Co-formulated Drugs Research Articles

Combining simplicity with cost-effectiveness: Investigation of potential counterfeit of proton pump inhibitors through simulated formulations using thin-layer chromatography

A simple, accurate and precise high-performance thin-layer chromatographic method has been developed and validated for the analysis of proton pump inhibitors (PPIs) and their co-formulated drugs, available as binary combination. Planar chromatographic separation was achieved using a single mobile phase comprising of toluene: iso-propranol: acetone: ammonia 5.0:2.3:2.5:0.2 (v/v/v/v) for the analysis of 14 analytes on aluminium-backed layer of silica gel 60 FG254. Densitometric determination of the separated spots was done at 290nm. The method was validated according to ICH guidelines for linearity, precision and accuracy, sensitivity, specificity and robustness. The method showed good linear response for the selected drugs as indicated by the high values of correlation coefficients (≥0.9993). The limit of detection and limit of quantiation were in the range of 6.9–159.2ng/band and 20.8–478.1ng/band respectively for all the analytes. The optimized conditions afforded adequate resolution of each PPI from their co-formulated drugs and provided unambiguous identification of the co-formulated drugs from their homologous retardation factors (hRf). The only limitation of the method was the inability to separate two PPIs, rabeprazole and lansoprazole from each other. Nevertheless, it is proposed that peak spectra recording and comparison with standard drug spot can be a viable option for assignment of TLC spots. The method performance was assessed by analyzing different laboratory simulated mixtures and some marketed formulations of the selected drugs. The developed method was successfully used to investigate potential counterfeit of PPIs through a series of simulated formulations with good accuracy and precision.

Green approach using monolithic column for simultaneous determination of coformulated drugs.

Green chemistry and sustainability is now entirely encompassed across the majority of pharmaceutical companies and research labs. Researchers' attention is careworn toward implementing the green analytical chemistry principles for more eco-friendly analytical methodologies. Solvents play a dominant role in determining the greenness of the analytical procedure. Using safer solvents, the greenness profile of the methodology could be increased remarkably. In this context, a green chromatographic method has been developed and validated for the simultaneous determination of phenylephrine, paracetamol, and guaifenesin in their ternary pharmaceutical mixture. The chromatographic separation was carried out using monolithic column and green solvents as mobile phase. The use of monolithic column allows efficient separation protocols at higher flow rates, which results in short time of analysis. Two-factor three-level experimental design was used to optimize the chromatographic conditions. The greenness profile of the proposed methodology was assessed using eco-scale as a green metrics and was found to be an excellent green method with regard to the usage and production of hazardous chemicals and solvents, energy consumption, and amount of produced waste. The proposed method improved the environmental impact without compromising the analytical performance criteria and could be used as a safer alternate for the routine analysis of the studied drugs.

Spectrophotometric Method for the Determination of Two Coformulated Drugs with Highly Different Concentrations. Application on Vildagliptin and Metformin Hydrochloride

A new smart simple validated spectrophotometric method was developed for the determination of two drugs one of which is in a very low concentration compared to the other. The method is based on spiking and dilution then simple mathematical manipulation of the absorbance spectra. This method was applied for the determination of a binary mixture of vildagliptin and metformin hydrochloride in the ratio 50:850 in laboratory prepared mixtures containing both drugs in this ratio and in pharmaceutical dosage form with good recoveries. The developed method was validated according to ICH guidelines and can be used for routine quality control testing.

Rapid and selective determination of pitavastatin calcium in presence of its degradation products and co-formulated drug by first-derivative micelle-enhanced and synchronous fluorimetric methods

New, selective and rapid methods are presented for determination of PIT in the presence of its hydrolytic degradation products and co-formulated drug, EZE. These methods are derivative micelle enhanced native fluorescence and synchronous fluorimetry.

Chromatographic analysis of multicomponent mixture of vitamins B1, B6, B12, benfotiamine and diclofenac; part II: LC-tandem MS/MS method for simultaneous quantification of five components mixture in pharmaceutical formulations and human plasma

A novel high performance LC-MS/MS method was established for the simultaneous determination of multivitamins B1, B6, B12 and benfotiamine and their co-formulated drug, diclofenac sodium, using torsemide as the internal standard.

The practice and clinical implications of tablet splitting in international health

ObjectiveTablet splitting is frequently performed to facilitate correct dosing, but the practice and implications in low-income settings have rarely been discussed.MethodsWe selected eight drugs, with narrow therapeutic indices or critical dosages, frequently divided in the Lao PDR (Laos). These were split, by common techniques used in Laos, by four nurses and four laypersons. The mean percentage deviation from the theoretical expected weight and weight loss of divided tablets/capsules were recorded.ResultsFive of eight study drugs failed, on splitting, to meet European Pharmacopoeia recommendations for tablet weight deviation from the expected weight of tablet/capsule halves with 10% deviating by more than 25%. There was a significant difference in splitting accuracy between nurses and laypersons (P = 0.027). Coated and unscored tablets were less accurately split than uncoated (P = 0.03 and 0.0019 for each half) and scored (0.0001 for both halves) tablets.ConclusionThese findings have potential clinical implications on treatment outcome and the development of antimicrobial resistance. Investment by drug companies in a wider range of dosage units, particularly for narrow therapeutic index and critical dosage medicines, is strongly recommended.

Simultaneous Determination of Floctafenine and its Hydrolytic Degradation Product Floctafenic Acid Using Micellar Liquid Chromatography with Applications to Tablets and Human Plasma

A stability-indicating micellar liquid chromatography (MLC) method was developed and validated for the assay of floctafenine (FLF) in the presence of its degradation product and main metabolite, floctafenic acid (FLA). The analysis was carried out on a CLC Shim-Pack octyl silane (C8) column (150 x 4.6 mm id, 5 microm particle size) using a micellar mobile phase consisting of 0.15 M sodium dodecyl sulfate, 10% n-propanol, and 0.3% triethylamine in 0.02 M orthophosphoric acid (pH = 3). The mobile phase was pumped at a flow rate of 1.0 mL/min with UV detection at 360 nm. The method showed good linearity for FLF and FLA over the concentration ranges of 0.5-25.0 and 0.4-10.0 microg/mL, with LODs of 0.16 and 0.12 microg/mL, respectively. The developed method was successfully applied to the determination of FLF in commercial dispersible tablets, with mean recovery of 98.87 +/- 1.37%. Also, the proposed method was specific for the analysis of FLF in presence of the co-formulated drug thiocolchicoside in laboratory-prepared tablets, with mean recovery of 100.50 +/- 1.07%. Statistical comparison of the results obtained by the proposed MLC method with those obtained by a comparison method showed good agreement. Moreover, the method was extended to study the degradation behavior of FLF under different International Conference on Harmonization recommended conditions such as alkaline, acidic, oxidative, thermal, and photolytic. The method was further applied for direct determination of FLA as the main metabolite of FLF in human plasma without prior extraction steps, with mean recovery of 110.50 +/- 6.5%.

Antiretroviral medication prescribing errors are common with hospitalization of HIV-infected patients

Errors in prescribing antiretroviral therapy (ART) often occur with the hospitalization of HIV-infected patients. The rapid identification and prevention of errors may reduce patient harm and healthcare-associated costs. A retrospective review of hospitalized HIV-infected patients was carried out between 1 January 2009 and 31 December 2011. Errors were documented as omission, underdose, overdose, duplicate therapy, incorrect scheduling and/or incorrect therapy. The time to error correction was recorded. Relative risks (RRs) were computed to evaluate patient characteristics and error rates. A total of 289 medication errors were identified in 146/416 admissions (35%). The most common was drug omission (69%). At an error rate of 31%, nucleoside reverse transcriptase inhibitors were associated with an increased risk of error when compared with protease inhibitors (RR 1.32; 95% CI 1.04-1.69) and co-formulated drugs (RR 1.59; 95% CI 1.19-2.09). Of the errors, 31% were corrected within the first 24 h, but over half (55%) were never remedied. Admissions with an omission error were 7.4 times more likely to have all errors corrected within 24 h than were admissions without an omission. Drug interactions with ART were detected on 51 occasions. For the study population (n = 177), an increased risk of admission error was observed for black (43%) compared with white (28%) individuals (RR 1.53; 95% CI 1.16-2.03) but no significant differences were observed between white patients and other minorities or between men and women. Errors in inpatient ART were common, and the majority were never detected. The most common errors involved omission of medication, and nucleoside reverse transcriptase inhibitors had the highest rate of prescribing error. Interventions to prevent and correct errors are urgently needed.

Robust analysis of the hydrophobic basic analytes loratadine and desloratadine in pharmaceutical preparations and biological fluids by sweeping—cyclodextrin-modified micellar electrokinetic chromatography

The analysis of hydrophobic basic analytes by micellar electrokinetic chromatography (MEKC) is usually challenging because of the tendency of these analytes to be adsorbed onto the inner capillary wall in addition to the difficulty to separate these compounds as they exhibit extremely high retention factors. A robust and reliable method for the simultaneous determination of loratadine (LOR) and its major metabolite desloratadine (DSL) is developed based on cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) with acidic sample matrix and basic background electrolyte (BGE). The influence of the sample matrix on the reachable focusing efficiency is studied. It is shown that the application of a low pH sample solution mitigates problems associated with the low solubility of the hydrophobic basic analytes in aqueous solution while having advantages with regard to on-line focusing. Moreover, the use of a basic BGE reduces the adsorption of these analytes in the separation compartment. The separation of the studied analytes is achieved in less than 7min using a BGE consisting of 10mmolL−1 disodium tetraborate buffer, pH 9.30 containing 40mmolL−1 SDS and 20mmolL−1 hydroxypropyl-β-CD while the sample solution is composed of 10mmolL−1 phosphoric acid, pH 2.15. A full validation study of the developed method based on the pharmacopeial guidelines is performed. The method is successfully applied to the analysis of the studied drugs in tablets without interference of tablet additives as well as the analysis of spiked human urine without any sample pretreatment. Furthermore, DSL can be detected as an impurity in LOR bulk powder at the stated pharmacopeial limit (0.1%, w/w). The selectivity of the developed method allows the analysis of LOR and DSL in combination with the co-formulated drug pseudoephedrine. It is shown that in CD-MEKC with basic BGE, solute–wall interactions are effectively suppressed allowing the development of efficient and precise methods for the determination of hydrophobic basic analytes, whereas the use of a low pH sample solution has a positive impact on the attainable sweeping efficiency without compromising peak shape and resolution.

Optimized administration regimen of lopinavir for a myocardial ischaemia reperfusion study in Sprague–Dawley rats

Pharmacokinetics of drugs may differ between small and large mammals (including humans); therefore, drug testing in animal models must be carefully designed. Sprague-Dawley rats were used in cardiac experiments, during which the lopinavir concentration in serum had to match human therapeutic levels (4-10 μg/mL). Lopinavir was administered as a co-formulated drug of lopinavir and ritonavir. It was found that after a single administration of a standard human peroral dose (lopinavir 13.3 mg/kg of body weight), the serum concentration of lopinavir was only one-tenth of the target level. It remained below the minimum target level even after 10-fold the standard dose was administered. After initial pilot tests, a dose escalation study was conducted with oral doses 10- and 15-fold the standard clinical dose of lopinavir (i.e. 133 and 200 mg/kg, respectively). A second administration 2 h later effectively increased and maintained higher concentrations during the experimental ischaemia and reperfusion periods. A dose-dependent increase in serum concentration of the drug was observed. Thus, the target therapeutic serum level of lopinavir in the rats was achieved by administrating 10- to 15-fold the standard human dose twice, separated by a 2 h interval.

Comparative ANNs with Different Input Layers and GA-PLS Study for Simultaneous Spectrofluorimetric Determination of Melatonin and Pyridoxine HCl in the Presence of Melatonin’s Main Impurity

Melatonin (MLT) has many health implications, therefore it is important to develop specific analytical methods for the determination of MLT in the presence of its main impurity, N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetaamide (DMLT) and pyridoxine HCl (PNH) as a co-formulated drug. This work describes simple, sensitive, and reliable four multivariate calibration methods, namely artificial neural network preceded by genetic algorithm (GA-ANN), principal component analysis (PCA-ANN) and wavelet transform procedures (WT-ANN) as well as partial least squares preceded by genetic algorithm (GA-PLS) for the spectrofluorimetric determination of MLT and PNH in the presence of DMLT. Analytical performance of the proposed methods was statistically validated with respect to linearity, accuracy, precision and specificity. The proposed methods were successfully applied for the assay of MLT in laboratory prepared mixtures containing up to 15% of DMLT and in commercial MLT tablets with recoveries of no less than 99.00%. No interference was observed from common pharmaceutical additives and the results compared favorably with those obtained by a reference method.

Simultaneous determination of metolazone and spironolactone in raw materials, combined tablets and human urine by high performance liquid chromatography

A new, specific and sensitive reversed-phase high performance liquid chromatographic method was developed for the simultaneous determination of two diuretic drugs; metolazone (MET) and spironolactone (SPL). Good chromatographic separation was achieved within 5.0 min on 150 mm × 4.6 mm i.d., 5 μm particle size Spherisorb-ODS 2 C18 column. A mobile phase containing a mixture of methanol and 0.02 M phosphate buffer (70 : 30) v/v at pH 3.0 was used. The analysis was performed at a flow rate of 1 mL min−1 with UV detection at 235 nm. Xipamide (XPM) was used as an internal standard (IS). The proposed method was rectilinear over the ranges of 0.05–1.0 μg mL−1 and 0.5–10.0 μg mL−1 with limits of detection (LOD) of 0.009, 0.04 ng mL−1 and limits of quantification (LOQ) of 0.03, 0.11 μg mL−1 for MET and SPL, respectively. The suggested method was successfully applied for the simultaneous analysis of the studied drugs in their laboratory prepared mixtures, single tablets and co-formulated tablets. The method was further extended to the determination of both drugs in spiked human urine. The mean percentage recoveries of MET and SPL in spiked human urine were 99.33 ± 2.37 and 99.72 ± 3.27, respectively. The proposed method was also applied for the determination of the studied drugs in the presence of some co-administered or co-formulated drugs without any interference. Statistical evaluation and comparison of the data obtained by the proposed and comparison methods revealed no significant difference between the two methods regarding accuracy and precision.

Validated HPTLC method for simultaneous determination of loratadine and desloratadine in presence of Co-formulated drug

A highly validated and selective high performance thin layer chromatography (HPTLC) method was developed for the determination of loratadine (LOR) and desloratadine (DES) in their pharmaceutical formulations. The proposed method was based on HPTLC separation of the two drugs followed by densitometric measurements of their spots at 254 nm. The separation was carried out on Merck HPTLC aluminum sheets of silica gel 60 F254 using methanol-ammonia (10:0.3, ν/ν) as mobile phase. The linear regression analysis data were used for the regression line in the range of 0.25–0.85 and 0.10–1.00 μg band−1 for LOR and DES, respectively. The method was successfully applied to the analysis of the two drugs in their commercial tablets, capsules, and syrups, and the results were in good agreement with those obtained with the comparison method. The proposed method is specific for the simultaneous determination of loratadine and desloratadine in the presence of other co-formulated drugs, such as pseudoephedrine. The method is...

Recommendations on Bioanalytical Method Stability Implications of Co-Administered And Co-Formulated Drugs By Global Cro Council For Bioanalysis (Gcc)

An open letter written by the Global CRO Council for Bioanalysis (GCC) describing the GCC survey results on stability data from co-administered and co-formulated drugs was sent to multiple regulatory authorities on 14 December 2011. This letter and further discussions at different GCC meetings led to subsequent recommendations on this topic of widespread interest within the bioanalytical community over the past 2 years.

Thermoanalytical investigation of some sulfone-containing drugs.

The thermal behavior of some sulfone-containing drugs, namely, dapsone (DDS), dimethylsulfone (MSM), and topiramate (TOP) in drug substances, and products were investigated using different thermal techniques. These include thermogravimetry (TGA), derivative thermogravimetry (DTG), differential thermal analysis (DTA), and differential scanning calorimetry (DSC). The thermogravimetric data allowed the determination of the kinetic parameters: activation energy (E a), frequency factor (A), and reaction order (n). The thermal degradation of dapsone and topiramate was followed a first-order kinetic behavior. The calculated data evidenced a zero-order kinetic for dimethylsulfone. The relative thermal stabilities of the studied drugs have been evaluated and follow the order DDS > TOP > MSM. The purity was determined using DSC for the studied compounds, in drug substances and products. The results were in agreement with the recommended pharmacopoeia and manufacturer methods. DSC curves obtained from the tablets suggest compatibility between the drugs, excipients and/or coformulated drugs. The fragmentation pathway of dapsone with mass spectrometry was taken as example, to correlate the thermal decomposition with the resulted MS-EI. The decomposition modes were investigated, and the possible fragmentation pathways were suggested by mass spectrometry.

Cobicistat-boosted elvitegravir-based fixed-dose combination antiretroviral therapy for HIV infection

A fixed-dose co-formulated antiretroviral drug containing elvitegravir, a new integrase strand transfer inhibitor, boosted by a novel pharmacokinetic enhancer cobicistat, and further containing the nucleoside pair of tenofovir and emtricitabine was recently approved by the U.S. Food and Drug Administration as a single-tablet, once-a-day treatment of HIV-1 infection in antiretroviral therapy-naive adults. This drug was found to be noninferior to two currently preferred antiretroviral regimens in clinical practice in two large, 48-week, phase III studies. Renal adverse effects limit its use to those with creatinine clearance > 70 mL/min; its considerable drug interaction potential requires care and attention when used. Nevertheless, the availability of this fixed-dose combination product is an important progress in the management of HIV infection for a number of reasons: It provides a third option for a one-pill, once-a-day antiretroviral regimen; it is the first such regimen that is not based on a non-nucleoside reverse transcriptase inhibitor; and it provides an alternative to ritonavir for the pharmaco-enhancement of other antiretroviral drugs.

Stability-indicating HPLC Method for the Determination of Atenolol in Pharmaceutical Preparations

A stability-indicating reversed-phase liquid chromatographic method for the determination of atenolol was developed. Different chromatographic conditions were carefully studied to optimize the parameters for the evaluation of the studied drug. The chromatographic assay involved the use of a C8 Column (250 mm×4.6 mm i.d., 5 μm) with a simple mobile phase composed of acetonitrile:methanol:0.02 M phosphate buffer, pH 5 (20:20:60) at a flow rate of 1 ml/min and UV detection at 226 nm. Pindolol was used as an internal standard. The method showed good linearity over the range of 0.05-10 μg/mL with a detection limit of 0.01 μg/mL and a quantitation limit of 0.03 μg/mL. The proposed method was successfully applied for the analysis of atenolol in three commercial tablets with average percent recoveries of 100.14 ± 1.04, 100.20 ± 0.92, 100.00 ± 0.91 and 100.75 ± 0.67, respectively. Several co-formulated and co-administered drugs did not interfere with the proposed method. The results were statistically compared with those obtained by the official method and were found to be in good agreement. The stability-indicating capability of the method was also tested after accelerated degradation of atenolol in acidic and basic media and after freezing and heating treatments.

Stability‐indicating micelle‐enhanced spectrofluorimetric method for determination of loratadine and desloratadine in dosage forms

A highly sensitive and simple spectrofluorimetric method was developed for the determination of loratadine (LRT) and desloratadine (DSL) in their pharmaceutical formulations. The proposed method is based on investigation of the fluorescence spectral behaviour of LRT and DSL in a sodium dodecyl sulphate (SDS) micellar system. In aqueous solution of acetate buffer of pH 4.5, the fluorescence intensities of both LRT and DSL were greatly enhanced (240%) in the presence of SDS. The fluorescence intensity was measured at 438 nm after excitation at 290 nm for both drugs. The fluorescence-concentration plots were rectilinear over the range 0.05-2.0 µg/mL for both LRT and DSL, with lower detection limits of 5.13 × 10(-3) and 6.35 × 10(-3) µg/mL for LRT and DSL, respectively. The method was successfully applied to the analysis of the two drugs in their commercial tablets, capsules and syrups, and the results were in good agreement with those obtained with the official or comparison methods. The proposed method is specific for the determination of LRT in the presence of other co-formulated drugs, such as pseudoephedrine. The application of the proposed method was extended to stability studies of LRT and DSL after exposure to different forced degradation conditions, such as acidic, alkaline and oxidative conditions, according to ICH guidelines.

A Research Agenda for Malaria Eradication: Drugs

Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission.

Stripping voltammetric determination of silymarin in formulations and human blood utilizing bare and modified carbon paste electrodes

Silymarin is one of the most powerful natural substances that have the ability to protect and rebuild the liver cells damaged by alcohol and other toxic substances. Silymarin showed two irreversible anodic peaks in buffered solutions (pH 2.5–8.0) at either the bare carbon paste electrode or the montmorillonite-Ca modified carbon paste one. These two peaks have been attributed to oxidation of the two phenolic OH groups at positions C-20 and C-7 of silymarin molecule. A square-wave adsorptive anodic stripping voltammetry method was optimized for determination of silymarin utilizing the bare and the modified carbon paste electrodes. The method was fully validated and successfully applied for the determination of silymarin in commercial formulations and human serum without prior extraction utilizing both carbon paste electrodes. Limits of quantitation of 1 × 10 −7 and 7 × 10 −9 mol L −1 silymarin have been achieved in bulk form or in formulations while 2 × 10 −7 and 8 × 10 −9 mol L −1 silymarin were achieved in spiked human serum utilizing the bare carbon paste electrode and the modified one, respectively. The two electrodes exhibited excellent selectivity towards silymarin even in the presence of 10 2to 10 3-fold excess of its co-formulated drugs, common excipients, and common metal ions. The pharmacokinetic parameters of silymarin in plasma of healthy human volunteers were estimated following the administration of a single oral dose of 120 mg silymarin utilizing the modified carbon paste electrode. The estimated pharmacokinetic parameters were favorably compared with those reported in literature.