Pre-nucleation Aggregates Research Articles

Using Prenucleation Aggregation of Caffeine-Benzoic Acid as a Rapid Indication of Co-crystallization from Solutions.

Co-crystal design is a convenient way to remedy the poor biopharmaceutical properties of drugs. Most studies focus on experimental co-crystal screening or computational prediction, but hardly any work has been done toward fast, efficient, and reliable prediction of solution crystallization for co-crystal formation. Here, we study the caffeine-benzoic acid co-crystal system, due to its reported difficulty to crystallize from the solution phase. With this work, we investigate whether there is a link between prenucleation aggregation in solution and co-crystal formation and how to harness this for crystallization prediction. 1H and 13C NMR spectroscopy is used to study the prenucleation interaction between caffeine and benzoic acid in methanol, acetone, and acetonitrile as examples of common solvents. In this system, crystallization from methanol leads to no co-crystallization, from acetone to concomitant crystallization of co-crystal and caffeine, and from acetonitrile to pure co-crystal formation from solution. Strong heteromeric dimers were found to exist in all three solvents. Ternary phase diagrams were defined and a solution-accessible co-crystal region was found for all solvents. For this system, the prenucleation clusters found in solution could be linked to the crystallization of the co-crystal. Crystallization from DMSO did not yield the co-crystal and there were no detectable prenucleation aggregates. NMR spectroscopy to probe dimers in solution can thus be used as a fast, reliable, and promising tool to predict co-crystallization from specific solvents and to screen for suitable solvents for manufacturing and scale-up.

In situ optical spectroscopy of crystallization: One crystal nucleation at a time.

While crystallization is a ubiquitous and an important process, the microscopic picture of crystal nucleation is yet to be established. Recent studies suggest that the nucleation process can be more complex than the view offered by the classical nucleation theory. Here, we implement single crystal nucleation spectroscopy (SCNS) by combining Raman microspectroscopy and optical trapping induced crystallization to spectroscopically investigate one crystal nucleation at a time. Raman spectral evolution during a single glycine crystal nucleation from water, measured by SCNS and analyzed by a nonsupervised spectral decomposition technique, uncovered the Raman spectrum of prenucleation aggregates and their critical role as an intermediate species in the dynamics. The agreement between the spectral feature of prenucleation aggregates and our simulation suggests that their structural order emerges through the dynamic formation of linear hydrogen-bonded networks. The present work provides a strong impetus for accelerating the investigation of crystal nucleation by optical spectroscopy.

Using HOESY NMR Spectroscopy to Characterize Prenucleation Aggregates

Prenucleation aggregates are important species in the crystallization pathway. Here, we combine heteronuclear Overhauser effect spectroscopy (HOESY) and molecular dynamics calculations to study solute molecule association in a model system─benzoic acid/pentafluorobenzoic acid. Our findings indicate that HOEs arise from diffusion-limited prenucleation aggregates and that association is solvent dependent.

Pre-nucleation cluster formation upon ethyl acetate addition to an aqueous solution of an anionic hydrotrope

Hydrotropes are used to solubilize poorly soluble solutes. Here the general features of the solution behaviour of the very common anionic hydrotrope sodium salicylate is investigated. With the use of density and scattering measurements, it is demonstrated that around the critical point neither pre-Ouzo structuring nor an Ouzo effect are present. By contrast, in a domain near the liquid-solid phase boundary, X-ray light and neutron scattering combined with a density excess determination prove the presence of dynamic aggregates. These aggregates are stabilized without any surfactants, but by selective solvation of ethyl acetate, reminiscent of stable liquid pre-nucleation aggregates. And most surprising: in water saturated by ethyl acetate (20% wt), sodium salicylate micellizes like a medium chain classical surfactant.

Pre-nucleation aggregation based on solvent microheterogeneity.

Investigation into pre-nucleation aggregates indicating hydrate formation of caffeine and theophylline in aqueous acetonitrile showed hydrate crystallisation at much lower water fraction than significant solute self-association. Molecular dynamics simulations indicate that the solvent separates on the molecular scale and that solute molecules preferentially localise on the phase interface.

Solvent effects of the structures of prenucleation aggregates of carbamazepine

Download options Please wait... Article information DOI https://doi.org/10.1039/C2CE25941A Article type Communication Submitted 12 Jun 2012 Accepted 03 Jul 2012 First published 16 Jul 2012 Download Citation CrystEngComm, 2012,14, 7115-7117 BibTex EndNote MEDLINE ProCite ReferenceManager RefWorks RIS Permissions Request permissions Solvent effects of the structures of prenucleation aggregates of carbamazepine C. A. Hunter, J. F. McCabe and A. Spitaleri, CrystEngComm, 2012, 14, 7115 DOI: 10.1039/C2CE25941A To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page. If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given. If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page. Read more about how to correctly acknowledge RSC content. Social activity Tweet Share Search articles by author Christopher A. Hunter James F. McCabe Andrea Spitaleri

A Computational Study of the Mechanism of the Selective Crystallization of α- and β-Glycine from Water and Methanol−Water Mixture

Understanding the control of polymorphism in organic crystals is of paramount importance to the pharmaceutical, chemical, and food industries. In this work, we investigated two mechanisms described in the literature about the selective crystallization of α- and β-glycine from water and from mixtures of water and methanol using molecular simulations. The link hypothesis (J. Phys. Chem. B 2008, 112, 7794; Cryst. Growth Des. 2006, 6, 1788; J. Inclusion Phenom. Mol. Recognit. Chem. 1990, 8, 395; J. Am. Chem. Soc. 1986, 108, 5871.), which tries to relate the structure of the polymorph obtained from crystallization to the structure of the prenucleation aggregates in the solutions, says the abundance of glycine cyclic dimers in aqueous solutions leads to the crystallization of α-glycine, the polymorph using cyclic dimers as the packing units. This hypothesis was studied first. We revisited the self-assembly of glycine molecules in solution using molecular dynamics to address the debate (Phys. Rev. Lett. 2007, 99, 115702; J. Phys. Chem. B 2008, 112, 7280; J. Am. Chem. Soc. 2008, 130, 13973.) about which is the dominating species in the glycine aqueous solutions and whether there is a link between the solution chemistry and the polymorphic outcome of crystallization. The structures of the glycine clusters were characterized using a structural parameter called cyclic dimer fraction. The glycine clusters in methanol-water mixtures have higher cyclic dimer compositions than those in the pure aqueous solutions. Moreover, the glycine open-chain dimer is more stable than the cyclic dimer regardless of the presence of methanol. All these suggest that the link hypothesis does not work for the polymorphic system of glycine, and the selective crystallization of α- and β-glycine from water and methanol-water mixture, respectively, is not due to the abundance of glycine aggregates in the solution phase with a similar structure to the crystallizing solid form. The hypothesis of the methanol inhibition on the growth of α-glycine {010} and {010} faces, proposed by Weissbuch (Angew. Chem., Int. Ed. 2005, 44, 3226.), was also studied. The interfaces between the {010} and {010} faces of both crystal forms (α and β) and both solvents (water and methanol-water 3:7 mixture) were studied using molecular simulation. No strong binding of methanol onto the {010} and {010} faces of both crystal forms was observed, and the addition of methanol dilutes the crystal-solvent interactions on all faces. Therefore, the selective crystallization of β and α-glycine with and without methanol does not follow either of the two mechanisms in the literature.

Induction and Inhibition of Preferential Enrichment by Controlling the Mode of the Polymorphic Transition with Seed Crystals

Both induction and inhibition of "preferential enrichment", an unusual symmetry-breaking enantiomeric-resolution phenomenon observed upon simple recrystallization of a certain kind of racemic crystals from organic solvents, have been successfully achieved by controlling the mode of the polymorphic transition during crystallization with appropriate seed crystals. Such control of the polymorphic transition can be interpreted in terms of a novel phenomenon consisting of 1) the adsorption of prenucleation aggregates, 2) the heterogeneous nucleation and crystal growth of a metastable crystalline form, and 3) the subsequent polymorphic transition into the more stable form; these three processes occur on the same surface of a seed crystal. We refer to this phenomenon as an "epitaxial transition", which has been confirmed by means of in situ attenuated total reflection (ATR) FTIR spectroscopy in solution and the solid state, differential scanning calorimetry (DSC) measurements of the deposited crystals, and X-ray crystallographic analysis of the single crystals or the direct-space approach employing the Monte Carlo method with the Rietveld refinement for the structure solution from the powder X-ray diffraction data.

Highly Ordered Titanyl Phthalocyanine Films Grown by Directional Crystallization on Oriented Poly(Tetrafluoroethylene) Substrate

Highly oriented films of titanyl phthalocyanine (TiOPc) were obtained by high-vacuum sublimation onto an oriented poly(tetrafluoroethylene) (PTFE) substrate. The dependence of the structure and morphology on deposition parameters (substrate temperature Ts, deposition time t, and deposition rate τ) was followed by X-ray diffraction, transmission electron microscopy (TEM), and atomic force microscopy (AFM) to uncover the origin of the oriented growth process. At Ts = 100 °C, an original growth mechanism was observed whereby α-TiOPc microcrystallites were formed by the static coalescence and reorganization of small amorphous aggregates in close contact. Nucleation of α-TiOPc is initiated at the PTFE macrosteps from which oriented crystallization propagates, leading to uniform α-TiOPc films with a twinned texture and a dense (0 1 0) contact plane. The molecules are in an edge-on orientation, with their molecular plane oriented parallel to the PTFE chains. At the mesoscale, the nucleation of crystalline α-TiOPc involves the alignment and oriented coalescence of amorphous prenucleation aggregates along the PTFE macrosteps, i.e., a graphoepitaxial process. At the molecular scale, it is proposed that the TiOPc orientation and the preferential nucleation of the α polymorph are enforced by the topography and structure of the PTFE macrosteps in conjunction with the requirement for a minimal nucleation free energy. The optical absorption of the films in the near infrared is found to be strongly correlated with the structural and morphological modifications in the films. The oriented character of the α-TiOPc films results in a strong polarization of the 850-nm band perpendicular to the PTFE chain axis direction.

A spectrophotometer-based method for crystallization induction time period measurement

A method for measurement of crystallization induction time periods using a spectrophotometer is described. The turbidity of lysozyme solutions at sodium chloride concentrations of 0%, 3%, 6%, 9% (w/v) in 0.1 M NaAc (pH 4.0) and a lysozyme concentration of 10 mg/ml was monitored at 350 nm and showed a dramatic increase after nucleation occurred. Heterogeneous sources of nucleation were removed via filtration with 100,000 and 500,000 MWCO filters. Larger pore size, 0.2 μm, filters were not able to remove these particles. The non-filtered and 0.2 μm filtered had the same turbidity profiles except that the 0.2 μm filtered had an induction time of 152 min compared with the 119 min induction time for the non-filtered solution. The 500,000 MWCO filter had a significant reduction in the formation of prenucleation aggregates and the induction time increased from 119 min for non-filtered to 178 min for the 500,000 MWCO filtered. Also, when the 100,000 MWCO filter was used there was no nucleation or crystallization over the 240 min time frame. The increase in turbidity was attributed to an increase in particle size and not to bacterial growth because the solutions were found to be free of bacteria or fungi by microbiological analysis. Results from hanging drop vapor diffusion crystallization on the same solutions used in the turbidity study indicate that the sources removed by filtration lead to nucleation. Finally, sodium azide was added to the solutions at a concentrations of 0.17% (w/w) and was found to interfere with or delay lysozyme nucleation.

Lack of evidence for prenucleation aggregate formation in lysozyme crystal growth solutions

There have been numerous claims of large concentrations of prenucleation aggregates in supersaturated as well as undersaturated lysozyme solutions at high salt concentrations. The presence of these aggregates was derived from measurements of the light or neutron scattering intensity, ultracentrifugation and dialysis behavior, as well as over-simplified crystal growth kinetics considerations. In all these interpretations it has been assumed that lysozyme solutions are either ideal or that protein interactions are independent of salt concentration. Contrary to these presumptions, our static and dynamic light scattering experiments provide evidence that lysozyme forms highly non-ideal, strongly interacting solutions. At low salt concentrations, the scattering intensities fall well below the values expected for an ideal, monomeric solution at the same protein concentration, while diffusivities increase with increasing protein concentration. Upon increase in salt concentration, these trends are eventually reversed. This enhancement in scattering intensity and decrease in diffusivity was widely interpreted as sign of aggregate formation. Yet, a quantitative interpretation of the scattering behavior over the whole salt concentration range can only be given in terms of a transition from net repulsion to net attraction between lysozyme monomers. Increased salt screening of the electrostatic repulsion among the protein macro-ions, together with attractive protein interactions, such as van der Waals, hydrophobic and hydration forces, provide an unambiguous mechanism for the observed transition and a more physical interpretation of the various observations.