Current Pharmaceutical Analysis - Volume 18, Issue 3, 2022

Abstract: Background: Several analytical approaches for assessing anti-cancer drugs in pharmaceutical formulations have been developed over the last few years. QbD plays an important role in establishing accurate analytical methods to analyze anti-cancer compounds. Quality by Design has become a risk analysis and a science-based strategy, implemented by experimental methods to optimize system output with known variables for data. The influence of highly complex and correlations of input variables on the output reactions of pharmaceutical drugs and empirical approaches have been widely used to explain the design of experiments. Objectives: The efficiency of the anti-cancer drugs and their formulation in the various dosage forms has been made convenient with the help of QbD designs such as Plackett Burman, full factorial design, etc. QbD contains various steps, which help enhance and sustain the quality of the drug in its dosage form. Conclusion: This review covers a basic, efficient, and accurate analytical approach technique using Quality by Design for anti-cancer drugs. Thus, an outline of the experimental methods used in anti-cancer drugs was identified and discussed.

Abstract: Brinzolamide is a treatment option for glaucoma. As glaucoma is the third leading cause of blindness, there is a need for analytical methods to obtain an effective drug with great precision and accuracy. Even if brinzolamide is official in IP and USP, different analytical methods still need to be brought in one place, which would help attain better results and easy comparison for other analysis specifications and procedures. This review helps to understand and gather different analysis techniques or biological fluid techniques of brinzolamide in a dosage form. These techniques include UV spectroscopy, HPLC, LC-MS, and TLC densitometry.

Background: Hydroxychloroquine (HCQ) was originally launched as an antimalarial drug, but now it is also used as a slow-acting anti-rheumatic drug. It contains equal proportions of (-)-(R)-hydroxychloroquine and (+)-(S)-hydroxychloroquine. Introduction: Hydroxychloroquine, a synthetic 4-aminoquinoline derivative, possesses antimalarial, anti-rheumatic activity and also exerts beneficial effects on lupus erythematous disease. Substantial levels of three metabolites of HCQ, which are desethylchloroquine (DCQ), bisdesethylhydroxychloroquine (BDCQ), and desethylhydroxychloroquine (DHCQ), have been determined by various analytical techniques from blood and plasma. Methods: Various analytical techniques have been reported for asynchronous and simultaneous estimation of HCQ and their metabolites in pharmaceuticals and biological samples like (serum, whole blood, and urine). The analytical techniques are Square-wave voltammetry employed with the cathodically pretreated boron-doped diamond electrode, fast UHPLC–fluorescent method, UV spectrophotometry, UHPLC-UV analysis, RP-HPLC, mass spectrometry, NMR, and CE. Results: We have complied various analytical methods to detect HCQ with its various metabolites simultaneously or alone in pharmaceutical dosage forms, biological and environmental samples. Conclusion: The authors believe that the above-mentioned studies compiled in this report will give a choice to readers to select the most appropriate and suitable method for the analysis of HCQ. Further, it is also believed that this study will help the researchers to develop a more sensitive, convenient, and rapid method for these based on literature reports.

Background: Verapamil is an excellent drug used for the medication of hypertension and trandolapril. It is an angiotensin-converting-enzyme inhibitor. Hence, it is an interesting method to develop a novel and reliable MS/UPLC strategy for the simultaneous development of verapamil and trandolapril. Objectives: This research study aims to develop a new, rapid, and sensitive UPLC-MS/MS method for the simultaneous estimation of verapamil and trandolapril in rat plasma using D6- verapamil and D6-trandolapril. Methods: Separation was carried on column Symmetry C18 column (150x4.6 mm, 3.5 μm) using isocratic elution with a buffer containing 1mL of formic acid in 1L of water and the mixture of two components like Buffer and Acetonitrile in the ratio of 80:20 as mobile phase with 1mL/min flow rate at ambient temperature. Results: Analysis was performed within 5 minutes over a good linear concentration range from 2.4 ng/mL to 48 ng/mL (r² = 0.9993 ± 0.018) for verapamil and 10 pg/mL to 200 pg/mL (r² = 0.9993 ± 0.006) for trandolapril. The extraction recoveries and matrix effect of verapamil and trandolapril were 98.45, 99.95, 98.12, 99.66% and 98.27, 99.89, 97.78, 99.23% respectively, at different QC concentration levels. Precision and recovery study results were determined within the acceptable limit. An electrospray ionization source was used to study verapamil and Trandolapril at m/z 454.72→182.16, 430.25→201.48, and IS for m/z 460.18→ 324.39, 436.28 → 340.52, which were ion pairs of mass analysis. This method has successfully been applied to explore verapamil (1.2 mg/kg) with its internal standard (D6-Verapamil), trandolapril (0.005 mg/kg) with its internal standard (D6-Trandolapril) extracted from rat plasma using liquid-liquid extraction. Conclusion: This manuscript focuses on the consistent evaluation of the key bioanalytical validation parameters, and the following are discussed: accuracy, precision, sensitivity, selectivity, standard curve, limits of quantification, range, recovery, and stability. These validation parameters are described, together with illustrations of validation methodology applied in the case of chromatographic methods used in bioanalysis.

Background: Bisphenol A (BPA) derivatives monomers as resins are common components in dental restorative materials and materials used for orthodontic treatment. However, they are a source for BP-A leakage, which can affect adult and child health as an endocrine disruptor. Objectives: This study aimed to investigate the level of BPA leakage from four selected weights (0.1, 0.2, 0.3, 0.4 mg) of five different resin combinations used in dental restorative materials. Methods: The resin combinations were cured with light for 20 seconds, kept in 1 mL of acetonitrile, and sonicated for 30 minutes. Separation was achieved by using BEH C18 (1.7 μm, 2.1 x 100 mm) analytical column (Waters^® Acquity UPLC) and a mobile phase composed of water and acetonitrile (68:32 v/v). Moreover, Waters^® Xevo G2-SQToF coupled with Waters® Acquity UPLC system with binary Solvent Manager (I-Class) via electrospray ionization (ESI) interface was used to confirm peaks identities. Results: BPA was detected in all resin combinations and in all selected sample weights. However, BPA was below the limit of quantification (LOQ) in all selected weights of the Filtek Z350 XT Universal Restorative System. The results show that BPA is still released from selected dental resin combinations available in the market despite the general concern about its potential adverse effects. Conclusion: Nevertheless, the amounts of BPA were within the acceptable levels indicated by the U.S. Environmental Protection Agency and the U.S. Department of Health and Human Services National Toxicology Program and represent a very small contribution to the total BPA exposure. The use of alternative materials such as high-viscosity glass ionomers, inorganic biomaterials, and ceramic would be ideal and healthier for adults and children.

Background: To mitigate diabetes and its complications in cardiovascular diseases, the antidiabetic agent Glimepiride (GLM) is usually administered with Ferulic Acid (FA) concomitantly in clinical settings. However, both drugs are prone to be metabolized partly by CYP2C9; thus, they have the potential drug-drug interaction affecting safety and efficacy. Objective: This study aimed to evaluate the Pharmacokinetic (PK) effects of ferulic acid on glimepiride and its metabolite hydroxy glimepiride (OH-GLM) in plasma by using the HPLCMS/ MS method. Methods: Healthy male Sprague Dawley (SD) rats were randomly divided into three groups and received intragastric administration of 0.5% sodium Carboxymethyl Cellulose (CMC), low-dose of FA (20 mg•kg^-1 ), and high-dose of FA (40 mg•kg^-1) for 8 days, respectively. Rats were given 0.5% sodium CMC or FA on the last day and then uniformly given 1.0 mg•kg^-1 glimepiride by gavage. Blood samples were obtained from retro-orbital plexus at the time points of 0.167, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after administration. Plasma samples were analyzed for GLM and its metabolite OH-GLM on an HPLC-MS/MS system. Results: No statistically significant difference was found in the effect of low-dose of FA on the pharmacokinetics of GLM. However, high-dose of FA significantly decreased Cmax of GLM by 30.05% and CLz/F of OH-GLM by 47.45% and increased Tmax and t1/2z of GLM by 95.87% and 140.00%, respectively. Conclusion: Low-dose of FA did not alter GLM metabolism, while high-dose treatment of FA apparently caused pharmacokinetics interaction with GLM in rats.

Background: Minodronic acid (MA) is a third-generation nitrogen-containing heterocyclic bisphosphonate used to treat osteoporosis. In the process of starting materials research and preparation, the key intermediate impurities and degradation impurities have a great impact on the quality control of the drug. Objectives: A sensitive, reliable, high-performance liquid chromatography (HPLC) method was developed and validated for the quantitative determination of MA and its related impurities (a total of 6 compounds, including 2 new impurities). Methods: The separation was achieved on an InertSustain ODS-4 C18 (250 mm × 4.6 mm, 5 μm) column using the mixture of 0.01 mol/L sodium pyrophosphate and 1 mmol tetrabutylammonium phosphate (the mobile phase pH was adjusted to 7.80 by phosphonic acid). Results: The quantitative analytical method was fully validated with respect to linearity (r > 0.999), sensitivity (limit of detection < 35 ng/mL), precision, accuracy (the recovery was between 98.7% and 104.2%), and robustness. Six process-related impurities in Minodronic Acid (MA) bulk drug were determined by high-performance liquid chromatography (HPLC). Furthermore, except for two starting materials, other four impurities were identified and characterized as 2-(imidazo[1,2-a] pyridin-3-yl) ethyl acetate (Imp-C), 2-(imidazo [1,2-a] pyridin- 3- yl)acetic acid (Imp-D), 3-(2-hydroxy-2,2- diphosphonoethyl)-4H-imidazo [1,2-a] pyridine -4- oxide (Imp-E) and 2,5- Dihydroxy- 3,6-bis(imidazo[1,2-a] pyridine-3-yl methyl) -2,5-dioxo- 1,4,2,5- dioxoDiphosphonium-3,6-diyl) bisphosphonic acid (Imp-F) using liquid chromatograph- mass spectrometer (LC-MS), MS/MS, Infrared Radiation and Nuclear Magnetic Resonance spectroscopy (¹H-NMR and ¹³C-NMR). To the best of our knowledge, two of them (Imp- E and Imp-F) are new compounds and have not been reported previously. Conclusion: The HPLC method was developed and optimized, which could be applied for quantitative detection of the impurities, and further quality evaluation of MA.

Background: Salviae miltiorrhizae Radix et Rhizoma (Red Sage root) is widely used in traditional Chinese medicine (TCM) for the treatment of Alzheimer’s disease (AD) with demonstrated curative effects, based on the concept of "one drug with multiple therapeutic targets," which appears to be a good strategy for AD treatment. Objective: This study aimed to develop of high-throughput screening (HTS) method for multitherapeutic target components found in complex TCMs, which are active against AD, using Red Sage root as the case study. Methods: Acetylcholinesterase (AChE) inhibitors (AChEIs) from Red Sage root extracts were pre-screened by ultrafiltration-HPLC (UF-HPLC) analysis, in which AChE was added to the extract and then ultrafiltered to remove non-binding compounds. Potential AChEIs were identified by HPLC analysis of compounds bound to AChE. A microplate-based HTS was then used to quantify the AChE inhibitory activity and antioxidant activity of the pre-screened compounds. Results: Pre-screening found ten potential inhibitors, which were identified by ESI-TOF/MS; six of these were purified by semi-preparative HPLC: Oleoyl neocryptotanshinone (1), Dihydrotanshinone 133; (2), Cryptotanshinone (3), Tanshinone 133; (4), Tanshinone 133;¡A (5) and Miltirone (6). All six compounds had good AChE inhibitory activity and weak DPPH scavenging capacity. Conclusion: This study provides a platform and technology support for the rapid discovery of multi-target components, potentially active against AD, from complex TCMs and with strong potential for adaptation to the discovery of treatments for other diseases.