Evaluation of in vitro dissolution profiles of modified-release metoprolol succinate tablets crushed using mortar and pestle technique

KIR F., Al-Sulaiti F. K., ŞAHİN S.

European Journal of Pharmaceutical Sciences, vol.194, 2024 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 194
  • Publication Date: 2024
  • Doi Number: 10.1016/j.ejps.2024.106694
  • Journal Name: European Journal of Pharmaceutical Sciences
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Keywords: Clinical pharmacokinetics, Crushing effect, Dissolution, Metoprolol, Pharmacokinetics
  • Hacettepe University Affiliated: Yes


Purpose: Clinical practice guidelines advise against crushing modified-release dosage forms. Metoprolol succinate modified-release (MS-MR) tablets are commonly crushed in clinical practice to facilitate administration to patients with swallowing difficulties or using feeding tubes. To date, the effect of this practice remains unexplored. The in vitro effects of crushing commercially available MS-MR tablets were explored using a holistic approach. Methods: Dissolution profiles of crushed versus whole MS-MR tablets were compared. Tablets were crushed to powder state using pragmatic method mimicking hospital practices. For standardization purposes, the same operator, duration (60 seconds), hand, and mortar-pestle apparatus were used. Dissolution studies were conducted per U.S. Pharmacopeia at pH 1.2, pH 4.5, and pH 6.8 with USP apparatus 2 (paddle) at rotation speed of 50 rpm at 37±0.5 °C in 500 mL dissolution media. Samples were withdrawn at predetermined time points. Percent drug dissolved was measured by validated UV–vis Spectrophotometry. Comprehensive analysis of the dissolution data was conducted using model-independent, model-dependent, and ANOVA-based approaches (SPSS v.23 at α=0.05). Similarity (f2) and difference (f1) factors were calculated to compare the dissolution profiles between crushed (CT) and whole tablets (WT). Goodness of fit (GOF) analysis examined the compliance between in vitro dissolution behaviors and several drug release models. Model selection was based on GOF plots, Akaike criteria and adjusted coefficient of determination (R2adj). Imaging and particle size distribution analysis were conducted to examine associated surface and morphologic changes. Results: The dissolution profiles were not similar at pH 4.5 (f2=45.43, f1=18.97) and pH 6.8 (f2=31.47, f1=32.94). CT best fitted with Higuchi (pH 1.2: R2adj=0.9990), Weibull (pH 4.5: R2adj=0.9884), and Korsmeyer-Peppas (pH 6.8: R2adj=0.9719). Contrastingly, WT best fitted with Hopfenberg (pH 1.2: R2adj=0.9986), logistic (pH 4.5: R2adj=0.9839) and first-order (pH 6.8: R2adj=0.9979) models. A significant difference in the dissolution profiles was found between CT and WT using multivariate analysis of variance per time points and between the tablet forms (p=0.004). This was confirmed by unparalleled dissolution profiles. Crushing resulted in variations in particle size and surface morphological changes to the micropellets. Conclusion: Crushing practices change the dissolution profile of MS-MR tablets by deforming the surface morphology of embedded micropellets. Amounts of drug dissolved between CT and WT were not the same at the compared time points across gastrointestinal pH ranges. This suggests potential clinical impact on plasma-concentration profiles of critically ill patients using feeding tube.