Exemestane dissolution case study

Introduction

Drug name:Exemestane
Drug type:Neutral
Formulation:Film coated immediate release tablet
BCS classification:Class II (low aqueous solubility, high permeability)
Indication:Treatment of advanced breast cancer (Aromatase inhibition)
Patient guidance:Take after a meal
background drug-particle

Exemestane dissolution
case study

Introduction

wave wave wave wave

Two different formulations were used in this case study;

Formulation name
Dose (mg)
Excipients

Aromasin (Pfizer)

25

Excipients

Silica colloidal hydrated, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, sodium starch glycollate (type A), polysorbate, polyvinyl alcohol, simeticone, macrogol, sucrose, magnesium carbonte light, methyl parahydroxybenxoate (E218), cetyl esters wax, talc, carnauba wax, ethyl alcohol, shellac, titanium oxide (E171) and iron oxides (E172).

Formulation name
Dose (mg)

Actavis

25

Excipients

Povidone K30, maize starch (bleached), starch, pregalatinized (partially), sodium starch glycolate type A, cellulose microcrystalline type 101, talc, silica colloidal anhydrous, magnesium stearate, polysorbate 80, polyvinyl alcohol (partially hydrolyzed), macrogol 3350 and titanium dioxide (E171).

These formulations were tested and compared in biorelevant media. Aromasin (Pfizer) is the originator formulation, and Actavis is a generic formulation, therefore they should be bioequivalent. The similarity of their dissolution profiles in biorelevant media gives an indication of how similarly they will behave in vivo.

Method

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.

Test product dose (mg)
25
Dissolution volume (mL)
900
Dilution factor for HPLC samples
3
Maximum concentration (mg/mL)
0.00926

Thus, 0.00926mg/mL represents 100% of the test dosage being dissolved. A stock solution was produced using reference exemestane [Sigma-Aldrich (PHR1634)] dissolved in mobile phase with a concentration of 0.0144mg/mL. This was used to produce the calibration standards, as below

Slide right ->

Stock solution (mL) Mobile phase (mL) Biorelevant media (mL) % Max dissolved Conc. (mg/mL)
0.2000 0.0000 0.100 103.68 0.0096
0.1500 0.0500 0.100 77.88 0.0072
0.1000 0.1000 0.100 51.92 0.0048
0.0750 0.1250 0.100 38.94 0.0036
0.0500 0.1500 0.100 25.96 0.0024
0.0250 0.1750 0.100 12.98 0.0012
0.0125 0.1875 0.100 6.49 0.0006

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;

f2 = 50 ∗ log⁡{ √1 + ( ) ∑(R t − T t ) 2 ∗ 100}

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.

wave wave wave wave

Results

Slide right ->

Fasted stomach (FaSSGF - pH 1.6)

graph1

In the fasted stomach the dissolution profiles closely resemble one another (f2 = 64.07), with the reference (Aromasin) being marginally quicker than the generic (Actavis). This suggests bioequivalence in vivo.

The % release of the Aromasin and Actavis after 60 minutes is 92.1% and 88.9% respectively. This suggests that most of the dosage will be in solution as it passes from the stomach to the intestine.

Fed gastric (pH 5.0)

graph2

In the fed state Aromasin exhibits a quicker dissolution (after 20 minutes: 90.1% in fed, 77.1% in fasted). Actavis exhibits a slower dissolution in fed gastric medium in the first 10 minutes (45.7% in fed, 55.5% in fasted), but is quicker for the remainder of the 2 hours (after 30 minutes: 90.8% in fed, 79.4% in fasted). Overall, both formulations exhibit quicker dissolution rates in the fed state, which suggests that more of the dose will be in solution as it passes into the small intestine.

The different food effects on the formulations mean that there is a significant difference between their dissolution profiles (f2= 38.14). This is most likely due to the slower release of Actavis in the first 10 minutes, as both profiles reach 100% release after 45 minutes.

Fasted intestine (FaSSIF - pH 6.5)

graph3

In the fasted intestine the dissolution profiles of both the reference (Aromasin) and generic (Actavis) formulation are very similar (f2 = 79.06). This level of similarity suggests that the two formulations are bioequivalent in vivo.

They both experience quick release in FaSSIF; over 80% release within 20 minutes. This suggests that most of the dosage will be available for absorption in the small intestine and is solubility rate limited.

Fed intestine (FeSSIF - pH 5.0)

graph4

The dissolution rate of both Aromasin and Actavis is marginally faster in the fed intestine compared to the fasted (Aromasin 100% release: 45 minutes in fed, 60 minutes in fasted). This slight difference is likely because of the increased levels of lipids in the fed state, given exemestane’s lipophilicity (LogP = 3.70).

Once again there is no significant difference between the two formulations (f2 = 73.61). This f2 value suggests bioequivalence.

Discussion

General behaviour and food effects

In the fasted stomach, exemestane exhibits moderately quick release, with roughly 90% dissolved after 60 minutes. This suggests that in the fasted state most of the dosage will be in solution as it passes into the fasted intestine. Coupled with the quick dissolution rate in the fasted intestine it is likely to be absorbed quickly.

However, exemestane dissolved faster in the fed stomach than in the fasted, with 100% release after 45 minutes. In the fed intestine the dissolution profile was marginally quicker, with 100% release after 45 minutes compared to 60 minutes in the fasted state. Exemestane is a highly lipophilic drug, and so is likely to be more soluble when lipid quantities are higher, as in the fed state. Patients taking exemestane after a high-fat breakfast experienced 40% higher plasma concentration of the drug, with a Tmax of roughly 1.2 hours (FDA, 2005)*.

Comparison of different formulations

The reference (Aromasin) and generic (Actavis) formulation had very similar dissolution profiles in all four biorelevant media. The f2 comparison value was >50 in FaSSIF, FeSSIF and FaSSGF, suggesting bioequivalence.

However, the f2 value for fed gastric medium was 38.14, which represents a significant difference. By referring to the graph, it can be assumed that this difference is a result of the first two time points (5 & 10 minutes), where Actavis has a slower dissolution rate. This difference is limited to these time points however; both formulations reach 100% release within 45 minutes. By considering the slowed gastric emptying in the fed state it is unlikely that there is much difference in vivo.

Summary

This case study demonstrated that exemestane is a lipophilic, solubility rate limited drug that has increased bioavailability in the fed state as a result.

The release profiles of the Actavis generic exemestane formulation closely resembled the Aromasin (Pfizer) reference formulation, suggesting bioequivalence. This case study shows the use of biorelevant media gives a quick and clear indication of whether two formulations will be bioequivalent in vivo, an essential hurdle to clear during generic drug development.

* https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020753s006lbl.pdf