研究目的
To elucidate spray dried dispersion dissolution mechanisms using Focused Beam Reflectance Measurement (FBRM) and assess the contribution of polymer chemistry and particle properties to performance.
研究成果
The study demonstrated that FBRM, used orthogonally with UV analysis, can categorize SDD dissolution mechanisms into erosion or disintegration. For the 25% BMS-708163/HPMC-AS SDD, an erosion mechanism was identified, with polymer succinoyl substitution, particle size, and surface area significantly impacting dissolution rates. This approach provides a screening tool for risk assessment and control strategy development in pharmaceutical formulations.
研究不足
The study focused on a specific API (BMS-708163) and polymer system (HPMC-AS), limiting generalizability. Physical stability data were not shown, and the impact of other excipient characteristics like viscosity was not explored. The FBRM method may not detect colloidal species below its detection limit, and the relationship between bulk density and dissolution was not established.
1：Experimental Design and Method Selection:
The study used a design to vary HPMC-AS polymer substitution and SDD particle properties through spray drying. FBRM and UV spectroscopy were employed orthogonally to monitor particle counts and API dissolution in USP 2 apparatus. A first-order kinetic model was fitted to dissolution data using MATLAB.
2：Sample Selection and Data Sources:
Eleven SDD batches were manufactured with 25% w/w BMS-708163 and various HPMC-AS grades, divided into Group 1 (varied polymer properties) and Group 2 (varied particle properties). Samples were from clinical supplies and lab-scale preparations.
3：List of Experimental Equipment and Materials:
Equipment included a PSD-1 spray drier, Malvern Mastersizer MS 2000 for particle size analysis, Quantachrome ASiQ2 for surface area measurement, USP 2 dissolution apparatus (VanKel), FBRM G400 probe (Mettler Toledo), and Fibre Optic UV probe (Opt-Diss). Materials included BMS-708163 API, HPMC-AS polymers from Shin Etsu, and dissolution media (pH
4：8 potassium phosphate buffer with 1% Brij). Experimental Procedures and Operational Workflow:
SDDs were spray-dried under varied conditions. Particle size, bulk density, and surface area were measured. Dissolution tests were conducted at 37°C, 75 rpm, with UV measurements every 10 seconds for 60 minutes and then every 30 minutes up to 120 minutes. FBRM monitored particle counts in situ with measurements every 10 seconds.
5：Data Analysis Methods:
Dissolution rates were calculated using a first-order model in MATLAB. FBRM data were log-transformed to calculate particle count decay rates. Statistical analysis included multiple linear regression to identify significant factors.
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