Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection. Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV), which inhibits reverse transcription, Hepatitis B virus (HBV) is highly endemic in South Africa and across sub-Saharan Africa, where around 8% of people are chronically infected, and rates of HBV-related liver cancer are some of the highest in the world. Globally, viral hepatitis causes approximately 1.3 million deaths every year more than either malaria or tuberculosis with around 240 million people chronically infected with HBV1. The currently available anti-HBV drugs show potent antiviral activity in patients with chronic hepatitis B; however, the resistance and cross-resistance to the drugs is a major obstacle in long-term treatment. Many studies have been conducted to understand the molecular basis of drug resistance, and the mechanistic characterization and molecular modeling of anti-HBV drugs complexed with HBV RT have been reported. Although the three-dimensional X-ray structure of HBV polymerase is not available, its homology model has been reported using the X-ray structure of HIV RT as a template [1-13]. Even though the homology models may not be accurate due to the low sequence homology between the overall HIV and HBV polymerase, the sequence conservation between the RT domains of HIV and HBV polymerase enables molecular modeling of HBV RT [14]. In particular, the residues around the active site that are responsible for recognizing the template-primer or an incoming nucleoside triphosphate are highly conserved. Nucleoside analogue HBV polymerase inhibitors cause chain termination after incorporation into the growing chain in the active site of HBV polymerase and consequently inhibit viral reverse transcriptase. Thus, the HBV homology model structure based on the crystal structure of HIV polymerase serves as a useful guide for understanding the molecular basis of HBV resistance to drugs..
The World Health Organization's (WHO) 2014 Guidelines for the screening, care and treatment of persons with hepatitis C infection state that worldwide more than 185 million people are infected with the hepatitis C virus (HCV) [3]. Of these people, 350 000 to 500 000 die each year. An estimated one third of those who become chronically infected develop liver cirrhosis or hepatocellular carcinoma. HCV infection can be cured, but most people infected with the virus are unaware of their infection and so do not seek timely treatment. Furthermore, treatment remains unavailable for many who have been diagnosed. Several medicines are available to treat HCV, including pegylated interferon and ribavirin but treatment duration is long, involves weekly injections, and side effects are considerable. With the development of new direct-acting antivirals, the treatment landscape is rapidly changing [4]. These new antivirals are expected to reach cure rates of more than 90% in persons with HCV infection across different genotypes, with fewer side effects and a shorter duration of treatment. Two new compounds, simeprevir and sofosbuvir, have recently been approved in the United States and Europe and are recommended by the new WHO treatment guidelines. Many others are in various stages of development. Sofosbuvir is marketed by Gilead Sciences, Inc. under the brand names Sovaldi and Virunon. In 2011, Gilead Sciences acquired Pharmasset Ltd., the company that developed the drug and filed the first patent in 2003. Sofosbuvir is a prodrug that is metabolized in the body to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-
The process is from the penultimate intermediate namely 5-(5-chlorosulphonyl-2-ethoxy phenyl) -1-methyl-3-N-propyl-1,6-dihydro-7H-pyrasolo-(4,3-d)pyrimidin-7-one, which is herein will be referred to as chlorosulphonyl intermediate ( 21). This intermediate is condensed with N-methylpiperazine (2) in a solvent preferably of chlorinated hydrocarbon in presence of a trisubstituted amine or in presence of mixture of such amines (Figure 3) [2].
The ICH guidelines on impurity have clearly defined the levels of toxic impurities and have become benchmark in establishing impurities in pharmaceutical drug products. The present article summarizes the concept of impurity profiling and presents a case study on impurity profiling of quantification of active pharmaceutical ingredient and impurities in sildenafil citrate purchased via internet and its relative outcomes.
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