(287c) Reactive Agglomeration: Improving Processability of Amorphous Solids in Precipitation Process

Production of amorphous solids using fast solvent evaporation methods or anti-solvent precipitation pose significant challenges in terms of processability, thermal stability and yield. Fast solvent evaporation using a spray dryer or a rota-vapour are limited by scale and require volatile solvents with adequate solubility. Alternatively, amorphous solids are generated through anti-solvent precipitation, wherein high supersaturation leads to formation of fine particles and create operational difficulties for filtration as large scales. Researchers have explored spherical agglomeration process to enlarge the size of precipitating solids; however it has limited choice of bridging solvents and critical process susceptibility to multiple variables such as wettability and residual solvent content of the solids etc. These challenges necessitate development of a large-scale feasible process for generation of amorphous solids.

We present here an innovative approach of coupling “anti-solvent precipitation with reactive crystallization” for generation of amorphous solids. In the present study, water-insoluble drug was dissolved in a weak acid (water-miscible) followed by gradual dropwise addition to a weak aqueous base solution. Each droplet, act as a template, wherein (I) diffusion/mixing of acid to aqueous base solution, (ii) reaction of acid and base and (iii) precipitation of the drug occurs instantaneously within the limiting boundary of receding droplet. These simultaneous events enable high-localized supersaturation and uneven precipitation throughout the droplet template. Diffusing solvent from the droplet template acts as solution channels linking the precipitated solids in the close vicinity. Drug precipitation in those channels forms bridges among the solids resulting in larger agglomerates of irregular shapes. These larger agglomerates formed at high-localized supersaturation are amorphous in nature and easy to filter. Use of weak acid and base decrease the probability of forming salts.

As a case study, a poorly water-soluble drug was selected for which generation of an amorphous form is desirable as it improves the bioavailability. Preliminary solubility screening was performed to identify suitable acid and its corresponding base. Drug was dissolved in the acid and thereafter added dropwise in an aqueous solution of weak base. Base quantity was stiochiometrically determined and a higher molar equivalent was used to ensure complete acid-base reaction. PATs (Process Analytical Technologies) such as FBRM (Focused Beam Reflectance Measurement) and PVM (particle vision microscopy) enabled real-time tracking of particle evolution and their size distribution. In comparison with reverse anti-solvent addition and spherical agglomeration, larger aggregates and lesser fines were observed by reactive agglomeration. The obtained solids were also characterized using several off-line analytical tools such as SEM (scanning electronic microscope), PXRD (powder x-ray diffraction) and MDSC (modulated-differential scanning calorimetry) which indicate the formation of large, irregular shaped aggregates with amorphous nature. The filtration rate of the agglomerates were measured using a standard filter apparatus and resulting filtration profiles showed less cake resistance and faster filtration rate. The feasible process thus developed was further optimized and scaled up to manufacturing scale.