The pectin/calcium interaction, which is the basis for biphasic release of indomethacin from the HPMC/pectin/calcium chloride matrix tablet, is susceptible to influence of a variety of variables that is supposed to be encountered by the oral route. In this study, the effect of influencing variables on biphasic release characteristics, the stability and the pharmacokinetics of the hybrid matrix tablet were investigated. An increasing tendency of the overall release rate was observed from pH 1.2 to 7.4. The power law correlation n values increased with pH, while the release lag time or 10% release time (T0.1) decreased at pH 6.8 and 7.4. Ionic strength in the release media also influenced the biphasic release significantly at sodium chloride levels of over 0.5%. Obvious increase in overall release rate was observed at sodium chloride level of 0.9% with an n value of 1.20 and a T0.1 of 3.4h. At sodium chloride levels of over 2%, the pectin/calcium interaction was disrupted resulting in very fast release of indomethacin. Release in gradient pH media was similar to that in pH 6.8 citrate buffer. When pectinase (Pectinex Ultra SP-L) was added into the release medium in 22.2 pg/ml or over, obvious triggering on drug release was observed. The stress testing showed increased release at extreme relative humidity of 92.5%. Both accelerated testing for 6m and long-term testing for 12 m affirmed fine stability, especially in release characteristics. Pharmacokinetic study in dogs gave Tmax/Cmax of 4h/604 ng/ml and 3h/1662 ng/ml for HPMC/pectin/calcium and HPMC/pectin tablet, respectively. The plasma indomethacin level of the calcium-containing tablet was maintained at a much lower level for 3h with a MRT of 7.13 h, longer than 3.97 and 5.61 h for indomethacin crude drug and HPMC/pectin tablet, confirming delayed absorption. The AUC of the HPMC/pectin/calcium tablet was lower than that of the HPMC/pectin tablet and indomethacin crude drug showing incomplete absorption. It is concluded that the HPMC/pectin/calcium matrix tablet is potentially useful for colon-specific drug delivery.