First derivative synchronous spectrofluorimetric analysis of bisoprolol fumarate and ivabradine in pharmaceutical and biological matrices. Investigation of the method greenness.

A novel, facile, rapid, and precise synchronous spectrofluorimetric method was evolved for the simultaneous estimation of bisoprolol fumarate and ivabradine in dosage forms and biological fluids. The estimation is based on measuring the first derivative of the synchronous fluorescence spectra of ivabradine and bisoprolol fumarate in ethanol at Δλ = 80 nm. The peak amplitudes are measured at 234.4 nm (zero-crossing point of ivabradine) and 244.0 nm (zero-crossing point of bisoprolol fumarate) to simultaneously analyze bisoprolol fumarate and ivabradine, respectively. The spectrofluorimetric method was optimized by investigating different solvent systems, pH values, and surfactants. The proposed method was linear over concentration ranges 30.0-200.0 ng/ml and 30.0-180.0 ng/ml for ivabradine and bisoprolol fumarate, respectively with detection limits of 4.88 and 5.28 ng/ml. The developed method was used for individual assay of the studied compounds in their pharmaceutical dosage forms with high percentage recoveries. Moreover, the method was applied to analyze ivabradine and bisoprolol fumarate in spiked human urine with percentage recoveries of 99.98 ± 1.16 and 99.95 ± 1.96 for ivabradine and bisoprolol fumarate, respectively. The method greenness was also investigated by Analytical GREEnness (AGREE), Analytical Eco-Scale, and Green Analytical Procedure Index (GAPI) metrics, which ensured the ecofriendship of the proposed method.

Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

Merck KGaA observed slight differences in the dissolution of Concor® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space." A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration-time curve were within the BE limits (0.8-1.25).

Bisoprolol-based 18F-PET tracer: Synthesis and preliminary in vivo validation of ß1-blocker selectivity for ß1-adrenergic receptors in the heart.

The selectivity of a drug toward various isoforms of the target protein family is important in terms of toxicology. Typically, drug or candidate selectivity is assessed by in vitro assays, but in vivo investigations are currently lacking. Positron emission tomography (PET) allows the non-invasive determination of the in vivo distribution of a radiolabeled drug, which can provide in vivo data regarding drug selectivity. Since the discovery of propranolol, a non-selective ß-blocker inhibiting both ß1- and ß2-adrenoreceptors (ß-ARs), various selective ß1-blockers, including bisoprolol, have been developed to overcome disadvantages associated with ß2-AR inhibition. As a proof of concept, we performed an in vivo PET study to understand the selectivity and efficacy of bisoprolol as a selective ß-blocker toward ß1-AR, as the heart and peripheral smooth muscles demonstrate distinct populations of ß1- and ß2-ARs. Biodistribution of 18F-labeled bisoprolol (1, [18F]bisoprolol) showed the retention of its uptake in the heart compared with other ß-AR-rich organs at late time points post-injection. The competitive blocking assay using unlabeled bisoprolol exhibited no inhibition of [18F]bisoprolol uptake in any organ but exhibited significantly rapid loss of radioactivity between two different time points in ß1-AR-rich organs such as the heart and brain. Furthermore, the organ-to-blood ratio revealed the slow excretion and better accumulation of [18F]bisoprolol inside the heart. Collectively, the ex vivo biodistribution and blocking study presented insightful evidence to better comprehend the in vivo distribution pattern of bisoprolol as a selective inhibitor targeting ß1-ARs in the heart and provided the possibility of PET as an in vivo technique for evaluating drug selectivity.

Bisoprolol: A comprehensive profile.

The present study describes a comprehensive profile of Bisoprolol including detailed nomenclature; formulae, elemental analysis, appearance, its uses, applications, and methods for the preparation are outlined. The profile contains physicochemical properties of Bisoprolol including pKa value, solubility, X-ray powder diffraction, and methods of analysis (including compendial, electrochemical, spectroscopic, chromatographic and capillary electrophoresis). The study also covers thermal analysis such as differential scanning calorimetry and thermogravimetry of Bisoprolol. Which gives a brief idea of melting point, glass transition as well as differentiation between anhydrous and hydrated forms. In addition to these functional groups and structural confirmation of bisoprolol also presented with the help of Fourier transform infrared spectrometry and nuclear magnetic resonance spectroscopy, respectively. The mass fragmentation pattern of bisoprolol fumarate was reported using the electrospray ionization technique. Some recently reported methods for pharmacokinetic analysis of bisoprolol using high-performance liquid chromatography as well as liquid chromatography-mass spectrometry were also included in the study.

Stability-Indicating RP-HPLC and CE Methods for Simultaneous Determination of Bisoprolol and Perindopril in Pharmaceutical Formulation: A Comparative Study.

Two fast, accurate and selective stability-indicating methods were developed and validated for the simultaneous determination of bisoprolol, perindopril and three of their possible degradation products. The first proposed method was a gradient reversed phase-high-performance liquid chromatography (HPLC) method, whereas the second was a capillary electrophoresis method. The structures of the obtained degradation products were elucidated using infrared and mass spectrometry. They were also confirmed to be either a drug impurity in the British Pharmacopoeia or a precursor to such impurity. The linearity for bisoprolol and perindopril was achieved in the range of 1-20 µg mL-1 and 5-30 µg mL-1 for HPLC and capillary electrophoresis methods, respectively. The proposed methods were validated according to the International Conference on Harmonisation guidelines. The HPLC method proved to be more sensitive and succeeded in the quantitative determination of the obtained degradation products. Also, it was able to quantify perindopril impurity up to three times lower than the desired limit set by the British Pharmacopoeia. They were successfully employed in the determination of bisoprolol and perindopril in their combined pharmaceutical formulation.

Assessment of the ecotoxicity of the pharmaceuticals bisoprolol, sotalol, and ranitidine using standard and behavioral endpoints.

The pharmaceuticals bisoprolol (BIS), sotalol (SOT), and ranitidine (RAN) are among the most consumed pharmaceuticals worldwide and are frequently detected in different aquatic ecosystems. However, very few ecotoxicity data are available in the literature for them. To help fill these data gaps, toxicity tests with the algae Raphidocelis subcapitata, the macrophyte Lemna minor, the cnidarian Hydra attenuata, the crustacean Daphnia similis, and the fish Danio rerio were performed for assessing the ecotoxicity of these pharmaceuticals. Standard, as well as non-standard endpoint, was evaluated, including the locomotor behavior of D. rerio larvae. Results obtained for SOT and RAN showed that acute adverse effects are not expected to occur on aquatic organisms at the concentrations at which these pharmaceuticals are usually found in fresh surface waters. On the other hand, BIS was classified as hazardous to the environment in the acute III category. Locomotor behavior of D. rerio larvae was not affected by BIS and RAN. A disturbance on the total swimming distance at the dark cycle was observed only for larvae exposed to the highest test concentration of 500 mg L-1 of SOT. D. similis reproduction was affected by BIS with an EC10 of 3.6 (0.1-34.0) mg L-1. A risk quotient (RQ) of 0.04 was calculated for BIS in fresh surface water, considering a worst-case scenario. To the best of our knowledge, this study presents the first chronic toxicity data with BIS on non-target organisms.

Molecular mechanism of ion-pair releasing from acrylic pressure sensitive adhesive containing carboxyl group: Roles of doubly ionic hydrogen bond in the controlled release process of bisoprolol ion-pair.

Though ion-pair strategy has been employed as an effective and promising method for controlling transdermal delivery of drugs, investigations into the underlying mechanisms involved in the controlled release process of ion-pairs are still limited. In the present study, a brand-new controlled release system combining acrylic pressure sensitive adhesive containing carboxyl group (carboxylic PSA) with ion-pair strategy was developed, and the molecular mechanism of ion-pair releasing from carboxylic PSA was systemically elucidated. Bisoprolol (BSP) and bisoprolol-lauric acid ion-pair (BSP-C12) were chosen as model drugs. Carboxylic PSA was designed and synthesized. Effect of ion-pair on controlling BSP release from carboxylic PSA was evaluated by in vitro drug release study, in vitro skin permeation study and pharmacokinetic study. Molecular mobility of PSA, along with the strength of drug-PSA interaction was evaluated by thermal analysis and dielectric spectroscopy. Molecular details of drug-PSA interaction were identified by FTIR, XPS and Raman. Roles of drug-PSA interaction in the controlled release process were clarified by molecular modeling. Results showed that BSP-C12 patch demonstrated a controlled release drug plasma profile, with lower Cmax (193 ±â€¯63 ng/mL) and longer MRT (19.9 ±â€¯3.4 h) compared to BSP patch (Cmax,BSP = 450 ±â€¯28 ng/mL, MRTBSP = 7.9 ±â€¯0.9 h). Besides, there was no significant difference between the AUC of BSP-C12 and BSP patch. It turned out that instead of PSA molecular mobility, molecular interaction between ion-pair and PSA played a dominant role in the controlled release process of BSP: as illustrated by FTIR, Raman and molecular docking, the ionic interaction between BSP-C12 and PSA determined the amount of BSP released, namely the thermodynamic process; while the doubly ionic hydrogen bond between BSP-C12 and PSA-COO- controlled the release rate, which was the kinetic process. In conclusion, it was found that the doubly ionic hydrogen bond formed between carboxylic PSA and ion-pair controlled the release profile of BSP, which broadened our understanding about the molecular mechanisms involved in ion-pair controlled release transdermal patches and contributed to the design of controlled release TDDS.

Mechanism study on ion-pair complexes controlling skin permeability: Effect of ion-pair dissociation in the viable epidermis on transdermal permeation of bisoprolol.

Though ion-pair strategy has been widely used in transdermal drug delivery system, knowledge about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes is still limited. In the present study, a homologous series of fatty acids were chosen to form model ion-pair complexes with bisoprolol (BSP) to rule out the influence of functional groups on polar surface area, stability and other physicochemical properties of ion-pair complexes. The ion-pair complexes were characterized by FTIR, thermal analysis, and 1H NMR. The skin permeability of BSP as well as its ion-pair complexes was investigated by in vitro skin permeation experiments then visualized by CLSM. The skin permeability coefficient (kp) of BSP ion-pair complex was negatively related to its n-octanol/water apparent partition coefficient (P'o/w) in the hydrophobic vehicle caprylic/capric triglyceride, (log kp=-1.657-1.229 log P'o/w), suggesting that the instability of ion-pair complexes due to their dissociation in the viable epidermis (VED) played an important role in controlling the skin permeability of BSP, which was further proved by 1H NMR and molecular docking. These findings broadened our understanding about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes.

Development of liquid chromatographic methods for enantioseparation and sensitive detection of ß-adrenolytics/ß2-agonists in human plasma using a single enantiomer reagent.

Enantioseparation of four commonly used ß-adrenolytics (bisoprolol, salbutamol, and carvedilol, marketed as racemic mixtures) has been achieved by both TLC and RPHPLC via an indirect approach. A new chiral reagent, (S)-naproxen benzotriazole ester, was synthesized and it was characterized by UV, IR, 1HNMR, elemental analysis and polarimetry. It was used to synthesize diastereomeric derivatives of the three ß-adrenolytics under microwave irradiation. TLC separation of diastereomeric derivatives was achieved which were then isolated by preparative approach; these were characterized and were used as standard reference for determining absolute configuration of diastereomeric derivatives and for establishing validated HPLC method for enantioseparation and sensitive detection of the three ß-adrenolytics in human plasma. Mobile phase in gradient mode containing methanol and aqueous triethylaminephosphate (TEAP) was successful for HPLC separation; conditions with respect to pH, flow rate, and buffer concentration were optimized. The method is capable to accurately quantitate ß-adrenolytics in human plasma with minimal sample clean-up and rapid separation by TLC and RPHPLC. The limit of detection values were 0.97 and 0.87ng/mL for diastereomeric derivatives of (S)- and (R)-bisoprolol, respectively, which are very low in comparison to literature reports.

Influence of Peroxide Impurities in Povidone on the Stability of Selected ß-Blockers with the Help of HPLC.

A present study was conducted to investigate compatibility of ß-blocker drugs( like atenolol, labetalol hydrochloride, bisoprolol fumarate, metoprolol succinate, carvedilol and propranolol hydrochloride) with the pharmaceutical excipient povidone. To check the influence of peroxide impurity present in povidone on the stability of ß-blockers, a binary mixture technique has been adopted. The binary mixtures (1:1) of ß-blockers with povidone excipient were stored for the duration of 6 months at accelerated conditions (40°C and 75% RH) and analyzed with the technique of high-performance liquid chromatography (HPLC). On analysis, HPLC results shows that, the percentage of total impurity for atenolol-2.15%, bisoprolol fumarate-3.55%, carvedilol-2.19%, and labetalol hydrochloride-1.89%, with respect to povidone. To verify the interaction of H2O2 present in povidone as an impurity, oxidative degradation of selected active pharmaceutical ingredients were performed and degradation profile were compared with that of degradation impurities generated in drug-excipient mixture at accelerated conditions. The relative retention time (RRT) of impurities generated in accelerated stability study samples resembles the RRT of degradation products generated by oxidative degradation of pure drugs. Thus, it confirms that degradation of ß-blockers with povidone was mediated by organic peroxides present as an impurity in povidone.

EFFECT OF HYDROPHILIC AND HYDROPHOBIC POLYMER ON IN VITRO DISSOLUTION AND PERMEATION OF BISOPROLOL FUMARATE THROUGH TRANSDERMAL PATCH.

A matrix transdermal patch of bisoprolol fumarate was formulated with different concentrations of Eudragit RS 100 and Methocel E5 with PEG 400 as plasticizer by solvent evaporation technique. Tween 80 was added to the optimized patch to evaluate the effect of permeation enhancer at different concentration through the excised rabbit's skin. The patches were analyzed for weight variation, drug content, swelling index, erosion studies, moisture content, moisture uptake, water vapor transmission rate (WVTR) and water vapor permeability (WVP). In vitro dissolution test was carried out in USP dissolution apparatus V to select the optimized formulation. In vitr skin permeation studies were done in Franz diffusion cell using rabbit skin as a model membrane. The cumulative drug release and flux were determined to compare the result of test patches with a control patch. The greatest enhancement ratio (ER) was obtained in F03-PE with 30% Tween 80. F03-PE seemed to follow zero order kinetics with super case II mechanism of drug release. Statistical ANOVA suggested that there was a significant difference in formulations, steady flux and cumulative permeation rate at different Tween 80 concentrations.

Forecasting oral absorption across biopharmaceutics classification system classes with physiologically based pharmacokinetic models.

OBJECTIVES: The aim of this study was (1) to determine how closely physiologically based pharmacokinetic (PBPK) models can predict oral bioavailability using a priori knowledge of drug-specific properties and (2) to examine the influence of the biopharmaceutics classification system class on the simulation success. METHODS: Simcyp Simulator, GastroPlus™ and GI-Sim were used. Compounds with published Biowaiver monographs (bisoprolol (BCS I), nifedipine (BCS II), cimetidine (BCS III), furosemide (BCS IV)) were selected to ensure availability of accurate and reproducible data for all required parameters. Simulation success was evaluated with the average fold error (AFE) and absolute average fold error (AAFE). Parameter sensitivity analysis (PSA) to selected parameters was performed. KEY FINDINGS: Plasma concentration-time profiles after intravenous administration were forecast within an AAFE < 3. The addition of absorption processes resulted in more variability in the prediction of the plasma profiles, irrespective of biopharmaceutics classification system (BCS) class. The reliability of literature permeability data was identified as a key issue in the accuracy of predicting oral drug absorption. CONCLUSION: For the four drugs studied, it appears that the forecasting accuracy of the PBPK models is related to the BCS class (BCS I > BCS II, BCS III > BCS IV). These results will need to be verified with additional drugs.

Prognostic Benefits of Carvedilol, Bisoprolol, and Metoprolol Controlled Release/Extended Release in Hemodialysis Patients with Heart Failure: A 10-Year Cohort.

BACKGROUND: Heart failure is a highly prevalent cardiovascular complication among patients receiving long-term hemodialysis, but the benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release on the outcomes of these patients remain unclear. In this study, we address the use of these 3 ß-blockers and their associations with mortality. METHODS AND RESULTS: Long-term hemodialysis patients, aged ≥35 years, with new-onset heart failure and receiving various medications were identified through the use of 1999-2010 data from the Taiwan National Health Insurance Research Database. From the total of 4435 heart failure patients, we selected 1700 new users of the 3 ß-blockers (study group) and 1700 nonusers (control group), by using matched cohorts according to their propensity scores, and then compared the 5-year all-cause mortality rates by using Cox proportional hazard regressions and time-dependent covariate adjustment. During 3944 person-years of follow-up, 666 (39.2%) deaths occurred within the study group, compared with 918 (54%) deaths during 2893 person-years of follow-up in the control group. The 5-year mortality rate for the study (control) group was 54.5% (70.3%); P<0.001. Adjusted hazard regression analyses revealed that the therapeutic effects of ß-blockers remained significant for all-cause mortality (hazard ratio 0.80, 95% CI 0.72 to 0.90). Subgroup analyses revealed that patients in the study group receiving ß-blockers plus renin-angiotensin system antagonists exhibited the lowest mortality rate, while the highest mortality rate was found among patients in the control group receiving neither ß-blockers nor renin-angiotensin system antagonists. CONCLUSIONS: This study demonstrates that the 3 ß-blockers were associated with improved survival in long-term hemodialysis patients with heart failure.

Preparation of bisoprolol fumarate nasal spray and its nasal delivery in rats.

The aim of the present work was to prepare a nasal spray of bisoprolol fumarate (BF). The Pharmacokinetics and relative bioavailability of the BF nasal formulation were evaluated in Wistar rats. The BF nasal spray after administration exhibited very fast absorption and higher plasma drug concentration. The maximum plasma concentration (C(max)) and the time to reach it (T(max)) were 409.5 ng/ml and 3.6 min for the BF nasal spray, 39.4 ng/ml and 26.7 min for the drug solution, respectively. The bioavailability of the BF nasal spray was greater than 1500.0%. Meantime, the effect of the BF nasal spray on nasal mucociliary movement was also studied with a toad palate model. The BF nasal preparation showed minor ciliotoxicity, but the adverse effect was temporary and reversible.

Application of HPLC to assess the compatibility of bisoprolol fumarate with selected excipients in mixtures by isothermal stress testing.

In the present study, the compatibility between bisoprolol fumarate and selected excipients (ascorbic acid, citric acid anhydrous, butylated hydroxyanisole, polyvinylpyrrolidone, glycerol, mannitol and sorbitol) in mixtures (1:10 ratio of drug and excipient) was investigated by subjecting the samples to isothermal stress conditions (90 °C for 48 h). A new HPLC method was developed, validated and employed for determining the drug content of the stressed compatibility samples. Results of HPLC revealed that major degradation of bisoprolol fumarate was observed with butylated hydroxyanisole (89.4%), citric acid anhydrous (89%), mannitol (77%) and glycerol (61.9%).

Dual-directional regulation of drug permeating amount by combining the technique of ion-pair complexation with chemical enhancers for the synchronous permeation of indapamide and bisoprolol in their compound patch through rabbit skin.

To achieve the synchronous skin permeation of indapamide (IND) and bisoprolol (BSP) in their compound patch, the techniques of ion-pair complexation and chemical enhancers were combined to dual-directionally regulate drug permeating amounts. Ion-pair complexes of BSP and various organic acids were formed by the technique of ion-pair complexation. Among the complexes formed, bisoprolol tartrate (BSP.T) down-regulated the permeating amount of BSP to the same extent as that of IND. Then, to simultaneously up-regulate the amounts of the two drugs, an enhancer combination of 15.8% Span80 (SP), 6.0% Azone (AZ) and 2.2% N-methyl pyrrolidone (NMP) was obtained by central composite design and exhibited an outstanding and simultaneous enhancement on IND and BSP with enhancing ratio (ER) of 4.52 and 3.49, respectively. The effect of the dual-directional regulation was evaluated by in vitro permeation experiments and in vivo pharmacokinetic studies. For IND and BSP, their observed permeation profiles were comparable and their MAT (mean absorption time) showed no significant difference, which both demonstrated these two drugs achieved the synchronous skin permeation in their compound patch by the dual-directional regulation strategy of combining the technique of ion-pair complexation with chemical enhancers.

Bisoprolol and bisoprolol-valsartan compatibility studied by differential scanning calorimetry, nuclear magnetic resonance and X-ray powder diffractometry.

PURPOSE: The objective of this study was to evaluate the thermal behavior of crystalline and amorphous bisoprolol fumarate and its compatibility with amorphous valsartan. This pharmacologically relevant drug combination is a potential candidate for fixed-dose combination formulation. METHODS: DSC and TMDSC were used to examine thermal behavior of bisoprolol fumarate. SSNMR and XRPD were applied to probe the solid state forms. The thermal behavior of physical mixtures with different concentrations of bisoprolol and valsartan were examined by DSC and TMDSC, and the observed interactions were investigated by XRPD, solution- and solid-state NMR. RESULTS: The phase transitions from thermal methods and solid-state NMR spectra of crystalline and amorphous bisoprolol fumarate are reported. Strong interactions between bisoprolol fumarate and valsartan were observed above 60 C, resulting in the formation of a new amorphous material. Solution- and solid-state NMR provided insight into the molecular nature of the incompatibility. CONCLUSIONS: A combined analysis of thermal methods, solution- and solid-state NMR and XRPD experiments allowed the investigation of the conformational and dynamic properties of bisoprolol fumarate. Since bisoprolol fumarate and valsartan react to form a new amorphous product, formulation of a fixed-dose combination would require separate reservoirs for bisoprolol and valsartan to prevent interactions. Similar problems might be expected with other excipients or APIs containing carboxylic groups.

IN VITRO TESTING OF XANTHAN/LIGNIN HYDROGELS AS CARRIERS FOR CONTROLLED DELIVERY OF BISOPROLOL FUMARATE.

AIM: To develop sustained release matrix tablets based on xanthan as highly water-soluble, cost-effective, non-toxic, easily available, and suitable hydrophilic systems. MATERIAL AND METHODS: Xanthan and lignin epoxy-modified resin (LER) mixture were crosslinked using epichlorohydrin as crosslinking agent leading to superabsorbent hydrogels with high swelling rate in aqueous mediums. RESULTS AND CONCLUSIONS: These hydrogels were tested as carries by the loading/delivery behaviour of bisoprolol fumarate in physiological conditions and based on the obtained results these hydrogels may show interest for application in medical and pharmaceutical areas. The amount of drug loaded in polymer networks was found to be ranging between 14.4% and 19.2%. Drug release was retarded and the release mechanism of the active principle was found to depend on matrix composition.

Spectrophotometric method for estimation of bisoprolol fumarate in tablets.

UNLABELLED: Bisoprolol fumarate is prescribed for the treatment of hypertension and angina pectoris. AIM: The purpose of this study was to develop a simple, sensitive, accurate, and reproducible method for estimation of bisoprolol fumarate in tablets. MATERIAL AND METHODS: The proposed method was based on a yellow colored complex formed with tropaeolin 00, extractable in dichloromethane with maximum absorbance at 412 nm. The method was validated statistically. RESULTS: The linearity domain was observed in the concentration of 5-30 microg/ml. The recovery studies confirmed the accuracy of the proposed method. CONCLUSIONS: The proposed method can be applied for the routine analysis of bisoprolol from formulations.