Stability of Aminophylline in Extemporaneously – Prepared Oral Suspensions

Abstract

Rationale: Oral aminophylline liquid formulations are not available in Canada. The advent of a commercially-available vehicle (1:1 Ora Sweet:Ora Plus) provides an alternative to extemporaneous compounding, but stability information is unavailable for aminophylline in oral suspensions prepared with this newer vehicle.

Objectives: To evaluate the stability of aminophylline 3 mg/mL (pediatric) and 21 mg/mL (adult) in the Ora Sweet:Ora Plus vehicle, at 4°C and 25°C, over a period of 91 days.

Methods: Triplicate suspensions were prepared in 50 mL amber glass prescription bottles using aminophylline injection 25 mg/mL. For each concentration, six bottles were filled; three were stored at 4°C (refrigerated) and three at 25°C (room temperature).  Samples were removed from each bottle initially and at weekly intervals, at which time their physical appearance, odour, and pH were also examined.  The samples were stored in a -85°C freezer until batch-analysis by a validated stability-indicating high performance liquid chromatography (HPLC) assay using ultraviolet detection at 254 nm.  Percent of initial drug concentration remaining was calculated for each sample.  Stability was defined as maintenance of at least 90% of initial drug concentration.

Results: The majority of the opaque white suspensions had a sweet smell and were easily resuspendable; however, the 21 mg/mL suspensions stored at 4°C formed white needle crystals within 7 days.  Other than the crystal formation, no significant changes in physical appearance, odour, or pH were observed over the course of the study.  The results of the HPLC analysis revealed that the 3 mg/mL suspensions at both temperatures (4°C and 25°C) and the 21 mg/mL suspensions at 25°C maintained at least 90% of their initial concentrations.  However, the 21 mg/mL suspensions stored at 4°C failed to maintain 90% of initial concentration.

Conclusions: At the end of 91 days, aminophylline is both chemically and physically stable in 1:1 Ora Sweet:Ora Plus as a 3 mg/mL suspension stored at 4°C and 25°C, and as a 21 mg/mL suspension stored at 25°C.  Accordingly, the expiration dates of these specific suspensions can be extended to 90 days.

Introduction

Aminophylline, the ethylenediamine salt equivalent to 79% theophylline, has long been used in pulmonary diseases including asthma, chronic bronchitis, and emphysema.  In our hospital, aminophylline is primarily used as a respiratory stimulant for first-line treatment of apnea of prematurity. Solid oral dosage forms of aminophylline are undesirable in this pediatric population.

While several liquid formulations of aminophylline are marketed in the United States, none are commercially available in Canada. Liquid theophylline preparations are available in Canada (e.g. Theolair® liquid (3M), Theophylline elixir (Technilab) and Theophylline solution (Desbergers); however, in some institutions such as ours, these preparations are not used due to concerns about potential excipient-related toxicities.

Commercially-available theophylline solution products contain excipients (e.g., sorbitol, alcohol, propylene glycol) that are inappropriate for the pediatric population, particularly the neonatal and infant age groups.  Specifically, Theolair® contains sorbitol which may be associated with gastrointestinal side effects such as osmotic diarrhea and abdominal pain. The alcohol content in theophylline elixir combined with the reduced activity of alcohol dehydrogenase in children may result in accumulation and potential acute toxicity until this enzyme system reaches adult levels of activity. Theophylline solutions that contain propylene glycol may put premature infants at risk for displacement of bilirubin and consequently hyperbilirubinemia. Excessive intake of propylene glycol and subsequent metabolism to lactic acid may also cause the development of hyperosmolality and lactic acidosis. Other additives such as flavouring agents and dyes may also be problematic.

As a result of our reluctance to use commercially available products, we extemporaneously compound oral aminophylline preparations for use in our pediatric patients.  To date, our oral aminophylline suspensions have been prepared in a methylcellulose vehicle and given, based on historical procedures, an empirical expiration date of 7 days.  The methylcellulose suspensions present some significant problems, including intensive labour, inability by community pharmacists to prepare, short expiration dates and inconvenience to outpatients; all of these factors are expected to lead to increased costs to the health-care system.

A commercially-available vehicle (1:1 mixture of Ora Sweet:Ora Plus (footnote a), a syrup and suspending agent, respectively) has recently emerged as an alternative to methylcellulose.  Ora Sweet (footnote a) contains purified water, sucrose, glycerin, sorbitol, and flavoring, with citric acid and sodium phosphate as buffers, and methyparaben and potassium sorbate as preservatives.  Ora Plus (footnote a) contains purified water, microcrystalline cellulose, carboxymethylcellulose sodium, xanthan gum, carrageenan, citric acid and sodium phosphate as buffers, simethicone as an antifoaming agent, and methylparaben and potassium sorbate as preservatives.  Ora Sweet:Ora Plus has been widely accepted as a suitable vehicle for use in the pediatric population due to the lack of inappropriate additives.  Furthermore, this newer vehicle is expected to eliminate many of the disadvantages associated with methylcellulose, since it is reportedly easier to work with and more readily available in the community.  However, stability information for aminophylline in Ora Sweet:Ora Plus is not currently available.

Pharmaceutical stability is defined as the extent to which a product retains, within specified limits and throughout its period of storage and use (i.e., shelf-life), the same properties and characteristics that it possessed at the time of manufacture. The types of stability pertinent to our study include chemical and physical stability.  Chemical stability refers to the integrity and labeled potency of the active ingredient and physical stability refers to the maintenance of the original physical properties and appearance.

Objective

The objective of the study was to evaluate the stability of aminophylline 3 mg/mL (pediatric) and 21 mg/mL (adult) in oral suspensions, extemporaneously prepared with the Ora Sweet:Ora Plus vehicle at 4°C and 25°C over a period of 91 days.

Methodology

Preparation of oral suspensions

The suspensions were prepared in triplicate using commercially-available aminophylline injection 25 mg/mL (footnote b) in the 1:1 Ora Sweet:Ora Plus vehicle.  The 3 mg/mL (pediatric) and 21 mg/mL (adult) concentrations represent those used in clinical practice.  For each concentration, six 50 mL amber glass prescription bottles were filled; three were stored in the refrigerator and three at room temperature.  The mean temperatures (± standard deviations) in these two environments over the course of the study were 3.0 ± 1.3°C and 25.2 ± 1.6°C.  All bottles were exposed only to the fluorescent lights in the laboratory.

Qualitative evaluation of physical appearance took place initially and at weekly intervals up to 91 days; aliquots were removed from all amber bottles and examined for colour changes and precipitates (against white and black backgrounds), odour changes, layering, sedimentation, caking, ease of resuspension, and gas formation.  pH was also determined at the same time (footnote c).  Immediately following these physical observations, each suspension bottle was manually shaken for 10 seconds, and initial and weekly samples were withdrawn.

These samples were stored in a -85°C freezer until batch-analysis by a stability-indicating high performance liquid chromatography (HPLC) method. Our column, mobile phase, and chromatographic conditions were identical to the methods previously reported. All samples were analyzed within a time period of less than one month.

For details on preparation of stock and standard solutions and preparation of samples, see Appendix.

Results

The regression analysis of the HPLC assay validation showed linearity over the working range of concentrations [r2 > 0.999 (n=5)].  The intra- and inter-day coefficients of variation (CV) for the three different concentrations were within the acceptable limits of < 1%.  For the 1 mg/mL standard solution, the CV for intra-day (n=4) and inter-day (n=4) variability were 0.08% and 0.65%, respectively;for the 3 mg/mL solution, the CV were 0.15% and 0.22%, respectively; and for the 5 mg/mL solution, the CV were 0.09% and 0.19%, respectively.

The qualitative evaluation of physical appearance showed no significant changes in the majority of suspensions.  Throughout the study, most of the opaque white suspensions had a sweet smell and were easily resuspendable.  The only exceptions were the 21 mg/mL suspensions at 4°C, which formed white needle-like crystals, variable in size, by Day 7.  Over the course of 91 days, the pH of the 3 mg/mL samples ranged from 5.5 to 6.0; the pH range of the 21 mg/mL samples was 8.5 to 9.2.  The mean pH ± standard deviations for these solutions were 5.7 ± 0.1 (3 mg/mL samples at 4°C), 5.6 ± 0.1 (3 mg/mL samples at 25°C), 9.0 ± 0.1 (21 mg/mL samples at 4°C), and 8.7 ± 0.1 (21 mg/mL samples at 25°C).  Overall, no major changes in physical appearance, odour, or pH were observed, other than the aforementioned crystal formation.

The retention time of aminophylline was 2.8 minutes, while the internal standard, 5-methylresorcinol, was retained for 6.5 minutes (Figure 1).

FIGURE 1. Representative chromatogram, showing the aminophylline peak at 2.8 minutes and the 5-methylresorcinol peak at 6.5 minutes.

Results of the HPLC analysis show that the 3 mg/mL suspensions at both temperatures (4°C and 25°C) and the 21 mg/mL suspensions at 25°C maintained at least 90% of their initial concentrations;however, the 21 mg/mL suspensions at 4°C failed to maintain 90% of initial concentration (Table 1).

TABLE 1. Average percent remaining of the triplicate samples over 91 days.

Initial Concentration* (mg/mL) 2.80 ± 0.07 2.79 ± 0.07 19.21 ± 0.60 19.48 ± 0.11
Storage Temperature (°C) 4 25 4 25
% Remaining* Day 7 99 ± 3.2 99 ± 4.5 81 ± 1.0 96 ± 2.9
Day 14 102 ± 9.8 99 ± 1.5 80 ± 1.9 99 ± 0.8
Day 21 95 ± 1.8 102 ± 6.5 76 ± 1.5 100 ± 0.5
Day 28 96 ± 7.4 91 ± 8.9 76 ± 5.3 94 ± 4.0
Day 35 94 ± 11.2 101 ± 6.1 77 ± 1.1 99 ± 1.5
Day 42 105 ± 2.6 103 ± 2.3 78 ± 0.5 101 ± 1.2
Day 49 102 ± 6.1 98 ± 0.5 76 ± 0.6 101 ± 0.4
Day 56 104 ± 13.8 103 ± 10.3 80 ± 6.4 99 ± 1.6
Day 63 100 ± 14.9 103 ± 2.5 77 ± 3.4 101 ± 1.5
Day 70 93 ± 4.1 97 ± 5.0 74 ± 1.3 101 ± 0.7
Day 77 93 ± 1.6 96 ± 1.3 75 ± 3.0 101 ± 0.9
Day 84 95 ± 5.3 95 ± 3.2 74 ± 1.7 100 ± 3.0
Day 91 100 ± 4.7 103 ± 6.1 82 ± 2.3 108 ± 1.2

*Mean ± standard deviation, n=3.

Discussion

To our knowledge, no published information regarding the stability of extemporaneously-prepared aminophylline in the Ora Sweet:Ora Plus vehicle existed prior to this study.  We were able to demonstrate that the expiration date for aminophylline oral suspensions can be extended past the traditional 7-day empirically determined limit for methylcellulose suspensions.  At the end of 91 days, we found aminophylline to be both chemically and physically stable in 1:1 Ora Sweet:Ora Plus as 3 mg/mL at 4°C and 25°C, and as 21 mg/mL at 25°C.The white needle crystal formation in the 21 mg/mL aminophylline suspensions at 4°C was unexpected.  Most likely, this observation can be explained by temperature effects on drug solubility, ultimately leading to crystal growth.  The crystal formation is also a probable explanation for the large drop in the percentage of drug remaining; since more drug has precipitated out as crystals, less is remaining in suspension (i.e. the portion from which the sample is taken).  The instability of the refrigerated high concentration extemporaneous aminophylline suspensions may warrant the use of commercial theophylline preparations for adults who cannot tolerate oral solid dosage forms.  This should not pose a problem since the additives used in commercial formulations pose less of a toxicity risk to adult patients.

The pH of the 3 mg/mL concentration was different from that of the 21 mg/mL suspensions. This is not surprising, given that the volume of the original 25 mg/mL injectable solution differs for the two concentrations.  The 3 mg/mL required only a small volume of injectable aminophylline which resulted in a small change from the pH of the Ora Sweet:Ora Plus vehicle.  However, the 21 mg/mL preparation was mostly injectable aminophylline and only a small amount of vehicle which resulted in a more alkaline pH.

Our preparation guidelines and storage recommendations for aminophylline suspensions in Ora Sweet:Ora Plus may enable improved patient care and reduced costs to the health-care system.  Labour costs (i.e., pharmacy technician time) appear to be lower when the suspensions are prepared in Ora Sweet:Ora Plus as compared with preparation using methylcellulose. Since the vehicle is commercially available, community pharmacists can prepare the Ora Sweet:Ora Plus suspensions, negating the need for outpatients to return to our institution for this purpose.  Although aminophylline tablets are likely more readily available in the community setting, the injection is advantageous since it overcomes the problem of incomplete tablet grinding or crushing, thus creating a more uniformly dispersed suspension.  Lastly, the longer expiration dates (91 days versus 7 days) reduce the number of dispensing events, and consequently lower costs for the patient.

Conclusions

At the end of 91 days, aminophylline is both chemically and physically stable in 1:1 Ora Sweet:Ora Plus as 3 mg/mL at 4°C and 25°C, and as 21 mg/mL at 25°C.  The expiration dates of these suspensions can be extended beyond our current practice of 7 days, leading to benefits for the patient, the pharmacy and the health-care system.  Due to crystal formation, aminophylline suspensions prepared according to our methods in Ora Sweet:Ora Plus were not physically stable as 21 mg/mL at 4°C.

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