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Ifosfamide is a well known prodrug for cancer treatment with cytochrome P450 metabolism. It is associated with both antitumor activity and toxicities. Isophosphoramide mustard is the bisalkylating active metabolite, and acrolein is a urotoxic side product. Because acrolein toxicity is limited by coadministration of sodium mercaptoethanesulfonate, the incidence of urotoxicity has been lowered. Current evidence suggests that chloroacetaldehyde, a side-chain oxidation metabolite, is responsible for neurotoxicity and nephrotoxicity. The aim of our research is to prevent chloroacetaldehyde formation using new enantioselectively synthesized ifosfamide analogs, i.e., C7,C9-dimethyl-ifosfamide. We hypothesize that reduced toxicogenic catabolism may induce less toxicity without changing anticancer activity. Metabolite determinations of the dimethyl-ifosfamide analogs were performed using liquid chromatography and tandem mass spectrometry after in vitro biotransformation by drug-induced rat liver microsomes and human microsomes expressing the main CYP3A4 and minor CYP2B6 enzymes. Both human and rat microsomes incubations produced the same N-deschloroalkylated and 4-hydroxylated metabolites. A coculture assay of 9L rat glioblastoma cells and rat microsomes was performed to evaluate their cytotoxicity. Finally, a mechanistic study using (31)P NMR kinetics allowed estimating the alkylating activity of the modified mustards. The results showed that C7,C9-dimethyl-ifosfamide exhibited increased activities, although they were still metabolized through the same N-deschloroalkylation pathway. Analogs were 4 to 6 times more cytotoxic than ifosfamide on 9L cells, and the generated dimethylated mustards were 28 times faster alkylating agents than ifosfamide mustards. Among these new ifosfamide analogs, the 7S,9R-enantiomer will be assessed for further in vivo investigations for its anticancer activity and its toxicological profile.

Melphalan is an alkylating agent frequently used in an intravenous formulation to treat hematologic malignancies and solid tumors in both adults and children. According to the manufacturer, melphalan is stable in sterile 0.9 % sodium chloride for 90 min at room temperature (RT). Several authors have studied the stability of different concentrations of melphalan; however, most were not adapted to the current manufacturing process applied in pharmaceutical centralized units. This study was conducted to determine the stability of melphalan in 0.9 % sodium chloride solutions at concentrations used for intravenous injection in practice. Melphalan is commonly prepared in diluted solutions ranging from 2 to 4 mg/ml for the treatment of adult patients and at lower concentrations (down to 0.5 mg/ml) for pediatric use. Accordingly, these were the three concentrations chosen for this study. Melphalan concentrations were measured with high-performance thin-layer chromatography (HPTLC). At RT, admixtures prepared at 4 mg/ml were stable for up to 8 h without protection from light; however, at lower concentrations, such as 0.5 and 2 mg/ml, stability did not exceed 2 h. When refrigerated, melphalan was stable for 24 h at 2 mg/ml; however, at 0.5 and 4 mg/ml, the drug was not stable. Melphalan solutions present with limited stability at 0.5, 2, and 4 mg/ml and are not adapted for delayed administration in pharmaceutical centralized units. However, at 4 mg/ml and at RT, a stability of 8 h is very interesting in practice and allows sufficient time for preparation, pharmaceutical control, transport, and administration.

A specific and sensitive quantitative assay has been developed using high performance liquid chromatography–electrospray ionization mass spectrometry (HPLC–ESI-MS) for the simultaneous quantitation of the antitumor drug ifosfamide (IFM) and its two metabolites, N2-deschloroethylifosfamide (N2-DCE-IFM) and N3-deschloroethylifosfamide (N3-DCE-IFM) in microsomal medium. The analytes and the internal standard (cyclophosphamide) were isolated by ethylacetate extraction from rat liver microsomes. They were analysed on a Nucleosil® C18 HD column (125 mm × 4 mm, 5 μm) using a step gradient with the mobile phase (2 mM ammonium formate and methanol). The HPLC–ESI-MS method used selected ion monitoring of ions m/z 199.1 Th and m/z 261.1 Th and was validated in the concentrations ranges of 100–5000 ng/mL for IFM and 50–2500 ng/mL for its N-deschloroethylated metabolites (DCE-IFM) with good accuracy and precision (CV less than 15%). The low limits of quantitation (LLOQ) were found at 50 ng/mL for N-deschloroethylated metabolites and at 100 ng/mL for the parent drug (IFM). The method was applied for the determination of ifosfamide and its N-deschloroethylated metabolites in rat microsomal incubations.

Morphine and meperidine in Patient-Controlled Analgesic devices are commonly used to treat chronic pain patients. These devices deliver a programmed amount of drug and allow self-administration by the patient depending on the pain. In our department of pharmacy, 300 devices were manufactured in 2003. The aim of this study was to assess their shelf-life. The devices were filled aseptically and without preservatives with 1 and 40 mg/ml morphine solution and 5 and 20 mg/ml meperidine and stored over 30 days at room temperature and protected from light. Culture assay of the solutions showed that they remained sterile for 30 days. No turbidity of any solutions from samples collected twice a week was noticed. pH and osmolarity remained constant. Drug concentrations were determined using stability indicating HPLC method, as we showed that degradation products can be separated from the drugs. Little loss of meperidine occurred within 21 days (

International audience; BACKGROUND AND OBJECTIVES: Busulfan is used as part of a conditioning regimen prior to hematopoietic stem cell transplantation for the treatment of certain cancers and immune deficiency syndromes. Due to its instability in aqueous preparations, busulfan for infusion is prepared from a concentrate and has a relatively short shelf life once prepared. The purpose of this study was to identify the most suitable storage container and temperature to maximize the shelf life of busulfan therapeutic infusions prepared from Busilvex(®).METHODS: Busilvex(®) 6 mg/mL was diluted to 0.55 mg/mL with 0.9 % NaCl and aliquots dispensed into polypropylene syringes, polyvinyl chloride bags, and glass bottles. Three storage temperatures were evaluated: 2-8 °C, 13-15 °C (thermostatically controlled chamber), and room temperature (20 ± 5 °C). At set time points, samples were analysed for busulfan content, using a high-performance liquid chromatography (HPLC) system with ultraviolet detection. The change in pH and osmolarity on storage was also determined, and solutions were inspected visually for formation of a precipitate or colour change. To determine the contribution of precipitation to loss of busulfan content on storage, samples from one time series were treated with the solvent dimethylacetamide prior to HPLC separation and quantitation of busulfan.RESULTS: The results of the active substance content monitoring study over a 48-h period demonstrate that busulfan solution is stable at a 5 % threshold, at 2-8 °C for 16 h in syringes, 14 h in glass bottles, and 6 h in bags. In addition, the period of stability decreases as the temperature increases (4 h at 20 ± 5 °C). The solution is considered to be stable, subject to precipitation liable to be observed regardless of the temperature.CONCLUSION: The best stability was observed for busulfan solutions placed at 2-8 °C in syringes. This study demonstrated that precipitation, in addition to hydrolysis, has a significant influence on the busulfan content.

Context The use of patient-controlled analgesia (PCA) allows patients to be managed at home and may increase the quality of life of patients with regard to drug administration. To ensure that intact drug is delivered to the patient in this setting, it is important to study its microbiological and physicochemical stability. Although these factors have been widely studied for many parenteral opioids, very few authors have investigated oxycodone stability associated with long-duration infusion in cancer patients. Objectives The aim of this study was to assess the microbiological and physicochemical stability of oxycodone hydrochloride solution in PCA devices and thereby to determine the feasibility of extending the expiration dates after mixing. Methods Sixteen CADD® reservoirs and 32 Rythmic® reservoirs were filled aseptically with pure (10mg/mL) and diluted (1mg/mL) oxycodone solution. Three different vehicles (0.9% sodium chloride, water for injection, and 5% dextrose) were used for dilution. Among the PCA systems stored over 28 days at room temperature, 16 Rythmic® reservoirs were protected from light. Microbiological stability was assessed by performing sterility tests. The physicochemical study was performed by determining aspect, pH, osmolality evolution, and weight. Drug concentrations were determined using the stability-indicating high performance liquid chromatography combined to ultraviolet detection technique. Results There was no significant change in pH, weight, and osmolality values of any solutions. No precipitation or change in color was observed in any of the sample solutions. There was no significant loss of oxycodone, and no trace of degradation products was detected. Conclusion This study indicates that pure and diluted oxycodone solutions in the PCA systems are stable for 28 days at room temperature when prepared aseptically.

In order to achieve the analytical assessment of the manufactured batches of chemotherapy preparations, post-production quality control has been developed. The common use of camptothecin derivatives (i.e. irinotecan (CPT-11) and topotecan (TPT)) as part of protocols in Institut Gustave Roussy (IGR) has led to develop an efficient analytical method that could assess an increasing number of samples with high throughput, good specificity and practicality. Due to the difference of concentration between batches containing irinotecan or topotecan, HPLC and HPTLC both combined with fluorescence detection were investigated. Those two techniques made identity, purity and quantitation assays possible. The chromatographic conditions that were chosen allowed identification of each drug through their rate of flow (Rf), 0.10 and 0.35, or their retention time (tR), 2 and 7 min for topotecan and irinotecan, respectively. A calibration curve was plotted for each molecule and validated by three quality controls (high, medium and low). Coefficients of variation of repeatability (CVr) and intermediate precision (CVi) were determined for both methods. Considering their values and the concentration ranges (from 100 to 500 mg/L for HPTLC and from 0.1 to 1 mg/L for HPLC), it was decided to perform analysis using HPTLC for irinotecan preparations and HPLC for topotecan preparations. These inferences seemed appropriate regarding the number of preparations to be assayed.

Cyclophosphamide is an alkylating agent widely used from cancer chemotherapy to immunotherapy purposes. In paediatrics oncology, oral cyclophosphamide prescribed at low dosages for a long time treatment is currently investigated. This treatment is a putative well tolerated regimen for children treated for a wide variety of recurrent solid tumours. For these purposes, new oral formulations more convenient for children than cyclophosphamide 50mg tablets are needed. Thus, we present a rapid method for the assay of cyclophosphamide in various pharmaceutical preparations using high-performance thin-layer chromatography (HPTLC) and derivatization with phosphomolybdic acid. This method is accurate and precise and allows quantitation of cyclophosphamide in aqueous solutions from 400 to 1200 microg/mL. It is suitable for quantitation and stability studies of cyclophosphamide in pharmaceutical products, i.e. capsules and infusion bags prepared in a hospital pharmacy. According to pharmaceutical guidelines, we demonstrated that low dose cyclophosphamide capsules, extemporaneously prepared for children, are stable at least for 70 days.

An instrumental quantitative high-performance thin-layer chromatographic (HPTLC) method has been developed for the determination of vinca-alkaloids (antineoplastic compounds) in chemotherapeutic infusion bags prepared in a hospital pharmacy. The method uses automated band application onto silica gel plates containing a fluorescent indicator and scanning densitometry of fluorescence-quenched zones of samples and standards. Samples were analyzed to check the content of the active substance against the label declaration of the preparation. The four compounds were separated using the following solvent system CH 2 Cl 2 –CH 3 OH (93:7, v/v). Vincristine (VCR) and vinorelbine (NVB) were assessed in the same run whilst vinblastine (VLB) and vindesine (VDS) were analyzed in a second run. HPTLC allows the identification and the quantitation of more than 20 samples in the same chromatographic run. The analysis of the samples requires 30 min compared with more than 2 h using a typical HPLC method. Moreover, there is no need for a conditioning step, as with HPLC, and each analysis by HPTLC is less expensive.

Adsorption of polluted solutions is performed by different kinds of activated carbon: grains, powder and fibers (cloth or felt). The adsorption is determined in batch reactor. Classic models are applied and kinetic constants are calculated. Results showed that performance of fibrous activated carbon (FAC) is significantly better than that of granular activated carbon (GAC), and is quite similar to that of powder activated carbon (PAC). Moreover, the adsorption capacities for phenol of FAC is markedly greater than GAC. Therefore the application of FAC adsorbers may lead to smaller adsorption reactors. The breakthrough curves obtained with FAC adsorbers are particularly steep, suggesting a smaller mass transfer resistance than for the GAC. The adsorption zone in the FAC bed is about 3.4 mm and is not dependent on the flow rate for the range 0.67–2.07 m • h-1.

In a context of day hospital care of cancer patients, a protocol combining etoposide and carboplatin is used in paediatrics. Disposable infusion devices can be used to improve patient quality of life and to optimize nursing time. Stability data are available for carboplatin in these devices but not for etoposide. The aim of this study was to determine the stability of etoposide solutions in these devices by monitoring the changing etoposide concentration. To study the changing etoposide concentration, we investigated three different concentrations, each in two different solvents: sodium chloride (NaCl) 0.9 % and dextrose 5 %, in Intermate(®) disposable infusion devices. Quantitative analyses were performed by high-performance liquid chromatography coupled with ultraviolet (UV) detection on samples collected over a 24-h study period. The results showed that 100 mg/L etoposide solutions were stable for 24 h in NaCl 0.9 % and for 12 h in dextrose 5 %, whatever the temperature. The 400-mg/L solutions were stable for 24 h in both diluents, whatever the temperature, whereas the 600-mg/L solutions when diluted in NaCl 0.9 % and dextrose 5 % in water were stable for 8 and 6 h, respectively. We found that precipitation was the main phenomenon responsible for decreased etoposide concentrations. This study allowed us to conclude that etoposide solutions prepared in Intermate(®) infusion devices are stable for day hospital administration in paediatrics. It will also allow us to conduct a future clinical study that will focus on the medico-economic feasibility of this protocol and on the evaluation of patient and nurse satisfaction.