Concerning Elusive Crystal Forms: The Case of Paracetamol

Increasing commercial application of state of the art crystal structure prediction to aid solid form discovery of new molecular entities allows the experimentalist to target the polymorphs with desired properties. Here we remind ourselves that in this field the gap between such prediction and experimentation can be vast, the latter depending strongly on kinetic processes not accounted for in the computations. Nowhere is this gap more evident than in examples of so-called "elusive" polymorphs, forms that have been found difficult to crystallize, sometimes taking years to appear or sometimes disappearing altogether. In attempting to probe the origins of such phenomena this work targets a well-known, relatively simple molecule, paracetamol (PCM), and explores the structural and kinetic origins of its elusive nature. It is noted that in general comparisons of the kinetic factors (nucleation and crystal growth) between polymorphs have rarely been reported and of course in cases where one or more forms is "elusive" this will, by definition, be essentially impossible. PCM however offers a unique opportunity and we show how the recent discovery of the impact of metacetamol (MCM) in stabilizing PCM form II can be used to advantage, enabling otherwise impossible comparative kinetic experiments to be made. Resulting from this study we now appreciate that MCM has a selective impact in blocking the growth of the thickness and width of PCM form I while it has no impact on form II. This is interpreted in terms of strong adsorption of MCM on the {011} faces (width and thickness) of form I in orientations that inhibit crystal growth ("wrong" orientations). Of more significance here is the use of the additive in allowing an otherwise impossible comparison of linear growth rates of forms I and II. This leads to the appreciation that only through calculation of growth volumes can we finally appreciate how the relative growth kinetics lead inevitably to the elusive nature of Form II.