Preparation Of Hydrochlorothiazide Tablets For 3D Printing And Effects Of Adhesives On The Printability Of Printed Tablets

Specific groups,such as infants,the elderly,specific ethnic groups,liver and kidney dysfunction groups have highly personalized medication needs.At the genetic level,the difference of CYP2D and CYP2C genotypes may even lead to a difference of more than 10 times of the dosage.Improper dosage would lead to increased side effects or weakened therapeutic effect.Individualized medication was the future trend of medical development.3D printing technology was based on the principle of layer by layer manufacturing technology.Its characteristics of personalization and small batch could provide the possibility of personalized manufacturing in the era of industrial mass production.In this study,we used pneumatic biological3D printer to prepare individual dose of hydrochlorothiazide printed tablets by selecting hydrochlorothiazide which was commonly used in c linic as model drug.Under the new process,the printability of the printing paste was deeply studied,and the mechanical properties and quality of the printed tablets were evaluated,so as to meet the requirements of Chinese Pharmacopoeia.At the same time,the effects of different kinds of adhesives on the quality of 3D printing tablets were explored.(1)Prescription screeningScreening of fillers.Corn starch,microcrystalline cellulose,lactose,Dextrin,direct pressure mannitol were selected by control variable method and single factor experiment.The binders were hydroxypropyl methylcellulose,sodium carboxymethylcellulose,povidone K90,polyethylene glycol,sodium alginate,povidone K30,xanthan gum,honey,gelatin and sodium alginate.Finally,it was found that corn starch and microcrystalline cellulose could be used as fillers in the proportion of53.8%:46.2%,with smooth pulp and continuous extrusion.Other fillers were not sticky enough,and could not be stacked on the upper surface of the first layer after the completion of a layer of silk.The integrity of the tablet was not enough,the tablet formability was not good,the bonding condition was general,and the whole tablet was cracked.Selection of adhesives.In this study,hpmc-e30,CMC-Na,pvp-k90,PEG6000,sodium alginate,pvp-k30,xanthan gum,honey,gelatin and sodium alginate were selected as binders.And the printing properties of the paste were studied,including the study of wire speed,10s extrusion weight and the printing speed of broken wire point.The binder was 8%HPMC,gelatin and sodium alginate.The paste was uniform and could be extruded smoothly from the nozzle.The other adhesives were too weak,the paste was wet,no viscosity,blocking the nozzle.According to the formability of the tablets,75%ethanol was selected as wetting agent.(2)Printing process screeningThe parameters of biological 3D printer software were stud ied by single factor.The results showed that the speed range was 6-10 mm/s,the nozzle diameter was 0.8 mm,the printing thickness was 90%of the layer thickness,the printing platform was hard cellophane,and the shape of 30edges.According to the D-V equation y=1.045x+2.5986,R~2=0.9901(d-dose,v-volume),y=0.2465x-1.3874,R~2=0.9952,the 3D printing model with target dose of 10mg was calculated,with layer height of1.44mm,diameter of 5.61mm,layer height of 1.44mm,diameter of7.38mm.(3)Study on Printability of pasteThe printability of the s ize was studied by printing model.The printable parameters include printing speed,10s extrusion weight and broken wire matching speed.HPMC could play a more adhesive role in corn starch MCC.CMC-Na gel could play a more important role in maize starch MCC.PVP gel could play a more important role in maize starch MCC.The stability of low consistency gel and corn starch MCC paste was higher than that of medium and high concentration,while the medium and high concentration paste was relatively stable.Low concentration of PVA gel and corn starch MCC slurry had poor compatibility with lactose,while corn starch MCC slurry with medium and high PEG gel had better stability than low concentration.There was no significant difference in the compatibility between lactose and corn starch MCC and sodium alginate gel.Low concentration gelatin could be prepared into paste with small density difference.(4)Print quality evaluationAfter printing,the quality evaluation,stability and influenc ing factors of 3D printing tablets were carried out.The mechanical properties of HPMC and gelatin sodium alginate tablets were 1.42±0.06mm and 1.45±0.07mm in thickness and 5.54±0.03mm and 7.35±0.04mm in diameter,respectively.The difference of tablet weight was 49.25±0.83mg and 50.76±0.98mg.The hardness was 16.3±2.5n and 15.1±3.5N.Through the microscopic observation,XRD and DSC analys is,the crystal form of hydrochlorothiazide did not change.63mg and 9.73mg respectively.82and 2.84 respectively.3D printing hydrochlorothiazide tablets remained stable within 30 days.The tablets remained stable under various factors.All the above are in accordance with the Chinese Pharmacopoeia 2015edition.