Physicochemical Stability of Ternary Mixtures of Sufentanil, Baclofen, and Ropivacaine in Polypropylene Syringes for Intrathecal Analgesia.

Intrathecal analgesia is a method using various molecules alone or in combination. Among these, a preparation of sufentanil-ropivacaine-baclofen is widely used. Instead of moving patients to the few expert centers taking charge of these specific preparations, it could be beneficial to transport syringes to peripheral centers who manage pump refills. The objective of this study was to determine the physicochemical compatibility and stability of a preparation of sufentanil, ropivacaine, and baclofen in polypropylene syringes. Drugs were mixed together at different concentrations and stored with light protection at 5°C ± 3°C and 25°C ± 2°C. The stabilities were determined by visual inspection, turbidity, pH measurement, and ultra-high-pressure liquid chromatography assay of drug concentrations. The concentrations of ropivacaine, baclofen, and sufentanil were stable after 7 days at 5°C ± 3°C and no degradation of product appeared. The drug mixtures were clear in appearance and no color change or precipitation was observed. Throughout this period, the absorbance and the pH value of samples remained stable. The preparations of sufentanil, baclofen, and ropivacaine remained stable for at least 7 days when stored in polypropylene syringes at 5°C ± 3°C.

Quality control and stability of ketamine, remifentanil, and sufentanil syringes in a pediatric operating theater.

BACKGROUND: Transforming a drug from its commercial form into a ready-to-use drug is common practice, especially in pediatrics. However, the risk of compounding error is real and data on drug stability in practice are not always available. AIMS: The aim of this study was to assess, in real conditions, both the error rate and stability of three drugs: ketamine, remifentanil, and sufentanil. METHODS: A new rapid and easy-to-use high-performance liquid chromatography method with a diode array detector has been developed and validated to quantify these drugs and detect their degradation products. Over a 1-month period, 151 syringes were collected in the postanesthesia care unit. Seventy-three were stock solution syringes containing a 10-fold dilution of commercial drugs and 78 were serial dilution syringes made from successive dilutions of stock solutions. A comparison between real and expected concentrations as well as the detection of possible degradation products was carried out on these samples. RESULTS: All stock solution syringes had good chemical stability throughout the working day. A 4-µg/mL remifentanil serial dilution syringe, however, had to be discarded as a degradation peak was detected. Overall, 15.3% (95% CI, 9.5-21.1%) of syringes had a drug concentration outside the ±10% acceptability range, that is, 11.0% (95% CI, 3.7-18.2%) and 19.5% (95% CI, 10.6%-28.4%) of stock and diluted syringes respectively, with drug amounts ranging from -25.3% to 22.0%. The highest error rates were observed with sufentanil syringes: 20% and 28% for stock solution and serial dilution, respectively. CONCLUSION: The study shows that stock solution syringes prepared in advance are chemically stable throughout the day, unlike certain serial dilution syringes, indicating that the latter should be prepared just before administration to ensure chemical stability. Our results show that the error rate for serial dilution syringes is twice that of stock solution. Different safety measures are under discussion and have to be further studied.

Synthesis of novel norsufentanil analogs via a four-component Ugi reaction and in vivo, docking, and QSAR studies of their analgesic activity.

Novel substituted amino acid tethered norsufentanil derivatives were synthesized by the four-component Ugi reaction. Norsufentanil was reacted with succinic anhydride to produce the corresponding carboxylic acid. The resulting carboxylic acid has undergone a multicomponent reaction with different aldehydes, amines, and isocyanides to produce a library of the desired compounds. In all cases, amide bond rotation was observed in the NMR spectra. In vivo analgesic activity of the synthesized compounds was evaluated by a tail flick test. Very encouraging results were obtained for a number of the synthesized products. Some of the synthesized compounds such as 5a, 5b, 5h, 5j, and 5r were found to be more potent than sufentanil, sufentanil citrate, and norsufentanil. Binding modes between the compounds and mu and delta-opioid receptors were studied by molecular docking method. The relationship between the molecular structural features and the analgesic activity was investigated by a quantitative structure-activity relationship model. The results of the molecular modeling studies and the in vivo analgesic activity suggested that the majority of the synthesized compounds were more potent than sufentanil and norsufentanil.

Physical Compatibility of Propofol-Sufentanil Mixtures.

BACKGROUND: Combined infusions of propofol and sufentanil preparations are frequently used in clinical practice to induce anesthesia and analgesia. However, the stability of propofol emulsions can be affected by dilution with another preparation, sometimes leading to particle coalescence and enlargement. Such unwanted effects can lead to fat embolism syndrome after intravenous application. This study describes the physical stability of 5 commercially available propofol preparations mixed with sufentanil citrate solutions. METHODS: Two common markers of emulsion stability were used in this study; namely, the zeta potential and size distribution of the emulsion droplets. Both were measured using dynamic light scattering. The data for the pure propofol preparations and their mixtures with sufentanil citrate solution were compared. RESULTS: The absolute value of zeta potential decreased in 4 of the 5 propofol preparations after they had been mixed with sufentanil citrate. This effect indicates a lowering of repulsive interactions between the emulsion droplets. Although this phenomenon tends to cause agglomeration, none of the studied mixtures displayed a substantial increase in droplet size within 24 hours of blending. However, our long-term stability study revealed the instability of some of the propofol-sufentanil samples. Two of the 5 studied mixtures displayed a continual increase in particle size. The same 2 preparations showed the greatest reductions in the absolute value of zeta potential, thereby confirming the correlation of both measurement methods. The increase in particle size was more distinct in the samples stored at higher temperatures and with higher sufentanil concentrations. CONCLUSIONS: To ensure the microbial stability of an emulsion infusion preparation, clinical regulations require that such preparations should be applied to patients within 12 hours of opening. In this respect, we can confirm that during this period, none of the studied propofol-sufentanil mixtures displayed any physical instability that could lead to particle enlargement; thus, fat embolism should not be a risk after their intravenous application. However, our long-term stability study revealed differences between commercially available preparations containing the same active ingredient; some of the mixtures showed an increase in particle size and polydispersity over a longer period. Although our results should not be generalized beyond the particular propofol-sufentanil preparations and concentrations studied here, they do suggest that, as a general principle, a compatibility study should be performed for any preparation before the first intravenous application to exclude the risk of droplet aggregation.

Miniaturized hollow fibre assisted liquid-phase microextraction and gas chromatography for determination of trace concentration of sufentanil and alfentanil in biological samples.

A simple and highly sensitive method that involves miniaturized hollow fibre assisted liquid-phase microextraction with gas chromatography-flame ionization detector was developed for the determination of trace concentration of sufentanil and alfentanil in biological samples. These drugs were extracted from 5 ml of aqueous solution with pH 10.0 into an organic extracting solvent (1-octanol) impregnated in the pores and lumen of a hollow fibre. After extraction for a prescribed time, 2.0 µl of the extraction solvent was injected directly in to the GC injection port. Under the optimized conditions, (1-octanol as extracting solvent, stirring rate of 700 rpm, 15% (w/v) salt addition, pH 10.0 and 25 min sampling time at 50 °C) large enrichment factors of 535 and 420 were achieved for sufentanil and alfentanil, respectively. Dynamic linear ranges were in the range of 0.05 to 500 ng/ml for sufentanil and 0.1 to 500 ng/ml for alfentanil. Limits of detection 0.01 and 0.02 ng/ml were obtained for sufentanil and alfentanil, respectively. The percent relative intra-day and inter-day standard deviations were found to be less than 8.4% (n = 5). Finally, this method was successfully applied for the separation, preconcentration and determination of trace concentration of sufentanil and alfentanil in plasma and urine samples.

Sufentanil-2-hydroxypropyl-ß-cyclodextrin inclusion complex for pain treatment: physicochemical, cytotoxicity, and pharmacological evaluation.

Sufentanil (SUF) is a synthetic analgesic opioid widely used for the management of acute and chronic pain. This drug was complexed with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and the physicochemical characterization, in vitro/ex vivo toxicity assays, and pharmacological evaluation were performed. Differential scanning calorimetry, Fourier transform infrared spectroscopy (FTIR) analysis, and X-ray powder diffraction showed the formation and the morphology of the complex. Nuclear magnetic resonance afforded data regarding inclusion complex stoichiometry (1:1) with an association binding constant (K(a)) value of 515.2 ± 1.2 M(-1) between SUF and HP-ß-CD. Complexation with HP-ß-CD protected SUF from light exposure and increased its photostability. Release kinetics revealed a decrease in SUF release rate (K(rel) = 7.05 ± 0.52 and 5.61 ± 0.39 min(-1/2) for SUF-HP-ß-CD and SUF, respectively) and reduced hemolytic or myotoxic effects after complexation. Time course of tail-flick test showed that the duration of analgesia induced by SUF (150.0 ± 34.6 min) was significantly increased (p < 0.001) after complexation with HP-ß-CD (355.7 ± 47.2 min) when injected at the same dose (1 µg kg(-1)), prolonging the duration of analgesia after intramuscular administration and representing an alternative on the development of effective and safe drug-delivery system for opioid analgesics.

Determination of fentanyl, metabolite and analogs in urine by GC/MS.

A rapid and sensitive method for the simultaneous determination of alfentanyl, sufentanyl and fentanyl (and its major metabolite norfentanyl) in urine was developed and validated. The method involved a liquid-liquid extraction in alkaline conditions, derivatization with pentafluoropropionic anhydride to improve the sensitivity for norfentanyl and subsequent analysis in GC/MS. The LODs are 0.08 ng ml(-1) for all substances (0.04 ng ml(-1) for alfentanyl). Intra- and inter-day precision coefficient of variation was always below 15%; mean relative error (accuracy) was always below 15%. The method was linear for all analytes, with quadratic regression of calibration curves always higher than 0.99. The method was applied to real samples of subjects who had received therapeutic doses of fentanyl, showing its suitability for the determination of low levels of these substances. The method was also applied to a subject whose death was attributed to fentanyl overdose.

Rapid UPLC-MS/MS method for the determination of sufentanil in human plasma and its application in target-controlled infusion system.

A rapid, selective and highly sensitive ultra-performance liquid-chromatography mass-spectrometry (UPLC-MS/MS) method has been developed and validated for the determination of sufentanil in human plasma. Sufentanil was separated on an ACQUITY™ UPLC BEH C(18) column (50 mm × 2.1 mm, ID 1.7 µm) and analyzed in positive-ion (PI) electrospray-ionization (ESI) mode. The mobile phase (MP) consisted of acetonitrile:water (45:55, v/v) under isocratic conditions at a flow rate of 0.2 ml/min. Sufentanil and internal-standard (IS) fentanyl were eluted at 1.47 and 1.16 min, respectively, and their responses were optimized at the transitions m/z 387.2>238.0 and m/z 337.2>188.0, respectively. The calibration curve was linear over the range 0.071-4.56 ng/ml, with coefficients of determination >0.999. The accuracy and precision of the method were between 96.49% and 100.37% (RSD<9%), and the mean recovery of sufentanil was 84.08 ± 7.29%. The method was successfully applied to evaluate the predictive accuracy of Gepts pharmacokinetic sets in a target-controlled infusion (TCI) model, and the Gepts parameters were capable of predicting sufentanil plasma concentrations when multi-level target concentrations were acquired during surgery.

A facile method for preparation of [(2)h(3)]-sufentanil and its metabolites.

An improved process for the synthesis of sufentanil with an overall yield of 26% is described. The reactive and high yielding N-debenzylation of the piperidine intermediate 7 using a mixture of Pd/C and Pd(OH)(2) was applied to other drug intermediates affording free amines in short reaction times. The deuterium-labeled sufentanil and the metabolite desmethylsufentanil were synthesized applying the optimized process.

Microbiological and physicochemical stability of fentanyl and sufentanil solutions for patient-controlled delivery systems.

The aim of this study was to assess the microbiological and physicochemical stability of opioid solutions containing fentanyl or sufentanil and thereby determine the feasibility of extending the expiration dates after mixing. Five systems containing fentanyl or sufentanil solutions at 50 microg/mL in portable patient-controlled analgesia (PCA) systems were filled and stored at room temperature for 14 days. They were sampled immediately after preparation, at day 3, and each day of the following weeks. Microbiological stability was assessed by performing sterility tests. The physicochemical study was performed by determining aspect, pH, and osmolality evolution. All samples were tested for appearance, change in color, and loss of concentration using an analytical method. There was no significant change in pH 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 fentanyl or sufentanil over 14 days (4.3% and 4.1%, respectively). This study indicates that both drug solutions in the PCA systems are stable for a minimum of 14 days at room temperature.

Identification of fentanyl, alfentanil, sufentanil, remifentanil and their major metabolites in human urine by liquid chromatography/tandem mass spectrometry for doping control purposes.

Since January 2005, the list of prohibited substances established by the World Anti-Doping Agency prohibits the opioid agent fentanyl as well as its related drugs in professional and amateur sports. Fast, reliable and robust analytical assays are required that allow the sensitive determination of these compounds or respective metabolites in human urine, and liquid chromatography interfaced to mass spectrometry has proven to be a suitable and powerful tool for drug testing for several years. A screening and confirmation method was developed that enables the identification of fentanyl, alfentanil, remifentanil and sufentanil as well as their N-dealkylated or de-esterified metabolites utilizing solid-phase extraction of a 2 mL urine aliquot followed by LC-electrospray-MS/MS analysis. The procedure was validated in terms of recovery (95.8-104.9%), lower limit of detection (0.5 ng mL-1), specificity and interday precision (3.9-19.8%) for the four opioid drugs and the metabolic product norfentanyl. In addition, the mass spectrometric behavior of fentanyl after electrospray ionization and collision-induced dissociation was studied by synthesis and analysis of structurally related compounds, and dissociation pathways were proposed allowing the characterization of target analytes and corresponding metabolites.

Quantitative determination of sufentanil in human plasma by liquid chromatography-tandem mass spectrometry.

A sensitive and specific method for the quantification of sufentanil in human plasma by liquid chromatography coupled with tandem mass spectrometry has been developed. Fentanyl was used as the internal standard. Rapid sample preparation involved purification on a C(18) solid-phase extraction column. Chromatographic separation of the analytes was obtained using an RP-C(18) mu-HPLC column. LC-MS-MS detection was performed by atmospheric pressure ionisation (API) source equipped with an ionspray (IS) interface operating in the positive ion mode. For unambiguous substance confirmation, three analyte precursor-product ion combinations were monitored during multiple reaction monitoring (MRM) LC-MS-MS analysis. The method's performance characteristics were evaluated in blank and spiked control plasma samples. Overall accuracy (relative error, R.E., %), repeatability (relative standard deviations, R.S.D., %) and within-laboratory reproducibility (R.S.D., %) ranged from -9.28 to -2.71%, from 6.42 to 2.82% and from 13.52 to 6.06%, respectively, for sufentanil. The limit of quantification for sufentanil in human plasma samples was 0.3 ng ml(-1). Due to its high sensitivity and specificity, the method was successfully employed for sufentanil determination in maternal plasma samples collected immediately before epidural administration of a single sufentanil dose to women in labour, 20 min after drug administration, and at birth in arterial and venous umbilical cord plasma samples from the newborn babies. Research is in progress to adopt the method for performance of complete pharmacokinetic studies of sufentanil in human plasma.

Stability of sufentanil and levobupivacaine solutions and a mixture in a 0.9% sodium chloride infusion stored in polypropylene syringes.

We have evaluated the chemical and microbiological stability of sufentanil citrate, levobupivacaine hydrochloride and a mixture in a 0.9% sodium chloride infusion in order to provide background information on the storage of a sufentanil-levobupivacaine mixture in polypropylene (PP) syringes. Chemical assays were performed by HPLC on days 0, 1, 2, 3, 8, 14, 23, 28 and 30 after storage at 4, 21, and 36 degrees C. Microbiological stability was evaluated under aseptic conditions using a laminar air flow station, with a grade A environment and a B background. The samples taken for microbiological analysis were collected immediately after preparation of the solutions and then after 7, 14, 21 and 28 days storage. At 4 degrees C the sufentanil citrate solution was stable for 23 days. At 21 degrees C the sufentanil citrate solution maintained chemical stability for 3 days, but thereafter the concentration of sufentanil decreased 15% from day 3 to day 8. At 36 degrees C a similar decrease was noticed from day 1 to day 3. On the contrary, the levobupivacaine hydrochloride solution maintained chemical stability for 28 days at 4 and 21 degrees C and for 23 days at 36 degrees C. The sufentanil-levobupivacaine mixture maintained chemical stability for 28 days at 4, 21 and 36 degrees C. The sufentanil and levobupivacaine solutions and the mixture studied maintained microbiological stability for 28 days. According to the chemical and microbiological stability studies, the sufentanil-levobupivacaine mixture in PP syringes could be stored for 28 days at 4 and 21 degrees C.

Stability of a sufentanil-ropivacaine mixture in a glass and a PVC reservoir.

BACKGROUND AND OBJECTIVE: Drug mixtures containing sufentanil may be unstable owing to absorption into the drug reservoirs of patient-controlled epidural analgesia systems that contain polyvinylchloride. The stability of sufentanil in a mixture of ropivacaine 0.2% in a 750 mL reservoir was therefore investigated. METHODS: During simulated epidural infusions of 5 mLh(-1) at 25 degrees C, sufentanil concentrations were measured for 96 h. Samples were taken from the reservoir and from the end of the epidural catheter under the following conditions: into glass or polyvinylchloride reservoirs containing ropivacaine 0.2% with sufentanil 1, 0.75 or 0.5 microg mL(-1); and into polyvinylchloride reservoirs with ropivacaine 0.2% and sufentanil 1 microg mL(-1) which were stored for 4 weeks at 8 degrees C. RESULTS: The different solutions remained stable over the observation period of 96 h. Using the same solutions, independent samples' ANOVA showed no difference in the sufentanil concentrations between the glass and polyvinylchloride reservoirs, or between the polyvinylchloride reservoirs when stored for 4 weeks. Correlations between the concentrations at the different measurement times were extremely high for the reservoir (r(min) = 0.98, r(max) = 1.00) and the catheter end (rmin = 0.86, r(max) = 1.00). CONCLUSIONS: Sufentanil citrate at 0.5-1.0 microg mL(-1) in an admixture of ropivacaine 0.29 for 5 days, which is the usual period for postoperative epidural analgesia, remains stable in a polyvinylchloride reservoir. There is no change in the drug concentration even if the reservoir is stored for 4 weeks at 8 degrees C.

Compatibility of ropivacaine with morphine, sufentanil, fentanyl, or clonidine.

BACKGROUND: Ropivacaine hydrochloride (HCl) ('Naropin') is a long-acting local anaesthetic agent, administered epidurally to patients undergoing various surgical procedures. A combination of local anaesthetic and opioid is often administered for the management of severe pain to ensure that a minimal dose of each is used. Ropivacaine might be used in combination with an alpha2-adrenergic agonist for the management of visceral pain. Stability data have shown that ropivacaine is compatible with the systemic narcotic opioid analgesics morphine sulphate, sufentanil citrate and fentanyl citrate for 14 days in a Polybag (AstraZeneca-AB, Sweden), but no data have been obtained for the longer-term compatibility of ropivacaine with these opioids or with the alpha2-adrenergic agonist clonidine HCl. OBJECTIVE: This study used the Mark II Polybag (AstraZeneca-AB, Sweden) to test the physical and chemical compatibility of these products for up to 30 days. METHODS: Ropivacaine HCl solution for epidural infusion, 2 mg/mL, in 200 mL Mark II Polybag and commercially available additives in glass ampoules or vials were used as starting material. Appropriate admixtures were made and their appearance, pH, and drug concentrations were monitored on days 0, 7, 14, and 30. The appearance of the admixtures was examined with the aid of a stereomicroscope (Olympus, no. 220186, New York, USA) at 10x magnification. Drug concentration and enantiomeric purity were determined using high-performance liquid chromatographic analysis. RESULTS: All combinations at all doses stayed within the compatibility criteria (if no visible signs of physical changes in the admixture appeared throughout the 30 days of storage, and if pH and drug concentrations in each admixture did not vary by more than 10% between day 0 and days 7, 14, or 30 in storage). In addition, there were no important differences in the enantiomeric purity of ropivacaine with each combination. CONCLUSION: The study demonstrated that ropivacaine was suitable for use in combination with the opioids morphine sulphate, sufentanil citrate, and fentanyl citrate, or with the alpha2-adrenergic agonist clonidine HCl, for up to 30 days of storage before the management of severe or visceral pain. From a microbiological point of view, combinations not prepared under aseptic conditions should be used immediately. 'Naropin' is a trade mark of the AstraZeneca group of companies.

Stability of sufentanil in human plasma samples.

The stability of sufentanil in human plasma kept under various storage conditions was investigated. Extraction was performed using solid phase extraction with new mixed-mode cation exchange Oasis MCX columns; quantification was carried out using gas chromatography equipped with a mass spectrometry detector. When plasma was left at 4 degrees C in nonsilanized tubes, concentrations of sufentanil decreased significantly during the first hour. In plasma samples kept at -25 degrees C for 8 hours in nonsilanized glass tubes, a significant decrease of sufentanil concentrations was found, with an average loss of 10.1% of the initial concentration. A significant decrease occurred when plasma was kept in silanized glass tubes for 12 hours at -25 degrees C. The current study emphasizes the importance of sampling and storage conditions for an accurate determination of sufentanil concentration in plasma.

The role of drug-lipid interactions on the disposition of liposome-formulated opioid analgesics in vitro and in vivo.

UNLABELLED: Although liposome encapsulation prolongs the duration of action of epidurally administered drugs, little is known about how liposome encapsulation affects opioids differently, or about how lipid content of liposomes alters the bioavailability of epidurally-administered opioids. To address these issues, morphine, alfentanil, fentanyl, and sufentanil were loaded into D-alpha-dipalmitoyl phosphatidylcholine multilamellar liposomes, and incorporation efficiency and in vitro release rates were determined. We then determined epidural morphine and sufentanil liposomes, at two different lipid/opioid ratios, in vivo in a pig model in which epidural and intrathecal spaces were continuously sampled via microdialysis. Liposome encapsulation efficiency was significantly more for sufentanil (100%) than for the other opioids (25%-30%). The in vitro release rate was slowest for morphine, intermediate for fentanyl and alfentanil, and fastest for sufentanil. In vivo, morphine was released more slowly than sufentanil. It is most important to note that increasing the lipid content of morphine liposomes increased the proportion of drug reaching the intrathecal space. In contrast, increasing the lipid content of sufentanil liposomes did not alter intrathecal movement but did decrease movement into plasma. Therefore, increasing drug hydrophobicity and lipid content of the liposomes modulates drug distribution in vivo. IMPLICATIONS: The degree of interaction between opioids and lipid bilayers in liposome-formulated opioids dictates the rates at which epidurally-administered drugs distribute into the intrathecal compartment and blood in potentiating analgesic effects.

Total synthesis of sufentanil.

Sufentanil, a potent anilidopiperidine analgesic, was synthesized from a simple thiophenylethylamine via six step sequence. The key parts of this synthesis involved an efficient construction of thiophenylethylpiperidone by aminomethano desilylation-cyclization followed by Swern oxidation and a direct regioselective N-nucleophilic spiral epoxide cleavage with aniline promoted by Lewis acids.