Solvent-Assisted Secondary Drying of Spray-Dried Polymers

Abstract

Purpose: The purpose of this work is to introduce solvent-assisted secondary drying, a method used to accelerate the residual solvent removal from spray dried materials. Spray-drying is used to manufacture amorphous solid dispersions, which enhance the bioavailability of active pharmaceutical ingredients (APIs) with low aqueous solubility. In the spray-drying process, API and excipients are co-dissolved in a volatile organic solvent, atomized into droplets through a nozzle, and introduced to a drying chamber containing heated nitrogen gas. The product dries rapidly to form a powder, but small amounts of residual solvent (typically, 1 to 10 wt%) remain in the product and must be removed in a secondary-drying process. For some spray-dried materials, secondary drying by traditional techniques can take days and requires balancing stability risks with process time.

Methods: Spray-dried polymers were secondary dried, comparing the results for three state-of-the-art methods that employed a jacketed, agitated-vessel dryer: (1) vacuum-only drying, (2) water-assisted drying, or (3) methanol-assisted drying. Samples of material were pulled at various time points and analyzed by gas chromatography (GC) and Karl Fischer (KF) titration to track the drying process.

Results: Model systems were chosen for which secondary drying is slow. For all cases studied, methanol-assisted drying outperformed the vacuum-only and water-assisted drying methods.

Conclusions: The observation that methanol-assisted drying is more effective than the other drying techniques is consistent with the free-volume theory of solvent diffusion in polymers.

Keywords: amorphous solid dispersion; diffusion; eudragit L100; secondary drying; spray-drying.

Fig. 1

Modified Ekato VPT agitated vacuum dryer set up for water- or methanol-assisted secondary drying.

Fig. 2

Glass transition temperature of PMMAMA polymer with absorbed solvents.

Fig. 3

Secondary drying for PMMAMA with residual acetone using three techniques (left), and uptake of assisting solvent (right). The grey shaded area indicates the target concentration ± 0.5% for assisting solvent absorbed during the experiment.

Fig. 4

Secondary drying for PMMAMA with residual THF using three techniques (left, and uptake of assisting solvent (right). The grey shaded area indicates the target concentration ± 0.5% for assisting solvent absorbed during the experiment. ICH limit is 0.076%, not shown.

Fig. 5

Secondary drying of CAP with residual THF using three techniques (left), and uptake of assisting solvent (right). The grey shaded area indicates the target concentration ± 0.5% for assisting solvent absorbed during the experiment.

Fig. 6

Normalized residual solvent (concentration of residual solvent during methanol-assisted drying divided by concentration of residual solvent during water-assisted drying) for the three polymer/solvent systems studied. Dotted line represents equal performance between methanol-assisted and water-assisted drying.