Response Surface Optimization of Croscarmellose Sodium Synthesis: Influence of Crosslinking Parameters on Swelling and Water Retention Properties

Croscarmellose sodium (CCS) is a crosslinked cellulose-based superdisintegrant, widely utilized to enhance the disintegration and dissolution behavior of drugs from pharmaceutical solid dosage forms. In the present study, CCS was synthesized through controlled crosslinking of sodium carboxymethyl cellulose (CMC) by one-step synthesis and optimized using Response Surface Methodology (RSM) based on the Box–Behnken Design (BBD). The effects of four independent variables, namely isopropyl alcohol (IPA) concentration (70–100% v/v), reaction time (2–4 h), reaction temperature (50–70 °C), and concentration of crosslinking agent (CLA) (glycolic acid used as the CLA) (10–20% w/w of CMC weight), on swelling index (SI) and water retention capacity (WRC) of synthesized CCS were systematically evaluated. A total of 29 experimental runs, each representing a unique combination of reaction conditions generated by a three-level Box–Behnken Design (BBD) using Design-Expert® software, were conducted to synthesize CCS samples. SI and WRC of each synthesized CCS sample were subsequently measured and used to develop statistically validated predictive models and identify the optimal synthesis conditions. The successful formation of croscarmellose sodium was critically confirmed by Fourier Transform Infrared (FTIR) spectroscopy. Analysis of variance (ANOVA) demonstrated that the developed models were statistically significant, with good predictive capability for both swelling index and water retention responses. A quadratic model adequately described the swelling index (R2 = 0.9041, adjusted R2 = 0.8083, p < 0.0001), whereas a linear model was selected for WRC (R2 = 0.6112, adjusted R2 = 0.5463, p < 0.0001). Reaction time and CLA concentration exhibited substantial influence on the functional properties of the synthesized CCS compared to other factors. The optimized synthesis conditions were identified as 93.23% IPA concentration, 4 h reaction time, 70 °C reaction temperature, and 10% CLA concentration. Under these conditions, the predicted swelling index and water retention capacity were 7.529 mL/g and 443.85%, respectively. Response surface analysis further revealed significant interaction effects among the synthesis variables, particularly between IPA concentration and reaction time. The findings of this study demonstrate that RSM-BBD is an effective statistical approach for optimizing cellulose-based superdisintegrant synthesis and provide valuable insights into the structure–property relationships governing the hydration and swelling behavior of CCS. The optimized CCS synthesized in this research thus shows potential for application as a high-performance pharmaceutical superdisintegrant in immediate-release tablet formulations.