Monophasic coamorphous sulpiride: a leap in physicochemical attributes and dual inhibition of GlyT1 and P-glycoprotein, supported by experimental and computational insights

Abstract

Study aimed to design and development of a supramolecular formulation of sulpiride (SUL) to enhance its solubility, dissolution and permeability by targeting a novel GlyT1 inhibition mechanism. SUL is commonly used to treat gastric and duodenal ulcers, migraine, anti-emetic, anti-depressive and anti-dyspeptic conditions. Additionally, Naringin (NARI) was incorporated as a co-former to enhance the drug’s intestinal permeability by targeting P-glycoprotein (P-gp) efflux inhibition. NARI, a flavonoid has diverse biological activities, including anti-apoptotic, anti-oxidant, and anti-inflammatory properties. This study aims to design and develop a supramolecular formulation of SUL with NARI to enhance its solubility, dissolution, and permeability by targeting a novel GlyT1 inhibition mechanism, extensive experimental characterization was performed using solid-state experimental techniques in conjunction with a computational approach. This approach included quantum mechanics-based molecular dynamics (MD) simulation and density functional theory (DFT) studies to investigate intermolecular interactions, phase transformation and various electronic structure-based properties. The findings of the miscibility study, radial distribution function (RDF) analysis, quantitative simulations of hydrogen/π–π bond interactions and geometry optimization aided in comprehending the coamorphization aspects of SUL-NARI Supramolecular systems. Molecular docking and MD simulation were performed for detailed binding affinity assessment and target validation. The solubility, dissolution and ex-vivo permeability studies demonstrated significant improvements with 31.88-fold, 9.13-fold and 1.83-fold increments, respectively. Furthermore, biological assessments revealed superior neuroprotective effects in the SUL-NARI coamorphous system compared to pure SUL. In conclusion, this study highlights the advantages of a drug-nutraceutical supramolecular formulation for improving the solubility and permeability of SUL, targeting novel schizophrenia treatment approaches through combined computational and experimental analyses.

Communicated by Ramaswamy H. Sarma

Keywords:

• Sulpiride
• naringin
• co-amorphous
• GlyT1 inhibition
• P-gp efflux
• DFT
• In-silico studies 

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

Acknowledgments

• The authors would like to acknowledge the financial support from the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Govt. of India.

• History of previous version of our study’s preprint is available on Research Square (© Research Square 2023). Ekta R. Pardhi, Devendra Singh Tomar, Rahul Khemchandani et al. A study of monophasic supramolecular formulation of SUL with P-gp efflux inhibitor to enhance solubility and intestinal permeability with molecular modeling insights, 31 May 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-2964902/v1].

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.