Stability of Domperidone in Extemporaneously Compounded Suspensions

Abstract

Introduction: The recent withdrawal from the market of cisapride has prompted many practitioners to prescribe domperidone as the agent of first choice for patients requiring a gastrointestinal motility-enhancing agent. While domperidone is available in a solid dosage form (i.e. tablet) for oral use, pediatric and other patients who are unable to swallow tablets require an alternative dosage form.

Objectives: To evaluate the stability of 1 and 10 mg/mL domperidone suspensions in a vehicle consisting of equal parts of Ora-Sweet and Ora-Plus after storage at 25oC and 4oC for a maximum of  91 days.

Methods: Suspensions of domperidone 1 and 10 mg/mL, prepared from domperidone maleate tablets, were placed in 50 mL amber plastic bottles. Three bottles of each suspension were stored at 25oC (room temperature) and 3 were stored at 4oC (refrigerated). Physical characteristics including pH, color, odor, viscosity, precipitation, and ease of resuspension were observed weekly for 91 days. Aliquots were removed from each bottle weekly and stored at -85oC until analysis using a high performance liquid chromatography method. A suspension was considered stable if it maintained 90% of its initial concentration.

Results: No change in pH was observed in suspensions of either concentration after storage at 25oC or 4oC for 91 days.  Changes in color and odor were not noticeable and viscosity was constant. Precipitates were easily resuspended and there was no caking or clumping of material. Suspensions of both concentrations of domperidone maintained at least 90% of initial concentration at both temperatures throughout the 91-day period.

Conclusions: Domperidone suspensions of both 1 and 10 mg/mL in a 1:1 mixture of Ora-Sweet and Ora-Plus were physically and chemically stable for a period of up to 91 days, both at room temperature and under refrigeration. The expiration date for these products can thus be set at 91 days.

Introduction

The recent withdrawal from the market of cisapride has prompted many practitioners to prescribe domperidone as the agent of first choice for patients requiring a motility-enhancing agent. While domperidone is available in tablet form for oral use, pediatric and other patients who are unable to swallow tablets require an alternative dosage form. As a result of its relative insolubility in water, the alternative oral preparation of domperidone is a suspension.  At our hospital, domperidone suspension has been extemporaneously compounded by crushing domperidone maleate tablets and suspending with a methylcellulose vehicle prepared by our pharmacy staff. The suspension was given an empirically-based expiration date of 8 days for refrigerated storage. This short expiration date meant that hospital pharmacy staff had to prepare the suspension frequently and discharged patients had to refill their prescriptions frequently.  This, and the additional work in preparing the methylcellulose vehicle, led to relatively high expenditures of both time and money for both parties.

A commercially-available vehicle (1:1 mixture of Ora-Sweet®:Ora-Plus®, a sweetening and suspending agent, respectively) has recently emerged as an alternative to methylcellulose. This newer vehicle eliminates many of the disadvantages associated with methylcellulose, since it is less labor-intensive, is available to both hospital and community pharmacies, and is consequently more convenient for outpatients. However, stability information for domperidone in Ora-Sweet®: Ora-Plus® does not currently exist.

This study involved an examination of the  physical characteristics and chemical stability (defined as maintenance of more than 90% of initial concentration) of extemporaneously prepared oral domperidone suspensions of 1 and 10 mg/mL in a 1:1 mixture of Ora-Sweet® and Ora-Plus®, stored at either 25oC or 4oC throughout a 91-day study period.

Methods

Preparation and Evaluation of Suspension

Domperidone suspensions (1 and 10 mg/mL) were prepared in triplicate from commercially-available tablets of domperidone maleate (Motilium®, Novopharm, Scarborough, Ontario), containing domperidone 10 mg per tablet, and mixed with equal parts of Ora-Sweet® and Ora-Plus® (Paddock Laboratories Inc., Minneapolis, MN, lots OE6324 and OH6525, respectively). Six replicates of each concentration were prepared in separate 50-mL amber plastic prescription bottles, three of which were stored at 25oC (room temperature) and three at 4oC (refrigerated). 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.  All suspensions were visually examined (against white and black background), for color changes and precipitates, odor changes, layering, sedimentation, ease of resuspension, and gas formation. A fresh sample of each concentration was prepared and compared to a 1 mg/mL sample at 25oC, 1 mg/mL at 4oC, 10 mg/mL at 25oC and 10 mg/mL at 4oC for each of the original samples. Immediately following these physical observations, each suspension bottle was manually shaken for 10 seconds, pH was determined, and initial and weekly samples were removed and stored at –85oC until batch-analysis by a stability-indicating high performance liquid chromatography (HPLC) method.

Preparation of Stock and Standards

Stock solutions of domperidone at 0.50, 0.250, 0.125, 0.0625, and 0.0312 mg/mL were prepared by dilution of analytical-grade domperidone (Apotex Inc, Toronto, Ontario, lot X99207) in HPLC-grade methanol (Fisher Scientific, Richmond, British Columbia, lot 002129). The internal standard was propranolol (Sigma Aldrich, Oakville, Ontario, lot 90K0523) 0.250 mg/mL in HPLC-grade methanol. Standard solutions were prepared by further diluting a 0.1 mL aliquot of each stock solution and a 0.1 mL aliquot of propranolol 0.250 mg/mL to 1 mL with HPLC-grade methanol to obtain final concentrations of 0.05, 0.025, 0.0125, 0.0062, and 0.0031 mg/mL domperidone. This dilution step was necessary to achieve optimal chromatographics. Prior to injection, all standard solutions were passed through a 0.45-mm  microfilter (Acrodisc GHP syringe filter, Gelman, Ann Arbor, Michigan, lot 5874) to prevent injection of impurities onto the column.

The HPLC instrumentation (model 2690, Waters Alliance System, Waters Ltd., Mississauga, Ontario) consisted of a delivery pump, an automatic injector equipped with a 200-uL injector, Nova Pak  3.9 x 20 mm guard column (Waters Ltd., lot W10721), a Nova-Pak C18 3.9 x 150 mm column (Waters Ltd., lot W02901M082), and an ultraviolet detector set at 205 nm (model 2487 dual-wavelength absorbance detector).  The mobile phase was developed in the authors’ laboratory and consisted of a 45:5:50  (v/v) mixture of methanol (Fisher Scientific, lot 002129): acetonitrile (Fisher Scientific, lot 007395): 0.02M potassium phosphate buffer (Sigma Aldrich, lot 90K0523, pH 3.0).  All solvents were HPLC-grade and filtered before use. The flow rate was set at 1.2 mL/min.

A 5-point calibration curve was prepared with a blank (methanol) at the beginning of each run to ensure that there was no carry-over from one run to the next.  The range of this calibration curve (0.031 to 0.05 mg/mL before dilution) encompasses the diluted concentrations of the 10 mg/mL and 1 mg/mL samples, respectively.  The calibration curve was generated by least-squares regression of the ratio of the peak area of domperidone to that of propranolol versus the concentration of each standard solution. The precision of the assay was evaluated by intra-day and inter-day validation methods.  Intra-day variation was determined by running 0.031, 0.125 and 0.250 mg/mL stock solutions (diluted to standards of 0.003, 0.0125, and 0.0250 mg/mL.) in quadruplicate throughout a single day, whereas the inter-day variation was determined by running the same concentrations (as in the testing for intra-day variation) in quadruplicate daily for 4 days.  The means, standard deviations, and coefficients of variation were calculated.  Acceptable limits for the coefficients of variation were defined a priori as less than 10%.

Degradation of Domperidone

Degradation of the drug was achieved as follows: domperidone (tablet 10mg/mL in methanol) was diluted 1:100 in water to a concentration of 0.1 mg/mL, and 0.5 mL hydrochloric acid 6N (Fisher Scientific, lot 299067) was added. This solution was incubated in a water bath at 95oC for 1 hour. Then, 0.5 mL of sodium hydroxide 10N (Fisher Scientific, lot SC9105042) was added and the solution was returned to the water bath at 95oC for 1 hour. After incubation, the solution was boiled for 15 minutes. The domperidone peak of the sample was compared to a standard (1 mg/mL) to determine changes in concentration, retention time, and peak shape.

Preparation of Samples

For each study sample, domperidone 1 mg/mL and 10 mg/mL were diluted to theoretical concentrations of 0.05 and 0.250 mg/mL, respectively. The diluted samples were centrifuged at 10,000 RPM for 5 min and then processed in a manner similar to that of the stock solutions.   Each solution was passed through a 0.45-mm microfilter before a 10-mL sample was withdrawn and injected onto the column.

Statistical Analysis

The means, standard deviations and coefficients of variation were calculated for samples analyzed in triplicate and quadruplicate.  For each study day, the percentage of the initial domperidone concentration remaining was calculated for each sample.  The percentage of domperidone remaining on day 91 was calculated from the concentration on day 91 as determined by linear regression and concentration observed on day zero, according to the following formula: concentration on day 91/concentration on day zero x 100.  The 95% confidence interval (CI) of the amount remaining on the last study day was calculated from the lower limit of the 95% CI of the slope of the curve relating concentration to time, determined by linear regression, according to the following formula: lower limit of the 95% CI of the concentration on day 91/concentration on day zero x 100. Stability was determined as maintenance of at least 90% of the initial domperidone concentration.

Results

Regression analysis of the HPLC assay validation showed linearity over the working range of concentrations, with coefficients of determination (r2) greater than 0.998 (n=4).  The intra-day (n=4) and inter-day (n=4) coefficients of variation for the 3 different concentrations were within acceptable limits: 2.13% and 9.1%, respectively for the 0.031 mg/mL solution: 0.29% and 1.62%, respectively for the 0.125 mg/mL: 0.28% and 0.68%, respectively for the 0.250 mg/mL solution.

When domperidone was subjected to degradation, a major degradation product eluted at 1.48 min and one other minor degradation product could be detected at 2.7 min in the chromatogram (Figure 1). Neither of these products interfered with the quantification of the parent compound, domperidone.

No significant changes in physical appearance or odor of the suspensions were observed throughout the 91 days. Each cloudy white suspension had a faint sweet smell, maintained the same viscosity, and was easily resuspended throughout the study period. Furthermore, no significant fluctuations in pH were observed. The mean pH (± standard deviation) was 4.27 ± 0.07 for the 1 mg/mL suspension stored at 25oC, 4.40 ± 0.09 for the 1 mg/mL suspension stored 4oC, 4.44 ± 0.06 for the 10 mg/mL suspension stored at 25oC, and 4.60 ± 0.10 for the 10 mg/mL suspension stored 4oC.

The retention time of domperidone was 2.2 minutes, while the retention time of the internal standard propranolol was 3.2 minutes (Figure 1).  Results of the HPLC analysis show that at both storage temperatures, the 1 mg/mL and 10 mg/mL suspensions maintained at least 90% of their initial concentrations on every study day (Table 1).  Furthermore, about 96% of the initial domperidone concentration remained on day 91, according to linear regression analysis of the concentration-time data, and the lower limit of the 95% confidence interval indicated that more than 92% of the initial concentration remained on day 91 (Table 1).

Table I. Mean Domperidone Concentration + Standard Deviation (and Mean Percentage Remaininga) during 91 Days of Storage at 25oC and 4oC

Study Day 1 mg/mLb 
25oC
1 mg/mL b
4oC
10 mg/mLb 
25oC
10 mg/mL b
4oC
0 1.14 ± 0.045 1.10 ± 0.116 10.00 ± 0.65 10.53 ± 0.63
7 1.15 ± 0.18 (97.8%) 1.12 ± 0.06 (101.6%) 10.10 ± 1.18 (100.4%) 10.99 ± 0.44 (104.3%)
14 1.09 ± 0.12 (96.3%) 1.08 ± 0.07 (97.9%) 10.10 ± 0.38 (100.6%) 9.97 ± 0.20 (94.6%)
21 1.11 ± 0.23 (97.0%) 0.99 ± 0.04 (90.1%) 9.90 ± 0.66 (98.2%) 9.83 ± 1.73 (93.3%)
28 1.13 ± 0.24 (99.1%) 1.18 ± 0.20 (106.8%) 9.44 ± 0.87 (93.9%) 10.70 ± 0.46 (101.9%)
35 1.36 ± 0.04 (119.1%) 1.24 ± 0.10 (112.7%) 9.90 ± 1.93 (98.7%) 10.00 ± 2.11 (94.8%)
42 1.07 ± 0.08 (96.6%) 1.03 ± 0.24 (93.1%) 10.00 ± 0.34 (99.7%) 10.12 ± 0.69 (96.1%)
49 1.10 ± 0.20 (96.1%) 1.18 ± 0.26 (106.9%) 10.10 ± 0.76 (100.9%) 9.67 ± 0.47 (91.7%)
56 1.21 ± 0.22 (109.4%) 1.04 ± 0.25 (93.8%) 10.29 ± 1.05 (102.3%) 9.64 ± 1.06 (91.5%)
63 1.05 ± 0.12 (92.5%) 1.03 ± 0.29 (93.4%) 11.55 ± 0.36 (114.8%) 9.69 ± 0.90 (92.0%)
70 1.05 ± 0.26 (92.1%) 1.06 ± 0.16 (96.1%) 10.30 ± 0.66 (102.4%) 10.02 ± 1.20 (95.2%)
77 1.17 ± 0.31 (102.2%) 1.08 ± 0.23 (99.8%) 10.50 ± 0.14 (104.2%) 10.57 ± 0.19 (100.3%)
84 1.09 ± 0.02 (95.7%) 1.05 ± 0.11 (95.6%) 9.72 ± 0.52 (96.7%) 10.74 ± 0.92 (101.9%)
91 1.11 ± 0.05 (97.4%) 1.02 ± 0.12 (92.7%) 9.91 ± 1.14 (98.5%) 19.97 ± 1.78 (94.5%)
% remaining on day 91c 103.93 106.55 96.32 102.68
Lower limit of 95% CI
for % remainingd
92.75 94.49 93.78 93.17

CI = confidence interval

aPercentage remaining was calculated in relation to the initial concentration (day zero)
bNominal concentration

cCalculated from concentration on day 91 as determined by linear regression and concentration observed on day zero, according to the following formula: concentration on day 91/concentration on day zero x 100.

dCalculated from lower limit of 95% CI of the slope of the curve relating concentration to time, determined by linear regression, according to the following formula: lower limit of 95% CI of concentration on day 91/concentration on day zero x 100.

Figure 1:

Upper panel: chromatogram showing domperidone peak at 2.2 min and the propranolol peak at 3.2 min.

Lower panel: chromatogram of the degradation study showing degradation products at 1.48 and 2.7 min, respectively.

Discussion

Until the time of this study, domperidone suspension had been prepared at our institution in a methylcellulose vehicle. This product had an expiration date of only 8 days when kept refrigerated. To our knowledge, there are no published stability studies on domperidone suspension prepared in a 1:1 mixture of Ora-Sweet® and Ora-Plus®.

In our weekly analysis of samples, color and odor changes were not noticeable, and samples were easily resuspended without caking, clumping, or crystal formation. Although these measures are qualitative, observations were documented by the same individual throughout the 91-day study period, thus eliminating potential inter-personnel bias. Variation in pH was not notable.

A limitation of this study design relates to the freezing of samples at –85oC until the time of batch analysis. It was assumed that domperidone would not degrade at this low temperature and that no volume losses would occur because of freeze-drying during storage. In addition, it was assumed that errors due to serial analysis would have been greater than any errors occurring with batch analysis. Furthermore, the variability in measured concentrations at various time points is greater than the assay’s coefficients of variation and suggests the need for the patient or caregiver to shake the suspension well before measuring each dose.

According to qualitative and HPLC analyses of weekly samples, domperidone suspensions of 1 mg/mL and 10 mg/mL stored at either 25oC or 4oC remained stable and maintained at least 90% of their original concentrations for up to 91 days. These results led to changes at our hospital for extemporaneous compounding of domperidone suspensions and the expiration date has been extended from 8 days to 3 months.

Funding Source

The study was supported by British Columbia’s Children’s Hospital Telethon Innovations Fund and the B.C. Research Institute of Child and Women’s Health Investigator Establishment Award. Analytical-grade domperidone was provided as a gift from Apotex Inc.

Acknowlegement

The authors would like to acknowledge Mr. Paul M. Koke for his assistance in project logistics.

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