Peak purity assessment in a triple-active fixed-dose combination drug product related substances method using a commercial two-dimensional liquid chromatography system

Objective: The objective of this study is to formulation and development of fixed-dose combination as a single dosage regimen by using the design of experiments (DOE) approach against the single dose of reference listed drugs of brand reyataz capsule 300 mg (atazanavir sulfate) and norvir tablets 100 mg (ritonavir tablets) to treat human immunodeficiency virus (HIV) Infections. Methods: Formulation was developed with each blend of ritonavir by using hot-melt extrusion and atazanavir sulfate by wet granulation process and compressed by bilayer technology followed by film coating. Formulation and process optimization by design of experiments (DOE) to evaluate dissolution and related substances of the finished product. Fractional factorial (22+3) and full factorial design (33+3) by using a design expert (version 11.0) were used to evaluate the formulation and process variables to prepare a robust formulation. Results: Results indicate that the sorbitan monolaurate range has played a key role to achieve the dissolution for ritonavir formulation. The studied temperature range and interaction of temperature and feed rate, temperature and screw speed during the hot-melt extrusion process impact on the related substances of the bi-layer tablet. Analysis of variance (ANOVA) also finding the P-value less than 0.0500 and the studied range was significant. Design space was established for the significant factors to control the results within the acceptable limits. The studied formulation and wet granulation process for atazanavir sulfate have no significant impact on dissolution and related substances of the finished product. Further, the studied hardness range of 16-28kp for bi-layer tablets has no critical impact on the dissolution. Optimum formulation and process of bi-layer tablets in F37 yielded similar drug release and related substances against the reference drug product. Conclusion: The present invention of fixed-dose combination can be recommended as a single dosage regimen with the consistent drug release and control of the unknown impurities in the prototype formulation against the individual reference drug product.

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Rapid Analytical Technique for the Quantification of Specified and Unspecified Impurities Present in Amlodipine besylate and Olmesartan medoxomil Fixed Dose Combination Drug Product Using Ethylene-Bridged RP-UPLC Column

Analytical Chemistry Letters ◽

10.1080/22297928.2016.1253500 ◽

2016 ◽

Vol 6 (6) ◽

pp. 795-819 ◽

Cited By ~ 1

Author(s):

Bhaskara P.V. Mantena ◽

Sumathi V. Rao ◽

D. Suryakala ◽

K. Ramakrishna ◽

R. Srikanth Reddy

Keyword(s):

Drug Product ◽

Olmesartan Medoxomil ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Amlodipine Besylate ◽

Combination Drug ◽

Analytical Technique ◽

Dose Combination

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Pharmacokinetic and Bioequivalence Study of Telzap AM® (Telmisartan/amlodipine Fixed-dose Combination) and Coadministered Mikardis® (Telmisartan) and Norvask® (Amlodipine) in Healthy Subjects

Drug development & registration ◽

10.33380/2305-2066-2020-9-4-155-163 ◽

2020 ◽

Vol 9 (4) ◽

pp. 155-163

Author(s):

V. Kubesh ◽

A. L. Khokhlov ◽

A. M. Shitova ◽

Yu. A. Dzhurko ◽

V. I. Kazey ◽

...

Keyword(s):

Confidence Intervals ◽

Drug Product ◽

Bioequivalence Study ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Combination Drug ◽

Drug Products ◽

Dose Combination

Introduction. A fixed dose combination of telmisartan and amlodipine is widely used in clinical practice during hypertension treatment. Combination of telmisartan and amlodipine demonstrates potentiating synergistic effect on blood pressure decrease. A bioequivalence study of Telzap® AM with coadministered Mikardis® and Norvask® was conducted with 60 volunteers.Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of the fixed dose combination drug product Telzap® AM (telmisartan + amlodipine, tablets, 80 + 10 mg, Zentiva ks company, Czech Republic) and coadministrated monocomponent drug products Mikardis® (telmisartan, tablets 80 mg, Beringer Ingelheim International GmbH, Germany) and Norvask® [amlodipine, tablets 10 mg, Pfizer HCP Corporation (USA), Russia] in healthy volunteers after a single administration under fasting.Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period replicate clinical trial was conducted. The concentrations of amlodipine and telmisartan in plasma samples were determined by a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals for the pharmacokinetic parameters Cmax and AUC0-72 were calculated.Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of amlodipine and telmisartan. All 90 % confidence intervals for the estimated pharmacokinetic parameters of amlodipine were in the range of 80–125 %, 90 % confidence intervals for telmisartan were within the bioequivalence range of 80–125 % for AUC0-72, and 76.73–130.32 % for Cmax.Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent.

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DERIVATIVES OF THE RATIO SPECTRA FOR DETERMINATION OF ACETYLSALICYLIC ACID, ACETAMINOPHEN, AND CAFFEINE IN FIXED-DOSE COMBINATION FORMULATIONS: APPLICATION TO DISSOLUTION STUDIES

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2020v12i6.39417 ◽

2020 ◽

pp. 253-257

Author(s):

JOSE RAUL MEDINA-LÓPEZ ◽

JOSUE GIOVANI PACHECO PINEDA ◽

PEDRO ALBERTO ROJAS GARFIAS ◽

NICASIO CASTRO CHÁVEZ

Keyword(s):

Drug Product ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Reference Drug ◽

Zero Crossing ◽

Dissolution Studies ◽

Derivative Method ◽

Dose Combination ◽

Derivatives Of

Objective: To develop a ratio-derivative spectrophotometric method for the simultaneous quantification of acetilsalycilic acid (ASA), acetaminophen (ACE), and caffeine (CAF) in fixed-dose combination formulations. The proposed method was applied to the reference drug product Excedrin® in dissolution studies. Methods: The method is based on the use of the first-and second-derivatives of the ratio spectra and measurements at zero-crossing wavelengths. The dissolution profiles of ASA, ACE, and CAF were obtained following pharmacopeial conditions, USP Apparatus 2 at 100 rpm and 900 ml of water. Dissolution samples were treated with the proposed UV-derivative method and the results were compared with those obtained with a validated HPLC procedure. The dissolution efficiency was used to compare dissolution profiles (HPLC vs. UV-derivative method). Results: The method was linear in the range of 5-25 µg/ml of ASA, 2.5-20 µg/ml of ACE, and 1-8 µg/ml of CAF (R2>0.999, *P<0.05). The precision and accuracy of synthetic mixtures were within acceptable criteria (2.11-3.43% and 96.78-104.15%, respectively). Nitrocellulose filters were the best option to filter samples and stability of all drugs was adequate when standard solutions were stored at 4 °C during 24 h. No significant differences were found between dissolution profiles (*P>0.05). Conclusion: The proposed UV-derivative method allows the simultaneous determination of ASA, ACE, and CAF in commercial formulations. The method is simple, accurate, and precise and can be used in dissolution studies. Spectrophotometric methods are of low cost and harmless to the environment and, therefore, a better alternative than chromatographic methods.

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Simultaneous Quantification of Acetaminophen, Caffeine, and Ibuprofen in Fixed Dose Combination Drug Using HPLC with UV Detection

Journal of Advances in Medical and Pharmaceutical Sciences ◽

10.9734/jamps/2019/v20i230105 ◽

2019 ◽

pp. 1-19

Author(s):

Emmanuel K. Darkwah ◽

Christopher K. Acquah ◽

Paul S. Lambon ◽

David K. Ameko ◽

Omotayo Akanji ◽

...

Keyword(s):

Internal Standard ◽

Uv Detection ◽

Fixed Dose Combination ◽

World Health ◽

Fixed Dose ◽

Good Resolution ◽

Combination Drug ◽

Simultaneous Quantification ◽

Combination Drugs ◽

Dose Combination

Combination therapy of analgesics is well suited for pain management especially in elderly patients and, has been recommended by the World Health Organization (WHO). Drug analysis plays an important role in the development, manufacture and therapeutic use of drug. In this study, a suitable, cost effective Isocratic HPLC-UV method (Reversed Phase) has been developed and validated for the simultaneous quantification of Acetaminophen, Caffeine, and Ibuprofen in fixed dose combination drugs, using a mobile phase combination of methanol and 0.025M Phosphate buffer –(adjusted to pH 3.2 with Orthophosphoric acid) in the ratio 85:15.A Vertex Column-Eurospher C18 (250 x 4.6 mm), flow rate of 1.0 ml/min at 25°C were the chromatographic conditions. With Piroxicam as internal standard, quantification was achieved with UV detection at 225 nm based on the peak area responses. A good resolution and a short run time (7mins) were achieved with the validated conditions. In consequence, statistical evaluation at the 95% confidence limits revealed that, the method was Linear; with an average correlation coefficient (R = 0.995), and accurate - (mean recovery 99.45% for Acetaminophen, 100.10% for Caffeine and 99.28% for Ibuprofen). With an instrument and intermediate precision RSDs>2.0, the method was found to be specific, Robust, and more economical. Six formulated combination products on the Ghana market were assayed using the validated method. The Acetaminophen, Caffeine and Ibuprofen contents in the combination drugs varied from 97.35% to 103.88%.

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