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PubMed1999

Stability and compatibility of an aerosol mixture including N-acetylcysteine, netilmicin and betamethasone.

The physicochemical stability and the compatibility between N-acetylcysteine (1 g/5 ml), betamethasone (4 mg/1 ml) and netilmicin (100 mg/1 ml) were studied at room temperature (25+/-2 degrees C) over 1 h. During this study, drug concentrations were measured using three separate HPLC methods with UV detection at t=0, 5, 10, 20, 30, and 60 min. The pH of the mixture was determined. Degradation products of the drugs were assayed using HPLC. This study demonstrates the stability and compatibility of the mixture over 1 h at room temperature. The pinkish non-remnant coloration observed when pouring N-acetylcysteine into a recipient has no effect on the stability of the drug.

Acetylcysteine↗
PubMed1998

Stability study of fotemustine in PVC infusion bags and sets under various conditions using a stability-indicating high-performance liquid chromatographic assay.

The stability and compatibility of fotemustine, a nitrosourea anticancer agent, in 5% dextrose solution with polyvinyl chloride (PVC) containers and administration sets were studied under different conditions of temperature and light. The drug was diluted to 0.8 and 2 mg ml(-1) in 100 or 250 ml 5% dextrose injection solutions for 1-h simulated infusions using PVC bags and administration sets with protection from light. After preparation in the PVC bags containing 5% dextrose, fotemustine was also prepared at the same concentrations and stored at 4 degrees C for 48 h and at room temperature (22 degrees C) or at sunray exposure ( > 30 degrees C) over 8 h with or without protection from light. The solution samples were removed immediately at various time points of simulated infusions and storage, and stored at -20 degrees C until analysis. The physical compatibility with PVC and chemical stability in solution of fotemustine were assessed by visual examination and by measuring the concentration of the drug in duplicate using a stability-indicating high-performance chromatographic assay. When admixed with a 5% dextrose solution, fotemustine 2 and 0.8 mg ml(-1) was compatible and stable over 1-h of simulated infusion using PVC bags through PVC administration sets with protection from light. On the other hand, in the same diluent, fotemustine was compatible and stable with PVC bags for at least 8 h at 22 degrees C with protection from light and for at least 48 h at 4 degrees C with protection from light. There were no pH variation, no visual change, no color change, no visible precipitation and no loss of the drug. Conversely, when the solutions were exposed to light (ambient or solar), the drug concentration decreased rapidly, leading to the production of a degradation product as shown by mass spectral analysis and a discoloration of the solutions. Finally, in all cases, no DEHP (di-2-ethylhexyl phthalate) was detected in the injection solution.

Chromatography, High Pressure Liquid↗
PubMed1999

Stability, compatibility and plasticizer extraction of quinine injection added to infusion solutions and stored in polyvinyl chloride (PVC) containers.

The stability of quinine was determined in various diluents and in polyvinyl chloride (PVC) containers. The release of diethyhexyl phthalate (DEHP) from PVC bags into intravenous infusions of quinine was also measured. We used an injection of two doses of quinine; quiniforme at 500 mg and quinimax at 400 mg in either 250- or 500-ml PVC infusion bags containing 5% dextrose, to give initial nominal concentrations of 2 or 1 mg ml(-1) quiniforme and 1.6 or 0.8 mg ml(-1) quinimax, the mean concentrations commonly used in clinical practice. Samples were assayed by stability-indicating high-performance liquid chromatography (HPLC) and the clarity was determined visually. Experiments were conducted to determine whether the stability and compatibility of quinine would be compromised, and whether DEHP would be leached from PVC bags and PVC administration sets during storage and simulated infusion. There was no substantial loss of quiniforme and quinimax over 1- or 2-h simulated infusion irrespective of the diluent, and storage during 8 h at 22 degrees C, 48 or 72 h at 4 degrees C and 96 h at 45 degrees C. Leaching of DEHP was also detected during simulated infusion delivery using PVC bags and PVC administration sets. The quantity was less than 2 microg ml(-1). During storage at 4 degrees C and room temperature the leaching of DEHP was low, but when the temperature was 45 degrees C the quantity was high, 21 microg ml(-1). To minimise patient exposure to DEHP, quinine solutions with all drugs should be infused immediately or stored for a maximum of 48 h at 4 degrees C.

Antimalarials↗
PubMed2003

Stability and compatibility of morphine-clonidine admixtures in an implantable infusion system.

Nonopioid analgesics are often coadministered with intrathecal morphine to increase efficacy. The purpose of this study was to evaluate stability and compatibility of morphine-clonidine admixtures with an implantable infusion system that is commonly used to treat pain patients. Infusion systems were filled with admixture and maintained at 37 degrees C for 90 days. Samples were collected monthly. Drug concentrations were determined using stability-indicating, high-performance liquid chromatography. For compatibility testing, individual materials comprising the fluid pathway of the device were immersed in clonidine solution and stored at 37 degrees C for various periods through 64 weeks and mechanical performance evaluated. After 3 months of containment in the infusion system, morphine and clonidine concentrations remained at > or = 94% of the theoretical starting concentrations. All device materials retained acceptable mechanical performance following clonidine exposure. These results demonstrate that morphine and clonidine are stable when combined in aqueous solution maintained at body temperature in an implantable infusion system for at least 3 months.

Analgesics↗
PubMed2003

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.

Anesthetics, Intravenous↗
PubMed1988

Interactions of non-steroidal anti-inflammatory drugs.

As NSAIDs are commonly used in patients receiving concomitant drug therapy, there is a risk of clinically significant drug interactions. Important interactions with NSAIDs involve one or both of two major mechanisms: pharmacokinetic (e.g. lithium, phenytoin and barbiturates) and pharmacodynamic (e.g. antihypertensive agents, diuretics). Prescription of a NSAID should be preceded by a careful evaluation of any coexisting pathology (such as renal dysfunction or hypertension) or concurrent drug therapy (such as anticonvulsant or anticoagulant agents) which may predispose a patient to the development of an interaction with potentially severe effects.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Stability and compatibility of tacrolimus and fluconazole in 0.9% sodium chloride.

OBJECTIVE: To determine the physical compatibility and chemical stability of tacrolimus injection and fluconazole injection combined in a range of concentrations used clinically for intravenous Y-site co-administration over 3 hours. DESIGN: Tacrolimus injection (Prograf) was combined with fluconazole injection (Diflucan) in volumetric glass flasks at room temperature (23 degrees C to 25 degrees C) to form final concentrations of 5 or 20 micrograms/mL and 500 or 1,500 micrograms/mL, respectively. Immediately after preparation and at 1.5 and 3 hours, triplicate samples and controls were visually inspected and assayed in duplicate by high-performance liquid chromatography; pH of the samples was also determined. SETTING: University of Michigan College of Pharmacy. PATIENTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Initial and subsequent concentrations of tacrolimus and fluconazole at 1.5 and 3 hours. RESULTS: More than 99% of the initial concentration of each drug remained in all samples throughout the study period. There was no color change, and the pH of the samples did not change appreciably. CONCLUSION: Tacrolimus and fluconazole are stable and compatible in a range of clinically used concentrations for 3 hours and can be intravenously co-administered through a Y-site.

Antifungal Agents↗
PubMed1990

Determination of solute-polymer interaction properties and their application to parenteral product container compatibility evaluations.

Kinetic and thermodynamic interaction properties between dialkyl phthalate test compounds and a polyolefin polymer were examined via a permeation-cell experimental design. Disappearance and appearance rates of solute in the receptor and donor solutions, as well as the equilibrium composition of the test system, are used to determine sorption and diffusion coefficients and the solute/polymer equilibrium binding constant. Sorption rate constants and diffusion coefficients exhibit Arrenhius-type behavior. The binding constants obtained correlate well with the solute's octanol-water partition coefficient. The kinetic and thermodynamic data generated combine with proposed interaction models to identify solute/polymer interactions (binding and leaching) pertinent to evaluating container/solution compatibility for parenteral products.

Diffusion↗
PubMed1998

Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin.

AIMS: The effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG-CoA reductase with different pharmacokinetic properties, were studied. METHODS: Two separate randomized, placebo-controlled, cross-over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h. RESULTS: Itraconazole had no significant effect on the Cmax (190 +/- 124 ng ml(-1) vs 197 +/- 189 ng ml(-1) (mean +/- s.d.)) or total AUC (368 +/- 153 ng ml(-1) h vs 324 +/- 155 ng ml(-1) h) of fluvastatin compared with placebo. However, the t1/2,z of fluvastatin was slightly prolonged by itraconazole (2.8 +/- 0.49 h vs 2.4 +/- 0.51 h; P < 0.05). The Cmax of lovastatin was increased about 15-fold (P < 0.01) and the total AUC more than 15-fold (P < 0.01) by itraconazole. Similarly, the Cmax and total AUC of lovastatin acid were increased about 12-fold (95% CI, 5.3 to 17.7-fold; P < 0.01) and 15-fold (95% CI, 4.6 to 26.2-fold; P < 0.01) by itraconazole, respectively. The t1/2,z of lovastatin averaged 3.7 +/- 3.8 h and that of lovastatin acid 4.7 +/- 4.0 h during the itraconazole phase; these variables could not be determined in all subjects during the placebo phase. CONCLUSIONS: Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.

Administration, Oral↗
PubMed1999

Compatibility of tirofiban HCl with dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride during simulated Y-site administration.

OBJECTIVE: To study the compatibility of tirofiban HCl injection 0-05 mg/ml with dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride infusion solutions during simulated Y-site administration. METHOD: Tirofiban HCl, dopamine HCl, famotidine, lidocaine HCl and potassium chloride infusions were each prepared from their respective concentrates as per current clinical preparation instructions in both 0.9% sodium chloride and 5% dextrose solutions at both the minimum and maximum concentrations normally administered. Sodium heparin premixed infusion solutions in 5% dextrose and 0-45% sodium chloride were used as-is. Tirofiban HCl solutions were combined 1:1 (simulated Y-site administration) with the dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride solutions in separate glass containers and polyvinylchloride Y-site infusion lines. Samples were held for 4 h at room temperature under ambient fluorescent light and were assayed for changes in drug content, degradation, pH, appearance and turbidity. Activity of sodium heparin solutions was measured using an aPTT coagulation assay. RESULTS: All mixtures remained clear and colourless with no visual indication of instability, i.e. precipitation. Clarity of solutions was confirmed by turbidometric analysis. There was no significant loss of drug, increase in known degradates, or appearance of unknown drug-related peaks as determined by HPLC. The activity of heparin in heparin-containing solutions remained unchanged. The pH of all test-solutions remained constant. CONCLUSION: Tirofiban HCl injection 0.05 mg/ml can be co-infused by Y-site administration with dopamine HCl, famotidine, sodium heparin, lidocaine HCl and potassium chloride injection solutions.

Chromatography, High Pressure Liquid↗
PubMed2005

Compatibility studies between ibuprofen or ketoprofen with cellulose ether polymer mixtures using thermal analysis.

Differential scanning calorimetry (DSC) was used to investigate and detect incompatibilities between drugs such as: ibuprofen (IBU) or ketoprofen (KETO) with cellulose ether derivatives, which are frequently applied on controlled release dosage forms. Binary mixtures concerning methylcellulose (MC25) or hydroxypropylcellulose (HPC) with hydroxypropylmethylcellulose (HPMC) K15M or K100M in different ratios were prepared and evaluated by the appearance, shift, or disappearance of peaks and/or variations in the corresponding DeltaH values. According to the DSC results, binary mixtures between those polymers were found to be compatible, but their mixture with IBU or KETO, promotes a solid-solid interaction mainly with 1:1:1 (w/w) ratio (drug-excipient). However, when the drug:excipient interactions were detected, they were not found to affect the drug bioavailability. DSC was successfully employed to evaluate the compatibility of the drugs with the selected polymers.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Drug-excipient compatibility testing using a high-throughput approach and statistical design.

The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of approximately 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40 degrees C/ 50 degrees C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.

Aspirin↗
PubMed2005

Drug-drug interaction studies on first-line anti-tuberculosis drugs.

The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner.

Antitubercular Agents↗
PubMed1994

Stability of cefodizime in solution and compatibility with other injectable drugs.

The stability of cefodizime in five intravenous infusion fluids (0.9% sodium chloride, 5% dextrose in water, 10% dextrose in water, 5% amino acid injection, 3% polygeline) was studied at room temperature and at 4 degrees C. The compatibility of cefodizime with commonly used injectable drugs (ranitidine, metoclopramide, folinic acid, furosemide, aminophilline, methylprednisolone, betamethasone, hydrocortisone, dexamethasone, ketoprofen, noramidopyrine, acetylcysteine, digoxin, diazepam, acetylsalicylic acid, chlorpromazine, clonidine, clomipramine) was studied in 0.9% sodium chloride and 5% dextrose at room temperature. At intervals during the storage periods (up to 24 hrs at room temperature; up to 6 days at 4 degrees C) color, clarity and solution pH were examined; cefodizime content was determined by a microbiological method. Cefodizime concentrations remained greater than 90% of the initial concentrations in all infusion fluids for at least 24 hrs at room temperature and 6 days at 4 degrees C. No visual changes or appreciable changes in pH were observed for any of the solutions. Immediate clouding was observed when chlorpromazine was combined with the solution of cefodizime. A color change was observed when acetylcysteine was mixed with cefodizime. An increase in pH was noted when aminophilline was added to the solution of cefodizime. However, cefodizime concentrations remained greater than 90% of the initial concentrations of the solutions after mixture with all the tested drugs for at least 24 hrs at room temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

Cefotaxime↗
PubMed2004

Drug-induced QT interval prolongation: regulatory perspectives and drug development.

Drug-induced torsade de pointes is a modern, iatrogenic challenge. This potentially fatal tachyarrhythmia is associated with many non-antiarrhythmic (including noncardiovascular) drugs, leading to a number of effective drugs being withdrawn from the market. Others have attracted severe prescribing restrictions while some new chemical entities have experienced difficulties in gaining regulatory approval. Since QT interval prolongation, a surrogate of torsade, is a mechanism-based concentration-dependent pharmacological effect, it is usually possible to characterise a drug for this toxicity during its development. The physicochemical and other pharmacological properties of a QT-prolonging drug modulate its clinical risk of torsade de pointes. Apart from these properties, the torsadogenic potential of a drug is also influenced clinically by a number of genetic and non-genetic factors. The former include polymorphisms of enzymes that metabolise the drug or its pharmacological target. Major non-genetic factors are the dose of the drug, co-medications especially metabolic inhibitors or other QT-prolonging drugs, presence of electrolyte imbalance and co-morbidity especially liver or cardiac disease, including pre-existing prolongation of the QT interval or bradycardia. Drug development programmes should be aimed at characterising the potency of a drug to prolong the OT interval and its interactions with these genetic and non-genetic variables, if valuable drugs are to gain approval and continue to be prescribed effectively and safely. Physicians too have an important role by ensuring that they adhere to prescribing information and monitor the patients as recommended.

Clinical Trials as Topic↗