Ibuprofen dissolution case study
Formulation:Film coated immediate release tables
BCS classification:BCS IIa (poorly soluble and highly permeable)
Food effect:None, can be taken with or without food
Patient guidance:Take with a drink of water
Two different formulations were used in this case study;
Maize starch, microcrystalline cellulose, croscarmellose sodium, povidone, colloidal anhydrous silica, alginic acid, sodium lauryl sulfate, sodium starch glycolate, magnesium stearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, polythene glycol, erythrosine (E127) and titanium dioxide (E171)
Brufen Forte (Mylan)
Microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, silicon dioxide, sodium lauryl sulphate, magnesium stearate, hypromellose, talk and titanium dioxide (E171)
These formulations were tested and compared in biorelevant media, to mimic a generic dissolution study, where the main aim is to ensure that the dissolution profiles of the test product and reference drug match. Performing such a study using biorelevant media also gives a clearer insight into how the drug will behave in vivo.
The Biorelevant pre-experimental tips on dissolution were carried out to ensure the USP2 and HPLC-UV analysis were working accurately and reliably. The tablets sank in the USP2 vessels, and no coning was observed at 75 rpm.
The calibration standards for HPLC analysis were produced according to the maximum concentration of the test dose, which is calculated below.
Thus, 0.0667mg/mL represents 100% of the test dosage being dissolved. A stock solution was produced using reference ibuprofen [Sigma-Aldrich (PHR1004)] dissolved in mobile phase with a concentration of 0.0800mg/mL. This was used to produce the calibration standards, as below.
|Stock solution (mL)||Mobile phase (mL)||Biorelevant media (mL)||% Max dissolved||Conc. (mg/mL)|
The two different ibuprofen formulations were then tested in 900mL of fasted (FaSSIF (pH6.5) & FaSSGF (pH1.6)) and fed (FeSSIF (pH 5.0) & fed gastric (pH 5.0)) media, over 2 hours with n=6, according to the Biorelevant fasted dissolution protocol.
To compare two dissolution profiles, the similarity factor (f2) is often used, as calculated below;
Where R and T refer to the reference and test product respectively, t represents a given time point, and n represents the number of time points measured. The f2 is not the most accurate measure of similarity and should be taken with caution, nonetheless it provides a useful benchmark.
Fasted stomach (FaSSGF - pH 1.6)
The dissolution profiles of the Almus and Brufen Forte match exactly (f2 = 97.17). In fasted stomach (FaSSGF), the dissolution rate of ibuprofen is low, with <5% drug release after 20 minutes, and it reaches a plateau of approximately 6.5% drug release after 120 minutes. Thus, very little drug is released in the fasted stomach, but it remains chemically stable.
Fed stomach (pH 5.0)
In the fed state both formulations exhibit a much quicker dissolution rate; >95% release within 45 minutes. This is most likely due to the increased pH (5.0 compared to 1.6). Therefore, it is likely that 100% of the dose will be in solution as it passes into the intestine, but the slower gastric emptying in the fed state means that the quicker release doesn’t necessarily lead to a quicker absorption. Almus is significantly slower than Brufen Forte (f2 =30.48), a difference that is pronounced in the first 45 minutes, after which both formulations reach 100% release.
Fasted intestine (FaSSIF - pH 6.5)
In the fasted intestine the dissolution profile of Almus is significantly slower than Brufen Forte (f2 = 32.76), after 10 minutes Brufen Forte has 74% release, while Almus has 40%. We hypothesise that this is due to the disintegration properties of the Almus tablet film coating.
This difference, however, is unlikely to have a strong effect in vivo as both profiles reach >90% release within 30 minutes. This dissolution rate coupled with the high permeability of ibuprofen suggests both tablets will achieve complete absorption in the intestine, Almus may just have a slightly delayed Tmax.
Fed intestine (FeSSIF - pH 5.0)
In the fed intestine compared to fasted, the dissolution rate of both formulations is slightly slower, respectively. This demonstrates that the presence of food has a weak effect on the dissolution rate, but >90% release within 60 minutes suggests that near complete absorption is likely to occur, just with a delayed Tmax compared to in the fasted state.
As in the fasted intestine, Almus was significantly slower (f2 = 35.25); 33% release after 15 minutes, compared to 63% release in Brufen Forte. The Almus tablets appeared to disintegrate much more slowly than Brufen Forte.
General behaviour and food effects
In the fasted stomach, ibuprofen undergoes minimal (6.5%) release due to the low pH but remains chemically stable. It then undergoes rapid and complete dissolution and absorption in the fasted-state intestine, reflecting ibuprofen’s efficacy when taken on an empty stomach.
In the fed state it achieves a much higher % release in the stomach (100%) due to the increased pH, but the slower gastric emptying coupled with the slower dissolution rate in the intestine means suggests a delayed Tmax . In vivo results of ibuprofen concentrations over time in the fed and fasted state support these conclusions (Koenigsknecht et. al, 2017)*.
Comparison of different formulations
The dissolution rates of Almus tablets were significantly slower (f2 < 50) than Brufen Forte in FaSSIF, FeSSIF and fed gastric medium. A low f2 value may be due to factors such as the excipient matrix or disintegration. The Almus (840mg tablet weight) displayed a slower disintegration of the film coating compared to the Brufen Forte (800mg tablet weight); the difference in weight suggests that it could be a thicker film coating, or the presence of extra excipients may be having an effect.
It is also important to note that at the site of absorption (the intestine) both formulations exhibit quick and complete dissolution in the fasted (>90% release within 30 minutes) and fed (>90% release in 60 minutes) state. Given ibuprofen’s high permeability, these results suggest that both formulations will achieve complete absorption of the dose in vivo, but Almus is likely have a slightly delayed T due to the formulation of the film coating.
This case study demonstrates how testing in biorelevant media can give the user a much clearer idea of how the test formulation behaves in the presence and absence of food in vivo, in this case the predicted food effects reflect data from an in vivo study. It also allows a precise comparison between different test formulations; the ability to discriminate subtle differences during formulation development is extremely valuable.
*M. J. Koenigsknecht et. al (2017, September 22). In Vivo Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract Under Fed and Fasted Conditions. Molecular Pharmaceutics. DOI: 10.1021/acs.molpharmaceut.7b00425