Bottom-up production of injectable itraconazole suspensions using membrane technology

Area of Science:

• Pharmaceutical Manufacturing
• Materials Science
• Chemical Engineering

Background:

• Bottom-up production of active pharmaceutical ingredient (API) crystal suspensions offers superior control over surface properties compared to top-down methods.
• Downstream processing, including separation and concentration, presents significant challenges in API crystal suspension manufacturing.

Purpose of the Study:

• To investigate membrane diafiltration as a unified solution for downstream processing of API crystal suspensions.
• To optimize solvent exchange, excipient levels, and API loading in itraconazole crystal suspensions produced via anti-solvent crystallization.

Main Methods:

• Utilized membrane diafiltration to replace N-methyl-2-pyrrolidone (NMP) with water in API crystal suspensions.
• Adjusted the concentration of d-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and increased the solid concentration of itraconazole.
• Monitored NMP and TPGS levels, TPGS-to-itraconazole ratio, and itraconazole loading.

Main Results:

• Reduced NMP concentration from 9 wt% to below 0.05 wt%, meeting European Medicine Agency guidelines.
• Decreased TPGS concentration from 0.475 wt% to 0.07 wt%, lowering the TPGS-to-itraconazole ratio from 1:2 to less than 1:50.
• Increased itraconazole loading from 1 wt% to 35.6 wt% without compromising crystal stability.

Conclusions:

• Membrane diafiltration provides a one-step solution for downstream challenges in bottom-up API crystal suspension production.
• This technique enhances API loading and reduces residual solvents and excipients, optimizing pharmaceutical manufacturing.
• The findings support the advancement of long-acting API crystal suspensions through scalable bottom-up production.