Tarek S. Belal

Posaconazole (PSZ), lipophilic antifungal drug, is used for prophylactic purposes in immunocompromised patients. Our aim is to study its pharmacokinetics and tissue distribution in different elevated lipoprotein levels in rat. To study PSZ pharmacokinetics and protein binding, rats (n=30) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by i.p. injection of (1g/kg) poloxamer 407 in rats. Serial blood samples were collected for 72h p.o. PSZ (40mg/kg). PSZ unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits. To study tissue distribution, rats (n=64) were allocated into NL and HL groups. After p.o. administration of PSZ 40mg/kg, blood samples were collected, lungs and liver tissues were extracted over 72h. Orally dosed rats showed two distinct Cmax peaks reflecting PSZ enterohepatic circulation. The incremental increase in lipoprotein levels have resulted in significant...

A number of synthetic cannabinoids such as the 1-alkyl-3-acylindoles are the target of significant designer drug activity. One of the first waves of these compounds identified in clandestine samples was 1-n-pentyl-3-(1-naphthoyl)indole, JWH-018. These totally synthetic molecules can be prepared in a number of regioisomeric forms. The electron ionization mass spectrometric (EI-MS) fragmentation of the 1-n-pentyl-3-(1-naphthoyl)indole is compared to its inverse isomer 1-naphthoyl-3-n-pentylindole. These two substances are directly available from indole using identical precursor reagents and similar reaction conditions. Stable isotope deuterium labeling of the three major regions of the JWH-018 molecule allows confirmation of the structures of the major fragment ions. The spectra for the 1-n-pentyl-3-(1-naphthoyl)-d5 -indole, 1-n-pentyl-3-(1-d7 -naphthoyl)indole and 1-d11 -n-pentyl-3-(1-naphthoyl)indole provide significant assistance in elucidating the structures for the major fragment...

The GC-MS properties of the synthetic cannabinoid drug of abuse 3-(1-naphthoyl)-1-pentylindole (JWH-018) and all 5 of its' regioisomeric 1-naphthoyl substituted 1-n-pentylindoles are compared in this report. These compounds have the 1-naphthoyl-group attached at each of the possible substituent positions of the indole ring. The six compounds have the same elemental composition C24H23NO and the same substituents attached to the indole ring. The electron ionization mass spectra showed equivalent regioisomeric major fragment ions resulting from cleavage of the groups attached to the central indole nucleus. The characteristic (M-17)(+) fragment ion at m/z 324 resulting from the loss of an OH group was significant in the EI-MS of 3-, 4-, 5- and 6-(1-naphthoyl)-1-pentylindole. Fragment ions occurred at m/z 127 and 155 for the naphthyl and naphthoyl cations common to all six regioisomeric substances. Indole containing fragments produced the cations at m/z 284, 270, 214 and 186. The unique fragment at m/z 141 observed in the 1,2- and 1,7-isomers resulted from a rearrangement involving the two indole substituents to yield the C10H7CH2(+) cation. The major points of EI-MS differentiation of the synthetic cannabinoid JWH-018 from the other five isomers are the high relative abundance of both the m/z 144 ion and the m/z 324 ion in the JWH-018 spectrum. GC separations on a capillary column containing a trifluoropropyl methyl polysiloxane (Rtx-200) stationary phase provided excellent resolution of these six compounds. The elution order appears related to the relative distance between the two indole substituents with the lowest retention associated with minimum distance between the groups attached to the indole nucleus.

The regioisomeric 1-n-pentyl-3-(methoxybenzoyl)indoles and the 1-n-pentyl-3-(methylbenzoyl)indoles represent potential designer modifications in the synthetic cannabinoid drug category. These six compounds were prepared by a two-step synthetic method. The analytical properties and methods of regioisomeric differentiation were developed in this study. The molecular ion represents the base peak in the EI mass spectra for most of the compounds in this group. The meta- and para-isomers in each series display fragment ions at equivalent masses with some differences in relative abundance of these ions. The ortho-substituted isomers for both the methoxybenzoyl and methylbenzoyl series show a unique fragment ion occurring at M-17. Deuterium labeling for the methoxy group in the ortho-methoxybenzoyl isomer (ortho-OCD3) confirmed the ortho-substituent as the source of the hydrogen in OH (M-17) elimination. The two sets of regioisomers were well resolved by capillary gas chromatography and the elution order reflected increasing molecular linearity. In both sets of compounds the ortho-isomer eluted first and the para-isomer showed the highest retention time. The HPLC separation showed the ortho-isomer eluting first and the meta-isomer eluting last in both sets of regioisomers.

Amlodipine besylate (AML) is available in fixed-dose combination tablets with either candesartan cilexetil (CAN) or telmisartan (TEL). This work describes a simple, selective and sensitive spectrofluorimetric method for analysis of AML/CAN and AML/TEL binary mixtures without prior separation. The method involves measurement of the native fluorescence of AML at excitation and emission wavelengths of 367 and 454 nm, respectively, in water without interference from either of the two drugs. By contrast, the intrinsic fluorescence of CAN was measured at excitation and emission wavelengths of 265 and 392 nm, respectively, in ethanol, while TEL was measured at 366 nm in 0.05 M sodium hydroxide solution using 294 nm as the excitation wavelength. The proposed spectrofluorimetric procedure was validated with respect to linearity, ranges, precision, accuracy, selectivity, robustness, detection and quantification limits. Regression analysis showed a good correlation between fluorescence intensity and concentration over the ranges 0.1-1.4, 0.025-0.25 and 0.0025-0.05 µg/mL for AML, CAN and TEL, respectively. Limits of detection were 0.034, 0.0063 and 0.0007 µg/mL for AML, CAN and TEL, respectively. The proposed method was successfully applied for the analysis of several synthetic binary mixtures of different ratios and laboratory-prepared tablets with good recoveries, and no interference from common pharmaceutical additives was observed.

A simple and selective HPLC with diode array detection stability-indicating method was developed for the simultaneous determination of the antihypertensive drugs carvedilol (CRV) and hydrochlorothiazide (HCT) in their combined formulations. Effective chromatographic separation was achieved using Zorbax SB-C8 column (4.6 × 250 mm, 5 μm) with gradient elution of the mobile phase composed of 0.025 M phosphoric acid and acetonitrile at a flow rate of 1 mL min−1. The multiple wavelength detector was set at 242 nm for measurement of CRV and 271 nm for HCT. Quantification was based on measuring the peak areas. The cited drugs were resolved with retention times 4.9 and 6.7 min for HCT and CRV, respectively. Analytical performance of the proposed HPLC procedure was thoroughly validated with respect to system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection and quantification limits. The linearity ranges were 5–300 and 5–200 μg mL−1 for CRV and HCT, respectively, with correlation coefficients >0.9996. Both drugs were subjected to stress conditions of acidic and alkaline hydrolysis, oxidation, photolysis and thermal degradation. The proposed method proved to be stability-indicating by resolution of the drugs from their forced degradation products. Moreover, specificity of the method was verified by resolution of both drugs from more than 20 pharmaceutical compounds of various medicinal categories. The validated HPLC method was applied to the analysis of the cited antihypertensive drugs in their combined tablet dosage forms. The proposed method made use of DAD as a tool for peak identity and purity confirmation.

ABSTRACT A simple, rapid and sensitive kinetic spectrophotometric method is described for the analysis of naftidrofuryl oxalate (NF) and vincamine (VN) in pure form and in their pharmaceutical preparations. The procedure was based on the kinetic investigation of the oxidation of the studied drugs with alkaline potassium permanganate and the absorbance of the produced manganate species was measured at 610 nm. Variables affecting the color development were investigated and the conditions were optimized.

ABSTRACT A sensitive and specific HPLC method was developed and validated for the simultaneous determination of vincamine and its potential degradant (metabolite), vincaminic acid. Chromatographic separation was achieved on a Spheri-5 RP-C8 (5 μm)(220× 4.6 mm id) column using a mobile phase composed of acetonitrile and 0.05 M sodium acetate, pH 4.0 (30: 70, v/v) at a flow rate of 1 mL/min. The UV detector was set at 270 nm and the quantitation of the analytes was based on the peak areas.

Abstract The side chain regioiomers of the 3-methoxy-4-methylphenethylamines and 4-methoxy-3-methyl-phenethylamines have mass spectra essentially equivalent to the controlled drug substance 3, 4-methylenedioxymethamphetamine (3, 4-MDMA), all have molecular weight of 193 and major fragment ions in their electron ionization mass spectra at m/z 58 and 135/136. Furthermore, the compounds in this study have ring substitutions in the same relative positions as 3, 4-MDMA.

A triple drug combination of amlodipine besylate (AML), valsartan (VAL), and hydrochlothiazide (HCT) was recently approved by the European Medicines Agency and the FDA for the treatment of moderate and severe hypertension. In this work, a simple, rapid, and reliable HPLC-DAD method was described for the simultaneous determination of the three antihypertensives. Chromatographic separation was achieved using Zorbax SB-C8 column with gradient elution of the mobile phase composed of 0.025 M phosphoric acid and acetonitrile. The gradient elution started with 30% (by volume) acetonitrile, ramped up linearly to 70% in 3 min then kept constant for the remainder of the run. The flow rate was 1 mL/min. The multiple wavelength detector was set at 238 nm for measurement of AML and 225 nm for VAL and HCT. Quantification was based on measuring peak areas. The analytes were resolved with retention times 4.2, 4.7, and 6.5 min for HCT, AML, and VAL, respectively. Analytical performance of the proposed procedure was validated with respect to system suitability, linearity, ranges, precision, accuracy, robustness, detection, and quantification limits. The linearity ranges were 5–100, 2.5–200, and 2.5–100 µg/mL for AML, VAL, and HCT, respectively. The validated HPLC method was extended to the analysis of this combination in several laboratory-prepared mixtures of different ratios. Specificity was tested by resolution of the three analytes from several pharmaceutical compounds of various medicinal categories. Finally, Exforge HCT® tablets were assayed using the developed procedure where no interfering peaks were encountered from the tablet additives.

Two sensitive and selective spectrophotometric and spectrofluoimetric procedures were developed for the determination of thonzylamine hydrochloride (THAH) in tablets and nasal drops. The methods are based on König reaction which resulted in an orange-yellow fluorescent product. The orange-yellow product of the interaction between the dicyclohexylcarbodiimide (DCC), THAH and dimethylbarbituric acid (DMBA) showed an absorption maximum at 492 nm, a first-derivative signal at 494 nm and a fluorescence emission peak at 518 nm (λex=492 nm). The orange-yellow color was found to be stable for at least 2 h. The reaction conditions were studied and optimized. The reaction obeys Beer’s law over the ranges 8–20 and 0.2–2.0 μg ml−1 for the derivative spectrophotometric and fluorimetric measurements, respectively. The detection limits were found to be 0.29 and 0.018 μg ml−1 for the spectrophotometric and fluorimetric measurements, respectively. The proposed methods were applied to the analysis of pharmaceutical formulations containing THAH, either alone or in combination with naphazoline nitrate.

A simple, specific and precise high performance liquid chromatographic method has been developed and validated for the simultaneous determination of methylparaben (MP), propylparaben (PP), and domperidone (DP) in oral suspension. Isocratic mobile phase consists of 0.5% w/v aqueous ammonium acetate buffer:methanol, 40:60 (v/v). Column containing octylsilyl chemically bonded to porous silica particles (Optimapak, OP C8, 150 mmx4.6 mm, 5 microm, stainless steel analytical column from RS tech) is used as stationary phase. The detection is carried out using variable wavelength UV-vis detector set at 280 nm. The solutions are chromatographed at constant flow rate of 1.0 mL/min. The method separates MP, PP, DP and droperidol (DR) impurity in less than 12 min with good resolution, peak shapes and minimal tailing. Retention times (RT) for MP, PP, DP and DR are about 3.4, 7.0, 9.0 and 10.9 min, respectively. Linearity range and percent recoveries for MP, PP and DP are 90-270, 10-30, 50-1500 microg/mL and 100.30%, 100.78% and 100.48%, respectively. Method was validated according to ICH guidelines and proved to be suitable for stability testing, homogeneity testing and quality control of these compounds in pharmaceutical preparations.