(672f) Investigating the Effect of Droplet Confinement and Porous Confinement on the Formation of Carbamazepine Polymorphs

Controlling crystal polymorphism is one of the greatest challenges in the development of active pharmaceutical ingredients (APIs). Polymorphs of an API are different structural arrangements of the same molecule in a crystal lattice [1]. Each polymorph has different physicochemical properties such as: stability, solubility, and bioavailability [2]. Moreover, crystal polymorphism has historically brought about a lot of issues in drug development and patient safety; well-known cases include HIV-1 drug, Ritonavir, and antacid drug, Zantac [3-5]. As a result, control over polymorphism in the pharmaceutical industry has been highly sought after.

This study outlines a systematic one-step approach to controlling the polymorphism of carbamazepine (CBZ) via droplet confinement using spray drying as a continuous method of manufacture. In this process, CBZ molecules are confined within spray dried droplets of varying sizes during the nucleation process to investigate whether different levels of confinement result in obtaining different polymorphic forms. Spray drying is a continuous method for converting a liquid feed solution or suspension to powder in a single step [6]. Different atomising gas flow rates were used to vary the size of the droplet produced in the spray dryer. As a result, a trend emerged in the polymorphic form of the spray dried powders with respect to the sprayed droplet sizes. PXRD confirmed the largest droplet size (~38.55 µm) produced both the stable polymorph, form III, and metastable form IV, whereas only the metastable polymorph, pure form IV, was isolated from the smallest droplet size (~5.39 µm). Accelerated stability tests revealed that smaller level of confinement yields particles with higher stability. The amount of the most stable polymorph of CBZ, form III, present in the particles produced by the larger droplets increased during the stability test. However, the particles produced by the smaller droplets, remained as pure metastable CBZ form IV throughout the stability study. To the best of our knowledge, this is the first study to successfully obtain pure CBZ metastable form IV in bulk using a scalable and controlled method of continuous manufacture.

Analytical techniques used in this study include particle size analysis (PSA) (fig.1A), Powder x-ray Diffraction (PXRD) (fig.1B), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC) and Fourier-Transform Infrared (FTIR) Spectroscopy.

As a follow up investigation, we conducted a systematic approach to controlling the polymorphism of CBZ via solid confinement within porous silica using spray drying and rotary evaporation. Silica is a biocompatible material which has the potential to stabilise metastable polymorphic forms of APIs with enhanced dissolution properties [7]. This hypothesis-driven investigation was carried out to explore the transferability of the concept that the size of a pore must be 20 times the molecular radius of a compound for controlled crystallisation to occur [8, 9]. Carbamazepine molecules were confined within silica pores of varying size during the nucleation process to investigate the effects of porous confinement size on its solid-state and the final polymorphic form. The critical size for crystallisation of CBZ in confinement is 20 times its molecular radius, 9.8 Å [10]. In order to clearly understand the effect of confinement, three silica samples were used in this study; one with a pore size smaller than the critical size for crystallisation to occur, a second with a pore size close to the critical size, and a third with a pore size larger than the critical size. Molecular dynamic simulations were employed as part of this investigation to predict the behaviour of different numbers of molecules confined within different pore sizes.

These methods of controlling the polymorphism of CBZ by different methods of confinement and stabilising metastable polymorphs through continuous methods of manufacture can have significant implications for controlling the polymorphism of other polymorphic APIs, cocrystals and multicomponent pharmaceuticals.

References:

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7. Gao, Y., et al., Multifunctional Role of Silica in Pharmaceutical Formulations. AAPS PharmSciTech, 2022. 23(4): p. 90.

Jones, E.C.L. and L.M. Bimbo, Crystallisation Behaviour of Pharmaceutical Compounds Confined within Mesoporous Silicon. Pharmaceutics, 2020. 12(3).

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