Seeded crystallization of β-L-glutamic acid in a continuous oscillatory baffled crystallizer

A continuously seeded l-glutamic acid cooling crystallization process, in a continuous oscillatory baffled crystallizer, was designed and operated to deliver control over polymorphic form. Different feed solution concentrations and seed loadings of β-l-glutamic acid crystals were examined. Steady-state operation, based on particle size distribution and polymorphic form, was demonstrated consistently after two residence times. Where bulk supersaturation remained in the range 2–3, the polymorphic phase purity of the thermodynamically stable β polymorph was retained. However, when the bulk supersaturation exceeded this range to values of 3–8, primary nucleation of the metastable α polymorph was observed, and product crystals were a mixed phase. In the absence of seeding the system could not be operated without significant encrustation to the vessel surface thus leading to loss of control, whereas a continuously seeded approach allowed robust processing for at least 10 h

Oscillatory flow reactors (OFRs) for continuous manufacturing and crystallization

Continuous crystallization is an attractive approach for the delivery of consistent particles with specified critical quality attributes (CQAs), which are attracting increased interest for the manufacture of high value materials, including fine chemicals and pharmaceuticals. Oscillatory flow reactors (OFRs) offer a suitable platform to deliver consistent operating conditions under plug-flow operation while maintaining a controlled steady state. This review provides a brief overview of OFR technology before outlining the operating principles and summarizing applications, emphasizing the use for controlled continuous crystallization. While significant progress has been made to date, areas for further development are highlighted that will enhance the range of applications and ease of implementation of OFR technology. These depend on specific applications but include scale down, materials of construction suitable for chemical compatibility, encrustation mitigation, the enhancement of robust operation via automation, process analytical technology (PAT), and real-time feedback control

From discovery to scale-up: alpha-lipoic acid : nicotinamide co-crystals in a continuous oscillatory baffled crystalliser

The crystalline nutritional supplement alpha-lipoic acid degrades rapidly on exposure to temperatures above its melting point 65 degrees C and to light. A small-scale experimental co-crystal screen has produced three novel co-crystals of alpha-lipoic acid that each display enhanced thermal stability and differences in aqueous solubilities compared to alpha-lipoic acid. In each case, the initial screening procedure produced tens of milligrams of material enabling initial identification, characterisation and crystal structure determination. The structure of the alpha-lipoic acid : nicotinamide co-crystal was determined by single crystal X-ray diffraction and used for subsequent phase identification. Scale-up of the co-crystallisation process of alpha-lipoic acid with nicotinamide was then investigated in a continuous oscillatory baffled crystalliser. Over 1 kg of solid co-crystals was produced using a continuous crystallisation process in a continuous oscillatory baffled crystalliser at a throughput of 350 g h-1 yielding a purity of 99% demonstrating this as an effective route to rapid scale-up of a novel co-crystal system

From discovery to scale-up: alpha-lipoic acid : nicotinamide co-crystals in a continuous oscillatory baffled crystalliser

The crystalline nutritional supplement alpha-lipoic acid degrades rapidly on exposure to temperatures above its melting point 65 degrees C and to light. A small-scale experimental co-crystal screen has produced three novel co-crystals of alpha-lipoic acid that each display enhanced thermal stability and differences in aqueous solubilities compared to alpha-lipoic acid. In each case, the initial screening procedure produced tens of milligrams of material enabling initial identification, characterisation and crystal structure determination. The structure of the alpha-lipoic acid : nicotinamide co-crystal was determined by single crystal X-ray diffraction and used for subsequent phase identification. Scale-up of the co-crystallisation process of alpha-lipoic acid with nicotinamide was then investigated in a continuous oscillatory baffled crystalliser. Over 1 kg of solid co-crystals was produced using a continuous crystallisation process in a continuous oscillatory baffled crystalliser at a throughput of 350 g h-1 yielding a purity of 99% demonstrating this as an effective route to rapid scale-up of a novel co-crystal system

Spray drying as a reliable route to produce metastable carbamazepine form IV

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

Temperature correction of spectra to improve solute concentration monitoring by in situ ultraviolet and mid-infrared spectrometries towards isothermal local model performance

Changes in temperature can significantly affect spectroscopic-based methods for in situ monitoring of processes. As varying temperature is inherent to many processes, associated temperature effects on spectra are unavoidable, which can hinder solute concentration determination. Ultraviolet (UV) and mid-infrared (IR) data were acquired for l-ascorbic acid (LAA) in MeCN/H2O (80:20 w/w) at different concentrations and temperatures. For both techniques, global partial least squares (PLS) models for prediction of LAA concentration constructed without preprocessing of the spectra required a high number of latent variables to account for the effects of temperature on the spectra (root mean square error of cross validation (RMSECV) of 0.18 and 0.16 g/100 g solvent, for UV and IR datasets, respectively). The PLS models constructed on the first derivative spectra required fewer latent variables, yielding variable results in accuracy (RMSECV of 0.23 and 0.06 g/100 g solvent, respectively). Corresponding isothermal local models constructed indicated improved model performance that required fewer latent variables in the absence of temperature effects (RMSECV of 0.01 and 0.04 g/100 g solvent, respectively). Temperature correction of the spectral data via loading space standardization (LSS) enabled the construction of global models using the same number of latent variables as the corresponding local model, which exhibited comparable model performance (RMSECV of 0.06 and 0.04 g/100 g solvent, respectively). The additional chemometric effort required for LSS is justified if prediction of solute concentration is required for in situ monitoring and control of cooling crystallization with an accuracy and precision approaching that attainable using an isothermal local model. However, the model performance with minimal preprocessing may be sufficient, for example, in the early phase development of a cooling crystallization process, where high accuracy is not always required. UV and IR spectrometries were used to determine solubility diagrams for LAA in MeCN/H2O (80:20 w/w), which were found to be accurate compared to those obtained using the traditional techniques of transmittance and gravimetric measurement. For both UV and IR spectrometries, solubility values obtained from models with LSS temperature correction were in better agreement with those determined gravimetrically. In this first example of the application of LSS to UV spectra, significant improvement in the predicted solute concentration is achieved with the additional chemometric effort. There is no extra experimental burden associated with the use of LSS if a structured approach is employed to acquire calibration data that account for both temperature and concentration

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

42 salt forms of tyramine: structural comparison and the occurrence of hydrate formation

The single-crystal diffraction structures of 38 salt forms of the base tyramine (4-hydroxyphenethylamine) are reported for the first time. Together with literature examples, these structures are discussed with respect to cation conformation, cation packing, hydrogen bonding and hydrate formation. It is found that isostructural cation packing can occur even with structurally different anions, with different hydration states and with different hydrogen bonding. Hydrate formation is found to be more likely both (i) when there is an increase in the total number of potential hydrogen bond acceptor and donor atoms; and (ii) when the ratio of potential hydrogen bond donor to acceptor atoms is low

Density and stability differences between enantiopure and racemic salts : construction and structural analysis of a systematic series of crystalline salt forms of methylephedrine

A data set of systematically related solid-state structures of pharmaceutical relevance has been created and used to investigate structural impact on physical propeities in 20 pairs of enantiopure and racemic methylephedrinium. salts. The structures are described and compared through graph-set analysis and the crystal packing similarity features of Mercury CSD 2.3. The commonest graph-set motif, C-2(2) (9), was found to be present in 22 of the 37 independent structures and was flexible enough to include both carboxylate and sulfonate functionalities. An equivalent C-2(1) (7) motif was present in all six halide structures investigated. Analysis of molecular structure found three common methylephedrinium cation conformations, while analysis of cation packing found six isostructural groups, each containing at least two salt structures and based on one of three common cation packing motifs. Melting points and crystallographically obtained densities were examined in detail for the 13 enantiopure and racemic structural pairs found to be chemically identical to each other. While average densities conform to Wallach's rule, 6 of the 13 individual pairings do not This does not support the structural justification normally given for Wallach's rule. One of the three observed common cation packing motifs is highly associated with failure of Wallach's rule, as are significant differences in hydrogen bonding between the enantiopure and racemic structures

Heat transfer and residence time distribution in plug flow continuous oscillatory baffled crystallisers

Heat transfer coefficients in a continuous oscillatory baffled crystalliser (COBC) with a nominal internal diameter of 15 mm have been determined as a function of flow and oscillatory conditions typically used under processing conditions. Residence time distribution measurements show a near plug flow with high Peclet numbers on the order of 100s to 1000s, although there was significant oscillation damping in longer COBC setups. Very rapid heat transfer was found under typical conditions, with overall heat transfer coefficients on the order of 100s W m-2 K-1. Furthermore, poor mixing in the COBC cooling jacket was observed when lower jacket flow rates were implemented in an attempt to decrease the rate of heat transfer, in order to achieve more gradual temperature profile along the crystalliser length. Utilising the experimentally determined overall heat transfer coefficients, a theoretical case study is presented to investigate the effects of the heat transfer rate on temperature and supersaturation profiles and to highlight potential fouling issues during a continuous plug flow cooling crystallisation