In present study describe the development of new method and parameter which will be considered during method development and validation. Article give brief idea for a simple, sensitive, precise and accurate High-performance thin-layer chromatographic method for simultaneous determination of Ritonavir and Atazanavir in their combined tablet dosage form has been developed, validated and used for determination of the compounds in commercial pharmaceutical products. Chromatographic separation will be achieved on different column like C8, C18, etc. used as the stationary phase and different mobile phase.
Keywords: High-performance thin-layer chromatography, Ritonavir, Atazanavi

Bhagat, Vishwas

Kanade, Akash Shankar

Shete, Rajkumar V.

Journal of Drug Delivery and Therapeutics (JDDT)

Kande et al                                                                                                               Journal of Drug Delivery & Therapeutics. 2019; 9(3):740-744 ISSN: 2250-1177                                                                                    [740]                                                                                    CODEN (USA): JDDTAO Available online on 22.05.2019 at http://jddtonline.info Journal of Drug Delivery and Therapeutics Open Access to Pharmaceutical and Medical Research © 2011-18, publisher and licensee JDDT, This is an Open Access article which permits unrestricted non-commercial use, provided the original work is properly cited Open  Access                                                                                                                                                               Review Article Simultaneous estimation of atazanavir and ritonavir in combined Tablet dosage form: A Review *Akash Shankar Kanade, Vishwas Bhagat, Rajkumar V. Shete Rajgad Dnyanpeeth’s College of Pharmacy, Bhor, Pune, Maharashtra 412206, India  ABSTRACT In present study describe the development of new method and parameter which will be considered during method development and validation. Article give brief idea for a simple, sensitive, precise and accurate High-performance thin-layer chromatographic method for simultaneous determination of Ritonavir and Atazanavir in their combined tablet dosage form has been developed, validated and used for determination of the compounds in commercial pharmaceutical products. Chromatographic separation will be achieved on different column like C8,  C18, etc. used as the stationary phase and different mobile phase.  Keywords: High-performance thin-layer chromatography, Ritonavir, Atazanavir   Article Info: Received 08 April 2019;     Review Completed 15 May 2019;     Accepted 20 May 2019;     Available online 22 May 2019 Cite this article as: Kanade AS, Bhagat V, Shete RV, Simultaneous estimation of atazanavir and ritonavir in combined Tablet dosage form: A Review, Journal of Drug Delivery and Therapeutics. 2019; 9(3):740-744     http://dx.doi.org/10.22270/jddt.v9i3.2725                                                   *Address for Correspondence:  Akash Shankar Kanade, Rajgad Dnyanpeeth’s College of Pharmacy, Bhor, Pune, Maharashtra 412206, India   1. INTRODUCTION Atazanavir Sulphate Methyl is a Antiretroviral drug N- [(1S)-1-{ [(2S,3S) - 3 - hydroxy-4- [(2S)-2- [(methoxycarbonyl) amino] -3, 3-dimethyl-N'-{[4-(pyridin-2-yl)phenyl]methyl} butanehydrazido]-1- phenylbutan-2-yl] carbamoyl}-2, 2 - dimethyl propyl] carbamate sulphate is a azapeptide HIV-1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. 1  Figure 1: chemical structure of Atazanavir Sulphate Ritonavir is a Antiretroviral drug 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2{[methyl({[2-(propan-2-yl)-1,3-tiazole-4-yl]methyl})carbamoyl]amino}butane mido]-1,6-diphenyl hexan-2-yl] carbamate. Ritonavir inhibits the HIV viral protease enzyme. This prevents cleavage of the gag-pol polyprotein and, therefore, improper viral assembly results. This subsequently results in noninfectious, immature viral particles. 2  Figure 2: chemical structure of Ritonavir Kande et al                                                                                                               Journal of Drug Delivery & Therapeutics. 2019; 9(3):740-744 ISSN: 2250-1177                                                                                    [741]                                                                                    CODEN (USA): JDDTAO methods reported for the simultaneous estimation of Atazanavir and Ritonavir gives out information that there are few separate methods reported for the quantitative estimation of Atazanavir sulfate in bulk, pharmaceutical dosage forms and in plasma by HPLC, likewise a very few methods have been reported for the quantitative estimation of Ritonavir by HPLC but till date no method has been reported for the simultaneous quantitative estimation of Atazanavir and Ritonavir by HPLC [3-8]. There is just one spectrophotometric method reported for the simultaneous estimation of Atazanavir sulfate and Ritonavir in tablets. The present developed method was used determine the Atazanavir and Ritonavir present in the formulation and method validated according to the ICH guidelines. 3 2. INTRODUCTION TO DRUG ANALYSIS  Analytical chemistry is a branch of chemistry that determines the nature and identity of a substance and its composition. In the early twentieth century there were only four accepted branches of chemistry namely, organic chemistry, inorganic chemistry, physical chemistry and biochemistry. Its importance grew, and in the process, absorbed techniques and skills from all other four branches so by the 1950s, analytical chemistry was finally accepted as a branch of chemistry in its own right. 4 The ability to provide timely, accurate, and reliable data is central to the discovery, development, and manufacture of pharmaceuticals. Analytical data are used to screen potential drug candidates, aid in the development of drug synthesis, support formulation studies, monitor the stability of bulk pharmaceuticals and formulated products, and test final products for release. The quality of analytical data is a key factor in the success of a drug development program. 5 3. INTRODUCTION TO HPLC HPLC originally referred to the fact that high pressure was needed to generate the flow required for liquid chromatography in packed columns. In the beginning, instrument components only had the capability of generating pressures of 500psi (35 bar). This was called High Pressure Liquid Chromatography (HPLC). 6 3.1 Instrumentation   Figure 3: Schematic Diagram of HPLC Instrument            Kande et al                                                                                                               Journal of Drug Delivery & Therapeutics. 2019; 9(3):740-744 ISSN: 2250-1177                                                                                    [742]                                                                                    CODEN (USA): JDDTAO 4. INTRODUCTION TO METHOD DEVELOPMENT & VALIDATION Method development and optimization in liquid chromatography is an attractive field of research for academia and industry. Complex mixtures or samples required systematic method development involving accurate modeling of the retention behavior of the analyte.  4.1   Critical steps for HPLC method development 7   Information on a sample, define separation goals  Need for special HPLC procedure, Sample pretreatment, etc  Choose Detector and detector settings  Choose LC Method, preliminary runs, estimate best separation conditions  Optimize separation conditions  Check for problems or requirements for special procedure  Recover purified material, qualitative Calibration, Quantitative Method  Validate Method for released routine laboratory   Table 1: Preferred experimental conditions for the initial HPLC run Separation variable Initial condition Column  Dimensions (length, diameter)  Particle size  Stationary phase   150 × 4.6mm 5μm(3.5μm alternatively) C8 or C18  Mobile phase  Solvent A and B  % of strong solvent  Buffer (compound, pH, and conc.)  pH range  Additives (e.g. Ion pair reagent, amine modifier)  Buffer- Acetonitrile  80-100%  25mM Potassium phosphate  2.0 < 3.0  Do not use initially  Flow rate 1.5-2.0 ml/min.  Temperature 350-450 C.  Sample size  Volume  Weight   < 25μl  < 100μg   4.2 Analytical Method Validation Parameters  Before performing validation of analytical method it is necessary to understand the validation parameters. The various Performance parameters, which are addressed in a validation exercise, are grouped as follows. 8  Kande et al                                                                                                               Journal of Drug Delivery & Therapeutics. 2019; 9(3):740-744 ISSN: 2250-1177                                                                                    [743]                                                                                    CODEN (USA): JDDTAO         Figure 4: Method Validation Parameters as per USP and ICH 5. PARAMETER FOR METHOD VALIDATION 5.1  Selectivity and Specificity:  The selectivity of an analytical method is its ability to measure accurately and specifically the analyte of interest in the presence of components that may be expected to be present in the sample matrix. 5.2 Linearity and Range: The linearity of an analytical method is its ability to elicit test results that are directly (or by a well defined mathematical transformation) proportional to the analyte concentration in samples within a given range. 9 5.3 Accuracy The accuracy of an analytical method may be defined as the closeness of the test results obtained by the method to the true value. It is the measure of the exactness of the analytical method developed. 10 5.4  Precision The precision of an analytical method is the degree of agreement among individual test results when the method is applied repeatedly to multiple samplings of homogenous samples. This is usually expressed as the standard deviation or the relative standard deviation (coefficient of variation). 11 5.4.1 Determination of Repeatability: Repeatability can be defined as the precision of the procedure when repeated by same analyst under the same operating conditions like same reagents, equipments, settings and laboratory over a short interval of time. 12 5.4.2 Determination of Reproducibility: Reproducibility means the precision of the  procedure when it is carried out under different conditions, usually in different laboratories on separate, putatively identical samples taken from the same homogeneous batch of material. 13 5.5  Limit of Detection and Limit of Quantization 5.5.1 Limit of Detection: The limit of detection is the parameter of limit tests. It is the lowest level of analyte that can be detected, but not necessarily determined in a quantitative fashion, using a specific method under the required experimental conditions. The limit test thus merely substantiates that the analyte concentration is above or below a certain level. 14 5.5.2 Limit of Quantitation: Limit of quantitation is a parameter of quantitative assays for low levels of compounds in sample matrices such as impurities in bulk drugs and degradation products in finished pharmaceuticals. The limit of quantitation is the lowest concentration of analyte in a sample that may be determined with acceptable accuracy and precision when the required procedure is applied. 15 5.6  Robustness and Ruggedness 5.6.1 Robustness: The robustness of an analytical method is a measure of its capacity to remain unaffected by small but deliberate variation in method parameters and provides an indication of its reliability during normal usage. The determination of robustness requires that methods characteristic are assessed when one or more operating parameter varied. 16 5.6.2 Ruggedness: The ruggedness of an analytical method is the degree of reproducibility of test results obtained by the analysis of the same samples under a variety of normal test conditions such as different laboratories, different analysts, using operational and environmental conditions that may differ but are still within the specified parameters of the assay. 17 5.7 Stability of Analytical Solution: Stability of the sample, standard and reagents is required for a reasonable time to generate reproducible and reliable results. 18 5.8  System Suitability:  System suitability is the checking of a system to ensure system performance before or during the analysis of unknowns. Parameters such as plate count, tailing factors, resolution and reproducibility (% RSD, retention time and area for six repetitions) are determined and compared against the specifications set for the method. 19  Table 2: System Suitability Parameters and Recommendations20 Parameters Recommendation Capacity Factor (k”) The peak should be well-resolved from other peaks and the void volume, generally K” > 2  Repeatability  RSD ≤ 1% N ≥ 5 is desirable  Relative retention  Not essential as the resolution stated  Resolution (Rs)   Rs of > 2 between the peak of interest and the closest eluting potential interferent (impurity, excipients, degradation products, internal standard, etc.)  Tailing factor (T)  T ≤ 2  Theoretical plates (N) In general should be > 2000 Kande et al                                                                                                               Journal of Drug Delivery & Therapeutics. 2019; 9(3):740-744 ISSN: 2250-1177                                                                                    [744]                                                                                    CODEN (USA): JDDTAO Table 3: Characteristics to be validated in HPLC 21 Characteristics Acceptance Criteria Accuracy / trueness Recovery 98-102% (individual) Precision RSD < 2% Repeatability RSD < 2% Intermediate Precision RSD < 2% Specificity/ Selectivity No interference Detection Limit  S/N > 2 or 3 Quantitation Limit S/N > 10 Linearity Correlation coefficient r2 > 0.999 Range 80-120% Stability >24 h or > 12 h  5.9 Development of Stability indicating HPLC Method 22  Figure 6: Overview of the Method Development Process 6. CONCLUSION The results of the validation study indicate that the analytical method developed for the determination of assay is found to be accurate and precise. The percentage RSD for all parameters was found to be less than two, which indicates the validity of the method and assay results obtained bythis method are in fair agreement. The method is both repeatable and rugged. 7. REFERENCES 1.  http://packageinserts.bms.com/pi/ pi_reyataz.pdf 2.  British Pharmacopoeia, British pharmacopoeia commission, London, UK. 2001; 1: 305. 3.  Srinivas Rao. Journal of Pharmaceutical and Biomedical Analysis. 2011; 55(1):31-47. 4. Arianna Loregia Journal of Pharmaceutical and Biomedical Analysis. 2011; 42(4):500-505. 5. Estelle Cateau Journal of Pharmaceutical and Biomedical Analysis. 2005; 39(3-4):791-795. 6. Chiranjeevi. International journal of pharmaceutical sciences and research IJPSR. 2011; 2(3). 7. Anindita Behera. Der Pharmacia letter. 2011; 3(1):145-151. 8. Nanda RK. Der Pharma Chemica. 2011; 3(3):84-88. 9. ICH Q2A. Guidelines on validation of analytical procedure; Definitions and terminology, Federal Register. 1995; 60:11260. 10. ICH Q2B. Guidelines on validation of analytical procedure; Methodology, Federal Register. 1996; 60:27464. 11. Gurdeep R. Chatwal, Sham K. Anand, “Instrumental Method of Chemical Analysis,” 5st Edition, PP- 2.567.  12. Lippncott Williams and Wilkins, “Remington the Science and Practice of pharmacy,” Vol. - I, 21st Edition, PP- 667 13. Gurdeep R. Chatwal, Sham K. Anand, “Instrumental Method of Chemical Analysis,” 5st Edition, PP- 2.624.  14. Gurdeep R. Chatwal, Sham K. Anand, “Instrumental Method of Chemical Analysis,” 5st Edition, PP- 2.570.  15. Ravi Shankar, “Instrumental Method of Analysis”, 2nd Edition, PP- 18-60. 16. Ravi Shankar, “Instrumental Method of Analysis”, Ind Edition, PP- 17-36. 17. C.B.U., Journal of Science,” Vol. - II Issue Oct. 2009, PP- 11-18.  18. International Journal of Pharmacy and Technology,” Vol. – II, Issue June 2010, PP- 429-439.  19. Zhao LZ, et. al., “Determination of Atazanavir and Ritonavir in human plasma by liquid chromatography– tandem mass spectrometry method: application to a bioequivalence study of two formulations in healthy volunteers”, Biomedical Chromatography 2008, 50. (5), 519–526. DOI: 10.1002/bmc.963 20. Bhargavi P, Lakshmi S, et. al., “Quantitative bioanalysis of Atazanavir and Ritonavir in Human plasma using LC-MS-MS”, IJIPLS 2011, 1(2), 39-48. 21. Berzas JJ, Rodriguez J and Castaneda G, “Simultaneous Determination ofEthinylestradiol and Atazanavir and Ritonavir by Derivative Spectrophotometry”, Analyst 1997, 122, 41-44. DOI: 10.1039/A604558H 22. Bhargavi P et al. “Quantitative bioanalysis of Atazanavir and Ritonavir in Human plasma using LC-MS-MS”, IJIPLS 2011, 1(2), 39-48.   

Simultaneous estimation of atazanavir and ritonavir in combined Tablet dosage form: A Review

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Simultaneous estimation of atazanavir and ritonavir in combined Tablet dosage form: A Review

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