Linagliptin Research Articles

Elucidation of DPP-4 involvement in systemic distribution and renal reabsorption of linagliptin by PBPK modeling with a cluster Gauss-Newton method.

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss-Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK-CGNM analysis using reported autoradiography data ([14C]-LNG) in wild-type and Dpp-4-deficient rats, DPP-4-specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP-4 and the reabsorption clearance for LNG-DPP-4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP-4 expressions and invitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high-affinity probe for DPP-4, comprehensive PBPK-CGNM analyses suggested a dynamic whole-body distribution of DPP-4, including its involvement in the renal reabsorption of LNG.

Design and Optimization of Solid Lipid Nanoparticles for Enhanced Therapeutic Activity of Linagliptin.

To augment oral bioavailability, linagliptin (LGP) loaded solid lipid nanoparticles (SLNs) have been formed using the solvent evaporation technique of emulsification. Utilizing the Box Behken design (BBD), examining the relation between independent and dependent variables was possible. Particle size (PS), entrapment efficiency (EE), and in-vitro drug release (DR) studies were considered response factors, whereas the various concentrations of lipid carrier, surfactant, and co-surfactant were considered process variables for optimization. The design expert program was used to obtain the optimized batch. At 24 hours, it was discovered that the optimized batch expected responses for PS, %EE, and %DR were 105.83 nm, 81.19, and 96.69%, respectively. The observed PS, %EE, and %DR responses of the optimized batch at 24 hours were determined to be 101.36 nm, 80.56, and 96.31%, respectively. There is no interaction seen in the basic physical mixing of drug and polymer, according to the FTIR spectra of pure drugs, polymers, and drug and polymer mixtures. The optimized formulation’s average size was found to be 138 nm by the particle size analysis. Similarly, a value of 0.255 was found by the polydispersity index (PDI). This suggests that the SLN in the formulation has a homogeneous size dispersion. With a zeta value of -32.8 mV, stability is indicated. Linagliptin was effectively developed as a drug with a 24-hour sustained release. Wistar rats were used in the in-vivo evaluation of linagliptin SLN formulations. The drug bioavailability increased five times (a highly significant fivefold increase) in LGP-loaded SLNs (AUC0-t ≈ 134.5 μg*h/mL) compared to raw LGP (AUC0-t = 27.23 μg*h/mL).

Near-Infrared Stimuli-Responsive Hydrogel Promotes Cell Migration for Accelerated Diabetic Wound Healing.

Diabetic wound healing including diabetic foot ulcers is a major clinical challenge, which could bring an increased level of mortality and morbidity. However, conventional wound dressings exhibit limited healing efficacy due to their lack of active modulation for the healing process. Here, a near-infrared (NIR) stimuli-responsive composite hydrogel dressing with the synergistic effect of both mechanical contraction and epithelial-mesenchymal transition (EMT) was developed to facilitate cell migration and vascularization for diabetic wound healing. In the methacrylated gelatin-based composite hydrogel, N-isopropylacrylamide and polydopamine nanoparticles were incorporated to endow the composite hydrogel with thermosensitive and photothermal properties. Linagliptin (LIN) was loaded into the composite hydrogel, and the drug release rate could be controlled by NIR laser irradiation. NIR-triggered on-demand active contraction of wound area and LIN release for biological stimulation were potentially realized in this responsive system due to the thermally induced sol-gel transition of the composite hydrogel. The release of loaded LIN could effectively promote cell migration by activating EMT and enhancing angiogenesis. In the full-thickness skin defect model, the LIN-loaded composite hydrogel with NIR laser irradiation had the highest wound closure rate as compared with the pure hydrogel and LIN-loaded hydrogel groups. Therefore, this composite hydrogel can serve as an excellent platform for promoting wound healing and will find more practical value in clinical treatment.

Miniaturized green capillary electrophoresis system for the simultaneous analysis of Linagliptin and cefiximein in plasma

A novel combination therapy, consisting of the antidiabetic drug linagliptin (LIN) and the third-generation cephalosporin antibiotic cefixime (CEF), has recently been introduced to combat infections in diabetic patients. However, there is no published method for their in-vivo simultaneous determination in clinical biological specimens to support their pharmacokinetics and therapeutic monitoring. This study focuses on the development of a miniaturized capillary electrophoresis system-assisted with photodiode array detection (CE-PDA) for the simultaneous determination of LIN and CEF in clinical settings for analysis of plasma samples containing LIN and CEF. The conditions of electrophoretic separation of LIN, CEF, and Ibuprofen (as an internal standard), and the analysis procedures were successfully established. The linear range of the CE-PDA method was determined to be 0.5–100 µg mL−1 for LIN and 1–100 µg mL−1 for CEF. The CE-PDA approach exhibited high sensitivity, with limits of quantitation of 0.9 µg mL−1 for LIN and 1.2 µg mL−1 for CEF. In addition, the CE-PDA system was validated, and subsequently applied to real plasma samples withdrawn from rats received concurrent administration of LIN and CEF. The plasma protein was precipitated by acetonitrile. The miniaturized features of the system and its environmental impact were confirmed using three different metric tools. Additionally, the proposed CE-PDA system proved to be time-saving and cost-effective, making it highly suitable for therapeutic drug monitoring of LIN and CEF in clinical settings.

Synergistic Antitumor and Apoptotic Activity of Sitagliptin or Linagliptin Plus Cisplatin Against A549 Lung Cancer Cells (an Invitro Study)

Objective: Lung cancer (LC) has the highest mortality rate globally. Most chemotherapeutic medicines now in use are cytotoxic, prompting the search for novel compounds with anticancer properties and improved safety profiles for normal cells. Dipeptidyl peptidase-4 inhibitors have demonstrated anticancer effects and apoptotic properties by specifically inhibiting dipeptidyl peptidase -4, a glycoprotein found in various organs that support the spread of cancer and tumor formation. Based on that, this study aimed to evaluate the cytotoxicity and apoptotic activity of sitagliptin (SITA) and linagliptin (LINA) against the lung cancer cell line (A549) alone and in combination with cisplatin (CP). Methods: A549 cells were categorized into six groups: control (untreated cells), CP-treated cells, SITA-treated cells, LINA-treated cells, CP plus SITA treated cells (1:1 ratio), and CP plus LINA treated cells (1:1 ratio). After 72 hours of incubation, cell viability (or cytotoxicity) and concentration required to inhibit 50% of cell viability (IC50) for each group were determined using an MTT assay. This method is safe and easy to use, has more reproducibility, and is commonly used for cell viability and cytotoxicity tests. Later, A549 cells were cultured in six flasks and exposed to the IC50 for 36 hours. Afterward, the cells were harvested and centrifuged, and the supernatant was removed. The remaining cell pellets were collected and lysed using a lysis buffer to measure B-cell lymphoma type 2 (BCL-2) levels with ELISA test kits. The data was collected and subjected to statistical analysis techniques. Results: MTT assay results determined that SITA and LINA significantly increased A549 cell cytotoxicity compared to the control group (P<0.0001). Moreover, combining SITA or LINA with CP showed markedly increased antitumor efficacy and more significant cytotoxicity directed toward A549 cells. Additionally, these combinations highly reduced IC50 in comparison to monotherapy. Considerably, both drugs showed remarkable apoptotic activity on A549 cells when used alone or combined with CP by decreasing BCL2 levels. Consequently, it potentiates apoptotic effects and cytotoxicity of CP against cancer cells. Interestingly, Lina was more potent than Sita regarding cytotoxicity and apoptotic activity on A549 cells. Conclusion: SITA and Lina exhibited significant cytotoxic and apoptotic effects against A549 cells through the induction of apoptosis. Notably, the results suggest a potential synergistic anticancer impact on CP.

Unveiling Pharmacokinetics and Drug Interaction of Linagliptin and Pioglitazone HCl in Rat Plasma Using LC-MS/MS.

The linagliptin (LIN) and pioglitazone HCl (PIO) combination, currently undergoing phase III clinical trials for diabetes mellitus treatment, demonstrated significant improvements in glycemic control. However, the absence of an analytical method for simultaneous determination in biological fluids highlights a crucial gap. This underscores the pressing need for sensitive bioanalytical methods, emphasizing the paramount importance of developing such tools to advance diabetes management strategies and enhance patient care. Herein, a sensitive reverse-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for simultaneous determination of LIN and PIO in rat plasma using alogliptin as an internal standard. Chromatographic separation was performed on an Agilent Eclipse Plus C18 (4.6 × 100 mm, 3.5 μm) using an isocratic mobile phase system consisting of ammonium formate (pH 4.5) and methanol using an acetonitrile-induced protein precipitation technique for sample preparation. Multiple reaction monitoring in positive ion mode was used for quantitation of the precursor to production at m/z 473.2 → 419.9 for LIN, 357.1 → 134.2 for PIO, and 340.3 → 116.1 for ALO. The linearity range was 0.5 to 100 and 1 to 2000 ng/mL for LIN and PIO, respectively. The developed method was validated as per US-FDA guidelines and successfully applied to clinical pharmacokinetic and drug-drug interaction studies with a single oral administration of LIN and PIO in rat plasma. Pharmacokinetic parameters of LIN were significantly influenced by the concomitant administration of PIO and vice versa. Molecular modeling revealed the significant interaction of LIN and PIO with P-glycoprotein. Therefore, the drug-drug interaction between LIN and PIO deserves further study to improve drug therapy and prevent dangerous adverse effects.

Green quantitative methods for linagliptin and empagliflozin in dosage forms

Abstract The frequent drugs prescribed for type 2 diabetes patients are linagliptin (LNG) and empagliflozin (EMG) in different drug formulations. The objective of this research is to create and validate selective and simple methods to evaluate both medications in their dosage forms. Method A for the assay of LNG is based on the drug oxidation using an iodate/iodide mixture, while Method B involves the determination of EMG using permanganate oxidation. The regression graphs had good linearity in the ranges of 0.25–20 and 0.20–1.5 µg·ml−1 for the two drugs, respectively. The limits of detection were 0.082 and 0.065 µg·ml−1 for LNG and EMG, respectively. The two methods were validated and applied for the assay of the drugs in dosage forms successfully.

Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous invivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

Development of Linagliptin Ultra Fine Solid Supersaturated Bio-SNEDDS Using Triangular Mixture Design for Enhancement of Oral Bioavailability: Impact of P-gp Inhibition

Linagliptin (LIN) is a newly developed dipeptidyl peptidase 4 (DPP-4) inhibitor oral antidiabetic drug. LIN is considered a P-gp substrate, thus suffers from poor bioavailability (< 30%). The aim of this study was to develop and characterize LIN bioactive self-nanoemulsifying drug delivery system to circumvent its poor bioavailability and enhance its therapeutic efficacy.
 Methodology: In this study, we developed solid supersaturated bioactive self-nanoemulsifying drug delivery system (Ss-bio-SNEDDS) of LIN, using clove oil as an oil phase, cremophor CO 40 as a surfactant, labrasol as a co-surfactant and Hydroxy-propyl-B-cyclodextrin (HPBCD) as a precipitation inhibitor (PI); all components are of established P-gp inhibition activity. Optimization was performed by means of triangular mixture design based on particle size, poly dispersity index (PDI) and percent transmittance. The two optimized formulations (F4 and F8) were designated and evaluated for stability and cloud point. Also, the effect of pH on particle size and PDI was assessed. Additionally, examination of particles’ surface morphology of the two optimized formulations was performed by transmission electron microscope (TEM). The prepared liquid supersaturated-SNEDDS (s-SNEDDS) were converted into solid supersaturated-SNEDDS (Ss-SNEDDS) via adsorption on microcrystalline cellulose (MCC). Further evaluations were carried out, including in vitro drug release, in vitro precipitation and in vivo studies.
 Results: The optimized formulations F4 and F8 manifested promising characteristics concerning particle size (< 50 nm), PDI (< 0.3) and percent transmittance (> 99%). Stability study showed no phase separation or precipitation with rapid emulsification time. The two optimized formulations showed high cloud point temperature (above 70°C). TEM images of F4 and F8 showed spheroid like appearance with relatively smooth surface. Results of the in vivo study in rats revealed a significant increase in AUC of solid-F4, solid-F8 and solid supersaturated-F4 (S-F4, S-F8 and Ss-F4) by 2.32, 2.89 and 2.54 folds, respectively compared to LIN solution; with a noticeable reduction in blood glucose level at each point.
 Conclusion: In a nutshell, Ss-bio-SNEDDS are considered as auspicious nano-carriers for LIN with the virtue of augmented bioavailability and possible dose reduction.

Simultaneous estimation of two anti-diabetic drugs; Linagliptin and empagliflozin in their tablet by chemometric spectrophotometry

Four spectrophotometric approaches had been established and optimized for the simultaneous estimation of two anti-diabetic drugs; linagliptin (LIN) and empagliflozin (EMP) in their bulk and tablet dosage form. LIN concentration could be first determined from the zero order spectra at its λmax (293 nm) without interference from EMP as at this wavelength EMP showed zero absorbance. The LIN and EMP zero order absorption spectra displayed considerable overlap which hindered the direct determination of EMP. Thus, four indirect spectrophotometric approaches were established and optimized for the determination and quantification of EMP concentrations in presence of LIN. Method (I) was ratio difference method (RD) which depended on the determination of difference amplitudes in the ratio spectra (ΔP) at 236 nm and 227 nm; ΔP(236-227) was directly proportional to EMP concentration. Method (II) was ratio derivative method (1DD) based on the measuring of the amplitude of first derivative of ratio spectra at 243 nm which was directly proportional to EMP concentration. For determination of EMP concentration using both method (I) and (II); LIN 7 µg/mL was used as the divisor. Method (III) was area under curve method (AUC) which depended on the measurement of area confined between 220 and 230 nm and 273–290 nm. Method (IV) was dual wavelength method (DWL) which based on measurement of absorbance difference (ΔA) in zero order spectra between 239.8 and 282.6 nm which was directly proportional to EMP concentration. The four developed methods were optimized and entirely validated regarding to ICH guidelines. The proposed spectrophotometric approaches were used for the quantification of LIN and EMP simultaneously in their tablet dosage form. F-test and t-test were applied for statistical comparison between the results obtained by the proposed approaches and that obtained by the reported method. There was no significant difference concerning to precision and accuracy.

Green and white MEKC for determination of different anti-diabetic binary mixtures and their triple-combo pill.

The work introduces green and white sustainable micellar electrokinetic chromatography (MEKC) procedure that could analyze therapeutically related drugs, empagliflozin (EMP), linagliptin (LIN) and metformin (MET) which are antidiabetic drugs with different mechanism of action, in their different pharmaceutical combinations. The method not only comply with the green analytical concepts, but also it is in line with sustainable analytical concepts as it is economic by applying the same operating conditions to analyze different pharmaceuticals in quality control (QC) labs which is a crucial step in QC labs and research centers to save time, effort, and money. Moreover, the method functionality regarding its scope with its achieved levels of accuracy, precision, low detection, and quantitation limits is tested using white assessment tool and compared with reported methods. The proposed MEKC coupled with a diode array detector (DAD) has been developed and validated for micro estimation of EMP and LIN in their low critical concentrations with MET in a ratio of (EMP: MET, 1:40) and (LIN: MET, 1:200). Separation was achieved within 6min using fused silica capillary (40cm × 50µm id) using 20mM Tris buffer (pH 10) in presence of 50mM sodium dodecyl sulphate and 10% v/v methanol. The concentration ranges of the studied anti-diabetic drugs were 10-500, 10-100 and 2.5-100µg. mL-1 for MET, EMP and LIN, respectively. The developed method is the first MEKC for concurrent determination of EMP, LIN and MET with high separation efficiency, low solvent consumption and regard as an easy green and white analytical tool. Moreover, Greenness and whiteness assessment were done via the most widely used Analytical Eco-Scale, the innovative AGREE tool and the RGB 12 algorithm.

Integrating micellar HPLC and green analytical chemistry tools in greenness assessment of five commonly Co-formulated antidiabetic drugs

The ecological impact of routine quality control activities in the pharmaceutical industry is crucial, producing large amounts of dangerous organic waste. For that, the use of mixed-micellar LC was found beneficial. When sodium dodecyl sulfate (SDS) is mixed with Brij-35 as surfactants in the mobile phase, no organic modifier was needed for enhancing the analytes' elution time or resolution. In the proposed study, five antidiabetic drugs belonging to different antidiabetic classes; namely metformin (MTF), glibenclamide (GBC), gliclazide (GCZ), linagliptin (LNT) and dapagliflozin (DPF), have been studied using organic-solvent free Micellar RP-HPLC technique. The combination of double or even triple antidiabetic therapies from different classes is common and was proved efficient for the control of type-2 diabetes. The optimal mobile phase was composed of 0.12 M SDS, 0.008 M Brij-35 and 0.15 M triethylamine in water, adjusted to pH 4.5. The flow rate was set at 1.5 mL min−1 on RP-monolithic column (100 × 4.6 mm). Photodiode array detection was set at wavelength 245 nm for MTF and 225 nm the other analytes. Linearity ranges were 50–600 μg mL−1 for MTF, and 5–60, 2.5–30, 7.5–60, and 2.5–30 μg mL−1 for DPF, LNT, GCZ and GBC, respectively (R2 ≥ 0.997). Trueness and precision have been established across the specified ranges with recovery percentages range 98–105% and relative standard deviation of the results less than 2.5%. The obtained results of resolution, peaks’ symmetry and theoretical plates for the drugs under study proved the analytical capability of using mixed-micellar mobile phases for elimination of the organic-solvents without affecting the separation efficiency.

Exploring the molecular mechanism of linagliptin in osteosarcoma cell lines for anti-cancer activity

BackgroundFinding new applications for widely used current drugs is a fast and effective technique for discovering new anticancer chemicals. Osteosarcoma (OS), the most prevalent form of bone cancer, has several side effects that significantly lower patients’ quality of life. This study aims to systematically examine the anti-cancer activity of linagliptin (LG) in the osteosarcoma cell line Saos-2. MethodsMTT assays and flow cytometry were used to assess cell viability and apoptosis, respectively. qPCR array experiments were carried out to determine target gene expressions and explain the molecular mechanism of LG’s action. ResultsLinagliptin treatment significantly decreased the viability of Saos-2 cells and hFOB1.19 cells (p < 0.001). The treatment also induced increased apoptotic effects in both Saos-2 cells (p < 0.001) and hFOB1.19 cells (p < 0.05). qPCR assays were conducted to assess cancer pathway analysis after applying specific quantities of LG to Saos-2 and hFOB1.19 cells. ConclusionThe findings of this study demonstrate that LG inhibits the proliferation of Saos-2 cells and induces cell death. LG supports cell death by suppressing the expression of specific genes involved in cancer pathways.

Review on Analytical Methods for Estimation of Antidiabetic Drugs: Empagliflozin, Linagliptin and Metformin Hydrochloride

Pharmaceutical analysis is necessary at all stages of the drug development process, including formulation development, stability studies, and quality control. It is also used for characterizing the composition of different dosage forms in quantitative and qualitative ways. Comprehensive literature survey forms the foundation stone for the focused analysis of research activity. This review article represents the collection and discussion of various analytical methods available in the literature for the determination of oral anti-diabetic drugs like Empagliflozin (EMPA), Linagliptin (LINA) and Metformin hydrochloride (MET) for the treatment of type II diabetes mellitus, consisting of UV, TLC, HPTLC, and HPLC. The anticipated review provides details about the comparative utilization of various analytical techniques for the determination of EMPA, LINA and MET. This review article can be effectively explored to conduct future analytical investigation for the estimation of selected drugs in pharmaceutical and biological samples.

Deduction of the operable design space of RP-HPLC technique for the simultaneous estimation of metformin, pioglitazone, and glimepiride

A reversed-phase RP-HPLC method was developed for the simultaneous determination of metformin hydrochloride (MET), pioglitazone (PIO), and glimepiride (GLM) in their combined dosage forms and spiked human plasma. Quality risk management principles for determining the critical method parameters (CMPs) and fractional factorial design were made to screen CMPs and subsequently, the Box–Behnken design was employed. The analytical Quality by Design (AQbD) paradigm was used to establish the method operable design region (MODR) for the developed method depended on understanding the quality target product profile (QTPP), analytical target profile (ATP), and risk assessment for different factors that affect the method performance to develop an accurate, precise, cost-effective, and environmentally benign method. The separation was carried out using a mobile phase composed of methanol: 0.05 M potassium dihydrogen phosphate buffer pH 3.7 with 0.05% TEA (78:22, v/v). The flow rate was 1.2 mL/min. DAD detector was set at 227 nm. Linagliptin (LIN) was used as an internal standard. The proposed method was validated according to The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The assay results obtained by using the developed method were statistically compared to those obtained by the reported HPLC method, and a satisfying agreement was observed.

Development and validation of a new analytical method for determination of linagliptin in bulk by visible spectrophotometer

A simple, economical, and specific analytical method has been developed for determining and validating linagliptin (LNG) in bulk. This method is based on a condensation reaction between a primary amine in LNG and an aldehyde group in P-dimethylaminobenzaldehyde (PDAB) to form the yellow Schiff base with a wavelength of 407 nm. The optimum experimental conditions for the formulation of the colored complex have been studied. The optimum conditions were 1 mL of 5% w/v reagent solution with methanol and distilled water as a solvent for both PDAB, LNG respectively, also adding 2 mL of HCl as an acidic medium, heating to 70–75 °C on a water bath for 35 min. Furthermore, the stoichiometry of the reaction has been studied according to Job’s and Molar ratio method which was expressing 1:1 for LNG and PDAB. The researcher modified the method. The results show that the linearity in the concentration range (5–45 µg/mL) with correlation coefficient R2 = 0.9989 with percent recovery (99.46–100.8%) and RSD was less than 2%, LOD and LOQ 1.5815 − 4.7924 μg/mL respectively. This method can show high quality and there is no significant interference with excipients and in pharmaceutical forms. None of the studies showed the development of this method before.

A Critical Review on Bioanalytical Methods Impurity Profiling, Degradation Study of Empagliflozin and Linagliptin

The development of sound Analytical method(s) is of supreme importance during the process of drug discovery, release to market and development, culminating in marketing approval. The objective of this paper is to review the method development, Impurity profile study, Degradation studies of the method for the drug production i.e Empagliflozin (EMP) and Linagliptin (LIN) from the developmental stage of the formulation to commercial batch of the product. Bioanalysis plays a vital role in drug discovery and development for the analysis of analytes (drugs, metabolites) in biological samples. To achieve a stable, reliable, and robust method one has to remove the interfaces from the sample matrix to improve bioanalytical system performance. This review provides an overview of the Impurity profile, Degradation study and various Analytical/Bio-Analytical method development of selected Anti-Diabetic drugs i.e EMP and LIN in single dosage form and their combination and a detailed investigation of different analytical techniques used for detection and quantification of these drugs on various matrices. Various techniques like spectroscopy, chromatography, electrochemical methods, and hyphenated techniques were reported to determine Anti-Diabetic drugs, either alone or in combination with other drugs, in different kinds of matrices like in bulk, existing dosage forms and also biological samples like plasma, serum, urine and myocardial tissue. Among various techniques used, HPLC, LC-MS systems are more commonly used because of their high sensitivity. This article summarizes the research works carried out since 2015 and intends to act as a handbook for future researchers.

Linagliptin drug molecule as corrosion inhibitor for mild steel in 1 M HCl solution: Electrochemical, SEM/XPS, DFT and MC/MD simulation approach

Linagliptin (LGP) was investigated as a mild steel (MS) corrosion inhibitor in 1 M HCl solution using combined experimental and theoretical explorations. The investigated molecule was revealed to reduce the corrosion of mild steel in an extremely acidic environment. LGP inhibitory effectiveness is temperature and inhibitor concentration dependent, reducing with rising temperature and increasing with increased LGP concentration. The maximum inhibition efficiencies deduced by weight loss, impedance and potentiodynamic measurements with 7.5 × 10−3 M LGP at 30 °C were 96.3%, 96% and 94%, respectively. The results of polarization measurement suggested a mixed-type inhibitory action of LGP, reducing the anodic/cathodic partial reaction. Adsorption of LGP onto the steel surface obeyed Langmuir isotherm, with a combination of chemical and physical adsorption. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) revealed the adsorbed inhibitor film layer shielding the mild steel from hostile acid ions. DFT/MD simulation approaches were used to investigate the adsorption orientation of LGP's molecule on the mild steel surface in aqueous environment. The experimental routes strongly conform with the theoretical findings.

Thermodynamic and Computational (DFT) Study of Non-Covalent Interaction Mechanisms of Charge Transfer Complex of Linagliptin with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and Chloranilic acid (CHA).

This study describes the non-covalent interactions of the charge transfer complex (CT), which was responsible for the synthesis of Linagliptin (LNG) with 2,3-Dichloro-5,6-Dicyano-1,4-benzoquinone (DDQ), or with Chloranilic acid (CHA) complexes in acetonitrile (MeCN) at temperatures of (25 ± 2 °C). Then, a UV–Vis spectrophotometer was utilized to identify Linagliptin (LNG) from these complexes. For the quantitative measurement of Linagliptin in bulk form, UV–Vis techniques have been developed and validated in accordance with ICH criteria for several aspects, including selectivity, linearity, accuracy, precision, LOD, LOQ, and robustness. The optimization of the complex synthesis was based on solvent polarization; the ratio of molecules in complexes; the association constant; and Gibbs energy (ΔG°). The experimental work is supported by the computational investigation of the complexes utilizing density functional theory as well as (QTAIM); (NCI) index; and (RDG). According to the optimized conditions, Beer’s law was observed between 2.5–100 and 5–100 µM with correlation coefficients of 1.9997 and 1.9998 for LGN-DDQ and LGN-CHA complexes, respectively. For LGN-DDQ and LGN-CHA complexes, the LOD and LOQ were (1.0844 and 1.4406 μM) and (3.2861 and 4.3655 μM), respectively. The approach was successfully used to measure LGN in its bulk form with high precision and accuracy.

DSC, FT-IR and NIR with Chemometric Assessment Using PCA and HCA for Estimation of the Chemical Stability of Oral Antidiabetic Drug Linagliptin in the Presence of Pharmaceutical Excipients.

Pharmaceutical excipients should not interact with active substances, however, in practice, they sometimes do it, affecting the efficacy, stability and safety of drugs. Thus, interactions between active substances and excipients are not desirable. For this reason, two component mixtures of oral antidiabetic drug linagliptin (LINA) with four excipients of different reactivity, i.e., lactose (LAC), mannitol (MAN), magnesium stearate (MGS) and polyvinylpyrrolidone (PVP), were prepared in a solid state. A high temperature and a high humidity of 60 °C and 70% RH, respectively, were applied as stressors in order to accelerate the potential interactions between LINA and excipients. Differential scanning calorimetry (DSC) as well as Fourier transform infrared (FT-IR) and near infrared (NIR) spectroscopy were used to estimate the changes due to potential interactions. In addition, chemometric computation of the data with principal component analysis (PCA) and hierarchical cluster analysis (HCA) was applied to adequately interpret the findings. Of the excipients used in the present experiment, all of them were not inert in relation to LINA. Some of the interactions were shown without any stressing, whereas others were observed under high-temperature/high-humidity conditions. Thus, it could be concluded that selection of appropriate excipients for LINA is very important question to minimize its degradation, especially when new types of formulations with LINA are being developed and manufactured.