Measuring and testing – Testing of material
Reexamination Certificate
2000-11-13
2002-12-24
Noland, Thomas P. (Department: 2856)
Measuring and testing
Testing of material
C073S863000
Reexamination Certificate
active
06497157
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the field of dissolution testing and, in particular, to apparatuses for intrinsic dissolution testing of pharmaceuticals in solid, semi-solid, and transdermal dosage form.
2. Description of the Related Art
In general, dissolution testing is used to determine the rate of dissolution of a material in a solvent or solution. For example, dissolution testing may be used to determine the rate of dissolution of pharmaceuticals in dosage form in specific dissolution mediums to simulate digestion in a human. The requirements for such dissolution testing apparatuses are provided in United States Pharmacopeia (USP), Edition XXII, Section 711, Dissolution (1990).
Conventional dissolution testing apparatuses have one or more dissolution vessels in which dissolution media may be placed. One conventional configuration of a dissolution testing apparatus has, for each dissolution vessel, a paddle-type stirring element consisting of a metal shaft with a metal blade at the end. After placing the dosage to be dissolved loose at the bottom of the vessel, the stirring element is lowered into the dissolution medium near the center of the vessel and rotated at a specified rate (typically measured in revolutions per minute (rpm)) for a specified duration. Samples of the dissolution media may be periodically withdrawn from the vessels to determine the degree of dissolution of the dosages as a function of time.
One of the problems with this conventional configuration for dissolution testing is that the total exposed surface area of the test sample changes (i.e., decreases) over the testing cycle as the dosage is dissolved. Since the instantaneous dissolution rate is a function of the current total exposed surface area of the test sample, it is hard to correlate how dissolution rate varies as a function of time when the surface area also changes over the testing cycle. To address this problem, intrinsic dissolution testing may be performed.
The intrinsic dissolution rate is defined as the rate of dissolution of a pure pharmaceutical active when conditions such as the total exposed surface area of the sample as well as the temperature, agitation-stirring speed, pH, and ionic strength of the dissolution medium are kept constant. The determination of the intrinsic dissolution rate allows for screening of drug candidates and in understanding their solution behavior under different bio-physiological conditions.
The implementation of “sameness” analysis has been presented and applied in a number of scientific guidelines for demonstrating formulation equivalencies among semi-solids, immediate-release solid oral, and extended-release solid oral dosage forms. Conventional test methods for these analyses involve the use of vertical diffusion cells, enhancer cells, and the USP apparatuses 1 and 2. The evaluation of the intrinsic dissolution of active pharmaceutical ingredients (API) is a means to demonstrate chemical equivalency. The need to demonstrate “sameness” among APIs has risen due to changes in the bulk active synthesis, the final crystallization steps, particle size and surface area, polymorphism and scale-up issues regarding batch-size and manufacturing site.
Currently the USP lists the Wood's Intrinsic Dissolution Apparatus from VanKel Industries, Inc., of Cary, N.C. as the official apparatus for determination of intrinsic dissolution rates. See USP 24-NF 19 Supplement 1, Section 1087, Intrinsic Dissolution (Released Nov. 1, 1999).
FIG. 1
shows a cross-sectional view of a prior-art intrinsic dissolution test configuration
100
based on the Wood's Intrinsic Dissolution Apparatus. Test configuration
100
comprises a rotatable shaft
102
positioned over the center of a round-bottomed dissolution vessel
104
. At the end of shaft
102
is a die
106
rigidly connected to shaft
102
by a die holder
108
. A drug pellet (i.e., the test sample) is formed and retained within a cylindrical recess
110
centered on the bottom face
112
of die
106
. After an appropriate dissolution medium (not shown) is placed within vessel
104
, shaft
102
is lowered into the dissolution medium within vessel
104
to position the bottom of die
106
at a specified distance (e.g., 1 to 1.5 inches) above the bottom of the vessel. During intrinsic dissolution testing, shaft
102
is rotated, thereby rotating the drug pellet contained within recess
110
. Dissolution is achieved by shear-like motion of the pellet within the dissolution medium. Since the drug pellet has the same shape as cylindrical recess
110
, in theory, the total exposed surface area of the test sample should remain substantially constant during the dissolution testing cycle as the drug pellet dissolves.
FIG. 2
shows an exploded, cross-sectional view of conventional equipment used to form the drug pellet within cylindrical recess
110
of die
106
of FIG.
1
. As shown in
FIG. 2
, die
106
is secured to a base plate
202
by a number of screw pins inserted through openings
204
in base plate
202
and screwed into corresponding tapped holes
206
on the bottom face
112
of die
106
. Test sample material
207
in powder form is then placed within a cylindrical die cavity
208
within die
106
, and pressure is applied with a plunger
210
to press the powdered material against base plate
202
to form a cylindrical drug pellet at the bottom of cavity
208
. Retaining male end
212
of plunger
210
within cavity
208
forms cylindrical recess
110
of FIG.
1
. Die holder
108
is then screwed onto threaded end
214
of die
106
with an intervening O ring or other gasket
216
that prevents the dissolution medium from reaching the drug pellet through the upper end of cavity
208
. Base plate
202
may then be removed (by removing the screw pins) to provide the subassembly of die holder
108
and die
106
shown in
FIG. 1
with a drug pellet formed and positioned within recess
110
of die
106
, ready for intrinsic dissolution testing.
One of the problems with the conventional intrinsic dissolution test configuration of
FIG. 1
relates to the formation of air bubbles at the exposed (i.e., bottom) surface of the test sample. Such air bubbles can interfere with dissolution testing by decreasing the effective dissolution rate. Air bubbles may come from different sources. First of all, air bubbles may be formed when the test sample is initially lowered from air into the dissolution medium. In addition, air bubbles may be formed as the test sample dissolves either from air trapped within the drug pellet or as a by-product of the dissolving of the sample material itself.
Another problem is that the shaft and die assembly of
FIG. 1
may wobble when operated at high rotation speeds (e.g., 100 rpm). Such wobbling may alter the effective dissolution rate, thereby leading to further inaccuracies in the test results.
In addition, the temperature of the dissolution medium may change (e.g., drop about 2° C.) when the relatively massive shaft and die assembly are first inserted into the dissolution medium, with heat being removed from the dissolution medium through the shaft.
SUMMARY OF THE INVENTION
The present invention is directed to a configuration for intrinsic dissolution testing that addresses these problems with the prior art. According to the present invention, a drug pellet is retained within a sample holder that is positioned at the bottom of the dissolution vessel with the drug pellet facing up. The dissolution medium may then be stirred, e.g., using a conventional rotating paddle positioned above the stationary sample holder.
Intrinsic dissolution testing equipment according to the present invention decreases the likelihood of air bubbles adversely affecting test results during the testing cycle. Moreover, since the sample holder is stationary during the testing cycle, any wobbling of the rotating paddle at high speeds will not directly affect the effective dissolution rate. In addition, since the sample holder is placed at the bottom of the vessel bef
Brinker Gerald
Cai Michael
Viegas Tacey X.
Distek Inc.
Mendelsohn Steve
Noland Thomas P.
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