Executive Summary : | Solubility of an active pharmaceutical ingredient (API) is one of the major drivers for its bioavailability. Majority of the new class of drugs are poorly water soluble and require modified dosage forms for optimal in vivo performance. For oral solid dosage forms, formulating an amorphous form of API provides advantage in this regard due to its higher solubility compared to a crystalline counterpart. However, due to its relatively lower thermodynamic stability, there is always a risk of conversion of amorphous state into a crystalline state, hence losing the advantage with higher kinetic solubility. Polymers are commonly used as stabilizers/crystallization inhibitors for API and the resulting binary phase is called as amorphous solid dispersion (ASD). Due to requirement of use of polymers at higher quantities and complex methods of preparations, ASDs suffer from various limitations. A relatively newer technology of co-amorphous dispersions wherein a small molecule is used instead of a polymer can be a good replacement to ASDs. Co-amorphous form provides clear advantage over the polymer based ASDs currently being used at industrial scale. Limited reports on drug-drug and drug-amino acid co-amorphous systems have indicated significant bioavailability enhancement of the primary drug component. In this regard, it is proposed to study a larger set of molecules including specifically designed co-formers that can offer combined benefits of polymer and small molecule additives. The study is aimed at transforming the co-amorphous dispersions into a platform technology. A rational design of such systems would be feasible through a combination of structural studies, molecular level characterization and calculation of interaction energies to build understanding of microstructure of co-amorphous phases, their stabilization mechanism, and events during dissolution. The tendency of moisture uptake or hygroscopicity, which is amongst the most prevalent problems for amorphous dispersions can be addressed by an intelligent choice of co-formers guided by a wealth of structural database, applying principles of structure-property relationship. Proven superiority of such co-amorphous formulations for both the processibility (improved powder properties, reduced hygroscopicity, etc.) and bioavailability (in vivo safety and improved PK parameters) would open up a more robust and commercially viable option in the challenging area of amorphous drug product development. The proposed work would be aimed at (i) establishing a protocol for rational choice of co-formers for preparing co-amorphous dispersions of APIs targeting a commercially viable generic formulation development for the poorly water-soluble APIs going to be off-patent in the near future (e.g. anticancer drug, Apalutamide) and (ii) advanced characterization techniques of amorphous systems understanding phenomenon of polyamorphism for achieving batch-to-batch consistency in materials properties and performance. |