Detecting absence of crystallinity in solid dosage forms with at-line terahertz process analytical technology.

Area of Science:

• Pharmaceutical Technology
• Spectroscopy
• Materials Science

Background:

• Amorphous solid dispersions (ASDs) improve drug solubility but are prone to recrystallization, making crystallinity absence a key quality attribute.
• Current non-destructive spectroscopic methods for monitoring amorphous dosage forms are limited in application.
• Ensuring the amorphous state is crucial for drug bioavailability and therapeutic efficacy.

Purpose of the Study:

• To establish terahertz time-domain spectroscopy (THz-TDS) as a non-destructive, at-line process analytical technology (PAT) for detecting crystallinity in solid dosage forms.
• To develop and validate simple, physically interpretable methods for assessing the absence of crystallinity using THz-TDS.
• To demonstrate the robustness and practicality of THz-TDS for quality control of amorphous solid dosages.

Main Methods:

• Utilized terahertz time-domain spectroscopy (THz-TDS) for non-destructive analysis of amorphous solid dispersions (ASDs).
• Developed two analytical approaches: absence of phonon absorption peaks and ratio of absorption coefficients.
• Evaluated the methods on salbutamol ASD tablets as a model system, assessing robustness to scattering and excipient effects.

Main Results:

• THz-TDS successfully and unambiguously determined the absence of crystallinity in salbutamol ASD tablets using two distinct methods.
• The developed THz-TDS methods proved robust against scattering and excipient absorption.
• Validation across multiple instruments and long-term storage confirmed the reliability of the THz-TDS approach.

Conclusions:

• Terahertz time-domain spectroscopy (THz-TDS) is a practical and robust at-line PAT for confirming the amorphous state in solid dosage forms.
• THz-TDS offers a feasible strategy for real-time release testing and can serve as a multi-attribute PAT.
• Future research will explore the potential of THz-TDS for predicting dissolution times of amorphous solid dosages.