Objective To clarify the effects of the suspension vehicle on the properties of an extemporaneously compounded nifedipine oral suspension (1 mg/ml) prepared from ground-up commercial nifedipine tablets.
Methods Oral suspensions of nifedipine were compounded with six different vehicles: commercial vehicles Suspension Diluent A, Ora-Plus/Ora-Sweet, Ora-Plus/Ora-Sweet SF and SyrSpend SF Cherry, and extemporaneously prepared Methylcellulose 1%/Syrup NF and Hypromellose 1%. The suspensions were stored at room temperature and analysed at 1, 2 and 4 weeks. The effect of mixing on the content uniformity was studied by evaluating two mixing protocols: inverting the bottle manually 10–15 times or inverting it three times. The concentration of nifedipine, the uniformity of mass and the sedimentation volume were determined.
Results The content uniformity of all the suspensions complied with the Pharmacopoeia test at all time points when they were mixed by inverting the bottle 10–15 times. Bottles inverted three times did not comply with the test at 1 week when Methylcellulose 1%/Syrup NF or Hypromellose 1% were used. The uniformity of mass was within acceptable limits in all suspensions. The sedimentation volume of the unmixed Methylcellulose 1%/Syrup NF and Hypromellose 1% was higher than that of the commercial vehicles.
Conclusions In order to comply with the Pharmacopeia test for content uniformity, suspensions compounded with Methylcellulose 1%/Syrup NF or Hypromellose 1% require mixing by inverting the bottle 10–15 times. In contrast, the commercial suspension vehicles passed the test if the bottle was inverted only three times.
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Extemporaneously compounded products are still needed for drug therapy in children despite the fact that extemporaneous compounding raises a variety of challenging issues compared to the use of registered products.1 As an example, the shelf-life of extemporaneously compounded products may not have been studied, and even when the shelf-life is determined, this is usually based on the chemical stability of the drug itself and not physical and microbiological stability or the uniformity of dosage units.1
A coarse suspension, which is a dispersion of finely divided, insoluble particles typically in an aqueous medium, is an example of a dosage form which has challenging physical stability properties.2 A good suspension settles slowly and is readily redispersed when the container is gently shaken.3 Thus, the physical stability of a suspension is typically determined by measuring its rate of sedimentation, the final volume of the sediment and the ease of redispersion of the suspension.2 Cake formation, as defined by the formation of a sediment that is very difficult to redisperse, is the most serious physical stability problem with suspensions.2–5 Physical instability not only spoils the product's appearance but also induces variability in dosing. As an example, Hurtado and Moffett reported the case of a neonate readmitted with an arrhythmia because an amiodarone suspension had been incorrectly compounded and the solids had settled into a hard mass at the bottom of the container.6
The ideal oral drug preparation should be accurate, effective, well tolerated, stable and affordable, and should have good palatability and a minimal dosing frequency.5 The challenging issues in compounding oral extemporaneous suspensions are the selection of the suspending vehicle and the crushing of the tablets required when the drug powder is not available. The time and technique of grinding can influence the resulting homogeneity of the powder mixture, for example, the particle size. The suspended particles should be small and uniformly sized to ensure a slow rate of sedimentation and accuracy of dosing.2 ,7 In practice, the particle size of a manually crushed tablet may not be uniform.8 Many commercial suspension vehicles as well as vehicles prepared in the dispensary can be used for the preparation of oral extemporaneous suspensions.5 ,9–14 The vehicles prepared in the dispensary can include methylcellulose and Syrup NF (Simple Syrup) in various ratios, Syrup NF alone, cherry syrup or other flavoured syrups alone or diluted with Syrup NF or purified water, Syrup NF with glycerine, glycerine with water, or water alone. In addition, xanthan gum, carmellose natrium, carrageenan or hypromellose may be used as viscosity-inducing agents instead of methylcellulose. Suspension vehicles commonly mentioned in the literature are the commercial Ora-Plus/Ora-Sweet in a 1 : 1 ratio and extemporaneously prepared Methylcellulose 1%/Syrup NF in different proportions.9–11
The aim of this study was to examine the effects of the suspension vehicle and amount of agitation on the properties of an extemporaneous nifedipine oral suspension prepared from ground-up commercial nifedipine tablets. Nifedipine has adequate stability in extemporaneous oral liquid formulations.15–18 In the study, content uniformity, uniformity of mass, and sedimentation volume were studied as a function of time for suspensions compounded with four commercial suspension vehicles and two vehicles prepared in the dispensary.
Materials and methods
Preparation of suspensions
Oral suspensions of nifedipine (1 mg/ml) were prepared by thoroughly grinding seven commercial nifedipine 10 mg tablets (Adalat 10 mg retard; Bayer, Leverkusen, Germany) in a mortar with a pestle in a dark room illuminated with a yellow light with a wavelength over 450 nm to prevent photodegradation of the light-sensitive nifedipine. Then, 70 ml of liquid suspension vehicle was added gradually to the powder. The details of the procedure can be found in online supplementary appendix 1. Three batches of each suspension type were compounded, except when four batches were needed (if the acceptance value (AV) did not comply with the Pharmacopoeia requirement).
Six different suspension vehicles were compared: four commercial vehicles and two vehicles extemporaneously prepared in the pharmacy of Kuopio University Hospital. Two suspension vehicles, Suspension Diluent A (Nova Laboratories, Leicester, UK) and SyrSpend SF Cherry (Gallipot, St. Paul, Minnesota, USA) were used undiluted. Ora-Plus (Paddock Laboratories, Minneapolis, Minnesota, USA) and Ora-Sweet (Paddock Laboratories) as well as Ora-Plus and Ora-Sweet SF (Paddock Laboratories) were combined in a ratio 1 : 1 according to the manufacturer's recommendation. Methylcellulose 1%/Syrup NF (Suspension Vehicle HSC) was compounded from 1% Methylcellulose (Methylcellulose powder USP 1500 cP; Sigma-Aldrich, St. Louis, Missouri, USA) HSC preserved with sodium benzoate (Ph.Eur.; Oriola, Espoo, Finland) and sugar (Ph.Eur., Tamro, Vantaa, Finland)-based Syrup NF in a ratio of 7 : 3 according to a traditional formula from the Hospital for Sick Children (online appendices 2–4).14 Sterilised Hypromellose (50 cP; Colorcon, Kent, England) 1% vehicle was used in this study, since it has been proved to be useful in neonatal nifedipine single-dose oral syringes (online appendix 5).8 ,18 The ingredients and selected properties of the liquid vehicles are compared in table 1.
The concentration of nifedipine was measured with a stability-indicating high performance liquid chromatographic (HPLC) method. The equipment consisted of an HPLC system (Agilent 1200 series binary pump SL, micro vacuum degasser, high performance autosampler SL, column thermostat SL, diode-array detector SL, and ChemStation for LC 3D software Rev. B.03.01 with spectral evaluation module; Agilent Technologies, Waldbronn, Germany) with a reversed phase column (Zorbax Eclipse Plus C-18, 3.5 ∝ m particle size, 100 × 3 mm; Agilent Technologies) and the photodiode array detector set at 332 nm. The isocratic mobile phase consisted of 60% methanol (HPLC gradient grade 8402; Mallinckrodt Baker, Deventer, The Netherlands) and 40% phosphate buffer (30 mM, pH 7.0) (Phosphoric acid, 6024; Mallinckrodt Baker). Water was purified using a Milli-Q Gradient system (Millipore, Milford, Massachusetts, USA). The column temperature was maintained at 35°C and mobile phase flow rate at 0.8 ml/min. The injection volume was 3.0 ∝ l and the run time 2.80 min.
Preparation of standard solutions and standard curve
Standard solutions of nifedipine at 60, 80, 100, 120 and 140 ∝ g/ml, ranging from 60% to 140% of the nominal concentration of the suspensions, were prepared from nifedipine (N7634; Sigma-Aldrich Chemie, Steinheim, Germany) stock solution (0.2 mg/ml in methanol) by further diluting it with methanol. All standard solutions were stored protected from light and their stability was determined with the validated HPLC method described below.
The HPLC method was validated according to the ICH guideline.19 In addition to the standard validation, the stability-indicating capability of the method was verified by forced degradation studies for all the analysed sample types as per ICH recommendations.20 All nifedipine sample suspensions were treated with either sodium hydroxide, hydrochloric acid, hydrogen peroxide and heated in a water bath at 70°C, or exposed to window light for 1 h. All suspensions were also allowed to stand at room temperature and protected from light for 1 month. The samples were then analysed and the specificity for nifedipine was evaluated by comparing the chromatograms of the nifedipine standard to the degraded sample. At the retention time of nifedipine (1.94 min), no chromatographically interfering peaks were observed and the peak spectra of a pure nifedipine standard and the suspension samples were identical. Additional assurance for the purity of the chromatographic peaks was obtained by using the HPLC instrument software to superimpose five spectra taken across the peaks to calculate the differences in the spectra. No evidence of interfering substances was found. Since the solvents, mobile phase and components of the suspension vehicles were also chromatographically separated from nifedipine, the method was found to be fit for its intended purpose.
A sample of 1.0 ml was taken with an oral syringe (Terumo 1 ml syringe; Terumo, Tokyo, Japan) via a 5 mm adapter after agitation of the suspension. HPLC-grade methanol was added to the light-protected sample to obtain a total volume of 10.0 ml. Using the validated method, the sample was mixed both by using a vortex mixer and by inverting the sample by hand and then blended by hand once an hour over 3 h to ensure the dissolution of nifedipine. A filtered (Premium Syringe filter with minitips 0.2 ∝ m; Agilent Technologies, Waldbronn, Germany) 0.5 ml sample of the resulting nifedipine solution was taken into a HPLC sample vial.
Uniformity of dosage units
The uniformity of dosage units was determined by applying the method for measuring content uniformity for liquid dosage forms described in the European Pharmacopoeia and USP.3 ,21 The test is not a pharmacopoeial requirement for multidose suspensions. Ten units of each suspension were tested. The preparation is said to comply with the test if the AV of the first 10 dosage units is at maximum 15.0. If the suspension did not meet the Pharmacopoeia requirement of AV 15.0, then according to our research protocol, that suspension lot was discarded and a new sample bottle was compounded and tested to confirm the result.
where reference value (M) is defined by the mean of the individual contents (—X) expressed as a percentage of the label claim, when the target content (T) is ≤101.5. The k is the acceptability constant which is 2.4 for 10 samples, and s is the sample standard deviation.
Two parallel nifedipine suspensions of each vehicle were examined. The content uniformity was tested immediately after preparation and after 1, 2 and 4 weeks of storage at room temperature (23 ± 2°C) protected from light. On week 3, only agitations were performed.
At each time point, 10 samples of 1.0 ml were taken with a syringe after mixing the sample bottle by either inverting the bottle 10–15 times or inverting the bottle only three times to mimic the shaking likely in daily practice.
Uniformity of mass
Uniformity of mass of delivered doses from multidose containers was investigated by using the method of the European Pharmacopoeia, which deviates from the USP test for deliverable volume.21 ,22 Twenty samples of 1.0 ml were taken from the freshly prepared nifedipine suspensions mixed by inverting the bottles 10–15 times (from two parallel sample bottles, 10 samples from each bottle). The samples were weighed using an analytical balance (Mettler Toledo AT261, Delta Range; Mettler-Toledo, Greifensee, Switzerland), and the suspensions complied with the test if not more than two of the 20 individual masses deviated from the average mass by more than 10% and none deviated by more than 20%.
The sedimentation volume of the nifedipine suspensions was observed visually over 4 weeks. Suspensions (20 ml) were stored in 25 ml cylindrical graduated flasks in the dark at room temperature (22 ± 2°C). The settled powder sediment on the bottom and the clear supernatant phase on the top of the suspension were measured during the first 6 h, then daily for 4 days and finally once a week for 4 weeks.
Uniformity of dosage units
The content uniformity of all nifedipine 1 mg/ml oral suspensions, compounded with six different suspension vehicles, complied with the test (AV ≤ 15) specified in the European Pharmacopoeia and USP at each time point when the suspension was mixed by inverting the bottle 10–15 times (table 2). However, when the suspension bottles were inverted only three times before sampling, the nifedipine suspensions compounded either with Methylcellulose 1%/Syrup NF or Hypromellose 1% vehicle did not comply with the content uniformity test after 1 week of storage (table 2). The mean nifedipine concentration was 0.28–0.29 mg/ml (table 3) and 0.72–0.77 mg/ml (table 4) in these Methylcellulose 1%/Syrup NF and Hypromellose 1% vehicles, respectively. In contrast, the four commercial suspensions complied with the test at each time point even when they were mixed only by inverting the bottles three times.
Uniformity of mass
The uniformity of mass of all freshly prepared nifedipine suspensions mixed by inverting the bottles 10–15 times complied with the test specified in the European Pharmacopoeia. The maximum deviation from the average mass was −1.2% for the nifedipine suspension made with Suspension Diluent A, ±1.4% with Ora-Plus/Ora-Sweet, −9.8% with Ora-Plus/Ora-Sweet SF and +1.5% with Methylcellulose 1%/Syrup NF vehicle. One individual mass of nifedipine suspension made with SyrSpend SF Cherry and one with Hypromellose 1% vehicle deviated by over 10% from the average mass (−10.4% and −12.7%, respectively).
The sedimentation volume of the unmixed nifedipine oral suspensions was studied for 4 weeks. No visible changes were observed in the suspensions made with Suspension Diluent A and SyrSpend SF Cherry vehicles. In all other suspensions, a slight sediment was noticed. Ora-Plus/Ora-Sweet and Hypromellose 1% had three distinct phases: a yellow solid powder sediment at the bottom of the graduate, a yellow suspension phase in the middle of the suspension and a clear supernatant phase at the top (12 ml and 5 ml, respectively).
After storage for 4 weeks, the unmixed suspensions were resuspended by inverting the graduated flasks several times. It could be clearly observed that the suspensions behaved differently during resuspension. Suspension Diluent A, Ora-Plus/Ora-Sweet and Ora-Plus/Ora-Sweet SF were readily dispersed into a uniform mixture. However, the SyrSpend SF Cherry suspension could not be mixed properly as it remained stuck to the walls of the cylindrical graduated flask. The Methylcellulose 1%/Syrup NF and Hypromellose 1% suspensions required 20–25 and 5–10 s of mixing, respectively, before they formed a uniform mixture.
The amount of shaking was very important in particular for redispersion of nifedipine suspensions compounded with vehicles that were prepared in the dispensary: poorly mixed suspensions did not comply with the requirements of the Pharmacopeia test for content uniformity. Thus incorrect dosage of the medicine could be a real possibility.
The compact sediment at the bottom of the container in nifedipine suspensions compounded with Methylcellulose 1%/Syrup NF or Hypromellose 1% required prolonged shaking before it reconstituted into a uniform suspension. According to guidelines, suspensions should always be shaken well before use to ensure uniform distribution of the solid in the vehicle.3 However, the pharmacopoeia term ‘Shake well before using’ may be understood in different ways in the pharmacy, on the ward and particularly at home. Special caution is thus needed in dispensing extemporaneously prepared oral suspensions in multidose containers8 ,18 since the variation between doses may be remarkable.
After 1 week of storage, the nifedipine suspension prepared with Methylcellulose 1%/Syrup NF failed to provide about 70% of its intended dose if it was shaken only three times (table 3). Because the doses drawn from the bottle were similar and the standard deviation was small, the most likely explanation is cake formation of the suspension. The nifedipine Hypromellose 1% suspension lost less than 30% of the dose during 1 week of storage (table 4). The doses were variable which might be a consequence of the intentional inadequate mixing.
Our results are in agreement with the general rule which recommends the use of commercially available suspension vehicles. The availability and quality of many commercial vehicles are good and thus they can be used with confidence in hospitalised patients and outpatients. Extemporaneously prepared Methylcellulose 1% suspension with Syrup NF is sometimes used in place of Ora-Plus and Ora-Sweet.9 We observed that the redispersion properties of Ora-Plus and Ora-Sweet were better than those of Methylcellulose 1% with Syrup NF. In this study, Methylcellulose 1% and Syrup NF were combined in the ratio 7 : 3 according to a traditional formula. It has been reported that Methylcellulose 1% and Syrup NF dilution in ratios greater than 1 : 1 failed the European Pharmacopoeia quality assurance criteria for efficacy of antimicrobial preservation.23 Sodium benzoate, which is used as preservative, is effective only at pH 5.0 or lower, while the pH of the vehicle was 6.6.12
Ingredients and properties of the vehicles
Excipients to be used in the preparation of suspensions for neonates and infants have to be selected carefully because there are some recommendations and limits of use (table 1). WHO has set an estimated total acceptable daily intake of 10 mg/kg for parabens and 2.5 mg/kg for saccharin sodium.24 Saccharin is approved for children over 3 years of age.5 ,24 ,25 Sodium benzoate can produce non-immunological contact urticaria and non-immunological immediate contact reactions.24 In the UK, the Food Advisory Committee has recommended that carrageenan should not be used as an additive in infant formulas.24 In addition, high osmolality vehicles are inadvisable for neonates and infants. Hypertonic solutions over 400 mOsm/kg may injure the gastrointestinal tract of neonates.12 ,26 These factors should be considered when designing formulations for infants.
Vigorous agitation, that is, inverting the bottle 10–15 times instead of three times, was critical for ensuring the reliability of nifedipine 1 mg/ml oral suspensions compounded extemporaneously from Methylcellulose 1%/Syrup NF or Hypromellose 1%. Nifedipine suspensions prepared with commercial suspension vehicles complied with the Pharmacopeia test for content uniformity of dosage units when mixed by inverting the bottle only three times.
υSelection of the correct suspension vehicle is important for the quality of extemporaneously prepared paediatric oral suspensions.
υInadequate agitation of the suspension may lead to incorrect dosage.
υDetermination of content uniformity is an applicable method for multidose suspensions although it is not a pharmacopoeial requirement.
The advice of Kirsi Kontra, Lic.Sc.(Pharm) is acknowledged. Dr Ewen MacDonald is thanked for reviewing the language of the article.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online appendix
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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