Scientific Insights for Informed Action

This Research Recap encapsulates a research study that looked at the effectiveness of a methanol-assisted secondary drying process to help overcome several challenges.

Amorphous solid dispersions (ASD) are used to improve the oral bioavailability of active pharmaceutical ingredients (APIs) that have low aqueous solubility. Spray drying using a volatile organic solvent is one technique used in ASD workflows, yet it typically leaves behind residual levels of solvent that exceed allowable limits according to the International Council for Harmonisation (ICH) guidelines for patient safety.¹ A secondary drying process is therefore used to remove residual solvents.

However, secondary-drying processes often create a manufacturing bottleneck due to the extended length of time required for removal of solvents. For example, secondary-drying by conventional vacuum-only and water-assisted methods can take days.² The physical stability of the product can be at risk during such long drying periods, presenting manufacturers with the need to balance production economics with product stability frameworks.²

An improved secondary drying process is needed to solve these challenges – one that meets ICH guidelines, protects product stability, and optimizes manufacturing timeframes.

Investigation

Lonza scientists confronted this challenge with a solution: introducing another solvent—methanol vapor—to accelerate the removal of spray-drying residual solvents.2 The effectiveness and timeframe of methanol-assisted secondary drying was compared to that of two traditional methods: water-assisted drying and vacuum-only drying. The three methods were all applied to three polymers: PMMAMA (Polymethyl methacrylate-co-methacrylic acid; trade name Eudragit® L100) with residual acetone, PMMAMA with residual tetrahydrofuran (THF), cellulose acetate phthalate (CAP) with residual THF.

All methods used jacketed, agitated-vessel dryers. Samples of the polymers were collected at various points in the secondary-drying process and quantified for water content, residual solvent concentrations, and the methanol mass fraction in the ingoing nitrogen stream of the methanol-assisted drying method.

Residual Solvent Removal

The methanol-assisted secondary drying outperformed both water-assisted and vacuum-only techniques, achieving 2- to 5-times faster solvent removal.

Methanol Removal

Following six hours of methanol-assisted drying, the PMMAMA with residual acetone sample underwent water-assisted drying for three hours to remove residual assisting methanol. The results showed that methanol was reduced from 5% to 0.7% w/w, which is slightly above its ICH limit of 0.3% w/w. It is projected that drying at a higher humidity and/or drying for two additional hours would reduce the residual methanol to below the ICH limit.

Implications

The results of the Lonza study demonstrate a way to transform secondary drying from a multishift bottleneck into an hours-scale step that reduces residual solvents to ICH limits. In addition, the shorter drying time reduces the potential for product instability. Acceleration of the secondary drying process can be a substantial improvement for ASD workflows.

Key Considerations in Solvent Selection

As solvent assisted secondary drying strategies gain interest, material quality and documentation become increasingly important considerations. Key criteria to consider when selecting a solvent provider include the following.

• Pharmacopeia, GMP, and Regulatory Alignment: Solvents must be manufactured and handled in line with current Good Manufacturing Practices and meet the requirements of applicable pharmacopeia and governmental standards, e.g., validated analytical methods, documented quality control systems, audit readiness, data transparency with Certificates of Analysis and purity profiles with consistency between batches.
• Traceability and Change Control: Manufacturers should be able to trace every solvent delivery to the raw materials, production conditions, and quality control test results. The manufacturer must have formal change notification procedures that enable assessment of impacts from such changes on quality control commitments.
• Supply Reliability and Continuity: Look for suppliers with multiple manufacturing sites, strong logistics capabilities, and thorough contingency plans to mitigate supply chain disruption.

References

International Council on Harmonisation (ICH). Harmonisation, I.C.o., Q3C impurities: residual solvents R6, FDA, Editor. 2019. https://www.ich.org/page/quality-guidelines.

Shepard, K. B.; Dower, A. M.; Ekdahl, A. M.; Morgen, M. M.; Baumann, J. M.; Vodak, D. T. Solvent-Assisted Secondary Drying of Spray-Dried Polymers. Pharm. Res. 2020, 37, 156. https://doi.org/10.1007/s11095-020-02890-0.