Formulation and stability study of an oral paediatric phenobarbital 1% solution containing hydroxypropyl-β-cyclodextrins

Abstract

Objectives

Phenobarbital is a barbiturate, used to treat focal and generalised epilepsy. Since the end of marketing of the oral solution KANEURON in 2017, phenobarbital tablets remain the only available dosage form. Development of an oral phenobarbital solution for paediatric use is therefore essential to fulfil clinical needs. A new formulation of phenobarbital with hydroxypropyl-β-cyclodextrins (HPBCD) was developed, and the physicochemical stability of the solution was evaluated.

Methods

Different excipients have been selected to formulate a solution of phenobarbital. Samples were dosed by High Performance Liquid Chromatography (HPLC) at 216 nm with a LiChroCART C18 endcapped column and mobile phase composed of phosphate buffer pH 3 and methanol (50:50 v/v). Linearity, accuracy, sensibility and specificity of the method were tested, and a forced degradation study was carried out. During stability study, content of phenobarbital, pH, osmolality of the phenobarbital solution and degradation products were followed up for 6 months in line with GERPAC guidelines.

Results

The stability indicating the character of the assay method has been validated. The physicochemical stability study shows that the phenobarbital solution formulated is stable for 6 months, in line with International Conference of Harmonisation (ICH) recommendations Q1A and Q3B (R2) regarding the content of phenobarbital and levels of degradation products (no degradation products >0.01%). Phenobarbital concentration was 101.59±2.6% of initial concentration in refrigerated samples and 101.14±0.5% at 20±5°C. No phenobarbital degradation products (>0.01%) were observed throughout the 6 months. No significant variation of pH or osmolality was observed.

Conclusions

HPBCD solubilise phenobarbital and create a homogeneous solution. These stability data set the shelf life of this new phenobarbital solution at up to 6 months. A microbiological stability study will be carried out to ensure the possibility of using this solution in children.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Since the end of marketing of the oral solution of KANEURON, there is no phenobarbital liquid oral form available and suitable for children. In 2001, the Department of Pharmaceutics of Fukuoka University in Japan highlighted inclusion complexes between barbiturates, including phenobarbital and hydroxy-propyl-β-cyclodextrins (HPBCD).

WHAT THIS STUDY ADDS

• Our study deals with the development of a new phenobarbital oral solution for paediatric use, containing HPBCD, to fulfil clinical needs.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Phenobarbital is an insoluble in water and a bitter active pharmaceutical ingredient. Our study confirmed that HPBCD contribute to solubilise phenobarbital and allowed us to create a homogeneous phenobarbital oral solution, physicochemically stable for 6 months, depending on organoleptic characteristics, content of active pharmaceutical ingredient, levels of degradation products, pH and osmolality.

Introduction

Phenobarbital (presented figure 1) is a barbiturate used to treat focal and generalised epilepsy, either as monotherapy or in combination with others antiepileptic treatments.¹ Epilepsy affects 600 000 people in France, half of whom are children.² Since KANEURON, an oral solution composed of glycerol and ethanol titrated at 63%, was discontinued, the only available oral dosage forms are tablets: ALEPSAL (Teofarma, France), FENEMAL (Takeda AS, Norway), GARDENAL (Sanofi, France), LUMINAL (Bracco Spa Div.Farmaceutica, Italy), PHENARBARBITONE MEDA (Meda AB, Sweden) and Phenobarbital (Streuli Pharma AG, Switzerland). Since most children under 6 years old cannot swallow tablets, this dosage form is not suitable for paediatric use. In fact, the only current alternative for these children is to grind the tablets in order to facilitate administration, which may lead to inaccuracy of the administered dose, expose nurses, families and their environment to the compound and be the cause of compliance and efficiency problems.

Figure 1.

Structure of phenobarbital at pH 5 (pKa=7.3).

This lack of precision can lead to an overdosage of phenobarbital, which is characterised by side effects such as nausea, vomiting, headache, mental clouding, mental confusion or even coma accompanied by a characteristic neurovegetative syndrome (ie, irregular bradypnea, tracheobronchial congestion, arterial hypotension).¹ Moreover, phenobarbital is a drug with a narrow therapeutic range and a carcinogenic, mutagenic or toxic to reproduction (CMR) IB substance class.³

Therefore, hospital preparation of a liquid oral form of phenobarbital is currently the best alternative, and different projects on this topic have already been published. One of those is an oral liquid form of phenobarbital without alcohol, developed at Pharmacie des Hôpitaux de Genève (HUG).⁴ The solution has a concentration of sodium phenobarbital of 5 g/L. It contains 40% v/v of glycerol (98%), 0.1% v/v of methyl and propylhydroxybenzoate as preservatives, sodium saccharin as sweetening agent and a raspberry/lemon combination as flavouring. The solution has been formulated to be the least toxic as possible for the paediatric population. However, we would like to avoid parabens, which can cause delayed hypersensitivity and are known as endocrine disruptors.⁵ Another study, published in 2008 and describing a solvency technique used to increase solubility of phenobarbital, showed that it can be easily dissolved in a mixture of glycerin, propylene glycol and water without the addition of alcohol. This formulation contains 10–12% propylene glycol, 26–28% glycerin and 2–6% USP syrup; however, the solution also contains parabens.⁶

Another way to dissolve phenobarbital and compatible with a paediatric usage is the use of acetem, a lipophilic solvent. However, its taste is not appreciated. Most volunteers of the study carried out by Yska et al ⁷ disliked the taste of a solution of phenobarbital formulated with acetem. As phenobarbital is already known for its unpleasant taste, acetem was therefore not retained.

Finally, in 2001, the Department of Pharmaceutics of Fukuoka University in Japan highlighted multimodal inclusion complexes between barbiturates, including phenobarbital and hydroxy-propyl-β-cyclodextrins (HPBCD).⁸ HPBCD have already been used to develop oral solutions.^9–11 Cyclodextrins are composed of a cyclic oligosaccharide with a hydrophobic interior and a hydrophilic exterior, and thus can solubilise hydrophobic compounds while also masking the unpleasant taste by forming a cyclodextrin compound complex. The use of this excipient to formulate an oral solution of phenobarbital is, then, particularly interesting.

The purpose of this study was therefore to formulate a galenic formulation of an oral solution suitable for paediatric use, with a physicochemical stability adapted for batch production, while respecting an established quality target product profile (QTPP).

Materials and methods

Chemical and reagents

The phenobarbital (C₁₂H₁₂N₂O₃) used was of pharmaceutical grade and purchased from INRESA (Bartenheim, France).

Citric acid monohydrate (C₆H₈O₇, H₂O), sodium citrate dihydrate (Na₃C₆H₅O₇, 2 H₂O) and potassium sorbate (C₆H₇KO₂) were all purchased from INRESA. HPBCD (KLEPTOSE) were acquired from Roquette Frères (Lestrem, France). Sucralose was from Leader Price (Vitry-sur-Seine, France).

Water for injection was purchased from Aguettant (Lyon, France). Orthophosphoric acid (H₃PO₄) was acquired from VWR (Fontenay-sous-Bois, France). Sodium dihydrogenophosphate (NaH₂PO₄) and methanol (MeOH) were from Sigma-Aldrich (Missouri, USA). All reagents and chemicals used in the study were of HPLC grade.

It must be noted that sucralose used for preparation is of food-grade quality, as we could not obtain pharmaceutical-grade quality sucralose at the time of the study. Sucralose from Leader Price contains 99% maltodextrins and 1% sucralose.

Equipment and chromatographic conditions

The study was conducted on a HPLC Ultimate 3000 system with a photodiode array detector PDA 3000 from Thermo Fisher Scientific (Waltham, Massachussetts, USA). Thermo Scientific Chromeleon 6.8 Chromatography Data System (Waltham, Massachussetts, USA) was used to process data.

For the chromatographic separation, reverse phase LiChroCART C18 endcapped column (5 µm, 250×4 mm) was used as stationary phase, and a mixture of phosphate buffer (0.01 M, adjusted pH 3 with orthophosphoric acid) and methanol (50:50, v/v) was used as mobile phase, with a flow rate of 1 mL/min. Column temperature was set at 25°C. Detection was performed at 216 nm with a full scan between 190 nm and 400 nm during the assay method validation and stability study. Finally, an injection volume of 25 µL was set. The pH was measured with a SevenMulti Metler Toledo pH metre (Columbus, Ohio, USA) and the osmolality was assessed with an advanced instrument osmometer, model 3320 A+ (Norwood, Massachusetts, USA).

Each solution was agitated before analysis with Vortex-Genie 2 Scientific Industries (Bohemia, New York, USA) and filtered with 0.45 µm sterile filter with Durapore PVDF membrane from Merck (Darmstadt, Germany).

Assay method validation

Method of quantification of phenobarbital

The HPLC method was developed and validated on three separate days to quantify phenobarbital. Linearity, accuracy and sensibility of the method were tested. Each day, solutions of phenobarbital were prepared without excipient, from independent weighing, with phosphate buffer 0.01 M, adjusted to pH 3 (with orthophosphoric acid) and methanol (50:50, v/v). One control range (at 60, 80, 100, 120 and 140×10^-3 g/L) and six controlled quality samples at 100×10^-3 g/L were analysed without or with excipients (HPBCD, citric acid monohydrate, sodium citrate dihydrate, potassium sorbate, sucralose). The dilution solvent used was composed of phosphate buffer 0.01 M adjusted to pH 3 and methanol (50:50, v/v). After vortex agitation, each solution was filtered and analysed by High-Performance Liquid Chromatography-Ultraviolet (HPLC-UV).

Limit for detection (LOD) and limit of quantification (LOQ) were evaluated on the signal-to-noise ratio (S/N) of phenobarbital using the equation LOD≥3 S/N and LOQ≥10 S/N respectively.

Stability indicating method

The stability indicating character of the HPLC-PDA method was validated in view of its specificity, its sensitivity and its degradation products obtained during forced degradation study. All degradation products were defined according to their relative retention time (RRT) and their normalised areas expressed as percentages.

Area normalisation (AN) was calculated for a given molecule “ $x$ ” with the formula:

$${\displaystyle \left(\mathrm{A}\mathrm{N}\right)\mathrm{x}\left(\mathrm{\%}\right)=\frac{\left(\mathrm{A}\mathrm{U}\mathrm{C}\right)\mathrm{x}}{\left(\mathrm{A}\mathrm{U}\mathrm{C}\right)\mathrm{P}\mathrm{h}\mathrm{e}\mathrm{n}\mathrm{o}\mathrm{b}\mathrm{a}\mathrm{r}\mathrm{b}\mathrm{i}\mathrm{t}\mathrm{a}\mathrm{l}+\sum \left(\mathrm{A}\mathrm{U}\mathrm{C}\mathrm{o}\mathrm{f}\mathrm{a}\mathrm{l}\mathrm{l}\mathrm{D}\mathrm{P}\mathrm{p}\mathrm{e}\mathrm{a}\mathrm{k}\mathrm{s}\right)}\mathrm{X}100}$$

with AUC indicating the area under the curve and DP indicating degradation products.

Forced degradation study

In line with GERPAC guidelines,¹² phenobarbital at 1 g/L (solvent: water/methanol 50/50 (v/v)) was stressed under different forced degradation conditions for 21 days (day 0 to day 21): basic hydrolysis (pH 12 and 13), acid hydrolysis (pH 1 and 2), hydrolysis at native pH (7.2) at 4°C and 60°C and photolysis reaction (visible light and 365 nm). Oxidative stress was done with H₂O₂ 3% and 15% for 2 days at 20°C. Samples (two vials for each condition studied) and controls were prepared at day 0 and analysed at day 0+2 hours, day 2, day 7 and day 21. All samples were prepared in tinted flasks (except for photolytic conditions) and stored at 20±5°C.

Formulation and preparation of the phenobarbital solution

To prepare 1 litre of phenobarbital-type solution at 10 g/L, 10 g of phenobarbital powder were poured into a 1 litre gauge flask, with 80 g of HPBCD. Then, 330 mL of pH 5 citrate buffer (containing 5.88 g of citric acid monohydrate and 21.18 g of sodium citrate dihydrate, dissolved in water for injection) were added to the powder. The solution was mixed with a magnetic stirrer for 15 min. Then, 2 g of potassium were added. The solution was mixed again with a magnetic stirrer for 10 min. A mixture of 37.5 g of maltodextrins and sucralose were added to the gauge flask, and the mixture was mixed with the magnetic stirrer until the solution became as clear as possible. Finally, water for injection was added to the mark of the gauge flask. The solution was left to stand for 24 hours at 20±5°C, before distribution into 60 mL vials for the stability study.

To identify the chromatographic peaks issued of excipients and to identify any impurities, which are not linked to the degradation of phenobarbital over time but to excipients, a control solution containing excipients only was prepared, following the same procedure as explained above.

Preparation of samples and physicochemical stability study

One litre of phenobarbital solution (cited at 2.4) was prepared and was left to stand for 24 hours at 20±5°C. After that, the solution was distributed into 60 mL glass vials: three vials for quantification of phenobarbital and degradation products study, one vial for osmolarity study and one vial for pH study, for each condition assayed (5±3°C and 20±5°C).

On each day of the study, calibration standards (at 60, 80, 100, 120 and 140×10^-3 g/L) and quality control (at 75, 100 and 125×10^-3 g/L) were prepared and analysed in order to produce a standard curve by linear regression.

Samples were diluted with a solvent composed of phosphate buffer 0.01 M, adjusted to pH 3 and methanol (50:50, v/v)) (1:100) to obtain an expected concentration of 100×10^-3 g/L. After vortex agitation, each sample was filtered and analysed by HPLC.

For each temperature, the loss of active pharmaceutical ingredient (API) and the formation of degradation products were assessed in triplicate each day on weeks W1, W2, W3, W4 and every 2 weeks until 6 months, according to GERPAC guidelines¹²

On each sampling day and for both storage conditions, the pH was measured once, and the osmolality was measured in duplicate each day.

Results

Assay method validation

Concerning the method of quantification, standard curves were made by linear regression of the peak areas of phenobarbital against concentrations. The method was shown to be linear (R²=0.9947) over a concentration range from 60 to 140x10^–3 g/L. The accuracy range was 98.95–101.05%. The between-day and within-day coefficients of variation were 3.215% and 0.950%, respectively. The matrix effect was evaluated by comparing phenobarbital concentrations measured with and without excipients. Five samples in each condition were assayed, and then averages were compared by student t-test (α=0.05) showing no significant interference from excipients.

Under these chromatographic conditions, citrate was eluted in solvent front (at RRT 0.39) and potassium sorbate was eluted after phenobarbital at RRT 1.2. Sucralose and cyclodextrins do not absorb at 216 nm.

No synthesis impurity of phenobarbital (which may result from the chemical reactions allowing the synthesis of raw material) over 0.01% was observed.

LOD and LOQ respond to ICH expectations, as LOD and LOQ determined for phenobarbital were, respectively, below 0.01×10^-3 g/L and 0.1×10^-3 g/L for an injection volume of 25 µL. ICH Q3B (R2) recommends reporting degradation products exceeding 0.1% and identification and qualification of degradation products exceeding 0.2%, considering maximum daily dose.¹³ The stability study of phenobarbital is carried out on a solution diluted at 100×10^-3 g/L. The sensitivity of the method is then sufficient to quantify the degradation products of phenobarbital ≥0.10% by area normalisation, corresponding to a concentration of 0.1×10^-3 g/L.

Forced degradation study

The objective of the forced degradation study was to obtain 5–15% of degradation of the API. Such degradation proportion is theoretically enough to observe the major degradation products likely to appear during stability study, while avoiding secondary or ternary degradation products, which can be observed in stronger degradation conditions but are unlikely to be detected in a real-life stability study.

Phenobarbital was not sensitive to oxidative and photolysis stress. In fact, no loss of phenobarbital and no degradation products over 0.1% threshold (normalised area) were reported after 2 days with H₂O₂ 3% and after 21 days of photo stress.

On the other hand, phenobarbital was sensitive to hydrolysis only at extremely basic pH. Indeed, 7% of phenobarbital was degraded at pH 13 after 2 days, and four degradation products were reported: DP1 (0.12%), DP3 (6.0%), DP4 (0.29%) and DP5 (0.36%), eluted respectively at RRT of 0.54, 0.82, 1.9 and 2.8. After 21 days at pH 13, phenobarbital was very degraded (50% loss of API) and many degradation products were formed. On the contrary, no loss of phenobarbital was observed after 21 days at pH 12 and only two small degradation products were reported: DP3 (0.21%) and DP4 (0.78%).

No loss of phenobarbital was observed in solution at acidic pH or at native pH (7.2) at 4°C, 20°C and 60°C. Two small degradation products were reported after 21 days at pH 2: DP2 (0.25%), eluted at RRT of 0.76 and DP4 (0.72%), also obtained at basic pH. DP3, the major degradation product obtained at pH 13, was not reported at acid or native pH.

The results of these stresses, presented in table 1 and figure 2, have proved the capacity of the method to separate the expected major degradation products from phenobarbital. In fact, the resolution between phenobarbital and degradation products was acceptable (RS>1.5). Moreover, this study has confirmed the choice to formulate a solution at neutral pH or slightly acidic pH to avoid degradation of phenobarbital.

Table 1.

Results of forced degradation study

		Basic hydrolysis		Acidic hydrolysis at pH 2 (21 days)
		At pH 13 (2 days)	At pH 12 (21 days)
Loss of API (%)		6.6%	−5.0%	−5.0%
Degradation products (area normalised)	DP1 (RRT 0.54)	0.12%
	DP2 (RRT 0.76)			0.25%
	DP3 (RRT 0.82)	6.00%	0.21%
	DP4 (RRT 1.9)	0.29%	0.78%	0.72%
	DP5 (RRT 2.8)	0.36%

API, active pharmaceutical ingredient; DP, degradation product; RRT, relative retention time.

Figure 2.

Chromatograms showing degradation of phenobarbital (a)after hydrolysis stress, (b)at native pH for 21 days, (c) at pH 13 for 2 days and at pH 12 for 21 days and (d) at pH 2 for 21 days.

Physicochemical stability study

After 6 months, phenobarbital concentration is 101.59±2.6% of initial concentration in samples stored at 5±3°C and 101.14±0.5% at 20±5°C (figure 3). No degradation products of phenobarbital (>0.01%) were observed throughout the 6 months.

Figure 3.

Evolution of phenobarbital concentration in solutions stored at 5±3°C (blue solid line) and at 20±5°C (orange broken line) during 24 weeks.

The phenobarbital samples were at pH 5.33 at day 0. After 6 months, the samples stored respectively at 5±3°C and 20±5°C were at pH 5.28 and at pH 5.34. The osmolality of the sample was 445.8 mOsm/kg H₂O at day 0. After 6 months, the osmolality of samples stored at 5±3°C and at 20±5°C were 452.0 mOsm/kg H₂O and 458.0 mOsm/kg H₂O, respectively. The pH and osmolality did not change significantly during the study (all results are presented in figure 4). The oral solution was clear and homogenous during each day of the stability study.

Figure 4.

Evolution of osmolality and pH of phenobarbital solution samples stored at 5±3°C (blue line) and at 20±5°C (orange line) during 24 weeks.

Discussion

The method of quantification was validated and the forced degradation demonstrated the stability, indicating that the character of the method was as expected in our QTPP, presented in table 2. Indeed, this method allows the separation of the active ingredient, its possible degradation products, and the chosen excipients, as well as being able to report any degradation products formed thanks to sufficient sensitivity.

Table 2.

Quality target product profile

QTPP element	Target	Justification
Dosage form	Oral solution with good taste	Suitable for children: easy to swallow (as children under 6 years old cannot easily swallow tablets) Good taste: acceptance of the product by children
Narrow therapeutic range of active ingredient product	Formulation of a solution allowing administration of a small volume of drug per day, by respecting the maximum daily doses of HPBCD recommended by the EMA5	Safer than crushed tablets that present a risk of imprecision of the administered dose Oral solution: volume adjusted to child weight
Forced degradation study	To identify sensibilities of the API and validate the stability indicating character of the method in line with GERPAC guidelines12
Method of quantification of API	HPLC method for dosage of API and identification of degradation products	To release batches and therefore set up the dose that will ensure drug availability to promote therapeutic effect
Stability and degradation products	ICH Q1A18 and ICH Q3B (R2)13	Quality requirement. Degradation products should be maintained below set limits to ensure safety and security
pH	Stable as recommended by GERPAC guidelines12	Impact on physicochemical stability
Osmolality	Stable as recommended by GERPAC guidelines12	Impact on physicochemical stability

API, active pharmaceutical ingredient; ICH, International Conference of Harmonisation; QTPP, quality target product profile.

The forced degradation study demonstrated that phenobarbital exposed to basic pH is very sensitive. These tests also showed that a formulation of a phenobarbital solution at acidic pH may be considered, as this product does not seem to be sensitive to hydrolysis at these pH levels or to oxidation induced by hydrogen peroxide.

It was therefore decided to buffer the solution at pH 5 with citrate buffer¹⁴ considering sensitive character of phenobarbital towards basic pH and the use of cyclodextrins. In fact, phenobarbital has a pKa of 7.3¹⁵ and an active ingredient must be non-ionised to be encapsulated within cyclodextrins.

Phenobarbital dosage ranges between 10 mg and 80 mg per day, depending on patient body weight,¹ which led us to choose solution of phenobarbital 10 g/L to give a maximum dosing volume of 10 mL for older children. This administrated volume is acceptable (QTPP presented table 2).

According to literature, phenobarbital forms an inclusion complex with hydroxypropyl-β-cyclodextrin at a 1:1 molar ratio.⁸ Several tests of solubility of phenobarbital (molecular mass 232.3 g/mol) with our HPBCD (molecular mass: 1501 g/mol)¹⁶ were carried out to solubilise the phenobarbital at the chosen concentration. It was then decided to formulate a phenobarbital solution concentrated at 80 g/L of HPBCD. The ratio of phenobarbital/HPBCD chosen was close to the one found by the team of 1:1.2 and avoids a loss of solubility (with formation of suspension) induced by a decrease of the temperature during conservation of the product in the refrigerator. Oral administration of HPBCD can cause adverse effects like diarrhoea with a daily dose >200 mg/kg.⁵ Moreover, it is not recommended to administer a daily dose of phenobarbital greater than 5 mg/kg. A formulation of a solution of phenobarbital at 1% with HPBCD concentrated at 8% allowed therefore to administer maximum 40 mg/kg of HPBCD per day, much lower than 200 mg/kg per day (the QTPP is therefore respected as presented in table 2).

It must be noticed that there is not enough information provided about HPBCD effects for children under 2 years of age. Thus, the risk-to-benefit ratio should be assessed on a case-by-case basis for children aged under 2.⁵

As a good taste contributes to medicine acceptability by children, work on flavouring was also realised with HPBCD. It is known that cyclodextrins can be used to mask bitter taste in drugs.¹⁷ Orlu-Gul et al ¹⁰ developed an oral paediatric hydrocortisone solution containing HPBCD for masking the unpleasant taste of hydrocortisone by incorporating the drug molecule into their cavity. Addition of aromas seemed not necessary, as HPBCD create a complex with phenobarbital, and the use of sucralose contribute to mask bitterness of phenobarbital. It seemed difficult to have our solution tested on children, given that the microbiological stability study has not yet been carried out. Taste was then assessed by pharmacists from the Pharmacy of Armand Trousseau Hospital (n=3). However, when microbiological stability is verified, a palatability study should still be carried out in children to verify that the taste of the solution is well accepted.

A physicochemical stability of the phenobarbital solution containing HPBCD, pH 5 citrate buffer, potassium sorbate, sucralose, maltodextrins and water was expected (QTPP presented table 2). Indeed, significant change for a drug product is defined by ICH Q1A¹⁸ as a 5% change in assay from its initial value; this limit has therefore been set. Moreover, ICH Q3B (R2)¹³ recommends identification and qualification of degradation products exceeding 0.2%, considering maximum daily dose. Therefore, these data set the shelf life of this new phenobarbital solution up to 6 months, with a degradation of the active ingredient product below 5% and no degradation products over 0.1% reported for both storage conditions. As we can notice in figure 3, phenobarbital concentration at week 1 is above the accepted limit, but this can be explained by an incorrect manipulation, probably when preparing the stock solution of the calibration range, as the concentration remained stable throughout the study during the 6 months after this point. HPBCD contribute to solubilise phenobarbital and create a homogeneous solution, and the stability of pH showed the buffer efficiency. Absence of significant pH or osmolarity changes proves that there is no instability of the formulation for 6 months. Furthermore, the narrow therapeutic range of this drug justifies the use of HPBCD: an oral solution reduces the risk of imprecision of the administered dose, in contrast to suspension that may sediment. Phenobarbital blood tests are recommended in the event of modification of doses or addition of another anti-epileptic, suspicion of intolerance or poor compliance. The potential modification of absorption of phenobarbital by the presence of cyclodextrins, a principle described by Wu and Xue with their oral solution of honokiol-HPBCD,⁹ will therefore not be a problem with pharmacological monitoring.

If microbiological stability, currently in progress, is confirmed, this new oral solution at hospital could overcome the lack of pharmaceutical phenobarbital forms for children from 2–6 years of age and responds to a real clinical need.

Conclusion

This study has formulated a phenobarbital solution, adapted to paediatric use, which is essential to compensate the end of commercialisation of KANEURON 5.4% and to avoid grinding tablets. Our physicochemical stability study shows that this phenobarbital solution is stable for 6 months. Once bioequivalence is assessed, the production of batches could be considered.

Data availability statement

No data are available.

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