Purpose: The finished drug product is essential in both modern and traditional medicine and is administered to the patient. Hence, the product has to be of good quality and performance to ensure maximum therapeutic effect after oral absorption.
In order to characterize the performance of such products, compendial dissolution techniques are widely used in the pharmaceutical companies. Even though it is an established area of pharmaceutical sciences, compendial equipment and methods can be limited in their ability to emulate all aspects of in vivo dissolution. This is due to the complex gastrointestinal (GI) environment, such as the effect of absorption and buffer composition/ capacity, and also the dynamics of transit between the different GI compartments.
Therefore, there is a need to optimize test method for drug products to reflect the dynamically changing conditions in the GI tract. Clinically performance tests can help to predict the in vivo performance of a drug product and this can be utilized to increase safety and efficacy of pharmaceutical products, and increase their performance.
This work investigated how biphasic dissolution can be used to address the deficiencies of the traditional dissolution tests to assess drug performance under physiologically relevant conditions.
the study mechanistically investigated key processes in the formulation development (such as different manufacturing processes and excipient composition) with the drug product performance by in vitro non compendial dissolution test at physiologically relevant buffer capacities and biphasic dissolution.
Methods: METHODS: Ibuprofen tablets (400mg) were prepared using different manufacturing processes (wet granulation vs direct compression), and different commonly used excipients (Mycrocrystaline cellulose -MCC, Calcium phosphate, calcium sulfate, calcium phosphate and dextrose monohydrate).
The tablet’s performance were assessed through a biphasic dissolution test. The biphasic system is composed of an organic layer on top of the aqueous layer. The organic layer (n-octanol) replicates the concurrent absorption that occurs in the GIT while the drug is being dissolved. And the aqueous media is a buffer with low capacity which is more physiologically relevant than compendial buffers. The organic layer is stirred with a mini-paddle attached to the aqueous paddle. Compendial dissolution tests were performed for comparison reasons. UV spectrophotometry was used to measure Ibuprofen concentration in both aqueous and organic layer.
The dissolution profiles were compared using a statistical f2 test.
Results: For the MCC, CaHPO4 and CaSO4 the U.S. Pharmacopeia dissolution tests showed no differences between the formulations or manufacturing processes. The low buffer capacity monophasic tests were able to differentiate between the granulate and direct compression formulations but did not reach 100% release, presumably due to media saturation. Additionally, the pH decreased with the drug release. With the biphasic system 100% drug release was obtained, and the additional sink assisted to maintain the medium pH at its initial value.
This higher release for the granulate formulation can be due to the smaller drug particle sizes in the granulates.
In the buffer with lower buffer capacity the dextrose granulate formulation showed a much lower release in the first 20 minutes compared to the other formulations. This can be attributed to a microclimate effect with a lower pH around the drug particle impacting drug dissolution. Once the granules disintegrated the dissolution became API controlled and the dissolution rate was comparable to the other formulations. The USP dissolution test conditions only showed a lower release at 5 minutes but were similar at later time points.
Conclusion: The non compedial dissolution test conditions were able to differentiate the formulations better than the USP methods. The additional sink is important to simulate the absorption process and to maintain the pH in the aqueous media, achieving 100%release. There is a major opportunity in developing in vivo predictive dissolution test methods by using physiologically relevant buffers and buffer strengths. This will benefit patient by having access to better and more efficient drug products, and industry will be able to shorten drug development time which will make new drugs more affordable.
Daniela Amaral Silva– University of Alberta - DDIC, Alberta