Stability and Compatibility of an Admixture Containing Hydromorphone, Bupivacaine, and Dexamethasone in 0.9% Sodium Chloride Injection for Intrathecal Analgesia

Introduction

Pain is often considered the most unbearable symptom among patients. Effective pain control facilitates earlier mobilization and faster recovery while shortening hospitalization and reducing treatment costs [1,2]. Several analgesic strategies, such as oral opioids, intrathecal morphine, local infiltration analgesia, and subcutaneous infusion of analgesics, have been widely adopted in clinical practice for pain control [3–5]. Among these strategies, intrathecal delivery of analgesics through implantable infusion pumps has become an effective option for refractory pain (eg, cancer-related pain) over the past few decades [6–8]. The intrathecal route can substantially improve the therapeutic index of analgesics relative to systemic administration alone. Additionally, intrathecal drug administration is relatively simple to perform and leads to fewer systemic side effects [9,10]. Continuous intrathecal analgesia provides long-term effective pain management and has been widely utilized to manage cancer-related and refractory non-cancer pain [11–13].

At present, opioids and local anesthetics represent the mainstay of intrathecal pain management [14]. Hydromorphone hydrochloride, a commonly used intrathecal opioid, is a semisynthetic hydrogenated ketone of morphine that primarily acts on μ-opioid receptors; compared with morphine, hydromorphone has approximately 5 to 7 times greater analgesic potency in humans. Moreover, hydromorphone does not induce histamine release after intravenous administration [15,16]. These efficacy and safety features have made it an accepted alternative to morphine for the treatment of both acute and chronic pain. Bupivacaine, a local anesthetic, is frequently used in combination with intrathecal opioids to reduce the incidence of opioid-related adverse effects. Furthermore, multiple studies have demonstrated that bupivacaine can synergistically enhance the efficacy of intrathecal opioids when used in combination regimens [17–19]. Some studies have demonstrated the clinical utility of long-term intrathecal bupivacaine as an adjunct to hydromorphone in patients with refractory cancer pain. However, in certain cases, intrathecal infusion of hydromorphone and bupivacaine alone provides insufficient analgesia, particularly for patients with tumor-induced inflammatory pain. Thus, corticosteroids such as dexamethasone are often used as adjuvant analgesics to suppress the inflammatory response [20]. Given that dexamethasone has limited water solubility, the dexamethasone sodium phosphate form is used in injectable formulations.

For intrathecal drug admixtures, stability refers to the maintenance of chemical potency, physical integrity, and sterility of a drug or drug combination within the pump reservoir over a prolonged implantation period; compatibility denotes the absence of deleterious physicochemical interactions among the combined drugs and between the drugs and the materials of the pump and catheter system [21]. Such studies are essential because instability or incompatibility may lead to catheter failure, inflammatory mass formation, or the delivery of toxic degradants into the cerebrospinal fluid, posing a risk of irreversible neurological injury [22].

Several studies have evaluated the stability of hydromorphone, bupivacaine, and dexamethasone when used alone or in combination [23–27]. For example, Macorigh et al reported that a mixture of hydromorphone (15 mg/mL) and bupivacaine (10 mg/mL) remained stable for up to 3 months at 37°C [23]. Additionally, intravenous mixtures of dexamethasone sodium phosphate at concentrations ranging from 0.08 to 0.4 mg/mL were compatible with 0.9% sodium chloride injection and 5% dextrose injection in polyvinyl chloride bags [26]. However, to our knowledge, no studies have investigated the compatibility and stability of a combination of hydromorphone, bupivacaine, and dexamethasone for intrathecal administration. The chemical structure of dexamethasone contains functional groups susceptible to oxidation, as well as acid- or base-catalyzed hydrolysis [26]. Therefore, the safety of this 3-drug mixture must be evaluated before its widespread clinical use.

In this study, the compatibility and stability of a mixture of hydromorphone hydrochloride, bupivacaine hydrochloride, and dexamethasone sodium phosphate in 0.9% sodium chloride injection were evaluated under simulated intrathecal infusion conditions at 4°C, 25°C, and 37°C for 20 days, in accordance with the International Conference on Harmonisation (ICH) guideline Q1A(R2). We aimed to provide a basis and reference for clinical practice.

Material and Methods

MATERIAL AND REAGENTS:

Commercially available ampoules of hydromorphone hydrochloride injection (2 mg/2 mL; lot 33A111013) were purchased from Yichang Renfu Pharmaceutical Co., Ltd. (Hubei, China). Bupivacaine hydrochloride injection (5 mL/37.5 mg; lot 23020410) was obtained from Changjiang Pharmaceutical Co., Ltd. (Anhui, China). Dexamethasone sodium phosphate injection (1 mL/5 mg; lot 2306041) was purchased from Sinopharm Group Rongsheng Pharmaceutical Co., Ltd. (Henan, China). Reference standards of bupivacaine hydrochloride (chemical purity >98%) and dexamethasone sodium phosphate (chemical purity >98%) were supplied by Tixiai (Shanghai) Chemical Industry Development Co., Ltd. (Shanghai, China), whereas the reference standard of hydromorphone hydrochloride (chemical purity >98%) was obtained from Yichang Renfu Pharmaceutical Co., Ltd. (Hubei, China). The 0.9% sodium chloride injection (250 mL/2.25 g; lot 2401113703) was supplied by Shijiazhuang Pharmaceutical Co., Ltd. (Shijiazhuang, China) and used to prepare the sample mixtures. All other chemicals and reagents used in this study were of analytical grade or higher; they were obtained from commercial sources.

PREPARATION AND STORAGE OF ADMIXTURES:

To simulate clinically relevant concentrations, 4 mL of hydromorphone hydrochloride injection (2 mg/2 mL), 20 mL of bupivacaine hydrochloride injection (5 mL/37.5 mg), and 1 mL of dexamethasone sodium phosphate injection (1 mL/5 mg) were transferred into the reservoir of a commercially available intrathecal infusion pump (Aipeng Medical Technology Co., Ltd., Jiangsu, China). Sufficient 0.9% sodium chloride injection was then added to achieve a total volume of 150 mL. After thorough mixing, the final concentrations of the admixtures were as follows: hydromorphone hydrochloride, 0.026 mg/mL; bupivacaine hydrochloride, 1 mg/mL; and dexamethasone sodium phosphate, 0.033 mg/mL. The admixtures were prepared in triplicate under aseptic conditions and stored at 4°C, 25°C, and 37°C. The intrathecal infusion pumps were not operated during storage, and the samples were maintained under static conditions.

PHYSICAL STABILITY STUDY:

Immediately after preparation and on each study day (ie, days 0, 5, 10, 15, and 20) at all 3 temperatures, physical compatibility was assessed by visual inspection for color changes and the presence of precipitation. The pH of the admixtures was measured using a precision pH meter (Model 925, Fisher Scientific, Toronto, Canada). Each sample was analyzed in triplicate (n=3).

CHROMATOGRAPHIC CONDITIONS: To evaluate chemical stability, a high-performance liquid chromatography (HPLC) method was established and validated to determine the concentrations of the 3 components in the mixtures. HPLC analysis was performed using an Ultimate 3000 system (Thermo Fisher Scientific, Waltham, MA, USA) equipped with a quaternary pump, column compartment, autosampler, online degasser, and spectrophotometric detector. Chromatographic separation was carried out on a Diamonsil C18 column (250×4.6 mm, 5 μm), with the column temperature maintained at 30°C. The mobile phase consisted of methanol and a 1 g/L sodium heptane sulfonate aqueous solution (57: 43, v/v), adjusted to pH 2.6 with H3PO4. The flow rate was 1.0 mL/min, and the injection volume was 20 μL. The detection wavelength was set at 230 nm for all 3 analytes, in accordance with a published report [26].

ANALYTICAL METHOD VALIDATION:

The proposed method was validated according to ICH guidelines by assessing linearity, limit of detection (LOD), limit of quantitation (LOQ), accuracy, and precision for the 3 analytes. Sensitivity was evaluated by determining the LOD and LOQ, defined as signal-to-noise ratios greater than 3 and 10, respectively. Linearity was established using 5-point calibration curves over the following concentration ranges: 0.006 to 0.106 mg/mL for hydromorphone hydrochloride, 0.25 to 4 mg/mL for bupivacaine hydrochloride, and 0.008 to 0.133 mg/mL for dexamethasone sodium phosphate. Linear regression analysis was performed by plotting peak area (y) against concentration (x), and the correlation coefficient (r²) was recorded. Three quality control samples were prepared for each analyte: hydromorphone hydrochloride (0.013, 0.026, and 0.053 mg/mL), bupivacaine hydrochloride (0.5, 1, and 2 mg/mL), and dexamethasone sodium phosphate (0.016, 0.033, and 0.066 mg/mL). Accuracy was evaluated based on recovery. Precision was assessed using the relative standard deviation (%) calculated from replicate measurements (n=5) of the middle concentration quality control samples on the same day.

STABILITY STUDY:

For the stability study, samples were withdrawn from infusion devices stored at the 3 temperatures and analyzed using the validated HPLC method at predetermined time points (days 0, 1, 3, 5, 7, 9, 11, 13, 15, and 20). The concentration of each analyte was calculated using the corresponding calibration curves. Each sample was analyzed in triplicate by HPLC.

DATA ANALYSIS:

Results are expressed as mean±standard deviation. The initial concentration of each analyte on day 0 was defined as 100%. Subsequent concentrations were expressed as a percentage of the initial concentration. Chemical stability was defined as retention of 90% to 110% of the initial concentration for each component [28]. Compatibility was regarded as the absence of precipitation or changes in physical appearance.

Results

PHYSICAL STABILITY STUDY:

Visual inspection revealed no color change, turbidity, precipitation, opacity, or gas formation at any time point in the admixtures stored at 4°C, 25°C, or 37°C. Table 1 shows the changes in pH during the study period. The pH ranged from 5.52 to 6.23 at 4°C, from 5.71 to 5.93 at 25°C, and from 5.42 to 6.19 at 37°C throughout the study. The admixtures remained stable at all 3 temperatures for up to 20 days. These results indicate that the mixtures were physically compatible under the tested conditions.

VALIDATION OF THE HPLC METHOD: An HPLC method was established and validated to simultaneously quantify hydromorphone hydrochloride, bupivacaine hydrochloride, and dexamethasone sodium phosphate. Under the selected chromatographic conditions, the 3 analytes were well separated without obvious interference in their quantification. Retention times were 3.590 minutes for hydromorphone hydrochloride, 5.703 minutes for bupivacaine hydrochloride, and 14.373 minutes for dexamethasone sodium phosphate (Figure 1). The linear regression equations, correlation coefficients, LODs, and LOQs for the 3 drugs are listed in Table 2. All analytes showed good linearity over the tested concentration ranges, with correlation coefficients (r2) greater than 0.999. Calibration ranges differed among the drugs, reflecting their respective clinical concentrations. Table 3 summarizes the accuracy data. Recoveries for all 3 drugs were close to 100%. Precision also was good, with relative standard deviation values below 2.5% for hydromorphone hydrochloride and dexamethasone sodium phosphate, and below 0.5% for bupivacaine hydrochloride, indicating good repeatability. These results suggested that the HPLC method provides sufficient accuracy and precision for quantifying all 3 drugs in the mixtures.

CHEMICAL STABILITY STUDY: In the chemical compatibility assessment, as shown in Figure 2, the concentrations of hydromorphone hydrochloride in the mixtures remained greater than 98.0% of the initial concentration after storage at all 3 temperatures for 20 days. For bupivacaine hydrochloride, all samples analyzed at the predetermined time points retained concentrations greater than 99.0% of the initial value (range: 99.7–111.7%), with a slight increase observed on day 9 at 37°C, followed by a decrease to less than 110% (Figure 3). Under storage conditions of 4°C, 25°C, and 37°C, the concentration of dexamethasone sodium phosphate ranged from 100.3% to 113.8% of the initial concentration over 20 days. At 37°C, a slight increase was observed on day 9, followed by a return to the acceptable range (Figure 4). These results indicate that the mixtures remained chemically stable for up to 20 days at 4°C, 25°C, and 37°C.

Discussion

Pain is a major concern for patients undergoing cancer chemotherapy. The use of drug combinations is a common clinical approach to manage refractory cancer pain. A combination of hydromorphone hydrochloride and bupivacaine hydrochloride via the intrathecal route is widely accepted for cancer pain relief. Previous studies have demonstrated the stability and compatibility of hydromorphone hydrochloride or bupivacaine hydrochloride alone in intrathecal infusion solutions [7,29]. Additionally, some investigations have shown that these 2 agents are physically and chemically compatible [23]. For intrathecal use of glucocorticoids, Nelson et al reported that continuous intrathecal administration of morphine combined with dexamethasone improved analgesic efficacy in patients with cancer-related bone pain due to malignant bone metastases [30]. Multiple studies also have evaluated the stability and compatibility of dexamethasone in combination with agents such as methotrexate, midazolam, and levobupivacaine [31–33]. However, no published data are available concerning the physicochemical compatibility of hydromorphone, bupivacaine, and dexamethasone in 0.9% sodium chloride injection for intrathecal analgesia. The present study aimed to address this gap.

In the present study, visual appearance and pH were used as indicators of physical compatibility. The results showed that the appearance of all tested samples remained unchanged at all 3 temperatures over 20 days. No precipitation or color change was observed in the mixtures of hydromorphone, bupivacaine, and dexamethasone. As shown in Table 1, no pronounced changes in pH were detected at 4°C, 25°C, or 37°C throughout the study period. The acceptable pH range for bupivacaine hydrochloride injection is 4.5 to 6.0, whereas that for hydromorphone hydrochloride injection is 5.0 to 6.0. Previous studies have shown that the pH of mixtures containing bupivacaine hydrochloride and hydromorphone hydrochloride remains stable for up to 3 months [23]. In contrast, dexamethasone sodium phosphate injection has an optimal pH range of 7.0 to 8.5, which is neutral to slightly alkaline. According to medication guidelines, dexamethasone sodium phosphate injection can be combined with 0.9% sodium chloride injection, with a resulting pH of approximately 4.5 to 7.0. Admixtures in the present study maintained relatively stable pH values within a neutral to slightly acidic range over 20 days. Previous reports have indicated that dexamethasone-hydromorphone mixtures may exhibit concentration-dependent incompatibility [24]. Thus, our use of a low concentration of dexamethasone sodium phosphate may explain the absence of precipitation and the stability of pH, consistent with previous findings.

Chemical stability is essential to ensure the safety and efficacy of clinical drugs. Drugs that exhibit substantial loss of content or generate unknown degradation products are not suitable for prolonged intrathecal use. Accordingly, chemical stability testing is necessary before the introduction of new drug admixtures into clinical practice. Chemical stability should be distinguished from broader clinical safety considerations, which include additional risks such as microbiological sterility and the neurotoxic potential of drug combinations or excipients. In the present study, an HPLC method was utilized to simultaneously quantify hydromorphone hydrochloride, bupivacaine hydrochloride, and dexamethasone sodium phosphate. The results showed that the concentration of each component remained above 98% of the initial value at all tested temperatures over 20 days, meeting predefined criteria for chemical stability. Previous studies have shown that changes in hydromorphone and bupivacaine concentrations after mixing remained below 5% during 3 months at 37°C [23]. Thus, the addition of dexamethasone sodium phosphate did not substantially affect the stability of the original formulation over 20 days. At 37°C, the concentrations of the 3 analytes slightly exceeded 110% at certain time points, then returned to the acceptable range and remained stable thereafter. This phenomenon may be attributable to systematic errors or interference from small bubbles or particulate matter during detection [34]. Overall, the concentrations of all 3 drugs in the mixtures remained above 98.0% of their initial values, satisfying predefined stability criteria. Our findings suggest that the combination of hydromorphone hydrochloride, bupivacaine hydrochloride, and dexamethasone sodium phosphate in 0.9% sodium chloride injection is physicochemically stable under the tested storage conditions (4°C, 25°C, and 37°C) for up to 20 days. We emphasize that these conclusions apply only to the tested concentrations, temperatures, and storage durations. Microbiological stability and in vivo safety require further investigation.

Due to interindividual differences in analgesic response, various concentration ratios of hydromorphone hydrochloride, bupivacaine hydrochloride, and dexamethasone sodium phosphate may affect the stability of the mixture in the pump reservoir. Compatibility assessments across a broader range of concentration combinations will be necessary to support wider clinical application in future studies. Additionally, the present study primarily evaluated drug stability under constant environmental conditions and did not investigate factors that may influence stability. Future work will focus on evaluating these factors to enrich the dataset and provide better guidance for clinical practice.

Conclusions

This study demonstrated that an admixture containing hydromorphone hydrochloride (0.026 mg/mL), bupivacaine hydrochloride (1 mg/mL), and dexamethasone sodium phosphate (0.033 mg/mL) in 0.9% sodium chloride – stored in a commercially available intrathecal infusion pump at 4°C, 25°C, or 37°C – did not exhibit substantial changes in appearance, pH, or drug content. Thus, the mixture was stable and compatible for at least 20 days under the tested conditions. These findings support the clinical use of this drug combination for intrathecal administration using the studied concentrations and storage conditions.