Methylcellulose

Abstract

The physical, chemical, and microbial stabilities of extemporaneously compounded oral liquid formulations of sotalol hydrochloride were studied. Sotalol hydrochloride oral liquid suspensions (5 mg/mL) were prepared from commercially available tablets (Betapace) in a 1:1 mixture of Ora-Plus: Ora-Sweet, a 1:1 mixture of Ora-Plus:Ora-Sweet SF, and a 1:2.4 mixture of simple syrup:methylcellulose vehicle. Six batches of each formulation were prepared; three were stored at refrigerated temperature (2° to 8°C) and three at room temperature (20° to 25°C). Samples were collected from each batch weekly for 6 weeks, and again at 12 weeks. Samples were analyzed by means of a high-performance liquid chromatographic method, and the concentrations obtained were compared to the theoretical time zero value. Samples were examined for pH, odor, color, and consistency changes. The suspensions also were evaluated for their microbial stability. Sotalol hydrochloride oral liquid suspensions (5 mg/mL) were chemically stable for 12 weeks regardless of storage conditions (room temperature or refrigerated). Bacterial growth was not supported by any of the formulations. Suspensions stored at refrigerated temperature retained better physical quality (e.g., odor, color, and consistency) than suspensions stored at room temperature. Overall, this study demonstrates that oral formulations of sotalol hydrochloride can be readily prepared with commercially available vehicles. The method of preparation is relatively simple, the materials are relatively inexpensive, and the products have a shelf-life of at least 12 weeks.

Introduction

Extemporaneous compounding is an activity in which an everincreasing number of pharmacists in community and institutional settings are involved. Many pharmacists frequently receive requests to compound medications extemporaneously into alternate dosage forms such as emulsions, syrups, and suspensions. Information on stability and compatibility of many such extemporaneous compounds is limited or not available.

Sotalol hydrochloride (HCl) is effective in treating life-threatening cardiac rhythm disorders in adults,1,2 and is useful in treating rhythm disorders in the pediatric population.3-6 Nevertheless, there are no commercially available oral dosage forms suitable for children or the elderly, many of whom cannot swallow solid dosage forms. Sotalol HCl is chemically stable in aqueous solution in the pH range of 4 to 5.7 Only limited information is available regarding the stability and physicochemical characteristics of sotalol HCl when extemporaneously compounded as an oral liquid formulation.7,8

In a collaborative study conducted by the Hospital for Sick Children in Canada and Bristol Laboratories, Dupuis and colleagues evaluated the physical, microbial, and chemical stability of an extemporaneously compounded sotalol HCl oral liquid formulation.7 The formulation (5 mg/mL) was prepared using the hospital's vehicle formula, which consisted of simple syrup and methylcellulose 1% gel. Although this study demonstrated the stability of this formulation of sotalol HCl, the vehicle utilized in the formulation is not commercially available. Commercially available vehicles differ in formulation additives such as preservatives, suspending agents, and flavoring agents, which could affect the stability of the compounded product. Thus, stability data are needed on extemporaneously compounded formulations using commercially available vehicles.

The objective of this study was to develop an extemporaneously compounded liquid sotalol HCl formulation, and to study its physical, chemical, and microbial stability over a 12-week period.

Materials and Methods

Chemicals

Sotalol HCl tablets (Lot w50048, Betapace 240 mg; Berlex Laboratories, Wayne, New Jersey) were purchased. Ora-Plus (Lot 8A6619), Ora-Sweet (Lot 7L6459), and Ora-Sweet SF (Lot 7H6273) were donated by Paddock Laboratories (Minneapolis, Minnesota). Ora-Plus contains microcrystalline cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, sodium phosphate, and citric acid, with a pH of approximately 4.2. Ora-Sweet contains sucrose, glycerin, sorbitol, citrus-berry flavor, sodium phosphate, and citric acid with a pH of approximately 4.2. Ora-Sweet SF (a sugar-free vehicle) contains glycerin, sorbitol, sodium saccharin, xanthan gum, citrus-berry flavor, citric acid, and sodium citrate with a pH of approximately 4.2. All three vehicles also contain potassium sorbate and methylparaben as preservatives. Methanol, hydrochloric acid, and benzyl alcohol were purchased from EM Sciences (Gibbstown, New Jersey). Methylcellulose (Lot 854188, cps 1500) and sodium benzoate (Lot 853519) were obtained from Fisher Scientific (Pittsburgh, Pennsylvania). High-performance liquid chromatographic (HPLC)-grade water was available in the laboratory. Analytical-grade sotalol HCl was donated by Berlex Laboratories.

Equipment

An Accumet-10 pH meter (Fischer Scientific) was used to determine the pH of the prepared formulations. The HPLC system consisted of the following: a P1000 isocratic pump (Spectra System P 1000; Thermo Separation Products, Riviera, Florida); a manual injector, µ-Bondapak C18 column, 100-µm, 30-cm x 3.9-mm (Waters Associates, Milford, Massachusetts); a UV 1000 detector (Thermo Separation Products); and System 2-Spectra P1000-Software (Thermo Separation Products) for data processing. Titan syringe filters, 0.45 pm, with nylon membrane were used for filtration.

Product Preparation

Sotalol HCl suspensions (240 mL) were prepared using three different vehicle formulas. The vehicle for Formulation 1 was a mixture (1:1) of Ora-Plus and Ora-Sweet. Formulation 2 contained Ora-Plus:Ora-Sweet SF (1:1). The vehicle for Formulation 3 was simple syrup and 1% methylcellulose gel (1:2.4). The final concentration of sotalol HCl in each suspension was 5 mg/mL. The method of preparation is shown in the accompanying box.

To ensure reproducibility of the results, six batches of each formulation were prepared and stored in 8-ounce, airtight, widemouth amber glass bottles, for a total of 18 samples. Of the six batches of each formulation, three were stored at refrigerated temperature (2° to 8°C) and three were stored at ambient temperature (20° to 25°C).

Stability Testing

Physical and chemical stability of the formulations were assessed over a 12-week period.

Chemical Stability

Samples of each formulation were collected weekly for the first 6 weeks, and again at 12 weeks. After the bottle containing the formulation was shaken manually for 15 seconds, a 10-mL aliquot was collected and analyzed for drug content. Stability was defined as the retention of 90% or more of the original theoretical drug concentration during the study period. The apparent pH of each formulation was determined immediately after preparation and again at each sampling interval.

Physical Stability

At each sampling interval, formulations were inspected visually against a white background for evidence of caking and color change. Consistency and ease of resuspension of any settled particles, as well as changes in odor, were evaluated at each sampling interval.

Microbial Growth

Within 24 hours of preparation, a 1-mL sample from each formulation (both refrigerated and stored at room temperature) was inoculated onto a blood agar Petri dish to test for microbial growth. This procedure was repeated 4 weeks after the suspensions were prepared. The blood agar Petri dishes were maintained at ambient room temperature and were inspected weekly for evidence of microbial growth for the duration of the study.

High-Performance Liquid Chromatographic Analysis

The concentration of sotalol HCl in the collected samples was measured by HPLC analysis. A novel HPLC assay for sotalol HCl was developed in the laboratory. The mobile phase consisted of HPLC-grade water and methanol (4:1 v/v), adjusted to pH 2.7 with 1 N hydrochloric acid. The mobile phase flow rate was 1 mL/min. The internal standard was analytical-grade benzyl alcohol. Standard curves were developed using a 1-mg/mL stock solution of sotalol HCl. The following standard concentrations were utilized: 10, 25, 50, and 100 pg/mL. For quality control purposes, check samples (representing sotalol HCl within the lower and upper ranges of the standard curve) also were analyzed.

Ten milliliters from each formulation was collected, placed in a centrifuge tube, and subjected to centrifugation at 3000 revolutions per minute for 10 minutes. Three milliliters of the supernatant were transferred with a 0.450-µm syringe filter into a test tube. From each filtrate, 1.5 mL was collected and transferred to a 100-mL volumetric flask. Then, 70 mL of internal standard solution (benzyl alcohol 15 µg/mL) was added and the sample was completed to volume with HPLC-grade water. A volume of 100 µL was injected into the HPLC system.

The effects of heat, sodium hydroxide (base catalyzed), and hydrochloric acid (acid catalyzed) on sotalol HCl were studied. Tenmilliliter aliquots of sotalol HCl solution (1 mg/mL) were placed in four 100-mL volumetric flasks. The contents of the first flask were completed to volume (100 mL) with HPLC-grade water and were designated as the control solution. One milliliter of 1 N hydrochloric acid was added to the second flask and the contents were completed to volume (100 mL) with HPLC-grade water (pH 2.02). One milliliter of 1 N sodium hydroxide was added to the third flask and the contents were completed to volume (100 mL) with HPLC-grade water (pH 12.04). The the contents of the fourth flask were completed to volume (100 mL) with HPLC-grade water and heated at 90°C. Each experimental condition was maintained for a period of 2 hours before analysis.

To determine whether the vehicles used in the suspensions interfered with the detection of intact drug, the different vehicles also were analyzed by HPLC. Stability was defined as the retention of 90% or more of the original theoretical drug concentration (75 µg/mL) during the study period.

Results and Discussion

All prepared formulations of sotalol HCl were assessed for physical stability. There was no discernable change in color or odor in any of the preparations studied. The slight berry tint of the preparations was maintained throughout the study, as assessed by visual inspection against a white background. All preparations maintained good consistency throughout the study. The formulations were easy to resuspend and no caking was observed. Suspensions formulated with methylcellulosersimple syrup vehicle showed precipitation of particles that were easily redispersed with manual agitation for a longer period of time than needed for the other formulations studied. Suspensions prepared with Ora-Plus:Ora-Sweet and OraPlus:Ora-Sweet SF vehicles appeared to suspend solid particles (i.e., tablet excipients) for longer periods of time.

By the second week of the study, formulations prepared with vehicles containing sugar (i.e., methylcellulose:simple syrup and Ora-Plus:Ora-Sweet) and stored at room temperature developed crystals around the bottle-cap area. There was no evidence of crystal formation in the suspensions stored under refrigeration. It is possible that this crystal formation was due to solvent evaporation followed by condensation. The potential disadvantages of sugar crystallization around the bottle-cap area are bacterial growth and cap-locking, which interferes with cap removal. The crystallization process was accompanied with a slight increase in apparent pH values (Table 1). It should be mentioned, however, that a slight increase in pH without crystallization was also observed in suspensions formulated with Ora-Plus:Ora-Sweet SF. This increase in pH could be attributed to a change in the ionic balance caused by minor attraction between buffering ions of the systems and colloidal components or to the lack of a buffering agent in suspensions formulated with methylcellulose and simple syrup.

On day 1, a 1-mL sample from each formulation was inoculated onto a blood agar Petri dish and evaluated for microbial growth. No microbial growth was observed 24 hours following inoculation with suspensions formulated with Ora-Plus:Ora-Sweet SF vehicle (when stored at room temperature or refrigerated temperature), or with those formulated Ora-Plus:Ora-Sweet vehicle and stored under refrigeration. Microbial growth was observed 24 hours following inoculation with suspensions formulated with methylcellulose:simple syrup vehicle (regardless of storage temperature) or with the OraPlus:Ora-Sweet vehicle stored at room temperature. Specifically, these formulations had evidence of growth of Staphylococcus species.

Microbial testing was repeated 4 weeks after suspension preparation. No evidence of bacterial growth was observed in any of these samples. It appears that the microorganisms isolated from the samples inoculated at the beginning of the study reflect contamination from sources other than the suspension components. The lack of evidence of bacterial growth in the bottles over the testing period is consistent with the presence of preservatives in the formulations.

An HPLC method was developed in the laboratory for measuring sotalol HCl concentrations. In a series of preliminary studies, the effects of heat, acid, and base on the stability of sotalol HCl solution were studied. As shown in Figure 1, no interfering peaks were observed, and the resultant chromatograms showed only the peak of the drug. This indicates that the method is valid under the conditions studied. Likewise, the different vehicles used to prepare the suspension formulations did not interfere with the HPLC assay (data not shown).

Sotalol HCl concentrations were measured at specific time intervals after storage at room temperature and refrigerated temperature. Concentrations obtained were compared to the theoretical time zero concentration (75 µg/mL). The results are presented in Table 2. Sample chromatograms comparing data obtained at baseline and week 12 are presented in Figure 2. Sotalol HCl concentrations measured in the formulations through week 12 were above 90% of the theoretical time zero concentration, as represented in Table 2.

Apparent pH values of all suspensions were measured at each testing interval (Table 1). The pH of all suspensions increased slightly throughout the study period regardless of storage condition. Suspensions stored at refrigerated temperature had apparently higher pH values than suspensions stored at room temperature.

In a previous study, Dupuis and colleagues reported that sotalol HCl extemporaneously compounded in a methylcellulose:simple syrup vehicle was chemically stable for at least 12 weeks and microbiologically stable for up to 8 weeks when stored under refrigeration.7 Nahata and Morosco conducted a study on the physical and chemical stability of sotalol HCl extemporaneously compounded in Ora-Plus:Ora-Sweet (1:1) and in 1% methylcelluloseisimple syrup (1:9) with a sotalol HCl concentration of 5 mg/mL using a different experimental design and method of analysis. They reported that sotalol HCl was chemically and physically stable for 3 months when stored at 25°C or at 4°C.8 These results were similar to the results obtained in the present study.

Conclusion

In this investigation, sotalol HCl was found to be physically and chemically stable and did not exhibit microbial growth when extemporaneously compounded as an oral liquid suspension with different vehicles such as Ora-Plus, Ora-Sweet, Ora-Sweet SF, and simple syrup. In addition, the developed method of analysis is simple and the mobile phase does not require an ion-pairing agent, unlike methods used in similar, previously published studies.

In conclusion, the physical, microbiological, and chemical data obtained from this study support a beyond-use date of 12 weeks for all the formulations studied when stored at refrigerated temperature or room temperature. Although suspensions prepared with methylcellulose:simple syrup were chemically and microbiologically stable when stored under refrigeration, the particles did not remain in suspension for long periods of time, requiring agitation for more time than the other formulations to redisperse the precipitate.

Suspensions prepared with Ora-Plus:Ora-Sweet and Ora-Plus: Ora-Sweet SF vehicles offer the following advantages:

* The vehicles are ready to use.

* The compounding procedure is relatively simple.

* The materials are relatively inexpensive.

References

1. Campell TJ, Gavaghan TP, Morgan JJ. Intravenous sotalol for the treatment of atrial fibrillation and flutter after cardiopulmonary bypass. Comparison with disopyramide and digoxin in a randomized trial. Br Heart J 1985; 54(1): 86-90.

2. Kunze KP, Schluter M, Kuck KH. Sotalol in patients with Wolff-Parkinson-White syndrome. Circulation 1987; 75(5): 1050-1057.

3. Pfammater JP, Paul T, Lehmann C et al. Efficacy and proarrhythmia of oral sotalol in pediatric patients. J Am Coll Cardiol 1995; 26(4): 1002-1007.

4. Maragnes P, Tipple M, Fournier A. Effectiveness of oral sotalol for treatment of pediatric arrhythmias. Am J Cardiol 1992; 69(8): 751-754.

5. Colloridi V, Perri C, Ventriglia F et al. Oral sotalol in pediatric atrial ectopic tachycardia. Am Heart J 1992; 123(1): 254-256.

6. Tanel RE, Walsh EP, Lulu JA et al. Sotalol for refractory arrhythmias in pediatric and young adult patients: Initial efficacy and long-term outcome. Am Heart J 1995; 130(4): 791-797.

7. Dupuis LL, James G, Bacola G. Stability of sotalol hydrochloride oral liquid formulation. Can J Hosp Pharm 1988; 41(3): 121-123.

8. Nahata M, Morosco R. Stability of sotalol in two liquid formulations at two temperatures. Ann Pharmacother 2003; 37(4): 506-509.

Madiha B. Sidhom, PhD

Division of Pharmaceutical Sciences

Long Island University

Brooklyn, New York

Nadya Rivera, PharmD

Division of Pharmacy Practice

Long Island University

Brooklyn, New York

Hassan Almoazen, PhD

Department of Pharmaceutical Sciences

Drake University

Des Moines, Iowa

David R. Taft, PhD

Division of Pharmaceutical Sciences

Long Island University

Brooklyn, New York

Harold L. Kirschenbaum, MS, PharmD

Division of Pharmacy Practice

Long Island University

Brooklyn, New York

Address correspondence to Madiha B. Sidhom, PhD, Division of Pharmaceutics, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201. E-mail: msidhom@liu.edu

Copyright International Journal of Pharmaceutical Compounding Sep/Oct 2005
Provided by ProQuest Information and Learning Company. All rights Reserved