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Impurity profiling of ibandronate sodium by HPLC-CAD.

Journal of pharmaceutical and biomedical analysis (2015-06-21)
Oliver Wahl, Ulrike Holzgrabe
ABSTRACT

The modern bisphosphonate drug ibandronate sodium, a challenging candidate for impurity profiling, was analyzed using high performance liquid chromatography (HPLC) combined with corona charged aerosol detection (CAD). Separation was achieved on a mixed mode column combining hydrophobic C18 and strong anion exchange retention mechanisms using a mass spectrometer compatible volatile mobile phase consisting of trifluoroacetic acid and acetonitrile while gradient elution was applied. The method was validated following the ICH guideline Q2(R1) and found suitable for the assessment of ibandronate's related substances. The observed CAD-response for all identified impurities was linear (R(2)>0.995) over a small concentration range (0.05-0.25) and a quantification limit of at least 0.03% was found. Four batches of two different manufacturers were tested by means of the method. None of the batches contained a single impurity above 0.05%. The major impurities of all batches were the synthesis by-products N-desmethyl- and N-despentyl ibandronate as well as N,N-dimethyl pamidronate.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ethanol, JIS first grade, 94.8-95.8%
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Hydrochloric acid solution, 1 M
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Acetone, SAJ first grade, ≥99.0%
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Hydrochloric acid solution, 6 M
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Methanol, SAJ first grade, ≥99.5%
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Acetone, ≥99.5%, for residue analysis
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Methanol, JIS 300, ≥99.8%, for residue analysis
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Hydrochloric acid solution, 12 M
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Hydrochloric acid solution, 0.2 M
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Hydrogen peroxide solution, SAJ first grade, ≥30.0%
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Hydrochloric acid solution, 0.05 M
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Acetone, for residue analysis, ≥99.5%
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Chloroform, JIS 300, ≥99.0%, for residue analysis
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Hydrochloric acid, SAJ first grade, 35.0-37.0%
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Hydrochloric acid solution, 0.02 M
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Hydrogen chloride solution, 3 M in cyclopentyl methyl ether (CPME)
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Methanol, SAJ special grade
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Acetone, for residue analysis, JIS 5000
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Acetone, suitable for HPLC
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Acetone, JIS special grade, ≥99.5%
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Chloroform, JIS special grade, ≥99.0%
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Chloroform, SAJ super special grade, ≥99.0%
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Chloroform, SAJ first grade, ≥99.0%, contains 0.4-0.8% ethanol
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Methanol, NMR reference standard
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Methanol, HPLC Plus, ≥99.9%, poly-coated bottles
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Acetonitrile solution, contains 0.05 % (w/v) ammonium formate, 5 % (v/v) water, 0.1 % (v/v) formic acid, suitable for HPLC
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Chloroform, suitable for HPLC
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Hydrochloric acid solution, 32 wt. % in H2O, FCC
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Acetonitrile solution, contains 10.0% acetone, 0.05% formic acid, 40.0% 2-propanol
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Chloroform, ACS reagent, ≥99.8%, contains amylenes as stabilizer