Parameter Drug EE (%) Particle size (nm) Zeta potential (mV) Coefficient p value Coefficient p value Coefficient p value Intercept 85.4405 < 0.0001* 162.826 < 0.0001* 28.0896 < 0.0001* X1 3.5735 0.0003* 16.2333 0.0054* − 3.5675 0.0050* X2 − 3.8271 0.0002* 18.3916 0.0028* 8.6821 < 0.0001* X3 − 2.0429 0.0064* 16.7166 0.0047* − 7.1571 < 0.0001* X1X2 − 2.0193 0.0315* 14.4667 0.0410* 0.4175 0.7481 X1X3 1.1877 0.1588 − 14.0668 0.0454* 1.8325 0.1860 X2X3 − 1.9454 0.0363* − 15.65 0.0305* 2.0833 0.1395 X12 − 6.9129 < 0.0001* 17.3868 0.0178* 1.5143 0.2538 X22 − 4.3391 0.0006* 26.7035 0.0021* 6.6986 0.0009* X32 − 0.1888 0.8044 47.3201 < 0.0001* 1.8436 0.1739