# Green manufacturing of amoxicillin trihydrate: a malic acid-assisted crystallization framework enhanced by Taguchi–ANN optimization

## TL;DR

This study presents a green method for making amoxicillin trihydrate using malic acid and advanced optimization techniques to improve purity, yield, and crystal quality.

## Contribution

A novel green crystallization framework using malic acid and Taguchi–ANN optimization for sustainable AMCT production.

## Key findings

- Malic acid reduces crystallite size from 85.9 to 66.4 nm and increases surface area from 5.27 to 11.07 m2 g−1.
- The ANN model achieved R2 > 0.99 for predicting purity and yield under optimized conditions.
- AMCT crystals with 99.21% purity and 61.82% yield were obtained using the proposed method.

## Abstract

Industrial production of amoxicillin trihydrate (AMCT) often suffers from low yield, impurity inclusion, and inconsistent crystal morphology. This study introduces a scalable green crystallization strategy using malic acid as a biodegradable habit modifier, developed as part of an improved eco-friendly AMCT manufacturing framework. A hybrid optimization approach integrating Taguchi design with Artificial Neural Network (ANN) modeling was employed to capture both linear and nonlinear interactions among critical process variables. Multi-technique characterization (XRD, FTIR, DSC, BET, LC-MS) confirmed that malic acid preserves lattice integrity while substantially refining particle attributes, reducing crystallite size from 85.9 to 66.4 nm and increasing specific surface area from 5.27 to 11.07 m2 g−1. This significant increase in surface area is a key physical factor theoretically favoring improved dissolution kinetics. The ANN model exhibited excellent predictive performance (R2 > 0.99) for both purity and yield. Under optimized conditions (2.5 M malic acid, pH 5.5, 60 min, 1500 rpm), AMCT crystals were obtained with 99.21% purity and 61.82% yield. These results demonstrate a robust, data-driven framework for sustainable AMCT production, providing a high-performance alternative to conventional mineral-acid-based crystallization methods.

Malic acid-assisted crystallization combined with Taguchi–ANN optimization improves yield, purity, and crystal quality of amoxicillin trihydrate.