THE SOLUBILITY OF MORPHINE AND THE STABILITY OF CONCENTRATED MORPHINESOLUTIONS IN GLASS, POLYPROPYLENE SYRINGES AND PVC CONTAINERS

Morphine solutions are frequently used in palliative settings for the treatment of severe cancer pain. There is, however, no complete inform ation concerning the solubility, isotonisation and shelf-life of these solutions. The solubility limits of morphine hydrochloride (M) were d etermined as 50 mg/ml in water and 5% dextrose, and 30 mg/ml in 0.9% N aCl at 22 degrees C, figures which decreased to 30 and 20 mg/ml, respe ctively at 4 degrees C. Isotonisation of the M solutions with NaCl or dextrose did not cause any solubility problems at room temperature. Th e stability of isotonic M solutions and M solutions in water was inves tigated over a concentration range of 10-50 mg/ml. All solutions were stored in borosilicate glass, polypropylene syringes and PVC container s at 4, 22 and 40 degrees C in the absence of light. Samples were take n immediately after preparation and after 1, 3, 7 and 14 days, 1, 2 an d 3 months of storage. All samples were evaluated visually (colour and precipitation) and pH and osmolality were measured. Determination of morphine, morphine-N-oxide, pseudomorphine and apomorphine was done wi th a reversed-phase ion-pair HPLC assay. During storage at 4 degrees C of M solutions at a concentration above 20 mg/ml, a white precipitate was formed that was difficult to redissolve. In all samples the pH an d the osmolality remained nearly unchanged over the study period, exce pt when stored in PVC containers at 22 and 40 degrees C where there wa s a gradual increase of the osmolality during storage. In the solution s stored in PVC containers at 22 and 40 degrees C an increase in M con centration of up to 105% of the theoretical concentration was detected after 1 month and 1 week, respectively. In all samples only two degra dation products were found: morphine-N-oxide and pseudomorphine. Durin g storage the concentration of both degradation products gradually inc reased, but remained below 0.4% for morphine-N-oxide and below 2% for pseudomorphine. The type of reservoir and the composition of the solut ion had only a minor influence on the degradation of M. This study ind icates that concentrated M solutions are stable for 3 months under all conditions tested, but should be stored at 22 degrees C to avoid prec ipitation. (C) 1997 Elsevier Science B.V.