Rapid validated liquid chromatographic method coupled with Tandem mass spectrometry for quantification of nintedanib in human plasma

Purpose: To develop and validate a fast, sensitive, and simple liquid chromatographic method coupled with tandem mass spectrometry for the determination of the potent tyrosine kinase inhibitor, ninetedanib (NTB) in plasma, utilizing cyclobenzaprine (CBP) as internal standard (IS).Methods: Separation of the two components (NTB and CBP) was performed on a pentafluorophenyl (PFP) reversed phase column (50 × 2 mm, 3μm) at ambient temperature using isocratic elution with acetonitrile-water (60:40, v/v) containing 0.01 M ammonium formate buffer (pH 4.2) at a flow rate of 0.4 mL/min. NTB and CBP were monitored by a triple quadrupole tandem mass spectrometer with electrospray ionization source in the positive ion mode. The current method was validated following the European Medicines Agency (EMA) guidelinesResults: The proposed method allowed rapid and specific quantification of NTB in the calibration range of 2 - 150 ng/mL and determination coefficient of ≥ 0.999. Intra- and inter-day accuracy and precision were < 4 % in all cases.Conclusion: The developed procedure is rapid, specific, reliable, and validated for quantification of NTB in human plasma, and thus can be applied efficiently for the analysis of clinical samples containing NTB.Keywords: Nintedanib assay, Cyclobenzaprine, LC-MS/MS, Validatio

Synthesis, biological evaluation and Structure Activity Relationships (SARs) study of 8-(substituted)aryloxycaffeine

AbstractA series of 8-(substituted)aryloxycaffeine were prepared from 8-bromocaffeine and (substituted)phenols by modified Ullmann reaction. In vitro antibacterial activity, inhibitory activity on topoisomerase II and pharmacological activities were evaluated for the synthesized 8-(substituted)aryloxycaffeine. Among the synthesized compounds, 8-(5-chloropyridin-3-yloxy)caffeine (3k) showed strong inhibitory activity (MIC=15.6μg/mL) against the tested gram negative (−) bacteria Salmonella enteritidis. 8-(quinolin-8-yloxy)caffeine (3g) showed the strongest inhibitory activity against topoisomerase II. And the compounds 8-(6-methylpyridin-2-yloxy)caffeine (3j) and 8-(3-chloro-6-(trifluoromethyl)pyridin-2-yloxy)caffeine (3m) showed analgesic effect without the central nervous system stimulation

Morfologi dan sintaksis bahasa Totoli

Pcnelitian morfologi dan sintnksis bahasa Totoli mcmpunyai tujuan rncmperoleh deskripsi tentang morfologi dan sintaksis. Dalam bidang morfologi dibahas afiksasi, 'redupklikasi, klitikalisasi, dan pemajemukan. Dalam bidang sintaksis dibahas frasa, klausa, kalimat, dan proses sintaksis. Untuk mencapai tujuan itu, dalam penelitian mi ditcrapkan analisis niorfologi olch Nisa dan Samsuri serta digunakan prinsip dasar untuk menentukan sistematikan bahasa. Selain itu, digunakan analisis sintaksis tagmemik oleh Cook

1-(5-Bromo-4-phenyl-1,3-thia­zol-2-yl)pyrrolidin-2-one

The asymmetric unit of the title compound, C13H11BrN2OS, consists of two crystallographically independent mol­ecules (A and B). In each mol­ecule, the pyrrolidine ring adopts an envelope conformation with a methyl­ene C atom as the flap atom. In mol­ecule A, the central thia­zole ring makes a dihedral angle of 36.69 (11)° with the adjacent phenyl ring, whereas the corresponding angle is 36.85 (12)° in mol­ecule B. The pyrrolidine ring is slightly twisted from the thia­zole ring, with C—N—C—N torsion angles of 4.8 (3) and 3.0 (4)° in mol­ecules A and B, respectively. In the crystal, C—H⋯π and π–π [centroid-to-centroid distance = 3.7539 (14) Å] inter­actions are observed. The crystal studied was a pseudo-merohedral twin with twin law (-100 0-10 101) and a refined component ratio of 0.7188 (5):0.2812 (5)

Liquid chromatographic-mass spectrometric method for determination of drug content uniformity of two commonly used dermatology medications in a split-tablet dosage form

Purpose: To develop and validate a simple, efficient and reliable Liquid  chromatographic-mass spectrometric (LC-MS/MS) method for the quantitative determination of two dermatological drugs, Lamisil® (terbinafine) and Proscar® (finasteride), in split tablet dosage form.Methods: Thirty tablets each of the 2 studied medications were randomly selected. Tablets were weighed and divided into 3 groups. Ten tablets of each drug were kept intact, another group of 10 tablets were manually split into halves using a tablet cutter and weighed with an analytical balance; a third group were split into quarters and weighed. All intact and split tablets were individually dissolved in a water: methanol mixture (4:1), sonicated, filtered and further diluted with mobile phase. Optimal chromatographic separation and mass spectrometric detection were achieved using an Agilent 1200 HPLC system coupled with an Agilent 6410 triple quadrupole mass spectrometer. Analytes were eluted through an Agilent eclipse plus C8 analytical column (150 mm × 4.6 mm, 5 μm) with a mobile phase composed of solvent A (water) containing 0.1% formic acid and 5mM ammonium formate pH 7.5, and solvent B (acetonitrile mixed with water in a ratio A:B 55:45) at a flow rate of 0.8 mL min-1 with a total run time of 12 min. Mass spectrometric detection was carried out using positive ionization mode with analyte quantitation monitored by multiple reaction monitoring (MRM) mode.Results: The proposed analytical method proved to be specific, robust and  adequately sensitive. The results showed a good linear fit over the concentration range of 20 - 100 ng mL-1 for both analytes, with a correlation coefficient (r2) ≥ 0.999 and 0.998 for finasteride and terbinafine, respectively. Following tablet splitting, the drug content of the split tablets fell outside of the proxy USP  specification for at least 14 halves (70 %) and 34 quarters (85 %) of FIN, as well as 16 halves (80 %) and 37 quarters (92.5 %) of TBN. Mean weight loss, after splitting, was 0.58 and 2.22 % for FIN half- and quarter tablets, respectively, and 3.96 and 4.09 % for TBN half- and quarter tablets,respectively.Conclusion: The proposed LC-MS/MS method has successfully been used to provide precise drug content uniformity of split tablets of FIN and TBN. Unequal distribution of the drug on the split tablets is indicated by the high standard deviation beyond the accepted value. Hence, it is recommended not to split non-scored tablets  especially, for those medications with significant toxicityKeywords: Tablet splitting, Finasteride, Terbinafine, Drug content uniformity,  LC-MS/M

N′-[(1E)-(2,6-Difluoro­phen­yl)methyl­idene]thio­phene-2-carbohydrazide

In the title compound, C12H8F2N2OS, the thienyl ring is disordered over two positions, with the S atom of the major component [occupancy = 75.03 (18)%] oriented away from an ortho-F atom of the benzene ring. The mol­ecule is nearly planar, the dihedral angle between the thio­phene and benzene rings being 6.19 (18) (in the major component) or 3.5 (6)° (in the minor component). The azomethine C=N double-bond in the mol­ecule is of an E configuration. In the crystal, mol­ecules are linked by pairs of N—H⋯O hydrogen bonds, generating inversion dimers

Liquid chromatographic-tandem mass spectrometric assay for simultaneous quantitation of tofacitinib, cabozantinib and afatinib in human plasma and urine

Purpose: To develop a simple, adequately sensitive, and practical liquid chromatographic-mass spectrometric method to simultaneously quantify three tyrosine kinase inhibitors, viz, tofacitinib (TOF), cabozantinib (CBZ) and afatinib (AFB) after their extraction from both human plasma and urine.Methods: Blood and urine samples were obtained from healthy volunteers who admitted to not being on any medications. The investigated analytes were chromatographically separated on a C18 column (Luna®-PFP 100Å column, 50 mm × 2.0 mm i.d., 3.0 μm) with the aid of a mobile phase containing A; acetonitrile (ACN) and B; 0.01 M ammonium formate buffer (pH 4.1) pumped at a rate of 0.3 mL.min-1 in the ratio A:B, 50:50 v/v. Analyte monitoring was achieved by tandem mass spectrometry interfaced with an electrospray ionization source with the aid of multiple reaction monitoring (MRM) mode for analytes quantification.Results: The proposed method permitted a specific and sensitive determination of the investigated TKIs in the linear range of 1.0 - 100 ng mL-1 with correlation coefficient (r2) of 0.9991, 0.9997, and 0.9998 for TOF, CBZ and AFB, respectively. The method was validated with regard to its limits of quantification (ranging from 0.91 to 1.24 ng mL-1 for the 3 analytes), intra- and inter assay accuracy (in the range -1.85 to 1.22 %) and precision (0.71 - 5.12 %). The method was also validated in terms of recovery from both studied matrices, robustness and matrix effect.Conclusion: The results obtained reveal that the developed method is simple, specific and highly efficient for routine determination of the studied analytes in human plasma and urine. It can be reliably applied for high throughput analysis of clinical samples containing the investigated analytes.Keywords: Tyrosine kinase inhibitors, Tofacitinib, Cabozantinib, Afatinib, LC-MS/MS, human plasm

N′-(Adamantan-2-yl­idene)thio­phene-2-carbohydrazide

In the title mol­ecule, C15H18N2OS, a small twist is noted, with the dihedral angle between the central carbohydrazone residue (r.m.s. deviation = 0.029 Å) and the thio­phene ring being 12.47 (10)°. The syn arrangement of the amide H and carbonyl O atoms allows for the formation of centrosymmetric dimers via N—H⋯O hydrogen bonds. These are linked in the three-dimensional structure by C—H⋯π inter­actions. The thio­phene ring is disordered over two co-planar orientations, the major component having a site-occupancy factor of 0.833 (2)