Effects of a structurally related substance on the crystallization of paracetamol

Abstract

Paracetamol (PCM) was crystallized from an isopropanol (IPA) solution containing various small amounts of metacetamol as an additive. The effect on the nucleation kinetics was studied by measuring the induction time to nucleation and the metastable zone width using focused beam reflectance measurements (FBRM) and attenuated total reflectance (ATR-UV/Vis) spectroscopy. Both the induction time and the metastable zone width were expressed as functions of the additive concentration. Small amounts of metacetamol (1–4 mol-%) were found to cause significant inhibition to the nucleation by extending both the induction time and the metastable zone width. A progressive change in the morphology of the paracetamol crystals from tabular to columnar habit was observed with increasing metacetamol concentration. The solvent also had a significant effect on the size of the paracetamol crystals as smaller crystals were obtained in IPA than in aqueous solution. The dissolution rate of paracetamol was improved by the incorporation of metacetamol with 4 mol-% having the most effect. A supersaturation control (SSC) approach was implemented for the PCM-IPA system with and without metacetamol in an attempt to control and obtain larger metacetamol-doped paracetamol crystals.

Key words： acetaminophen; metacetamol; crystallization; metastable zone width; induction time; supersaturation control

Acknowledgments

European Research Council Grant No. 280106+ CrySys and Engineering and Physical Science Research Council, UK, Centre for Continuous Manufacturing and Crystallization.

Nomenclature
τ	Induction time to nucleation
J	Rate of nucleation
γ	Surface free energy between the nucleus and supersaturated solution
V	Molecular volume
T	Temperature or absolute temperature
Tset	Setpoint temperature
Tlim	Nucleation temperature
ΔTmax	Maximum supercooling
T0	Saturation temperature
A	Pre-exponential factor
kB	Boltzmann constant
Δθ	Degree of undercooling
S	Supersaturation or absolute supersaturation
Sse	Setpoint supersaturation
C	Solution concentration
Csol	Equilibrium solubility
cs	Equilibrium solubility
c	Concentration at 45°C
R	Cooling rate
r*	Radius of critical nucleus

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