqueous solutions of lactose were mixed isothermally with antisolvents using a concentric capillary mixer. Process parameters investigated were the choice of antisolvent (acetone or isopropanol), concentration of lactose solution, total mass flow rate, and the ratio of mass flow rates of lactose solution and antisolvent. Using a D-optimal DoE a statistically significant sample set was chosen to explore and quantify the effects of these parameters. The responses measured were the solid state of the lactose crystallized, induction time, solid yield and particle size. Mixtures of α-lactose monohydrate and β-lactose were crystallized under most conditions with β-lactose content increasing with increasing amount of antisolvent. Pure α-lactose monohydrate was crystallized using acetone as the antisolvent, with mass flow ratios near 1:1, and near saturated solutions of lactose. A higher resolution DoE was adopted for acetone and was processed using multivariate methods to obtain a crystallization diagram of lactose. The model was used to create an optimized process to produce α-lactose monohydrate and predicted results agreed well with those obtained experimentally, validating the model. The solid state of lactose, induction time, and solid yield were accurately predicted.

Carbamazepine is an active pharmaceutical ingredient used in the treatment of epilepsy that can form at least five polymorphic forms. Metastable form IV was originally discovered from crystallisation with polymer additives however has not been observed from subsequent solvent only crystallisation efforts. This work reports the reproducible formation of phase pure crystalline form IV by spray drying of methanolic carbamazepine solution. Characterisation of the material was carried out using diffraction, SEM and DSC. In situ Raman spectroscopy was used to monitor the spray dried product during the spray drying process. This work demonstrates spray drying provides a robust method for the production of form IV carbamazepine and the combination of high supersaturation and rapid solid isolation from solution overcomes the apparent limitation of more traditional solution crystallisation approaches to produce metastable crystalline forms.

Introduction and objectives: In moving from batch to continuous manufacturing of pharmaceutical products, knowledge of all experimental variables is required to help control and achieve a stable system that yields a consistent product with the desired attributes. Spectroscopic tools are often used to provide point measurements at key points in the process. Here we demonstrate the applicability of Hyperspectral Imaging (HSI) to continuous nuclaetion processes. The objective of the work described here was to show how HSI can be used to monitor mixing processes by providing spatially discriminated near-infrared spectra, yielding vital process information that has only previously been estimated using simulation techniques such as computational fluid dynamics (CFD). Methods: Water (antisolvent) and an IPA/water mixture (solvent) containing dissolved paracetamol seed crystals were mixed in a tube by introducing the antisolvent jet at different flow rates, and the resulting mixing in the tube was imaged with an InnoSpec RedEye camera in the spectral range 950 to 1700 nm. Microscope images of the resultant crystals from each different flow rate were taken to confirm that differences in the final crystal product were observed. Machine learning techniques in the form of Support Vector Machine (SVM) analysis were used to analyse and automatically separate the spectral data of the solvent/antisolvent mix into the different components. Results: The antisolvent jet, which resulted in nucleation near the point of injection, could clearly be identified and therefore monitored after application of the SVM. Differences between different flow rates and concentrations were observed from the hyperspectral images obtained, and these differences carried through to the shape and size of the final crystals obtained. Conclusions: We have demonstrated the applicability of HSI and advanced data processing techniques to the monitoring of mixing dynamics, in particular those used in continuous pharmaceutical processing such as solvent/antisolvent crystallisation.

Off-line techniques such as differential scanning calorimetry (DSC) can be used to characterize solidified extrudates from a hot-melt extrusion (HME) process. However, off-line measurements are not representative of the melt mixture in the HME barrel. THz-Raman spectroscopy can be used to monitor solid dispersions of the melt mixture in situ. To avoid needing off-line reference measurements, calibration-free methods for spectral analysis are advantageous. Multivariate curve resolution (MCR) is a calibration-free method of resolving mixture spectra into pure component contributions using an iterative optimization within a set of constraints. The outputs are pure component spectra and concentration profiles for each component.

Introduction to inclusion complexes ▪ Cyclodextrins (CDs) are cyclic oligosaccharides which have three forms, α, β, and γ, that represent six, seven, or eight glucopyranose units, respectively ▪ CDs consist of a hydrophobic internal cavity and a hydrophilic external surface which can incorporate with many organic and inorganic molecules to form inclusion complexes ▪ Formation of inclusion complexes with CDs can increase the stability, bioavailability, and aqueous solubility of the guest molecules, such as drugs, which makes inclusion complexes not only applicable in pharmaceuticals, but also food processing and environmental and chemical engineering ▪ Metal-organic frameworks (MOFs) are crystalline materials consisting of metal centres and organic linkers that have extraordinary properties due to their high surface area, adjustable pore size and thermal stability ▪ Depending on the framework MOFs can be first generation MOF, second generation MOF (rigid MOF) or third generation MOF (flexible MOF). ▪ MOFs offer new opportunities for inclusion of guest molecules compared to traditional organic hosts