Physicochemical Properties of Branded and Generic Infusion Fluid Preparations: Results of a Comparative Experimental Study on Type 2 Hypotonic Infusion Fluid

Summary

In Japan, four different types of hypotonic infusion fluids, namely, types 1–4, are available and used depending on the patient’s condition. Although branded and generic products for each type of hypotonic infusion fluid are available, their physicochemical properties are unknown. For types 1 and 3 fluids, differences in the physicochemical properties of branded and generic products lead to different adverse events when administered. In the present study, we measured titration acidity, pH, and osmolality of branded and generic type 2 hypotonic infusion fluids, which have recently been recognized as useful for maintenance infusion among pediatric patients. We herein assessed their physicochemical information required while selecting a product in clinical practice. Experiments were performed using one branded and two generic products of type 2 hypotonic infusion fluids. Titration acidity was measured via neutralization titration, osmolality was measured via freezing point depression, and pH was measured via potentiometry using a glass electrode. Significant differences in titration acidity, which is a risk factor for metabolic acidosis, and pH, which is a risk factor for pH-dependent changes upon mixing, were observed between the branded and generic products. Our study indicates that titration acidity and pH should be evaluated appropriately to avoid adverse events in clinical practice while selecting a product of type 2 hypotonic infusion fluids. Our findings highlight the importance of evaluating the differences between branded and generic products, specifically when selecting it for pediatric patients with incompletely developed renal function and patients with impaired renal function.

INTRODUCTION

In Japan, four types of hypotonic infusion fluids, i.e., types 1–4, are available and used depending on the patient’s condition.¹⁾ The components of these four types of hypotonic infusion fluids are shown in Table 1.

Table 1. Branded Formulations of Hypotonic Solution Types 1–4

Classification	Componentsa
	Na+ (mEq/L)	K+ (mEq/L)	Mg2+ (mEq/L)	Cl− (mEq/L)	L-Lactate− (mEq/L)	P (mmol/L)	Glucose (%)
Type 1	90	—	—	70	20	—	2.6
Type 2	84	20	—	66	20	10	3.2
Type 3	35	20	—	35	20	—	4.3
Type 4	30	—	—	20	—	—	4.3

^aData were derived from the package insert of each drug.

Type 1 hypotonic infusion fluid (type 1) is used as a starting solution for the dehydration caused by unknown pathology, such as renal insufficiency.¹⁾ Type 2 hypotonic infusion fluid (type 2) is used for maintaining hydration after the recovery of urine volume.¹⁾ Type 3 hypotonic infusion fluid (type 3) is extensively used as a maintenance infusion fluid.¹⁾ Type 4 hypotonic infusion fluid (type 4), which does not contain potassium ions, is used as a maintenance infusion fluid for patients with renal failure and adrenocortical insufficiency.¹⁾ However, in pediatric patients, isotonic solutions (e.g., 0.9% saline solution) have been recommended as maintenance infusion fluids in many countries, including Japan, because hypotonic infusion fluids tend to cause hospital-acquired hyponatremia (i.e., medically induced hyponatremia).^2–5) Recently, it has been reported that in pediatric patients, half saline (0.45% saline in 5% glucose) as a maintenance infusion solution does not significantly increase the risk of hyponatremia compared with saline (0.9% saline in 5% glucose),^6,7) and hypotonic fluid (80 mEq/L sodium ions and 20 mEq/L potassium ions in 5% glucose) do not cause low sodium ions below 132 mEq/L.⁸⁾ Furthermore, these reports suggested that approximately 0.45% saline with potassium in 5% glucose might be useful for avoiding adverse events. In Japan, a formulation like half saline is considered type 2 (average: 73 mEq/L sodium ions and 20 mEq/L potassium ions). Based on the abovementioned findings and facts, we predicted that type 2 hypotonic infusion fluid would be more frequently used as a maintenance infusion solution for pediatric patients than other types.

The use of generic forms has been increasing annually, and it reached 80% in March 2022.⁹⁾ In Japan, type 2 hypotonic infusion fluid is available in both branded and generic forms. We previously reported that titration acidity, pH, and osmolality differ among the branded and generic versions of electrolyte infusions, mainly because of fixed acids included in the formulation, which are not listed on the package insert.¹⁰⁾ Information on titration acidity and osmolality need not be included in drug package inserts or interview forms. In addition, this information is not available from common sources of pharmaceutical information, such as the Information Package of Quality of Prescription Drugs, the so-called “Blue Book,”¹¹⁾ which contains information on generic drugs widely used in medical practice in Japan. However, titration acidity and pH of infusion fluids are known to affect the acid–base equilibrium of blood¹²⁾ and produce pH changes upon mixing,¹³⁾ whereas extremely high osmolality induces vascular pain.¹⁴⁾ Based on these facts, we considered that examining the titration acidity, pH, and osmolality of type 2 hypotonic infusion fluid, even for the same component preparation, would be useful for avoiding any risk while determining the indications for the preparation. We assumed that the abovementioned three parameters would differ between the branded and generic products of type 2 hypotonic infusion fluid as these products might contain fixed acids that are not listed on the package insert. Fixed acids are added as a stabilizer to the infusion formulation. We have previously reported that differences in these parameters were mainly attributable to different fixed acids present in products.^15–17)

This study aimed to measure titration acidity, pH, and osmolality of branded and generic products of type 2 hypotonic infusion fluid, and it suggested the information that should be evaluated while selecting a product of type 2 hypotonic infusion fluid in clinical practice.

MATERIALS AND METHODS

Experimental Materials

Experiments were conducted using one branded (“Brand”) and two generic (“Generic 1” and “Generic 2”) formulations of type 2 hypotonic infusion fluid (Table 2).

Table 2. Branded and Generic Formulations of Type 2 Hypotonic Infusion Fluids

Classification	Componentsa
	Na+ (mEq/L)	K+ (mEq/L)	Mg2+ (mEq/L)	Cl− (mEq/L)	L-Lactate− (mEq/L)	P (mmol/L)	Glucose (%)
Brand drug (“Brand”)	84	20	—	66	20	10	3.2
Generic drug (“Generic 1”)	60	25	2	49	25	6.5	2.35
Generic drug (“Generic 2”)	77.5	30	—	59	48.5	—	1.45

^aData were derived from the package insert of each drug.

Measurement of Titration Acidity, pH, and Osmotic Pressure

Titration acidity and pH of all formulations were measured as previously described.¹⁷⁾ The room temperature ranged from 23.0 to 24.0°C when the pH of each sample stabilized. The osmotic pressure of all formulations was also measured as previously described.¹⁷⁾ Measurements of titration acidity, pH, and osmotic pressure were performed on five preparations each of Brand, Generic 1, and Generic 2 formulations with the same lot numbers.

Statistical Analysis

Normality was tested using the Shapiro–Wilk W test, and multiple group comparisons were assessed using the Tukey–Kramer test for titration acidity and Steel–Dwass test for pH and osmolality. Statistical analyses were performed using JMP^® 14 software (SAS Institute Inc., Cary). Statistical significance was set at p<0.05.

RESULTS

Experiments were conducted using the same methods as described in previous studies.^15–17) Titration acidity, pH, and osmolality differed between the branded and generic versions of type 2 hypotonic infusion fluid as well as between the branded and generic versions of other electrolyte infusions in previous studies.^15–17)

Results of Titration Acidity

Significant differences in titration acidity were observed between Brand and Generic 1 [mean±standard deviation (SD): 9.82±0.10 mEq/L vs. 13.04±0.04 mEq/L, respectively; p<0.0001], Brand and Generic 2 (9.82±0.10 mEq/L vs. 0.19±0.00 mEq/L, respectively; p<0.0001), and Generic 1 and Generic 2 (13.04±0.04 mEq/L vs. 0.19±0.00 mEq/L, respectively; p<0.0001) (Fig. 1).

Fig. 1. Comparison of Titration Acidity among Brand, Generic 1, and Generic 2

The x-axis shows the branded and generic products, and the y-axis shows the titration acidity. Data are presented as mean±SD. ** p<0.0001.

Results of pH

Significant differences in pH were found between Brand and Generic 2 [median (interquartile range, IQR): 4.91 (4.89–4.92) vs. 6.20 (6.20–6.22), respectively; p=0.0250], Brand and Generic 1 [4.91 (4.89–4.92) vs. 4.83 (4.81–4.83), respectively; p=0.0287], and Generic 2 and Generic 1 [median (IQR): 6.20 (6.20–6.22) vs. 4.83 (4.81–4.83), respectively; p=0.0239] (Fig. 2).

Fig. 2. Comparison of pH among Brand, Generic 1, and Generic 2

The x-axis shows the branded and generic products, and the y-axis shows the pH. Data are presented as median (interquartile range). The upper and lower ends of the box represent the third and first quartiles, respectively. * p<0.05.

Results of Osmolality

Significant differences in osmolality were observed between Brand and Generic 1 [median (IQR): 368 (368–370) vs. 291 (290–291), respectively; p=0.0294], Brand and Generic 2 [368 (368–370) vs. 274 (274–276), respectively; p=0.0313], and Generic 1 and Generic 2 [291 (290–291) vs. 274 (274–276), respectively; p=0.0294] (Fig. 3).

Fig. 3. Comparison of Osmolality among Brand, Generic 1, and Generic 2

The x-axis shows the branded and generic products, and the y-axis shows the osmolality. Data are presented as median (interquartile range). The upper and lower ends of the box represent the third and first quartiles, respectively. * p<0.05.

DISCUSSION

Based on the results of our comparative experiment on branded and generic products of type 2 hypotonic infusion fluid, we speculated the adverse events that could occur in patients as a result of the differences in titration acidity, pH, and osmolality between branded and generic products.

In clinical terms, titration acidity is expressed as the amount of base (0.1 mol/L NaOH) needed to titrate an infusion fluid preparation to the pH of human blood (7.4).¹⁸⁾ In contrast, the pH of an infusion fluid preparation is a value that denotes the concentration of the hydrogen ions in a solution.¹⁹⁾ Fixed acids are often added to infusion formulations to maintain acidic pH and stabilize the solution, which in turn affects titration acidity. However, some fixed acids, such as acetic acid, do not need to be listed on the drug package insert.¹⁰⁾ Acetic acid is a weak acid; thus, its dissociation is low in acidic solutions and is not accurately reflected in the pH of acidic solutions. However, it dissociates to almost 100% in a weakly basic solution of pH 7.4. When acetic acid is added, the titration acidity increases significantly compared with the decrease in pH value. Thus, addition of fixed acids, which are not listed on the package insert, is one reason for the difference in titration acidity and pH among preparations of the same component. Moreover, administration of a product with high titration acidity increases the risk of metabolic acidosis in pediatric patients with immature renal function as well as in patients with impaired renal function, since fixed acids are processed by the kidneys.¹²⁾

In this study, significant differences in titration acidity were observed among all type 2 products evaluated. Generic 1 had the highest titration acidity, suggesting a higher risk of developing metabolic acidosis with its use. The rate at which fixed acids are normally processed by the human body is 1 mEq/kg,²⁰⁾ e.g., 50 mEq for a person weighing 50 kg. Furthermore, using the same example, if 1000 mL of Generic 1 is administered daily, the kidneys will process 63.04 mEq of fixed acids, which is 1.26 times higher than the normal human acid-processing capacity. Hence, the risk due to differences in titration acidity among products of type 2 hypotonic infusion fluid should be evaluated to select an appropriate product to be administered, particularly in pediatric patients with low renal function.

The present study revealed significant differences in pH among all type 2 products investigated. Different pH of infusions may result in different pH-dependent changes. Examples of possible differences in pH-dependent changes at different pH of the infusion solutions are shown in Fig. 4.

Fig. 4. Predicting Whether Doxapram Hydrochloride Hydrate Can be Mixed with Brand and Generic 2

*¹The pH values for Brand and Generic 2 are the experimental data in this study. *²The pH, final pH, and change-point pH of DOPRAM^® 400 mg injectable and appearance change (white turbidity) were obtained from the pH variation test*³ results in the DOPRAM^® injectable 400 mg interview form.²¹⁾ These data are the results of experiments conducted by Kissei Pharmaceutical Co., Ltd. and are presented in the interview form.²¹⁾ Note that an interview form is a type of drug instruction manual for pharmacists, which is produced by pharmaceutical companies to supplement the package insert. *³The pH variation test is conducted by adding a small amount of 0.1 M hydrochloric acid reagent or 0.1 M sodium hydroxide reagent drop by drop with up to 10 mL of injection solution to extract the pH-dependent change in appearance. The change-point pH is defined as the pH at the time of appearance change, and the final pH is defined as the pH at the time of addition of 10 mL of 0.1 M HCl or 0.1 M sodium hydroxide reagent in the absence of appearance change.

Figure 4 presents the possible pH-dependent change that might occur when DOPRAM^® 400 mg injectable (Doxapram Hydrochloride Hydrate)²¹⁾ is added through a side tube to an infusion bag of Brand and Generic 2, based on the results of the pH variation test of DOPRAM^® 400 mg injectable conducted by the manufacturer, ²¹⁾ and the experimental results in this study. Doxapram, a weakly basic substance, is dissolved in cationic form by adding hydrochloric acid to produce hydrochloride (pKa=6.7).²¹⁾ It is anticipated that the proportion of insoluble molecular forms will increase and the solution may become turbid if the pH of the infusion is higher than the change-point pH (5.8)²¹⁾ of DOPRAM^® 400 mg injectable. If DOPRAM^® 400 mg injectable solution is administered through the side tube for Brand (pH 4.91) and Generic 2 (pH 6.20), no change is expected for Brand, whereas the solution is expected to become cloudy for Generic 2 (Fig. 4).

In addition to DOPRAM^® 400 mg injectable solution, several other medicines, such as Perdipine^® Injection 10 mg (pH 3.66, change-point pH 5.19),²²⁾ DROLEPTAN^® Injection 25 mg pH 3.3, change-point pH 5.9),²³⁾ Ciproxan^® intravenous injection 200 mg (pH 4.27, change-point pH 5.25),²⁴⁾ and Haloperidol INJECTION 5 mg “YOSHITOMI” (pH 4.06, change-point pH 5.36),²⁵⁾ might be available for administration through the side tube of Brand (pH 4.91) and not Generic 2 (pH 6.20). At present, it is impossible to obtain all experimental data on every compounding change from the manufacturer or from any publicly available source such as “Chushayakuchozai kansamanyuaru 2021.”²⁶⁾ Therefore, it is conceivable that predicting the potential for pH-dependent changes based on pH of infusion fluids and pH variation test data of drugs is a realistic risk avoidance approach in clinical practice. Taken together, we consider that evaluating the pH of branded and generic infusion fluids is essential for selecting an appropriate formulation.

The theoretical osmotic pressure of each product can be calculated based on its components. However, it is difficult to predict the theoretical osmotic pressure since electrolytes that ionize are not always 100% ionized at the pH of each product. In the present study, the osmolality of type 2 hypotonic infusion fluid ranged from 274 to 368 mOsm/kg, with significant differences among all combinations. Generally, the value at which people feel vascular pain is approximately 600 mOsm/kg.¹⁴⁾ This shows that the risk of vascular pain was not considered a clinical probability in the present study.

We considered that differences in titration acidity and pH between branded and generic products may contribute to the different potential for adverse events among type 2 hypotonic infusion fluid formulations. Furthermore, this study suggested that titration acidity and pH need to be evaluated appropriately while selecting a product of type 2 hypotonic infusion fluid in clinical practice, especially for pediatric patients with immature renal function and those with impaired renal function. The results of this study support our previous studies on isotonic infusion fluids¹⁵⁾ and type 3¹⁶⁾ and type 1¹⁷⁾ hypotonic infusion fluids.

The present study had a limitation. The data on titration acidity, pH, and osmolality obtained in this study were for the type 2 formulation alone. In clinical practice, electrolytes and other substances may be added depending on the patient’s condition; thus, the results of the present study may not be valid in all cases where type 2 hypotonic infusion fluid was administered. However, although we cannot take a priori experimental data for every condition, we can make predictions based on the data of the present study. Furthermore, our findings are essential for predicting the risk of administering type 2 hypotonic infusion fluid to pediatric patients and patients with certain conditions, such as impaired renal function and hypernatremia.

The present study suggested that titration acidity and pH of type 2 hypotonic infusion fluid formulations should be evaluated to avoid any risks, especially in pediatric patients with immature renal function or those with impaired renal function. Information, such as that provided in this report, should be continuously updated on clinical sites to ensure optimal risk management in clinical practice.

Acknowledgements

We express our sincere gratitude to Assoc. prof. Keisuke Imada of School of Pharmacy, Tokyo University of Pharmacy and Life Sciences for their guidance in this report and all laboratories for their support and cooperation in advancing the research.

Conflict of Interest

The authors declare no conflict of interest.

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