(14a) Sustained Supersaturation of Erlotinib Sdd Ternary Amorphous Systems

As more low-solubility drug candidates enter the pharmaceutical development pipeline, the need for solubilization-enhancing technologies is ever greater. In an amorphous dispersion, the solubility of a drug is enhanced by kinetically trapping the molecules into the higher-energy amorphous state, often realizing a 5-50x enhancement in solubility relative to the crystalline state. Spray dried dispersions (SDDs), containing amorphous drug and a concentration-enhancing matrix polymer are a scalable and mature technology which takes advantage of the amorphous drug solubility enhancement. Typically, an SDD must meet numerous performance metrics including rapid dissolution rate, sustainment of supersaturation, physical stability, chemical stability and manufacturability. We have successfully formulated over 1,000 low-solubility compounds as SDDs over the past two decades.

Despite this success, for some compounds it can be challenging to meet all of the performance requirements using only one excipient in the SDD system. In these cases, a multi-component amorphous system approach may warranted, in which two excipients are utilized, each tailored to separately achieve specific performance metrics. In this presentation, we discuss the case study of erlotinib, a rapidly-crystallizing compound which requires both fast dissolution and sustained supersaturation. In this case, erlotinib SDD is spray dried with a fast-dissolving matrix polymer (Eudragit L100) and formulated with a crystallization-inhibiting polymer (HPMC) to maximize both dissolution rate and sustainment. The combination of Eudragit L100 and HPMC succeeds by increasing the in vitro test AUC over ten-fold compared to binary SDD formulations.