Characterization of potential degradation products of brexpiprazole by liquid chromatography/quadrupole-time-of-flight mass spectrometry and nuclear magnetic resonance, and prediction of their physicochemical properties by ADMET Predictor™.

RATIONALE: Brexpiprazole (BRZ) was subjected to hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress degradation in solutions prepared in a mixture of acetonitrile-water (70:30 v/v). The oxidative study was additionally done in methanol-buffer mixture at pH 3, 7 and 11. Also, compatibility of the drug with selected excipients was investigated in the solid state. Additionally, physicochemical and ADMET properties of BRZ and its degradation products (DPs) were predicted using ADMET Predictor™ software. It provides the conditions for quality control of BRZ and its derivatives during manufacturing, processing and storage conditions. METHODS: The formed DPs were separated from the drug and among themselves on a C-18 column utilizing mobile phase composed of methanol and ammonium formate buffer (10mM, pH 4.0), which was run in a gradient mode. Characterization of DPs was carried out by first establishing the mass fragmentation pathway of the drug based on its liquid chromatography/quadrupole-time-of-flight mass spectrometry (LC/Q-TOF-MS) data, followed by LC/Q-TOF-MS studies of DPs. Three DPs were isolated and, along with the drug, they were subjected to 1D (1 H, 13 C and DEPT-135) and 2D (COSY and HSQC) NMR studies for confirmation of their structures. RESULTS: BRZ was observed to be susceptible to hydrolytic (neutral, acid and alkali), photolytic and oxidative degradation conditions; it was stable on thermal exposure. A total of 12 DPs (BRZ-1 to BRZ-12) were formed in solution state. Mechanisms of BRZ degradation were postulated. CONCLUSIONS: The extent of degradation of BRZ in different stress conditions highlights that stability of BRZ in drug formulations can be improved (i) by using excipients that can impart a low-pH microenvironment, (ii) by addition of antioxidants and (iii) through protection from light.

Development of stability-indicating method for separation and characterization of benidipine forced degradation products using LC-MS/MS.

The present study describes forced degradation of benidipine (BEN) as per  Q1A (R2) and Q1B guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. BEN degraded under hydrolysis (neutral, acidic, and alkaline), hydrogen peroxide induced oxidation, and UV light mediated photolytic degradation. A total of 14 degradation products (DPs) were found in all degradation studies, comprising 4 hydrolytic DPs, 8 oxidative DPs, and 4 photolytic DPs. A selective stability-indicating method was developed using an XBridge BEH C18 column with gradient elution program consisting of ammonium acetate (10 mM, 4.8 pH, acetic acid) and acetonitrile. The flow rate was maintained at 1 ml min-1 . All DPs were separated well using the developed HPLC method and were characterized using LC-MS/MS data. As this method is effective in identifying and separating BEN and its DPs with sufficient resolution, it can be used in laboratories for quality control of drugs in daily routine analysis and stability studies.

Preparation and Comparison of Oral Bioavailability for Different Nano-formulations of Olaparib.

Olaparib (OLA) is a poly ADP ribose polymerase (PARP) inhibitor approved for germline BRCA-mutated (gBRCAm) advanced ovarian cancer and breast cancer. Low oral bioavailability of this drug requires increase in the dose and frequency causing haematological toxicity in the patients. The purpose of this study is to prepare different nano-formulations of OLA lipospheres (LP) by melt dispersion and nano-suspensions (NSP) by solvent evaporation (SE) and wet milling (WM) techniques and compare oral bioavailability of these formulations. Size of the nano-formulations OLA-LP, OLA-NSPSE and OLA-NSPWM were found to be 126.71 ± 4.54, 128.6 ± 2.34 and 531.1 ± 5.34 nm with polydispersity index below 0.3. In vitro release studies were performed by dialysis bag method where the sustained drug release was observed from nano-formulations until 9 h with Higuchi for OLA suspended in 2.5% w/v sodium carboxy methyl cellulose (OLA-SP), OLA-LP and OLA-NSPWM and Peppas for OLA-NSPSE-based drug release kinetics. In vivo pharmacokinetic studies, haematological toxicity and distribution studies were performed on rats. Results showed that there was an improvement in Cmax, AUCtotal, t1/2 and MRT by OLA nano-formulations when compared with OLA-SP. OLA-SP has shown reduction in WBC, platelets and lymphocytes at 12 and 36 h time points; however, no reduction in cell count was observed with OLA nano-formulations. Distribution studies proved FITC nano-formulations were most rapidly absorbed and distributed when compared with FITC-loaded suspension. From the above results, it was concluded that OLA nano-formulations can be an alternative to enhance the oral bioavailability and to reduce the haematological toxicity of OLA.