Synthesis Of Deracoxib,Preparation Of Chewable Tablets And Its Quality Standard Study

Osteoarthritis（OA）,a chronic disease in older animals,has a high incidence and causes pain that can seriously affect the way animals move.The traditional treatment of osteoarthritis is based on cyclooxygenase-1 inhibitors,which are associated with many adverse effects,such as abdominal discomfort,vomiting,loss of appetite and other digestive symptoms,and in severe cases,gastrointestinal bleeding or perforation.Deracoxib belongs to the cyclooxygenase-2（COX-2）inhibitor,and is one of the animal-specific drugs in this family.Deracoxib is increasingly used in veterinary clinics as being able to specifically avoid gastrointestinal adverse reactions.In this study,we firstly obtained the three main synthetic routes of deracoxib by replacing the intermediate reagents of the synthesis reaction according to patent US5760068,using 2-fluoroanisole as the starting material and obtaining the target product4-[5-（3-fluoro-4-methoxyphenyl）-3-difluoromethyl-1H-imidazol-1-yl]benzenesulfonamide,i.e.deracoxib,by a three-step reaction,which has low solvent toxicity,low cost and high yield.The structure of deracoxib was confirmed by NMR hydrogen spectroscopy,IR spectroscopy and mass spectrometry.The physical properties such as solubility,melting point and wettability of the synthesized deracoxib were investigated by quality standards.The results showed that the melting point of deracoxib was 163.7-164.1℃,slightly hygroscopic,soluble in DMSO,slightly soluble in methanol and acetonitrile,insoluble in water,and the imperfection,incineration residue and dry weight loss were in accordance with the pharmacopoeia standard.The maximum absorption was observed at 252 nm by UV spectrophotometer,and the peak time in high performance liquid chromatography was consistent with that of the control.An HPLC method was established for the determination of the relevant substances of deracoxib.The quantification was performed using the principal component auto-control method.The chromatographic conditions were:Waters C18（4.6 mm×250 mm,5μm）,mobile phase A:ammonium acetate buffer,mobile phase B:acetonitrile,gradient elution of mobile phase A and mobile phase B in one line ratio,UV detection wavelength:225 nm,column temperature:30℃,flow rate:1m L/min,injection volume:10μL.the running time was 40 min.the results showed that The specificity and destructive tests showed that the impurity peaks of deracoxib were well separated from the main peaks,and the limits of detection and quantification were 0.2μg/m L and 0.8μg/m L,respectively.the RSD of the reproducibility test was 1.17%and the precision RSD was 1.27%for the determination of the impurity content of six parallel samples,with good durability and good stability of the solution within 10 h;The chromatographic conditions were as follows:Waters C18（4.6 mm×250 mm,5μm）,ammonium acetate buffer:acetonitrile（52:48）as mobile phase,detection wavelength 252 nm,flow rate 1 m L/min,column temperature 30℃,good linearity in the range of 0.25-10μg/m L,limit of quantification and limit of detection The limits of quantification and limits of detection were 0.1μg/m L and 0.25μg/m L,respectively.The average recovery was 99.19%,the precision RSD was 0.25%,the reproducibility RSD was0.53%,and the stability of the solution was good within 10 h.Secondly,a UV spectrophotometric method was established in this study to detect the solubility of deracoxib chewable tablets.The samples were pre-treated by grinding and centrifugation,and the determination method was paddle method with 0.8%sodium dodecyl sulfate（SDS）as the dissolution medium at 50 r/min.The samples were taken and filtered,and the samples were diluted 2 times after filtration,and the dissolution was measured at UV-spectrophotometric 252 nm to calculate the dissolution degree.The results showed that the established UV spectrophotometric method is simple and feasible to operate,the results are accurate and can be used for the determination of the dissolution degree of deracoxib chewable tablets.On the basis of the established UV spectrophotometric dissolution method,Deramaxx?,which is marketed abroad,was used as the reference formulation,and the similarity factor f₂was used as the main index to prepare the excipients for the chewable tablets of deracoxib by single-factor test and raw and excipient compatibility test.24%,sodium carboxymethyl cellulose:15%,povidone K30:11%,sodium dodecyl sulfate:1%,magnesium stearate:3%,aspartame:1%.Quality standard studies were conducted on the chewable tablets of deracoxib to investigate the shape,weight variation,fragility,dissolution determination and content determination of the chewable tablets.The results showed that the chewable tablets were uniform in size,color,smooth and complete surface;the weight difference limit was less than 5%for the three batches of samples above 0.3g;the weight loss was less than 1%for the three batches of samples in crispness and fragility;the dissolution limit was more than 75%at 30 min;the content determination was within 80%-120%for the three batches of samples,and all of them were in accordance with the provisions of the Veterinary Pharmacopoeia of the People’s Republic of China.In conclusion,the HPLC method and UV method were established in this study to detect the dissolution of the relevant substances of deracoxib API and deracoxib chewable tablets respectively,which have the advantages of rapidity,accuracy and specificity and can meet the corresponding detection requirements.The consistency between the chewable tablets and the reference preparation Deramaxx?,the formulation process is practical and feasible,and the quality control method is accurate and scientifically reasonable.The results of the study provide a theoretical basis and research foundation for the synthesis and application of the formulation of deracoxib.