Abstract: OBJECTIVE To prepare 3D printed aminophylline split-dose tablets with stable properties, the compatibility of drug and excipients was investigated by examining their physicochemical properties. METHODS 3D printed aminophylline split-dose tablets with different prescriptions and processes were first prepared and tested according to the method in Chinese Pharmacopeia 2020 Edition to determine the factors affecting the stability of the drug. Then the 3D printed aminophylline split-dose tablets were analyzed by differential scanning calorimetry(DSC), X-ray powder diffraction(XRPD), Fourier transform infrared spectroscopy(FTIR), and HPLC to reveal the compatibility of drug and excipients and the mechanism affecting the stability of the drug. Based on the results of the study, 3D printed aminophylline split-dose tablets with stable properties were prepared and their quality was investigated. RESULTS According to the method of Chinese Pharmacopoeia 2020 edition, the content of anhydrous theophylline and ethylenediamine was preliminarily determined, and the factors affecting the stability of the drug were the addition of filler. The two 3D printed aminophylline dispensed tablets with MCC or lactose were detected by DSC and XRPD with the disappearance of the characteristic peaks of the drug; FTIR showed that the absorption peaks of the functional groups of the reaction products overlapped with those of the drug, which widened the characteristic bands; HPLC showed small impurity peaks in the detection of anhydrous theophylline, indicating the presence of a small amount of sugar degradation products in MCC, while lactose was not suitable for the determination of aminophylline. Therefore, the prescription of 3D printed aminophylline divided-dose tablets was filled with non-sugar anhydrous calcium hydrogen phosphate, the drug prescription was designed and the tablets were printed according to the clinical requirement specifications. The drug content and dissolution degree of the obtained tablets were by the Chinese Pharmacopoeia 2020 edition, and the drug characteristic peaks in DSC, FTIR, and XRPD spectra were not affected by the excipients, and the drug was well compatible with the excipients. CONCLUSION When adding excipients to 3D printed drug-dosed tablets, it is necessary to investigate the compatibility of the drug and the excipients. A small amount of impurity-reducing sugar in MCC will undergo a Maillard reaction with ethylenediamine in aminophylline. When preparing 3D printed dosed tablets, it is necessary to choose excipients that do not affect the stability of the drug.