Combined use of cyclodextrins and hydroxypropylmethylcellulose stearoxy ether (Sangelose®) for the preparation of orally disintegrating tablets of type-2 antidiabetes agent glimepiride

Despite recent advances in the formulation of orally disintegrating tablets (ODTs), the efforts to enhance the swallowing of the drug after disintegration have been limited. In this study, the feasibility of the combined use of cyclodextrins (CyDs) and a functional drug carrier, hydroxypropylmethylcellulose stearoxy ether (Sangelose^®) was investigated to improve usability of ODTs. Glimepiride, a potent third generation hypoglycemic agent for type 2 diabetes was used as a model drug, because it is poorly water-soluble and elimination half life is fairly short. The direct compression method was employed for the preparation of glimepiride tablets, containing CyDs and Sangelose^®, and various characteristics of the tablets were examined. In the cases of α-CyD and β-CyD, a short disintegration time with an appropriate hardness was obtained, complying with ODT criteria. On the other hand, γ-CyD, HP-β-CyD and HB-β-CyD increased in the hardness and disintegration time of the tablets. The rheological evaluation revealed that CyDs, except γ-CyD, significantly reduced the viscosity of the fluids after disintegration of the tablets, suggesting an ease of swallowing. This was ascribable to the complexation of the hydrophobic stearoyl moiety of Sangelose^® with CyDs after dissolution, leading to the inhibition of the polymer–polymer interaction of Sangelose^® and to the decrease in viscosity of the solution. The interaction of glimepiride with α- and β-CyDs was studied by the solubility method, demonstrating that glimepiride formed water-soluble complexes with these CyDs. Results obtained here suggested that α-CyD and β-CyD can be particularly useful for the Sangelose^®-based ODT formulation, compared to γ-CyD, HP-β-CyD and HB-β-CyD, because of the short disintegration time of the tablets containing α-CyD and β-CyD, their shear-thinning effect on Sangelose^® solutions and their solubility enhancing effect on the drug.     

Development and Validation of a High Performance Liquid Chromatographic Method for the Determination of Voriconazole Content in Tablets

This paper describes the validation of an isocratic HPLC method for the assay of voriconazole in tablets. The method employs a Merck LiChrospher^? 100 RP-8 (125 × 4.6 mm I.D., 5 μm particle size) column, with a mobile phase of methanol : triethylamine solutions 0.6 %, pH 6.0 (50:50, v/v) and UV detection at 255 nm. A linear response (r > 0.9999) was observed in the range of 20.0–100.0 μg mL⁻¹. The method showed good recoveries (average 100.4%) and the relative standard deviation intra and inter-day were ≤ 1.0 %. Validation parameters as specificity and robustness were also determined. The method can be used for both quality control assay of voriconazole in tablets and for stability studies as the method separates voriconazole from its degradation products and tablet excipients.     

Determination of Carbamazepine in Pharmaceutical Dosage Form Using GC-FID

The present work describes the methodology and validation of gas chromatography with flame ionization detection (GC-FID) for the determination of carbamazepine with internal standard (diazepam) in pharmaceutical preparations. The method was linear from 2–30 μg mL⁻¹. The RSD values for precision was less than 9%, accuracy (relative error) was better than 11% (n = 6). The developed method was successfully applied for the assay of pharmaceutical dosage forms which do not require any preliminary separation or treatment of the samples. The RSD values for Tegretol^® tablets (200 mg) and Karberol^® tablets (200 mg) was found to be 4.03 and 3.25%, respectively. The results obtained from this method were compared with the reference method (LC) reported in literature and no significant difference was found statistically.

     

Development of a green stability-indicating HPLC–DAD method for the determination of donepezil hydrochloride in the presence of its related substance and degradation products

A simple, eco-friendly, stability-indicating HPLC method was developed for the determination of donepezil hydrochloride (DH) in tablet dosage form in the presence of its pharmacopoeia-related compound (donepezil-related compound A) and its different degradation products. The chromatographic conditions were optimized to achieve the highest performance parameters using Zorbax Eclipse Plus C18 rapid resolution column (4.6?×?100?mm, 3.5?µm), with a mobile phase composed of 72.5% acetate buffer pH 5.5 and 27.5% ethanol, flowing at 1?mL?min^?1. The diode array detector (DAD) was set at 315?nm and the column oven was adjusted at 45°C. Linear response (r?=?0.9999) was observed over the range of 2–28?µg?mL^?1 of donepezil, with detection and quantitation limits of 0.031 and 0.103?µg?mL^?1, respectively. Forced degradation studies were performed on standard DH and test Demepezil® 5-mg tablets under various conditions and the method was found to be stability indicating. The purity of DH peak was confirmed using the DAD. In the developed method, two principles of green chromatography were adopted (reduce and replace) by reducing solvent consumption through the utilization of a short column (10?cm) with a smaller particle size (3.5?µm) instead of a normal 25?cm with a 5?µm particle size and by replacing hazardous solvents of the official United States Pharmacopoeia method as acetonitrile with ethanol. Furthermore, the greenness of the method was assessed using three assessment tools.     

Determination of Dydrogesterone in Human Plasma by Tandem Mass Spectrometry: Application to Therapeutic Drug Monitoring of Dydrogesterone in Gynecological Disorders

A sensitive and specific tandem mass spectrometric (MS–MS) method was developed and validated for the determination of dydrogesterone (Duphaston^®), an orally active synthetic progestogen, in human plasma. Multiple reaction monitoring (MRM) scans at m/z 313.1 > 105.5 (dydrogesterone) and m/z 393 > 147 (dexamethasone, internal standard) were selected to determine dydrogesterone by the internal standard method. Linear correlations (r: ～0.99 ± 0.05) of the calibration curves were established over the concentration range 10–60 ng mL^?1 with a lower limit of quantification (LLQ) of 10 ng mL^?1 (RSD% 14.9 and %DEVs ?10.5 to +15.6). Solid-phase extraction (SPE) technique was used for extraction of dydrogesterone and internal standard from patient plasma samples using Oasis^® Max C18 cartridges. Ion suppression studies indicated negligible effects of plasma matrix on the mass ions detection of dydrogesterone and IS, when measured in MRM mode. Validation data showed that RSD% values were <22.0%, whereas %DEV values were in the range of ?20.2 to +13.3 for intra- and inter-day precision and accuracy, respectively. Analytical recoveries of dydrogesterone from supplemented plasma samples with the drug were in the range of 100.7–112%, indicating the efficiency of the SPE for separation of dydrogesterone from human plasma. Stability studies conducted at ?20 °C, showed that dydrogesterone was stable in plasma as indicated from the measured degradation kinetic parameters. The developed method was applied for monitoring plasma levels of dydrogesterone in 25 patients treated with Duphaston^® tablets at a dose of 10 mg three times daily. Mean plasma concentration of 16.1 ± 3.5 ng mL^?1 of dydrogesterone were measured at the steady state. The data suggest the utility of tandem mass method in therapeutic drug monitoring of plasma levels of dydrogesterone in gynecological disorders treated with Duphaston^® tablets.     

LC Determination of Helicidum in Beagle Dog Plasma: Study on the Pharmacokinetics of Helicidum Orally Disintegrating Tablets Compared to Conventional Tablets

A sensitive and reproducible liquid chromatographic method with UV detection was described for the determination of helicidum in beagle dog plasma. Sample preparation was accomplished through protein precipitation with 15% perchloric acid and chromatographic separation was performed on a reversed phase C₁₈ column at 30 °C. Mobile phase consisted of a mixture of acetonitrile–water at a flow rate of 1.0 mL min^?1. Wavelength was set at 270 nm. The method was applied to a pharmacokinetic study of two formulations of helicidum. No statistical difference in the t _1/2 (AUC_0–5, AUC_0–∞) between the two formulations were observed. The t _max of helicidum ODTs is significantly shorter than that of conventional tablets (0.84 h vs. 1.33 h, P< 0.05).     

LC Determination of Helicidum in Beagle Dog Plasma: Study on the Pharmacokinetics of Helicidum Orally Disintegrating Tablets Compared to Conventional Tablets

A sensitive and reproducible liquid chromatographic method with UV detection was described for the determination of helicidum in beagle dog plasma. Sample preparation was accomplished through protein precipitation with 15% perchloric acid and chromatographic separation was performed on a reversed phase C₁₈ column at 30 °C. Mobile phase consisted of a mixture of acetonitrile–water at a flow rate of 1.0 mL min⁻¹. Wavelength was set at 270 nm. The method was applied to a pharmacokinetic study of two formulations of helicidum. No statistical difference in the t _1/2 (AUC_0–5, AUC_0–∞) between the two formulations were observed. The t _max of helicidum ODTs is significantly shorter than that of conventional tablets (0.84 h vs. 1.33 h, P< 0.05).

     

Boronate-Containing Copolymer Grafted on Eupergit C as Matrix for Affinity Chromatography: Isotherms and Kinetics Study

A stability-indicating HPLC method has been developed and subsequently validated for the simultaneous determination of domperidone and pantoprazole in commercial tablets. The proposed HPLC method utilizes Phenomenex^® Gemini C₁₈ column (150 mm × 4.6 mm i.d., 5 μm) and mobile phase consisting of methanol-acetonitrile-20 mM dipotassium hydrogen phosphate and phosphoric acid buffer pH 7.0 (20:33:47, v/v/v) at a flow rate of 1.19 mL min^?1. Quantitation was achieved with UV detection at 285 nm based on peak area with linear calibration curves at concentration ranges 0.5–5.0 μg mL^?1 for domperidone and 1.0–10 μg mL^?1 for pantoprazole (R ² > 0.999 for both drugs). The method was validated in terms of accuracy, precision, linearity, limits of detection, limits of quantitation and robustness. This method has been successively applied to pharmaceutical formulation and no interference from the tablet excipients was found. Domperidone, pantoprazole and their combination drug product were exposed to acid, base and neutral hydrolysis, oxidation, dry heat and photolytic stress conditions and the stressed samples were analyzed by the proposed method. As the proposed method could effectively separate the drug from its degradation products, it can be employed as stability-indicating method for the determination of instability of these drugs in bulk and commercial products.     

Development of a Diamond Nanoparticles-based Nanosensor for Detection and Determination of Antiviral Drug Favipiravir

This study developed a nanosensor for the detection and determination of favipiravir, a presumed drug that has potential therapeutic efficacy in treating COVID-19 patients, from tablets and serum samples. This nanosensor was obtained by adding the optimum amount of diamond nanoparticles into carbon paste. For the determination of favipiravir adsorptive stripping differential pulse (AdSDPV) and adsorptive stripping square wave voltammetry (AdSSWV) were used. Limit of detection values were found as 4.83×10⁻⁹ M and 2.44×10⁻⁷ M for bulk and 5.18×10⁻⁸ M and 4.38×10⁻⁸ M for serum samples using AdSDPV and AdSSWV, respectively. Recovery studies made of the tablet and serum produced satisfactory results.     

Development and Validation of an RP-HPLC Method for Determination of Valganciclovir in Human Serum and Tablets

This paper describes the validation of an isocratic high-performance liquid chromatographic method for the assay of valganciclovir in raw materials, tablets and human serum samples. Valganciclovir and fluvastatin (internal standard) were well separated using a reversed phase column and a mobile phase consisting of a mixture of acetonitrile:methanol:KH₂PO₄ (0.02 M) (40:20:40; v/v/v) (at pH 5.0). The mobile phase was pumped at 1.0 mL min⁻¹ flow rate and valganciclovir was detected by diode-array detection at 255 nm. The retention times for valganciclovir and fluvastatin were 3.41 and 5.60 min, respectively. A linear response (r > 0.999) was observed in the range of 10–30,000 ng mL⁻¹ in mobile phase and serum. The limit of detection and limit of quantification were found as 2.95 and 9.82 ng mL⁻¹ in mobile phase and 1.73 and 5.77 ng mL⁻¹ in human serum samples, respectively. Validation parameters as precision, accuracy, selectivity, reproducibility and system suitability tests were also determined. The method can be used for valganciclovir assay of tablets and human serum samples as the method separates valganciclovir from tablet excipients and endogenous substances.

     

Development of thermogravimetric method to quantitative determination of mebendazole

The objective of this work was to develop and validate a fast and reproducible method able to determine the concentration of mebendazole in raw materials and tablets. The samples were analyzed by dynamic thermogravimetry, in the heating rates of 10, 20, 40, 60 and 80°C min^–1, in the atmospheres of nitrogen and nitrogen with synthetic air. Obtained data were used in the equations of Antoine and Langmuir, with the purpose to get the pressure curves of those. Vapor pressure curves of drug and tablet of mebendazole were evaluated using the mathematical indexes of difference factor, f ₁, and similarity factor, f ₂, to compare its profiles. The data showed that there is no significant difference between the vapor pressure profiles of drug and tablet of mebendazole in both environmental conditions studied, what confirms that the process is really vaporization. The concentration of mebendazole was determined in the raw material and tablets with the drug.     

Development of thermogravimetric method for quantitative determination of metronidazole

The objective of this work was to develop and validate a fast and reproducible method to determine the concentration of metronidazole in drug substance and tablets. The samples were analyzed by dynamic thermogravimetry, using 10, 20, 40, 60 and 80°C min^–1 heating rates in nitrogen and in nitrogen with synthetic air. Obtained data were used in the Antoine and Langmuir equations in order to have the pressure curves. Vapor pressure curves of drug and tablet of metronidazole were evaluated using the mathematical indexes of difference factor, f ₁, and similarity factor, f ₂, to compare their profiles. The data showed that there is no significant difference between the vapor pressure profiles of drug and tablet of metronidazole in both environmental conditions, which confirms that the process is really vaporization. The concentration of metronidazole was determined in the raw material and tablets of the drug.     

Assessment of pharmacokinetic interaction between piracetam and l‐carnitine in healthy subjects

A rapid, sensitive and specific method for quantifying piracetam in human plasma using Piracetam d‐8 as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by one‐step precipitation of protein using an acetonitrile (100%). The extracts were analyzed by high‐performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC‐MS/MS). The method had a chromatographic run time of 3.8 min and a linear calibration curve over the range 0.5–50 µg/mL (r > 0.99). This LC‐MS‐MS procedure was used to assess the bioavailability of two piracetam formulations: piracetam + l‐carnitine (Piracar®; 270/330 mg tablet) and piracetam (Nootropil®; 800 mg tablet) in healthy volunteers of both sexes. The geometric means with corresponding 90% confidence interval (CI) for test/reference percentage ratios were 88.49% (90% CI = 81.19 – 96.46) for peak concentration/dose and 102.55% (90% CI = 100.62 – 104.51) for AUC_inf/dose. The limit of quantitation of 0.5 µg/mL is well suited for pharmacokinetic studies in healthy volunteers. It was concluded that piracetam (Piracar®; 270/330 mg tablet) has a bioavailability equivalent to the piracetam (Nootropil®; 800 mg tablet) formulation with regard to both the rate and the extent of absorption. Copyright © 2015 John Wiley & Sons, Ltd.     

Capillary Electrophoretic Determination of Citalopram in Pharmaceutical Tablets and Serum

Determination of citalopram by capillary electrophoresis is described. Compounds were separated at 28 kV in 75 μm i.d. fused silica capillary tubing (total length 85 cm, effective length 65 cm) with 10 mM borate buffer, pH 8.5, containing 10% (v/v) methanol as running buffer. Citalopram and propylparaben (IS) appeared at 3.5 and 5.5 min, respectively. Repeatable linear results were obtained. The limits of detection and quantification were 5.73 × 10⁻⁶ and 1.72 × 10⁻⁵ M, respectively. When citalopram was determined in a pharmaceutical tablet by capillary electrophoresis and by a UV-spectrophotometric method differences between the results were not significant. The citalopram content of tablets was 100.8 ± 2.95% of the label claim. The amount found in serum was 26.7 ± 0.1% of the free drug, indicating that 73.3% of the drug was bound to protein.     

Graphite-Polyurethane Composite Electrode as an Amperometric Flow Detector in the Determination of Atenolol

Abstract

A bare graphite-polyurethane composite was evaluated as an amperometric detector in the flow injection determination of atenolol in pharmaceutical formulations. Using a flow injection analysis (FIA) procedure, a linear analytical curve was observed in the 0.2–3.0 mmol L^?1 range with a minimum detectable net concentration limit of detection (LOD = 18.1 µmol L^?1 and 90 determinations h^?1. Interferences from propranolol and furosemide were observed but not from the other components of the tablet. Thus, it was possible to determine atenolol in tablets without interference and with results that agreed with high performance liquid chromatography (HPLC) procedure with a 95% confidence level in a fast and accurate procedure.     

Study of dosimetric properties of acetylsalicylic acid in pharmaceutical preparations by EPR spectroscopy

Electron paramagnetic resonance (EPR) was used to investigate the dosimetric properties of two pharmaceutical preparations containing acetylsalicylic acid, Aspirin® and Cafiaspirin®. The EPR spectra of the irradiated samples were found to have an asymmetric absorption characterized by a major resonance at g = 2.0033. Dose response was investigated between dose ranges of 2 to 95 kGy for ⁶⁰Co-gamma rays. Fading characteristics and dependence on temperature irradiation were also studied. We suggest that commercial Aspirin® and Cafiaspirin® tablets can be used as dosimeters in the case of a short accident.     

Development, characterization and performance evaluation of oro-dispersible tablet containing aceclofenac hydroxypropyl-β-cyclodextrin binary system

The purpose of this research was to mask the intensely bitter taste of aceclofenac (ACF) and to formulate oro dispersible tablet (ODT) of the taste-masked drug. Taste masking was done by complexing aceclofenac with Hydroxypropyl-β-Cyclodextrin (HPβCD) by different methods. Phase solubility studies indicated complex with possible stoichiometry of 1:1 and a stability constant of 221.11 M^?1. The complexes were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the ACF within the nonpolar cavity of HPβCD in the neutralization method (NM). Remarkable improvement in the in vitro drug release profiles in pH 6.8 phosphate buffer was observed with all complexes, especially the neutralization. The complexes of ACF–HPβCD (1:1) was compressed into tablet and properties of tablets such as tensile strength, wetting time, in vitro disintegration time, and disintegration in the oral cavity were investigated to elucidate the wetting and disintegration characteristics of tablets. Polyplasdone XL-10 7% wt/wt gave the minimum disintegration time. Tablets of batch F4 containing Avicel 200 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12 s, than the marketed tablet (128 s). Good correlation between in vitro disintegration with in-house developed method and in the oral cavity was recognized. Taste evaluation of ODT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value. Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity.     

Diffusivity of amorphous drug in solid dispersion

Filmy solid dispersion of terfenadine (TFD), fenofibrate (FFB), and carbamazepine (CBZ) and methacrylic acid methyl methacrylate copolymer (Eudragit^®) was prepared by evaporating their solution. Raman and IR measurements for the filmy samples were performed. Concentration profile of TFD, FFB, and CBZ in solid dispersions was evaluated by their characteristic peaks, and then their diffusion rate constants were calculated. The start point of the crystallization peak under isothermal condition was determined by XRD–DSC. Viscoelastic character of Eudragit^® was evaluated by dynamic mechanical analysis (DMA). The distribution map of drugs in their solid dispersions showed the diffusion state of drugs during storage. The concentration profile of TFD, FFB, and CBZ in the solid dispersion was calculated from obtained mapping data. The diffusion rate constant of both drug in Eudragit^® EPO was higher than that in Eudragit^® RLPO. The induction period of crystallization from amorphous CBZ was gradually delayed with increasing amounts of Eudragit^®. The IR peak due to C=O was shifted to higher wave number; it suggested that there were some molecular interactions between CBZ and Eudragit^®. From the results of the change in the interaction of drug-Eudragit^®, it may be concluded that the diffusivity of drug molecule in polymer closely related to the delay of the induction period of crystallization of amorphous. DMA measurement clarified the difference in the viscosity of Eudragit^® having different functional groups and molecular mass. These results suggested that the retardation of crystallization by Eudragit^® could be related to the sample viscosity.     

Determination of Abacavir, Lamivudine and Zidovudine in Pharmaceutical Tablets, Human Serum and in Drug Dissolution Studies by HPLC

A simple, accurate, precise and fully automated method for the simultaneous determination of abacavir, lamivudine and zidovudine in pharmaceutical tablets, human serum samples and drug dissolution studies has been developed. Separation was performed on a 5 μm Zorbax^® C₁₈ column (150 × 4.6 mm ID) with methanol:water:phosphate buffer at pH 5.65 (80:10:10; v/v/v) isocratic elution in less than 7 min with a flow rate of 0.6 mL min^?1.Good sensitivity for all analytes was observed with UV detection at 275 nm. The method allowed quantitation over the 500–3,000 ng mL^?1 range for abacavir and 500–5,000 ng mL^?1 range for lamivudine and zidovudine. The method has been applied, without any interference from excipients or endogenous substances, for the simultaneous determination of these three compounds in tablets. Human serum and drug dissolution studies.