Nucleation and Growth of Pharmaceutical Crystals

Research output: ThesisDoctoral Thesis

Abstract

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.
LanguageEnglish
QualificationPhD
Awarding Institution
  • University Of Strathclyde
Supervisors/Advisors
  • Johnston, Blair, Supervisor
  • Florence, Alastair, Supervisor
Award date5 Jun 2019
Place of PublicationGlasgow
Publisher
Publication statusPublished - 1 Apr 2019

Fingerprint

olanzapine
Crystallization
Pharmaceutical Preparations
Growth

Keywords

  • crystal growth
  • crystal growth from solution
  • olanzapine
  • hydrate
  • two-step nucleation
  • nucleation
  • growth kinetics
  • growth unit
  • dimer
  • atomic force microscopy
  • light scattering

Cite this

Warzecha, M. (2019). Nucleation and Growth of Pharmaceutical Crystals. Glasgow: University of Strathclyde.
Warzecha, Monika. / Nucleation and Growth of Pharmaceutical Crystals. Glasgow : University of Strathclyde, 2019. 197 p.
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title = "Nucleation and Growth of Pharmaceutical Crystals",
abstract = "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.",
keywords = "crystal growth, crystal growth from solution, olanzapine, hydrate, two-step nucleation, nucleation, growth kinetics, growth unit, dimer, atomic force microscopy, light scattering",
author = "Monika Warzecha",
year = "2019",
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day = "1",
language = "English",
publisher = "University of Strathclyde",
school = "University Of Strathclyde",

}

Warzecha, M 2019, 'Nucleation and Growth of Pharmaceutical Crystals', PhD, University Of Strathclyde, Glasgow.

Nucleation and Growth of Pharmaceutical Crystals. / Warzecha, Monika.

Glasgow : University of Strathclyde, 2019. 197 p.

Research output: ThesisDoctoral Thesis

TY - THES

T1 - Nucleation and Growth of Pharmaceutical Crystals

AU - Warzecha, Monika

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

KW - crystal growth

KW - crystal growth from solution

KW - olanzapine

KW - hydrate

KW - two-step nucleation

KW - nucleation

KW - growth kinetics

KW - growth unit

KW - dimer

KW - atomic force microscopy

KW - light scattering

M3 - Doctoral Thesis

PB - University of Strathclyde

CY - Glasgow

ER -

Warzecha M. Nucleation and Growth of Pharmaceutical Crystals. Glasgow: University of Strathclyde, 2019. 197 p.