# Effect of Spinacia oleracea on In Vitro Disintegration and Dissolution of Clopidogrel Bisulfate Tablets

## TL;DR

This study shows that spinach can reduce the dissolution of clopidogrel tablets in lab conditions, possibly affecting drug effectiveness.

## Contribution

The study identifies spinach as a potential inhibitor of clopidogrel dissolution through pH changes and physical interactions.

## Key findings

- Clopidogrel dissolution decreased with higher spinach concentrations in both HCl and phosphate buffers.
- Spinach increased pH and solution viscosity, reducing drug release and tablet disintegration.
- In vitro–in vivo correlations were weak, suggesting further in vivo studies are needed.

## Abstract

Drug–food interactions may compromise therapeutic efficacy, particularly for life‐saving medications such as anticoagulants. Changes in gastric fluid properties, including pH modification and surface film formation, can alter drug dissolution and release. This study evaluated a potential interaction between clopidogrel and spinach and explored the underlying mechanisms. In vitro disintegration and dissolution studies were conducted using HCl and phosphate buffers with and without 5% and 7.5% spinach extract. Drug release was quantified by high‐performance liquid chromatography (HPLC), with six media conditions analyzed in triplicate. Disintegration testing was performed in simulated gastric and intestinal fluids and in the presence of spinach leaves to assess the effect of film formation on tablet wetting and disintegration. In vitro–in vivo extrapolation (IVIVE) was assessed using GastroPlus software. Clopidogrel dissolution decreased with increasing spinach concentration in both media. In HCl buffer, dissolution declined from 99% to 94% and 89%, while in phosphate buffer it decreased from 71% to 66% and 56%. These effects were associated with increased pH (HCl: 1.91, 2.83, 2.98; phosphate: 6.81, 8.83, 6.84), increased solution viscosity, 17.63 to 17.67 and 17.70 in HCl buffer, and from 17.44 to 17.50 and 17.54 in phosphate buffer. Moreover, reduced fluid penetration was due to spinach leaves coverage. IVIVE analysis showed weak correlations (R
2 = 0.74 in HCl and 0.69 in phosphate buffer). Spinach reduced clopidogrel dissolution in vitro, with statistically significant effects at 5% spinach in HCl buffer (ANOVA test, p‐value 0.019) and 7.5% in phosphate buffer (ANOVA test, p‐value < 0.001). This interaction appears to be mediated by pH alteration, physical film formation, and potentially metal–drug complexation. Confirmation through in vivo studies is warranted.