State-of-the-Art Computational Investigation of Long-release Hydrochlorothiazide Formulation for Myocardial Infarction Prevention.

Abstract

Aim: The present investigation aims to employ a quality-by-design (QbD) approach to prioritize critical factors for the drug formulation and, thus, the number of experimental runs to be performed for the identification of critical quality attributes (CQA) while maintaining an adequate risk profile.

Background: Hydrochlorothiazide (HCT), a diuretic class of drug, is often recommended with antihypertensives to prevent the problem of early morning heart attack (myocardial infarction).

Method: Prior knowledge was systematically applied during the early development phase of risk assessment using the fishbone diagram and qualitative risk assessment, resulting in 17 factors that may influence the final quality of long-action hydrochlorothiazide tablets. A quantitative evaluation using Failure Mode Effect and Criticality Analysis (FMECA) was conducted on 11 preselected variables with medium and high risk, employing the Plackett-Burman (PB) design.

Results: Utilizing logical reasoning, literature review, and preliminary data analysis, we minimized the number of experiments to a manageable level and further streamlined them using FMECA. Plackett-Burman design findings revealed that only three critical factors impacted selected quality attributes.

Conclusion: The quality risk management tool has successfully helped to identify critical variables affecting critical quality attributes and reduce the number of experimental runs to a manageable level.