Hydroxypropyl Methylcellulose as a Novel Tool for Isothermal Solution Crystallization of Micronized Paracetamol

Pulmonary inhalation is increasingly
being selected as a preferred
route for the delivery of both small and large drug macromolecules
for the treatment of a range of pathologies. The direct crystallization
of micronized powders, in particular, paracetamol, remains difficult,
as it requires the ability to work in high solution supersaturations
where agglomeration, wall crusting, and heterogeneous nucleation hinder
the control of crystal size and crystal size distribution. Polymer
additives are recognized to help drive the production of a given polymorph
or controlling crystal shape by means of adsorption on the crystal
surface. With the aim of exploiting the polymer-control nucleation
and growth of crystals for enhanced direct crystallization of micronized
powders, batch cooling crystallization of paracetamol in water was
carried out in the presence of 0.1–0.8% w/w hydroxypropyl methylcellulose
(HPMC). In the presence of polymer, the onset of nucleation was delayed
and extended beyond the cooling time of the solution, resulting in
an isothermal cooling crystallization and the production of micronized
paracetamol with a mean crystal size D50, in the range of 15–20 μm and an improved crystal size
distribution. Equally, the rate generation of solution cloudiness
was reduced by over 3-fold for the highest HPMC concentration tested,
with no detectable impact on final product yield. The mechanisms for
nucleation delay and growth inhibition by HPMC is unknown; however,
a modification of crystal’s shape observed upon the addition
of HPMC to the solution suggested it might be related to mass transfer
limitations and intermolecular hydrogen bonding between the large
HPMC
and the small drug molecules. This technique can potentially be used
for direct crystallization of other micronized drugs.