Publications by authors named "Nourah Z Alzoman"

25 Publications

  • Page 1 of 1

Synthesis, spectroscopic and computational studies on hydrogen bonded charge transfer complex of duvelisib with chloranilic acid: Application to development of novel 96-microwell spectrophotometric assay.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Aug 21;264:120287. Epub 2021 Aug 21.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt. Electronic address:

Duvelisib (DUV) is a is a small-molecule with inhibitory action for phosphoinositide 3-kinase (PI3K). It has been recently approved for the effective treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Novel charge transfer complex (CTC) between DUV, as electron donor, with chloranilic acid (CLA), as π electron acceptor has been synthesized and characterized using different spectroscopic and thermogravimetric techniques. UV-visible spectroscopy ascertained the formation of the CTC in different solvents of varying polarity indexes and dielectric constants via formation of new broad absorption band with maximum absorption peak (λ) in the range of 488-532 nm. The molar absorptivity of the CTC was dependent on the polarity index and dielectric constant of the solvent; the correlation coefficients were 0.9955 and 0.9749, respectively. The stoichiometric ratio of DUV:CLA was 1:1. Electronic spectral analysis was conducted for characterization of the complex in terms of its electronic constants. Computational calculation for atomic charges of energy minimized DUV was conducted and the site of interaction on DUV molecule was assigned. The solid-state CTC of DUV:CLA (1:1) was synthesized, and its structure was characterized by UV-visible, mass, FT-IR, and H NMR spectroscopic techniques. Both FT-IR and H NMR confirmed that both CT and hydrogen bonding contributed to the molecular composition of the complex. The reaction was adopted as a basis for developing a novel 96-microwell spectrophotometric assay (MW-SPA) for DUV. The assay limits of detection and quantitation were 0.57 and 1.72 µg/well, respectively. The assay was validated and all validation parameters were acceptable. The method was implemented successfully with great precision and accuracy to the analysis of the DUV in its bulk and capsules.
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http://dx.doi.org/10.1016/j.saa.2021.120287DOI Listing
August 2021

Development and validation of UPLC-MS/MS method for the simultaneous quantification of anaplastic lymphoma kinase inhibitors, alectinib, ceritinib, and crizotinib in Wistar rat plasma with application to bromelain-induced pharmacokinetic interaction.

J Pharm Biomed Anal 2021 Sep 22;204:114276. Epub 2021 Jul 22.

College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh, 11495, P.O. Box 22452, Saudi Arabia.

Bromelain, the aqueous extract of pineapple, has been used as a food supplement with reported nutritional and therapeutic benefits. Bromelain has anti-cancer, anti-inflammatory, antithrombotic, and fibrinolytic effects. Anaplastic lymphoma kinase (ALK) inhibitors, including alectinib (ALC), ceritinib (CER), and crizotinib (CRZ), have been efficiently used in the management of non-small cell lung cancer (NSCLC). The solubility of ALC, CER, and CRZ is much higher at low acidic pH (pH 1) and it decreases as the pH increases affecting their absorption with a subsequent decrease in their bioavailability. It was thought that the intake of bromelain could result in a decrease in the bioavailability of ALC, CER, and CRZ due to bromelain-induced alkalizing effect following digestion. On the contrary, bromelain could possibly increase plasma exposure of the cited drugs due to its known muco-permeation enhancing effect. The therapeutic-anticancer effect of bromelain can be possibly increased/enhanced with concomitant intake of other anticancer medications or it can add to the value of food supplements for its known nutritional benefits. Thus, this work aims at studying the possibility of any PK interaction when bromelain was taken while on ALC/CER/CRZ therapy. In this work, a new UPLC-MS/MS method was developed and validated for the simultaneous determination of ALC, CER, and CRZ in rat plasma. Further application of the proposed method was performed to test the possibility of the PK interaction between bromelain and the selected ALK inhibitors in Wistar rats. Simple protein precipitation with acetonitrile was used for sample preparation. Chromatographic analysis was performed on Waters BEH™ C18 column with a mixture of acetonitrile/water containing 0.1 % formic acid (70: 30, v/v) as the mobile phase. The method permitted the analysis of ALC, CER, and CRZ in concentration ranges of 2-200, 0.4-200, and 4.0-200 ng/mL, respectively. Bromelain administration caused a significant decrease in plasma levels of CER and CRZ with lowered C, AUC and AUC, along with an increase in the apparent clearance. However, no significant effect was noticed with ALC. Thus, attention should be paid to avoid the intake of bromelain with CER or CRZ.
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http://dx.doi.org/10.1016/j.jpba.2021.114276DOI Listing
September 2021

Determination of tetracycline, oxytetracycline and chlortetracycline residues in seafood products of Saudi Arabia using high performance liquid chromatography-Photo diode array detection.

Saudi Pharm J 2021 Jun 23;29(6):566-575. Epub 2021 Apr 23.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.

Residues of oxytetracycline, tetracycline and chlortetracycline in seafood products of Saudi Arabia were detected by using a simple, sensitive and rapid method via HPLC-PDA. The protein precipitation method that was used for sample extraction demonstrated high recoveries of OTC, TC and CTC. The limits of detection were 0.015 µg/g and 0.025,0.062 µg/g for all TCs in fish and shellfish, respectively. The limits of quantitation were 0.125 µg/g and 0.175 µg/g for all TCs in fish and shellfish, respectively. The method was precise and accurate since the RSD was less than 2%, while the % recovery was 95-105%. This study determined the occurrence of OTC, TC and CTC in seafood products that are sold in KSA's markets. The overall occurrence of these three medications in 249 seafood products was 24%(n = 60), while 15%(n = 37) exceeded the MRL. Thus, our recommendations are to enhance the monitoring of food production prior to marketing and to educate people regarding the proper disposal of antibiotics.
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http://dx.doi.org/10.1016/j.jsps.2021.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233539PMC
June 2021

A Highly Sensitive Nonextraction-Assisted HPLC Method with Fluorescence Detection for Quantification of Duvelisib in Plasma Samples and its Application to Pharmacokinetic Study in Rats.

Drug Des Devel Ther 2021 21;15:2667-2677. Epub 2021 Jun 21.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.

Background: Duvelisib (DUV) is a new oral phosphoinositide-3-kinase (PI3K)-δ and PI3K-γ inhibitor. It has been recently granted an accelerated approval for treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). It is also effective in therapy of T-cell lymphoma, solid tumors, and non-Hodgkin's lymphoma. In literature, there is no method valid for quantitation of DUV in human plasma for its therapeutic monitoring and pharmacokinetic studies.

Purpose: The purpose of this study is the establishment of a highly sensitive HPLC method with fluorescence detection for quantitation of DUV in plasma for its therapeutic monitoring and pharmacokinetic studies of DUV.

Methods: The resolution of DUV and the internal standard (IS) olaparib (OLA) was achieved on Nucleosil CN column, with a mobile phase composed of acetonitrile:water (25:75, v/v) at a flow rate of 1.7 mL min. The fluorescence of both DUV and OLA was detected at 410 nm after excitation at 280 nm. The method was validated according to the guidelines of bioanalytical method validation.

Results: The method was linear in the range of 5-100 ng mL, and its limit of detection (LOD) and limit of quantitation (LOQ) were 2.12 ng mL and 7 ng mL, respectively. The precisions of the method were ≤ 8.26%, and its accuracies were ≥ 95.32%. All the other validation parameters were satisfactory. The proposed method was successfully employed to the investigation of the pharmacokinetic profile of DUV in rats following a 25 mg/kg single dose of oral administration.

Conclusion: The method is characterized with high sensitivity, accuracy, simple sample pretreatment, rapidity, eco-friendly as it consumes low volumes of organic solvent in the mobile phase and has high analysis throughput as its run time was short (~ 10 min).
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http://dx.doi.org/10.2147/DDDT.S318714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232391PMC
June 2021

Innovative use of σ and π electron acceptors in the development of three high throughput 96-microwell spectrophotometric assays for crizotinib.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Oct 30;259:119884. Epub 2021 Apr 30.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Crizotinib (CZT) is a potent and selective tyrosine kinase inhibitor used for treatment of non-small cell lung cancer (NSCLC). The development of high-throughput assays for its quality control (QC) is very essential to assure its therapeutic benefits. CZT molecule has multiple electron-donating atoms that can contribute to the formation of colored charge-transfer (CT) complex with iodine as σ-electron acceptor and with 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (CHBQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π-electron acceptors. These reactions were prospective basis for development of three innovative 96-microwell-based spectrophotometric assays for CZT. The reactions of CZT with iodine, CHBQ and TCNQ were performed in 96-microwell assay plates and absorbances of the CT complexes were measured by microwell absorbance reader at their corresponding maximum absorption peaks. The measured absorbances were correlated with the CZT concentrations in its sample solutions. Beer's law was obeyed with excellent correlation coefficients in the range of 0.5-30, 2-500, and 5-500 µg mL for assays using iodine, CHBQ and TCNQ, respectively. The limits of detection were 2.17, 0.85 and 6.23 µg mL for assays using iodine, CHBQ and TCNQ, respectively. The validation studies confirmed the accuracy and precision of all the proposed assays. The assays were successfully applied in the determination of CZT in Xalkori capsules. The proposed assays have very simple procedures to run in QC laboratories. Also, both assays enable analyst to process large number of samples and use of very small volumes of the organic solvent (ecofriendly and inexpensive).
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http://dx.doi.org/10.1016/j.saa.2021.119884DOI Listing
October 2021

Spectrophotometric and computational investigations of charge transfer complexes of chloranilic acid with tyrosine kinase inhibitors and application to development of novel universal 96-microwell assay for their determination in pharmaceutical formulations.

Spectrochim Acta A Mol Biomol Spectrosc 2021 May 18;252:119482. Epub 2021 Jan 18.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

The tyrosine kinase inhibitors (TKIs) are chemotherapeutic drugs used for targeted therapy of various types of cancer. In literature, there is no existing universal chromogenic reagent used for development of spectrophotometric assay for all TKIs regardless the diversity of their chemical structures. This work discusses, for the first time, the experimental and computational evaluation of chloranilic acid (CLA) as a universal chromogenic reagent for developing a novel 96-microwell spectrophotometric assay (MW-SPA) for TKIs. The reaction of CLA with seven TKIs was examined in different organic solvents of various dielectric constants and polarity indexes. The reaction resulted in an instantaneous formation of intensely purple coloured products with all the investigated TKIs. Spectrophotometric investigations confirmed that the reactions proceeded via the formation of charge-transfer complexes (CTC). The physical parameters (molar absorptivity, molar ratio, association constant and standard free energy) were determined for the CTC of all TKIs. Computational calculations for the relative electron densities on each atom of the TKI molecule and molecular modelling for the CTC were conducted, and the site(s) of interaction on each TKI molecule were determined. Under the optimized conditions, Beer's law correlating the absorbances of the CTC with the concentrations of TKIs were obeyed in the range of 5-500 µg/well with good correlation coefficients (0.9991-0.9998). The limits of detection and quantitation were in the ranges of 1.89-5.09 and 5.74-15.42 µg/well, respectively. The proposed MW-SPA showed high precisions as the values of the relative standard deviations did not exceed 2.01 and 2.45% for the intra- and inter-assay precision, respectively. The accuracy of MW-SPA was proved by recovery studies as the recovery values were in the range of 98.8-103.7%. The proposed MW-SPA was successfully applied for the determination of all TKIs in their bulk forms and pharmaceutical formulations (tablets) with good accuracy and precisions. The proposed MW-SPA is the first assay that can analyse all the TKIs on a single assay system without modifications in the detection wavelength. Additional advantages of the proposed MW-SPA are simple, economic, and more importantly have high throughput. Therefore, the assay can be helpful and beneficial for routine analysis of TKIs in their pharmaceutical formulations in quality control laboratories.
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http://dx.doi.org/10.1016/j.saa.2021.119482DOI Listing
May 2021

Flavoured water consumption alters pharmacokinetic parameters and increases exposure of erlotinib and gefitinib in a preclinical study using Wistar rats.

PeerJ 2020 22;8:e9881. Epub 2020 Sep 22.

Biological Products Evaluation Directorate, Saudi Food and Drug Authority, Riyadh, Saudi Arabia.

Background: Erlotinib (ERL) and Gefitinib (GEF) are considered first line therapy for the management of non-small cell lung carcinoma (NSCLC). Like other tyrosine kinase inhibitors (TKIs), ERL and GEF are mainly metabolized by the cytochrome P450 (CYP450) CYP3A4 isoform and are substrates for transporter proteins with marked inter-/intra-individual pharmacokinetic (PK) variability. Therefore, ERL and GEF are candidates for drug-drug and food-drug interactions with a consequent effect on drug exposure and/or drug-related toxicities. In recent years, the consumption of flavoured water (FW) has gained in popularity. Among multiple ingredients, fruit extracts, which might constitute bioactive flavonoids, can possess an inhibitory effect on the CYP450 enzymes or transporter proteins. Therefore, in this study we investigated the effects of different types of FW on the PK parameters of ERL and GEF in Wistar rats.

Methods: ERL and GEF PK parameters in different groups of rats after four weeks consumption of different flavours of FW, namely berry, peach, lime, and pineapple, were determined from plasma drug concentrations using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

Results: Data indicated that tested FWs altered the PK parameters of both ERL and GEF differently. Lime water had the highest impact on most of ERL and GEF PK parameters, with a significant increase in C (95% for ERL, 58% for GEF), AUC (111% for ERL, 203% for GEF), and AUC (200% for ERL, 203% for GEF), along with a significant decrease in the apparent oral clearance of both drugs (65% for ERL, 67% for GEF). The order by which FW affected the PK parameters for ERL and GEF was as follows: lime > pineapple > berry > peach.

Conclusion: The present study indicates that drinking FW could be of significance in rats receiving ERL or GEF. Our results indicate that the alteration in PKs was mostly recorded with lime, resulting in an enhanced bioavailability, and reduced apparent oral clearance of the drugs. Peach FW had a minimum effect on the PK parameters of ERL and no significant effect on GEF PKs. Accordingly, it might be of clinical importance to evaluate the PK parameters of ERL and GEF in human subjects who consume FW while receiving therapy.
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http://dx.doi.org/10.7717/peerj.9881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518156PMC
September 2020

Development and validation of UPLC-MS/MS method for studying the pharmacokinetic interaction of dasabuvir and tamoxifen, 4-hydroxytamoxifen in Wistar rats.

Sci Rep 2020 02 26;10(1):3521. Epub 2020 Feb 26.

College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh, 11495, P.O. Box 22452, Saudi Arabia.

Hepatitis C virus (HCV) is the main cause of chronic hepatitis and probably liver cirrhosis. Dasabuvir (DSV) is a direct-acting antiviral agent with efficiency in managing HCV. The anti-viral activity of the anti-estrogen drug tamoxifen (TAM) suggested the synergistic effect of DSV and TAM for blocking the replication of HCV. However, being substrates and inhibitors of efflux transporters (TAM inhibits P-gp, DSV inhibits P-gp and BCRP), there is a possibility for a pharmacokinetic (PK) drug-drug interaction. In this work, a new UPLC-MS/MS method was developed and validated for the simultaneous determination of TAM, its active metabolite 4-hydroxy tamoxifen (TOH), and DSV in rat plasma. The method was applied to investigate the PK interaction between DSV and TAM/TOH following the co-administration of DSV and TAM to Wistar rats. Chromatographic analysis was performed on Waters BEH C18 column using a mobile phase of acetonitrile/water containing 0.1% formic acid (80: 20, v/v). The method allowed the determination of concentration ranges 20-1000, 0.1-500, 0.5-500 ng/mL for DSV, TAM, and TOH, respectively. Unexpectedly, results revealed the absence of PK interactions between DSV and TAM/TOH, compared with their single administration, suggesting the safety of co-administering DSV/TAM as an anti-viral combination without the need of dosage adjustment.
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http://dx.doi.org/10.1038/s41598-020-60613-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044166PMC
February 2020

A Pharmacokinetic Interaction Study of Sorafenib and Iced Teas in Rats Using UPLC-MS/MS: An Illustration of Beverage-Drug Interaction.

Biomed Res Int 2019 28;2019:2410845. Epub 2019 Nov 28.

Saudi Food and Drug Authority, Biologics and Evaluation Department, Riyadh, Saudi Arabia.

Iced teas (ITs), also known as ready-to-drink teas, have gained much popularity among many nations. The modulatory effect of tea beverages on CYP3A4 increases the possibility of their potential interactions with many coadministered medications. Being a substrate of CYP3A4, sorafenib (SOR), the first-line therapy for the treatment of hepatocellular carcinoma, shows a great probability to exhibit pharmacokinetic (PK) interaction with ITs. For this purpose, different groups of Wistar rats were given oral doses of SOR (40 mg/kg), along with different types of ITs. The concentration of SOR in rat plasma was determined using UPLC-MS/MS. Chromatographic analysis was performed on a C18 analytical column, Acquity UPLC BEH™ (100 × 1.0 mm, i.d., 1.7 m particle size), using erlotinib (ERL) as an internal standard. Isocratic elution was performed with a mobile phase consisting of two solvents: solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid), in a ratio of 30 : 70, v/v, respectively. Quantitation was performed using MRM of the transitions from protonated precursor ions [M+H] to product ions at 465.12 > 252.02 (SOR) and 394.29 > 278.19 (ERL). The method was fully validated as per the FDA guidance for bioanalytical method validation in the concentration range of 2.5-500 ng/mL. Different PK parameters were calculated for SOR in all rat groups and groups administered with ITs and SOR, compared with groups with simply water and SOR. Experimental data revealed that ITs caused a general reduction in SOR bioavailability; an approximate reduction of 30% was recorded for all types of tested ITs. These data indicate that ITs could affect the PK profile of SOR in rats.
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http://dx.doi.org/10.1155/2019/2410845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907072PMC
May 2020

UPLC-MS/MS study of the effect of dandelion root extract on the plasma levels of the selected irreversible tyrosine kinase inhibitors dasatinib, imatinib and nilotinib in rats: Potential risk of pharmacokinetic interactions.

Biomed Chromatogr 2019 Dec 1;33(12):e4674. Epub 2019 Sep 1.

College of Pharmacy, Department of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Tyrosine kinase inhibitor treatments for chronic myeloid leukaemia based on nilotinib (NIL), dasatinib (DAS) and imatinib (IMA) have improved patient quality of life and have turned chronic myeloid leukemia from a fatal disease into a chronic disease. Dandelion is a rich source of phenolic compounds with strong biological properties, and the effects of using this plant in the treatment of different illnesses can be linked to the presence of various polyphenols found in the different parts of the plant. Thus, dandelion can potentially be used as a nutraceutical (dietary antioxidant) to prevent different disorders associated with oxidative stress, i.e. cardiovascular disorders, cancer and inflammatory processes. Mutual interference between a drug and a food constituent may result in altered pharmacokinetics of the drug and undesired or even dangerous clinical situations. In the present study, a bioanalytical ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) method was developed and validated for the quantification of DAS, IMA and NIL in rat plasma. Sample preparation was carried out using solid-phase extraction with C cartridges with a good extraction recovery of ≥94.37% for the three drugs. The method was fully validated as per the US Food and Drug Administration guidelines.
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http://dx.doi.org/10.1002/bmc.4674DOI Listing
December 2019

Ultra-performance LC-MS/MS study of the pharmacokinetic interaction of imatinib with selected vitamin preparations in rats.

Bioanalysis 2018 Jul;10(14):1099-1113

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.

Aim: The growing interest of cancerous patients in using vitamins, while on imatinib (IMA) therapy, increased the risk of their pharmacokinetic interactions.

Methodology: Ultra-performance LC-MS/MS method was developed and validated for the determination of IMA following oral administration of selected vitamin preparations (vitamin A, E, D3 and C) in rat plasma using a hybrid sample preparation technique of protein precipitation followed by SPE.

Results: The method showed good linear response for IMA over the concentration range 1-500 ng/ml. Co-administered vitamin preparations could affect IMA pharmacokinetic profiling through either an increase (vitamin A and E) or a decrease (vitamin C) in IMA bioavailability. Vitamin D3 produced no significant effect on IMA bioavailability.

Conclusion: Particular concern should be paid when vitamin preparations are administered with IMA.
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http://dx.doi.org/10.4155/bio-2018-0043DOI Listing
July 2018

Validated UPLC-MS/MS method for the quantification of dasatinib in plasma: Application to pharmacokinetic interaction studies with nutraceuticals in Wistar rats.

PLoS One 2018 14;13(6):e0199208. Epub 2018 Jun 14.

College of Pharmacy, Department of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Dasatinib (DAS) is a tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia and in the management of ulcerative colitis (UC). Since some nutraceuticals (e.g. curcumin, olive oil, and cocoa extract) could alter the function of ABC transporters and /or CYP450 enzymes, DAS bioavailability could potentially be affected following their co-administration. This work aims at studying the possibility of PK interaction between DAS and the selected nutraceuticals in UC rats using UPLC- MS/MS. Chromatographic analysis was carried out using BEH C 18 column (Waters) with a mobile phase consisting of acetonitrile and 50% aqueous methanol, 65:35, v/v, each with 0.1% formic acid and using erlotinib (ERL) as an internal standard (IS). DAS quantitation was carried out using multiple reaction monitoring (MRM) with positive ionization of the transitions at m/z 488.03 > 400.92 (DAS), and m/z 394.29 > 278.19 (ERL). Method validation was assessed as per the FDA guidelines for bioanalytical methods for DAS determination within the concentration range 1-500 ng/mL. No significant effect on the oral bioavailability of DAS was reported with any of the studied nutraceuticals. Thus, the concomitant administration of these nutraceuticals with DAS could be considered safe with a necessity to perform more detailed clinical investigations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199208PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002064PMC
December 2018

UPLC-ESI-MS/MS study of the effect of green tea extract on the oral bioavailability of erlotinib and lapatinib in rats: Potential risk of pharmacokinetic interaction.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Apr 27;1049-1050:30-40. Epub 2017 Feb 27.

College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.

Green tea (GT) is one of the most consumed beverages worldwide. Tyrosine kinase inhibitors (TKIs) belong to the oral targeted therapy that gained much interest in oncology practice, among which are erlotinib (ERL) and lapatinib (LAP). Since green tea polyphenols (GTP) are known to be inhibitors of receptor tyrosine kinases, GTE could likely potentiate the anticancer effect of TKIs, but with a possibility of pharmacokinetic (PK) interaction with co-administered TKIs. In this study, the effect of GTE on the PK of ERL/LAP in rats was studied. UPLC-ESI-MS/MS method has been developed and validated for the quantification of ERL and LAP in rat plasma, using gefitinib (GEF) as the internal standard. Plasma samples were treated extensively by protein precipitation (PPT) followed by solid phase extraction (SPE) using octadecyl C 18/14% cartridges. Chromatographic analysis was carried out on Acquity UPLC BEH™ C18 column with a mobile phase consisting of water: acetonitrile (20: 80, v/v), each with 0.15% formic acid. Quantification was performed in the positive electrospray ionization (ESI+) mode with multiple reaction monitoring (MRM) of the transitions m/z 394.29→278.19 (ERL), m/z 581.07→365.13 (LAP), and m/z 447.08→128.21 (GEF). The method was fully validated as per the FDA guidelines showing linearity over the range of 0.4-1000 (ERL) and 0.6-1000 (LAP) ng/mL with very low lower limit of quantification (LLOQ) of 0.4 and 0.6ng/mL for ERL and LAP, respectively. The applicability of the method was extended to perform a comparative study of the PK of ERL/LAP following short-term and long-term administration of GTE, compared with their single oral administration. The results revealed that a significant reduction in the oral bioavailability was recorded with both ERL and LAP following the ingestion of GTE particularly for short-term administration. A reduction in C (AUC) by 67.60% (69.50%) and 70.20% (73.96%), was recorded with short-term administration of GTE, compared with only 16.03% (21.09%) and 13.53% (22.12%) reduction for ERL and LAP, respectively, with long-term administration. Thus patients taking TKIs should preferably avoid drinking GT or ingesting GTE capsules during the period of treatment with TKIs.
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http://dx.doi.org/10.1016/j.jchromb.2017.02.029DOI Listing
April 2017

Comparative pharmacokinetic profiles of selected irreversible tyrosine kinase inhibitors, neratinib and pelitinib, with apigenin in rat plasma by UPLC-MS/MS.

J Pharm Biomed Anal 2017 Apr 31;137:258-267. Epub 2017 Jan 31.

College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University Riyadh 11495, P.O. Box 22452, Saudi Arabia.

Neratinib (NER) and pelitinib (PEL) are irreversible tyrosine kinase inhibitors (TKIs) that have been recently employed in cancer treatment. Apigenin (API), among other flavonoids, is known to have antioxidant, anti-proliferative, and carcinogenic effect. API can potentiate the antitumor effect of chemotherapeutic agents and/or alleviate the side effects of many anticancer agents. Since TKIs are mostly metabolized by CYP3A4 enzymes and that API could alter the enzymatic activity, potential drug interactions could be expected following their co-aministration. In the present study, a bioanalytical UPLC-MS/MS method has been developed and validated for the quantification of NER and PEL in rat plasma, using domperidone (DOM) as an internal standard. Sample preparation was carried out using solid phase extraction (SPE) with C18 cartridges with good extraction recovery of not less than 92.42% (NER) and 89.73% (PEL). Chromatographic analysis was performed on a Waters BEH C18 column with a mobile phase composed of acetonitrile and water, (70:30, v/v), each with 0.1% formic acid. Quantitation was performed using multiple reaction monitoring (MRM) of the transitions from protonated precursor ions [M+H], at m/z 557.30 (NER), m/z 468.21 (PEL), and at m/z 426.27 (DOM), to selected product ions at m/z 112.05 (NER), m/z 395.22 (PEL), and at m/z 175.18 (DOM). The method was fully validated as per the FDA guidelines over the concentration range of 0.5-200ng/mL with very low lower limit of quantification (LLOQ) of 0.5ng/mL for both NER and PEL. The intra- and inter-day assay precision and accuracy were evaluated for both drugs and the calculated values of percentage relative standards deviations (%RSD) and relative errors (%E) were within the acceptable limits (<15%) for concentrations other than LLOQ and 20% for LLOQ. The applicability of the method was extended to study the possibility of drug interactions following the oral co-administration of NER/PEL with API. Thus, this study could be readily applied in therapeutic drug monitoring (TDM) of cancerous patients receiving such drug combinations.
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http://dx.doi.org/10.1016/j.jpba.2017.01.039DOI Listing
April 2017

Simultaneous determination of erlotinib and tamoxifen in rat plasma using UPLC-MS/MS: Application to pharmacokinetic interaction studies.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Aug 28;1028:100-110. Epub 2016 May 28.

College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.

Tamoxifen (TAM) is a non-steroidal estrogen receptor antagonist that enhances erlotinib (ERL)-induced cytotoxicity in the treatment of NSCLC. ERL and TAM are metabolized by CYP3A4 enzymes. In addition, both drugs have the potential of altering the enzymatic activity through either inhibition (ERL) or induction (TAM). Thus it was expected that pharmacokinetics (PK) drug-drug interactions (DDIs) could be encountered following their co-administration. In this respect, a bioanalytical UPLC-MS/MS method has been developed and validated for the simultaneous determination of ERL and TAM in rat plasma samples, using ondansetron (OND) as an internal standard (IS). Plasma samples were prepared using mixed mode cationic solid phase extraction (SPE) STRATA™ -X-C 33μm cartridges with good extraction recovery of both drugs from rat plasma (Er% from -13.92 to -3.32). The drugs were separated on a Waters BEH™ C18 column with an isocratic elution using a mobile phase composed of a mixture of acetonitrile and water, each with 0.15% formic acid, in the ratio of 80: 20, v/v. Quantitation was carried out using the positive ionization mode with multiple reaction monitoring (MRM) at m/z 394.20>278.04 (ERL), m/z 372.25>72.01 (TAM), and m/z 294.18>170.16 (OND). The method was fully validated as per the FDA guidelines over the concentration range of 0.2-50ng/mL with very low lower limit of quantification (LLOQ) of 0.2ng/mL for both ERL and TAM. The intra- and inter-day assay precision (in terms of relative standard deviation, RSD) and accuracy (in terms of percentage relative error, % Er) were evaluated for both drugs and the calculated values evaluated at four different concentration levels were within the acceptable limits (<15%) for concentrations other than LLOQ and 20% for LLOQ. The method was successfully applied to the study of possible PK-DDI following the oral administration of ERL and TAM in a combination, compared to their single administration.
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http://dx.doi.org/10.1016/j.jchromb.2016.05.033DOI Listing
August 2016

Simultaneous determination of selected tyrosine kinase inhibitors with corticosteroids and antiemetics in rat plasma by solid phase extraction and ultra-performance liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic interaction studies.

J Pharm Biomed Anal 2016 May 5;124:216-227. Epub 2016 Mar 5.

College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia.

A sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry method has been developed and validated for the simultaneous analysis of selected tyrosine kinase inhibitors (TKIs)(gefitinib GEF, erlotinib ERL), corticosteroids (dexamethasone DEX, prednisolone PRED), and the antiemetic ondansetron (OND) in rat plasma samples. After the addition of domperidone (DOM) as internal standard (IS), spiked plasma samples were prepared using the solid phase extraction (SPE) C 18 cartridges. Chromatographic separation was performed on a Waters BEH C18 column with an isocratic elution using a mobile phase composed of acetonitrile and water, each with 0.1% formic acid, (80: 20, v/v), at a flow rate of 0.2 mL/min. Quantitation of the analytes was performed using the multiple reaction monitoring (MRM) mode with the positive ionization mode at m/z 447.25>128.08 (GEF), m/z 394.20>278.04 (ERL), m/z 393.30>147.04 (DEX), m/z 361.29>147.02 (PRED), m/z 294.18>170.16 (OND), and m/z 426.26>175.07 (DOM). The method was validated over the concentration range of 0.025-100 (GEF, ERL, OND) and 0.05-100 ng/mL plasma (PRED, DEX) with very low lower limit of quantification of 0.025 (GEF, ERL, OND) and 0.05 ng/mL (DEX, PRED). The intra- and inter-day precision (RSD%) evaluated at four different concentration levels were within the acceptable limits (<15%). The method provided good extraction recovery of all analytes from rat plasma (Er% from -14.05 to -1.08). The validated method was successfully applied to the pharmacokinetic studies following the oral administration of selected combinations of the studied drugs. This study can be readily applied in therapeutic drug monitoring (TDM) in patients receiving these drug combinations as well as investigation of possible drug interactions between TKIs and DEX/PRED/OND.
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http://dx.doi.org/10.1016/j.jpba.2016.03.013DOI Listing
May 2016

A Validated Stability-Indicating and Stereoselective HPLC Method for the Determination of Lenalidomide Enantiomers in Bulk Form and Capsules.

Authors:
Nourah Z Alzoman

J Chromatogr Sci 2016 May-Jun;54(5):730-5. Epub 2016 Feb 4.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 22452, Riyadh 11495, Saudi Arabia

A simple, rapid and stability-indicating chiral HPLC (CHR-HPLC) method was designed for the enantiomeric separation of lenalidomide (LDM) in the presence of its degradation products. LDM was exposed to different accelerated stress factors. The degradation products were well resolved from the pure drug enantiomers. Separation of the LDM enantiomers was achieved on a LUX 5U cellulose-2 chiral column (250 × 4.6 mm i.d.) with a mobile phase consisting of methanol : glacial acetic acid : triethyl amine (100 : 0.01 : 0.01, v/v/v) at a flow rate of 1.2 mL/min. The detection wavelength was 220 nm, and ornidazole was the internal standard. The chiral method was validated in terms of its specificity, linearity, range, precision and accuracy as well as solution stability, robustness, limit of detection and limit of quantification. The calibration curve was linear for concentrations ranging from 2 to 1,000 ng/mL (r= 0.9999) for both LDM enantiomers. The proposed method, which met International Conference on Harmonization/Food and Drug Administration regulatory requirements, was utilized successfully for the determination of LDM in bulk and in capsules with acceptable accuracy and precision; the label demand percentages were 100.09 ± 0.80 and 99.97 ± 0.93 for the S-(-) and R-(+)-LDM enantiomers, respectively. Based on these results, this method should have great value when applied to quality control and stability studies of LDM.
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http://dx.doi.org/10.1093/chromsci/bmv247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890444PMC
December 2016

Charge-transfer reaction of 2,3-dichloro-1,4-naphthoquinone with crizotinib: Spectrophotometric study, computational molecular modeling and use in development of microwell assay for crizotinib.

Saudi Pharm J 2015 Jan 14;23(1):75-84. Epub 2014 Jun 14.

Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.

The reaction of 2,3-dichloro-1,4-naphthoquinone (DCNQ) with crizotinib (CZT; a novel drug used for treatment of non-small cell lung cancer) was investigated in different solvents of varying dielectric constants and polarity indexes. The reaction produced a red-colored product. Spectrophotometric investigations confirmed that the reaction proceeded through charge-transfer (CT) complex formation. The molar absorptivity of the complex was found to be linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9567 and 0.9069, respectively. The stoichiometric ratio of DCNQ:CZT was found to be 2:1 and the association constant of the complex was found to be 1.07 × 10(2) l/mol. The kinetics of the reaction was studied; the order of the reaction, rate and rate constant were determined. Computational molecular modeling for the complex between DCNQ and CZT was conducted, the sites of interaction on CZT molecule were determined, and the mechanism of the reaction was postulated. The reaction was employed as a basis in the development of a novel 96-microwell assay for CZT in a linear range of 4-500 μg/ml. The assay limits of detection and quantitation were 2.06 and 6.23 μg/ml, respectively. The assay was validated as per the guidelines of the International Conference on Harmonization (ICH) and successfully applied to the analysis of CZT in its bulk and capsules with good accuracy and precision. The assay has high throughput and consumes a minimum volume of organic solvents thus it reduces the exposures of the analysts to the toxic effects of organic solvents, and significantly reduces the analysis cost.
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http://dx.doi.org/10.1016/j.jsps.2014.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310957PMC
January 2015

Spectroscopic investigation (FT-IR and FT-Raman), vibrational assignments, HOMO-LUMO, NBO, MEP analysis and molecular docking study of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-(phenylsulfanyl)-pyrimidine-5-carbonitrile, a potential chemotherapeutic agent.

Spectrochim Acta A Mol Biomol Spectrosc 2015 Mar 24;139:413-24. Epub 2014 Dec 24.

Department of Chemistry, Dr. H.S. Gour Central University, Sagar, M.P., India.

Vibrational spectral analysis of 2-[(4-chlorobenzyl)sulfanyl]-4-(2-methylpropyl)-6-(phenylsulfanyl)-pyrimidine-5-carbonitrile was carried out using FT-IR and FT-Raman spectroscopic techniques. The equilibrium geometry and vibrational wave numbers have been computed using density functional B3LYP method with 6-311++G(d,p)(5D,7F) as basis set. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using NBO analysis. The nonlinear optical behavior of the title compound is also theoretically predicted. From the MEP, it is evident that the negative charge covers the C≡N group and the positive region is over the phenyl and the pyrimidine rings. From the potential energy scan it is clear that the lone pairs of the sulfur atom prefer to point away from the pyrimidine ring and the C≡N group resulting with two possible minimum conformations at the N4C8S1C25 angle equal nearly 0° or 150°. Molecular docking results suggest that the compound might exhibit inhibitory activity against GPb and may act as potential anti-diabetic compound.
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http://dx.doi.org/10.1016/j.saa.2014.12.043DOI Listing
March 2015

Crystal structure of 2-(adamantan-1-yl)-5-(4-bromo-phen-yl)-1,3,4-oxa-diazole.

Acta Crystallogr Sect E Struct Rep Online 2014 Dec 5;70(Pt 12):o1231-2. Epub 2014 Nov 5.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riaydh 11451, Saudi Arabia ; X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia.

In the title mol-ecule, C18H19BrN2O, the benzene ring is inclined to the oxa-diazole ring by 10.44 (8)°. In the crystal, C-H⋯π inter-actions link the mol-ecules in a head-to-tail fashion, forming chains extending along the c-axis direction. The chains are further connected by π-π stacking inter-actions, with centroid-centroid distances of 3.6385 (7) Å, forming layers parallel to the bc plane.
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http://dx.doi.org/10.1107/S1600536814023861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257436PMC
December 2014

Novel stereoselective high-performance liquid chromatographic method for simultaneous determination of guaifenesin and ketorolac enantiomers in human plasma.

Chirality 2014 Oct 8;26(10):629-39. Epub 2014 Jul 8.

College of Pharmacy, Department of Pharmaceutical Chemistry, King Saud University, Riyadh, Saudi Arabia; Faculty of Pharmacy, Department of Pharmaceutical Analytical Chemistry, University of Alexandria, Alexandria, Egypt.

A novel method was developed for the simultaneous determination of guaifenesin (GUA) and ketorolac tromethamine (KET) enantiomers in plasma samples. Since GUA probably increases the absorption of coadministered drugs (e.g., KET), it would be extremely important to monitor KET plasma levels for the purpose of dose adjustment with a subsequent decrease in the side effects. Enantiomeric resolution was achieved on a polysaccharide-based chiral stationary phase, amylose-2, as a chiral selector under the normal phase (NP) mode and using ornidazole (ORN) as internal standard. This innovative method has the advantage of the ease and reliability of sample preparation for plasma samples. Sample clean-up was based on simply using methanol for protein precipitation followed by direct extraction of drug residues using ethanol. Both GUA and KET enantiomers were separated using an isocratic mobile phase composed of hexane/isopropanol/trifluoroacetic acid, 85:15:0.05 v/v/v. Peak area ratios were linear over the range 0.05-20 µg/mL for the four enantiomers S (+) GUA, R (-) GUA, R (+) KET, and S (-) KET. The method was fully validated according to the International Conference on Harmonization (ICH) guidelines in terms of system suitability, specificity, accuracy, precision, robustness, and solution stability. Finally, this procedure was innovative to apply the rationale of developing a chiral high-performance liquid chromatography (HPLC) procedure for the simultaneous quantitative analysis of drug isomers in clinical samples.
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http://dx.doi.org/10.1002/chir.22354DOI Listing
October 2014

Charge-transfer reaction of 1,4-benzoquinone with crizotinib: spectrophotometric study, computational molecular modeling and use in development of microwell assay for crizotinib.

Spectrochim Acta A Mol Biomol Spectrosc 2014 Oct 2;131:347-54. Epub 2014 May 2.

Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.

The reaction of 1,4-benzoquinone (BQ) with crizotinib (CZT); a novel drug used for treatment of non-small cell lung cancer) was investigated in different solvents of varying dielectric constants and polarity indexes. The reaction resulted in the formation of a red-colored product. Spectrophotometric investigations confirmed that the reaction proceeded through charge-transfer (CT) complex formation. The molar absorptivity of the complex was found to be linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9425 and 0.8340, respectively. The stoichiometric ratio of BQ:CZT was found to be 2:1 and the association constant of the complex was found to be 0.26×10(3)lmol(-1). The kinetics of the reaction was studied; the order of the reaction, rate and rate constant were determined. Computational molecular modeling for the complex between BQ and CZT was conducted, the sites of interaction on CZT molecule were determined, and the mechanism of the reaction was postulated. The reaction was employed as a basis in the development of a novel 96-microwell assay for CZT. The assay limits of detection and quantitation were 5.2 and 15.6μgml(-1), respectively. The assay was validated as per the guidelines of the International Conference on Harmonization (ICH) and successfully applied to the analysis of CZT in its bulk and capsules with good accuracy and precision. The assay has high throughput and consumes minimum volume of organic solvent thus it reduces the exposures of the analysts to the toxic effects of organic solvents, and significantly reduces the analysis cost.
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http://dx.doi.org/10.1016/j.saa.2014.04.099DOI Listing
October 2014

A highly sensitive polyclonal antibody-based ELISA for therapeutic monitoring and pharmacokinetic studies of lenalidomide.

J Immunoassay Immunochem 2014 ;35(2):130-8

a Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.

This article describes, for the first time, a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) for therapeutic monitoring and pharmacokinetic studies of lenalidomide (LND), the potent drug for treatment of multiple myeloma (MM). The assay employed a polyclonal antibody that specifically recognizes LND with high affinity, and LND conjugate of bovine serum albumin (LND-BSA) immobilized onto microplate wells as a solid phase. The assay involved a competitive binding reaction between LND, in plasma sample, and the immobilized LND-BSA for the binding sites on a limited amount of the anti-LND antibody. The assay limit of detection was 0.05 ng/mL and the effective working range at relative standard deviations (RSD) of ≤5% was 0.1-20 ng/mL. Analytical recovery of LND from spiked plasma was 100.98 ± 3.05. The precisions of the assay were satisfactory; RSD was 2.96-6.67% and 4.46-7.14%, for the intra- and inter-assay precision, respectively. The procedure is convenient, and one can analyze ∼200 samples per working day, facilitating the processing of large-number batch of samples in clinical laboratories. The proposed ELISA has a great value in routine analysis of LND for its therapeutic monitoring and pharmacokinetic studies.
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http://dx.doi.org/10.1080/15321819.2013.824898DOI Listing
December 2014

Validated stability-indicating capillary electrophoresis method for the separation and determination of a fixed-dose combination of carvedilol and hydrochlorothiazide in tablets.

J AOAC Int 2013 Sep-Oct;96(5):951-9

King Saud University, College of Pharmacy, Department of Pharmaceutical Chemistry, Riyadh 11495, PO Box 22452, Saudi Arabia.

A novel, fast, sensitive, and specific capillary electrophoresis (CE) technique coupled to a diode array detector has been developed for the separation and simultaneous determination of carvedilol (CRV) and hydrochlorothiazide (HCT) in two combination formulations. The proposed method utilized a fused silica capillary (55 cm x75 microm id) and the background electrolyte solution phosphate buffer (12.5 mM, pH 7.4)-methanol (95+5, v/v). The separation was achieved at 30 kV applied voltage and 24 degree C. Atorvastatin (80 microg/mL) was chosen as the internal standard. The described method was linear over the range of 1-200 and 0.2-150 microg/mL for CRV and HCT, respectively. Intraday and interday RSD (n = 6) was < or =1.4%. The LOD values of CRV and HCT were 0.26 and 0.07 microg/mL, respectively. The validated CE method was successfully applied to the analysis of two commercial tablet dosage forms. Forced degradation studies were performed on bulk samples of the two drugs using thermal, photolytic, hydrolytic, and oxidative stress conditions, and the stressed samples were analyzed by the proposed method. Degradation products produced as a result of stress studies did not interfere with the determination of CRV and HCT; the assay could, therefore, be considered stability-indicating.
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http://dx.doi.org/10.5740/jaoacint.11-245DOI Listing
January 2014

Analytical study for the charge-transfer complexes of rosuvastatin calcium with π-acceptors.

Molecules 2013 Jul 3;18(7):7711-25. Epub 2013 Jul 3.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Studies were carried out to investigate the charge-transfer (CT) reaction of ROS-Ca, as a n-electron donor with various p-acceptors: tetracyanoethylene, p-chloranilic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 2,3,5,6-tetrabromo-1,4-benzoquinone, 1,3,5-trinitrobenzene, 2,3,5,6-tetrachloro-1,4-benzoquinone, 7,7,8,8-tetracyano-quinodimethane, and 2,4,7-trinitro-9-fluorenone. Different colored CT complexes were obtained. The reaction mechanism and site of interaction were determined by ultraviolet-visible spectrophotometric techniques and computational molecular modeling. The formation of the colored complexes was utilized in the development of simple, rapid and accurate spectrophotometric methods for the determination of ROS-Ca. Under the optimum reaction conditions, linear relationships with good correlation coefficients (0.9984-0.9995) were found between the absorbances and the concentrations of ROS-Ca in the range of 2-200 mg mL⁻¹. The limits of detection ranged from 0.41 to 12.24 mg mL⁻¹. No interference could be observed from the additives commonly present in the tablets or from the drugs that are co-formulated with ROS-Ca in its combined formulations. The methods were successfully applied to the analysis of tablets with good accuracy and precision; the recovery percentages ranged from 99.54-100.46 ± 1.58-1.82%. The results were compared favorably with the reported method. The proposed methods are practical and valuable for routine application in quality control laboratories for determination of ROS-Ca in its bulk form and tablets.
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http://dx.doi.org/10.3390/molecules18077711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269705PMC
July 2013
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