No abstract

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.

The resolution of enantiomers can be achieved by preferential crystallization as soon as they crystallize as a conglomerate. However, several successive and alternate crystallizations of each enantiomer as well as seeds of both enantiomers are required for this process to be efficient. The performance can be increased by using two tanks coupled via the liquid phase. In one subcooled tank, the crystallization of a single enantiomer is carried out by enantioselective seeding, while a suspension of racemic mixture in equilibrium at the saturation temperature with the liquid phase is present in a second tank. Over the course of the crystallization, the concentration of the seeded enantiomer decreases. Because of the liquid exchange, the crystallizing enantiomer becomes undersaturated in the second tank, leading to its selective dissolution. Crystallization and dissolution continue simultaneously in both tanks until the solid phase in the second tank becomes enantiopure. At this point, both suspensions can be filtrated, and each tank yields a pure enantiomer. The proof of principle has been successfully given for the resolution of DL-threonine. Besides reducing the number of steps needed to access both pure enantiomers, this process was found to be more productive than conventional alternatives of resolution by preferential crystallization. ■ INTRODUCTIONWhen a chiral molecule cannot be synthetized from a molecule of the chiral pool, a 50/50 mixture of both enantiomers is often obtained. In this case, the target enantiomer has to be separated from its antipode in a second step. Because of their mirror symmetry, most of their properties are identical, and dedicated resolution techniques are required. If the enantiomers form a conglomerate, their resolution by preferential crystallization is possible. 1 A supersaturated racemic solution eventually gives birth to nuclei of both enantiomers at the same time, leading to a racemic solid. However, if enantiopure seeds are introduced into the solution prior to nucleation, these seeds grow. The solid phase remains in the state of single chirality until the nucleation phenomenon occurs. Up to this point, the racemic mixture can be resolved yielding an enantiopure product. The mass of recovered enantiopure solid is however quite small as compared to the initial mixture (the yield of a single crystallization step is often about 10%). This can be improved by recycling the liquid phase, to selectively crystallize the antipode after the addition of racemic mixture and new seeding. Preferential crystallization therefore consists of successive and alternate crystallization steps of the enantiomers. The application of preferential crystallization requires a good knowledge of the thermodynamic and kinetic properties of the target molecules and involves a significant amount of manual handling. 2 The technology is time and cost consuming and can be difficult to apply for nonspecialists.During the past decade, a new variant of preferential crystallization has been developed. 3 Instead of c...

For pairs of enantiomers crystallizing as a conglomerate, several process strategies can be used to resolve them by preferential crystallization (PC). Usually, a main limitation is the nucleation of the counter enantiomer, which restricts productivities. The performance of PC can be strongly increased, when crystallization and selective dissolution are combined by coupling two crystallizers via the liquid phase. In doing so, one crystallizer contains a saturated racemic suspension, while the other is in a supersaturated state and initially seeded with pure enantiomer. The crystallization of the seeds in the corresponding tank leads to a transient undersaturation in the other tank and, thus, to a selective dissolution from the racemate. Due to the exchange of solution, crystallization is accelerated, while the solid racemate is purified. The process described, has been investigated in detail using a well-established population balance model, which was shown to be in good agreement with experimental results presented recently in ref 1. A parametric study was done, which revealed regions, in which the process can be operated at high productivity, yielding both enantiomers in pure form. The achieved understanding of the influence of the investigated process parameters on the performance can help to further improve and optimize the process.

No abstract

Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behavior in antisolvent crystallization is very limited, and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallization of glycine from water utilizing methanol, ethanol, and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallization across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well-defined induction times were detected across most of the metastable zone, which shows that primary nucleation is significant at supersaturations much lower than those identified in conventional metastable zone width measurements. As supersaturation increases toward the metastable zone limit, crystal growth and secondary nucleation are likely to become rate-limiting factors in the observed induction times for antisolvent crystallization. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvent effects on nucleation with their effects on mixing, leading to crossover of mixing and nucleation time scales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallization processes.

The resolution of this derivative was optimized at 2-L scale in methanol by using two preferential crystallization modes (auto-seeded polythermic programmed preferential crystallization, hereafter AS3PC, and seeded isothermal preferential crystallization, hereafter SIPC) and by tuning the starting temperature. The results evidenced that the AS3PC mode is more efficient than the SIPC mode, and the higher the starting temperature, the higher the productivity. Despite a careful tuning of the operating conditions and a stable conglomerate offering a full chiral discrimination in the solid state, the enantiomeric excess of the crude solid obtained by preferential crystallization remained lower than 90%. However, this can be improved up to 99% by a single recrystallization of the methanol solvate of the imeglimin-2,4-dichlorophenylacetate since it crystallizes as a stable conglomerate without any detectable partial solid solution.

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure–activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvementsincluding increase of the relative oral bioavailability F rel from 3 to ≥100%led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 (46) representsto the best of our knowledgethe first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.