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Lee: Physicochemical stability of mixtures of non-steroidal anti-inflammatory drugs such as ketorolac and diclofenac and antiemetics such as ondansetron and ramosetron: an in vitro study
Experimental Research Articles

Korean J Pain 2025;38(2):103-115.

Published online: 1 April 2025

DOI: https://doi.org/10.3344/kjp.24316.

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

Chung Hun Lee

Department of Anesthesiology and Pain Medicine, Korea University Medical Center, Guro Hospital, Seoul, Korea

Correspondence: Chung Hun Lee Department of Anesthesiology and Pain Medicine, Korea University Medical Center, Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea, Tel: +82-2-2626-1870, Fax: +82-2-2626-1438, E-mail: bodlch@naver.com

Edited by:

Handling Editor: Francis S. Nahm

Received 20 September 2024       Revised 28 December 2024       Accepted 2 January 2025

© The Korean Pain Society, 2025

(open-access):

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 11 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.

Keywords: Chromatography, High Pressure Liquid, Crystallization, Diclofenac, Drug Stability, Ketorolac, Ondansetron

INTRODUCTION

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, thereby inhibiting prostaglandin production and alleviating acute pain, inflammation, secondary hyperalgesia, and central sensitization [1,2]. Recently, multimodal analgesia has received attention in the field of postoperative pain management, particularly owing to its ability to reduce the need for opioids and their associated side effects [3,4]. The use of NSAIDs with opioid-sparing effects is strongly recommended to optimize drug efficacy while minimizing the risk of side effects [5,6]. Among the NSAIDs, COX-1 inhibitors are commonly used postoperatively because they provide pain relief with fewer cardiovascular side effects [7,8]. Ketorolac and diclofenac, notable COX-1 inhibitors with opioid-sparing effects, are widely used in clinical practice [5,7,9–14]. However, compared to COX-2 inhibitors, COX-1 inhibitors are associated with a higher incidence of nausea and a greater risk of peptic ulcers [7,8]. Antiemetics are therefore frequently used in perioperative care to manage NSAID-induced nausea, peptic ulcers [15], and postoperative nausea and vomiting (PONV) [16], which commonly occur after surgery. The use of antiemetics has recently been recommended to reduce the incidence of PONV and minimize preoperative opioid use [17,18], with 5-hydroxytryptamine 3 receptor antagonists being proposed as the gold standard for PONV management [17,18]. Among them, ondansetron and ramosetron are preferred because of their superior effectiveness [17–20]. As a result, simultaneous administration of NSAIDs and antiemetics is common [8,21,22].
The administration of each drug through separate intravenous (IV) lines or the same IV line at different times is recommended to minimize drug interactions. However, NSAIDs and antiemetics may be administered simultaneously if IV patient-controlled analgesia (PCA) is used, drugs are mixed with IV fluids, or there is only one venous access catheter [23]. Simultaneous administration can cause physical or chemical changes in each drug, potentially altering their therapeutic properties and causing unknown side-effects [24,25]. These physicochemical reactions may impair drug efficacy or, in the event of crystal formation, cause IV catheter occlusion, toxic compound formation, embolism, or local/systemic inflammatory reactions, potentially resulting in life-threatening pulmonary embolism [25–29].
The purpose of this study was to determine the in vitro physicochemical stability of a mixture of NSAIDs, such as ketorolac or diclofenac—known for their opioid-sparing effects and increasing use in pain management—and antiemetics, such as ondansetron or ramosetron, which are regarded as the gold standard for PONV control.

MATERIALS AND METHODS

1. Materials

Ketorolac tromethamine (Kerola injection, 30 mg/mL, 1 mL; Dong Kwang Pharm Co., Ltd.), diclofenac sodium (Diclofenac injection, 37.5 mg/mL, 2 mL; Guju Pharm Co., Ltd.), ondansetron hydrochloride (Ondansetron injection, 2.5 mg/mL, 4 mL; Hana Pharm Co., Ltd.), and ramosetron hydrochloride (Nasea injection, 0.15 mg/mL, 2 mL; Astellas Pharma, Inc.) were commercially obtained (Table 1).
Additionally, 0.9% normal saline (isotonic sodium chloride, 20 mL/ampule; Dai Han Pharm, Co., Ltd.) was prepared, and polypropylene syringes were used to store the mixed drugs.

2. Drug mixture preparation

Four drug mixtures were prepared, each containing a 1:1 mixture of ketorolac or diclofenac with either ondansetron or ramosetron stock solutions (Table 2). The concentrations of each drug in the mixtures were as follows: ketorolac, 15 mg/mL; diclofenac, 18.75 mg/mL; ondansetron, 1.25 mg/mL; and ramosetron, 0.075 mg/mL.
The mixtures were stored in propylene syringes commonly used in clinical practice. The propylene syringes containing the drug mixtures were stored at a constant temperature of 24°C and exposed to light to simulate clinical conditions.
To ensure accuracy of the analysis, five mixtures of each combination were prepared, yielding a total of 20 drug mixtures. All mixtures were prepared under aseptic conditions using surgical masks, caps, overshoes, gowns, and sterile gloves.

3. Evaluating drug mixture stability

1) Physical study

Samples (2 mL) were taken from each mixture immediately after mixing, as well as 1 hour and 2 hours later, and placed in colorless silicate glass test tubes. Color, turbidity, and precipitation were visually inspected against white and black backgrounds. Additionally, the presence of fine crystals was determined and crystal size was measured using an optical microscope (Olympus BX51; Olympus Corp.) at a magnification of ×200. Optical microscopy was performed after directly transferring the sample from the stored propylene syringe onto a glass slide. The physical stability of the mixture was defined as the preservation of the transparent, colorless, and particle-free properties of the original solution [30].

2) Chemical study

(1) pH

The pH of the samples was measured at three time-points: immediately after mixing, and 1 hour and 2 hours post-mixing, using a PHS-3C digital pH meter (Orion Star A212; Thermo Fisher Scientific). Data from five replicates of each mixture were used to calculate the mean and standard deviation of the pH values at each time point.

(2) Evaluating drug concentrations

High-performance liquid chromatography (HPLC) was used to measure the drug concentrations in each mixture to determine whether the original drug concentrations were maintained and to identify any decomposition peaks. Prior to mixture analysis, HPLC was also performed on the individual drug components to identify their respective peaks.
Samples (10 μL) were collected from all mixtures immediately after mixing and at 1 hour and 2 hours post-mixing. Reversed-phase HPLC was performed using an Agilent Technologies 1200 Series HPLC system (Agilent Technologies), consisting of a G1311A quaternary pump, G1322A vacuum degasser, G1329A autosampler, and G1315C ultraviolet–visible light detector. The system was operated with an Agilent Technologies software program. HPLC separation was carried out using a Luna 5 μm C18 column (inner diameter, 250 × 10 mm). The eluent comprised a gradient of 0.05% trifluoroacetic acid in water and 0.05% trifluoroacetic acid in acetonitrile, at a flow rate of 2 mL/min. The flow conditions were as follows: from 0 to 30 minutes, the acetonitrile concentration was increased from 30 to 70%, and from 30 to 50 minutes, the eluent consisted of 10% water and 90% acetonitrile. The ultraviolet–visible light detector wavelengths were set at 270, 290, and 310 nm for the detection of each drug. The column was maintained at room temperature, and the injection volume was 10 μL. For each mixture, the concentration of each drug immediately after mixing was set to 100, and the change in drug concentration over time was calculated. Data from the five replicates of each combination were used to calculate the mean and standard deviation of the concentration change ratio over time. Concentration stability was defined as maintaining 90%–110% of the initial drug concentration, according to the current United States Pharmacopeial Convention Monograph [31].

4. Analytic validation

According to the guidelines developed by the International Conference on Harmonization [32], the validation of analytical techniques must include the demonstration of linearity, accuracy, and repeatability.

1) Linearity

The relationship between the peak area of each drug and amount of drug applied was determined using linear regression analysis over a predefined range. Accuracy was determined using the calibration curve by analyzing four different concentrations of each drug.

2) Accuracy

Accuracy was assessed by calculating the relative standard deviation (RSD) or coefficient of variation of accuracy (CVa). This involved comparing theoretical concentrations derived from four different drug concentrations, each measured four times, with the experimental concentrations obtained from the mixture. The CVa was calculated for each drug in each combination using the following formula: CVa = RSD × 100.

3) Repeatability

Visual and microscopic confirmation of crystal formation, pH analysis, and HPLC analysis were performed by the same investigator using the same equipment, laboratory, and procedures. The analysis of the homogeneous mixture was repeated five times in the same manner, and the RSD was calculated using the mean and standard deviation of the repeated values. This is expressed as the coefficient of variation of repeatability (CVr). The CVr was calculated for each drug in each combination using the following formula: CVr = RSD × 100.

RESULTS

1. Physical stability

Mixtures of ketorolac or diclofenac and ramosetron remained colorless and transparent for up to 2 hours, with no noticeable particles or sediments observed under the microscope (Fig. 1). Mixtures of ketorolac or diclofenac and ondansetron formed noticeable particles within 2 hours after mixing (Fig. 2). Microscopic observation of the mixtures of ketorolac or diclofenac and ondansetron revealed the formation of crystals 10–20 μm in size immediately post-mixing. The size of these crystals increased with time, with some of them measuring 50 μm after 2 hours (Fig. 3).
As no evidence of incompatibility (precipitation, turbidity, color change, or opacity) was observed in the mixtures of ketorolac or diclofenac and ramosetron, they can be regarded as physically compatible (Supplementary File 1, 2).

2. Chemical stability

The pH changed by less than 0.16 in all drug mixtures at all time points. This represented a difference of less than 3% compared with the pH value immediately after mixing. No acidification or alkalinization was observed over time (Table 3, Supplementary File 3).
All drugs were successfully separated using HPLC. The concentration of each drug in the mixtures was determined by integrating the surface areas of the chromatographic peaks. The retention times of ketorolac, diclofenac, ondansetron, and ramosetron were approximately 17.7, 25.3, 9.0, and 9.2 minutes, respectively (Fig. 4).
For each mixture, the concentration of each drug immediately after mixing was set to 100, and the change ratio over time was calculated. The average change ratio over time is shown in Fig. 5.
As presented in Fig. 5, the concentration of each drug in the mixtures (ketorolac, diclofenac, ondansetron, and ramosetron) remained between 90% and 110% of the initial concentration for up to 2 hours after mixing. No decomposition peaks were detected (Supplementary File 4).

3. Analytic validation

Calibration was performed using a linear regression analysis of each drug concentration (Supplementary File 5, 6). The equations were as follows: for ketorolac, y = 2,008.9 (x) – 343.1, with a calculated average R2 of 0.9993; for diclofenac, y = 908.3 (x) – 4.9, with a calculated average R2 of 0.9974; for ondansetron, y = 471.7 (x) – 9.5, with a calculated average R2 of 0.9999; and for ramosetron, y = 34.8 (x) – 0.8, with a calculated average R2 of 0.9999 (Fig. 6).
All drugs demonstrated a strong linear response and excellent correlation coefficient (R2) between the peak area and concentration, enabling accurate estimation of drug concentrations in the mixtures.
The accuracy of the method was demonstrated by the close average and RSD values of less than 1% across the four analyses of the four drug concentrations. The CVa between the calculated theoretical and experimental concentrations was 1.7%–1.8% for ketorolac (accuracy: 98.3%), 0.2% for diclofenac (accuracy: 99.8%), 0.8%–1.2% for ondansetron (accuracy: 98.8%), and 0.3%–0.4% for ramosetron (accuracy: 99.6%). The CVa was less than 1.8% for all drugs in all combinations.
The CVr for each drug was calculated using the values obtained from five replicates of the four mixture combinations. The CVr values for each drug were 2.1%–2.4% for ketorolac (accuracy: 97.6%), 1.2%–2% for diclofenac (accuracy: 98%), 1%–1.6% for ondansetron (accuracy: 98.4%), and 0.6%–1.9% for ramosetron (accuracy: 98.1%). For all drugs in all combinations, the CVr was less than 2.4%.

DISCUSSION

This study assessed the physicochemical stability of mixtures of NSAIDs (ketorolac or diclofenac) and antiemetics (ondansetron or ramosetron). No crystal formation was observed visually or microscopically in the mixtures of ketorolac or diclofenac and ramosetron when stored for up to 2 hours after mixing. Additionally, no significant changes were noted in the pH levels. HPLC analysis confirmed the stability of the drug concentrations in these mixtures for up to 2 hours, providing evidence of physicochemical stability. In contrast, the mixtures of ketorolac or diclofenac and ondansetron exhibited formation of crystals measuring 10–50 μm in size, which were observed microscopically immediately after mixing up to 2 hours after mixing. However, no significant changes in pH were observed and HPLC analysis confirmed that the concentrations of the two drug components in each mixture were stable for up to 2 hours after mixing.
Patients receive multiple medications during perioperative care, with the number of IV drugs prescribed often exceeding the number of available venous access sites. A Y-site connector or staggered administration can be used to separate the drugs. However, a continuously administered medication may be mixed with additional medications administered intermittently. This mixing of medications before entry into the bloodstream introduces the risk of physicochemical incompatibility [23]. Given the lack of definitive evidence supporting specific combinations or routes of administration, the benefits and risks to patients must be assessed on a case-by-case basis, and compatibility must be ensured prior to the concurrent administration of medications. This study aimed to address this information gap.
Studies on the physicochemical stability of NSAIDs, antiemetics, individual drugs, and other drug mixtures have been conducted sporadically. Hu et al. [33] reported that dezocine and ketorolac tromethamine remained physicochemically stable for up to 12 hours at room temperature when mixed in 0.9% sodium chloride. Song [34] reported that ramosetron hydrochloride, when injected at a concentration of 0.3 mg/100 mL in 5% glucose solution, remained stable for 10 hours at room temperature. Xia and Chen [35] reported that a mixture of ramosetron hydrochloride and midazolam hydrochloride was stable for 14 days at room temperature or in a refrigerator. Guo and Chen [36] demonstrated that dezocine and ramosetron mixed in 0.9% sodium chloride were stable when stored for 14 days. Additionally, an IV perfusion mixture containing tramadol, ranitidine, ketorolac, and metoclopramide in a 0.9% sodium chloride solution was subjected to visual inspection and drug concentration analysis after 48 hours at room temperature and was reported to be stable [37].
Although most studies on drug mixtures have reported stability under clinical and laboratory conditions, some have indicated that NSAIDs may be unstable in mixtures depending on the solution. Devarajan et al. [38] reported that ketorolac may become unstable due to acid-base reactions when mixed with drugs in an acidic environment, as ketorolac generates byproducts when mixed with hydrochloric acid. A study in 2021 that examined the stability of a PCA mixture for postoperative pain relief reported that when fentanyl, oxycodone, or ketorolac were combined with ondansetron or ramosetron, the concentration of ketorolac in the mixture decreased by more than 10% after 24 hours [39]. This decrease was attributed to the pH of the drug mixture, as ketorolac concentration decreased only in low-pH environments. These results are consistent with those of previous studies that identified pH variations as a primary factor contributing to the physicochemical instability of drug mixtures [38–40].
However, the same study of PCA mixtures reported no crystal formation upon microscopic examination [39]. The absence of visible crystals may be due to the decomposition products being diluted within the mixture or not passing through the filter of the portable balloon injection device. In contrast, the present study investigated the physicochemical stability of drug mixtures stored in syringes, similar to the conditions encountered in the clinic, without employing a filter to remove the crystals. Unlike previous studies, the present study found crystal formation in mixtures of ketorolac or diclofenac with ondansetron both visually and microscopically. However, the concentration of each drug in the mixture remained stable for up to 2 hours after mixing.
To explain this, the authors propose the following hypotheses. First, the concentration of each drug may have changed immediately after mixing, and subsequently remained stable. However, this is unlikely as the CVa of the drug concentrations was less than 5% for all drugs. The second hypothesis posits that crystal formation in the drug mixtures may have resulted from interactions between excipients rather than between the main drugs. The ondansetron preparation used in this study contained additives such as hydrochloric acid, sodium citrate hydrate, citric acid hydrate, and sodium chloride, while ramosetron contained hydrochloric acid, lactic acid, and sodium hydroxide. In addition, ketorolac contained additives such as sodium hydroxide, sodium chloride, and ethanol, while diclofenac contained benzyl alcohol, sodium hydroxide, and sodium bisulfite. The variations between the additives in ondansetron and ramosetron may have led to different reactions with the additives in ketorolac and diclofenac. However, direct evidence supporting this hypothesis has not yet been reported. This hypothesis needs to be verified through a physicochemical stability study of the drug, including the excipients. Previous studies support the notion that the presence of additives can affect drug stability. In 2024, Kim et al. [41] suggested that interactions between additives and ropivacaine could not be solely explained by acid-base reactions in their study of a mixture involving ropivacaine, dexamethasone, and betamethasone. They hypothesized that the concentration of acidic ropivacaine hydrochloride decreased in the more acidic mixture of betamethasone and ropivacaine, but the concentration of ropivacaine did not decrease in the more basic mixture of dexamethasone and ropivacaine, which may be due to the preservative additionally included in betamethasone [41]. However, this study did not provide direct evidence of an interaction between the excipient and ropivacaine; therefore, further studies are needed to confirm this hypothesis.
The third hypothesis posits that the observed differences in results may be attributed to the study duration. The previous study by Kim et al. [39] observed a decrease in the ketorolac concentration in an IV PCA mixture of more than 10% after 24 hours. However, as the present study did not involve IV PCA, the authors focused on determining the stability of the drug mixture when mixed with fluids or directly injected as a bolus into the venous access catheter. Consequently, the stability of the mixture was observed for only 2 hours after mixing, which may have been too early to detect a gradual decrease in concentration.
Additional analyses of mixtures of ketorolac, diclofenac, ondansetron, and ramosetron obtained from various manufacturers with different preservatives; stability studies of different preservatives; and studies with durations of at least 24 hours are necessary to test these hypotheses.
Previous drug mixture studies have often inferred instability from changes in pH along with visual and microscopic observations of crystal formation [40,42–46]. Conversely, no changes were founds in pH. However, the chemical characteristics of the mixture (e.g., pH) can be useful in predicting drug incompatibility, although visual monitoring of precipitate formation is still necessary.
Some limitations of this study should be considered when interpreting the results. This in vitro study showed that mixtures of ketorolac or diclofenac and ramosetron were physicochemically stable for up to 2 hours after mixing. Therefore, this study does not reflect long-term mixing conditions, such as those observed in IV PCA, but rather represents a short-term mixing environment that may occur during a bolus infusion. In addition, in vitro stability does not prove that the pharmacokinetics and pharmacodynamics remain unchanged in vivo. Clinical trials are required to confirm the in vivo pharmacokinetic and pharmacodynamic properties of these drugs. The second limitation is that the purpose of this study was to examine the physicochemical stability of two drug mixtures; therefore, the study was conducted using a 1:1 drug mixture ratio. However, in actual clinical practice, various drug mixtures may be used, and the physicochemical stability results observed in this study may not apply to mixtures with other ratios. Consequently, future studies should evaluate the stability of drug mixtures commonly used in actual clinical practice.
The results of this study suggest that mixtures of ketorolac or diclofenac with ramosetron are physically and chemically stable. The combination of ketorolac or diclofenac with ondansetron should be avoided because of potential crystal formation, which is observable both visually and microscopically, despite the fact that the concentration of each drug remained stable. However, since this study was conducted in a laboratory setting, caution is advised when applying its findings directly to clinical practice. Additional research is needed to determine the cause of the instability in mixtures of ketorolac or diclofenac and ondansetron.

ACKNOWLEDGMENTS

The authors express their deepest gratitude to Choi Yun-Hyeok of the Gyeonggi Economic Science Promotion Agency for his invaluable assistance with HPLC. Additionally, we thank Editage (www. editage.co.kr) for providing excellent English language editing assistance.

Notes

DATA AVAILABILITY

The datasets generated and analyzed in this study are available in the OSF repository (https://osf.io/ujzp7/). These datasets have also been submitted along with the manuscript as additional supporting information. Supporting Information files: Supplementary file 1: Images from the visual observation of all mixtures; Supplementary file 2: Optical microscopy images for all mixtures; Supplementary file 3: pH values at each time point for all mixtures; Supplementary file 4: Concentration of each drug in all mixtures over time; Supplementary file 5: Calibration curve for the calibration of each drug concentration; Supplementary file 6: Chromatograms of each drug before mixing.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Chung Hun Lee: Writing/manuscript preparation.

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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.
kjp-38-2-103-f1.tif
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.
kjp-38-2-103-f2.tif
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.
kjp-38-2-103-f3.tif
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.
kjp-38-2-103-f4.tif
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.
kjp-38-2-103-f5.tif
Fig. 6
Calibration curves for each drug: (A) ketorolac, (B) diclofenac, (C) ondansetron, and (D) ramosetron.
kjp-38-2-103-f6.tif
Table 1
Concentration, chemical formula, molecular weight, and pH of the drugs
Drug Concentration before mixing (mg/mL) Chemical formula Molecular weight
(g/mol)		 pH
Ketorolac tromethamine 30 C15H13NO3 255 6.61
Diclofenac sodium 37.5 C14H11Cl2NO2 296 7.63
Ondansetron hydrochloride 2.5 C18H19N3O 293 2.85
Ramosetron hydrochloride 0.15 C17H17N3O 279 3.89
Table 2
Drug combinations evaluated in this study
Mixture Analgesic (non-steroidal anti-inflammatory drug) Antiemetic Total volume (mL) (mixing ratio)
Mixture 1 Ketorolac 4 mL Ondansetron 4 mL 8 mL (1:1)
Mixture 2 Ketorolac 4 mL Ramosetron 4 mL 8 mL (1:1)
Mixture 3 Diclofenac 4 mL Ondansetron 4 mL 8 mL (1:1)
Mixture 4 Diclofenac 4 mL Ramosetron 4 mL 8 mL (1:1)
Table 3
pH values of the drug mixtures
Mixture Mixture contents Time after mixing
Immediately 1 hr 2 hr
Mixture 1 Ketorolac + Ondansetron 5.85 ± 0.05
(100)		 5.88 ± 0.06
(100.59 ± 0.01)		 5.86 ± 0.02
(100.28 ± 0.01)
Mixture 2 Ketorolac + Ramosetron 6.47 ± 0.11
(100)		 6.41 ± 0.07
(99.11 ± 0.01)		 6.44 ± 0.08
(99.48 ± 0.01)
Mixture 3 Diclofenac + Ondansetron 7.20 ± 0.05
(100)		 7.19 ± 0.04
(99.95 ± 0.01)		 7.13 ± 0.01
(99.00 ± 0.01)
Mixture 4 Diclofenac + Ramosetron 7.47 ± 0.08
(100)		 7.63 ± 0.03
(102.12 ± 0.01)		 7.54 ± 0.06
(100.91 ± 0.01)

Measured pH values are expressed as the mean ± standard deviation. The values in parentheses represent relative pH changes, calculated by setting the pH measured immediately after mixing as the 100% reference point.

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