Intemational Journal of Pharmaceutics ELSEVIER International Journal of Pharmaceutics 146 (1997) 213 223
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intemational journal of pharmaceutics ELSEVIER International Journal of Pharmaceutics 146 (1997) 213 223 The solubility of morphine and the stability of concentrated morphine solutions in glass, polypropylene syringes and PVC containers A. Vermeire, J.P. Remon* Laboratory of Pharmaceutical Technology, University of Gent, Harelbekestraat 72, 9000 Gent, Belgium Received 6 September 1996; revised 4 November 1996; accepted 20 November 1996 Abstract Morphine solutions are frequently used in palliative settings for the treatment of severe cancer pain. There is, however, no complete information concerning the solubility, isotonisation and shelf-life of these solutions. The solubility limits of morphine hydrochloride (M) were determined as 50 mg/ml in water and 5% dextrose, and 30 mg/ml in 0.9% NaCI at 22°C, figures which decreased to 30 and 20 mg/ml, respectively at 4°C. Isotonisation of the M solutions with NaC1 or dextrose did not cause any solubility problems at room temperature. The stability of isotonic M solutions and M solutions in water was investigated over a concentration range of 10-50 mg/ml. All solutions were stored in borosilicate glass, polypropylene syringes and PVC containers at 4, 22 and 40°C in the absence of light. Samples were taken immediately after preparation and after 1, 3, 7 and 14 days, 1, 2 and 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 with a reversed-phase ion-pair HPLC assay. During storage at 4°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 and the osmolality remained nearly unchanged over the study period, except when stored in PVC containers at 22 and 40°C where there was a gradual increase of the osmolality during storage. In the solutions stored in PVC containers at 22 and 40°C an increase in M concentration of up to 105% of the theoretical concentration was detected after 1 month and 1 week, respectively. In all samples only two degradation products were found: morphine-N-oxide and pseudomorphine. During storage the concentra- tion of both degradation products gradually increased, but remained below 0.4% for morphine-N-oxide and below 2% for pseudomorphine. The type of reservoir and the composition of the solution had only a minor influence on the degradation of M. This study indicates that concentrated M solutions are stable for 3 months under all conditions tested, but should be stored at 22°C to avoid precipitation. © 1997 Elsevier Science B.V. Keywords: Morphine hydrochloride; Stability; HPLC analysis; Solubility; Osmolality * Corresponding author.: Tel.: + 32 9 2648054; fax: + 32 9 2228236; e-mail: [email protected] 0378-5173/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S0378-51 73(96)048 1 3-2 214 A. Vermeire, J.P. Remon / International Journal of Pharmaceutics 146 (1997) 213-223 1. Introduction analysis ammonium acetate (pro analyse, UCB, Leuven, Belgium), sodium dodecyl sulphate The use of pre-filled morphine syringes for the (puriss. for ion pair chromatography, Fluka treatment of chronic pain in cancer patients has Chemie, Buchs, Switzerland), anhydrous acetic become common practice. Although the stability acid (Lab Chemistry, Novolab, Belgium), sodium of morphine solutions for intrathecal or epidural metabisulphite (Aldrich Chemie, Steinheim, Ger- administration has been extensively studied, there many) and acetonitrile (Minimal Transmission are no extensive data concerning the stability of Level, Analytical Sciences, Labscan, Dublin, Ire- the concentrated morphine solutions used for sub- land) were used. As reference substances M (Bel- cutaneous infusion. Roksvaag et al. (1980); Deeks gopia, Louvain-La-Neuve, Belgium), morphine- et al. (1983); Bray et al. (1986); Caute et al. N-oxide (Macfarlan Smith, Edinburgh, UK), (1988); Hung et al. (1988); Walker et al. (1989); pseudomorphine (Macfarlan Smith, Edinburgh, Airman et al. (1990); Duafala et al. (1990); UK) and apomorphine hydrochloride (Federa, Dolezalova (1992); Roos et al. (1992) and Strong Brussels, Belgium) were used. Codeine (Belgopia, et al. (1994) studied the stability of low concentra- Louvain-La-Neuve, Belgium) was used as the in- tions of morphine and/or evaluated the stability ternal standard. The stability of M was investi- by determination of morphine without quantify- gated in the reservoirs most commonly used for ing the degradation products. The degradation portable infusion pumps in palliative care, i.e. process of morphine to morphine-N-oxide and polypropylene syringes (10 ml, Becton Dickinson pseudomorphine is well known (Yeh and Lach Benelux, Aalst, Belgium) and PVC containers (50 (1961)). Orr et al. (1982) also identified apomor- ml, Pharmacia, Brussels, Belgium), and in borosil- phine as a degradation product during storage of icate glass (Corning glass ware, Novolab, Ger- morphine hydrochloride solutions in plastic sy- aardsbergen, Belgium). The borosilicate tubes ringes. In none of the above mentioned studies were closed with polyethylene caps (B6ttger, Bo- was morphine-N-oxide determined. Besides stabil- denmais, Germany), the syringes were closed with ity, there is also the problem of solubility when luer tip caps (Becton Dickinson Benelux, Aalst, highly concentrated morphine solutions have to Belgium) and the containers were closed with be prepared. In the literature no data were found polyethylene caps (Pharmacia, Brussels, Belgium). concerning the solubility of morphine in isotonic solutions. In this study the solubility and the 2.2. Methods osmolality of the morphine solutions was deter- mined. For the evaluation of the stability of iso- 2.2.1. Solubility tonised and non-isotonised morphine hydro- The solubility of M was investigated in freshly chloride solutions the concentration of morphine, distilled water, 0.9% NaC1 and 5% dextrose solu- morphine-N-oxide, pseudomorphine and apomor- tions at 4, 10, 15, 20, 25, 30, 35 and 40°C, phine in the solutions was measured. respectively. Temperatures up to 20°C were ob- tained using a crysostate (Vel, Leuven, Belgium), higher temperatures were obtained using a Ter- 2. Materials and methods maks (Led Techno, Eksel, Belgium). Supersatu- rated solutions of M were prepared by weighing 2. I. Materials 1.00 g of M in a 10-ml volumetric flask. The solution was stirred with a magnetic stirrer for 24 For the preparation of the solutions morphine h at the tested temperature. The filter was kept at hydrochloride (M) (Betgopia, Louvain-La-Neuve, the same temperature for 24 h. After 24 h the Belgium), freshly distilled water, 0.9% NaC1 solu- solution was filtered through a cellulose acetate tion (Baxter, Brussels, Belgium) and 5% dextrose membrane filter in a polycarbonate housing (Min- solution (Baxter, Brussels, Belgium) were used. isart NML, Sartorius, G6ttingen, Germany). The For the preparation of the solutions for HPLC filtrate was diluted (1/50; v/v) with freshly distilled A. Vermeire, J.P. Remon /International Journal of Pharmaceutics 146 (1997) 213-223 215 100 } 6O 4O 2O 0 0 10 20 30 40 50 Temperature (°C) Fig. 1. Solubility of morphine hydrochloride in water (D), 0.9% NaCI (~) and 5% dextrose (~) solutions as a function of temperature. water and the absorbance was measured using 2.2.3. HPLC analysis' an UV spectrophotometer (DU-65, Beckmann For the determination of M and its degradation Instruments, Fullerton, USA) operating at a products an ion-pair reversed phase HPLC wavelength of 284 nm. Each test was performed method was optimised and validated. The HPLC in triplicate. The adsorption of M to the filters analysis was carried out using an isocratic pump was determined for each concentration of the (L-7100, Lachrom, Merck, Overijse, Belgium) op- drug in water, 0.9% NaC1 and 5% dextrose solu- erating at a flow rate of 1 ml/min and a variable tions. wavelength detector (UV 2000, Spectra System, Thermo Separation Products, Wilrijk, Belgium) 2.2.2. Isotonisation operating at a wavelength of 254 nm. Samples The osmolality of M solutions in pure water were diluted and mixed with the internal standard was determined as follows. M solutions were pre- using an autoinjector (Autoinjector 234, Gilson, pared in five different concentrations (10, 20, 30, Analis, Gent, Belgium), and injected through a 40 and 50 mg/ml) in freshly distilled water and the Rheodyne valve (Type 7010, Analis, Gent, Bel- osmolality was measured using an osmometer gium) fitted with a 20/~1 sample loop. Separation (Type M, measuring cell 150 /tl, Knauer, Berlin, of the components was performed on a 250 x 4.6 Germany). Each concentration was prepared in mm stainless steel column, packed with 5 /Lm triplicate and the average osmolality was used for particle size Ultrasphere ODS bonded silica further calculations. The osmolality was plotted (Beckman Instruments, Fullerton, USA). The against the M concentration and the curve was chromatograms were processed using the Spectra analyzed by linear regression. The percentages Physics software package PC 1000 (Thermo Sepa- water and isotonic solution required to prepare an ration Products, Wilrijk, Belgium). The mobile isotonic M solution were calculated from the ratio phase consisted of 37.5% (v/v) acetonitrite in wa- of the M concentration to be prepared and the ter, with 5 mM sodium dodecyl sulphate, 0.08 M isotonic M concentration. ammonium acetate, and the pH was adjusted to 216 A. Vermeire, J.P. Remon / International Journal of Pharmaceutics 146 (1997) 213-223 4.93 with anhydrous acetic acid. The internal 2.2.4. Stability study standard solution consisted of 200/zg/ml codeine For the stability study isotonic M solutions and and was prepared in eluent. For M a 50 mg/ml M solutions in water were prepared in concentra- stock solution was prepared, for the degradation tions of 10, 20, 30, 40 and 50 mg/ml.