(T6158V) Machine Vision Enabled Salt Dissolution Analysis

Purpose: Salt formation is a well-established method to increase the solubility of ionizable drug candidates.¹ However, the possible conversion of salt to its original form of free acid or base – disproportionation – can have a drastic effect on solubility and consequently bioavailability of a drug.² Therefore, during the salt selection process, salt dissolution behavior should be well understood. Improved understanding, the purpose of this study, could be achieved by a method that enables simultaneous screening of small sample amounts and detailed dissolution process analysis.

Methods: The SPA technology consists of a flow-through cell and a custom-made data analysis algorithm (Figure 1). The flow-through cell enables dissolution and imaging of particles under constant flow – sink conditions. Therefore, according to Noyes and Whitney, the dissolution rate becomes dependent on only the concentration of drug in the stagnant layer surrounding the particle. The custom-made algorithm enables analysis of captured images and extracting the solubility data. We have used SPA to monitor dissolution behavior and measure solubility of three model drugs in both salt and free form. Solubility of diclofenac sodium, naproxen sodium and verapamil hydrochloride from pH 2.0 up to pH 9.0 was measured in a fast and low sample consumption ( < 1 mg) manner. For comparison, also shake-flask experiments were conducted. At the end of the shake-flask experiments, the solid-state of the remaining solid was assessed by XRPD and pH was measured.

Results: We have successfully determined the pH-solubility profile, intrinsic solubility, common-ion effect, pKa, pH_max and K_sp values of model compounds. The pH-solubility profile of naproxen sodium and naproxen free acid is presented in Figure 2. Moreover, a potentially higher energy thermodynamic solid-state form of diclofenac free acid, a conversion into needle-shaped naproxen free acid (Figure 3) and an intriguing conversion to liquid verapamil free base were observed upon disproportionation of the respective salts.

Conclusion: The SPA method enabled, with a particle-scale resolution, in situ observation of the disproportionation process and its immediate effect on morphology and solubility of the dissolving species. As such, the method offers a low sample consumption platform for fast yet elaborate characterization of salt dissolution behavior.

References:
1) Serajuddin, A. T. M. Salt formation to improve drug solubility. Adv. Drug Deliv. Rev. 2007, 59, 603–616.
2) Thakral, N. K.; Kelly, R. C. Salt disproportionation: A material science perspective. Int. J. Pharm. 2017, 520, 228–240.

Acknowledgement: J. Stukelj, M. Agopov, J. Yliruusi and S. Svanbäck are shareholders at The Solubility Company Oy.

Figure 2. Solubility versus pH plot of naproxen sodium and naproxen free acid as assessed using the SPA and "shake-flask" methods.


Figure 1. Schematics of the SPA set-up.


Figure 3. Disproportionation of naproxen sodium particles at pH 3 as observed with the SPA method.