Characterization of Phase Separation Propensity for Amorphous Spray Dried Dispersions

Area of Science:

• Pharmaceutical Sciences
• Materials Science

Background:

• Spray dried dispersions (SDDs) are crucial for enhancing oral bioavailability of poorly soluble drugs.
• Physical stability of SDDs is critical for consistent drug product performance.
• Hydroxypropylmethylcellulose acetyl succinate M grade (HPMCAS-M) is a common polymer for SDD formulations.

Purpose of the Study:

• To demonstrate a generalized screening approach for SDD physical stability using isothermal calorimetry.
• To evaluate the physical stability of SDDs containing two active pharmaceutical ingredients (APIs), BMS-903452 and BMS-986034, formulated with HPMCAS-M.
• To investigate the propensity of SDDs to phase separate and crystallize under humid stress conditions.

Main Methods:

• Isothermal calorimetry (Thermal Activity Monitor, TAM) was used as a primary stress screen at 37 °C and 100% relative humidity (RH) for 3 days.
• Orthogonal analytical techniques including powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR), and solid-state nuclear magnetic resonance (ssNMR) were employed.
• Formulations were analyzed before and after thermal stress to assess physical changes.

Main Results:

• BMS-903452 formulated as an SDD at 30% (wt/wt %) demonstrated exceptional physical stability, withstanding 40 °C/75% RH for 6 months without crystallization or performance loss.
• In contrast, SDDs of the chemical analogue BMS-986034 in HPMCAS-M exhibited phase separation and crystallization upon exposure to 37 °C/100% RH, even at various drug loads.
• Isothermal calorimetry effectively identified phase separation events in BMS-986034 SDDs, which were corroborated by pXRD analysis showing crystalline material.

Conclusions:

• Isothermal calorimetry serves as a valuable screening tool for assessing SDD physical performance and drug-polymer miscibility under humid stress.
• Orthogonal analytical techniques are essential for a comprehensive understanding of SDD physical stability and for confirming calorimetric observations.
• The study highlights the differential physical stability of chemically similar APIs when formulated as SDDs, emphasizing the need for tailored formulation development.