Category: Formulation and Quality
Purpose: Lipid drug formulations are a cost effective strategy to address poor aqueous solubility of Active Pharmaceutical Ingredients (APIs), creating a molecularly dispersed dosage form that produces a stable lipid-drug emulsion upon entering the gastrointestinal tract. Nevertheless, identifying a high drug load, lipid-based formulation is a costly and time consuming process requiring trial and error. The API must remain in an amorphous state during processing and in the finished drug product; precipitation or aggregation of the API could impact the bioavailability and drug product efficacy. There is a critical need to develop Process Analytical Technologies (PATs) that can quickly monitor and assess Critical Quality Attributes (CQAs) during development. To address this need, we’ve developed a strategy using Raman Spectroscopy as a high-throughput solubility screening platform to identify optimal lipid based drug formulations and serve as a PAT to monitor drug product CQAs.
Methods: We used Raman Spectroscopy as a development platform to streamline formulation and process development for lipid-based formulations for APIs with poor aqueous solubility. This was accomplished by analyzing several lipid based drug formulations for drug molecules with demonstrated solubility issues. Spectral scans were performed on the formulated lipid matrices containing a specific drug molecule and different combinations of lipid based excipients. An algorithm was developed using the Python coding language to clean and analyzed the multiple sets of spectral data. Exploratory data analysis was conducted by Principle Component Analysis (PCA) and Partial Least Squares (PLS) Regression to quantify API solubility in the lipid matrix and predict formulations in which the API was completely in solution. Solubility of the API in the lipid matrix was confirmed using standard methods to evaluate drug solubility in lipid excipients, specifically: assay by High Performance Liquid Chromatography (HPLC), Dynamic Scanning Calorimetry (DSC) and Polarized Light Microscopy (PLM).
Results: The predicted API solubility determined by the algorithm and assay by HPLC were compared by linear regression. For less complex formulations containing one API and up to 3 excipients, a R2 between 0.80 – 0.90 could be obtained. These results indicate that exploratory data analysis could be used to develop models capable of quickly analyzing Raman spectra and evaluate lipid-based drug formulations. Raman Spectroscopy along with such models can be used as a PAT to monitor and define CQA during process development. Figure 1 shows a flow chart showing how Raman Spectroscopy can be utilized to streamline development of lipid-based formulations and process development.
Conclusion: We’ve demonstrated a strategy to use Raman Spectroscopy as a platform to enable high-throughput solubility screening of multiple lipid based drug formulations. This platform can be used to streamline early development of lipid based drug formulations, identifying formulations that maintain the API in an amorphous state. The platform can further be used during process development as a PAT to monitor and define drug product CQAs. This platform will potentially streamline drug development during multiple stages of development through commercialization.
Venkata Voleti– Cincinnati, Ohio