Fully-automated system for dissolution rate of solid oral dosage forms according to the paddle method

This paper describes a fully-automated system (AUTO DISS®) for the determination of active ingredient release of solid oral dosage forms according to the paddle method of the US Pharmacopoeia (USP) and European Pharmacopoeia. Twenty batches can be tested continuously, with the six individuals (tablets, capsules etc.) of one batch being examined synchronous. The components of the AUTO DISS® system are presented and the operating steps of automatic filling with dissolution medium, dropping in of tablets, sampling and cleaning of vessels are described. Suitability for testing controlled-release drugs by means of automated buffer change from simulated gastric fluid to simulated intestinal fluid according to USP is also demonstrated. On-line determination of active ingredient concentration, as well as evaluation and documentation of measured values, is possible using an integrated automatic sampler in combination with various measuring instruments. The AUTO DISS® system is shown to be both rugged and accurate.


Introduction
Dissolution testing of solid oral dosage forms plays an important part in: (1) The development of new products, especially for optimizing the bioavailability of a drug substance.
(2) Stability testing, i.e. to detect changes in drug release as a result of different storage conditions.
(3) Quality control testing, i.e. to establish lot-to-lot equivalence of formulations.
The most widely used dissolution method is the paddle method, proposed by Levy and Hayes in 1960 [1] and modifed by Poole [2]. This test is an essential item in almost all pharmacopoeias. Data for registration at the CTA (Clinical Trial Application) and NDA (New Drug Application) stage must be included in the submitted documentation.
As the manual procedure ofdissolution testing is expensive and time-consuming, researchers began proposing ways of automating the sampling and determination of the dissolved drug soon after the introduction of dissolution testing [3][4][5][6][7][8][9]. Sampling techniques are now highly advanced and complete installations are offered by vendors. These approaches to automating dissolution have reduced the time required for the test. The scope of automation, however, is restricted to testing a single batch. A fully automated system capable of analysing more than one batch must perform additional activities such as sampling, dropping of tablets into vessels, draining of dissolution medium, cleaning and drying of vessels mechanically.
Dissolution testing can be automated using laboratory robots [10][11][12]. These systems are now sophisticated enough to execute more complicated operational steps of the kind required in dissolution testing.
One serious disadvantage of robotic automation, however, is that all working steps have to be carried out sequentially, resulting in long processing times. Dissolution profiles with short sampling intervals are especially problematic.
Moreover, because of their limited flexibility robotic systems are frequently ill-suited to processing smaller series of test samples involving a frequent change of method.
The present paper describes a more advanced system [13][14][15], it differs from laboratory robotic systems in that it can carry out all operating steps synchronously. The apparatus (AUTO DISS(R), Manufacturer: Pharma Test, Apparatebau GmbH Siemens Strasse 5, D63512 Hainburg, Germany) is also suitable for fully automated testing of sustained-release dosage forms. This requires mechanically implemented change of buffer from simulated gastric fluid to simulated intestinal fluid according to USP.

Concept
In drug release testing by the paddle method, the following basic operations can be combined into a single cycle: (1) Filling of vessels with dissolution medium.
(2) Heating of medium to required temperature.
(3) Dropping of dosage forms into vessels. (4) Adjustment of paddle speed.    implemented and a printout obtained via the PC-based controller after the analytical determination. Method and data management is performed on a data-base system.

Components
The (1) (2) (5) (6) system comprises the following elements (see figure ): Paddle apparatus with six vessels for tests and two vessels for blank and reference standard. The vessels and paddles are modified to allow draining of medium, rinsing and drying to be carried out automatically.
Magazines for each vessel (under nitrogen) storing tablets or capsules for up to 20 batches. An automatic system equipped with syringes and valves for filling the vessels with dissolution medium, changing the pH of the medium (important for sustained-release dosage forms) and transferring the samples to an autosampler.  The dimensions of the vessel and paddle correspond precisely to those specified in the USP XXII. A valve assembly consisting of the following parts is flange-mounted on the base of the dissolution vessel (1): a stainless steel screw thread (3) joined to the vessel and the screw-on valve assembly (4). Permanently connected to part (4) is the guide bush (6) and (8) containing the freely movable Teflon plug (2) and steel spring (7). Also mounted on part (4) is the olive (5) as connector branch for a drain tube. The stirrer consists of the paddle (11) which is welded to the metal tube (10). The paddle shaft (9) is connected to the channels (12) in the paddle. Figure 2 also shows the upper end of the paddle shaft (9) and (10), which projects above the drive unit housing of the drug release apparatus (18). The metal housing (16) encases the paddle shaft and is fixed with the lock nut (17) and the paired seal rings (15), the upper shaft seal ring being connected to the screw fitting (14). The connecting branch (13) for water and compressed air supply is joined directly to the screw fitting (14).

Sample magazine
The sample magazine is installed above the front part of the drug release apparatus. This magazine consists of a stainless-steel plate with a 15 mm diameter hole for each dissolution vessel. The plate is provided with circular, rotatable Teflon disks with a diameter of 14 cm and a thickness of 16 mm.
Located around the periphery of each disk are 20 holes each with an internal diameter of 14 mm; these holes serve as containers for the dosage forms under test. With the aid of a motor, all six disks can be rotated synchronously so that the solid dosage form drops into the release medium when the hole in the disk is aligned directly above the hole in the plate. The sample magazine is protected against external influences by an acrylic glass hood. The magazine can also be aerated with air or nitrogen to prevent after-hardening of tablets or adhesion of soft gelatin capsules to the container wall due to steam from the heating bath during prolonged residence times.

Dispenser station
The dispenser station consists of eight syringe units which supply the sample vessels and the vessels for blank or reference standard solutions. The dilutors (50 ml volume), which are driven by the same motor, are used to fill the dissolution vessels with medium, withdraw samples and transfer the solutions to the automatic sampler, and to modify the pH of the dissolution medium when testing controlled release drugs. Each dilutor is connected to an eight-way valve. These valves allow media, such as buffer solutions or various release solutions, to be transferred to the vessels.  Autosampler A Gilson 232/401 is preferred as autosampler, as it has a maximum capacity of 360 samples; it can also be used simultaneously as a sample injection system, as it has rheodyne valves. With the aid of the Gilson dilutor the collected test solutions can be transferred directly to the measuring instruments, such as spectrophotometer, highperformance liquid chromatograph or flow-injection system.

Controller
The AUTO-DISS apparatus is controlled and monitored by a microprocessor (MS DOS, IBM compatible). Standard software is employed for entering and storing methods and data for evaluation and documentation.
Software for on-line processing by means ofGilson 232/401 Operating procedure The operating procedure for one cycle, in which all the steps from filling the vessels with dissolution medium to cleaning and drying of the vessels are controlled automatically via a microcomputer, is shown in figure 3. As many as 20 cycles can be processed automatically in succession, with up to six individual tablets being tested per cycle. Before starting serial testing, parametrization is performed via the dialogue program. The following variables are established: (1) Number ofcycles (max N 20, i.e. 20 x 6 tablets).
(3) Temperature of dissolution medium (rain RT/max 45C).     After establishing the parameters, the dissolution vessels are filled simultaneously with dissolution medium from a storage vessel by means of a syringe system. After a constant temperature has been reached, the microcomputer activates the drive motor for the sample magazine. When the motor has moved the sample magazine one step hole onward, it is switched off by the microcomputer. The samples to be tested fall simultaneously through specially positioned holes into the individual dissolution vessels. The paddles are then set in motion. The solutions to be measured are transferred according to a preselected program via the dispenser station directly to a Gilson 232 autosampler, or, optionally, to the multicell transport system of a spectrophotometer. For sustained-release preparations, the dispenser station also changes the pH buffer from simulated gastric fluid in all dissolution vessels simultaneously. In accordance with Method A of USP XXII, 250 ml quantities of buffer solution are pumped from storage containers through integrated valve circuits directly into the receiving vessels each containing 750 ml 0"IN hydrochloric acid. Automatic drainage of the dissolution medium, cleaning and drying of t'he vessels and .paddles are described in detail in [13,14]. After this cleaning step, the first cycle is completed and the dissolution vessels can be refilled with dissolution medium.

Suitability and validation of the AUTO DISS system
To prove the suitability of the dissolution tester, a series of experiments was performed. In the following the results and experimental procedure according to USP XXII for dissolution testing of calibrator tablets are presented; buffer change experiments are then described which prove the suitability of the AUTO DISS system for testing the release of sustained-release dosage forms; and, finally, the robustness of the system is demonstrated by a 700 hour continuous test. Dissolulion @prednisone and salicylic acid tablets Prednisone tablets Test preparation: prednisone tablets 50 mg, lot J.
Evaluation: The dissolved active ingredient concentrations were determined against prednisone USP XXII retrence standard.
Evaluation" The dissolved active ingredient concentrations were determined against salicyclic acid USP XXII reference standard.
Results: The active ingredient release specifications are complied with by the prednisone and the salicylic acid tablets, since all the individual values are within the specified tolerance limits. It is noticeable that the standard deviations within the test series show comparatively low values. The reproducibility of the tablet release profile is therefore good, and the dissolution vessels are very homogeneous in relation to each other.

pH change
In vitro simulation of the conditions in the gastrointestinal tract, especially in testing of sustained-release or enteric dosage forms, requires a pH change from simulated gastric fluid to simulated intestinal fluid. These tests involving buffer change are very time-consuming and should therefore be automated. The AUTO .DISS system was therefore designed to provide automated change of buffer, for which the following criterion must be met.
The US Pharmacopoeia stipulates a pH of 6"8 with a tolerance of __.0"05 pH units when changing the buffer from simulated gastric fluid (0"1 mol/1 hydrochloric acid) to simulated intestinal fluid with the aid of phosphate buffer solutions. To ensure compliance with this narrow tolerance, the AUTO DISS system incorporates a highly precise dispenser station with additional switching valves for solvents for all dissolution vessels.

Robustness of the AUTO DISS system
The AUTO DISS apparatus was subjected to a stress test in which the system was kept in continuous operation for about 700 hours. Analyses were performed both on development products with a low active ingredient content (pramipexole tablets 0"1 mg) and on licensed products of the Lonarid series (tablets with 500mg paracetamol, 0"5 mg dihydroergotamine and 10 mg codeine phosphate). Altogether 526 batches and/or stability samples were tested during the investigational period (N 6; 3156 samples). As well as checking the reproducibility of the products (of known content uniformity), particular attention was paid to assessing the mechanical robustness of the AUTO DISS apparatus.

Comment
During the 700 hour long-term test, no mechanical deficiencies were observed, except for a rapidly repaired leak in one dilutor. All other mechanical moving parts, such as media drain valves, eight-way valves, dispenser unit and the Gilson 232/401 autosampler, worked perfectly. Neither were there problems with the sintered glass filters for the samples, problems of entrainment of active ingredients in the cleaning operations or problems of adsorption on tubing.
All the individual data recorded were within the specified requirements. The reproducibility of the groups of investigated products exhibited similar coefficients of variation as the content uniformity of the corresponding products. It can therefore be concluded that the entire system operates reproducibly. The positive general impression obtained for the AUTO DISS apparatus allows the conclusion that the system is extremely reliable and therefore suitable for use in the development and quality-control areas.

Discussion
Manual testing of active ingredient release from oral dosage forms using the paddle method is the most time- Xm consuming operation in the analytical characterization of drugs. Filling, buffer change (for controlled-release drugs), emptying and cleaning operations in particular are mindless activities for laboratory staff. Automating these operations results not only in more streamlined performance of dissolution testing but also in standardization of techniques. With the AUTO DISS system, as many as 20 determinations can be carried out in a 24-hour rhythm. This represents a considerable increase in capacity. Combining the various analytical methods, for example spectrophotometry (including diode array spectroscopy), liquid chromatography and flow injection analysis with the AUTO DISS system increases the flexibility of the system. The requirement for laboratory staff is thereby reduced and technicians are relieved of time-consuming routine work.