Development and optimization of a novel spectroscopic method to monitor crystallization behavior of BCS-II drug

TL;DR

A new spectroscopic method was developed to better monitor and understand the crystallization behavior of a class II drug, improving formulation design and absorption prediction.

Contribution

A novel UV absorbance graphical method (UV-GM) was developed and validated for detecting early nucleation events with higher precision.

Findings

The UV-GM showed higher precision with R2 values of 0.8611–0.9439 compared to other methods.

UV-GM enables characterization of phase separation and supersaturation potential for drug formulation design.

The novel method is cost-effective, time-saving, and reliable for estimating nucleation induction times.

Abstract

This study investigated the crystallization behavior of dextromethorphan hydrobromide, a class II drug, to improve understanding of its supersaturation potential and formulation design. Conventional methods often lack the sensitivity or scalability needed for accurate detection of early nucleation events. To overcome these limitations, a novel process tracks real-time absorbance below turbidity levels to detect early molecular aggregation and phase separation. Crystallization kinetics of the drug was assessed at concentrations of 0.1, 0.2, and 0.3 mg/mL using three analytical techniques, namely, isothermal crystallization (baseline), ultraviolet (UV) absorbance (turbidity monitoring, UV-TM), and an optimized UV absorbance graphical method (UV-GM) (novel process). Induction times were recorded for each method, and statistical analysis was performed. In the descriptive statistics analysis, the one-sample test, and Pearson’s correlation were applied to evaluate consistency, variance, and the strength of association (R2 values) among the methods, thereby validating the reliability and precision of the developed UV-GM. As a result, at drug concentrations of 0.1, 0.2, and 0.3 mg/mL, nucleation induction times for isothermal crystallization were 80, 40, and 20 min; for UV-TM, 30, 20, and 5 min; and for UV-GM, 20, 20, and 10 min. The UV-GM demonstrated the highest precision with R2 values ranging from 0.8611 to 0.9439, compared to UV-TM (0.8223–0.9443) and isothermal crystallization (0.5444–0.6525), confirming itss superior reliability. Thus, it was concluded that the UV-GM offers a consistent, precise, cost-effective, and time-saving approach for estimating nucleation induction time. It also enables characterization of liquid–liquid phase separation, metastable zone width, and supersaturation potential, supporting rational formulation design and prediction of oral absorption in supersaturated systems.

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