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

Research output: Contribution to conferencePoster

Abstract

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.

Conference

Conference48th BACG Annual Conference
CountryUnited Kingdom
CityManchester
Period27/06/1730/06/17
Internet address

Fingerprint

olanzapine
Crystallization
Solubility
Atomic Force Microscopy
Behavior Control
Water
Entropy
Population Characteristics
Bipolar Disorder
Thermodynamics
Pharmaceutical Preparations

Keywords

  • crystal growth
  • crystal nuclei
  • cluster formation

Cite this

Warzecha, M., Vekilov, P. G., & Florence, A. (2017). The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms. Poster session presented at 48th BACG Annual Conference, Manchester, United Kingdom.
Warzecha, Monika ; Vekilov, Peter G. ; Florence, Alastair. / The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms. Poster session presented at 48th BACG Annual Conference, Manchester, United Kingdom.1 p.
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Warzecha, M, Vekilov, PG & Florence, A 2017, 'The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms' 48th BACG Annual Conference, Manchester, United Kingdom, 27/06/17 - 30/06/17, .

The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms. / Warzecha, Monika; Vekilov, Peter G. ; Florence, Alastair.

2017. Poster session presented at 48th BACG Annual Conference, Manchester, United Kingdom.

Research output: Contribution to conferencePoster

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T1 - The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms

AU - Warzecha, Monika

AU - Vekilov, Peter G.

AU - Florence, Alastair

PY - 2017/6/27

Y1 - 2017/6/27

N2 - 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.

AB - 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.

KW - crystal growth

KW - crystal nuclei

KW - cluster formation

UR - http://www.bacg-2017.co.uk/home

M3 - Poster

ER -

Warzecha M, Vekilov PG, Florence A. The solute-rich mesoscopic precursors of crystal nuclei of olanzapine solid forms. 2017. Poster session presented at 48th BACG Annual Conference, Manchester, United Kingdom.