Continuous total spontaneous resolution

We achieved chiral symmetry breaking through continuous crystallizations, which enables the continuous industrial production of chirally pure crystals. For this, a novel recycling platform that mimics a continuous cooling crystallization process with a hot concentrated feed and an outflow of cold suspension was developed and tested. A virtually enantiopure steady-state was realized by seeding a clear supersaturated achiral solution with enantiopure seed crystals at the start of the experiment. Seeding with the enantiopure form ensured that fragments of the seeded form were continuously created through secondary nucleation. Below the metastable zone limit, the product continued to consist of crystals of the same handedness as the seeded form provided that long residence times were applied in combination with sufficiently high feed concentrations. Short residence times in combination with low feed concentrations led to fouling-induced formation of both chiral forms and a decrease in the product's enantiomeric excess. Overall these results demonstrate the feasibility of continuous total spontaneous resolution of chiral pharmaceutical products in an industrial setting. This continuous manufacturing approach provides many benefits including ease of operation, consistent product quality, and a high degree of process control

Thermodynamic properties of paracetamol impurities 4-nitrophenol and 4\u27-chloroacetanilide and the impact of such impurities on the crystallisation of paracetamol from solution

The impact of structurally-related additives and impurities on active pharmaceutical ingredients is an essential yet poorly understood area. This work describes the characterisation of temperature-dependent solid-liquid properties of 4-nitrophenol and 4′chloroacetanilide in four different alcohols and their effect as impurities on the crystallisation of paracetamol. The solubility of 4-nitrophenol appeared to be significantly higher than paracetamol whereas the solubility of 4′chloroacetanilide was lower than paracetamol. The solubility difference between the impurities could be rationalised based on their molecular structure and hydrogen bonding interactions. The solubility data was modelled using empirical and thermodynamic models. Recrystallisation of paracetamol from solutions containing the highly soluble 4-nitrophenol impurity resulted in small uniformly sized high purity paracetamol crystals whereas the presence of the poorly soluble 4′chloroacetanilide impurity induced the formation of large needle shaped crystals of paracetamol. These differences in crystallisation are a consequence of the solubility difference and the different functional groups of paracetamol and its impurities. Overall this study serves as fundamental information for the development of crystallisation approaches for the purification of paracetamol from its main impurities

Thermodynamic properties of paracetamol impurities 4-nitrophenol and 4'-chloroacetanilide and the impact of such impurities on the crystallisation of paracetamol from solution

The impact of structurally-related additives and impurities on active pharmaceutical ingredients is an essential yet poorly understood area. This work describes the characterisation of temperature-dependent solid-liquid properties of 4-nitrophenol and 4′chloroacetanilide in four different alcohols and their effect as impurities on the crystallisation of paracetamol. The solubility of 4-nitrophenol appeared to be significantly higher than paracetamol whereas the solubility of 4′chloroacetanilide was lower than paracetamol. The solubility difference between the impurities could be rationalised based on their molecular structure and hydrogen bonding interactions. The solubility data was modelled using empirical and thermodynamic models. Recrystallisation of paracetamol from solutions containing the highly soluble 4-nitrophenol impurity resulted in small uniformly sized high purity paracetamol crystals whereas the presence of the poorly soluble 4′chloroacetanilide impurity induced the formation of large needle shaped crystals of paracetamol. These differences in crystallisation are a consequence of the solubility difference and the different functional groups of paracetamol and its impurities. Overall this study serves as fundamental information for the development of crystallisation approaches for the purification of paracetamol from its main impurities

Organic salts of pharmaceutical impurity ρ-Aminophenol

The presence of impurities can drastically affect the efficacy and safety of pharmaceutical entities. ρ-Aminophenol (PAP) is one of the main impurities of paracetamol (PA) that can potentially show toxic effects such as maternal toxicity and nephrotoxicity. The removal of PAP from PA is challenging and diffi cult to achieve through regular crystallization approaches. In this regard, we report four new salts of PAP with salicylic acid (SA), oxalic acid (OX), l-tartaric acid (TA), and (1S)-(+)-10-camphorsulfonic acid (CSA). All the PAP salts were analyzed using single-crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The presence of minute amounts of PAP in paracetamol solids gives a dark color to the product that was diffi cult to remove through crystallization. In our study, we found that the addition of small quantities of the aforementioned acids helps to remove PAP from PA during the filtration and washings. This shows that salt formation could be used to efficiently remove challenging impurities

Effects of scale-up on the mechanism and kinetics of crystal nucleation

Insight into nucleation kinetics and other nucleation parameters can be obtained from probability distributions of induction time measurements in combination with the classical nucleation theory. In this work, induction times of crystallization were recorded using a robust and automated methodology involving a focused beam reflectance measurement probe. This methodology is easily interchangeable between different crystallizers which allowed us to investigate the effects of scale-up on the kinetics of crystal nucleation of paracetamol from 2-propanol in four different crystallizers, ranging from small magnetically stirred 10 mL solutions to overhead-stirred solutions of 680 mL. The nucleation rate was an order of magnitude faster in the magnetically stirred crystallizer as compared to the crystallizers involving overhead stirring. The thermodynamic part of the nucleation rate expression did not significantly change the nucleation rate, whereas the kinetic nucleation parameter was found to be the rate-determining process when the crystallization process was scaled-up. In particular, the shear rate was rationalized to be the part of the kinetic parameter that changes most significantly when the crystallization process was scaled-up. The effect of shear rate on the nucleation kinetics decreases with increasing volume and plateaus when the volume becomes too large. In this work, the nucleation mechanism was also investigated using the chiral sodium chlorate system. These experiments showed that the single nucleus mechanism is the underlying nucleation mechanism in all four tested crystallization setups when supersaturation remains the same. When the supersaturation was changed continuously through cooling, crystallization was driven by a multinucleus mechanism. The automated and robust method used to measure induction times can easily be extended to other crystallizers, enabling the measurement of induction times beyond small crystallizer volumes