Stability of Methadone Hydrochloride for Injection in Saline Solution

Abstract

Background: Until October 2014, methadone hydrochloride forinjection (10 mg/mL) was available in Canada through Health Canada’s Special Access Programme. Diluted to 5 mg/mL in saline, it was used in pediatrics for acute and cancer-related pain. More recently, the department of pharmacy of the Centre hospitalier universitaire Sainte-Justine in Montréal, Quebec, proposed compounding a solution of methadone hydrochloride for injection (5 mg/mL) from bulk powder and saline solution for pediatric administration.Objective: To assess the stability of the proposed compounded preparation.Methods: Solutions of methadone hydrochloride in saline were prepared from bulk powder and stored in clear glass vials for up to 180 days at room temperature (25 °C) or with refrigeration (5 °C), with testing on days 0, 7, 14, 30, 60, 90, and 180. The appearance of the solutions and presence of particulate matter were assessed. A stability-indicating highperformance liquid chromatography (HPLC) method was developed to assay the concentration of methadone over time.Results: No notable changes in appearance of the methadone solution were observed, particle counts did not exceed limits specified by the United States Pharmacopeia, and no microbial growth was observed. The HPLC analysis showed that the concentration of methadone remained above 90% on all study days.Conclusions:Methadone hydrochloride for injection prepared from bulk powder in saline solution at a concentration of 5 mg/mL remained chemically stable for at least 180 days when stored in clear glass vials at 5 °C and at 25 °C.RÉSUMÉContexte : Jusqu’en octobre 2014, le chlorhydrate de méthadone pourinjection (10 mg/mL) était disponible au Canada à l’aide du Programme d’accès spécial de Santé Canada. Dilué à 5 mg/mL dans une solutionsaline, il était utilisé en pédiatrie contre les douleurs aigües et celles liées au cancer. Plus récemment, le département de pharmacie du Centre hospitalier universitaire Sainte-Justine de Montréal au Québec a proposé de préparer une solution de chlorhydrate de méthadone pour injection (5 mg/mL) à partir d’une poudre en vrac et d’une solution saline en vue de l’administrer en pédiatrie.Objectif : Évaluer la stabilité de la préparation proposée.Méthodes : Les préparations de chlorhydrate de méthadone diluées dans une solution saline se font à partir d’une poudre en vrac, elles sont stockées dans des fioles en verre transparent pendant180 jours à la température ambiante (25 °C) ou réfrigérées (5 °C) et sont soumises à des tests les jours 0, 7, 14, 30, 60, 90 et 180. L’apparence des solutions et la présence de substances particulaires ont fait l’objet d’une évaluation. Une méthode de chromatographie liquide à haute performance (CLHP) indiquant la stabilité a été développée pour tester la concentration de methadone dans le temps.Résultats : Aucun changement notable de l’apparence de la solution de méthadone n’a été observé, le nombre de particules ne dépassait pas les limites précisées par l’United States Pharmacopeia et aucune croissance microbienne n’a été observée. L’analyse CLHP a indiqué que la concentration de méthadone était demeurée au-delà de 90% durant toute la durée de l’étude.Conclusions : Le chlorhydrate de méthadone pour injection préparé à partir de poudre en vrac dans une solution saline à une concentration de5 mg/mL est resté chimiquement stable pendant au moins 180 jours lorsqu’il était stocké dans des fioles en verre transparent à 5 °C et à 25 °C

Stability of dilutions of methadone alone, and in combination with lidocaine and ketamine

“…This is consistent with the results of previous studies. Denson et al (1991) reported that methadone, diluted to 1, 2 or 5 mg/ml with 0.9% NaCl, is stable for at least 30 days at room temperature, while Friciu et al (2020) demonstrated that methadone retains chemical stability for at least 180 days at a concentration of 5 mg/ml in 0.9% NaCl and stored at either 5°C or 25°C. Ketamine remains stable for a minimum of 365 days when diluted to 1 mg/ml in 0.9% NaCl and stored at 40°C in polypropylene syringes, and for at least 180 days at a 50 mg/ml dilution in polypropylene syringes at 25°C (Stucki et al 2008, Huvelle et al 2016.…”

Medication Safety—A Global Health Priority

“…Vaillancourt and others 13 describe their audit of cannabis use in a pediatric hospital. The previously mentioned study by Friciu and others 9 is also of relevance to pediatric medication safety, as this formulation of methadone is used for acute and cancer pain in children. Audits are important for seeing patterns of medication use and informing future research and interventions, and the investigation of issues such as medication stability is also vital to ensure patient safety.…”

“…The pharmacist's role in pain management is expanding, as evidenced by the study on opioid controls reported by Videau and others, 7 the comparison of topical amitriptyline formulas to improve clinical efficacy in neuropathic pain reported by Shakshuki and others, 8 , and the investigation of methadone stability by Friciu and others. 9 These papers all provide evidence on how to improve the safety and efficacy of pain medicines, and they all reflect work to ensure that medicines do their work without hurting the patient.…”

Development and validation of a HPLC-UV method for methadone hydrochloride quantification in a new oral solution with preservatives to be implemented in physicochemical stability studies

“…It should be note that the methadone analyzed with these methods was either found in concentrations different from 10 mg/ml, or they were preparations for intravenous administration, or they were compounded with other vehicles than water (sodium chloride [ 11 , 12 ], various drinks [ 13 ], syrups, suspension and sugar-free vehicles [ 14 ]) and none of the pharmaceuticals analyzed for oral administration contained exactly the same preservatives (only methylparaben) [ 9 ] used in our new formulation [ 15 ], so they really were not suitable for us. Furthermore, these methods use columns that are no longer used, such as µBondapak or Radpak-Novapak, a type A silica-based column with a lot of silanolic activity and therefore a high possibility of deformation tailing.…”