Nucleation and growth of pharmaceutical crystals

Investigating nucleation, crystal growth and solid-state transformations at the nanoscale are of significant interest, as more complex routes have roused questions about the classical view of these processes. This thesis reports the characterisation of prenucleation clusters in olanzapine (OZPN) aqueous solutions, their role in non-classical heteronucleation of OZPN hydrates and during crystal growth mechanism.;Atomic force microscopy studies of the (100)OZPNI face of OZPN I crystals in contact with water show the formation, growth, and order of dense nanodroplets leading to crystallization of OZPN dihydrate on the surface of OZPN I. Dihydrate polymorphic form is driven by a templating effect of the underlying OZPN I lattice. The size and volume fraction of nanodroplets in purely aqueous and mixed ethanol and water OZPN solutions show that their radius is steady in time at ca. 35 nm and it is independent of the OZPN concentration and the solvent composition.;The OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviours are consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. Although the presence of prenucleation clusters is critical during OZPN phase transformation, it was observed that clusters do not take part in a growth mechanism and OZPN layers are generated by a spiral growth. Step velocity shows a nonlinear dependence on OZPN concentration.;The proposed growth model suggests that OZPN layers propagate by incorporation of OZPN dimers present as a minor species in OZPN solution. The growth by dimers is faster not owing to spatial or entropic factors or weakly bound solvent, but to the accumulation of dimers on crystal surfaces due to stronger binding. These findings provide guidance towards enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems.Investigating nucleation, crystal growth and solid-state transformations at the nanoscale are of significant interest, as more complex routes have roused questions about the classical view of these processes. This thesis reports the characterisation of prenucleation clusters in olanzapine (OZPN) aqueous solutions, their role in non-classical heteronucleation of OZPN hydrates and during crystal growth mechanism.;Atomic force microscopy studies of the (100)OZPNI face of OZPN I crystals in contact with water show the formation, growth, and order of dense nanodroplets leading to crystallization of OZPN dihydrate on the surface of OZPN I. Dihydrate polymorphic form is driven by a templating effect of the underlying OZPN I lattice. The size and volume fraction of nanodroplets in purely aqueous and mixed ethanol and water OZPN solutions show that their radius is steady in time at ca. 35 nm and it is independent of the OZPN concentration and the solvent composition.;The OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviours are consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. Although the presence of prenucleation clusters is critical during OZPN phase transformation, it was observed that clusters do not take part in a growth mechanism and OZPN layers are generated by a spiral growth. Step velocity shows a nonlinear dependence on OZPN concentration.;The proposed growth model suggests that OZPN layers propagate by incorporation of OZPN dimers present as a minor species in OZPN solution. The growth by dimers is faster not owing to spatial or entropic factors or weakly bound solvent, but to the accumulation of dimers on crystal surfaces due to stronger binding. These findings provide guidance towards enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems

Wpływ metody in vitro na zdrowie i funkcjonowanie kobiety oraz relacje małżeńskie

The article describes functioning of a woman undergoing in vitro fertilization and the influence of this method on relationship between husband and wife. The author seeks the answer to some questions: why do some couples decide on in vitro fertilization? What moral dilemmas do they meet on the way to achieve their goal etc. In order to find the answer of these questions the author drafted the questionnaire form and made it available on portals: abrahamisara.pl, babyboom.pl, kafeteria.pl, gazeta.pl, I am supporting in vitro - facebook and others. The questionnaire survey lasted about one year (2014). It revealed numerous threats to the mother as well as to the child associated with some clinical practices with in vitro fertilization, threatening human rights, the dignity of human person and of marriage.Celem artykułu jest ukazanie funkcjonowania kobiety w programie in vitro oraz wpływ tej metody na relacje wewnątrzmałżeńskie. Autorka poszukuje odpowiedzi na pytania: czym kierują się osoby decydujące się na procedurę sztucznego zapłodnienia, jakie są moralne dylematy osób podchodzących do programu in vitro itp. W celu znalezienia odpowiedzi autorka sporządziła ankietę i udostępniła ją na portalach: abrahamisara.pl, babyboom.pl, kafeteria.pl, gazeta.pl, popieram in vitro – Facebook i inne. Badania trwały około jednego roku (2014). Ujawniły one liczne zagrożenia zarówno dla matki, jak i dziecka, związane z niektórymi praktykami klinicznymi związanymi z praktyką in vitro, które uwłaczają godności zarówno osoby ludzkiej, jak i małżeństwa

The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms

Olanzapine (OZPN) is a BCS class II drug used to treat schizophrenia (bipolar disorder). OZPN exhibits rich solid-state diversity. To date, 60 distinct forms have been identified, including 3 polymorphs (I, II, III), 52 crystalline solvates, 3 dihydrates (DB, DD, DE), a disordered higher hydrate, plus an amorphous form. Atomic Force Microscopy (AFM) results suggest that the nucleation of OZPN DD on the surface of OZPN I in water may follow a non-classical mechanisms that includes formation of solute-rich mesoscopic clusters [1]. Since the solubility of OZPN I in water is very low, the kinetics of transformation are difficult to monitor. To increase the solubility of OZPN I, we added different ratios of a co-solvent, ethanol. AFM observations revealed that clusters similar to those seen in purely aqueous environments are present on the surface of OZPN:EtOH:H2O crystals in contact with both supersaturated and undersaturated EtOH/H2O solutions. To establish the mechanism of cluster formation, we monitored the dependence of the cluster size and volume fraction on time, OZPN concentration, and co-solvent concentration using Brownian Microscopy (BM). The characteristics of the cluster population were correlated with the standard enthalpy, entropy and free energy of crystallization obtained from temperature dependence of the solubility of OZPN:EtOH:H2O crystals. We verified, using small angle x-ray scattering, that the crystal form was preserved at all solvent compositions. We observed that the cluster radius was constant, at R ≈ 37 nm, in all solvent compositions tested and at all times. The volume of the cluster population φ mapped the non-monotonic dependence of the crystallization enthalpy on the EtOH content, indicating that φ is determined by the thermodynamics of the solute-solvent interactions. The decoupled behaviour of R suggests that, in contrast to φ, the cluster size is kinetically determined. These conclusions comply with the prediction of a model of mesoscopic solvent rich clusters, based on formation of transient solute oligomers in the solutions [3]. These are the first observations of solute-rich clusters in solutions of pharmaceutically active compounds and of their role in the nucleation of crystals and the transformations between crystal forms. The suggested cluster formation mechanism may point to means to control these behaviours that are crucial for the properties of pharmaceutical preparations.  References:[1] M. Warzecha, R. Guo, R. M. Bhardwaj, S. M. Reutzel-Edens, S. L. Price, D. Lamprou and A. J. Florence, In preparation 2017.[2] Gebauer, D., Kellermeier, M., Gale, J. D., Bergström, L. & Cölfen, H. Pre-nucleation clusters as solute precursors in crystallisation. Chem. Soc. Rev. 2014, 43, 2348 [3] Vekilov, P. G. The two-step mechanism of nucleation of crystals in solution. Nanoscale, 2010, 2, 2346

Impact of substituent effects on the Raman spectra of structurally related N-substituted diketopyrrolopyrroles

This document is the Accepted Manuscript version of the following article: Jesus Calvo-Castro, et al, ‘Impact of substituent effects on the Raman spectra of structurally related N-substituted diketopyrrolopyrroles’, Vibrational Spectroscopy, Vol. 83, pp. 8-16, March 2016, doi: https://doi.org/10.1016/j.vibspec.2015.12.004. This manuscript version is made available under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.Control over vibrational frequency modes is important in optimising the performance and behaviour of conjugated organic materials employed as charge transfer mediators and optical components in optoelectronic devices. Raman spectroscopy represents a powerful technique that can be employed to determine the structural implications of molecular substitution on photophysical properties in such conjugated organic environments. Herein, we report for the first time, the optimised geometries for a series of eight systematically varied N-substituted diketopyrrolopyrroles as well as their experimental and computed Raman spectra, with special emphasis placed upon their spectral band assignments. Clear out-of-plane structural re-arrangements, including pyramidalisation of the lactam nitrogens arising from intramolecular H-bonding interactions were observed upon N-substitution in the reported systems, leading to significant vibrational frequency shifts for ν(Nsingle bondC) and ν(Cdouble bond; length as m-dashO) modes. In addition, mode scaling factors were determined and found to be comparable with those reported previously, employed using the same density functional. The following study addresses the implications of structural variation on the progression of those intense Raman modes which play a key role in tuning the photophysical properties of N-substituted diketopyrrolopyrrole systems and as such should be of broad interest to those developing functional materials based upon this molecular motifPeer reviewe

Atomic force microscopy studies on two-step nucleation and epitaxial growth

Continues advancement and rapid development of techniques operating at the nanoscale open new opportunities to revise and question commonly accepted nucleation and crystal growth theories. Atomic Force Microscopy (AFM) has been successfully involved in various aspects of active pharmaceutical ingredient (API) characterisation including crystal growth, stability of solid dispersions, surface morphology, phase changes and dissolution [1]. Recent studies conducted on proteins crystallisation at nanoscale show new evidence disproving generally accepted Classical Nuclea/on Theory (CNT)[2]. Currently, ‘dense liquid droplets’ seen in protein crystallisation and ‘pre-nucleation clusters’ [3] seen mostly in inorganic salt crystallisation, are two main concepts of non-classical nucleation theory, although no significant progress has been made towards better understanding of mechanisms controlling heterogeneous nucleation in small organic molecules systems, what is in particular interest, as an epitaxial ordering phenomenon is frequently used to enhance nucleation rates and control properties of materials. Our studies present a new light on heteronucleation and the epitaxial growth mechanisms based epitaxial growth of olanzapine dihydrate D on the surface of olanzapine form I (OZPN I) both in high humidity conditions and water solu*on. Results obtained from Peak Force Quan/ta/ve Nanomechanical Mapping Atomic Force Microscopy (PF- QNM-AFM) [4] indicate the presence of intermediate dense liquid-like phase in process of dihydrate D nucleation

Impact of systematic structural variation on the energetics of π−π stacking interactions and associated computed charge transfer integrals of crystalline diketopyrrolopyrroles

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth & Design, copyright © 2014 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see DOI: https://doi.org/10.1021/cg5010165, or ACS Articles on Request http://pubs.acs.org/page/policy/articlesonrequest/index.html/Control over solid state structure is critical for effective performance in optoelectronic devices bearing π-conjugated charge mediating organic materials. A series of five structurally related N-benzyl-substituted diketopyrrolopyrroles (DPPs) differing ... Novel crystal structures demonstrating long molecular axis, slipped, π−π cofacial stacking motifs and associated semiconductor bands in a series of N-benzylated diketopyrrolopyrroles are reported. Through variation of just 2 atoms from 60, clear crystal structure/(computed) charge transport activity interdependency is observed, with two structures exhibiting hole transport integrals comparable to Rubrene, a highly effective positive charge carrying, organic, crystalline materialPeer reviewedFinal Accepted Versio

Crystallisation of oxcarbazepine form III : emergence of crystals with variable twisted habit

The emergence of crystal structures with twisted morphologies is well-documented [1]. Twisted single crystals have been observed nanoscopically, mesoscopically, and macroscopically and pose challenges with respect to structural characterisation as they lack long-range translational symmetry. Crystal structure prediction (CSP) capabilities can be employed in polymorph screening studies for aiding in the identification of thermodynamically feasible solid forms and assisting experimentalists in performing targeted screening [2,3]. Recent evidence suggests that combining CSP with powder X-ray diffraction data can assist in solving the structure of polymorphic crystals with twisted habit [4]. Oxcarbazepine (OXCBZ) is a commercially available anticonvulsant known to crystallise in at least three polymorphic forms, two of which (form I and form II) have been fully characterised structurally [5]. OXCBZ form III was originally obtained by slow evaporation, at room temperature, from methanol solutions containing additives. Whilst various analytical data were reported, the small size and poor quality of the crystals prevented structure determination. Here, we report experimental protocols for the crystallisation of OXCBZ III from both solution and the vapour phase. Our approach combined CSP studies of the OXCBZ energy landscape with physical vapour deposition and solution-based, automated polymorph screening experiments. Vapour deposition of OXCBZ resulted in the formation of micron-sized needle and fibre-like form III crystals with variable twisted habit. In order to obtain greater insight into these twisted structures, a series of SEM and AFM studies have been performed to develop understanding of their initial formation and evolution over time

Intermolecular interactions and energetics in the crystalline π–π stacks and associated model dimer systems of asymmetric halogenated diketopyrrolopyrroles

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth & Design, © 2016 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see DOI: 10.1021/acs.cgd.5b01656/Four novel structurally analogous asymmetric, halogenated N-benzyl substituted diketopyrrolopyrroles (DPP) have been synthesized, and their crystal structures obtained. All four crystal structures exhibit π–π stacks with very small displacements along their short molecular axes, which based upon our previous studies involving symmetrical DPPs is a characteristic of N-benzyl substitution. Intermolecular interaction energies were computed for extracted crystal π–π dimer pairs by means of M06-2X density functional at the 6-311G(d) level to investigate the most energetically favored position of the halogen atoms in FBDPP and ClBDPP structures. In addition, effective stabilization energies arising from both benzyl and halogen substitution in these derivatives and in BrBDPP and IBDPP π–π dimer pairs were determined in order to probe the impact of these groups on the resulting dimer stability. Effects of the intermonomer displacements along the long molecular axis, which have been shown by us previously to significantly influence wavefunction overlap and effective electronic coupling, were investigated in detail using aligned and anti-aligned model systems of ClDPP and BrDPP. The predictions of these model systems are remarkably consistent with the observed displacements in their crystal derived π–π dimer pair equivalents, offering insight into the effective role of intermolecular contacts in crystal structures involving this molecular motif, particularly with a view toward crystal engineering in these systems. As a result, we believe that this study should be of significant interest to the growing DPP based materials community and in general to those investigating the detailed manner by which substituents can be employed in the supramolecular design of crystalline molecular architectures.Peer reviewedFinal Accepted Versio

Mesoscopic solute-rich clusters in olanzapine solutions

An organic molecule may crystallize in numerous distinct lattices, and the slow and unpredictable transitions between multiple crystal forms are a significant concern in its pharmaceutical application. Recent results indicate that the transformation of olanzapine (OZPN) from anhydrous to hydrate crystals is mediated by mesoscopic solute-rich clusters. Here we demonstrate the existence of such clusters in undersaturated OZPN solutions in purely aqueous and mixed EtOH/aqueous solvents. The clusters occupy about 10–8 to 10–7 of the solution volume and capture ca. 10–7 to 10–5 of the dissolved OZPN. The average cluster radius is steady in time at about 35 nm and independent of the OZPN concentration and the solvent composition, whereas the OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviors are in dire conflict with classical theories of phase transformation and recent aggregation models. They are, however, consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. We propose that a transient dimer, which may be akin to the centrosymmetric dimer present in all of the 60 known OZPN crystal structures, may underlie cluster formation. The finding of cluster formation in organic systems and the proposed cluster mechanism provide guidance toward enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems

True absolute determination of photoluminescence quantum yields by coupling multiwavelength thermal lens and photoluminescence spectroscopies

© Royal Society of Chemistry 2020. This is the accepted manuscript version of an article which has been published in final form at https://dx.doi.org/10.1039/D0CP03794J.Photoluminescence quantum yields denote a critical variable to characterise a fluorophore and its potential performance. Their determination, by means of methodologies employing reference standard materials, innevitably leads to large uncertainties. In response to this, herein we report for the first time an innovative and elegant methodology, whereby the use of neat solvent/reference material required by thermal lens approaches is eliminated by coupling it to photoluminescence spectroscopy, allowing for the discrimination between materials with similar photoluminescence quantum yields. To achieve that, both radiative and non-radiative transitions are simultaneously measured by means of a photoluminescence spectrometer coupled to a multiwavelength thermal lens spectroscopy setup in a mode-mismatched dual-beam configuration, respectively. The absorption factor independent ratio of the thermal lens and photoluminescence signals can then be used to determine the fluorescence quantum yield both accurately and precisely. We validated our reported method by means of rhodamine 6G and further applied in three novel structurally related diketopyrrolopyrrole based materials to, contrary to results obtained by other methods, unveil significant differences in their photoluminescence quantum yields.Peer reviewe