Band 2, Heft 4 - Special Issue: Stability Studies in Hospital Pharmacies, Guest Editor: Jean Vigneron

Background Profound knowledge about the physicochemical stability is necessary in order to determine the “beyond-use-dates” of ready-to-administer preparations after reconstitution and dilution. This is especially true for unstable azanucleoside drugs like decitabine. The aim of this study was to determine the physicochemical stability of decitabine after reconstitution and dilution of Dacogen ® 50 mg lyophilized powder. Decitabine concentration of Dacogen ® powder reconstituted with cold water for injections (5 mg/mL) has been determined after storage in the original vials under refrigeration for 48 hours and in single use syringes in a freezer at –25 °C for 28 days. Concentration of diluted decitabine infusion solutions (0.5 mg/mL) prepared in prefilled 0.9 % NaCl polyolefine (PO) infusion bags has been determined after storage under refrigeration (2–8 °C) for 48 hours. Methods To determine the stability of frozen Dacogen ® solutions the powder was reconstituted with 10 mL of cold (2–8 °C) sterile water for injections, transferred into 1 mL plastic polycarbonate (PC)/polypropylene (PP) syringes and stored at –25 °C. Decitabine concentrations were determined on day 0, 22 and 28 after thawing at room temperature immediately before assaying. In parallel, pH-values were determined. To determine the stability of reconstituted Dacogen ® 50 mg powder in the original glass vials, three Dacogen ® 50 mg vials were aseptically reconstituted with 10 mL of cold sterile water. The reconstituted solutions were stored under refrigeration and decitabine concentrations were determined at 0, 3, 7, 12 and 24 hours after reconstitution. The pH-values were determined at 0, 7 and 24 hours. Diluted Dacogen ® test solutions were aseptically prepared by adding 2 mL of the reconstituted Dacogen ® solution from each of the three vials to 18 mL cold (2–8 °C) 0.9 % NaCl solution in prefilled multi-layer PO infusion bags of the nominal value 50 mL. Test solutions of the nominal concentration 0.5 mg/mL were stored under refrigeration. Decitabine concentrations were determined at 0, 5, 8, 12, 24 and 48 hours after preparation. The pH-values were determined at 0, 8, 24 and 48 hours. Each sample was assayed by a validated stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) assay with photodiode array detection. Results When test solutions of reconstituted Dacogen ® solution were stored frozen at −25 °C, decitabine concentrations decreased less than 2 % and no degradation products were detected in the HPLC chromatograms over the storage period of 28 days. In reconstituted test solutions in glass vials and in diluted test solutions in infusion bags stored under refrigeration decitabine concentrations remained above 90 % of the initial concentration for 12 hours and 24 hours, respectively. Several peaks of degradation products were observed which explicitly increased over time. In all test solutions the pH-values amounted to pH 7 and remained unchanged. No particulate matter and no colour changes were observed over the test period. Conclusions Reconstituted decitabine solution (Dacogen ® 50 mg powder) stored in 1 mL PC/PP syringes and frozen at −25 °C is physicochemically stable for at least 28 days. Decitabine solution in glass vials after reconstitution with cold sterile water for injections and in PO infusion bags after dilution with cold 0.9 % NaCl solution and stored under refrigeration is physicochemically stable for approximately 12 hours and 24 hours, respectively. The results of our study facilitate the preparation of Dacogen ® powder in pharmacy based centralized preparation units.

Background In the University Medical Centre Mainz, standard concentrations are defined for medicinal products to be administered by continuous injection with syringe pumps in adult intensive care patients. The objective of this study was to evaluate the physicochemical stability of ready-to-use and ready-to-administer preparations containing Epinephrine (E) and Norepinephrine (NE) in standardized concentrations and prepared batch wise in the pharmacy department as basis for assigning shelf-lives. Methods E 20 µg/mL and NE 10 µg/mL in disposable syringes and NE 40, 100, 200, 400 µg/ml in 50 ml amber type I glass vials were prepared batch wise and the concentrations were analyzed by stability-indicating, validated reversed-phase HPLC-PDA assays. Test solutions for long-term stability studies were stored under refrigeration (2–8 °C) for 6–12 months or at elevated temperatures (21–27 °C) light protected for up to 6 months or without light protection for up to one month. Osmolality and pH were measured on predefined intervals. Results The concentrations of E in 50 mL syringes and NE in 10 mL syringes remained unchanged over a period of 6 months when stored at 2–8 °C. NE preparations of different concentrations prepared in amber glass vials remained stable over a study period of 12 months. At RT the shelf-life decreased to about 6 months and the exposure to mixed daylight at RT caused loss of stability in only few days. Conclusions Batch wise preparation of ready-to-administer (RTA) preparations containing 20 µg/mL E or 10 µg/mL NE in disposable syringes as well as ready-to-use (RTU) preparations containing 40, 100, 200 and 400 µg/mL NE was successfully implemented in a pharmacy department. Storage of the preparations at refrigerated temperatures is required to obtain acceptable shelf-lives of 6–12 months. Elevated temperatures and especially exposure to mixed daylight significantly decreased the shelf life.

Background The association of morphine and baclofen is used for the treatment of spasticity related pain. Moving these patients is sometimes difficult. In order to transport these syringes for pump refilling, it could be interesting to demonstrate the stability of the mixture, and so to be able to ensure the best transport conditions of syringes. Methods A stability indicating UPLC-DAD method was developed and validated according to the ICH guidelines. Two mixtures of morphine and baclofen – a low concentration mixture (morphine 1 mg/mL – baclofen 0.08 mg/mL) and a high concentration mixture (morphine 10 mg/mL – baclofen 1.6 mg/mL) stored in 5±3 °C and 25±2 °C were evaluated for seven days and compared to the initial observed concentrations. Results The stability of the low and high mixture is demonstrated for both storage conditions for seven days thanks to relative concentrations (95 % confidence intervals of the mean of 3 samples) systematically positioned between 95 % and 105 %. No degradation product was observed during the stability study. Conclusion This study shows the stability of a weakly concentrated mixture and a highly concentrated mixture of morphine and baclofen. Extrapolation of these data to an intermediate mixture may be considered. Further studies will support this hypothesis. This result will allow the transport of the preparation under optimal conditions. Advance preparations for intrathecal pump refills could also be feasible.

Preservative free ophthalmic formulations need to be packaged either as single doses, or using specially designed sterility preserving multidose eyedroppers. Our objective was to evaluate potential sorption phenomena between a device with a silicone sterility preserving membrane and the delivered drops of several ophthalmic solutions. Cyclosporine, rifamycin, latanoprost, timolol and norfloxacin were used as model drugs. Quantification of the active substance in delivered drops (1 to 4 drops per day) from low density polyethylene (LDPE) bottles without any sterility preserving device and from LDPE bottles with a sterility preserving silicone membrane (LDPE-Si) was performed for 14 days (n≥3), using validated HPLC methods. For cyclosporine, mean concentrations did not vary by more than 10 % from reference concentrations for either LDPE or LDPE-Si eyedroppers, but for LDPE-Si, the concentrations of the 1 mg.ml-1 cyclosporine micellar solution were found to be significantly lower than for those from LDPE eyedroppers (p=0.0127). For LDPE-Si, rifamycin mean concentrations decreased by 11.2 % throughout the 14 day study period, but didn’t vary by more than 10 % for LDPE and glass eyedroppers. However, rifamycin concentrations from LDPE-Si were not significantly different from those from LDPE eyedroppers. For latanoprost, whilst mean concentrations did not vary by more than 10 % from reference concentration for LDPE eyedroppers, for LDPE-Si eyedroppers concentrations decreased by 76.4 % at their lowest concentration and never returned to their initial level. For timolol and norfloxacin, mean concentrations did not vary by more than 10 % for either LDPE or LDPE-Si eyedroppers and no significant difference was found between the 2 eyedroppers concentrations. Our results are in favor of an absence of significant sorption between LDPE-Si eyedroppers for timolol or norfloxacin ophthalmic solutions. Further studies should be performed on cyclosporine ophthalmic micellar solutions and rifamycin ophthalmic solutions before any definite conclusions can be made. Finally, our results show that latanoprost ophthalmic solutions shouldn’t be used with LDPE-Si eyedroppers as the loss of active substance would cause a sever under-dosing.

Background Dexamethasone is commonly used to treat a wide variety of diseases including oncological disorders. The aim of this study was to propose a liquid formulation of dexamethasone. Therefore we have developed and assessed the stability of a 5 mg/mL dexamethasone oral suspension. Methods A stability-indicating analytical method, using HPLC-UV, was developed and fully validated according to well-recognized international guidelines. The dexamethasone suspension was prepared using dexamethasone acetate powder and Ora-Sweet ® plus Ora-Plus ® suspending vehicles (1:1, v:v). Compounded oral suspension were packaged in amber type I glass bottles. In order to assess physical and chemical stability of dexamethasone in oral suspension, six batches of the formulation were prepared and stored at 4±2 °C or at 21±3 °C. Physical parameters (appearance, pH) were assessed as well as dexamethasone content, at day 0, 7, 14, 30 and 60. Results The mean dexamethasone concentration of the compounded oral suspensions was equal to 5.07±0.17 mg/mL. No colour modifications, precipitate or suspending troubles was observed throughout the storage period and the pH of the oral suspensions was decreased slightly, from 4.41±0.01 to 4.20±0.02. According to the dexamethasone content determined by HPLC-UV, whatever storage condition was used, no significant degradation of dexamethasone occurred over the 60 days of the study period. Conclusion Dexamethasone oral suspension prepared according to our conditions is stable over 60 days under regular storage temperatures (at 4±2 °C or at 21±3 °C).