Michel Bauer

NMR study of desmotropy in Irbesartan, a tetrazole-containing pharmaceutical compound

Irbesartan, a novel anti-hypertensive agent (Angiotensin II antagonist), has been found to exist in two crystal forms. The solution-state structure and the solid-state structure of the two forms, designated Form A and Form B, have been probed using a series of NMR methods and correlated with single-crystal X-ray results for Form B. The prototropic tautomerism generally exhibited by tetrazole ring systems has been probed using solid-state NMR and it is seen that Irbesartan offers a rare example of desmotropic behaviour, whereby the isolated crystal forms are stable in the solid state yet related through a tautomeric equilibrium in the solution state. Nitrogen-15 solid-state CPMAS data have been used to understand the structures of the stable Irbesartan crystal forms. Form B is shown to undergo an exchange process involving the tetrazole ring. Two-dimensional EXSY 15N spectra are used to understand this process, which involves simultaneous proton-hopping and internal rotation.

Rimonabant Dimorphism and Its Pressure–Temperature Phase Diagram: A Delicate Case of Overall Monotropic Behavior

Crystalline polymorphism occurs frequently in the solid state of active pharmaceutical ingredients, and this is problematic for the development of a suitable dose form. Rimonabant, an active pharmaceutical ingredient developed by Sanofi and discontinued because of side effects, exhibits dimorphism; both solid forms have nearly the same melting temperatures, melting enthalpies, and specific volumes. Although the problem may well be academic from an industrial point of view, the present case demonstrates the usefulness of constructing pressure-temperature phase diagrams by direct measurement as well as by topological approach. The system is overall monotropic and form II is the more stable solid form. Interestingly, the more stable form does not possess any hydrogen bonds, whereas the less stable one does.

Stabilization of rasburicase and physico-chemical characterization of the resulting injectable formulation.

Rasburicase (Fasturtec®/Elitek®) is a new generation of recombinant urate oxidase administred therapeutically by intravenous infusion for the prevention or treatment of hyperuricemia during chemotherapy. To ensure a long storage period, a freeze‐dried formulation was developed to guarantee the molecular integrity and enzyme activity. Screening of potential excipients was the first stage of the preformulation study. The selection was based on stability results (rasburicase solution with excipient) obtained with the isoelectric focusing profiles and residual enzyme activity. The different excipients were classified as stabilising, neutral or destabilising. A stability study was then carried out on different freeze‐dried formulations containing the usual bulking agents for freeze‐drying, excipients with a high glass transition temperature or competitive enzyme inhibitors having a stabilising effect. A mannitol/alanine mixture in phosphate buffer was selected from these preliminary results. Finally, the optimal content of mannitol and alanine in the freeze‐dried powder was determined by an experimental design study. The water content and the appearance of the “cake”, the osmolality, pH, clarity, and enzyme activity of the reconstituted solution were assessed. The formula with a mannitol/alanine ratio of 0.7 was found to be the best composition. Differential scanning calorimetry and ThermoStimulated Current technique experiments were carried out to study the amorphous phase. A glass transition temperature of about 45–50°C was found. Glassy state is known to preserve stability, which was verified by the real stability data. X‐ray diffraction studies have shown that alanine is in a crystallised state and that mannitol remains amorphous. Crystallised excipients participate in forming the structure of the powder and therefore help to prevent any collapse. Amorphous mannitol creates a surrounding medium favourable to the stability of the protein.