(M0930-09-62) A Tactic for Resolving Lactose Matrix Interference with Residual Heptane in GC Analysis of an API cPAD Formulation

Purpose: Co-Precipitated Amorphous Dispersion (cPAD) is a process for the manufacture of amorphous solid dispersions that has positive differentiating attributes including flexibility and speed compared to more established spray-drying and hot-melt extrusion technologies. To leverage cPAD as a formulation option, a cPAD batch was prepared for in-vivo PK studies ahead of future scale-up for chronic toxicology studies. Challenges for analytical release include the quantitation of small molecule process impurities in the presence of both API and excipients consisting of 23% of API in a mixture of 46% of Hydroxypropylmethylcellulose acetate succinate H-grade (HPMCAS-H), 8% of Hydroxypropyl methylcellulose (HPMC) or hypromellose, and 23% of lactose monohydrate. Levels of residual solvents tetrahydrofuran (THF) and heptane needed to be determined in the cPAD material. While the validated gas chromatography (GC) Fast Universal Method was successfully applied for residual THF, interference from a lactose matrix made quantitation of heptane challenging. Lowering the GC inlet and detector temperature from 240^oC to 190^oC successfully resolved the lactose matrix interference issue without the need for making a drastic change to the GC method. The rationale for this temperature modification tactic will be discussed in this poster.

Methods: Column: DB-624, 20 m × 0.18 mm, 1.0 μm film thickness Temperature Program: 45°C for 1.5 min; 25°C/min to 95°C; 35°C/min to 200°C; hold at 200°C for 0.5 min [6.94 miutes total]
Injector: 190^oC; Split/splitless 75:1
Detector: FID at 190^oC
Carrier Gas: Helium Gas, Constant Flowrate, 1.3mg/mL
Make up Gas Helium, constant flow at 25 mL/min.
Injection Volume: 1 μL

Results: Initial attempts to eliminate matrix interference through varying inlet split ratio and oven temperature program were unsuccessful. Identified that lactose monohydrate melting point (202°C) is close to GC inlet and detector temperature (240°C) found that the melting → hypothesized that melting lactose could stick to inlet and result in matrix interference. Lowering temperature below lactose melting point successfully eliminated the matrix interference.

Conclusion: Modification of temperature parameter enabled accurate quantitation of residual heptane. This approach is an alternate to headspace GC and can be evaluated for any future GC analysis that shows matrix interference.

Inlet and FID Temperature @240oC

Inlet and FID Temperature 190oC