Controlling polymorphism in the transition from batch to continuous crystallization represents a major obstacle for the pharmaceutical industry. This work demonstrates a novel methodology to control the polymorphism of carbamazepine (CBZ) nanoparticles, a highly polymorphic BCS class II drug, using a continuous supercritical CO 2 antisolvent-assisted nano spray drying (SASD) process. We show herein that when supersaturation conditions are achieved in the highpressure SASD nozzle in the presence of anionic additives (e.g., sodium stearate, sodium dodecyl sulfate), nanoparticles of the metastable CBZ form II (using sodium stearate) or the stable CBZ form III (using sodium dodecyl sulfate) are obtained from methanol solutions, respectively. This novel methodology provides control over the final polymorphic form of CBZ obtained by (1) templating the desired polymorphic form when supercritical CO 2 supersaturates the CBZadditive methanol solution in the nozzle and (2) avoiding/minimizing the occurrence of any possible polymorphic transformation by immediately spray drying the supercritical antisolvent induced suspension into a dried fine powder. These results contrast with those obtained when using nonsupersaturating conditions in the SASD nozzle (amorphous CBZ is obtained, regardless of the additive used) and when using conventional spray drying (SD) where there is no antisolvent effect in the nozzle (CBZ form IV is obtained, regardless of the additive used). The impact that the mass ratio of methanol and supercritical CO 2 has on the supersaturation and consequently on the polymorphic outcome of carbamazepine obtained from batch and continuous supercritical CO 2 antisolvent crystallization processes is also discussed.
Supercritical
CO2 antisolvent crystallization typically
promotes the formation of metastable polymorphic forms of pharmaceutical
drugs. However, using this technological approach in combination with
the use of distinct molecular additives can provide further control
over the final polymorphic form obtained. The work presented herein
investigates the influence of critical processing variables of a CO2 antisolvent crystallization process in the presence of molecular
additives with respect to the polymorphism of carbamazepine (CBZ),
a highly polymorphic BCS class II drug. A Design of Experiments (DoE)
approach was performed to assess the outcome of CBZ polymorphism,
impacted by CO2 antisolvent processing variables such as
pressure, temperature, and CO2 addition rate when anionic
additives (sodium stearate or sodium dodecyl sulfate) were selected.
Statistical analysis revealed that the combination of temperature
and CO2 addition rate show statistically significant impact
(p < 0.05) on the final CBZ polymorphic form obtained
when no additive was present during short hold studies. However, when
using 5% w/w additive in the CBZ methanol solutions, CBZ samples produced
from CO2 antisolvent crystallization correspond to form
II (when using sodium stearate as the additive) or form III (when
using sodium dodecyl sulfate as the additive) for most samples, regardless
of the processing conditions used. An investigation into the polymorphic
stability of these CBZ samples was undertaken, allowing the precipitated
CBZ to remain immersed in the supercritical media (supercritical CO2 and methanol) for a prolonged period (60 h). Carbamazepine
samples that were initially form II began to convert to the stable
form III at lower temperature (40 °C), while samples that were
initially form III showed almost no conversion.
The polymorphic control of the co-crystal carbamazepine–saccharin (CBZ–SAC) metastable form II was achieved by nano-droplet confinement in tandem with droplet surface charging induced by electrospraying the precursor solution.
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