Probes da Distek não causam interferência.

Tem sido uma constante, escutar comentários a respeito de probes estacionários de amostragem da Distek. Por isso, transcrevemos, abaixo, um estudo da Farmacopéia dos Estados Unidos (USP) divulgando os resultados de testes de dissolução, usando probes da Distek. Analise e verifique os fatos verdadeiros e entenda, por que a Distek, mais uma vez, se mostrou confiável, tecnicamente (sublinhamos alguns trechos para destaque). Se desejar ver uma cópia do registro original, clique aqui para consultar (se você tiver o Adobe Acrobat Reader instalado em seu computador) ou para baixar o arquivo USP-DISTEK.pdf (954 Kb).

1996 The United States Pharmacopeial Convention, Inc.

Pharmacopeial Forum - Volume 22, Number 3, pp. 2423-2424
May-June 1996

STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies of the USPC or the USP Committee of Revision

Dissolution Calibrator Tablets: A Recommendation for New Calibrator Tablets to Replace Both Current USP Calibrator Tablets

Terry W. Moore, Food and Drug Administration, Division of Drugs Analysis1
Ralph F. Shangraw and Yacoub Habib, University of Maryland at Baltimore

Introduction

The Food and Drug Administration’s Division of Drugs Analysis (DDA) published articles in 1983 (1) and 1995 (2) showing that the USP Prednisone and Salicylic Acid Calibrator Tablets are not suitable for calibrating dissolution apparatus or detecting dissolved gases in the medium. In 1979 DDA found a commercial 10-mg prednisone tablet, which was called the NCDA #2. These tablets were not found useful for calibrating the basket method, but when the paddle method was used, NCDA #2 was extremely sensitive to dissolved gases in the medium and was more sensitive to system alignment than the USP calibrator tablets. At DDA we have been using these tablets as na in-house calibrator tablet since 1979.
The NCDA #2 calibrator tablet method calls for testing six tablets at 50 rpm with the paddle in 50 mL of degassed water for 30 minutes. The acceptance limits were set in 1980. A range of 30% to 50% of label claim dissolved was established for individual tablets, and range of 35% to 43% was established for the mean of six tablets. Technique and equipment have improved considerably since the original ranges were established. Recently we have re-evaluated these ranges based on the data collected over the past 3 years and have revised them. The new ranges are 28% to 44% of label claim for individual tablets and 30% to 40% for the mean six tablets.
In 1994 we provided the University of Maryland at Baltimore (UMAB) with a tablet formulation that we thought would produce tablets with characteristics similar to NCDA #2. In December 1994 eight different tablets lots were made at UMAB with various combinations of disintegrant blending times, and compression force. Tests at DDA showed that all lots were extremely sensitive to dissolved gases in the medium. Lot 2H was chosen for further tests because the results in degassed water duplicated most nearly the NCDA #2 results. In March 1995 and July 1995 two additional lots (2H-2 and 2H-3) were made at UMAB to see if the lots could be reproduced and retain their sensitivity to the parameters that affect dissolution results. The results with the NCDA #2 tablets have shown that the tablets have remained stable over the past 16 years (3). The new formulations should remain just as stable.


Experimental Conditions

Apparatus - A Distek Dissolution Apparatus Model 2100, with Distek paddles, baskets, and vessels, was used.2 Distek vessels are supplied with self-centering plastic collars that will center the vessels to within USP specification of ± 2 mm. For all runs, except as noted in Table 1, each vessel was centered as precisely as possible at the top of the vessel with a nylon VanKel centering tool3 by rotating the vessel in the designated apparatus plate. Each vessel was marked and returned to the same hole and in the same orientation for all runs.

A Hewlett-Packard (HP) Automated Multi-Bath Dissolution Testing System4 with a 5-mm flow cell was used for all automated sampling from the dissolution vessels. Distek sampling probes (1,68-mm OD stainless steel capillary probes fitted with na external 10-µm Distek disposable filter) were used for all tests, except where noted in the tables. It has been shown that the Distek probes do not affect dissolution results (2).

For all tests with the paddle, the paddles were turning in the medium at 50 rpm before the tablets were dropped into the medium, except where noted in Table 2. For all tests with the basket, the baskets were turning before they were lowered into the medium.

The apparatus was set to conform with all USP specifications except where those specifications were deliberately changed, as noted in the tables.

Reagents - The purified water in our laboratory at DDA contains a large amount of dissolved gases. The amount of these dissolved gases may vary daily. All degassing for this study was done by DDA in-house degassing procedure, as follows.

A 5-gallon glass carboy is fitted with a 2-hole rubber stopper, and a short glass tube of nominal 9-mm OD is inserted in the stopper and connected to a filter flask trap and utility electric vacuum pump. A longer 9-mm OD glass tube is inserted in the other stopper hole so that the end of the tube is less than 1 cm from the button of the carboy. The other end is connected to a closed-tube manometer capable of measuring pressure in the 0 to 150 mm Hg range. The manometer is equipped with na adjustable small air leak valve. The pressure inside the carboy is adjusted to a manometer reading of 140 to 150 mm Hg by partially closing off the leak valve. The medium is equilibrated by bubbling air through it at this pressure for ³ 20 minutes. The stopper is loosened, or the vessel is otherwise vented to atmospheric pressure, and the pump is shut off. The long tube can be conveniently used as a siphon for the degassed liquid.

This degassing procedure has been shown to be as effective as the procedure described in the USP and has the advantage of taking 20 minutes to degas 18 liters compared to several hours by the USP method (4).


Discussion of Parameters and Results

Initially we tested lots NCDA #2, 2H, and 2H-2 with the paddle method (see Table 1). A few months later, we retested these lots with the paddle method using degassed medium with a properly set up apparatus and then with four different parameters (see Table 2). We then tested them with the basket method (see Table 3). When we received lot 2H-3, we tested it first by using degassed water with a properly set up apparatus and then by changing the other parameters (see Tables 1 and 2). The NCDA #2 results are listed in the tables to show the similarity of its dissolution characteristics to the 2H lots.

The Paddle Method

DISSOLVED GASES - Table 1 shows the average increased dissolution results with nondegassed water for lots 2H, 2H-2, and 2H-3 of 30.2%, 33.9%, and 33.6%, respectively.

These tablets are extremely sensitive to dissolved gases in the medium.

VESSEL CENTERING - Table 1 shows that when the vessels are offset 1 mm from being centered, increased average dissolution results of 3.0%, 3.8% and 2.8% are obtained for lots 2H, 2H-2, and 2H-3, respectively. When the vessels are offset 2 mm from being centered, Table 1 shows average increased dissolution results of 8.3%, 10.4%, and 5.2% for lots 2H, 2H-2, and 2H-3, respectively.

For one set of experiments the plastic centering collar of each vessel was removed, the paddle depth was reset, and each vessel was centered with a Distek centering tool called the CenterChek. The paddles were lowered into the empty vessels, the tool was attached to the paddle shaft at the 400-mL mark on the vessel, the rotation was set at 10 rpm, and each vessel was adjusted until it was almost perfectly centered.

Table 2 shows that when the vessels are recentered with the Distek CenterChek, the dissolution averages are decreased by 1.1%, 1.1%, and 2.5% for lots 2H, 2H-2, and 2H-3, respectively.

These tablets are very sensitive to vessel centering. Centering the vessel near its lower part where dissolution actually takes place is a more accurate way to center vessels than at the top, where there is a greater chance of the vessel being nonuniform.

VESSEL VERTICALITY - After vessels where centered, a dime, 1-mm thick, was placed under the plastic Distek centering collar on one side of each vessel. Table 1 shows that the average results for lots 2H, 2H-2, and 2H-3 increased by 4.2%, 4.6%, and 1.9%, respectively.

These tablets are sensitive to vessel verticality.

SAMPLING FILTERS AND LARGE PROBES - The HP automated sampling system comes equipped with small HP filter tips (6.43 mm OD X 10.90 mm long) attached to a large 3.21-mm OD Teflon probe, which remains in the dissolution medium throughout the run. Table 2 shows increased average results of 0.9%, 1.7%, and 0.4% for lots 2H, 2H-2, and 2H-3, respectively.

The Hanson automated sampling system consists of a large filter tip (7.50 mm OD X 21.25 mm long) attached to a large 3.20-mm OD probe. During dissolution, the tip and the probe are out of the medium. Near the specified sampling time, they are automatically lowered into the medium, where they remain for approximately 35 seconds. This time can be varied.

It was thought that dissolution results might increase with samples that require profiles, where sampling is repeated many times. To simulate this sampling process, Hanson filters were attached to HP probes and manually lowered into the dissolution medium at 10, 20, and 30 minutes, remaining in the medium for 35 seconds each time. Table 1 shows a very slight increase of 1.3% and 0.8% in lots 2H and 2H-3, respectively, and a slight decrease of 0.4% in lot 2H-2. This sampling system did not increase dissolution results when three sampling times were used.

As Table 1 shows, leaving the Hanson filters and HP probes in the vessel throughout the 30-minute run increased average results by 4.9%, 2.8%, and 2.8% for lots 2H, 2H-2, and 2H-3, respectively.

Large sampling probes and filters used with automated sampling systems disrupt the flow of medium around the tablets or capsules in the bottom of the vessels and may affect dissolution results (5).

The results above show that the 2H lots are sensitive to large filter tips attached to large diameter probes that remain in the medium throughout the run.


1Terry W. Moore is a chemist with the Food and Drug Administration, Division of Drug Analysis, 1114 Market Street, Room 1002, St. Louis, MO 63101.
2Distek, Inc., 121 North Center Drive, North Brunswick, NJ 08902-4905.
3VanKel Industries, Inc., 36 Meridian Road, Edison, NJ 08820.
4Hewlett-Packard Corp., P.O. Box 10301, Palo Alto, CA 94303-0890



© 1997 The United States Pharmacopeial Convention, Inc.

Pharmacopeial Forum - Volume 23, Number 6, p. 5353 Nov.-Dec. 1997

STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies of the USPC or the USP Committee of Revision

Benchmark Conditions - The apparatus was set to conform to the USP specifications as closely as possible. Each Distek sampling probe was manually placed in the medium immediately before the 30-minute aliquot was drawn.

Probes in Vessels Throughout Run - For the first deviation from the benchmark conditions, the Distek probes were placed into the medium before the tablets were dropped into the vessels and left in the vessels for the duration of the test. Since there were no significant differences in results, this deviation was used, for convenience, in all of the following tests.

Hanson Filters Lowered into Medium Just Before Sampling - The Hanson3 automated sampling system uses a large filter tip (7.50 mm o.d. X 21.25 mm long) attached to a large (3.20 mm o.d.) probe. The HP sampling probes that are provided with the HP automated sampling system are similar in size to the Hanson probes and were used in the testing of the Hanson filters. At the beginning of a dissolution test, the Hanson automated sampling system holds the filter tips and probes above the medium. Near the specified sampling time they are automatically lowered into the medium and after the specified time are lifted out of the medium to the original position. The time the probes remain in the vessels may be adjusted. For this test, we arbitrarily chose 35 seconds. For the paddle test these probes were lowered into the medium 35 seconds before the 30-minute aliquot was taken. The Distek probes remained in the vessels throughout the run and were used to withdraw the sample aliquot. This test was not done with the baskets.

Hanson Filters in Vessels Throughout Run - The Hanson filters attached to HP probes were left in the vessels throughout the run for both paddle and basket tests to see whether large filters and probes would change the dissolution results from the benchmark.

Hanson Filters Simulating a 30-Minute Profile Run at 10-Minute Intervals - This test was conducted to determine if dissolution results can be affected by the Hanson automated sampling system's large probes and filters for samples requiring profiles. To simulate the Hanson sampling-system process, Hanson filters were attached to HP probes and manually lowered into the dissolution medium at 10, 20, and 30 minutes, remaining in the medium for 35 seconds each time. The Distek probes remained in the vessels throughout the run and were used to withdraw the sample aliquots. This test was done only with the paddles.

Nondegassed Medium - Our purified water, under pressure, was collected from an outlet and used directly. This medium is supersaturated with air at room temperature.

Vessel Off-centering - The Distek plastic centering collars were removed from all 6 vessels, the vessels were recentered, and the paddle or basket depth was reset. For tests with the paddle method, the vessels were moved off-center by 1 mm and then by 2 mm. For the tests with the basket method, the vessels were offset by the 2-mm distance only.

Vessel Verticality - The vessels were centered in the normal way as described under Apparatus. For the tests with the paddle method, a penny, 1 mm thick, was placed under the plastic Distek centering collar on one side of each vessel, and the dissolution tests were carried out. The test was then repeated with two pennies to elevate one side of each vessel to 2 mm. For tests with the basket method, the vessels were tilted 2 mm only.

Tablet Introduction and Paddle Rotation - This test deviated from the USP paddle procedure and our benchmark conditions because the paddles were rotating in the medium before the tablets were dropped into the vessel.

Temperature of Medium - The USP requirement for temperature is to have the medium at 37 ± 0.5°. For these tests, the temperature of the medium was adjusted to 25º, 34º, 40º, and 50º.

Rotation Speed - The USP requirement for paddle or basket rotation speed is that it be within 4% of the specified speed. The apparatus can be maintained at the specified speed at a tolerance much closer than 4%. The tablets were tested at 48, 52, and 53 rpm for the paddles and at 48, 52, 96, and 104 rpm for the baskets.

Paddle and Basket Depth - The USP requires a distance of 25 ± 2 mm between the paddle blade or basket and the inside bottom of the vessel. Tests were conducted at distances of 20, 23, 27, and 30 mm for the paddles and 20 and 30 mm for the baskets.

Vibration - The USP requires that no part of the assembly contribute significant vibration. For this test, the rubber feet of a vacuum pump were removed and the pump was placed on top of the Distek apparatus and turned on. Strong vibration was observed over the entire apparatus, stirring elements and vessels.

Results and Discussion


The content uniformity test results are listed in Table 1. Small differences are seen among the averages; however, the results fall well within the USP 23 tolerances.

Table 2 shows that the dissolution results for the paddle method at 50 rpm are very uniform among the samples taken at the five different production times.

Dissolution profiles for these tablets (Table 3) are similar to that of NCDA #2. Virtually all of the active ingredient will dissolve when the agitation of the medium is increased, but only a fraction (ca. 30%, 55%, and 85%) of the total dissolves when the tests are conducted under USP conditions for 30 minutes. This is a desirable characteristic for a calibrator tablet. Most deviations from the USP conditions tend to increase the agitation of the tablet material for the paddle method. The basket method is more complex in its response to agitation because dissolution occurs inside the basket as well as in the vessel.


3Hanson Research Corp., 9810 Variel Avenue, Chatsworth, CA 91311.


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