Insight into the Role of Additives in Controlling Polymorphic Outcome: A CO₂-Antisolvent Crystallization Process of Carbamazepine

Abstract

Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge in pharmaceutical science and engineering. For instance, CO 2antisolvent crystallization typically favors the formation of metastable forms of carbamazepine (CBZ), a highly polymorphic drug, with impurities of other forms. This work demonstrates for the first time that a supercritical CO 2antisolvent crystallization process in combination with certain molecular additives allows control of the polymorphic outcome of CBZ. We show herein that in the presence of sodium stearate and Eudragit L-100, needle-shaped crystals of CBZ form II are obtained, while blocky-shaped crystals of CBZ form III are obtained in the presence of Kollidon VA64, sodium dodecyl sulfate, ethyl cellulose, and maltitol. This selectivity for pure forms in this supercritical set up contrasts to the results when the same set of additives where used in a solvent evaporation method that yielded mixtures of form I, II, and III. The type of additive used in the CO 2 -antisolvent crystallization process impacted both the product crystal polymorphic form and size. A detailed molecular-level analysis along with density functional theory calculations allowed us to give a mechanistic insight into the role of sodium stearate and Eudragit L-100 in facilitating nucleation of the metastable form II.

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…where a set of excipients involving surfactants and polymers used to control polymorphic form (Padrela, Zeglinski, and Ryan 2017). The goal of the study was to stabilize metastable polymorphic form of API and elucidation of a molecular level mechanism for the same.…”

“…Different polymorphic forms were differently crystallized on different functionality vials. Padrela et al used gas‐antisolvent method for crystallization of an API where a set of excipients involving surfactants and polymers used to control polymorphic form (Padrela, Zeglinski, and Ryan ). The goal of the study was to stabilize metastable polymorphic form of API and elucidation of a molecular level mechanism for the same.…”

“…Air‐jet in the supersaturated solution of the API has also been investigated as one of the approaches, wherein the air bubble served as a heterosurface (Capellades et al, ). Intentional incorporation of the heterosurface in the process has been widely studied to understand the role of the surface topography and surface chemistry on the crystallization of the API (Arribas Bueno et al, ; Arribas Bueno, Crowley, Hodnett, Hudson, & Davern, ; Chadwick et al, ; Padrela et al, ; Quon et al, ). Current section deals with the variety of heterosurfaces that have been employed for pharmaceutical heterogeneous crystallization.…”

“…The isomorphous compounds have been explored to induce crystallization by mechanisms involving the crystallographic features. Biocompatible carbohydrates or sugars have been choice of heteronuclent amongst common pharmaceutical excipients (Arribas Bueno et al, ; Arribas Bueno et al, ; Chadwick et al, ; Chadwick et al, ; López‐Mejías et al, ; Padrela et al, ; Quon et al, ; Wijethunga et al, ). The sugars have been explored for a variety of applications from polymorph control to improvement in process efficiency.…”

Recrystallization and Production of Spherical Submicron Particles of Sulfasalazine Using a Supercritical Antisolvent Process

“…Because of the advantages of carbon dioxide (CO 2 ), namely its nontoxicity, nonflammability, environmental friendliness, and mild supercritical conditions, CO 2 is recognized as a green solvent and is commonly used in the SAS process. In the literature, the SAS process has been demonstrated to be superior to the conventional crystallization process for the modification of the solid-state properties of pharmaceutical and biological compounds, such as baicalein, curcumin, palmitoylethanolamide, quercetin, β-carotene, ellagic acid, etoposide, indomethacin, mangiferin, rutin, tetracycline, aescin, carbamazepine, curcumin, gefitinib, levofloxacin, primidone, warfarin, and naringenin [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Using SAS, crystals with sizes in the range of microns to nanometers, regular crystal habit, and narrow size distribution can be produced.…”