Ecological spectroscopic methodologies for quantifying co-administered drugs in human plasma by photochemical quantum mechanical simulation.

Urinary tract infections (UTIs) constitute the second most prevalent bacterial infections in the elderly demographic. The treatment landscape involves various antibiotics targeting the causative organisms; nevertheless, the emergence of resistance significantly impacts therapeutic effectiveness. Presently, a fixed-dose pharmaceutical combination is advocated to optimize patient outcomes by mitigating the risks of bacterial resistance and associated side effects. Ofloxacin (OFL) and cefpodoxime proxetil (CPD) combinations, co-administered with flavoxate hydrochloride (FLV), have demonstrated efficacy in UTI cases, offering relief from concomitant symptoms. In the pharmaceutical market, fixed-dose combinations have gained prominence, driven by advantages such as enhanced patient medication adherence and compliance. In the realm of analytical chemistry, the integration of green practices in the initial phases of method development is exemplified by the Greenness by Design (GbD) strategy. While univariate spectroscopic methods are conventionally considered suboptimal compared to chemometric techniques for resolving intricate mixtures, GbD approach, when applied to UV spectroscopy, enable univariate methods to attain comparable or superior outcomes. GbD adopts a systematic approach to optimize experimental conditions, minimizing environmental impact and maximizing analytical performance. Critical to GbD applications in UV spectroscopy is solvent selection, influencing spectral resolution and measurement sensitivity. GbD employs a combination of in-vitro and in-silico experiments to evaluate solute-solvent interactions with underlying photochemical quantum phenomena affecting the resulting spectral morphology, identifying an optimal compromise solvent with high resolution and minimal ecological impact. Consequently, it facilitates the efficient resolution of spectral overlapping and determination of complex mixtures in UV spectroscopy using univariate methods. Comparative analysis with chemometric techniques, acknowledged as potent spectral resolving methods, demonstrated that GbD-based univariate methods performed equivalently. The methodology was validated according to ICH recommendations, establishing a linear quantitation range (2-30 µg/mL) and a limit of detection (0.355-0.414 µg/mL) for the three drugs in human plasma. The greenness of the developed methodology was affirmed through the AGREE assessment protocol, confirming its environmentally conscious attributes.

Innovative and sustainable deconvoluted amplitude factor spectrophotometric method for the resolution of various severely overlapping pharmaceutical mixtures: Applying the complex-GAPI-tool.

UV spectroscopy is considered the simplest, the most money and time investor technique in analytical research. Besides its lowered solvent and energy consumption leading to greener outcomes, its practicality is wide and suitable for a wide range of applications. Multicomponent mixtures are always representing themselves as a problematic challenge for any analytical technique fortunately UV spectroscopic methods found many ways to tackle these mixtures. Fourier self-deconvolution (FSD) was recently applied in UV spectroscopy as an effective tool for the resolution of binary mixtures unfortunately like any other method may fail to completely resolve severely overlapping mixtures. In this paper, we epitomize the newly developed deconvoluted amplitude factor (DAF) spectrophotometric approach which couples the concepts of both the FSD and the amplitude factor methods for the resolution of tadalafil (TAD) in its binary mixtures with dapoxetine hydrochloride (DAP) or tamsulosin hydrochloride (TAM). The embraced approach was assessed regarding its greenness utilizing different assessing protocols to give evident proof for its sustainability. The innovative approach showed an enhancement in the resolution of binary mixtures and showed high sensitivity as noticed from limits of detection and quantitation which were (0.374, 1.136 µg/mL), (0.269, 0.817 µg/mL), and (0.518, 1.569 µg/mL) for TAD, DAP, and TAM, respectively. The method was validated as per ICH guidelines recommendations and also was statistically compared with recently reported methods which revealed no statistically significant difference. A very handy and reader-friendly data presentation approach was followed for the ease of statistical data interpretation and evaluation.

Eco-Friendly UV-Spectrophotometric Methods Employing Magnetic Nano-Composite Polymer for the Extraction and Analysis of Sexual Boosters in Adulterated Food Products: Application of Computer-Aided Design.

BACKGROUND: Solid phase extraction (SPE) techniques, based on computationally designed magnetic-based multi-targeting molecular imprinted polymer (MT-MIP), combined with UV spectrophotometric approaches provide advantages in the examination of counterfeit samples. OBJECTIVE: The current work describes an innovative and sustainable methodology for the simultaneous determination of tadalafil (TAD) and dapoxetine hydrochloride (DAP) in aphrodisiac counterfeit products (honey and instant coffee) utilizing SPE exploiting MT-MIP. Additionally, an innovative UV spectrophotometric method capable of resolving TAD in its pharmaceutical binary mixtures with DAP was developed. A novel computational approach was implemented to tailor the synthesis and design of the MT-MIP particles. METHODS: We applied a newly developed UV spectrophotometric method which was based on a Fourier self-deconvolution (FSD) method coupled with the isoabsorptive point for determination of TAD and DAP in pharmaceutical dosage form. We also applied an SPE process based on MT-MIP designed particles, assisting in the analysis of both drugs in counterfeit food samples. The SPE process and the UV spectroscopic methodology were assessed regarding their greenness using the pioneering green analytical procedure index (GAPI), analytical greeness including sample preparation (AGREEprep) and AGREE tools. The synthesized MT-MIP particles were characterized by scanning electron microscopy and energy-dispersive x-ray spectroscopy. RESULTS: The suggested spectrophotometric methods revealed a wide linear concentration range of 2-50 µg/mL with lower LODs in the range of 0.604-0.994 µg/mL. Additionally, the suggested method demonstrated the utmost sensitivity and eco-friendliness for their target in its mixed dosage form and counterfeit food products. CONCLUSION: The SPE process and the developed analytical UV spectroscopic methodology were validated as per the ICH guidelines, and were found to be suitable for overseeing some counterfeiting activities in commercially available honey and instant coffee aphrodisiac products. HIGHLIGHTS: An SPE method based on MT-MIP magnetic-based polymer and a UV spectroscopic method were successfully developed for analysis of TAD and DAP in different matrices.

Greenness-by-design approach for developing novel UV spectrophotometric methodologies resolving a quaternary overlapping mixture.

Greenness-by-design (GbD) is an approach that integrates green chemistry principles into the method development stage of analytical processes, aiming to reduce their environmental impact. In this work, we applied GbD to a novel univariate double divisor corrected amplitude (DDCA) method that can resolve a quaternary pharmaceutical mixture in a fixed-dose polypill product. We also used a genetic algorithm as a chemometric modeling technique to select the informative variables for the analysis of the overlapping mixture. This resulted in more accurate and efficient predictive models. We used a computational approach to study the effect of solvents on the spectral resolution of the mixture and to minimize the spectral interferences caused by the solvent, thus achieving spectral resolution with minimal analytical effort and ecological footprint. The validated methods showed wide linear concentration ranges for the four components (1-30 µg/mL for losartan, 2.5-30 µg/mL for atorvastatin and aspirin, and 2.5-35 µg/mL for atenolol) and achieved high scores on the hexagon and spider charts, demonstrating their eco-friendliness.

Computer-Aided Design of Eco-Friendly Imprinted Polymer Decorated Sensors Augmented by Self-Validated Ensemble Modeling Designs for the Quantitation of Drotaverine Hydrochloride in Dosage Form and Human Plasma.

BACKGROUND: Computationally designed molecular imprinted polymer (MIP) incorporation into electrochemical sensors has many advantages to the performance of the designed sensors. The innovative self-validated ensemble modeling (SVEM) approach is a smart machine learning-based (ML) technique that enables the design of more accurate predictive models using smaller data sets. OBJECTIVE: The novel SVEM experimental design methodology is exploited here exclusively to optimize the composition of four eco-friendly PVC membranes augmented by a computationally designed magnetic molecularly imprinted polymer to quantitatively determine drotaverine hydrochloride (DVN) in its combined dosage form and human plasma. Furthermore, the application of hybrid computational simulations such as molecular dynamics and quantum mechanical calculations (MD/QM) is a time-saving and eco-friendly provider for the tailored design of the MIP particles. METHOD: Here, for the first time, the predictive power of ML is assembled with computational simulations to develop four PVC-based sensors decorated by computationally designed MIP particles using four different experimental designs known as central composite, SVEM-LASSO, SVEM-FWD, and SVEM-PFWD. The pioneering AGREE approach further assessed the greenness of the analytical methods, proving their eco-friendliness. RESULTS: The proposed sensors showed decent Nernstian responses toward DVN in the range of 58.60-59.09 mV/decade with a linear quantitative range of 1 × 10-7 - 1 × 10-2 M and limits of detection in the range of 9.55 × 10-8 to 7.08 × 10-8 M. Moreover, the proposed sensors showed ultimate eco-friendliness and selectivity for their target in its combined dosage form and spiked human plasma. CONCLUSIONS: The proposed sensors were validated in accordance with International Union of Pure and Applied Chemistry (IUPAC) recommendations, proving their sensitivity and selectivity for drotaverine determination in dosage form and human plasma. HIGHLIGHTS: This work presents the first ever application of both the innovative SVEM designs and MD/QM simulations in the optimization and fabrication of drotaverine-sensitive and selective MIP-decorated PVC sensors.

A screen printed methodology optimized by molecular dynamics simulation and Lean Six Sigma for the determination of xylometazoline in the presence of benzalkonium chloride in nasal drops.

A new chemically disposable screen-printed modified electrode with yttrium doped manganese oxide (Mn2O3/Y2O3) nanocomposite at screen printed electrode was mainly constructed to quantify xylometazoline hydrochloride (XMZ). The crystallographic parameters were estimated from the XRD spectrum, suggesting that Mn2O3 of cubic phase with average grain size ∼ 77 nm. The SEM images revealed that Y3+ dopants had improved the surface topology. The findings indicate that morphological features play a vital role in improving the electronic properties of the fabricated electrode. Augmentation of Six Sigma (SS) with molecular dynamics simulation (MD) as a theoretical study was widely adopted to improve the current process as a quality management methodology by measuring the process capability to determine if the process meets the desired specification limits. Process capability is determined through measuring the variability in the process output and comparing these variations with the desired specifications. Also, it assures a robust method specification at a high level of targeted performance and statistical confidence. A greenness assessment procedure utilizing the eco-scale algorism was conducted to prove the greenness of the proposed methodology. Additionally, the proposed sensor presented a high sensitivity over the concentration range (1x10-6-1x10-2 mol L-1) of a detection limit 3.93 × 10-7 mol L-1 with the Nernstian cationic slope of 58.18 ± 0.76 mV decade-1 at 25 ± 1 °C.

An eco-friendly modified methodology for the resolution of binary pharmaceutical mixtures based on self-deconvolution of the UV spectrophotometric spectra in the Fourier domain: Application of Fourier self-deconvolution in UV spectroscopy.

UV spectrophotometry is a rapid and robust technique in resolving several challenging pharmaceutical combinations. Several mathematical treatments are available for the resolution of complex multicomponent UV spectra as; wavelet transformation, derivatization, and deconvolution-curve fitting models. Fourier self deconvolution (FSD) is a mathematical computational methodology for resolving interfering signals in many disciplines and applications. In the current work, we describe a modified FSD based methodology in resolving different binary pharmaceutical mixtures, which overcome the complexity of applying the traditional deconvolution-curve fitting technique on UV spectroscopic spectral data. The current approach differs from the conventional FSD by using the individual spectra of each component as a probing tool to avoid artifacts or errors on the deconvoluted spectra for accuracy of determinations. The utilized approach managed to resolve the binary mixtures of telmisartan/hydrochlorothiazide and ramipril/hydrochlorothiazide in their pharmaceutical dosage forms. The advantage of the current methodology over the traditional deconvolution-curve fitting is the simplicity of application, less time consuming, no need for sophisticated software, and higher sensitivity as revealed by the limit of detection (LOD). The linear ranges for telmisartan, ramipril, and hydrochlorothiazide were 1-25 µg/ml, 5-35 µg/ml, and 1-10 µg/ml, respectively, and the LOD values were in the ranges of 0.067-0.747 µg/ml. The developed FSD approach was validated as per the ICH recommendations regarding the accuracy, precision, linearity, selectivity, and limits of detection and quantitation. The recoveries obtained from the proposed approach were statistically compared with the corresponding reported methods and found no statistical difference between the obtained results.

Advanced eco-friendly UV spectrophotometric approach for resolving overlapped spectral signals of antihypertensive agents in their binary and tertiary pharmaceutical dosage form.

Cardiovascular disorders are among the foremost causes of death worldwide, especially hypertension, a silent killer syndrome that requires multiple drug therapy for proper management. This work presents novel and green spectrophotometric methods for the concurrent analysis of Amlodipine (AML), Telmisartan (TEL), Hydrochlorothiazide (HCTZ), and Chlorthalidone (CLO) in their pharmaceutical dosage form. The suggested methods were Fourier-self deconvolution, amplitude factor, and first derivative methods developed and validated for the simultaneous determination of a tertiary mixture of AML, TEL, and HCTZ in TELVAS 3D 80 mg tablet and a binary mixture of TEL and CLO in TELMIKIND-CT 40 tablets. The investigated methods revealed limits of detection 0.7283 µg/ml for AML and ranging from 0.0121 to 0.0433, 0.1547 to 0.1767 µg/ml and 0.0578 to 0.1262 µg/ml for TEL, HCTZ, and CLO, respectively.The greenness of the suggested techniques was examined by an eco-scale scoring method called the penalty points, which revealed that the methods were excellent green regarding several parameters as reagents, instrument, and waste safety. The introduced methods' validity was investigated by resolving prepared laboratory mixtures containing different AML, TEL, HCTZ, or TEL and CLO ratios. Furthermore, the introduced methods were ensured by the standard addition technique. Finally, the obtained results were statistically compared by the reported spectrophotometric methods, showing no significant difference concerning precision and accuracy.

Spectral analysis of severely overlapping spectra based on newly developed mathematical filtration techniques and ratio spectra manipulations: An application to the concurrent determination of dapoxetine and sildenafil in combined dosage form.

BACKGROUND: Dapoxetine hydrochloride (DAP) and sildenafil citrate (SIL) have proven clinically effective in the treatment of comorbid conditions like erectile dysfunction and premature ejaculation. The analysis of DAP and SIL combinations represents a challenge because of the severe overlap of these compounds' spectra. Six newly developed methods were proven effective for resolving such a challenging overlap. They also exhibited the advantage of simplicity as they depend on the zero-order spectrum and only require simple mathematical handling. OBJECTIVE: We suggested six simple, precise, and sensitive spectrophotometric methods based on mathematical filtration techniques and ratio spectra manipulations to resolve the spectra of DAP and SIL in their bulk and combined pharmaceutical dosage form and estimate the relevant individual concentrations. METHODS: The first three methods were based on the zero-order range and involved modest mathematical manipulations. They are the induced dual-wavelength, Fourier self-deconvolution, and absorptivity factor spectrophotometric methods. Three other methods that are based on ratio spectra manipulation were developed: ratio difference, mean centering of the ratio spectra, and derivative ratio spectrum. RESULTS: We determined the performance of the suggested methods for estimating DAP and SIL in their laboratory mixtures and their combined pharmaceutical dosage form. The linear ranges for DAP and SIL were 1-40 µg/ml and 2-60 µg/ml, respectively. The detection limits were in the 0.18-1.10 µg/ml range for DAP and in the 0.68-1.11 µg/ml range for SIL. The developed methods were validated as per the ICH guidelines for linearity, detection limit, quantitation limit, selectivity, precision, and accuracy. Normal probability, interval, and Tukey's simultaneous significant difference plots were utilized to confirm and better visualize the analysis of variance test results. Statistically, no significant difference was observed to exist between results obtained from the hereby developed and the previously reported methods.

Smart UV spectrophotometric methods based on simple mathematical filtration for the simultaneous determination of celecoxib and ramipril in their pharmaceutical mixtures with amlodipine: A comparative statistical study.

Two newly introduced pharmaceutical mixtures of amlodipine/celecoxib and amlodipine/ramipril were developed to manage hypertension and the associated osteoarthritis. The current work presents three newly developed UV spectrophotometric methods depending on minimal mathematical manipulations on the zero-order spectrum namely: absorption correction, induced dual-wavelength, and Fourier self deconvoluted method; for the simultaneous determination of celecoxib and ramipril in their pharmaceutical combined dosage forms with amlodipine. In absorption correction and induced dual-wavelength method, celecoxib and ramipril were determined at 253 and 222 nm for absorption correction and (251-270 nm) and (222-230 nm) for induced dual-wavelength method, respectively from the zero-order spectrum after calculating the absorption correction and equality factors for amlodipine. Amlodipine itself was determined at 361 nm from the zero-order spectrum in both methods. In Fourier self deconvoluted method, celecoxib and amlodipine zero-order spectra were deconvoluted, using the spectrophotometer software built-in Fourier wavelet function, and then was determined at 360 and 269 nm, respectively. The proposed methods were simple, accurate, and sensitive requiring minimal mathematical manipulations saving the time needed for analysis. The methods were linear over the range of (5-60 µg/ml), (5-30 µg/ml), and (5-110 µg/ml) for each of amlodipine, celecoxib, and ramipril, respectively. The limit of detection was in the range of (0.5781-0.7132 µg/ml) for amlodipine, (0.6497-1.0450 µg/ml) for celecoxib, and (0.0001-0.0003 µg/ml) for ramipril that indicated the sensitivity of these suggested methods. All methods were validated as per ICH recommendations regarding linearity, range, accuracy, precision, and selectivity. A statistical comparative study executed for the proposed methods with each other and with the reported methods showed no significant difference between the proposed methods and the reported methods.

Smart UV spectrophotometric methods based on simple mathematical filtration and classical methods for the simultaneous determination of tamsulosin and solifenacin: A comparative study of efficacy and spectral resolution.

Treatment protocols combining tamsulosin and solifenacin proved better management of the complicated urinary tract symptoms. The pharmaceutical preparations of tamsulosin and solifenacin suffered from the high difference in their ratio, 0.4 mg tamsulosin and 6 mg solifenacin, and strong spectral overlap. Here, we developed four simple, accurate and selective spectrophotometric methods based on simple mathematical manipulations. These methods require the simplest mathematical filtration using short steps performed using built-in functions of the spectrophotometer operating software utilizing zero-order or derivative spectra. These methods are namely absorption correction method (ACM), induced dual-wavelength (IDW), absorptivity factor method (AFM) and first derivative method (D1). The linear ranges were 15-70 µg/ml and 100-1200 µg/ml for TAM and SFN, respectively. The limits of quantitation were in the range of 3.8-4.05 µg/ml and 23.34-59.05 µg/ml, while the limits of detection were in the range of 1.25-1.34 µg/ml and 7.7-24.6 µg/ml for TAM and SFN, respectively. All validation parameters investigated as per ICH guidelines. A statistical comparison executed for the proposed methods with each other and with the reported methods showed no significant difference between the proposed and the reported methods.

An enhanced first derivative synchronous spectrofluorimetric method for determination of the newly co-formulated drugs, amlodipine and celecoxib in pharmaceutical preparation and human plasma.

BACKGROUND: A new combination of amlodipine and celecoxib has been recently introduced in order to relieve the symptoms of osteoarthritis and help treat hypertension that commonly associated with osteoarthritis. OBJECTIVE: The current study is the first to develop and optimize a sensitive, simple and accurate first derivative synchronous spectrofluorimetric method for the simultaneous determination of amlodipine and celecoxib in bulk powder, pharmaceutical preparation and spiked human plasma. METHOD: The method implies the use of synchronous methodology using Δλ = 100 nm and measuring the fluorescence amplitudes of the first derivative each at the zero-crossing point of the other. For amlodipine and celecoxib, the emission wavelengths were at 455 nm and 368 nm, after excitation at 367 nm and 264 nm, respectively. RESULTS: The method was found to be linear over a wide concentration ranges of (5-600 ng/ml), (100-2000 ng/ml) with lower limits of detection of (1.16 ng/ml) and (17.16 ng/ml) for amlodipine and celecoxib, respectively. Enhancement of the fluorescence intensity was achieved by complex formation between the studied drugs and the surfactant sodium dodecyl sulfate and optimizing other experimental conditions. The method was further extended for application for determination of the studied drugs in spiked human plasma with excellent % recoveries of (95.20 ± 6.095) and (98.67 ± 6.394) for amlodipine and celecoxib, respectively. Validation of the method was successfully implemented according to recommendations delivered by guidelines of the International Conference on Harmonization.

A retrospective cohort study evaluating efficacy in high-risk patients with chronic lower extremity ulcers treated with negative pressure wound therapy.

The purpose of this study was to evaluate the efficacy of negative pressure wound therapy (NPWT) compared with standard of care on wound healing in high-risk patients with multiple significant comorbidities and chronic lower extremity ulcers (LEUs) across the continuum of care settings. A retrospective cohort study of 'real-world' high-risk patients was conducted using Boston University Medical Center electronic medical records, along with chart abstraction to capture detailed medical history, comorbidities, healing outcomes and ulcer characteristics. A total of 342 patients, 171 NPWT patients with LEUs were matched with 171 non-NPWT patients with respect to age and gender, were included in this cohort from 2002 to 2010. The hazard ratios (HRs) were estimated by COX proportional hazard models after adjusting for potential confounders. The NPWT patients were 2·63 times (95% CI = 1·87-3·70) more likely to achieve wound closure compared with non-NPWT patients. Moreover, incidence of wound closure in NPWT patients were increased in diabetic ulcers (HR = 3·26, 95% CI = 2·21-4·83), arterial ulcers (HR = 2·27, CI = 1·56-3·78) and venous ulcers (HR = 6·31, 95% CI = 1·49-26·6) compared with non-NPWT patients. In addition, wound healing appeared to be positively affected by the timing of NPWT application. Compared with later NPWT users (1 year or later after ulcer onset), early NPWT users (within 3 months after ulcer onset) and intermediate NPWT users (4-12 months after ulcer onset) were 3·38 and 2·18 times more likely to achieve wound healing, respectively. This study showed that despite the greater significant comorbidities, patients receiving NPWT healed faster. Early use of NPWT demonstrated better healing. The longer the interval before intervention is with NPWT, the higher the correlation is with poor outcome.

A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers.

Non-contact low-frequency ultrasound (NCLF-US) devices have been increasingly used for the treatment of chronic non-healing wounds. The appropriate dose for NCLF-US is still in debate. The aims of this pilot study were to evaluate the relationship between dose and duration of treatment for subjects with non-healing diabetic foot ulcers (DFUs) and to explore the correlation between wound healing and change of cytokine/proteinase/growth factor profile. This was a prospective randomised clinical study designed to evaluate subjects with non-healing DFUs for 5 weeks receiving standard of care and/or NCLF-US treatment. Subjects were randomly assigned to one of the three groups: application of NCLF-US thrice per week (Group 1), NCLF-US once per week (Group 2) and the control (Group 3) that received no NCLF-US. All subjects received standard wound care plus offloading for a total of 4 weeks. Percent area reduction (PAR) of each wound compared with baseline was evaluated weekly. Profiles of cytokines/proteinase/growth factors in wound fluid and biopsied tissue were quantified to explore the correlation between wound healing and cytokines/growth factor expression. Twelve DFU patients, 2 (16·7%) type 1 and 10 (83·3%) type 2 diabetics, with an average age of 58 ± 10 years and a total of 12 foot ulcers were enrolled. Average ulcer duration was 36·44 ± 24·78 weeks and the average ABI was 0·91 ± 0·06. Group 1 showed significant wound area reduction at weeks 3, 4 and 5 compared with baseline, with the greatest PAR, 86% (P < 0·05); Groups 2 and 3 showed 25% PAR and 39% PAR, respectively, but there were no statistically significant differences between Groups 2 and 3 over time. Biochemical and histological analyses indicated a trend towards reduction of pro-inflammatory cytokines (IL-6, IL-8, IL-1ß, TNF-α and GM-CSF), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and macrophages in response to NCLF-US consistent with wound reduction, when compared with control group subjects. This proof-of-concept pilot study demonstrates that NCLF-US is effective in treating neuropathic diabetic foot ulcers through, at least in part, inhibiting pro-inflammatory cytokines in chronic wound and improving tissue regeneration. Therapeutic application of NFLU, thrice (3) per week, renders the best wound area reduction.