Modeling Olanzapine Solution Growth Morphologies

Abstract

The ability to predict crystal growth habits is an important component of drug design, enabling a targeted sweep of optimal growth conditions that confer desirable properties. This article presents an investigation into the shape of olanzapine crystals grown from various solvents, exemplifying how mechanistic models of spiral growth can be applied to small molecule therapeutics. Olanzapine is recognized as the most effective treatment for schizophrenia, but a mechanistic treatment of the underlying crystal growth has yet to be established. We model spiral growth of olanzapine form I from five solvents (acetone, ethyl acetate, toluene, methyl isobutyl ketone, and n-butyl acetate), considering a dimeric growth unit and periodic bond chains consisting of interdimer bonds. The centrosymmetric dimers are stabilized by multiple C–H···π contacts. The {1 0 0} face family dominates the predicted crystal habits, in agreement with our experiments; this morphology stems from the in-plane hydrogen bonds that are exposed on the {1 0 0} surface. The close agreement between predicted morphologies and experimental determinations lends support to the hypothesis that olanzapine grows as a dimer from these solvents. This mechanistic treatment can be readily applied to other compounds.

Is zeroth order crystal structure prediction (CSP_0) coming to maturity? What should we aim for in an ideal crystal structure prediction code?

“…derived from MD. 56 If we need to be reliant on MD to predict nucleation, growth and transformation rates, we are starting to enter the realm of multi-scale approximations to solving the appropriate nuclear and electronic time-dependent Schrödinger equation for the real system. We have lost the simplication of distinguishing between thermodynamics and kinetics.…”

Crystal Morphology Prediction of Olanzapine Forms III and IV

“…Thereby, the morphology prediction of OZPN by spiral growth mechanistic model is rational and acceptable. Based on this model, Luo [ 4 ] and Sun [ 22 ] have predicted the crystal morphologies of OZPN forms I and II, which match excellently with the observed crystal shapes from ethanol solvent. In this work, we used the same spiral growth model to predict the morphologies of OZPN form III and form IV from different solvents, that haven't been available by the experiment.…”

Can molecular flexibility control crystallization? The case ofparasubstituted benzoic acids

“…3 then shows the dependence of the rate parameter J / M on supersaturation ( S = x / x sat ). We note that ‘normalising’ the data to account for solubility differences between systems and solvents also follows from the work of Sun et al on crystal growth 31 and our earlier work on p -aminobenzoic acid. 23 …”