An Integrative QbD Approach for the Development and Optimization of Controlled Release Compressed Coated Formulation of Water-Soluble Drugs.

Controlled release dosage forms maintain regulated pharmacokinetic profile of drug substance within its therapeutic window by ensuring constant plasma concentrations. Controlled release formulations not only increase the therapeutic efficacy of drug substances but also reduce their dose-related side effects. Present investigation was conducted to develop, optimize, and validate compressed coated controlled release tablet formulation for highly water-soluble drug substances which have no rate-controlling factor towards its release from dosage form. Drug dispersed waxy core tablet, press coated within the swellable hydrophilic polymeric barrier layer, was developed and optimized via quality by design approach (QbD) using Box-Behnken design. The optimized formulation was characterized and validated using in vitro quality control parameters. Attributes identified under SUPAC guidelines, such as drug release rates at 30 min, 6 h, and 12 h, were considered as the critical quality attributes (CQAs) that significantly affected efficiency of the compressed coated controlled release tablets. CQAs screened using risk assessment and Pareto chart analyses were used for optimizing controlled release dosage form. Findings revealed that tablets containing drug to wax ratio of 1:1, hydrophilic swellable polymer concentration of 200 mg, and prepared using compression pressure of 6.5 kg/cm2 exhibited the highest desirability indices in terms of controlling the release rate of drug substance. Optimized formulation was also evaluated for swelling rate, erosion rate, and other post-compression parameters, including release kinetics. Fickian diffusion-based zero-order controlled release of BCS class I drug substance was achieved through the developed dosage form.

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples.

BACKGROUND: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. METHODS: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. RESULTS: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. CONCLUSION: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

Measurements, Thermodynamic Modeling, and a Hydrogen Bonding Study on the Solubilities of Metoprolol Succinate in Organic Solvents.

The solubilities of metoprolol succinate (a cardioselective ß1 adrenergic receptor) in methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, and acetone were measured at temperatures ranging from (278.2 to 318.2) K using a solid⁻liquid equilibrium method. The solubility of metoprolol succinate increases with increasing temperature. At a fixed temperature, the solubility decreases in the order methanol > ethanol > n-butanol > n-propanol > isopropanol > acetone > ethyl acetate. The enthalpy of fusion and the melting point of metoprolol succinate were determined by differential scanning calorimetry. The thermodynamic properties of the dissolution process, determined by a van't Hoff analysis, have been obtained and are discussed. The modified Apelblat equation, Wilson model, and non-random two-liquid (NRTL) model were employed to correlate the solubilities of metoprolol succinate in different solvents. Finally, a quantitative structure⁻property relationship (QSPR) study of physical properties of solvents and density functional theory simulations of hydrogen-bonding structure were carried out to give the explanation for the sequence of solubility in alcohols. The density functional theory (DFT) calculations well illustrated that the solubility of metoprolol succinate in various alcohols can be mainly attributed to the intra- and intermolecular hydrogen bonds in metoprolol succinate-solvent complexes.

Effect of Metoprolol Succinate in Patients with Stable Angina and Elevated Heart Rate Receiving Low-Dose ß-Blocker Therapy.

Aims: ß-blockers are underused in Chinese patients with coronary heart disease. The prescribed dose is often low. The aim of this study was to investigate the effect of metoprolol succinate doses of 95 mg and 190 mg on heart rate (HR) control, as well as drug tolerance, in Chinese patients with stable angina, low-dose ß-blocker use and unsatisfactory HR control. Methods: This was a multicenter, randomized, open-label, parallel-group trial in 15 clinical sites. Patients with stable angina, taking low-dose ß-blockers (equivalent to metoprolol succinate 23.75-47.5 mg/day), and having a resting HR of ≥ 65 bpm were enrolled and randomized to either the metoprolol 95-mg group or the 190-mg group. The change in 24-h average HR from baseline recorded by Holter monitoring and the percentages of patients with resting HR controlled to ≤ 60 bpm were compared between the two groups. Results: Two hundred thirty-one patients entered the intent-to-treat population for the main analysis. The change in 24-h average HR from baseline was -0.62 ± 0.66 bpm in the 95 mg group and -2.99 ± 0.62 bpm in the 190 mg group (p = 0.0077) after 8 weeks of treatment. The percentages of patients with resting HR controlled to ≤ 60 bpm were 24.1% (95% CI: 16.35%, 31.93%) and 40.0% (95% CI: 31.05%, 48.95%), respectively (p = 0.0019). Only 4 and 2 of the patients, respectively, discontinued the study drugs because of hypotension or bradycardia. Conclusions: The metoprolol succinate dose of 190 mg is superior to the 95 mg dose in terms of HR control, in Chinese patients with stable angina, low-dose ß-blocker use and unsatisfactory HR control. Both doses were well tolerated.

Probing the mechanism of interaction of metoprolol succinate with human serum albumin by spectroscopic and molecular docking analysis.

In the present work, the mechanism of the interaction between a ß1 receptor blocker, metoprolol succinate (MS) and human serum albumin (HSA) under physiological conditions was investigated by spectroscopic techniques, namely fluorescence, Fourier transform infra-red spectroscopy (FT-IR), fluorescence lifetime decay and circular dichroism (CD) as well as molecular docking and cyclic voltammetric methods. The fluorescence and lifetime decay results indicated that MS quenched the intrinsic intensity of HSA through a static quenching mechanism. The Stern-Volmer quenching constants and binding constants for the MS-HSA system at 293, 298 and 303 K were obtained from the Stern-Volmer plot. Thermodynamic parameters for the interaction of MS with HSA were evaluated; negative values of entropy change (ΔG°) indicated the spontaneity of the MS and HSA interaction. Thermodynamic parameters such as negative ΔH° and positive ΔS° values revealed that hydrogen bonding and hydrophobic forces played a major role in MS-HSA interaction and stabilized the complex. The binding site for MS in HSA was identified by competitive site probe experiments and molecular docking studies. These results indicated that MS was bound to HSA at Sudlow's site I. The efficiency of energy transfer and the distance between the donor (HSA) and acceptor (MS) was calculated based on the theory of Fosters' resonance energy transfer (FRET). Three-dimensional fluorescence spectra and CD results revealed that the binding of MS to HSA resulted in an obvious change in the conformation of HSA. Cyclic voltammograms of the MS-HSA system also confirmed the interaction between MS and HSA. Furthermore, the effects of metal ions on the binding of MS to HSA were also studied.

Novel ethylcellulose-coated pellets for controlled release of metoprolol succinate without lag phase: characterization, optimization and in vivo evaluation.

The objective of this study was to develop a novel ethylcellulose (EC)-coated pellet with partial active dose as a pore former for the controlled release of water-soluble metoprolol succinate (MS) without an initial lag phase (slow/non-drug release phase). MS-layered cores with a high drug-loading efficiency (97%, w/w), a smooth surface, and an acceptable level of resistance to abrasion were first obtained by spraying a concentrated drug solution (60% w/w at 70 °C) on non-pareils in the absence of other binders. The presence of the drug in an EC coating solution significantly improved the coating process by reducing pellet stickiness. Central composite design and response surface methodology was employed to optimize and explore the effect of pore former MS level (X1) and EC coating level (X2) on the drug release. The pore former level had a positive effect on the MS release and the coating level had a negative effect. The level of X1 and X2 of the optimization were 17% and 23%, respectively, and the cumulative percent of MS released within 1 h was up to 9.2%. Accordingly, the initial lag phase associated with in vitro drug release from EC-coated pellets was absent when MS drug was used as a pore former, which was further confirmed by in vivo drug release in beagle dogs. Thus, a novel approach for the controlled release of MS from coated pellets without lag phase has been successfully developed, which is valuable for the advancement of sustained-release pellets.

Area under the curve and ratio difference spectrophotometric methods with evaluation of the greenness for simultaneous determination of olmesartan medoxomil and metoprolol succinate.

The aim of this study is to develop and validate two simple spectrophotometric methods for simultaneous determination of metoprolol succinate (MET) and olmesartan medoxomil (OLM) in tablet form. Method (I) was area under the curve (AUC) method. This approach involved the measuring of the area over a variety of wavelengths. Two wavelength ranges; 213-230 nm and 244-266 nm were chosen for determination of MET and OLM, respectively. Method (II) was ratio difference spectrophotometricmethod. For determination of MET, the ratio spectra were generated using 15 µg/mL OLM as a divisor then the peak to trough amplitudes between 221 nm and 245 nm were displayed versus the corresponding concentrations of MET. For determination of OLM, the peak-to-peak amplitudes between 247 and 293 nm were chosen and found to be directly proportional to OLM concentrations using 15 µg/mL MET as a divisor. The linearity ranges were 2-30 µg/mL and 2-25 µg/mL for MET and OLM, respectively. The assay results showed good mean %recovery ± SD as well as good agreement with that of the reported method. The developed methods were validated according to ICH guidelines. The developed methods are accurate, precise, eco-friendly and could be applied successfully to estimate OLM and MET in their combined dosage form.

Coupling of synchronous fluorescence spectroscopy with derivative amplitude outcomes for simultaneous determination of metoprolol succinate and olmesartan medoxomil in combined pharmaceutical preparation: Application in spiked human plasma.

For the first time a spectrofluorimetric method had been achieved for the concurrent analysis of metoprolol succinate (MET) and olmesartan medoxomil (OLM). The approach depended on assessing the first order derivative (1D) of the synchronous fluorescence intensity of the two drugs in aqueous solution at Δλ of 100 nm. The amplitudes of 1D at 300 nm and 347 nm were measured for MET and OLM, respectively. The linearity ranges were 100-1000 ng/mL and 100-5000 ng/mL for OLM and MET, respectively. This approach is uncomplicated, repetitive, quick, and affordable. The results of analysis had been statistically verified. The validation assessments were carried out following the recommendations of The International Council for Harmonization (ICH). This technique could be employed to assess marketed formulation. The method was sensitive with limits of detection (LOD) of 32 ng/ml and 14 ng/mL for MET and OLM, respectively. Limits of quantitation (LOQ) were 99 ng/ml for MET and 44 ng/mL for OLM. So it can be applied to determine both drugs in spiked human plasma within the linearity ranges of 100-1000 ng/mL for OLM and 100-1500 ng/mL for MET.

Five-year results of heart rate control with ivabradine or metoprolol succinate in patients after heart transplantation.

BACKGROUND: Cardiac graft denervation causes inadequate sinus tachycardia in patients after heart transplantation (HTX) which is associated with reduced survival. This study investigated the 5-year results of heart rate control with ivabradine or metoprolol succinate in patients after HTX. METHODS: This registry study analyzed 104 patients receiving either ivabradine (n = 50) or metoprolol succinate (n = 54) within 5 years after HTX. Analysis included patient characteristics, medication, echocardiographic features, cardiac catheterization data, cardiac biomarkers, heart rates, and post-transplant survival including causes of death. RESULTS: Demographics and post-transplant medication revealed no significant differences except for ivabradine and metoprolol succinate use. At 5-year follow-up, patients with ivabradine had a significantly lower heart rate (73.3 bpm) compared to baseline (88.6 bpm; P < 0.01) and to metoprolol succinate (80.4 bpm; P < 0.01), a reduced left ventricular mass (154.8 g) compared to baseline (179.5 g; P < 0.01) and to metoprolol succinate (177.3 g; P < 0.01), a lower left ventricular end-diastolic pressure (LVEDP; 12.0 mmHg) compared to baseline (15.5 mmHg; P < 0.01) and to metoprolol succinate (17.1 mmHg; P < 0.01), and a reduced NT-proBNP level (525.4 pg/ml) compared to baseline (3826.3 pg/ml; P < 0.01) and to metoprolol succinate (1038.9 pg/ml; P < 0.01). Five-year post-transplant survival was significantly better in patients with ivabradine (90.0%) versus metoprolol succinate (68.5%; P < 0.01). CONCLUSION: Patients receiving ivabradine showed a superior heart rate reduction and a better left ventricular diastolic function along with an improved 5-year survival after HTX.

Perspective on the Role of Four Beta-blockers in Heart Failure.

BACKGROUND: The current recommendations of the American College of Cardiology/ American Heart Association and a previous Bayesian analysis clearly show a mortality benefit with the use of ß- blockers in chronic HF, especially for bisoprolol, carvedilol, and sustained-release metoprolol succinate. OBJECTIVE: The main objective was to report the evidence on the use of the afore-mentioned ß-blockers in subjects with heart failure and to characterize the stages of heart failure in response to the four different ß-blockers. Furthermore, it shed light on the patient's satisfaction and improved quality of life using the afore-mentioned ß-blockers in subjects with heart failure. METHODS: The current perspective presented the clinical outcomes, including hospitalization, morbidity, mortality, patient's satisfaction, and quality of life, of four beta (ß)-blockers, namely bisoprolol, carvedilol, metoprolol succinate, and nebivolol in different stages of heart failure. RESULTS: The use of these three agents should be recommended for all stable subjects with current or previous symptoms of heart failure and heart failure with reduced ejection fraction unless there is any contraindication. The fore-mentioned ß-blockers (bisoprolol, carvedilol, and metoprolol succinate) can be initiated early, even in stable and symptom-free (at rest) subjects with heart failure. ß-blockers in heart failure should be commenced at small doses and then titrated upward as tolerated to achieve the desired clinical effects on heart rate and symptom control. CONCLUSION: Cardiologists should weigh the benefit-risk in subjects with heart failure and other coexisting cardiovascular problems such as atrial fibrillation and diabetes.

Development of Extended-Release Mini-Tablets Containing Metoprolol Supported by Design of Experiments and Physiologically Based Biopharmaceutics Modeling.

The development of extended-release dosage forms with adequate drug release is a challenge for pharmaceutical companies, mainly when the drug presents high solubility, as in Biopharmaceutics Classification System (BCS) class I. This study aimed to develop extended-release mini-tablets containing metoprolol succinate (MS), while integrating design of experiments (DOE) and physiologically based biopharmaceutics modeling (PBBM), to predict its absorption and to run virtual bioequivalence (VBE) studies in both fasted and fed states. Core mini-tablet formulations (F1, F2, and F3) were prepared by direct compression and coated using nine coating formulations planned using DOE, while varying the percentages of the controlled-release and the pore-forming polymers. The coated mini-tablets were submitted to a dissolution test; additional formulations were prepared that were optimized by simulating the dissolution profiles, and the best one was submitted to VBE studies using GastroPlus® software. An optimized formulation (FO) containing a mixture of immediate and extended-release mini-tablets showed to be bioequivalent to the reference drug product containing MS when running VBE studies in both fasted and fed states. The integration of DOE and PBBM showed to be an interesting approach in the development of extended-release mini-tablet formulation containing MS, and can be used to rationalize the development of dosage forms.

Amiodarone vs. metoprolol succinate in HFrEF complicated with persistent atrial fibrillation with rapid ventricular response: A prospective observational study.

Background: ß-blockers have been recommended for patients with heart failure (HF) and atrial fibrillation (AF), but studies have shown that ß-blockers do not reduce all-cause mortality or cardiovascular mortality in patients with HF and AF. Objective: To investigate the difference in efficacy between oral amiodarone and metoprolol succinate for patients with HF with reduced ejection fraction (HFrEF) and persistent atrial fibrillation (pAF) with rapid ventricular response (RVR). Methods: Patients with HFrEF complicated with pAF with RVR treated in the People's Hospital of Chongqing Hechuan between March 2018 and March 2019 were enrolled in this prospective observational study. The primary outcomes were cardiovascular mortality and the first hospitalization for HF rate. The secondary outcomes were type B pro-brain natriuretic peptide (NT-proBNP) before/after treatment, left ventricular ejection fraction (LVEF) before/after treatment, average heart rate (AhR), and the rate of sinus rhythm after 1 year of follow-up. Results: A total of 242 patients with HFrEF complicated with pAF with RVR were enrolled and divided into amiodarone + perindopril + spironolactone+ routine drug (amiodarone group, n = 121) and metoprolol succinate + perindopril + spironolactone +routine drug (metoprolol succinate group, n = 121) according to their treatment strategy. Cardiovascular mortality (4.9 vs. 12.4%, HR: 2.500, 95%CI: 1.002-6.237, P = 0.040) and first hospitalization for HF (52.9 vs. 67.8%, HR: 1.281, 95%CI: 1.033-1.589, P = 0.024) were significantly lower in the amiodarone group than in the metoprolol group. The mean ventricular rate in the amiodarone group was significantly lower than in the metoprolol group (64.5 ± 3.2 vs. 72.4 ± 4.2, P < 0.001). After 1 year of follow-up, the sinus rhythm rate was significantly higher in the amiodarone group than in the metoprolol group (38.8 vs. 7.4%, HR: 0.191, 95%CI: 0.098-0.374, P < 0.001). The difference in proBNP (3,914.88 vs. 2,558.07, P < 0.001) and LVEF (-6.89 vs. -0.98, P < 0.001) before and after treatment was significantly higher in the amiodarone group than in the metoprolol group. Conclusion: In conclusion, in this prospective observational study, the amiodarone group had lower risk of cardiovascular death and the first hospitalization for HF than metoprolol in HFrEF and persistent atrial fibrillation (pAF) with RVR. The mechanism may be related to improved cardiac function, rhythm control and ventricular rate control. Registration number: ChiCTR2200057816; Registered 7 March 2022-Retrospectively registered: http://www.medresman.org.cn/pub/cn/proj/projectshshow.aspx?proj=4222.

Chemometric spectrophotometric methods for simultaneous estimation of metoprolol succinate and amlodipine besylate in their tablet formulation.

Two simple chemometric spectrophotometric methods; isosbestic point and dual wavelength methods were developed, validated and applied to the determination of metoprolol succinate in presence of amlodipine besylate in their binary mixtures and in combined tablet formulation while amlodipine besylate was determined by direct spectrophotometry at λ = 365 nm within linearity range of 2-25 µg/mL. The mean percentage recovery ± SD was 99.921 ± 0.089 for amlodipine besylate. Two proposed chemometric spectrophotometric methods were developed for the spectral resolution of metoprolol succinate in presence of amlodipine besylate without preliminary separation with a linearity range of 2-30 µg/mL metoprolol succinate. The first method depended on measuring the absorbance at the isosbestic point at λ = 226 nm. The mean percentage recovery ± SD was 100.110 ± 0.249 for metoprolol succinate. The second method was dual wavelength method, metoprolol could be determined alone using the absorbance difference between 226 nm and 248.7 nm where the absorbance difference was zero for amlodipine at these two wavelengths. The mean percentage recovery ± SD was 99.734 ± 0.438 for metoprolol succinate using dual wavelength method. The developed methods were validated as per ICH guidelines and were successfully applied to analysis of cited drugs in their synthetic tablet formulation. The results obtained by the developed methods were statistically compared to those obtained by a reported one using t-test and F- test. Good agreement was observed.

Development of a Scalable Process of Film-Coated bi-Layer Tablet Containing Sustained-Release Metoprolol Succinate and Immediate-Release Amlodipine Besylate.

The development of new drugs that combine active ingredients for the treatment hypertension is critically essential owing to its offering advantages for both patients and manufacturers. In this study, for the first time, detailed development of a scalable process of film-coated bi-layer tablets containing sustained-release metoprolol succinate and immediate-release amlodipine besylate in a batch size of 10,000 tablets is reported. The processing parameters of the manufacturing process during dry mixing-, drying-, dry mixing- completion stages were systematically investigated, and the evaluation of the film-coated bi-layer tablet properties was well established. The optimal preparation conditions for metoprolol succinate layer were 6 min- dry mixing with a high-speed mixer (120 rpm and 1400 rpm), 30-min drying with a fluid bed dryer, and 5-min- mixing completion at 25 rpm. For the preparation of amlodipine besylate layer, the optimal dry-mixing time using a cube mixer (25 rpm) was found to be 5 min. The average weight of metoprolol succinate layers and bi-layer tablets were controlled at 240-260 mg and 384-416 mg, respectively. Shewhart R chart and X¯ charts of all three sampling lots were satisfactory, confirming that the present scalable process was stable and successful. This study confirms that the manufacturing process is reproducible, robust; and it yields a consistent product that meets specifications.

Formulation Development and In-vitro/Ex-vivo Evaluation for a Polysaccharide-based Colon Targeted Matrix Tablet.

OBJECTIVE: The objective of this study was to develop and optimize a microflora-triggered colon targeted sustained-release dosage form using Gum Ghatti (GG) and Hydroxypropyl Methylcellulose (HPMC K100). METHODS: GG and HPMC K100 were used to prepare microflora triggered colon targeted sustained- release dosage form. For evaluation, two different tablets comprising metoprolol succinate and mesalamine as an active ingredient were used with the objective of developing a platform technology for various categories of drugs. The tablets were coated with Eudragit® L100 and Eudragit® S100 to provide enteric coating and evaluated for hardness, thickness, friability, weight variation, disintegration, and drug content. in vitro release studies for the prepared tablets were carried out mimicking the physiological transit time. Further, the effects of microflora were evaluated using rat cecal content. RESULTS: The in vitro dissolution profile of coated matrix tablets showed that 86.03±0.43% of metoprolol succinate and 80.26±0.67% of mesalamine were released at the end of 12 h. The ex vivo dissolution profile of coated matrix tablets showed that 96.50±0.27% of metoprolol succinate and 92.58±0.39% of mesalamine were released at the end of 12 h in the presence of rat ceacal content. The developed formulation was stable when subjected to the standard ICH stability study conditions. CONCLUSION: The result of this study showed that gum ghatti together with hydroxypropyl methylcellulose could be successfully used for the preparation of microflora-triggered colon targeted matrix tablets.

Static and dynamic structural features of single pellets determine the release behaviors of metoprolol succinate sustained-release tablets.

The multiple-unit sustained-release (MUSR) dosage forms containing numerous sustained-release subunits present a reliable choice for oral formulation of controlled release systems. As a typical MUSR, the metoprolol succinate sustained-release tablet is an advanced system with limited researches devoted to relating its structure to the drug release phase other than the preparation process and modulation to the release behaviors. This research details a three-dimension method to image the internal structure and detail drug release features of commercial metoprolol succinate sustained-release tablets and component individual single pellets. As such, a new perspective for MUSR dosage form is provided. Using high energy synchrotron radiation X-ray microcomputed tomography (SR-µCT), the in-situ structure parameters were obtained nondestructively. It was demonstrated that the average number of spherical pellets in a tablet was 853 ± 12 (n = 3). The average volume of the pellets was 0.09 ± 0.01 mm3, the diameter was 0.55 ± 0.03 mm, and the sphericity was 0.87 ± 0.06. These data reflected the numerical features of pellets in MUSR tablets, which were helpful for reverse engineering to MUSR. Based on the three dimensional model generated by image processing and analysis software, the pellet structures were divided into three layers of typical depot sustained release system: pellet core, drug-containing layer and outer film. The dynamic structural features determined refer to the changes of structures in pellets during in vitro drug release, with evidence that the coating layer on the pellets maintained a spherical morphology whilst numerous valleys appeared on the surface. The material constitution and distribution in coating layer were evaluated by synchrotron radiation-based Fourier transform infrared mapping and results indicated a composition of hydroxypropyl methylcellulose dispersed in ethyl cellulose. Knowledge of these structural characteristics confirmed that the mechanism of sustained drug release was membrane controlled and consistent with the drug release profiles. In conclusion, the structural investigation provided knowledge of the intrinsic quality of metoprolol succinate sustained-release tablets and offers guidance for reverse engineering of MUSR.

Elucidation of the Controlled-Release Behavior of Metoprolol Succinate from Directly Compressed Xanthan Gum/Chitosan Polymers: Computational and Experimental Studies.

The development and evaluation of a controlled-release (CR) pharmaceutical solid dosage form comprising xanthan gum (XG), low molecular weight chitosan (LCS), and metoprolol succinate (MS) are reported. The research is, partly, based upon the utilization of computational tools: in this case, molecular dynamics simulations (MDs) and the response surface method (RSM) in order to underpin the design/prediction and to minimize the experimental work required to achieve the desired pharmaceutical outcomes. The capability of the system to control the release of MS was studied as a function of LCS (% w/w) and total polymer (LCS and xanthan gum (XG)) to drug ratio (P/D) at different tablet tensile strengths. MDs trajectories, obtained by using different ratios of XG/LCS as well as XG and high molecular weight chitosan (HCS), showed that the driving force for the interaction between XG and LCS is electrostatic in nature, the most favorable complex is formed when LCS is used at 15% (w/w) and, importantly, the interaction between XG and LCS is more favorable than that between XG and HCS. RSM outputs revealed that the release of the drug from the LCS/XG matrix is highly dependent on both the % LCS and the P/D ratio and that the required CR effect can be achieved when using weight fractions of LCS ≤ 20% and P/D ratios ≥2.6:1. Results obtained from in vitro drug release and swelling studies on the prepared tablets showed that using LCS at the weight fractions suggested by MDs and RSM data plays a major role in overcoming the high sensitivity of the controlled drug release effect of XG on ionic strength and pH changes of the dissolution media. In addition, it was found that polymer relaxation is the major contributor to the release of MS from LCS/XG tablets. Using Raman spectroscopy, MS was shown to be localized more in the core of the tablets at the initial stages of dissolution due to film formation between LCS and XG on the tablet surface, which prevents excess water penetration into the matrix. In the later stages of the dissolution process, the film starts to dissolve/erode, allowing full tablet hydration and a uniform drug distribution in the swollen tablet.

A comparison of anti-arrhythmic efficacy of carvedilol vs metoprolol succinate in patients with implantable cardioverter-defibrillators.

BACKGROUND: The effects of carvedilol and metoprolol succinate on appropriate and inappropriate implantable cardioverter defibrillator (ICD) therapy in patients with heart failure with reduced ejection fraction (HFrEF) are not fully understood. HYPOTHESIS: The hypothesis of our study is possible carvedilol superiority over metoprolol in patients with ICD. METHODS: All patients with ICD registered to a single device clinic between 1/2012 and 6/2017 (n = 569) were identified. Patients with systolic heart failure (left ventricular ejection fraction ≤40%) treated with carvedilol vs metoprolol succinate were compared. Primary endpoint was difference in survival free of appropriate device therapy (shock or anti-tachycardia pacing, ATP). Secondary endpoints were freedom from inappropriate therapy (shock or ATP) and all cause death. RESULTS: A total of 225 patients were included in the analysis with median follow up of 57 months (IQR 33.7-90). The 2 groups were comparable in the baseline characteristics. Carvedilol was superior to metoprolol succinate in improving survival free of appropriate ICD therapy (HR 0.42; 95% CI 0.24-0.72, P = 0.01). This difference was driven by reduction in survival free of appropriate shocks (HR 0.30; 95% CI 0.15-0.63, P = -0.01) while there was no significant difference in appropriate ATP (HR 0.55; 95% CI 0.28-1.1, P = 0.12). There was no significant difference in time to inappropriate shocks (HR 1.02; 95% CI 0.19-5.6, P = 0.97), inappropriate ATP (HR 0.93, OR 0.24-3.5, p value 0.9) or all cause death (HR 0.8; 95% CI 0.42-1.5, P = 0.52). CONCLUSIONS: This study suggests that carvedilol use was associated with improved survival free of appropriate ICD therapy compared to metoprolol succinate in patients with HFrEF.

Quantitative analysis of 3-isopropylamino-1,2-propanediol as a degradation product of metoprolol in pharmaceutical dosage forms by HILIC-CAD.

Aryloxypropanolamine is an essential structural scaffold for a variety of ß-adrenergic receptor antagonists such as metoprolol. Molecules with such a structural motif tend to degrade into α, ß-hydroxypropanolamine impurities via a radical-initiated oxidation pathway. These impurities are typically polar and nonchromophoric, and are thus often overlooked using traditional reversed phase chromatography and UV detection. In this work, stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product, which is a specified impurity of metoprolol in the European Pharmacopoeia (impurity N). To ensure the safety and quality of metoprolol drug products, hydrophilic interaction chromatography (HILIC) methods using Halo Penta HILIC column (150 mm × 4.6 mm, 5 µm) coupled with charged aerosol detection (CAD) were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection, metoprolol tartrate tablets, and metoprolol succinate extended-release tablets. These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity, linearity, accuracy, and precision, and have been successfully applied to determine impurity N in metoprolol drug products.

Effect of the Surface Hydrophobicity Degree on the In Vitro Release of Polar and Non-Polar Drugs from Polyelectrolyte Matrix Tablets.

This work is the continuation of a series of studies focused on establishing the relationship between the surface thermodynamic properties of polyelectrolyte matrix tablets and drug release mechanisms. In this case, two model drugs with different polarity features, such as carbamazepine (non-polar) and metoprolol succinate (polar) were used in combination with polymeric material hydroxypropyl-methyl cellulose (HPMC) and two polyelectrolytes derived from maleic anhydride corresponding to the sodium salts of poly(maleic acid-alt-ethylene) and poly(maleic acid-alt-octadecene) named PAM-0Na and PAM-18Na, respectively. The polymers were obtained and characterized as reported previously. Surface studies were performed by the sessile drop method, whilst the surface free energy was determined through Owens, Wendt, Rable and Kaeble (OWRK) semi-empirical model. By contrast, the drug release studies were performed by in vitro dissolution tests, where data were analyzed through dissolution efficiency. The results showed that, depending on the drug polarity, type and polymer proportion, surface properties and drug release processes are significantly affected.