Validated stability indicating assay method of olaparib: LC-ESI-Q-TOF-MS/MS and NMR studies for characterization of its new hydrolytic and oxidative forced degradation products.

Olaparib (OLA) is a poly ADP ribose polymerase (PARP) enzyme inhibitor used to treat prostate, ovarian and breast cancer. The drug substance OLA was subjected to forced degradation as per ICH prescribed guidelines. It was degraded in hydrolytic (acidic and basic) and oxidative stress conditions and yielded four degradation products (DPs) while it remained stable in neutral hydrolytic, dry heat and photolytic stress conditions. A stability indicating assay method was developed to separate OLA and its DPs using InertSustain C18 column (250 × 4.6 mm, 5 μm) with a gradient mobile phase of 10 mM ammonium acetate (pH 4.5) and acetonitrile (ACN) at a flow rate of 1 mL min-1. The characterization of DPs was carried out by using liquid chromatography-electrospray ionization-quadrupole-time of flight tandem mass spectrometry (LC-ESI-Q-TOF-MS/MS). Major degradation products (DP-1 and DP-2) were isolated by using preparative HPLC and structures were further confirmed by using NMR spectroscopy. All the obtained DPs were new and not reported previously. The developed chromatographic method was validated as per ICH Q2 (R1) guideline and USP general chapter on method validation.

Thummar M ，Kuswah BS ，Samanthula G ，Bulbake U ，Gour J ，Khan W ... -  《-》

Liquid chromatography/electrospray ionization tandem mass spectrometry study of repaglinide and its forced degradation products.

Stress stability studies of drugs have been recognized as an essential part of the drug development process. These studies are used to investigate the intrinsic stability of the drugs and for the development of a selective stability indicating assay method (SIAM). Stress testing is also useful for the formulation and packaging development, shelf-life determination and designing of manufacturing processes. As per regulatory guidelines, stress degradation studies and structural characterization should be carried out to establish degradation pathways of the drug, which is essential from both the efficacy and safety point of view. As the stress stability studies of repaglinide have not been reported in the literature, the present study has been undertaken. Repaglinide (RP), an oral anti-diabetic drug, was subjected to hydrolysis (acidic, alkaline and neutral), oxidation, photolysis and thermal stress conditions as per International Conference on Harmonization (ICH) guidelines Q1A (R2). The chromatographic separation of the drug and its degradation products (DPs) was achieved on an Agilent XDB C-18 column using the gradient elution method with a mobile phase consisting of 20 mM ammonium acetate and acetonitrile at flow rate of 1.0 mL min-1 . The DPs were characterized using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) in combination with accurate mass measurements. The drug degraded under hydrolytic and oxidative stress, while it was stable under thermal and photolytic stress conditions. In total, six DPs were formed and the LC/MS method described here can resolve all DPs from the parent as well as from each other under various stress conditions. To elucidate the structures of DPs, fragmentation of the [M + H]+ ions of RP and its DPs was studied by using LC/ESI-MS/MS combined with accurate mass measurements. The forced degradation of RP carried out as per ICH guidelines results in the formation of six degradation products which have been characterized using LC/MS/MS in combination with accurate mass measurements.

Purna Chander C ，Raju B ，Ramesh M ，Shankar G ，Srinivas R ... -  《-》

Identification and characterization of stressed degradation products of prulifloxacin using LC-ESI-MS/Q-TOF, MSn experiments: development of a validated specific stability-indicating LC-MS method.

A rapid, specific and novel gradient LC-MS method has been developed and validated for the identification and characterization of stressed degradation products (DPs) of prulifloxacin (PF) using liquid chromatography combined with quadrupole time-of-flight electrospray ionization tandem mass spectrometry (LC/Q-TOF-ESI-MS/MS). PF was subjected to hydrolytic (acidic, alkaline and neutral), oxidation, photolytic and thermal stress, as per ICH guidelines Q1A (R2). The drug showed extensive degradation in hydrolytic and oxidative, while it was stable to thermal and photolytic stress conditions. In total, 13 DPs were formed and the chromatographic separation of drug and its DPs was achieved on a C-18 column (4.6 × 250 mm, 5 μm) using gradient elution method. All the DPs have been identified and characterized using MS(n) experiments and accurate mass measurements. The LC-MS method was validated with respect to specificity, linearity, accuracy, precision and robustness.

Raju B ，Ramesh M ，Srinivas R ，Raju SS ，Venkateswarlu Y ... -  《-》

Structural characterization of alkaline and oxidative stressed degradation products of lurasidone using LC/ESI/QTOF/MS/MS.

A selective, accurate, precise and robust stability indicating liquid chromatography assay method was developed for the monitoring of a novel antipsychotic drug, lurasidone, in the presence of its degradation products (DPs). Also, we investigated degradation behavior of the drug under various stressed conditions such as hydrolytic (acidic, basic and neutral), oxidation, photolytic and thermal. The drug was found to be degraded under base hydrolytic and oxidative conditions, while it was stable in acid and neutral hydrolytic, photolytic and thermal conditions. The method showed adequate separation of lurasidone and its DPs on Xterra C18 (150 mm × 4.6 mm i.d., 3.5 μm) column using 20 mM ammonium formate (pH 3.0): acetonitrile as a mobile phase in gradient elution mode at a flow rate of 0.6 mL/min. This method was extended to liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC/ESI/QTOF/MS/MS) for structural characterization of DPs. A total of five DPs were characterized by LC/ESI/QTOF/MS/MS studies. Most probable mechanisms for the formation of DPs were proposed. The developed method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonization Guideline Q2 (R1).

Kumar Talluri MVN ，Dharavath S ，Kalariya PD ，Prasanth B ，Srinivas R ... -  《-》

LC-MS-MS Characterization of Forced Degradation Products of Fidarestat, a Novel Aldose Reductase Inhibitor: Development and Validation of a Stability-Indicating RP-HPLC Method.

An accurate, precise, robust and selective stability-indicating liquid chromatographic (LC) method has been developed for the monitoring of fidarestat in the presence of its forced degradants. The drug was subjected to hydrolysis (acid, alkali and neutral degradation), oxidation, photolysis and thermal stress conditions. The drug degraded significantly under hydrolytic (basic, acidic and neutral) and oxidative stress conditions, whereas it was found to be stable in photolytic and thermal conditions. The chromatographic separation was achieved on a Grace C18, (250 mm × 4.6 mm × 5 μm) column using gradient mobile phase system consisting of 10 mM of ammonium acetate buffer at pH 4 and acetonitrile at a flow rate of 1 mL/min with UV detection at 283 nm. The developed method was extended to liquid chromatography quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS-MS) for characterization of all the degradation products. A total of five new degradation products were identified and characterized by LC-QTOF-MS-MS. The developed LC method was validated as per ICH guideline Q2 (R1). The proposed method was found to be successively applied for the quality control of fidarestat in bulk drug analysis.

Talluri MV ，Khatoon L ，Kalariya PD ，Chavan BB ，Ragampeta S ... -  《-》