Preparation of Emulsions by High-Pressure Homogenization

For scale-up evaluation, larger batch (20–200 mL) emulsions were prepared using an EmulsiFlex C5 air-driven high-pressure homogenizer (Avestin Inc., Ottawa, Canada). The homogenizer was immersed in a room temperature water bath (T ∼ 20 °C) and allowed to thermally equilibrate for at least 15 min. The experimental setup is shown in SI Figure 2B. The homogenizer was first primed with water and adjusted to the desired homogenizing pressure (15,000 psi) by regulating the backpressure on the homogenizing valve to approximately 30 psi. Pressure to the feed pump and the homogenizing valve was supplied by a house compressed air feed at approximately 100 psi. After priming, 4 mL of the holdup volume remained in the internal volume of the system. The amount of water in the aqueous phase of each pre-emulsion mixture was reduced by 4 mL to account for this holdup volume.

After priming the system, desired volumes of pre-emulsion aqueous and organic solutions, containing dissolved delamanid and stabilizer(s), were mixed to achieve a final volume of 100 mL. The mixture was manually shaken for 10 s and then added to the homogenizer feed reservoir. The homogenizing valve backpressure was manually regulated during homogenization to maintain the desired homogenizing pressure of 15 000 psi. The homogenized sample was collected after each pass through the system, after which it was readded to the feed reservoir and rehomogenized until the desired number of passes was achieved (typically 3 or 4 passes). Dichloromethane loss during homogenization was measured as a function of batch size and number of passes (SI Figures 3 and 4). Sample temperature was measured for selected batches (SI Figures 5 and 6 and SI Tables 1 and 2). Particle size was measured by dynamic light scattering immediately after emulsification and periodically over 24 h.