Users Online: 328 | Home Print this page Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
SHORT COMMUNICATION
Year : 2011  |  Volume : 1  |  Issue : 1  |  Page : 48-52

Chemical stability of tramadol hydrochloride injection admixed with selected pain drugs


1 Department of Chemistry and Pharmaceutical Technology, Faculty of Pharmacy, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy
2 Pharmacy Department, ISMETT - Via Ernesto Tricomi, 1 90127 Palermo, Italy

Date of Submission06-Oct-2010
Date of Decision23-Nov-2010
Date of Acceptance24-Nov-2010
Date of Web Publication16-Feb-2011

Correspondence Address:
V Di Stefano
via Archirafi 32, 90123 Palermo
Italy
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-973X.76729

Rights and Permissions
  Abstract 

Background: Tramadol hydrochloride (HCl) and ketorolac tromethamine are analgesic drugs, which are commonly used in combination in postoperative pain management. According to some studies, metoclopramide and magnesium sulfate (MgSO 4 ) as adjuvant agents can improve analgesia and decrease the need for other pain drugs. Materials and Methods: The chemical stability of tramadol HCl combined with ketorolac tromethamine and metoclopramide HCl has been studied using a stability-indicating high-performance liquid chromatographic assay method. Calibration curves were produced using linear regression of the peak area against concentration of each drug, with an r 2 value ≥ 0.96. Our aim was to investigate the stability of admixture solution of tramadol HCl combined with ketorolac tromethamine and metoclopramide HCl for 48 h (25ºC) and 5 days (5ºC), with MgSO 4 , which has never been assessed. Results: Data obtained for admixtures prepared and stored at temperatures of 25ºC and 5ºC, show that all drugs have reached at least 98% of the initial concentration. Conclusions: For the purpose of pre-preparing drug admixtures to use with confidence, tramadol HCl infusions may be prepared in advance and then thawed before use in clinical units. On the basis of our results, the intravenous mixture of tramadol (7.69 mg/mL), metoclopramide (0.19 mg/mL), ketorolac (1.15 mg/mL), and magnesium sulfate (77 mg/mL) may be considered for a possible commercial formulation.

Keywords: Admixture, analgesia, ketorolac tromethamine, magnesium sulfate, metoclopramide hydrochloride, stability


How to cite this article:
Di Stefano V, Pitonzo R, Bavetta S, Polidori P, Sidoti M G. Chemical stability of tramadol hydrochloride injection admixed with selected pain drugs. Int J Pharma Investig 2011;1:48-52

How to cite this URL:
Di Stefano V, Pitonzo R, Bavetta S, Polidori P, Sidoti M G. Chemical stability of tramadol hydrochloride injection admixed with selected pain drugs. Int J Pharma Investig [serial online] 2011 [cited 2017 Sep 26];1:48-52. Available from: http://www.jpionline.org/text.asp?2011/1/1/48/76729


  Introduction Top


Appropriate management of moderate postoperative pain is well achieved associating several analgesic drugs with adjuvant agents through synergistic interaction. The potential advantage of this combined therapy is related to the minimization of the incidences of adverse effects of each drug and to the improvement of the outcome. Postoperative clinical situations, such as difficult patient extubation, respiratory depression due to opioids, and cardiovascular side effects, require a combined therapy to improve analgesia quality and decrease adverse effects of each drug when used alone. [1] This has led to administering pain drugs in continuous intravenous (IV) infusion with different mechanisms and sites of action, together with adjuvant agents.

Tramadol hydrochloride (HCl) and ketorolac tromethamine are analgesic drugs commonly used in combination in postoperative pain management. [2] Tramadol HCl is a synthetic, centrally acting analgesic with no anti-inflammatory activity and one of the most interesting and useful weak opioids for treatment of moderate to moderately severe pain with weak μ-receptor agonist properties and noradrenergic and serotonergic neurotransmission effects. [3],[4],[5],[6],[7],[8],[9]

Ketorolac tromethamine is a potent nonsteroidal anti-inflammatory drug (NSAID) with analgesic efficacy similar to opioids. [2],[8],[9] This drug is administered to treat moderate pain or, combined with reduced opioid doses, for severe pain. [10] According to some studies, metoclopramide HCl as an adjuvant agent can improve analgesia and decrease the need for other pain drugs; it is a dopamine and 5-HT receptor antagonist, commonly used as a prokinetic and antiemetic. Also, this has been recently investigated as an agent that can enhance the efficacy of analgesic drugs. [9],[11],[12],[13] Some studies have also suggested a role of magnesium sulfate (MgSO 4 ) as an adjuvant agent, an N-methyl-d-aspartate receptor antagonist, in the management of postoperative pain. The perioperative administration of IV MgSO 4 is associated with smaller analgesic requirements, and magnesium sulfate could be of interest as an adjuvant to postoperative analgesia. [14],[15],[16]

The aim of this study was to investigate the chemical stability of tramadol HCl combined with ketorolac tromethamine and metoclopramide HCl in solution for 48 h (25ºC) and 5 days (5ºC), with the presence of MgSO 4 .


  Materials and Methods Top


Preparation of stock solutions

Metoclopramide HCl (Metoclopramide Cloridrato Mayne Pharma, Biologici Italia Laboratories S.r.l., Milan, Italy) 2 mg/mL, tramadol HCl (Contramal; Grόnenthal, GmbH, Stolberg, Germany) 20 mg/mL, and ketorolac tromethamine (Lixidol; Roche S.p.A., Milan, Italy) 6 mg/mL stock solutions were prepared in high-performance liquid chromatographic (HPLC)-grade deionized water and stored at 4ºC during experimental assay. Well-defined volume samples were drawn from each stock solution, joined, and diluted in deionized water to produce 5 working standard solutions, with concentrations in the range of 0.5-1.5 μg/mL for metoclopramide HCl, 20-60 μg/mL for tramadol HCl, and 3-9 μg/mL for ketorolac tromethamine.

Every 48 h the working standard solutions were prepared from stock solutions and stored at 4ºC. Limit of Quantitation (LOQ) values were found to be 1, 0.5, and 0.1 μg/mL for tramadol, ketorolac, and metoclopramide, respectively. Limit of Detection (LOD) values were 0.05, 0.2, and 0.1 μg/mL for tramadol, ketorolac, and metoclopramide. Precision and accuracy were determined on spiked samples at 4 concentrations with respect to a calibration graph prepared every day (n = 3). The precision of the method was evaluated as the intra- and interday Relative Standard Deviation (RSD) of the measured peak areas by assaying spiked samples at 4 different concentrations. All samples for these purposes were freshly prepared, including preparing the standard solution from the same stock solution.

Admixture preparation and analysis

Six drug admixtures were prepared by transferring the contents of one ampule of metoclopramide HCl, 4 ampules of tramadol HCl, 2 ampules of ketorolac tromethamine, and 4 ampules of MgSO 4 (1 g/10 mL ampule, Magnesio Solfato Monico; Monico S.p.A., Venezia Mestre, Italy) to give each a final volume of 52 mL. All the solutions were prepared on different days, stored at 25ºC and assessed over a period of 48 h. Solutions were stored in amber colored glass bottles with air-tight caps to protect them from direct light exposure. The nominal concentration of each drug in all prepared solutions was 0.19 mg/mL for metoclopramide HCl, 7.69 mg/mL for tramadol HCl, and 1.15 mg/mL for ketorolac tromethamine. All the drug admixtures were visually inspected immediately after preparation (0 h) and at 24 and 48 h against a black and white background to ensure any physical changes (eg, color, phase separation, precipitation).

A 100 μL sample was drawn from each solution at intervals of 0 (initial), 24, and 48 h and diluted to 20 mL with deionized water; we prepared solutions in triplicate at each time interval to have 54 samples. Twenty microliters of each sample was injected into the HPLC system to determine concentration of each drug.

As previously described, 6 drug admixtures were prepared on different days, stored at 5ºC (refrigerated), assessed, and visually inspected at intervals of 0 (initial), 1, 3, and 5 days. A 100 μL of sample was drawn from each solution and diluted to 20 mL with deionized water; we prepared solutions in triplicate at each time interval to have 72 samples. Twenty microliters of each sample was injected into the HPLC system to determine concentration of each drug.

High-performance liquid chromatography

The HPLC method developed by Kόηόk et al was modified for use in this study. [17],[18] The instrumentation included a binary pump (Model G1312A; Agilent Technologies; Hewlett-Packard, Waldbronn, Germany) and an ultraviolet (UV)-variable wavelength detector (Model G1314A; Agilent). At the beginning of our study, we looked for the maximum UV absorption wavelength for each drug solution on the basis of UV spectra for each solution. As we used UV-variable wavelength detector, and metoclopramide and tramadol retention times were very close reciprocally, we found that 271 nm was the best wavelength for both drugs to have good sensitivity and maximum signal/noise ratio. For ketorolac drug solutions, we found that 323 nm was the best absorption wavelength. Separation was achieved using a reversed-phase C 18 5 μm particle size column (Luna C 18 (2) 100A, 150 Χ 4.6 mm; Chemtek Analytica Srl, Anzola Emilia (BO), Italy), equipped with a 2-cm precolumn, which was maintained at 25ºC with a column temperature controller (Thermosphere TS-130; Phenomenex, Torrance, California). HPLC-gradient analysis were performed using the following mobile phase: 0.01 M phosphate buffer, potassium dihydrogen phosphate [KH 2 PO 4 ] ultra for molecular biology (Fluka and Riedel-de Haλn, Buchs SG, Switzerland) and acetonitrile (Sigma-Aldrich Supelco, Bellefonte, Pennsylvania) (75:25, v/v) with the addition of 0.1% triethylamine, adjusted to pH 3 with phosphoric acid (solvent A) and H 2 O-acetonitrile (50:50, v/v, solvent B). The elution-gradient program was 0-6 min 0% B, 6-10 min 80% B, 10-15 min 0% B [Table 1].
Table 1 :The elution-gradient program

Click here to view


Each mobile phase was prepared fresh daily, filtered through a 0.45 μm Χ 47 mm nylon membrane filter (Supelco, Bellefonte, Pennsylvania Nylon 66 Filter Membranes pore size 0.20 μm, diameter 47 mm), and degassed ultrasonically for 20 min before use. The flow rate was 1 mL/min, and the injected volume was 20 μL. The run time was 15 min and the approximate retention times for metoclopramide, tramadol, and ketorolac were 2.8, 3.4, and 13.4 min, respectively [Figure 1].
Figure 1 :A typical HPLC– UV chromatogram of metoclopramide hydrochloride (a), tramadol hydrochloride (b), and ketorolac tromethamine (c), eluted at 2.8, 3.4, and 13.4 min, respectively.

Click here to view


Data analysis

Calibration curves were produced using linear regression of the peak area against concentration of each drug [Table 2]. We obtained 5 calibration curves for each drug and all the curves were linear over the concentration ranges considered for each drug: metoclopramide HCl r 2 = 0.991; tramadol HCl r 2 = 0.995; ketorolac tromethamine r 2 = 0.961. The results were averaged and analyzed by linear simple regression model of y = mx + q by the least-squares method. The t test was used to examine the concentration difference at each time, and the significance level of a error was less than 0.001.
Table 2 :Linear simple regression model (y = mx + q) by the least-squares method

Click here to view


All the data reported in [Table 3] and [Table 4] were submitted to ANOVA and differences analyzed by Tukey's honestly significant differences test. No significant admixture and time-dependent effect interactions were observed (P ≥ 0.05).


  Results and Discussion Top


At the Mediterranean Institute for Transplantation and Highly Specialized Therapies (ISMETT, Palermo, Italy) is already using an experimental protocol for the treatment of moderate to severe pain, which involves the administration of intravenous mixture of tramadol (7.69 mg/mL), metoclopramide (0.19 mg/mL), ketorolac (1.15 mg/mL), and magnesium sulfate (77 mg/mL). To use this drug combination is necessary that the drugs are compatible with each other and the mixture is stable over time.

Drugs stability was detected for solutions stored at 25ºC and 5ºC. [Table 3] shows drugs solution concentration after storage period up to 48 h. The data obtained are in agreement with data reported in the literature regarding a mixture of tramadol, ketorolac, metoclopramide, and ranitidine in a solution for intravenous perfusion. [9]
Table 3 :Percentage ± %SD of metoclopramide hydrochloride, tramadol hydrochloride, and
ketorolac tromethamine remaining in the admixtures with magnesium sulfate after storage at 25°C
for 48 h


Click here to view


Data reported in [Table 4] show the remaining percentage of drug concentrations in all admixtures prepared and assessed over a period of 5 days. It is possible to observe constant percentage concentrations remaining for all the 3 drugs at 1, 3, and 5 days when stored at 5ºC. We believe that the information has clinical utility in facilitating the preparation and dispensing of the tramadol, metoclopramide, ketorolac, and magnesium sulfate mixture in postoperative pain management. On the basis of our results, the mixture may be considered for a possible commercial formulation, at the concentrations listed.
Table 4 :Percentage ± %SD of metoclopramide hydrochloride, tramadol hydrochloride, and ketorolac
tromethamine remaining in the admixtures with magnesium sulfate stored at 5°C for 5 days


Click here to view



  Conclusions Top


In this study, precise and accurate HPLC method suitable for stability evaluation of tramadol HCl combined with ketorolac tromethamine and metoclopramide HCl is described. The physical appearance of the solutions remained constant during the study period, without the formation of any visible discoloration, cloudiness, or precipitation. In admixtures containing MgSO 4 and stored at 25ºC, each drug, at the same time, reached at least 98% of the initial concentration during 48 h. Solutions prepared adding MgSO 4 assessed over a period of 5 days at 5ºC show the lower confidence limit of the estimated regression line of the concentration at 98% of the initial concentration. Within these limits, for the purpose of pre-preparing drug admixtures to use with confidence, tramadol HCl infusions may be prepared in advance and then thawed before use in clinical units. Moreover, information about the chemical stability of the drugs could be utilized in further investigations focused on IV infusion solutions.

 
  References Top

1.Joris J, Kaba A, Lamy M. Transition between anesthesia and post-operative analgesia: Relevance of intra-operative administration of analgesics. Acta Anaesthesiol Belg 2001;52:271-9.  Back to cited text no. 1
    
2.López-Muñoz FJ, Díaz-Reval MI, Terrón JA, Déciga-Campos M. Analysis of the analgesic interactions between ketorolac and tramadol during arthritic nociception in rat. Eur J Pharmacol 2004;484:157-65.  Back to cited text no. 2
    
3.Lehmann KA. Tramadol in acute pain. Drugs 1997;53:25-33.  Back to cited text no. 3
    
4.Klotz U. Tramadol-the impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain. Arzneimittelforschung 2003;53:681-7.  Back to cited text no. 4
    
5.Abanmy NO, Zaghloul IY, Radwan MA. Compatibility of tramadol hydrochloride injection with selected drugs and solutions. Am J Health Syst Pharm 2005;62:1299-302.  Back to cited text no. 5
    
6.Barcia E, Martín A, Azuara ML, Sánchez Negro S. Tramadol and Hyoscine N-bromide combined in infusion solutions: Compatibility and stability. Support Care Cancer 2007;15:57-62.  Back to cited text no. 6
    
7.Scott LJ, Perry CM. Tramadol: A review of its use in perioperative pain. Drugs 2000;60:1 39-45.  Back to cited text no. 7
    
8.Tzu FL, Feng-Sheng L, Wei-Han C, Yu-Chang Y, Chih-Peng L, Shou-Zen F, et al. Compatibility and stability of binary mixtures of ketorolac tromethamine and tramadol hydrochloride injection concentrate and diluted infusion solution. Acta Anaesthesiol Taiwan 2010;48:117-21.  Back to cited text no. 8
    
9.Cabrera J, Mancuso M, Cabrera-Fránquiz F, Limiñana J, Díez A. Stability and compatibility of the mixture of tramadol, ketorolac, metoclopramide and ranitidine in a solution for intravenous perfusion. Farm Hosp 2010.  Back to cited text no. 9
    
10.World Health Organization. Care pain relief and palliative care. Technical report series no 804 1990. Available from: http://www.who.int/cancer/palliative . [accessed on 2009 Oct 1].  Back to cited text no. 10
    
11.Ceyhan A, Ustun H, Altunatmaz K, Ide T, Unal N. Is metoclopramide an alternative to tramadol in management of post-operative pain? An experimental study. J Vet Med A Physiol Pathol Clin Med 2005;52:249-53.  Back to cited text no. 11
    
12.Gibbs RD, Movinsky BA, Pellegrini J, Vacchiano CA. The morphine-sparing effect of metoclopramide on postoperative laparoscopic tubal ligation patients. AANA J 2002;70:27-32.  Back to cited text no. 12
    
13.Majedi H, Rabiee M, Khan ZH, Hassannasab B. A comparison of metoclopramide and lidocaine for preventing pain on injection of diazepam. Anaesth Analg 2002;95:1297-9.  Back to cited text no. 13
    
14.Unlügenç H, Gündüz M, Ozalevli M, Akman H. A comparative study on the analgesic effect of tramadol, tramadol plus magnesium, and tramadol plus ketamine for postoperative pain management alter major abdominal surgery. Acta Anaesthesiol Scand 2002;46:1025-30.  Back to cited text no. 14
    
15.Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology 1996;84:340- 7.  Back to cited text no. 15
    
16.Koinig H, Wallner T, Marhofer P, Andel H, Hörauf K, Mayer N. Magnesium sulfate reduces intra- and postoperative analgesic requirements. Anesth Analg 1998;87:206-10.  Back to cited text no. 16
    
17.Küçük A, Kadioðlu Y. Determination of tramadol hydrochloride in ampoule dosage forms by using UV spectrophotometric and HPLC-DAD methods in methanol and water media. IL Farmaco 2005;60:163-9.  Back to cited text no. 17
    
18.Küçük A, Kadioðlu Y, Çelebi F. Investigation of the pharmacokinetics and determination of tramadol in Rabbit plasma by a high-performance liquid chromatography-diode array detector method using liquid-liquid extraction. J Chromatogr B Analyt Technol Biomed Life Sci 2005;816:203-8.  Back to cited text no. 18
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


This article has been cited by
1 LC and LC–MS study for simultaneous determination of tramadol hydrochloride and ketorolac tromethamine in bulk and formulation with their major degradation products
Vrushali S. Tambe,M.N. Deodhar,Vijayalakshmi Prakya
Bulletin of Faculty of Pharmacy, Cairo University. 2016;
[Pubmed] | [DOI]
2 Highly Selective Sensing Platform Utilizing Graphene Oxide and Multiwalled Carbon Nanotubes for the Sensitive Determination of Tramadol in the Presence of Co-Formulated Drugs
Mona A. Mohamed,Shimaa A. Atty,Nahla N. Salama,Craig E. Banks
Electroanalysis. 2016;
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and Me...
Results and Disc...
Conclusions
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed8417    
    Printed261    
    Emailed0    
    PDF Downloaded570    
    Comments [Add]    
    Cited by others 2    

Recommend this journal