Improvements to biorelevant dissolution testing: lyophilized media, buffer alternatives and miniaturized apparatus

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Dissolution in different steps of pharmaceutical drug development was considered in this work. Dissolution is used as informative tool throughout the entire development process: After identification of a possible drug candidate, intrinsic dissolution in different buffer media is tested for physicochemical characterization. In galenics dissolution is used to develop and optimize formulations by comparative release studies. During scale-up dissolution testing is used to observe influence of process or parameter changes.
For regulatory affairs all of these dissolution studies are of interest and many have to be presented to the authorities.
Most of the dissolution testing designs in pharmaceutical development are following pharmacopoeial monographs or general chapters and official guidelines. In addition these “official” dissolution testing setups, a progression of more innovative dissolution methods closer to physiological conditions are used. Devices simulating movement and flow of the GIT combined with media simulating the gastrointestinal fluids are often used. Disadvantages of these methods are that they are time-consuming and expensive, both of which limit throughput.

The aims of this thesis were to (a) reduce time consumption regarding preparation of biorelevant dissolution, (b) increase biorelevance of the media FaSSIF and FeSSIF by substituting the non-physiological buffer systems for bicarbonate and © to increase throughput by miniaturization of dissolution devices.

To meet the first goal a novel preparation method for the biorelevant media FaSSIF and FeSSIF was established. The conventional method uses chlorinated organic solvent, is time-consuming in preparation (approx. 2 hours) and needs to be done daily. The investigated method uses freeze-drying for the preparation of instant biorelevant media. The instant media only consist of bile salt and lecithin in mixed micelles. In situ preparation is done by simply adding blank buffer to the rapidly dissolving lyophilisate. Freeze-dried product gave comparable results to freshly prepared media and improved reproducibility.
Comparison to commercial available instant media indicated superiority of the freeze-drying method.

Next, a buffer system based on the more physiological bicarbonate buffer was investigated. A method to maintain a stable buffer system throughout the dissolution testing. The buffer therefore was created by sparging carbon dioxide into alkali saline solution to forming carbonate and bicarbonate as buffer system. At equilibrium the media was transferred to the vessels and supply of carbon dioxide continued by sparging the gas above the solution. Therewith bubble formation could be minimized, although not excluded. Only a small range of buffer strength and pH combinations was possible. The lowest pH still providing effective buffer capacity (5 mmol/l/∆pH) was 5.5. Physiologically relevant buffer capacities of 10 and 30 mmol/l/∆pH were tested at pH 6.5.
The buffer turned out to be very sensitive against pH modifying agents by loosening its buffer capacity and strength. Standard deviations were generally higher. No superiority over conventional buffer systems like phosphate or acetate buffer regarding IVIVC was given.
Therefore it is concluded that bicarbonate buffer is not a suitable medium for in vitro dissolution testing.

Subsequently methods for small scale dissolution testing were established. Improvement of throughput in dissolution testing was achieved. The investigated BI miniDiss method can be used to test release profiles of small particulate formulations or intermediates. High throughput excipient screening for early formulation is possible by using the well-plate method.

In the first series of tests, downscaling by factor 10 was conducted by miniaturizing and automating standard dissolution apparatus. Small vessels of 20 ml volume and paddles of about 8 mm diameter were used. Automating was done by sampling through paddle hollow shafts and online UV/VIS measurement. Since no filtration was possible due to the small sample volume, the true % dissolved was calculated using mathematical scatter correction of spectra from turbid solutions. In this way, release profiles comparable to standard dissolution testing were obtained.
Cleaning and restart is accelerated and therewith throughput increased. The 10fold reduced consumption of drug formulation reduces API consumption, so that a larger variety of formulations can be prepared and tested with the same amount of API.
The BI miniDiss is limited to multiparticulates like pellets, extrudates, minitablets, granules or intermediates. Downscaling of matrix or IR tablets will likely result in different results due to changed surface to volume ratio.

The well-plate method offers a miniaturization of factor 100. Dissolution of multiparticulates showed significant differences compared to standard methods. However, ranking of formulations was possible in several cases. The well-plate method is not suitable for conducting comparative release profiles. However, it can be used for selection of excipients by supersaturation testing. It is an informative tool in early formulation screening helping to optimize formulation of poorly soluble compounds.

As last part of the work, the BI miniDiss was used to screen various buffers to finding the best media for IVIVC, retrospectively. The BI miniDiss proved to be useful as a fast and cost and effective screening method.

In summary, several improvements in dissolution for pharmaceutical development purposes have been developed regarding consumption of API, costs and efficiency. An easy and rapid preparation of biorelevant media was established making their use in pharmaceutical development and routine quality control more feasible. The miniaturized dissolution methods and the improved high-throughput fulfil demands from pharmaceutical industries to facilitate API-saving methods in development.