Mechanosynthesis of Stable Salt Hydrates of Allopurinol with Enhanced Dissolution, Diffusion, and Pharmacokinetics

Richu Bagya Varsa S; Noopur Pandey; Animesh Ghosh; Anubha Srivastava; Pavan Kumar Puram; Sai Teja Meka; Vladimir V Chernyshev; Palash Sanphui

doi:10.1021/acsomega.3c05263

Mechanosynthesis of Stable Salt Hydrates of Allopurinol with Enhanced Dissolution, Diffusion, and Pharmacokinetics

ACS Omega. 2023 Sep 7;8(37):34120-34133. doi: 10.1021/acsomega.3c05263. eCollection 2023 Sep 19.

Authors

Richu Bagya Varsa S¹, Noopur Pandey², Animesh Ghosh², Anubha Srivastava³, Pavan Kumar Puram⁴, Sai Teja Meka⁴, Vladimir V Chernyshev^{5

6}, Palash Sanphui¹

Affiliations

¹ Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Chennai, Tamil Nadu 603203, India.
² Solid State Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
³ Department of Physics, University of Lucknow, University Road, Lucknow 226007, Uttar Pradesh, India.
⁴ Foundation for Neglected Disease Research, Doddaballapur, Bangalore 561203, India.
⁵ Department of Chemistry, M. V. Lomonosov Moscow State University, 1-3 Leninskie Gory, Moscow 119991, Russian Federation.
⁶ A. N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, 31 Leninsky Prospect, Moscow 119071, Russian Federation.

Abstract

Allopurinol (ALO) is a medication that treats gout and kidney stones by lowering uric acid synthesis in the blood. The biopharmaceutics classification system (BCS) IV drug exhibits poor aqueous solubility, permeability, and bioavailability. To overcome the bottlenecks of ALO, salts with maleic acid (MLE) and oxalic acid (OXA) were synthesized using the solvent-assisted grinding method. The novel multicomponent solids were characterized by PXRD, DSC, TGA, FT-IR, and SEM images. The crystal structures of these salts with variable stoichiometry were obtained using Rietveld refinement from the high-resolution PXRD data. The proton from the dicarboxylic acid is transferred to the most basic pyrimidine "N" of ALO. The N-H···N hydrogen-bonded ALO homodimer is replaced by the N⁺-H···O^- ionic interactions in ALO-OXA (2:1:0.4) and ALO-MLE (1:1:1) salt hydrates. The organic salts improved solubility and dissolution up to 5-fold and the diffusion permeability up to 12 times compared to the native drug in a luminal pH 6.8 phosphate buffer medium. The salt hydrates were exceptionally stable during storage at 30 ± 5 °C and 75 ± 5% relative humidity. Superior dissolution and diffusion permeability of the ALO-MLE salt resulted in improved pharmacokinetics (peak plasma concentration) that offers a promising solid dosage form with enhanced bioavailability and lower dosage formulation.