Preparation and characterization of amino acids-based trimethoprim salts.

Amr Elshaer,Afzal R Mohammed,Peter Hanson,Tony Worthington,Peter Lambert

doi:10.3390/pharmaceutics4010179

Abstract

Trimethoprim (TMP) is a dihydrofolate reductase (DHFR) inhibitor which prevents the conversion of dihydrofolic acid into tetrahydrofolic acid, resulting in the depletion of the latter and leading to bacterial death. Oral bioavailability of TMP is hindered by both its low solubility and low permeability. This study aims to prepare novel salts of TMP using anionic amino acids; aspartic and glutamic acid as counter ions in order to improve solubility and dissolution. TMP salts were prepared by lyophilisation and characterized using FT-IR spectroscopy, proton nuclear magnetic resonance (1HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). Both the amino acids formed salts with TMP in a 1:1 molar ratio and showed a 280 fold improvement in solubility. Investigation of the microbiological activity of the prepared salts against TMP sensitive Escherichia coli showed that the new salts not only retained antibacterial activity but also exhibited higher zone of inhibition which was attributed to improved physicochemical characters such as higher solubility and dissolution. The results are an important finding that could potentially impact on faster onset of antibacterial activity and reduced therapeutic dose when administered to patients. Studies are underway investigating the effect of ion-pairing TMP with amino acids on the permeability profile of the drug.

Highlights

Trimethoprim (Figure 1) [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine], is a synthetic antibacterial agent belonging to a group of compounds known as diaminopyrimidines
The present study aims to improve the solubility of TMP through salt formation with anionic amino acids, namely glutamic acid and aspartic acid and characterize the prepared salts using Fourier Transform Infrared Spectroscopy (FT-IR)
Prior to preparing TMP salts, a solubility phase diagram was first constructed between TMP and two acidic amino acids; aspartic acid and glutamic acid as previously discussed by ElShaer et al [15]

Summary

Introduction

Trimethoprim (Figure 1) [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine], is a synthetic antibacterial agent belonging to a group of compounds known as diaminopyrimidines It was first synthesized as a dihydrofolate reductase inhibitor (DHFR) and used mainly in combination with sulfonamides to treat pneumonia and urinary tract infections. Low aqueous solubility of TMP [1] reduces the bioavailability from oral formulations. In order to improve TMP dissolution profile, a study conducted by Li et al utilized β-cyclodextrin to form a complex with TMP [2]. The study concluded that the high surface area of contact between TMP and the cyclodextrin along with reduction in drug crystalinity were responsible for improvement in TMP solubility [2]. Investigation of alternative approaches to improve the solubility of TMP would have a high impact on oral administration of the drug

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Conclusion