Stability of Oral Suspensions of Ursodiol Made From Tablets

Cary E. Johnson and Darcie D. Streetman

Disclosures

Am J Health Syst Pharm. 2002;59(4) 

In This Article

Methods

A liquid suspension of ursodiol 50 mg/ mL (equivalent to 1 tablet per teaspoon) was prepared by crushing 12 250-mg tablets of ursodiol[a] in a glass mortar. Thirty milliliters of Ora- Plus[b] and 30 mL of either strawberry syrup or Ora-Sweet SF[c] were mixed and added to the crushed ursodiol to make a final volume of 60 mL. The strawberry syrup was prepared by mixing 3200 mL of simple syrup, NF,[d] and 600 mL of strawberry fountain syrup.[e]

Six identical samples of each preparation (Ora-Plus and strawberry syrup, and Ora-Plus and Ora-Sweet SF) were prepared and placed into 2- oz amber plastic prescription bottles with child-resistant caps.[f] Three samples of each preparation were stored either at room temperature (23-25 °C) or in the refrigerator (3-5 °C). A 1-mL sample was withdrawn from each of the 12 bottles with a micropipette immediately after preparation and at 7, 15, 30, 60, and 90 days. After further dilution to an expected concentration of 1250 µg/mL with methanol, the samples were assayed in duplicate by HPLC.

The HPLC method developed by Baillet-Guffroy et al.[9] was used for the ursodiol assay. The instrumentation included a constant flow solvent-delivery system[g] and a 250 x 4.6 mm inside diameter, 5-µm particle column[h] maintained at 40 °C with a column heater.[i] A variablevolume injector,[j] an ultraviolet light detectork set at 201 nm, and a recording integrator[l] were also used. The mobile phase consisted of methanol and aqueous 0.01 M dihydrogen potassium phosphate buffer (75:25, by volume) delivered at a rate of 1.2 mL/ min. The pH of the mobile phase was adjusted to 5.25 with dilute phosphoric acid after the addition of methanol.

The stability-indicating capacity of the assay was previously determined in our laboratory and was reevaluated for this experiment.[7] Decomposition of ursodiol[a] was forced by allowing two separate 50-mg/mL samples to stand in direct sunlight for 90 days after adjusting the pH to 12 with 1 N sodium hydroxide or to a pH of 2 with 1 N sulfuric acid solution. The solutions were then heated to 60 °C for two hours. The pH was corrected to 7, and the solutions were diluted with mobile phase to an expected concentration of 1250 µg/mL and assayed. Approximately 50% degradation was achieved with the basic solution, and 75% was achieved with the acidic solution; no interfering peaks were found. The peak for ursodiol appeared at 6.6 minutes. Peaks for two unidentified degradation products were noted at 10.2 and 12 minutes.

A 25-mg/mL stock solution of analytic grade ursodiol[m] was prepared in methanol on each day of sample analysis. Standard samples of ursodiol were prepared by diluting the stock solution with methanol to 1100, 1125, 1250, 1375, and 1500 µg/ mL. A 1250-µg/mL concentration of ursodiol was assayed in duplicate from approximately every tenth sample as an external control. A standard curve was produced on each day of sample analysis by linear regression of the peak heights of ursodiol against ursodiol[a] concentration. The standard curve was linear (r 2 > 0.999) over the working range of concentrations. The between-day and withinday coefficients of variation for the ursodiol assay were 2.42% and 1.23%, respectively.

Each of the ursodiol samples was shaken thoroughly by hand immediately before assay. All samples were centrifuged at 1000 rpm for two minutes to separate the insoluble components. Fifteen microliters of each sample was injected into the HPLC system, and each sample was assayed in duplicate. The samples were visually examined for any color change, evaluated for odor, pH tested,[n] and taste tested on each day of analysis. Microbiological testing was not performed because each vehicle contained effective preservatives.

The stability of ursodiol was assessed by evaluating the percentage of the initial concentration remaining at each time interval. Stability was defined as the retention of at least 90% of the initial concentration. The percentage remaining at 90 days in sugar-free preparations was compared with corresponding percentages remaining in regular preparations using the Mann-Whitney U test. The remaining percentages at 90 days in refrigerated and room temperature preparations were also compared using the Mann-Whitney U test (overall and within sugar-free and regular groups). All p values of <0.05 were considered significant. All data were analyzed by using SPSS for Windows release 10.0.5 (SPSS Inc., Chicago, IL).

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