Failure Mode Critical Effect Analysis and Design of Experiment-Based Robust Chromatographic Method for Simultaneous Estimation Lornoxicam and Eperisone Hydrochloride.

Failure mode critical effect analysis and design of experiment-based high performance thin layer chromatography (HPTLC) method has been developed for simultaneous estimation of lornoxicam (LOC) and eperisone hydrochloride (EPR). Failure modes were identified on the basis of prior knowledge and experimental data with the help of Ishikawa diagram for the development of method. The criticality of failure mode was assessed by giving risk priority number and criticality rank on the basis of preliminary experimental trials. The identified critical failure modes were analyzed for their effect by design of experiment (DoE)-based Plackett-Burman screening design. From 11 critical factors, the volume of methanol and modifier in mobile phase composition were found as critical failure modes. Critical failure mode was further analyzed by DoE based on central composite design for study of their relationship with resolution of both drugs. Quadratic model suggested by design was further used for failure mode risk control and navigation of design space for a resolution of both drugs more than 1.5. Failure mode risk control strategy was set for robust HPTLC method for simultaneous estimation of both drugs in laboratory mixture. Developed and validated HPTLC method was applied for assay of LOC and EPR in their laboratory mixture and assay values were found in good agreement with a spiked amount of drugs.

Inhibidores de ciclooxigenasa para impedir la vitreorretinopatía proliferativa: ¿aptos para uso clínico? / Cyclooxygenases inhibitors for preventing the proliferative vitreoretinopathy: Ready for clinical use?

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MXene with Great Adsorption Ability toward Organic Dye: An Excellent Material for Constructing a Ratiometric Electrochemical Sensing Platform.

Ratiometric electrochemical sensors coupled with an intrinsic built-in correction have received much attention in biochemical analysis, which can effectively avoid potential impacts from both intrinsic and extrinsic factors. However, the complex modification procedure and the unstable reference signal limit development and application of ratiometric sensing. To address these issues, we proposed a novel ratiometric electrochemical platform based on MXene. Introduction of built-in correction was realized via simple one-step incubation of MXene in solution containing the reference molecule methylene blue (MB), and their firm electrostatic interaction ensures the strong adsorption capability of MXene toward MB. Remarkable enhancement in repeatibility and stability compared with nonratio sensor was proved by detecting the model analyte piroxicam. Furthermore, compatibility of the ratio sensor was demonstrated by integrating copper nanoparticles (CuNPs) into the platform. It turned out that sensing performance of the hybrid electrochemical sensor was significantly improved owing to synergistic effect of MXene and CuNPs, where the former affords a large specific surface area as well as quick electron transport, and the latter possess decent electrical catalytic ability. In all, the proposed ratiometric sensor based on MXene features easy preparation, superb reproducibility, robustness, and broad applicability, affording the platform highly competitive and reliable in the determination of a wide range of substances.

With or Without Internal Standard in HPLC Bioanalysis. A Case Study.

The mandatory strategy of using internal standard in HPLC is still controversial. Despite that the introduction of internal standard methodology in the early stage of development of HPLC technology was used to improve method accuracy and precision, there are still practical situations in which a simple external standard quantification is adequate. The aim of the study is to compare the determination of meloxicam (MXC) in human plasma by HPLC with or without using an internal standard according to some key points related to the reason of introducing the internal standardization such as the reducing of sample preparation errors or variability for low injection volumes. The HPLC analysis was performed on reversed phase with UV detection after protein precipitation. Piroxicam (PXC) was used as an internal standard. The two methods are compared in terms of accuracy and precision over the same concentration range. The stability of the analyte has been proved. According to the results, the quantitative determination of MXC in human plasma after simple protein precipitation by using PXC as an internal standard does not bring any significant improvement of accuracy and precision of the experimental measurements.

Smart bi-metallic perovskite nanofibers as selective and reusable sensors of nano-level concentrations of non-steroidal anti-inflammatory drugs.

A strategy for trace-level carbon-based electrochemical sensors is investigated via exploring the interesting properties of BaNb2O6 nanofibers (NFs). Utilizing adsorptive stripping square wave voltammetry (ASSWV), an electrochemical sensing platform was developed based on BaNb2O6 nanofibers-modified carbon paste electrode (CPE) for the sensitive detection of lornoxicam (LOR). Different techniques were used to characterize the fabricated BaNb2O6 perovskite NFs. The obtained data show the feasibility to electro-oxidize LOR and paracetamol (PAR) on the surface of the fabricated sensor. The amount of nanofiber and testing conditions were optimized using response surface methodology and ASSWV technique. The optimized BaNb2O6/CPE sensor exhibits low detection limit of 6.39 × 10-10 mol L-1, even in the presence of the co-formulated drug paracetamol (PAR). The sensor was successfully applied for biological applications.

Determination of piroxicam from rat articular tissue and plasma based on LC-MS/MS.

Osteoarthritis (OA) is the most common type of arthritis. To manage OA, in general, oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) is used. Recently, the analgesic and anti-inflammatory efficacy of piroxicam (PX), a long-acting NSAID, by intra-articular (IA) administration in OA was reported, and the possibility that PX is distributed in articular tissues at a certain concentration was raised. Thus, herein, novel LC-MS/MS methods to detect PX in rat articular tissue and plasma are presented. For articular tissue, solvent extraction with acetonitrile for 12 h was employed and a protein precipitation method was used for the preparation of a plasma sample. The developed methods were validated by following the FDA guidelines, and the validated methods were successfully applied to a PK study of IA PX. The present study presents, to our knowledge, the first method of determining a drug in articular tissue. Additionally, the level of PX in articular tissue after IA PX administration was experimentally confirmed for the first time using the present methods. Therefore, the present methods provide a new direction for in vivo evaluation for IA PX formulations and contribute to the development of alternative IA PX formulations with better effects for the treatment of OA.

Miniaturized X-ray powder diffraction assay (MixRay) for quantitative kinetic analysis of solvent-mediated phase transformations in pharmaceutics.

Many pharmaceutical compounds exhibit polymorphism, which may result in solvent-mediated phase transformations. Since the polymorphic form has an essential influence on physicochemical characteristics such as solubility or dissolution rate, it is crucial to know the exact polymorphic composition of a drug throughout pharmaceutical development. This study addressed the need to perform quantitative X-ray analysis of polymorphic mixtures on a 96-well scale (MixRay). A calibration of polymorphic mixtures (anhydrate and hydrate) was performed with three model drugs, caffeine, piroxicam, and testosterone, and linear correlations were obtained for all compounds. The MixRay approach for piroxicam was applied to a solubility and residual solid screening assay (SORESOS) to quantify the amount of hydrate and anhydrate corresponding to kinetic bulk concentrations. Changes in these drug concentrations correlated well with the kinetic changes in the residual solid. The influence of excipients on the solid state and kinetic concentrations of piroxicam was also studied. Excipients strongly affected polymorphic transformation kinetics of piroxicam and concentrations after 24h depended on the excipient used. The new calibration X-ray method combined with bulk concentration analysis provides a valuable tool for both pharmaceutical profiling and early formulation development.

Determination of Degradation Products of Cyclobenzaprine Hydrochloride, Lidocaine and Piroxicam in a Semi-Topical Formulation: MS-MS Confirmation of Unknown Impurities.

Association of cyclobenzaprine hydrochloride, piroxicam and lidocaine in a topical formulation is one of the newest innovations in the pharmaceutical formulary field. In this study, a reversed-phase liquid chromatographic method was developed for the establishment of the impurities of cyclobenzaprine hydrochloride, lidocaine and piroxicam in the semisolid topical formulation. In this study, we not only determined 2,6-dimethylaniline, 2-pyrydilamine but also specified impurities of cyclobenzaprine hydrochloride (dibenzosuberenone, amitriptyline, carbinole, cyclobenzaprine N-oxide and anthrachinone). The target compounds were determined using a mobile phase that consisted of a mixture of phosphate buffer (0.025 M; pH 6.2)-acetonitrile-methanol (60 : 13 : 27, v/v/v). A minimum of three supplementary possible degradation products were determined. Using mass spectrometry, the unspecified impurities were identified and the use of correlation matrices permitted the association with the possible source compounds. The chromatographic conditions were qualified and validated according to ICH guideline requirements to confirm specificity, linearity, accuracy and precision.

Quantification of piroxicam and 5'-hydroxypiroxicam in human plasma and saliva using liquid chromatography-tandem mass spectrometry following oral administration.

Saliva sampling used to quantify piroxicam and 5'-hydroxypiroxicam is a noninvasive and painless method when compared to sequential blood sampling. For that, a rapid, selective and sensitive liquid chromatography-tandem mass spectrometric method for simultaneous determination of piroxicam and 5'-hydroxypiroxicam in saliva and human plasma was developed and validated. Piroxicam and its major metabolite were separated using a LiChroCART 125-4 RP Select-B Sorbent C18 column using a mixture of methanol and 2% phosphoric acid (pH 2.7) (70:30, v/v) for the mobile phase with a flow injection of 1mL/min. The run time was 4min. Volunteers had saliva and blood sampled before, 1, 2, 3, 4, 5, 6, 8, 11, 24, 48 and 72h after taking a 20mg oral dose of piroxicam. The pharmacokinetic parameters of piroxicam in plasma samples were as follows: AUC0-72 (64819hng/mL), predicted clearance (0.2L/h), distribution volume (14.8L), elimination half-life (50.7h) and saliva/plasma concentration ratio (0.003). The estimation of all pharmacokinetic parameters for 5'-hydroxypiroxicam would require collections beyond 72h; however, it was possible to quantify the mean maximum concentration (133ng/mL), time to peak concentration (53.6h), mean AUC0-72 (6213hng/mL), predicted clearance (110.3L/h) and saliva/plasma concentration ratio (0.04). The developed methods proved effective and sensitive for determining the lower quantification limit of piroxicam in plasma (6.1ng/mL) and saliva (0.15ng/mL) and of 5'-hydroxypiroxicam in plasma (1.2ng/mL) and saliva (0.15ng/mL).

Towards improved solubility of poorly water-soluble drugs: cryogenic co-grinding of piroxicam with carrier polymers.

Amorphous solid dispersions (SDs) open up exciting opportunities in formulating poorly water-soluble active pharmaceutical ingredients (APIs). In the present study, novel catalytic pretreated softwood cellulose (CPSC) and polyvinylpyrrolidone (PVP) were investigated as carrier polymers for preparing and stabilizing cryogenic co-ground SDs of poorly water-soluble piroxicam (PRX). CPSC was isolated from pine wood (Pinus sylvestris). Raman and Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used for characterizing the solid-state changes and drug-polymer interactions. High-resolution scanning electron microscope (SEM) was used to analyze the particle size and surface morphology of starting materials and final cryogenic co-ground SDs. In addition, the molecular aspects of drug-polymer interactions and stabilization mechanisms are presented. The results showed that the carrier polymer influenced both the degree of amorphization of PRX and stabilization against crystallization. The cryogenic co-ground SDs prepared from PVP showed an enhanced dissolution rate of PRX, while the corresponding SDs prepared from CPSC exhibited a clear sustained release behavior. In conclusion, cryogenic co-grinding provides a versatile method for preparing amorphous SDs of poorly water-soluble APIs. The solid-state stability and dissolution behavior of such co-ground SDs are to a great extent dependent on the carrier polymer used.

Green analytical determination of emerging pollutants in environmental waters using excitation-emission photoinduced fluorescence data and multivariate calibration.

An eco-friendly strategy for the simultaneous quantification of three emerging pharmaceutical contaminants is presented. The proposed analytical method, which involves photochemically induced fluorescence matrix data combined with second-order chemometric analysis, was used for the determination of carbamazepine, ofloxacin and piroxicam in water samples of different complexity without the need of chromatographic separation. Excitation-emission photoinduced fluorescence matrices were obtained after UV irradiation, and processed with second-order algorithms. Only one of the tested algorithms was able to overcome the strong spectral overlapping among the studied pollutants and allowed their successful quantitation in very interferent media. The method sensitivity in superficial and underground water samples was enhanced by a simple solid-phase extraction with C18 membranes, which was successful for the extraction/preconcentration of the pollutants at trace levels. Detection limits in preconcentrated (1:125) real water samples ranged from 0.04 to 0.3 ng mL(-1). Relative prediction errors around 10% were achieved. The proposed strategy is significantly simpler and greener than liquid chromatography-mass spectrometry methods, without compromising the analytical quality of the results.

Green synthesis and molecular recognition ability of patuletin coated gold nanoparticles.

Patuletin isolated from Tagetespatula was used as a capping and reducing agent to synthesize in one pot gold nanoparticles capped with patuletin. Conjugation of gold with patuletin was confirmed by FT-IR and UV-visible spectroscopy and amount of patuletin conjugated to gold nanoparticles was found to be 63.2% by weight. Particle sizes were measured by atomic force microscopy (AFM) and were found to have a mean diameter of about 45 nm. Patuletin-coated gold nanoparticles were found to be highly fluorescent. To examine their potential as chemical sensors, they were contacted with fourteen different drugs. Of these drugs, only one, piroxicam, was found to quench luminescence. Quenching obeyed Beer's law in a concentration range of 20-260 µM. Important for molecular recognition applications, fluorescence quenching by piroxicam was not affected by pH variation, elevated temperatures, addition of other drugs and addition of blood plasma to the colloidal suspensions.

[Determination of twelve chemical drugs illegally added in herbal tea by ultra high performance liquid chromatography-tandem mass spectrometry coupled with modified QuEChERS].

An ultra high performance liquid chromatography-tandem mass spectrometry method with modified QuEChERS procedure for sample preparation was developed for the simultaneous determination of 12 chemical drugs (chlorpheniramine, piroxicam, α-asarone etc) illegally added in herbal tea. The samples were extracted with acetonitrile, purified with QuEChERS procedure and filtrated by 0.22 µm microporous filters. The separation was carried on an XBridge BEH C18 column (100 mm x 2.1 mm, 3.5 µm) by a gradient elution using acetonitrile/0.1% (v/v) formic acid aqueous solution as mobile phases. The analytes were detected by tandem mass spectrometry with positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode, and quantified by external standard calibration method. The correlation coefficients of the standard calibration curves for the 12 analytes were all above 0.997. The limits of detection ranged from 0.1 µg/L to 2.1 µg/L, and the limits of quantification ranged from 0.4 g/L to 8.0 µg/L. The average recoveries of the 12 analytes spiked at three levels in blank samples ranged from 62.7% to 95.2% with the RSDs from 1.3% to 10.8%. The samples bought from markets were screened, and some of the samples showed positive for these analytes. The method developed is easy to operate, sensitive, and with good purification effect. It can be applied to the rapid determination of the 12 chemical drugs illegally added in herbal tea.

A high sensitive biosensor based on FePt/CNTs nanocomposite/N-(4-hydroxyphenyl)-3,5-dinitrobenzamide modified carbon paste electrode for simultaneous determination of glutathione and piroxicam.

This study describes the development, electrochemical characterization and utilization of novel modified N-(4-hydroxyphenyl)-3,5-dinitrobenzamide-FePt/CNTs carbon paste electrode for the electrocatalytic determination of glutathione (GSH) in the presence of piroxicam (PXM) for the first time. The synthesized nanocomposite was characterized with different methods such as TEM and XRD. The modified electrode exhibited a potent and persistent electron mediating behavior followed by well-separated oxidation peaks of GSH and PXM. The peak currents were linearly dependent on GSH and PXM concentrations in the range of 0.004-340 and 0.5-550 µmol L(-1), with detection limits of 1.0 nmol L(-1) and 0.1 µmolL(-1), respectively. The modified electrode was successfully used for the determination of the analytes in real samples with satisfactory results.

Coformer screening using thermal analysis based on binary phase diagrams.

PURPOSE: The advent of cocrystals has demonstrated a growing need for efficient and comprehensive coformer screening in search of better development forms, including salt forms. Here, we investigated a coformer screening system for salts and cocrystals based on binary phase diagrams using thermal analysis and examined the effectiveness of the method. METHODS: Indomethacin and tenoxicam were used as models of active pharmaceutical ingredients (APIs). Physical mixtures of an API and 42 kinds of coformers were analyzed using Differential Scanning Calorimetry (DSC) and X-ray DSC. We also conducted coformer screening using a conventional slurry method and compared these results with those from the thermal analysis method and previous studies. RESULTS: Compared with the slurry method, the thermal analysis method was a high-performance screening system, particularly for APIs with low solubility and/or propensity to form solvates. However, this method faced hurdles for screening coformers combined with an API in the presence of kinetic hindrance for salt or cocrystal formation during heating or if there is degradation near the metastable eutectic temperature. CONCLUSIONS: The thermal analysis and slurry methods are considered complementary to each other for coformer screening. Feasibility of the thermal analysis method in drug discovery practice is ensured given its small scale and high throughput.

Liquid chromatographic method for the simultaneous determination of captopril, piroxicam, and amlodipine in bulk drug, pharmaceutical formulation, and human serum by programming the detector.

A highly sensitive LC method with UV detection has been developed for the simultaneous determination of coadministered drugs captopril, piroxicam, and amlodipine in bulk drug, pharmaceutical formulations, and human serum at the isosbestic point (235 nm) and at individual λmax (220, 255, and 238 nm, respectively) by programming the detector with time to match the individual analyte's chromophore, which enhanced the sensitivity with linear range. The assay involved an isocratic elution of analytes on a Bondapak C18 (10 µm, 25 × 0.46 cm) column at ambient temperature using a mobile phase of methanol/water 80:20 at pH 2.9 and a flow rate of 1.0 mL/min. Linearity was found to be 0.25-25, 0.10-6.0, and 0.20-13.0 µg/mL with correlation coefficient >0.998 and detection limits of 7.39, 3.90, and 9.38 ng/mL, respectively, whereas calibration curves for wavelength-programmed analysis were 0.10-6.0, 0.04-2.56, and 0.10-10.0 µg/mL with correlation coefficient >0.998 and detection limits of 5.79, 2.68, and 3.87 ng/mL, respectively. All the validated parameters were in the acceptable range. The recovery of drugs was 99.32-100.39 and 98.65-101.96% in pharmaceutical formulation and human serum, respectively, at the isosbestic point and at individual λmax . This method is applicable for the analysis of drugs in bulk drug, tablets, serum, and in clinical samples without interference of excipients or endogenous serum components.

Foreign matter identification from solid dosage forms.

Despite the increased request for robust quality systems, the end product may contain unidentified defects or discoloured regions. The foreign matter has to be monitored, identified and its source defined in order to prevent further contamination. However, the identification task can be complicated, since the origin and nature of foreign matter are various. The aim of this study is to provide an efficient foreign matter identification procedure for various substances possibly originating from pharmaceutical manufacturing environment. The surface or cross-section of the uncoated and coated tablets was analysed by utilization of different analytical techniques, such as light microscopy (LM), scanning electron microscopy in combination with energy dispersive X-ray microanalysis (SEM/EDX), Fourier transform infrared spectroscopy (FT-IR) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The results indicate that the combination of different analytical techniques proved to be a powerful approach in foreign matter identification. Light microscopy and SEM generate information on the morphology of foreign matter particles. EDX provides elemental analysis, which most often serves as final confirmation of the identification. However, FT-IR can be used to obtain information on the compounds chemical structure and conformation, and ToF-SIMS provides sensitivity in cases, where the entire solid dosage form is contaminated with foreign matter.

Improvement of drug loading onto ion exchange resin by cyclodextrin inclusion complex.

CONTEXT: Ion exchange resins have ability to exchange their counter ions for ionized drug in the surrounding medium, yielding "drug resin complex." Cyclodextrin can be applied for enhancement of drug solubility and stability. OBJECTIVE: Cyclodextrin inclusion complex of poorly water-soluble NSAIDs, i.e. meloxicam and piroxicam, was characterized and its novel application for improving drug loading onto an anionic exchange resin, i.e. Dowex® 1×2, was investigated. METHODS: ß-Cyclodextrin (ß-CD) and hydroxypropyl ß-cyclodextrin (HP-ß-CD) were used for the preparation of inclusion complex with drugs in solution state at various pH. The inclusion complex was characterized by phase solubility, continuous variation, spectroscopic and electrochemistry methods. Then, the drug with and without cyclodextrin were equilibrated with resin at 1:1 and 1:2 weight ratio of drug and resin. RESULTS AND DISCUSSION: Solubility of the drugs was found to increase with increasing cyclodextrin concentration and pH. The increased solubility was explained predominantly due to the formation of inclusion complex at low pH and the increased ionization of drug at high pH. According to characterization studies, the inclusion complex was successfully formed with a 1:1 stoichiometry. The presence of cyclodextrin in the loading solution resulted in the improvement of drug loading onto resin. CONCLUSIONS: Enhancing drug loading onto ion-exchange resin via the formation of cyclodextrin inclusion complex is usable in the development of ion-exchange based drug delivery systems, which will beneficially reduce the use of harmful acidic or basic and organic chemicals.

Characterization of two polymorphs of lornoxicam.

OBJECTIVES: The aim of the study was to prepare and to characterize two polymorphs of lornoxicam, a water-insoluble non-steroidal anti-inflammatory drug, which has thus far received no exploration of its polymorphs. METHODS: Form I and form II of lornoxicam were prepared by recrystallization and characterized by X-ray powder diffractometry (XRPD), thermal analysis, Fourier transform infrared spectroscopy and scanning electron microscopy. The solubility and dissolution of both polymorphs were also determined and compared to provide the basis for polymorph selection in formulation. KEY FINDINGS: The crystal structures of the two polymorphs were established by the experimental XRPD patterns. Form I was demonstrated to be triclinic with two kinds of intermolecular hydrogen bonds, while form II was orthorhombic with two kinds of intramolecular hydrogen bonds. The morphologies of form I and form II were observed to be rectangle and approximately oval, respectively. CONCLUSIONS: Form II had the significantly higher solubility and dissolution and would be the suitable polymorph for the preparation of oral and injectable dosage forms of lornoxicam.

A new method for a quantitative determination of piroxicam in pharmaceutical formulations using FT-IR spectrometry.

A Fourier transform infrared (FT-IR) spectrometric method was developed for the rapid, and direct measurement of piroxicam (Pir) in pharmaceutical drugs. Pir is a well known and very effective antiinflammatory drug. Pir can be determined by various methods and now we are adding a new one that uses a Fourier transform infrared spectrophotometric technique. Conventional spectra were compared for best determination of active substance in pharmaceutical formulations. The Beer-Lambert law and two chemometric approaches, partial least squares (PLS) and principal component regression (PCR+) methods, were tried in data processing.