Cinnarizine dissolution case study
Formulation:Film coated immediate release tablet
BCS classification:Class II (low aqueous solubility, high permeability)
Indication:Treatment of motion sickness/vertigo
Food effect:Take after food (as per SmPC)
The branded original formulation was used in this case study;
Lactose monohydrate, maize starch, sucrose, talc, magnesium stearate & povidone.
This formulation was tested and compared in different biorelevant media, to assess how pH changes induced by the presence of food influences the dissolution of cinnarizine. Cinnarizine is lipophilic (LogP = 5.77) and basic, so therefore it is expected to be more soluble in media with low pHs and high fat content.
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, 5.56 µg/mL represents 100% of the test dosage being dissolved. A stock solution was produced using reference cinnarizine [Sigma-Aldrich (C5270)] dissolved in mobile phase with a concentration of 10 µg/mL. This was used to produce the calibration standards, as below.
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|Stock solution (mL)||Mobile phase (mL)||Media (mL)||% Max dissolved||Conc. (µg/mL)|
The cinnarizine was tested in 6 different biorelevant media (Table 2), over 2 hours with n=6, according to the Biorelevant fasted dissolution protocol.
|Fasted stomach (FaSSGF)||1.6|
|Fasted intestine (FaSSIF)||6.5|
|Fed gastric - early (immediately after food*)||6.0|
|Fed gastric - middle (0.5-1 hours after food*)||5.0|
|Fed gastric - late (4-5 hours after food*)||3.0|
|Fed intestine (FeSSIF)||5.0|
N.B. * = These time points are estimates based on in vivo data ((Jantratid & Dressman, 2009), (Koziolek et. al, 2014) & (Abuhelwa et. al, 2016)) and serve as a mechanism of looking more biologically at drug dissolution over time.
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Fasted stomach (FaSSGF - pH 1.6)
Cinnarizine exhibited very quick release in the fasted stomach; >75% after 20 minutes. It plateaus at roughly 85%, suggesting that it is solubility rate limited. Most of the dose will be in solution as it passes into the intestine.
Fed gastric (pH 3, 5, 6)
Cinnarizine was tested in fed stomach media at pH 6.0, 5.0 and 3.0, which represent early, middle and late stage respectively.
The dissolution profile of pH6 has the lowest solubility; 24% after 30 minutes, and 63% after 120 minutes. It does not appear to plateau within 120 minutes, suggesting that it has not reached maximum solubility. At pH5 there is a similar dissolution profile but with a higher solubility than pH6; 34% release after 30 minutes, and 78% release after 120 minutes. pH3 has the highest solubility out of the three pHs, as it plateaus at roughly 85% after 45 minutes. These results highlight the pH sensitivity of cinnarizine and demonstrate that it has higher solubility and quicker dissolution at lower pHs.
Fasted intestine (FaSSIF - pH 6.5)
The dissolution rate of cinnarizine in fasted intestinal media is very slow, with low solubility, explained by the high pH. There is 12% release after 2 hours.
Fed intestine (FeSSIF - pH 5.0)
The lower pH of fed intestinal media compared to fasted explains why cinnarizine has a higher solubility; 69% after 120 minutes. There is no obvious plateau, suggesting maximum solubility has not been reached.
These results show that as the dose passes into the intestine, it is likely that any undissolved drug will go into solution much quicker in the fed state compared to fasted.
This case study established that the two main drivers of food effects on the dissolution of cinnarizine are pH and fat content.
As cinnarizine is a base, it has a quicker dissolution in media with lower pHs. It has a rapid dissolution in the fasted stomach (pH 1.6, 86% after 45 minutes), but the dose then moves to the fasted intestine (pH 6.5), where the higher pH means it has a much lower solubility (12% after 120 minutes). This may result in precipitation and therefore less effective absorption (Berlin et. al, 2014).
In the fed state the pH of the stomach is increased, especially in the early stages after a meal. By testing in three different pHs representing different times after food, the results demonstrated that the solubility of cinnarizine increases with decreasing pHs. In the fed intestine the pH is also lower (5 compared to 6.5) which means that cinnarizine is much more soluble (69% compared to 12% after 120 minutes).
Taken together these results support the conclusion that cinnarizine dissolves quickest when taken after a meal.
Effect of high fat content
Cinnarizine is a highly lipophilic drug (LogP = 5.77) which means that it is more soluble in fats than in water. By comparing the dissolution profiles in different media with the close pH values, the effects of a high fat FDA meal can be examined.
Fed stomach medium (pH6) has a much higher fat content than fasted intestinal medium (FaSSIF - pH6.5), with a similar pH. After 120 minutes 78% of the dose had dissolved in the fed stomach medium, compared to 12% in FaSSIF. FaSSIF has a slightly higher pH which will have a minor influence but the difference in % release is largely due to the increased fat content in fed media compared to fasted.
These results confirm that cinnarizine has a higher solubility in media with higher fat content, again supporting the conclusion that it is absorbed more effectively when taken after food.
By looking at the chemistry of a drug, predictions can be made about the influence of pH and fat content, and by testing with biorelevant media these effects can be quantified. In addition, the introduction of fed stomach medium at three different pHs provides a more biological approach, accounting for the dynamic nature of gastrointestinal fluids.
The changing pH of stomach fluid over time coupled with consideration of gastric emptying gives clear and reproducible predictions about how cinnarizine behaves as it moves through the GI tract.
From a bioavailability perspective the results discussed show that cinnarizine is likely to be absorbed more effectively when taken with high fat food compared to without. From a patient’s perspective this is not ideal when used as an antiemetic to treat motion sickness as food intake may be limited.
Ahmad Y. Abuhelwa, D. R. (2016). A Quantitative Review and MetThe AAPS Journal.
Dressman, E. J. (2009). Biorelevant Dissolution Media Simulationg the Proximal Human Gastrointestinal Tract: An Update. Dissolution Technologies, 21-25.
Mark Berlin, K.-H. P. (2014). Prediction of oral absorption of cinnarizine – A highly supersaturating poorly soluble weak base with borderline permeability. European Journal of Pharmaceutics and Biopharmceutics. doi:10.1016/j.ejpb.2014.08.011
Mirko Koziolek, M. G.-P. (2014). Intragastric Volume Changes after Intake of a High-Caloric, High-Fat Standard Breakfast in Healthy Human Subjects Investigated by MRI. Molecular Pharmaceutics. doi:10.1021/mp500022u