Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction

Abstract

Understanding the transitions between polymorphs is essential in the development of strategies for manufacturing and maximizing the efficiency of pharmaceuticals. However, this can be extremely challenging: crystallization can be influenced by subtle changes in environment such as temperature and mixing intensity or even imperfections in the crystallizer walls. Here, we highlight the importance of in situ measurements in understanding crystallization mechanisms, where a segmented flow crystallizer was used to study the crystallization of the pharmaceuticals urea:barbituric acid (UBA) and carbamazepine (CBZ). The reactor provides highly reproducible reaction conditions, while in situ synchrotron powder X-ray diffraction (PXRD) enables us to monitor the evolution of this system. UBA has two polymorphs of almost equivalent free-energy and so is typically obtained as a polymorphic mixture. In situ PXRD uncovered a progression of polymorphs from UBA III to the thermodynamic polymorph UBA I, where different positions along the length of the tubular flow crystallizer correspond to different reaction times. Addition of UBA I seed crystals modified this pathway such that only UBA I was observed throughout, while transformation from UBA III into UBA I still occurred in the presence of UBA III seeds. Information regarding the mixing-dependent kinetics of the CBZ form II to III transformation was also uncovered in a series of seeded and unseeded flow crystallization runs, despite atypical habit expression. These results illustrate the importance of coupling controlled reaction environments with in situ XRD to study the phase relationships in polymorphic materials. ASSOCIATED CONTENT Supporting InformationDetailed information regarding the experimental set-up, methodology and supporting experimental results is supplied as a word document, and a video showing the unusual needle habit of CBZ form III is supplied as a mp4 file in the supporting information. This material is available free of charge via the Internet at http://pubs.acs.org

Chasing the Co-crystal Disappearing Polymorph with Ab Initio Methods

“…Authors observed the transformation of P­(III) into the P­(I) form in a MeOH slurry. In contrast, the reverse partial transition was indicated for a dry P­(I) sample under ambient conditions . The summary of all experiments studying UBA polymorphs is provided in Table S4.…”

“…To overcome these limitations, molecular dynamics methods were introduced to the studies of polymorphism. , Recently, metadynamics simulations , were used to analyze the disappearing conformational polymorph of succinic acid . In our studies, Born–Oppenheimer molecular dynamics (BOMD) calculations were used to investigate the self-assembly and stability of three urea–barbituric acid (UBA) polymorphs. , The BOMD results were compared with the analysis of H-bond propensities, coordination scores (CS), and the previous experimental data in the context of known thermodynamic stability rules. , Despite numerous experimental and theoretical trials, the “metastability” of the polar UBA polymorph is still unclear. − To our knowledge, UBA form (II) can be called one of the first known examples of disappearing co-crystal polymorphs.…”

Evaluation of microflow configurations for scale inhibition and serial X-ray diffraction analysis of crystallization processes

“…We additionally show that nucleating agents that promote crystallization in the "bulk" of the droplet further reduce scaling and are an excellent system for studying with DMC-XRD. The seeding of crystallising solutions with a target material is of great importance in the pharmaceutical and chemical industries, [36][37][38][39] and has recently been recognized as a way to reduce the clogging of flow crystallisers. 40 The results presented here demonstrate that foreign material which promotes heterogeneous nucleation in solution can also reduce scale build-up on reactor surfaces.…”

Time-Resolved X-ray Phase-Contrast Imaging (XPCI) of Nucleation and Crystal Growth in the Anti-Solvent Crystallization of Lovastatin

“…6,8,9 However, experimental unravelling of the molecular basis of these nucleation processes (and indeed also of more recently alternative molecular pathways 2,3,8,10,11 ) faces a fundamental challenge, namely that nucleation events are rare and stochastic in time and space. To an extent, localization of homogeneous events by, e.g, use of liquid-liquid interfaces 9 and droplets [12][13][14] has been used to overcome the spatial challenge, enabling time-resolved monitoring of structure and composition by X-ray absorption, 9,15,16 Raman 14,17 and UV/Vis spectroscopy, 17,18 SAXS 18,19 and XRD/WAXS. 13,18 However, localization is associated with confinement in small volumes, and is often introducing some degree of heterogeneity, which influences observable nucleation behavior.…”

“…To an extent, localization of homogeneous events by, e.g, use of liquid-liquid interfaces 9 and droplets [12][13][14] has been used to overcome the spatial challenge, enabling time-resolved monitoring of structure and composition by X-ray absorption, 9,15,16 Raman 14,17 and UV/Vis spectroscopy, 17,18 SAXS 18,19 and XRD/WAXS. 13,18 However, localization is associated with confinement in small volumes, and is often introducing some degree of heterogeneity, which influences observable nucleation behavior. Indeed, for heterogeneous nucleation, methods such as atomic force microscopy (AFM), scanning electron microscopy (SEM), photoelectron emission microscopy (PEEM) and scanning tunneling microscopy (STM) have been extensively used to image nucleation and crystal growth events.…”