Investigating the fundamentals of drug crystal growth using Atomic Force Microscopy

Thompson, Claire (2003) Investigating the fundamentals of drug crystal growth using Atomic Force Microscopy. PhD thesis, University of Nottingham.

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Abstract

The importance of crystals to the pharmaceutical industry is evident - over 90% of pharmaceutical products contain a drug in crystalline form. However, the crystallization phenomena of drug compounds are poorly understood. An increased understanding of these processes may allow a greater degree of control over the crystallization outcomes, such as morphology, purity, or stability. In these studies, we have applied Atomic Force Microscopy (AFM) to the in situ investigations of drug crystal growth.

We utilized AFM to assess the growth on the (001) face of aspirin crystals at two supersaturations, elucidating both the growth mechanisms and kinetics at each supersaturation. We also investigated the nucleation of aspirin crystals, using microcontact printing to arrange aspirin-binding and non-binding self-assembled monolayers (SAMs) onto surfaces. This facilitated the visualization, using AFM, of the growth of aspirin crystals adhered to the surface. Additionally, secondary nucleation was observed on the growing crystals.

The effect of the additives acetanilide and metacetamol on the morphology and growth on the (001) face of paracetamol was investigated. The presence of metacetamol significantly reduced the growth rate on the face, with respect to pure paracetamol solutions. The growing steps exhibited a pinned appearance, consistent with the Cabrera and Vermilyea model. Conversely, acetanilide caused dissolution to occur.

Finally, we assessed the capabilities of AFM in following the structural transformations of crystals, which can occur in unstable pharmaceutical compounds. We employed AFM to determine the process by which anion exchange, and the subsequent structural transformations, of the co-ordination polymers {[Ag(4,4'-bipy)]BF4} and {[Ag(4,4'-bipy)]NO3} occur. AFM data verified that the anion exchange process is solvent-mediated. The mechanisms underlying this process are discussed herein.

These results reiterate the capability of AFM to monitor dynamic events on crystal surfaces. Analogous studies could be applied to numerous pharmaceutical compounds, thus facilitating the optimization of their crystallization parameters. In essence, future experiments using AFM may afford greater control over crystallization, and prevent the production of unwanted or unstable pharmaceutical compounds.

Item Type:Thesis (PhD)
Supervisors:Roberts, C.J.
Davies, M.C.
Tendler, S.J.B.
Wilkinson, M.J.
Uncontrolled Keywords:additive, anion exchange, aspirin, atomic force microscopy, co-ordination polymer, crystal growth, impurity, paracetamol, self-assembled monolayer, solvent-mediated transformation.
Faculties/Schools:UK Campuses > Faculty of Science > School of Pharmacy
ID Code:86
Deposited By:Claire Thompson
Deposited On:17 Jan 2005
Last Modified:06 Feb 2009 14:44

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