Purpose: Twelve-hour extended release (ER) bi-layer guaifenesin tablets are available as an over-the-counter expectorant in two strengths, 600 mg and 120 mg. USP Monographs: Guaifenesin Tablets describes dissolution as medium: water, 900 mL; apparatus 2, 50 rpm; time, 45 min. Judging from the running time, it is for immediate-release (IR) tablets. We previously proposed to use 50% MeOH as well as USP monograph mobile phase (water, methanol, and glacial acetic acid in 60:40:1.5) to quantify a 12-h 50 rpm dissolution study using 900 mL water at 37±0.5 °C (as monograph suggested) and found both mobile phases quantify 12-h release dissolution samples very closely. The objective of this project was to further examine how dissolution method design (one-stage in water versus two-stage in 0.1 N HCl x 3 h and pH 6.8 x 9 h) and mobile phase factor (USP described versus 50 % MeOH) impacted the release of guaifenesin from the aforementioned 12-h ER bi-layer tablets.
Methods: For two stage dissolution study, a tablet was placed in USP Dissolution Apparatus 2 with 750 mL of 0.1 N HCl in each vessel maintaining at 37±0.5 °C and stirred at 50 rpm for 3 h and, then 250 mL of 0.2 M tribasic sodium phosphate was added, then 2 N NaOH was used to adjust pH to 6.8. The study continued for another 9 h. Sampling schedule was the same for both groups: 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h and 12 h. One part of sample was diluted with 4 parts of 45% methanol (diluent) prior to LC assay.
Results: The release profiles using the USP monograph mobile phase to quantify the samples collected from both dissolution methods (one-stage in water and two-stage: acid and buffer) were found almost identical (n = 4), when the dissolution duration and temperature, paddle stir rate, and sampling schedule were kept the same. When each set of two-stage dissolution samples (n = 4) assayed by two different mobile phases: 50% MeOH and USP monograph mobile phase (pH 3.08) was compared next, both mobile phases were able to quantify the acid stage dissolution samples similarly. But 50% MeOH could only quantify buffer stage samples parallel with those quantify by USP monograph mobile phase with a significant drop in the extent of release (5.94% ± 1.89%, n = 4) when 250 mL of 0.2 N tribasic sodium phosphate and 2 N NaOH was used to adjust the pH into 6.8.
Conclusion: The USP Guaifenesin Monograph mobile phase was able to quantify one-stage (in water) release profiles similarly to those of two-stage (acid x 3 h and buffer stage x 9 h) of 12-h ER bi-layer tablets, which ingredients include FD&C blue #1 aluminum lake (colorant), hypromellose (controlled-release agent), magnesium stearate (lubricant), microcrystalline cellulose (diluent and disintegrant), sodium starch glycolate, (disintegrant), Carbomer 934P NF (gelling agent). The dissolution medium in USP Monographs: Guaifenesin Tablet was 900 mL water, while the two-stage dissolution suggested in General Chapters: <711> Dissolution was 750 mL 0.1 N HCl and then add 250 mL of 0.2 M tribasic sodium phosphate to pH 6.8 in total of 1000 mL. A correction factor must be added prior to the comparison of in vitro releases from these two methods. The drop of extent of release in all pH 6.8 samples of the two-stage dissolution method was probably due to the limit of buffering capacity of 50% NaOH to function as mobile phase. As time efficacy brings affordable products to patients, hope more of such studies to be investigated whether water may be used as the dissolution medium for ER tablets.