- 4:30 PM

Mapping the State of a Pharmaceutical Co-Precipitation Process: an Integrated Process Analytical Technology (Pat) Approach

Huiquan Wu and Mansoor A. Khan. Cder, FDA, 10903 New Hampshire Ave, White Oak LS 64, Room 1080, HFD-940, Silver Spring, MD 20993

In the area of pharmaceutical formulation development, co-precipitation of poorly soluble drugs with polymers as an important technique to improve drugs' dissolution and absorption since 1960s has been modified to prepare extended release preparations in recent years. Some reports are available in the open literature includes optimization of process variables for the preparation of ibuprofen co-precipitates with Eudragit S100, screening of process and formulation variables for the preparation of extended release Naproxen tablets with Eudragit L 100-55, etc. However, not much work has been reported in the open literature regarding using cutting-edge PAT tools to gain detail process information and process understanding for co-precipitate process.

On the other hand, crystallization as a critical unit operation for the pharmaceutical API production has attracted a lot of attentions. Online process analyzers offer excellent opportunities to gain detailed process information such as illustrating the progress of the multi-phase process and elaborating the sequential events that take place during the process.

In this work, an integrated online process monitoring approach was developed for a pharmaceutical co-precipitate PAT application. The model drug naproxen with polymer Eudragit L100 was co-precipitated using a binary solvent system. The co-precipitate process was followed in real time using an on-line acoustic-optic tunable-filter (AOTF) based Near Infrared (NIR) spectrometer coupled with near real-time measurement of turbidity of the 4-component system. By examining the NIR spectra and turbidity curve together, sequential events such as incubation, nucleation, and growth during the process can be identified, such that the state of the process can be visualized in a three-dimensional space. The final co-precipitate product can be characterized using off-line NIR. The composition of the final co-precipitate product can be quantified through pre-established multivariate calibration model in this work. This work provides a concrete case study that focuses on process for pharmaceutical PAT application.