Amiodarone hydrochloride is a class III antiarrhythmic drug indicated for the treatment of ventricular and supraventricular tachycardias. Oral amiodarone is only available in a tablet dosage form, which is not suitable for pediatric use. The stability of amiodarone hydrochloride suspension at 5 mg/mL was assessed in SyrSpend® SF PH4 (liquid) but oral amiodarone is typically given as a loading dose of 10–15 mg/kg/day for 4–10 days and then reduced to a maintenance dose of 5 mg/kg/day, making the 20 mg/mL concentration a better option. A hospital preparation of 20 mg/mL amiodarone hydrochloride oral suspension was developed. The purpose of this study was to determine the physicochemical stability of a 20 mg/mL amiodarone hydrochloride oral multidose suspension in a commercial compounding excipient, SyrSpend® SF PH4 (liquid) at ambient temperature and under dark conditions.
Three batches of oral suspension were prepared using amiodarone hydrochloride powder and SyrSpend SF PH4 (liquid). The suspensions were stored at room temperature and protected from light (amber glass vials). A sample was withdrawn from each bottle immediately after preparation and at 1, 2, 5, 10, 15, 30, 60, and 90 days. After additional dilution to an expected concentration of 100 μg/mL with methanol, the samples were assayed in triplicate using a stability-indicating high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The physicochemical properties (pH, osmolality, amiodarone concentration, macroscopic changes) were assessed over 90 days at each day of analysis. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point and defined as retention of at least 95% of the initial concentration of amiodarone hydrochloride.
After 90 days, the study showed that amiodarone hydrochloride concentrations did not go below 95% of the initial drug concentration. Neither degradation products nor changes of physicochemical properties were detected.
Compounded oral suspensions of 20 mg/mL amiodarone hydrochloride in SyrSpend® SF PH4 (liquid) were stable for at least 90 days when stored in amber glass bottles at room temperature.
Amiodarone hydrochloride is a predominately Class III antiarrhythmic agent that also acts as a class Ia, II, and IV antiarrhythmic and inhibits adrenergic stimulation (alpha and beta-blocking properties). Its main electrophysiological action is to prolong the action potential duration and refractory period of all cardiac structures resulting in a reduction of membrane excitability in myocardial tissue. These effects make it useful in the management of both atrial and ventricular tachyarrhythmias .
Amiodarone has been shown by numerous studies to be an effective antiarrhythmic for children in the treatment of ventricular and supraventricular tachycardias, including those associated with Wolff-Parkinson-White Syndrome , , , .
So far, there are no age-appropriate, authorized and commercially available amiodarone dosage forms for administration to the pediatric population. Unlike in adults where oral solid dosage forms such as tablets or capsules are acceptable to the majority of patients, children require dosage forms adapted to their abilities (e.g. acceptability, swallowability) and their needs for variable dose with age/weight/Surface Area. Because of dose versatility and ease of administration, liquid formulations are often preferred for children, infants and neonates in contrast to solid forms , , , , .
Since the introduction of the Pediatric Regulation , many initiatives have been taken to improve the availability of pediatric drug formulations: smaller tablets and capsules are emerging as a viable substitute for conventional solid dosage types. For instance, minitablets have been developed for ease of administration and numerous studies have shown that infants of 6–12 months can swallow 2 mm minitablets easily [11, 12]. This opens the perspective for introducing small-sized solid forms for children. Manufacturers have yet to adapt authorized medicines to meet the needs of pediatric patients.
For now, hospital pharmacies still play a key role in providing drugs to treat this various population.
Amiodarone hydrochloride is widely dispensed as a compounded suspension or as capsules for pediatric or geriatric patients. Several stability data for extemporaneously compounded amiodarone formulations in commercially available vehicles have previously been reported , , , , .
Liquid preparations may be easier to administer compared to solid dosage forms but usually, dissolved forms are more susceptible to chemical instability and degradation than the solid-state form [6, 8, 9]. We decided to rely on the commercial compounding vehicle, SyrSpend® SF PH4 , which has been designed to have extensive compatibility behavior with a wide range of active pharmaceutical ingredients (API), to prepare a liquid suspension form. Many studies have approved the compatibility between API and this vehicle , , , ,  but no study evaluated the physicochemical stability of amiodarone oral suspension at 20 mg/mL, using SyrSpend® SF PH4.
The aim of this study was to determine the physicochemical stability of a 20 mg/mL amiodarone hydrochloride oral multidose suspension in a commercial compounding excipient, SyrSpend® SF PH4, at ambient temperature and under dark conditions.
Materials and methods
Chemicals and reagents
Amiodarone hydrochloride (batch number: 16E13956) (Figure 1) powder was purchased from Inresa (Bartenheim, France) and SyrSpend® SF PH4 (liquid) (batch number: 1910994) from Fagron (Thiais, France).
High-performance liquid chromatography (HPLC)-grade acetonitrile was purchased from Fisher Chemical (Illkirch-Graffenstaden, France) and methanol was from Carlo Erba Reagents (Val de Reuil, France). Ammonium acetate was from Merck (Darmstadt, Germany), acetic acid glacial 99.7% and water LC-MS grade were from Fisher Chemical (Illkirch-Graffenstaden, France).
Amiodarone certified standard (purity>99%) was procured from Sigma-Aldrich-Merck (Darmstadt, Germany) and was used for analytical validation to ensure the identity of the active product ingredient (API).
Hydrochloric acid (HCl) solutions 0.1 and 1 M, sodium hydroxide (NaOH) 0.1 and 1 M were from Merck (Darmstadt, Germany), hydrogen peroxide solutions (H2O2) 3% (w/w) and 30% (w/w) were respectively acquired from Gifrer (Decines-Charpieu, France) and Cooper (Melun, France).
Preparation of oral suspensions
Three different batches of amiodarone hydrochloride suspension were prepared according to the Good Manufacturing Practices  using amiodarone hydrochloride powder and the ready-to-use suspending vehicle SyrSpend® SF PH4 (liquid).
First, the exact amount of amiodarone hydrochloride powder was weighed (1,300 mg) in order to obtain the targeted concentration of 20 mg/mL; next, the particle size of the powder was reduced to a fine uniform consistency in a ceramic mortar; then, the powder was levigated with a small amount of SyrSpend® SF PH4 (liquid) to form a uniform paste. Finally, the SyrSpend® SF PH4 was added in small portions to the final volume (65 mL), mixing thoroughly after each addition of SyrSpend® SF PH4, to form a homogenous suspension. 60 mL of the suspension was transferred to a 60 mL amber type 1 glass bottle, mixed well, labeled, and stored at room temperature (23 °C ± 2 °C) throughout the study.
Before analysis, the bottles were shaken until homogenous.
The entire preparation was carried out in a clean area to limit microbiological contaminations.
Analytical method development
Instrumentation and chromatographic conditions
Amiodarone hydrochloride concentrations of each sample were measured by HPLC with UV detection. The HPLC system consisted of a 717 plus autosampler, 2487 UV detector, and a HPLC 515 pump (Waters Corporation, Milford, MA, USA).
The amiodarone hydrochloride assay described in the European Pharmacopoeia (EP) was not appropriate for routine quantification of amiodarone hydrochloride regarding the long retention time (24 min) .
Chromatographic separation of the analytes was performed using a Waters Xterra RP C18 5 µm column (4.6 × 150 mm). The mobile phase consisted of a mixture of 10 mM ammonium acetate buffer, adjusted to pH 3.8 with glacial acetic acid, and acetonitrile (40:60 v/v).
The flow rate was adjusted at 1 mL/min, the sample injection volume was 10 µL and the run time was 10 min per sample.
The wavelength of the detector was set at 254 nm. The system (autosampler/oven) was operated at 23 °C ± 2 °C.
Data were acquired and processed using the EMPOWER Software (Waters Corporation, Milford, MA, USA).
Preparation of stock and working solutions
Calibration and quality control (QC) stock solutions were independently prepared in 10 mL volumetric flasks by dissolving 200 mg of amiodarone hydrochloride powder in methanol to obtain a concentration of amiodarone hydrochloride of 20 mg/mL.
Each calibration solution and each QC solution were diluted with methanol to obtain working solutions at five concentration levels (60, 80, 100, 120, and 140 μg/mL) and three concentration levels (80, 100, and 120 μg/mL) for calibration samples and QC samples respectively–assay range was set between 60 and 140% of the target concentration (100 μg/mL).
Extraction procedure of amiodarone from suspension
Each suspension was hand-shaken before the samples were collected.
Every single sample collected was transferred to a test tube, diluted (1:20 v/v) in methanol and vortexed, to ensure the dissolution of amiodarone hydrochloride.
The samples were then centrifuged at 4,000 rpm for 5 min to sediment insoluble excipients of the compounding vehicle. A final dilution (1:10 v/v) of supernatant with methanol was performed to obtain a 100 μg/mL solution of amiodarone hydrochloride.
The samples were last analyzed by HPLC-UV.
Analytical method validation
Method validation is the process of ensuring that a test procedure performs within acceptable standards of reliability, accuracy, and precision for its intended purpose. The HPLC method was validated according to the International Conference on Harmonization (ICH) guidelines (Q2R1) including the assessment of system linearity, accuracy, precision (repeatability, intermediate precision), and specificity .
Also, the stability-indicating capacity of the HPLC-UV method was assessed according to the Group of Evaluation and Research for Protection in Areas under Control (GERPAC) guidelines .
System suitability testing
Capacity factor (k′), retention time, and tailing factor (T) of amiodarone hydrochloride, were assessed.
The value of k′ has to be between 2 and 10 and the resolution value has to be equal to or greater than 1.5 between the API peak and the other analyte peak to ensure a correct separation and an accurate measure of the area of each peak. A T between 0.8<AS<1.5 was considered acceptable.
The linearity was assessed by three calibration curves (five concentrations range) performed on three different days with the calibration samples. The assay range was set at 60–140% of the target concentration (100 μg/mL).
Linearity was determined through analysis of the coefficient of determination (r2), y-intercept, and slope of the regression line and determination of residual values expressed as percentage of the theoretical value.
The method was considered linear if r2 was greater than 0.99 for the mean standard curve, the homogeneity of variances was verified, the slope was statistically significantly different from zero, and the threshold value for residual values was 5%.
The matrix effect was evaluated by comparing two types of calibration range samples: a range containing API alone diluted in methanol vs. a range containing API reconstituted with SyrSpend® SF PH4 (liquid) and diluted in methanol to reproduce the composition of the finished pharmaceutical formulation. The y-intercept and slope of linear regression lines were compared using a Student’s t-test with an authorized risk α=5%.
Accuracy was determined by nine replicate analyses of the QC samples (realized in triplicate each day, for three days). For each QC, the ratio between the concentration observed for each range point and the theoretical concentration was calculated.
The acceptance criterion for accuracy bias was less than 5%.
Repeatability of this method was measured by making six sample determinations at 100% concentration of the QC solution (100 μg/mL).
Intermediate precision was determined by making six sample determinations at 100% concentration of the QC solution (100 μg/mL), each day, for three days.
Repeatability and intermediate precision were determined using the Relative Standard Variation (RSD). The acceptance criterion for RSD was 5%.
The stability-indicating capacity of the method was evaluated by verifying that degradation products did not co-elute with amiodarone hydrochloride.
To demonstrate the specificity of the method, samples of amiodarone were subjected to various stress conditions. The degradation was confirmed if a reduction of more than 5% of amiodarone hydrochloride concentration was observed.
To study the stability-indicating capacity of the HPLC-UV method, working solutions at a concentration corresponding to the concentration of the middle of the calibration range (100 μg/mL), were prepared with and without the presence of the vehicle. They were subsequently exposed to forced degradation under various conditions: heat, acid, base, and oxidative conditions. The percentage of degradation of the amiodarone hydrochloride was quantified and the degradation products were evaluated but not identified.
Thermal, acid, and base degradations, were assessed with amiodarone solutions exposed in a water bath heated to 80 °C for 1 h. Oxidative degradation was assessed with amiodarone solutions exposed in a water bath heated to 100 °C for 3 h.
Acid hydrolysis was studied by adding 1 mL of HCl solutions at 0.1 and 1 M in 1 mL of amiodarone solution. After the exposure time, the reaction was stopped and neutralization was performed with 1 mL of NaOH solutions at 0.1 and 1 M respectively. The alkaline hydrolysis was assessed by adding 1 mL of NaOH solutions at 0.1 or 1 M and neutralized with 1 mL of HCl at the same concentration after exposure time. Finally, the oxidative degradation was carried out by adding 3 mL of H2O2 30% in 1 mL of amiodarone solution.
Degradation products were observed at 254 nm.
Stability study of amiodarone hydrochloride suspension
Three batches of amiodarone hydrochloride oral suspensions were prepared at day 0. At each time point of the study (days 0, 1, 2, 5, 10, 15, 30, 60, 90), physical and chemical parameters were analyzed on the three batches according to the ICH guidelines .
The organoleptic properties of the suspension were evaluated. Formulations were visually inspected at each time point for color change, odor change, homogeneity, and precipitation.
The preparation was considered physically to be stable if no changes were observed.
At each time point, the chemical stability of amiodarone hydrochloride was determined.
Measure of concentration
Amiodarone hydrochloride concentration was quantified in triplicates immediately after preparation and after 1, 2, 5, 10, 15, 30, 60, and 90 days. Before removing samples, the containers were hand-shaken to ensure a homogenous suspension.
Then, a sample of each preparation was diluted (1:20 v/v) in methanol and centrifuged at 4,000 rpm for 5 min to sediment insoluble excipients. Another dilution (1:10 v/v) of supernatant was performed in methanol before HPLC analysis.
The chemical stability was assessed by calculating the percentage of the nominal value remaining at each time point. Stability was defined as the retention of at least 95% of the initial concentration and if no degradation product appeared. Also, the calculated lower limit of the 95% confidence interval was to be at least 95% of the initial concentration at the end of each study period.
Note: drug concentration in samples taken at time zero was designated as 100%.
Osmolality was measured by the freezing point depression method using an Advanced Instruments Model 3250 Osmometer (Radiometer, Neuilly-Plaisance, France). A sample of each suspension was collected and diluted (1:2 v/v) in water for injection before measurement.
pH was determined using a calibrated pHenomenal VWR® pH-meter (VWR Chemicals, Fontenay-sous-Bois, France).
Statistical analysis was performed by Excel® software (Microsoft Office, USA). All statistical tests were undertaken with an authorized risk α of 5%.
Analytical method validation
System suitability testing
In chromatographic conditions, the analysis showed that the retention time of amiodarone was approximately 5 min (Figure 2). The capacity factor k′ and the theoretical plates were respectively 2.32 and 4.241. The tailing factor did not exceed 1.5 (T=1.45). Retention time of Syrspend SF PH4 was approximatively 2.8 (Figure 3).
The results showed that the method was linear (Table 1). The mean equation of the linear regression line was: y=18,337.2 x (±323.2) – 12,858.3 (±33,592).
|API||Reconstituted form, RF|
|Coefficient of determination R2, mean, n=3||0.996||0.999|
|Slope, mean, n=3||18,337.2||18,632.7|
|Standard deviation of the slope, mean, n=3||323.2||174.1|
|Intercept, mean, n=3||−12,858.3||14,246.8|
|Standard deviation of the intercept, mean, n=3||33,592.0||18,081.0|
|Homogeneity of variances
Cochrane test C (α=5%, k=5, df=2)
( C calculated=0.40< C critical value=0.68)
( C calculated=0.48< C critical value=0.68)
Student test t (α=5%, df=13)
( t calculated=56.73> t critical value=2.16)
( t calculated=107.09> t critical value=2.16)
|Maximum residual value||3.1%||1.8%|
C , Cochrane test; t , Student test.
The coefficient of determination was higher than 0.99 and residual values were lower than 5%.
No matrix effect was observed between curves with and without SyrSpend® SF PH4 (liquid). The slopes and intercepts did not show statistically significant differences between the calibration set composed of API alone and the calibration set composed of API reconstituted in excipient (p-values=0.42 and 0.48 for slope and y-intercept, respectively).
The accuracy rates for the 60 μg/mL, 100 μg/mL and 120 μg/mL QC were estimated to be 0.50% [−0.98; 1.98]; 0.29% [−1.62; 2.20] and 0.10% [−2.16; 2.37] respectively.
The RSD of repeatability and the intermediate precision were inferior to 5% and were estimated to 0.41% and 0.60% respectively.
The chromatogram of amiodarone solution which was not exposed to stressed conditions is presented in Figure 4A.
No degradation products appeared when exposed to heat. The percentage of thermal degradation was 15% (Figure 4B).
For acid-induced degradation, no degradation products were observed and the percentage of degradation was 5% with HCl 0.1 M and 9% with HCl 1 M (Figure 4C, D).
Exposure to alkaline and oxidative conditions lead to the emerging of degradation products. The degradation products were well-resolved from the amiodarone peak. The degradation products were not identified.
For base-induced degradation, two degradation products were observed and the percentage of degradation was 22% with NaOH 0.1 M and 30% with NaOH 1 M (Figure 4E, F).
Upon treatment with 30% H2O2 at 100 °C for 3 h, the degradation was over 50% with the formation of two degradation products (Figure 4H).
Stability study of amiodarone hydrochloride suspension
Throughout the study period, all samples were physically stable: no aspect, color or odor changes were observed in any samples. Furthermore, neither precipitation, nor caking, nor irreversible loss of suspension was detected.
The mean amiodarone hydrochloride concentration of the compounded oral suspensions was equal to 18.89 ± 0.64 mg/mL where 18.89 mg/mL represents the initial concentration of the API.
Regarding chemical stability, amiodarone concentrations were within ±5% of the nominal value over 90 days (Figure 5).
No additional chromatographic peak appeared over the 90 day study (Figure 6).
The pH remained stable over the testing period and no significant variation of osmolality occurred across the three batches over the 90 day study. No statistical changes in osmolality (p-value=0.87) or pH value (p-value=0.21) were observed using Kruskal Wallis statistical analysis (α=0.05) (Figure 7).
Liquid oral formulations of API are essential in pediatrics, enabling better dosage adaptations. Non-suitable forms, non-adapted medication dosages, and contraindicated excipients are commonly encountered issues when commercially pediatric forms are not available.
A universal suspension vehicle, SyrSpend® SF PH4 (liquid), was used for the development of a 20 mg/mL amiodarone hydrochloride formula.
SyrSpend® SF PH4 (liquid) is a food starch-based suspension vehicle containing a patented Active Suspending Technology that holds API particles in suspension and accelerates redistribution of suspended medication for more accurate dosing at each administration.
SyrSpend® SF PH4 has low osmolality (<50 mOsm/kg) minimizing gastrointestinal complications and is formulated without alcohol, parabens, benzyl alcohol, propylene glycol, sorbitol, carrageenan, sugars, gluten, dyes, and glycerin. However, it is preserved in sodium benzoate (<0.1%). The acceptable daily intake for benzoic acid has been established to 0–5 mg/kg bw according to the opinion of the Scientific Committee on Consumer Products (SCCP) . However, neonates have an immature metabolism capacity for benzoic acid, and a safe level of excipient exposure has not been determined. Therefore, it is not recommended for newborns less than 56 days of life due to the risk of developing kernicterus. Preservative-free formulations should be considered for this vulnerable population.
Syrspend® SF PH4 Dry  is a free of potentially harmful excipients vehicle that can be interesting to use as a compounding base instead of Syrspend® SF PH4 liquid. However, it is preservative-free suggesting that the risk of microbiological growth or contamination is higher. Therefore, microbiological stability studies should be performed even though the microbiological stability of many oral suspensions compounded using Syrspend® SF PH4 Dry have been previously assessed by the manufacturer [19, 33]. Unfortunately, we lack materials in our laboratory to conduct such studies.
Besides, Syrspend® SF PH4 Dry is not flavored (sweet neutral taste). Taste has an important role, especially when it comes to children’s compliance to the treatment. Children receiving a nicely flavored liquid might be more likely to ingest the entire prescribed volume.
Even if the administration of benzoate in neonates is not recommended, toxicity was only reported from a dosage of 30 mg/kg per day [34, 35]. Syrspend® SF PH4 liquid contains less than 0.1% of sodium benzoate. That means that toxicity would occur for volumes of Syrspend SF PH4 greater than 10 mL/kg per day. The sodium benzoate exposure in neonates with a 20 mg/mL amiodarone hydrochloride suspension remains negligible as the volumes ingested are small at usual dosage. Therefore, Syrspend® SF PH4 liquid remains a good compromise.
Bonsergent, Chaigneau, Lalli et al., developed an amiodarone liquid formulation also dosed at 20 mg/mL, compounded with Inorpha® , another excipient vehicle, alcohol, paraben, and sodium benzoate free, stable, and usable in neonates (osmolality=170 mOsm/kg). The study was presented in a conference paper. Neither the method used for the study nor the results were detailed. However, the graphical representation of concentration evolution tends to fluctuate considerably throughout the course of the study. Besides, higher concentrations are found at days 42, 49 and 55 and may suggest problems homogenizing the suspension or difficulties to put back into suspension. These variations were even further pronounced under refrigerated conditions. It seemed interesting to have stability data with another ready-to-use vehicle as an alternative.
Geiger et al. , assessed the stability of 5 mg/mL amiodarone hydrochloride in Syrspend® SF PH4 liquid. The concentration being lower, the volume to administer will be higher and therefore the benzoate quantity to administer would also be higher. A 20 mg/mL concentration suspension makes it possible to administer smaller volumes and therefore reduce sodium benzoate exposure in children. The dose volume is also a major consideration for the acceptability of a liquid formulation .
The purpose of this study was to develop an assay to analyze amiodarone hydrochloride’s stability in a commercial compounding excipient with HPLC-UV. In general, the use of conventional liquid chromatography is ideal for the methods used in stability studies of medicinal preparations. This separative technique allows the components of a mixture to be isolated and quantified.
The presented results suggest that amiodarone hydrochloride 20 mg/mL in SyrSpend® SF PH4 (liquid) suspension is stable regarding its physicochemical properties when stored in amber glass bottles at room temperature, over 3 months (90 days).
As for HPLC-UV method validation, all the parameters satisfied the acceptance criteria. The method developed is linear (coefficient of determination of the mean greater than 0.99), accurate and precise (values inferior to 5%). The method is stability-indicating and reliable to detect potential degradation products. The results are consistent with those of forced degradation studies previously conducted on the drug [13, 15, 16, 36, 37]. Also, the linearity and the absence of matrix effect allow future preparation of calibration sets with only API diluted in methanol without the need of adding the vehicle.
Moreover, no interference with the SyrSpend® SF PH4 was observed. The peak of amiodarone hydrochloride, observed at a retention time of 5 min, was clearly separated from the peaks of excipients.
However, because of the lack of equipment at our lab, no photodegradation assay nor rheological analyses were carried out. To prevent photosensitivity, the suspensions were packaged in amber vials.
Besides, the UV detector used in the study was not a DAD, meaning that the peak purity was not fully determined. Degradation products that did not absorb at the chosen wavelength (254 and 220 nm) were not assessed in this study.
However, we recently redid the stability-indicating study using another HPLC system including a DAD detector (Thermo Scientific DAD-3000 RS). API oral suspension was subjected to the same experimental conditions as described in the “materials and methods” section in accordance with ICH Q1 international guidelines.
Degradation products did not coelute with the API. Amiodarone peak purity was greater than 0.999, showing no co-elution peaks via three-dimensional chromatograms.
After 3 months, no variation of the amiodarone hydrochloride content in the suspension was observed.
This content was higher than 95% of the initial value and no macroscopic changes were detected. No variation of pH and osmolality measurements were observed. These results are consistent with the absence of degradation products which could be seen in the chromatograms.
The microbiological stability of this suspension was not evaluated because of lake of materials in the laboratory.
In conclusion, amiodarone hydrochloride 20 mg/mL in SyrSpend® SF PH4 (liquid) suspension appears to be stable concerning its physicochemical properties for at least 90 days when stored in amber glass bottles at room temperature.
We thank the pharmaceutical technicians of our pharmaceutical technology department for manufacturing the batches for the stability study.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.
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