Study On The Preparation And Quality Of EBTP Oral Solid Dosages

2-ethoxy-5-(3,4,5-trimethoxyphenethyl)phenol phosphate disodium salt(EBTP),a prodrug of 2-ethoxy-5-(3,4,5-trimethoxyphenethyl)phenol(EBT),whose target is tubulin,which is the first vascular targeting agent clinily in the world.This article designs and prepares EBTP tablets and capsules,preliminary research on its formulation process,quality standard and stability.The details are as follows:(1)Pre-prescription research of EBTP API:EBTP infrared spectrum characteristic peak analysis results matches whose structure;The XRD pattern results expressed in 2θangles show that the three solvents have the same crystal form;The particle size distribution measurement results show that the EBTP hold large size,90≤D90≤100μm;Using the shake flask,the solubility results show that EBTP is easily soluble in water and methanol,slightly soluble in ethanol,and insoluble in tetrahydrofuran and n-hexane;The oil-water partition coefficient results show that EBTP has strong water solubility,whose is suitable for oral solid preparations.(2)EBTP tablet prescription screening and process optimization:The results of the compatibility of raw materials and excipients show that the excipients have almost no effect on EBTP;Single factor investigation has obtained the dosage range of microcrystalline cellulose and micro powder silica gel,Central Composite Design-Response Surface Methodology was further used to optimize the prescription,whose(specification is 100 mg,based on 1000 tablets)is:EBTP 100 g,microcrystalline cellulose 100 g,croscarmellose sodium 5.0 g,micronized silica gel20 g,sodium stearyl fumarate 2.5 g.The verification was carried out,and the results of three batches of prescriptions showed that the prescription ratio was excellent and repeatable.The optimized prescription is directly compressed with dry powder,and the obtained tablets have strong formability,with a hardness in the range of 6-8kg,and the difference in tablet weight within 5%,which meets the requirements of the pharmacopoeia.(3)Quality research of EBTP tablets:This product is a white round slice,and the content limit is 95.0%to 105.0%.Chromatographic conditions for the determination of EBTP related substances by HPLC:Column:Phenomenex-luna(4.6×250 mm,5μm);mobile phase is acetonitrile-30 mmol potassium dihydrogen phosphate water(30:70,v/v),flow rate is 1.0 m L/min,detection wavelength is 220 nm,The column temperature is 30℃,and the injection volume is 5μL.The method verification results show that the linear equation of EBT is A=1.30×104C+12.299(r=0.9999)in the concentration range of 0.005 to 1.00μg/m L,which has high accuracy and strong specificity.HPLC method is used to determine the content of EBTP tablets,whose verification results show that the linear equation of EBTP is A=4.05×10~6C+36481(r=0.9996)in the concentration range of 5 to 1000μg/m L.This method has high accuracy and good specificity.The UV spectrophotometry and HPLC method were established to determine the in vitro dissolution of EBTP tablets,The paddle method was selected,the speed was 75 r/min,the dissolution medium was 900 m L of water,and the experiment was ended in 45 minutes.Both methods have a good linear relationship,high accuracy and good specificity.(4)Stability study of EBTP tablets:The experimental results of influencing factors showes humidity has a greater impact on EBTP tablets,so they must be sealed and stored dry.Accelerated test results showes that the appearance of this product is round and there is no obvious change in dissolution,content,and impurities.The six-month long-term test results show that the product has a round appearance and no obvious changes in dissolution,content,and impurities.(5)EBTP capsule preparation technology and preliminary quality research:Single factor investigation determined the dosage of microcrystalline cellulose and micronized silica gel,and further optimized the capsule prescription by orthogonal design.The optimized prescription(specification is 150 mg,based on 1000 capsules):EBTP 150 g,microcrystalline cellulose 150 g,micro-powder silica gel 30 g,sodium stearyl fumarate 20 g.The preparation process is that the dry powder is directly filled on the capsule plate.The RSD of the three batches of samples in the prescription verification is less than 2%.The obtained capsules have uniform content,small difference in filling volume,and good repeatability.And conducted a preliminary study on the quality of EBTP capsules,including HPLC method to determine the content and in vitro dissolution of EBTP capsules.