provide a more comprehensive scientific basis for the overall evaluation of vildagliptin quality.
Product Information：
Product Number: B047002
English Name: Bromocriptine EP Impurity B
English Alias: (6aR,9R)-N-((2R,5S,10aS,10bS)-10b-hydroxy-5-isobutyl-2-isopropyl-3,6-dioxooctahydro-2H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
CAS Number: 511-09-1
Molecular Formula: C32H41N5O5
Molecular Weight: 575.70
Advantages：
High purity and precise structural confirmation：HPLC purity ≥99.0%, with the structure confirmed by 1H NMR, 13C NMR, HRMS, and single-crystal X-ray diffraction, meeting the strict standards of the European Pharmacopoeia (EP) for impurity reference substances, enabling accurate qualitative and quantitative analysis.
Good chemical stability：Stable for up to 36 months when stored at -20°C in the dark; in an acetonitrile - water mixed solution system, the degradation rate is <1% after being placed at room temperature for 14 days, satisfying the needs of long-term quality monitoring and stability studies.
Strong process relevance：As a key side-reaction impurity in bromocriptine synthesis, it can accurately reflect the process control of cyclization, condensation, and other reaction steps, providing a clear direction for process optimization.
Applications：
Pharmaceutical quality control：Used for the detection of Bromocriptine EP Impurity B in bromocriptine active pharmaceutical ingredients (APIs) and formulations by LC - MS/MS or HPLC, controlling its content according to EP standards to ensure that the drug quality meets the specifications of dopamine receptor agonist drugs.
Synthesis process optimization：During bromocriptine production, by monitoring the content of this impurity and adjusting parameters such as the temperature of the cyclization reaction and the type of catalyst (for example, reducing the reaction temperature from 80°C to 60°C reduces the impurity content from 0.8% to 0.1%), the synthesis process can be optimized to reduce impurity formation.
Development and validation of analytical methods：As a standard reference substance, it is used to establish and validate specific detection methods, such as ultra-performance liquid chromatography - diode array detection (UPLC - DAD), to achieve accurate quantification of impurities (limit of quantitation LOQ = 0.05μg/mL).
Toxicological and safety research：Provides samples for evaluating the potential impact of this impurity on drug safety, facilitating in vitro cytotoxicity tests and in vivo pharmacokinetic studies to meet the requirements for impurity safety assessment in drug registration applications.
Background Description：
Bromocriptine, an ergot alkaloid derivative, is a dopamine receptor agonist clinically used for the treatment of Parkinson's disease, hyperprolactinemia, and other diseases. During bromocriptine synthesis, due to complex multi-step reactions (such as cyclization, condensation, and substitution reactions), impurities like Bromocriptine EP Impurity B may be generated if reaction conditions are not properly controlled. According to the European Pharmacopoeia (EP) and relevant ICH guidelines, to ensure the safety, effectiveness, and quality control of drugs, strict detection and limit control of such process-related impurities are required.
Research Status：
Development of detection technology：Currently, UPLC - MS/MS is the mainstream method, using a C18 column (1.7μm, 2.1×100mm) with a mobile phase of 0.1% formic acid aqueous solution - acetonitrile for gradient elution. Combined with the multiple reaction monitoring (MRM) mode, the limit of detection (LOD) can be as low as 0.01ppm, enabling precise detection of trace impurities.
Study on formation mechanism：This impurity mainly originates from abnormal intramolecular condensation or isomerization of intermediates during cyclization reactions. Research has found that the impurity formation increases significantly when there is an excess of acid catalyst in the reaction system or the reaction time is too long. By optimizing the reaction solvent (such as replacing dichloromethane with toluene) and adding specific stabilizers, the impurity formation rate can be effectively reduced by more than 85%.
Progress in safety evaluation：In vitro cytotoxicity tests show that this impurity has a certain inhibitory effect on nerve cells at high concentrations (≥100μg/mL); in long-term toxicity tests in rats, mild abnormalities in liver function indicators were observed in the high-dose group (50mg/kg). Based on these studies, the industry recommends controlling the limit of this impurity at ≤0.1% to ensure the safety of clinical drug use.
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