The solution to finding the best formulation

Rolf Rolli, ceo of Swiss company Sotax, discusses recent developments in the dissolution testing of tablets

Since its introduction in the 1960s and acceptance by health regulatory authorities in the 1970s, in vitro dissolution testing of drug formulations has grown rapidly.In vitro dissolution tests are performed to support the rate and amount of drug substance dissolved in certain time intervals. They represent an important tool for characterisation of the biopharmaceutical quality of finished drug products during development and quality control of mainly solid pharmaceutical dosage forms.

Dissolution is an important process in the absorption of the drug into the system. It depends on several characteristics of the drug, such as solubility, particle size and specific surface area, and the formulation of the product. Dissolution testing helps to differentiate between alternative formulations of solid and semi-solid products during preclinical development and clinical trials by choosing the optimal formulation with respect to pharmacokinetics and pharmacodynamics.

Dissolution tests are also an important tool for stability testing to guarantee the properties over the shelf-life during clinical trials and after approval. Furthermore, the tests serve an important role for scale up post approval changes (Supac). Recent research had led to the development of in vitro dissolution tests as a replacement for human and animal bioequivalence studies.

Much time and effort has been invested in automation of dissolution tests. Robotic solutions with sequential operation were introduced as well as the simultaneous operation concept developed by Sotax.

The first guidelines for dissolution testing of solid oral products were published in 1981 and updated in 1997 for beaker methods. The beaker method represents a closed system with a defined volume. The quantity of dissolution medium is limited by the volume of the vessel holding the medium, and this may cause dissolution problems particularly for drugs of low solubility. Agitation is provided by rotation of the stirrer consisting of a basket (apparatus 1) or a paddle (apparatus 2). The paddle is the most widely used method today.

There are a number of limitations with the methods, such as pH changes, which are not so easily performed in a closed system, and in vitro/in vivo correlation is not always good due to the accumulation of the drug in the closed system. Other forms of apparatus were introduced to solve the problems caused by low solubility and limited possibilities for pH changes: apparatus 3 and apparatus 4. Apparatus 4, the most widely used, is a flow-through system that eliminates the drawbacks of limited volume and difficult pH changes. The volume of dissolution medium as well as the release rate depends on the flow rate (4-50ml/min) and the testing time. Agitation is provided by a sinusoidal flow characteristic (pulsation) of the liquid. Several types of cells are available (see Figure 1).

As this USP 4 method is more laborious than USP 1 and 2 methods, Sotax developed a stand-alone unit, the CE 7smart, which is equipped with automated features such as test preparation, solvent change and system cleaning. In an off-line configuration a splitter is used to reduce the sample volume. For medium change procedures the media selector is used. The WinSOTAX software operates the system and executes all necessary calculations

For transdermal products and other formulations apparatus 5, 6 and 7, as defined in the USP methods, were introduced, but these are of lesser importance.

An increasing number of modified drug release products require dissolution tests running for several hours. Laboratories automate dissolution tests to increase capacity and to improve accuracy as manually performed tests lead to high variances in results. Automation concepts offer the advantage of reproducible results and generate all required documentation including calculations, statistical data and graphs. The introduction of 21 CFR part 11 and the FDA's drive for electronic records are further reasons to decide on automated laboratory tests.

Reduction of the costs per test is another consideration. The amount of documentation required for quality control tests is growing, and as a result, the output per lab technician on average is four 30min tests per day, during a normal 8h working day. This results in only 800 tests per year per person. The output could become even lower due to the introduction of the 35h working week in a number of countries and further increases in documentation. This would increase the cost per dissolution test further as additional manual dissolution bath and more staff would be required. To maintain or lower the cost per test an investment in automation is the first choice.

There are different options to automate USP 1 and 2 methods. One of the most laborious operations in a dissolution test is the medium preparation. Some laboratories have outsourced it and use prefabricated media in plastic bags. This reduces the time considerably and improves accuracy as the medium is produced in large quantities, is analysed and shelf-life tested and supplied with CoA. However, the logistical problems of transporting and storing the media are considerable.

A better option is a medium preparation device. Some are simple desktop models with limited volume and features, while others are movable but rather large. The Sotax MPS is a compact model with the following features:

• Mobile and space saving unit;

• Open system, easy to clean, observe and validate;

• Exact preheating of the medium to test temperature and reliable degassing of the dissolution medium

• Continuous maintenance of selected temperature;

• Fast and accurate volumetric filling of test-vessels at 2000 ml/min;

• Use of concentrates with on-line preparation or by sequential addition

• Option of gravimetric self-calibration with built-in balance and automatic report generation.

A fully automated test instrument enables testing of 2000 batches or more per year with limited presence of personnel. When only single tests have to be automated, semi-automated solutions are important. These can be based on a modular concept and can be customised. Off-line and on-line solutions or a combination are available.

In the application of off-line systems the dissolution test and the subsequent monitoring of the samples are separated - very beneficial if shared equipment like spectrophotometers or HPLCs are used to analyse the samples.

There are also different on-line system options available, which measure samples directly, including:

• UV on-line systems with a spectrophotometer

• UV on-line systems with fibre optic probes

• HPLC on-line systems

• Combined system on/off-line

UV on-line systems with a spectrophotometer are widely used and are reliable semi-automated solutions.

With the modular concept, many other hardware configurations like double systems are possible for bio-equivalence studies. In addition, systems allowing pH changes with a media selector for up to three media are possible and enable in vitro/in vivo studies or tests for extended release forms to be performed. Additional options like solvent replacement after sampling and solvent addition for pH change are available.

Also the on-line/off-line option gives the laboratory flexibility either to measure on-line or collect a sample or both. This may be used for multi component drugs where one active substance is measured by means of UV and the other with HPLC.

In addition, in UV measurement a collection of samples is popular as this retainer sample may be tested in case of an unexpected result. In this case only the collected sample is retested and for investigation the test does not have to be completely repeated.

HPLC has replaced UV detection in many cases although the cost of equipment and reagents is much higher. HPLC and dissolution testing do not match very well, as dissolution tests results in a high number of samples, which the HPLC system can be slow to analyse. Sample buffer storage must be used and fraction collection still remains for most labs the optimal solution. But HPLC on-line has its niche applications, with longer test times with one or two sample points. HPLC on-line can also be used for dissolution tests overnight and at weekends. A hardware solution is available which is connected to most commercially available HPLCs.

However, laboratories achieve the highest productivity gain with fully automated systems. There are different system types, such as robotic systems with moving arms, upgrades of regular baths with sampling, medium feed and cleaning devices on the market. A more advanced system is the Sotax AT 70smart. The system is a fully integrated automation system managing all operations in all seven vessels simultaneously. This results in enormous time savings, Figure 2. With this system, up to 15 USP 2 tests are fully automated, from the tablet input up to the print out of the report. The main features are:

• Mechanically very robust to be used 24 hours a day;

• Bottom valves and efficient cleaning system guaranteeing no carryover from test to test;

• High accuracy and reproducibility.

All steps are done simultaneously in all seven vessels for maximum speed, and a high throughput autocompliance concept automatically adjusts paddle height, wobble, sampling position, centreing and sealing of the unit to limit loss through evaporation to <0.5%/24h.

The advanced tablet dissolution software, WinSOTAX, controls the system and contains the methods by which all parameters are specified for the tests. A batch run of methods is programmed. With the start of the run the specified method is loaded and executed starting with media selection and preparation, the supply of tablets, and the test execution with sampling, the filter changes and sample evaluation.

The AT 70smart is equipped with a very efficient cleaning system, with two rotating cleaning heads which spray cleaning solution via four bars into all angles of the system. This prevents any carryover and cross contamination from test to test.

Tests with baskets require additionally the Basket Station BS60. Up to 10 USP 1 tests can be loaded. Several design features prevent any cross contamination at change of the basket. The holding systems for fresh and contaminated baskets are not identical. At test end baskets are precleaned and during lift up of the stirrer unit, shock stops force drops to fall into the vessel. Then the baskets are moved out of the tester and stored in a container and the next six baskets are transferred.

The software for an automated system is considered even more important than the hardware. Since the introduction of 21 CFR Part 11 with its very strict regulations regarding development documentation, change controls and data security, most suppliers are in the process of renewing the software.

top priority

Today, the validation of systems has become the top priority of the pharmaceutical industry laboratory, and manufacturers have worked together with leading pharmaceutical firms to create validation documents including SOPs and test protocols, which are available in different languages.

Dissolution tests are very important to characterise the biopharmaceutical quality of a drug product during development and regular manufacture. Furthermore, dissolution tests are now recognised by the health authorities as one of the most important tests to detect manufacturing variances and maintain a stable quality for a predictive biopharmaceutical response. This has led to an increased number of dissolution tests for the laboratories.

The development and use of automated dissolution test systems helps to cope with the increased number of tests. The required documentation imposes a very heavy burden on the work time of the lab staff.

Automation enables laboratories to be more efficient and to improve the accuracy of their data. Some available automation concepts are very flexible, easy to validate and can be used 24 hours non stop.

Finally the high gain in productivity gives a very quick return on investment. Therefore automation is expected to increase its market share while manual systems are used only for long tests or minor products.