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An experimental study on polymorph control and continuous heterogeneous crystallization of carbamazepine

Introduction

The pharmaceutical industry is transitioning from batch to continuous manufacturing (CM), motivated by the significantly reduced costs and improved quality associated with the latter. Orkambi and Prezista tablets have been produced using CM by Vertex Pharmaceuticals and Janssen Pharmaceuticals, respectively. More specifically, they have implemented continuous solutions for their downstream manufacturing processes (i.e., drug product). The end-to-end continuous manufacturing from raw material to final dosage (i.e., integrating drug substance and drug product manufacturing processes) is the next step in this transition, and has already been demonstrated at MIT.

A key unit operation in the end-to-end CM of pharmaceuticals is continuous crystallization, which separates the active pharmaceutical ingredient (API) from the liquid phase and helps with purification prior to downstream processing. For most small molecule drug products, the final dosage form is a uniform compression or encapsulation of API(s) and excipient). After crystallization of the API, subsequent steps (e.g., filtration, drying, milling, blending with excipients, granulation, sieving, tablet pressing, etc.) are required. As the number of steps increase, so do the challenges, risks, technical hurdles, and considerations.

Some steps can be eliminated (e.g., milling, sieving, granulation, etc.) if API is directly crystallized on the surface of an excipient within the crystallizer in a continuous crystallization process. This type of crystallization is called continuous heterogeneous crystallization. A common small molecule drug, carbamazepine (CBZ, 5Hdibenzazepine-5-carboxamide), is used in the treatment of epilepsy and trigeminal neuralgia as a first generation anticonvulsant.

There are five anhydrous polymorphs of CBZ (i.e., I, II, III, IV, and V), a dihydrate, and several other solvates (e.g., monoacetonate) that have been reported.

Abstract

Forms I-III and dihydrate carbamazepine (CBZ) were prepared and confirmed by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Influences of supersaturation (σ), stirring, anti-solvent (H2O), and polymer type on the resultant polymorph are discussed. For a CBZ ethanol solution at 5 ºC, more than 10 h was required to form crystals when σ was 0.5, while less than 2s was required when σ was increased to 9.0.

Very fine needle-shaped Form II crystals were obtained when σ ≥ 7.5. Higher stirring rates facilitated the formation of Form III CBZ. Continuous heterogeneous crystallization of Form III on Polyvinyl alcohol (PVA, MW 89,000-98,000) was achieved in a one-stage mixed suspension mixed product removal (MSMPR) crystallizer at 15 ºC and 300 rpm. At 5 ºC and 40 rpm, only Form II crystals were obtained. However, Form II CBZ gradually transformed to Form III within 2 residence times, and the transition process was irreversible.

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