Abstract

Bisphosphonates are used to treat various skeletal disorders, as they modulate bone metabolism by inhibition of the osteoclast-mediated bone resorption. These compounds are both polar and ionic, and therefore, by using reversed phase liquid chromatography are eluted rapidly. Hydrophilic interaction liquid chromatography (HILIC) is an advantageous technique for the separation and analysis of polar molecules. As the elution order in HILIC is reversed to reversed phase liquid chromatography, a reasonable retention and selectivity for polar compounds is expected. In this work the retention mechanism of three bisphosponates, namely risedronate, tiludronate and zoledronate, was investigated under zwitterionic HILIC conditions. The key factors influencing the retention of the analytes on a zwitterionic ZIC®-pHILIC column (150.0 × 2.1 mm i.d., 200 Å, 3.5 μm) have been systematically investigated. It was found that apart from partition, electrostatic repulsions play an important role in the retention of bisphosphonates. Peak tailing of risedronate and zoledronate was improved by the addition of sodium pyrophosphate in the mobile phase. A zwitterionic hydrophilic interaction liquid chromatography-photodiode array (HILIC-PDA) method was further optimized and fully validated to quantitate risedronate in commercial film-coated tablets. The calibration curves for risedronate showed good linearity (r > 0.9991) within the calibration range tested. The intra- and inter-day coefficient of variation (CV) values was less than 0.6%, while the relative percentage error (%Er) was less than −2.3%. Accelerated stability studies of risedronate conducted under several degradation conditions including hydrolysis, oxidation and heat demonstrated the selectivity of the procedure. A short-run analysis of not more than 6 min allowed the analysis of large samples per day. The applicability of the method for the quantitation of risedronate was demonstrated via the analysis of commercial tablets containing this compound.

Highlights

  • Bisphosphonates belong to a unique class of drugs which are chemically stable analogues of the inorganic pyrophosphate anion, a secondary product of various biochemical processes.Separations 2019, 6, 6; doi:10.3390/separations6010006 www.mdpi.com/journal/separationsThe concentration levels of pyrophosphate anion in blood are associated with the mechanism of bone calcification [1]

  • The three bisphosphonates drugs studied in this work are divided into two groups: two nitrogen-containing compounds and one acidic compound

  • The separation mechanism in Hydrophilic interaction liquid chromatography (HILIC) is more complicated in regards to reversed phase HPLC due to the various kinds of interactions that rule the retention

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Summary

Introduction

Bisphosphonates belong to a unique class of drugs which are chemically stable analogues of the inorganic pyrophosphate anion, a secondary product of various biochemical processes.Separations 2019, 6, 6; doi:10.3390/separations6010006 www.mdpi.com/journal/separationsThe concentration levels of pyrophosphate anion in blood are associated with the mechanism of bone calcification [1]. The skeletal accumulation of bisphosphonates (on the skeleton) depends highly on the disposal of hydroxyapatite binding sites. Non-nitrogen containing bisphosphonates are accumulated into newly formed adenosine triphosphate (ATP) analogues and inhibit ATP-dependent processes, leading to osteoclast apoptosis [2]. Nitrogen containing bisphosphonates inhibit the action of the enzyme farnesyl pyrophosphate synthase (FPPS) enzyme, which is involved in the mevalonate pathway [3]. These drugs have become the therapy of choice for the management of various skeletal disorders such as several types of osteoporosis, hypercalcemia, Paget disease and malignancy metastatic to bone [4]. Despite the well-recognized benefits of bisphosphonates, these drugs may cause osteonecrosis of the jaw [5,6]

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