Analysis of Two Commercially Available Bortezomib Products: Differences in Assay of Active Agent and Impurity Profile

Abstract

The analytical properties of two commercially available bortezomib products (VELCADE® and Bortenat) were compared using nuclear magnetic resonance, mass spectrometry, high-performance liquid chromatography, and gas chromatography. The data showed differences between the two products. Based on these data, Bortenat samples contained more active ingredients than indicated by the label (mean, 116.5% and 117.9% of label, in 2-mg and 3.5-mg vials, respectively). In comparison, VELCADE samples contained a mean of 99.3% of active ingredient, which was consistent with the approved specification range (US, 90–110%; EU, 95–105%). Clinical data demonstrate that patients exposed to higher than recommended doses of bortezomib on the standard twice-weekly dosing schedule are likely to have an increased risk of major toxicities. Bortenat 2-mg vials contained an isovaleraldehyde impurity; the origin of this is unknown. Additionally, the ratio of boronic acid to boronic ester differed between Bortenat 2 mg (0.27:1) and 3.5 mg (0.13:1) and VELCADE (0.10:1) samples reconstituted in saline indicating that the Bortenat product is not equivalent to the VELCADE product.

Interaction of Model Aryl- and Alkyl-Boronic Acids and 1,2-Diols in Aqueous Solution

“…The low aqueous solubility and poor chemical stability of bortezomib was an issue in its formulation development. [3][4][5][6][7][8] For example, the intravenous and current subcutaneous formulation of bortezomib is a lyophilized formulation from 1% mannitol where mannitol ester formation was confirmed. [3][4][5] The solubility of bortezomib in water is about 0.5-0.6 mg/mL, whereas in the presence of 1% mannitol, a solubility of 4 mg/mL has been reported because of ester formation.…”

“…The interest in boronic acid derivatives as drugs has increased since the introduction and approval of bortezomib, a drug used to treat multiple myeloma, and boronophenylalanine, or BPA, a clinically useful agent for boron neutron capture cancer therapy. The low aqueous solubility and poor chemical stability of bortezomib was an issue in its formulation development . For example, the intravenous and current subcutaneous formulation of bortezomib is a lyophilized formulation from 1% mannitol where mannitol ester formation was confirmed .…”

Antineoplastic drugs and their analysis: a state of the art review

“…306 Byrn et al propose different methods to compare the contents and impurity profile of two pharmaceutical formulations available on the US market. 563 The presence of an additional impurity as well as a different inactive/active form ratio between the two formulations demonstrated that they were not strictly equivalent.…”

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

“…In India there is another commercially available bortezomib product called Bortenat (Natco Pharma, Hyderabad, India), reportedly containing substantially more active entity than declared, potentially resulting in increased toxicity [128].…”