Controlling Polymorphism of Carbamazepine Nanoparticles in a Continuous Supercritical-CO₂-Assisted Spray Drying Process

Abstract

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.

Applications of Supercritical Anti-Solvent Process in Preparation of Solid Multicomponent Systems

“…This step is similar to the semi-continuous SAS process, and it is possible to control the solid-state properties of APIs by controlling the supersaturation/nucleation events. In general, the ratio of SCF to solution is considerably high in the continuous process when compared to the values obtained in the batch or semi-continuous SAS experiments, strongly ensuring that anti-solvent nucleation are occurring in the nozzle [ 75 ]. The generated nano-suspension is then spray-dried after the nozzle orifice.…”

“…In fact, the study of Long et al [75] have demonstrated that the polymorphic outcome of carbamazepine (CBZ) were controllable by using different additives in a continuous SAS process: (1) when using ethyl cellulose as an additive, amorphous CBZ was obtained;…”

“…Thanks to its similarity and compatibility to spray drying, the continuous SAS process is expected to produce solid dispersions with unique superiority. In fact, the study of Long et al [ 75 ] have demonstrated that the polymorphic outcome of carbamazepine (CBZ) were controllable by using different additives in a continuous SAS process: (1) when using ethyl cellulose as an additive, amorphous CBZ was obtained; (2) when using either maltitol or L-Eudragit 100-55 as additives, pure CBZ form I was obtained; (3) when using sodium stearate as additive, pure CBZ form II was obtained; and (4) when using sodium dodecyl sulfate as an additive, pure CBZ form III was obtained. However, only CBZ form IV was consistently produced by conventional spray drying, irrespective of the additive selected.…”

Cortisone and cortisol break hydrogen-bonding rules to make a drug–prodrug solid solution

“…Such qualitative conclusions are confirmed by Rietveld refinement, according to which the relative amount of each phase coincides with that of the starting materials (Table S1). On the contrary, the same technique indicates that a single microcrystalline phase is obtained when CO 2 is employed in a supercritical CO 2 assisted spray drying (SASD) process (Long et al, 2019(Long et al, , 2020Padrela et al, 2017) (Fig. 3).…”

Nanoparticles and Nanocrystals by Supercritical CO2-Assisted Techniques for Pharmaceutical Applications: A Review

“…Droplet agglomeration is also avoided with the improved and faster mixing promoted in SAS-EM, leading to the formation of droplets and, consequently, smaller particles than those produced by the conventional SAS process. Long et al [103] used the supercritical CO 2 antisolventassisted nano spray-drying (SASD) process to control the polymorphism of carbamazepine nanoparticles; in the SASD process, CO 2 mixes with the solution containing the active principle in a small-volume high-pressure coaxial nozzle, in which supersaturation occurs. In this process, the atomization is involved in the method itself, resulting in the generation of a spray of ultrafine droplets in which the solvent is removed by thermal means.…”