Formulation development and stability testing of oral morphine solution utilizing preformulation approach.

PURPOSE Prefomulation approach utilizing the fractional-ordered randomized blocked design was employed for the formulation development and stability testing of morphine solution. METHODS Factors expecting to affect the stability of morphine were evaluated, i.e., vehicle, antioxidant, chelating agent, and pH of the solution. Eight formulations of a possible 16 were prepared according to the block design. The stability of the preparations was tested after 35 days of storage. The data of preformulation study were used for formulation development. RESULTS The presence of glycerin and ethylenediamine-tetraacetic acid in the formulation, and the pH of the solution adjusted to 4, stabilized morphine. The concentration of morphine decreased drastically in the formulations containing sodium metabisulfite, and those pH adjusted to 6. After 35 days, only 65% of morphine was found in the formulation containing sodium metabisulfite and pH adjusted to 6. The results of preformulation study were used for preparing oral morphine preparations. Samples were kept in amber glass bottles and stored at 4 degrees C and 25 degrees C/75% RH for 13 months. No precipitation of the four formulations was detected. Only a decrease of odor and a small increase of pH value of the preparations (< 0.3 units) were observed. More than 97% of morphine remained in all samples. The samples were free from microbial contamination. CONCLUSION Stable morphine solution formulations can be achieved with the utilization of the preformulation approach. They were stable more than 13 months when stored at 4 degrees C and 25 degrees C/75% RH.