Korean J Pain.  2025 Apr;38(2):103-115. 10.3344/kjp.24316.

Physicochemical stability of mixtures of nonsteroidal anti-inflammatory drugs such as ketorolac and diclofenac and antiemetics such as ondansetron and ramosetron: an in vitro study

• Lee CH

• KMID: 2566643
• DOI: http://doi.org/10.3344/kjp.24316

Abstract

Background
Drugs administered intravenously during the postoperative period can mix before entering the bloodstream. This study assessed the stability of mixtures of non-steroidal anti-inflammatory drugs (ketorolac and diclofenac) and antiemetics (ondansetron and ramosetron) to determine their suitability for concurrent administration.
Methods
Ketorolac or diclofenac was combined with ondansetron or ramosetron at a 1:1 volume ratio. Each mixture was stored in a propylene syringe at 24°C for 2 hours. The mixtures were assessed visually, and the pH was measured. Additionally, the drug concentrations were determined using high-performance liquid chromatography (HPLC).
Results
Mixtures of ketorolac or diclofenac and ramosetron showed no crystal formation or pH changes, and HPLC analysis confirmed that the drug concentrations remained stable. In contrast, mixtures of ketorolac or diclofenac and ondansetron exhibited the visible formation of 10–50 μm crystals under a microscope. However, there were no changes in the pH levels, and HPLC analysis indicated that the drug concentrations remained stable for both the mixtures.
Conclusions
Mixtures of ketorolac or diclofenac and ramosetron demonstrated physical and chemical stability for up to 2 hours, indicating that their concurrent use is feasible. Conversely, mixtures of ketorolac or diclofenac and ondansetron should be avoided due to the formation of crystals, even though the concentration of each drug remained stable.

Keyword

Chromatography; High Pressure Liquid; Crystallization; Diclofenac; Drug Stability; Ketorolac; Ondansetron

Figure

• 

  Fig. 1 Macroscopic and microscopic images of a mixture of ketorolac or diclofenac and ramosetron over time, shown against a black and white background: (A) ketorolac and ramosetron 2 hr after mixing on a black background, (B) diclofenac and ramosetron 2 hr after mixing on a black background, (C) ketorolac and ramosetron 2 hr after mixing on a white background, (D) diclofenac and ramosetron 2 hr after mixing on a white background, (E) microscopic images of a mixture of ketorolac and ramosetron 2 hr after mixing, and (F) microscopic images of a mixture of diclofenac and ramosetron 2 hr after mixing.

• 

  Fig. 2 Macroscopic photographs of mixtures of ketorolac or diclofenac and ondansetron over time, shown against a black and white background: (A) ketorolac and ondansetron immediately after mixing on a black background, (B) ketorolac and ondansetron 1 hr after mixing on a black background, (C) ketorolac and ondansetron 2 hr after mixing on a black background, (D) diclofenac and ondansetron immediately after mixing on a black background, (E) diclofenac and ondansetron 1 hr after mixing on a black background, (F) diclofenac and ondansetron 2 hr after mixing on a black background, (G) ketorolac and ondansetron immediately after mixing on a white background, (H) ketorolac and ondansetron 1 hr after mixing on a white background, (I) ketorolac and ondansetron 2 hr after mixing on a white background, (J) diclofenac and ondansetron immediately after mixing on a white background, (K) diclofenac and ondansetron 1 hr after mixing on a white background, and (L) diclofenac and ondansetron 2 hr after mixing on a white background.

• 

  Fig. 3 Microscopic photographs of mixtures of ketorolac or diclofenac and ondansetron over time: (A) ketorolac and ondansetron immediately after mixing, (B) ketorolac and ondansetron 1 hr after mixing, (C) ketorolac and ondansetron 2 hr after mixing, (D) diclofenac and ondansetron immediately after mixing, (E) diclofenac and ondansetron 1 hr after mixing, and (F) diclofenac and ondansetron 2 hr after mixing.

• 

  Fig. 4 Chromatograms of each of the four mixtures immediately after mixing: (A) ketorolac and ondansetron, ultraviolet–visible light detector wavelength 290 nm; (B) diclofenac and ondansetron, ultraviolet–visible light detector wavelength 290 nm; (C) ketorolac and ramosetron, ultraviolet–visible light detector wavelength 310 nm; and (D) diclofenac and ramosetron, ultraviolet–visible light detector wavelength 310 nm.

• 

  Fig. 5 Rates of change in the concentration of each drug in the four mixtures over time: (A) ketorolac and ondansetron, (B) diclofenac and ondansetron, (C) ketorolac and ramosetron, and (D) diclofenac and ramosetron.

• 

  Fig. 6 Calibration curves for each drug: (A) ketorolac, (B) diclofenac, (C) ondansetron, and (D) ramosetron.

Reference

1. Brooks PM, Day RO. 1991; Nonsteroidal antiinflammatory drugs--differences and similarities. N Engl J Med. 324:1716–25. Erratum in: N Engl J Med 1991; 325: 747. DOI: 10.1056/NEJM199106133242407. PMID: 2034249.

2. Thapa P, Euasobhon P. 2018; Chronic postsurgical pain: current evidence for prevention and management. Korean J Pain. 31:155–73. DOI: 10.3344/kjp.2018.31.3.155. PMID: 30013730. PMCID: PMC6037807.

3. Kim M, Park SK, Kim WM, Kim E, Kim H, Park JM, et al. 2024; Updated guidelines for prescribing opioids to treat patients with chronic non-cancer pain in Korea: developed by committee on hospice and palliative care of the Korean Pain Society. Korean J Pain. 37:119–31. DOI: 10.3344/kjp.24022. PMID: 38557654. PMCID: PMC10985489.

4. Kim KH, Seo HJ, Abdi S, Huh B. 2020; All about pain pharmacology: what pain physicians should know. Korean J Pain. 33:108–20. DOI: 10.3344/kjp.2020.33.2.108. PMID: 32235011. PMCID: PMC7136290.

5. Park I, Hong S, Kim SY, Hwang JW, Do SH, Na HS. 2024; Reduced side effects and improved pain management by continuous ketorolac infusion with patient-controlled fentanyl injection compared with single fentanyl administration in pelviscopic gynecologic surgery: a randomized, double-blind, controlled study. Korean J Anesthesiol. 77:77–84. DOI: 10.4097/kja.23217. PMID: 37312413. PMCID: PMC10834721.

6. American Society of Anesthesiologists Task Force on Acute Pain Management. 2012; Practice guidelines for acute pain management in the perioperative setting: an updated report by the. Anesthesiology. 116:248–73. DOI: 10.1097/ALN.0b013e31823c1030. PMID: 22227789.

7. Lenz H, Raeder J. 2008; Comparison of etoricoxib vs. ketorolac in postoperative pain relief. Acta Anaesthesiol Scand. 52:1278–84. DOI: 10.1111/j.1399-6576.2008.01760.x. PMID: 18823469.

8. Beverly A, Kaye AD, Ljungqvist O, Urman RD. 2017; Essential elements of multimodal analgesia in enhanced recovery after surgery (ERAS) guidelines. Anesthesiol Clin. 35:e115–43. DOI: 10.1016/j.anclin.2017.01.018. PMID: 28526156.

9. Chen JY, Ko TL, Wen YR, Wu SC, Chou YH, Yien HW, et al. 2009; Opioid-sparing effects of ketorolac and its correlation with the recovery of postoperative bowel function in colorectal surgery patients: a prospective randomized double-blinded study. Clin J Pain. 25:485–9. DOI: 10.1097/AJP.0b013e31819a506b. PMID: 19542795.

10. Heo DY, Hwang BM. 2014; Intravenous patient-controlled analgesia has a positive effect on the prognosis of delirium in patients undergoing orthopedic surgery. Korean J Pain. 27:271–7. DOI: 10.3344/kjp.2014.27.3.271. PMID: 25031814. PMCID: PMC4099241.

11. Lee SY, Lee WH, Lee EH, Han KC, Ko YK. 2010; The effects of paracetamol, ketorolac, and paracetamol plus morphine on pain control after thyroidectomy. Korean J Pain. 23:124–30. DOI: 10.3344/kjp.2010.23.2.124. PMID: 20556214. PMCID: PMC2886239.

12. Kamel EZ, Abd-Elshafy SK, Sayed JA, Mostafa MM, Seddik MI. 2018; Pain alleviation in patients undergoing cardiac surgery; presternal local anesthetic and magnesium infiltration versus conventional intravenous analgesia: a randomized double-blind study. Korean J Pain. 31:93–101. DOI: 10.3344/kjp.2018.31.2.93. PMID: 29686807. PMCID: PMC5904353.

13. Gan TJ. 2010; Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin. 26:1715–31. DOI: 10.1185/03007995.2010.486301. PMID: 20470236.

14. Park CG, Kim JS, Lee WH. 2006; The effect of stellate ganglion block for controlling postoperative pain after the shoulder joint surgery. Korean J Pain. 19:197–201. DOI: 10.3344/kjp.2006.19.2.197.

15. Ramesh ST, Asad M, Dhamanigi SS, Prasad VS. 2009; Effect of central administration of ondansetron, a 5-hydroxytryptamine-3 receptor antagonist on gastric and duodenal ulcers. Fundam Clin Pharmacol. 23:303–9. DOI: 10.1111/j.1472-8206.2009.00668.x. PMID: 19527299.

16. Lee MJ, Lee KC, Kim HY, Lee WS, Seo WJ, Lee C. 2015; Comparison of ramosetron plus dexamethasone with ramosetron alone on postoperative nausea, vomiting, shivering and pain after thyroid surgery. Korean J Pain. 28:39–44. DOI: 10.3344/kjp.2015.28.1.39. PMID: 25589945. PMCID: PMC4293505.

17. Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, et al. 2020; Fourth consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 131:411–48. Erratum in: Anesth Analg 2020; 131: e241. DOI: 10.1213/ANE.0000000000005245. PMID: 33094991.

18. Chatterjee S, Rudra A, Sengupta S. 2011; Current concepts in the management of postoperative nausea and vomiting. Anesthesiol Res Pract. 2011:748031. DOI: 10.1155/2011/748031. PMID: 22110499. PMCID: PMC3216269.

19. Hwang BM, Yang HS, Hahm KD, Leem JG. 2004; The effect of the granisetron and ramosetron on the prevention of postoperative nausea and vomiting during intravenous patient controlled analgesia with fentanyl after total knee replacement surgery. Korean J Pain. 17:222–7. DOI: 10.3344/jkps.2004.17.2.222.

20. Lee KH, Shin HS, Jeon YH, Kim SO, Hong JG. 2001; Comparison of ondansetron with ondansetron and dexamethasone in preventing of PONV in major gynecologic surgery. Korean J Pain. 14:76–82.

21. Heo BH, Park JH, Choi JI, Kim WM, Lee HG, Cho SY, et al. 2015; A comparative efficacy of propacetamol and ketorolac in postoperative patient controlled analgesia. Korean J Pain. 28:203–9. DOI: 10.3344/kjp.2015.28.3.203. PMID: 26175881. PMCID: PMC4500785.

22. Lee HM, Kil HK, Koo BN, Song MS, Park JH. 2020; Comparison of sufentanil- and fentanyl-based intravenous patient-controlled analgesia on postoperative nausea and vomiting after laparoscopic nephrectomy: a prospective, double-blind, randomized-controlled trial. Int J Med Sci. 17:207–13. DOI: 10.7150/ijms.39374. PMID: 32038104. PMCID: PMC6990885.

23. Oduyale MS, Patel N, Borthwick M, Claus S. 2020; Co-administration of multiple intravenous medicines: intensive care nurses' views and perspectives. Nurs Crit Care. 25:156–64. DOI: 10.1111/nicc.12497. PMID: 31950570.

24. Gikic M, Di Paolo ER, Pannatier A, Cotting J. 2000; Evaluation of physicochemical incompatibilities during parenteral drug administration in a paediatric intensive care unit. Pharm World Sci. 22:88–91. DOI: 10.1023/A:1008780126781. PMID: 11028261.

25. Trissel LA. 2011. Handbook on inject able drugs. 16th ed. American Society of Health System Pharmacists.

26. Collins JL, Lutz RJ. 1991; In vitro study of simultaneous infusion of incompatible drugs in multilumen catheters. Heart Lung. 20:271–7.

27. Steadman E, Raisch DW, Bennett CL, Esterly JS, Becker T, Postelnick M, et al. 2010; Evaluation of a potential clinical interaction between ceftriaxone and calcium. Antimicrob Agents Chemother. 54:1534–40. DOI: 10.1128/AAC.01111-09. PMID: 20086152. PMCID: PMC2849391.

28. Tissot E, Cornette C, Limat S, Mourand JL, Becker M, Etievent JP, et al. 2003; Observational study of potential risk factors of medication administration errors. Pharm World Sci. 25:264–8. DOI: 10.1023/B:PHAR.0000006519.44483.a0. PMID: 14689814.

29. Braun Hospital Guidlines Drug Incompatibility. Prevention of risk in infusion therapy [Internet]. B. Braun SE;https://www.safeinfusiontherapy.com.

30. Trissel LA, Martinez JF. 1993; Physical compatibility of melphalan with selected drugs during simulated Y-site administration. Am J Hosp Pharm. 50:2359–63. DOI: 10.1093/ajhp/50.11.2359.

31. United States Pharmacopeial Convention. 2007. The United States pharmacopeia, 30th rev., and the national formulary. 25th ed. United States Pharmacopeial Convention.

32. Food and Drug Administration. 1997. Q2B validation of analytical procedures: methodology. Food and Drug Administration;https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q2b-validation-analytical-procedures-methodology.

33. Hu HX, Yao JC, Song HY. 2013; Compatible changes of dezocine injection mixed with ketorolac tromenthamine injection and the analgesic test. Chin Hosp Pharm J. 33:2050–3.

34. Song F. 2008; Compatibility of ramosetron hydrochloride for injection with 4 kinds of injections. Anhui Med Pharm J. 12:15–6.

35. Xia J, Chen P. 2020; Stability and compatibility of ramosetron with midazolam in 0.9% sodium chloride injection for postoperative nausea and vomiting administration. Drug Des Devel Ther. 14:1169–76. DOI: 10.2147/DDDT.S244439. PMID: 32256048. PMCID: PMC7085948.

36. Guo Z, Chen P. 2022; Physical compatibility and chemical stability of dezocine and ramosetron in 0.9% sodium chloride injection for patient-controlled analgesia administration. Medicine (Baltimore). 101:e31546. DOI: 10.1097/MD.0000000000031546. PMID: 36397408. PMCID: PMC9666202.

37. Cabrera J, Mancuso M, Cabrera-Fránquiz F, Limiñana J, Díez A. 2011; Stability and compatibility of the mixture of tramadol, ketorolac, metoclopramide and ranitidine in a solution for intravenous perfusion. Farm Hosp. 35:80–3. DOI: 10.1016/S2173-5085(11)70013-2.

38. Devarajan PV, Gore SP, Chavan SV. 2000; HPTLC determination of ketorolac tromethamine. J Pharm Biomed Anal. 22:679–83. DOI: 10.1016/S0731-7085(99)00296-4. PMID: 10768358.

39. Kim YS, Lee CH, Kim AR, Choi SS, Lee MK, Kim H, et al. 2021; Microbiological and physicochemical stability of fentanyl, oxycodone, hydromorphone, ketorolac, ramosetron, and ondansetron for intravenous patient-controlled analgesia: an in vitro study. Pain Physician. 24:E829–37. DOI: 10.36076/ppj.2021.24.E829.

40. Hwang H, Park J, Lee WK, Lee WH, Leigh JH, Lee JJ, et al. 2016; Crystallization of local anesthetics when mixed with corticosteroid solutions. Ann Rehabil Med. 40:21–7. DOI: 10.5535/arm.2016.40.1.21. PMID: 26949665. PMCID: PMC4775754.

41. Kim H, Choi SS, Kang TH, Byun SY, Lee CH. 2024; Physicochemical stability and compatibility of mixtures of ropivacaine with dexamethasone or betamethasone for epidural steroid injections: an in vitro study. Pain Physician. 27:E89–98. DOI: 10.36076/ppj.2024.27.E89.

42. Choi EJ, Kim DH, Han WK, Lee HJ, Kang I, Nahm FS, et al. 2021; Non-particulate steroids (betamethasone sodium phosphate, dexamethasone sodium phosphate, and dexamethasone palmitate) combined with local anesthetics (ropivacaine, levobupivacaine, bupivacaine, and lidocaine): a potentially unsafe mixture. J Pain Res. 14:1495–504. DOI: 10.2147/JPR.S311573. PMID: 34079364. PMCID: PMC8166310.

43. Fulling PD, Peterfreund RA. 2000; Alkalinization and precipitation characteristics of 0.2% ropivacaine. Reg Anesth Pain Med. 25:518–21. DOI: 10.1097/00115550-200009000-00014.

44. Brandis K. 2011; Alkalinisation of local anaesthetic solutions. Aust Prescr. 34:173–5. DOI: 10.18773/austprescr.2011.091.

45. Hoerner E, Stundner O, Putz G, Steinfeldt T, Mathis S, Gasteiger L. 2022; Crystallization of ropivacaine and bupivacaine when mixed with different adjuvants: a semiquantitative light microscopy analysis. Reg Anesth Pain Med. 47:625–9. DOI: 10.1136/rapm-2022-103610. PMID: 35738668.

46. Milner QJ, Guard BC, Allen JG. 2000; Alkalinization of amide local anaesthetics by addition of 1% sodium bicarbonate solution. Eur J Anaesthesiol. 17:38–42. DOI: 10.1046/j.1365-2346.2000.00596.x. PMID: 10758442.