Bottom-up particle engineering via solvent-mediated polymorphic transformation: a novel strategy for pharmaceutical...

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Chemical Engineering

Background:

• Bictegravir free acid possesses a complex polymorph landscape, posing manufacturing challenges.
• Initial top-down particle engineering (crystallization/micronization) resulted in poor API flowability for long-acting injectable (LAI) formulation development.

Purpose of the Study:

• To develop a novel bottom-up particle engineering strategy for bictegravir API.
• To overcome processability challenges associated with bictegravir's complex polymorph landscape.
• To achieve critical quality attributes for LAI formulation manufacturing.

Main Methods:

• Utilized solvent-mediated polymorphic transformation (SMPT) using hydrated forms as precursors.
• Developed two SMPT processes to convert metastable forms to the most stable polymorph.
• Employed Raman spectroscopy for real-time transformation monitoring.
• Applied multivariate analysis to optimize particle size and operating conditions.

Main Results:

• Achieved API with small particle size and narrow, unimodal particle size distribution.
• Significantly enhanced API flowability, meeting LAI formulation requirements.
• Successfully converted metastable polymorphs and pseudopolymorphs to the stable form.

Conclusions:

• A novel bottom-up particle engineering strategy effectively addresses bictegravir's complex polymorph landscape.
• Harnessing hydrated forms and SMPT provides a versatile method for improving API processability.
• This methodology is applicable to compounds with accessible hydrates and a metastable-to-stable SMPT pathway yielding favorable crystal habits.