It is a well established practice in the pharmaceutical industry to test the dissolution properties of solid dosage form pharmaceuticals. The term solid dosage form as used herein means any dosage form, other than a liquid, and which can be delivered into the body of a being. Examples of such dosage forms are tablets, capsules, caplets, pills, suppositories, transdermal patches, etc. Moreover, the dosage forms may be immediate release or timed release.
As is known, dissolution is the process by which a solid substance dissolves in a solvent and is controlled by the affinity between it and the solvent. The sequence of events in a typical dissolution process entails several actions, e.g., the wetting of the dosage form, the subsequent penetration of the dissolution liquid into the dosage form, etc. Once this has occurred there are different modalities of release of the active ingredient(s) from the dosage form, such as erosion, diffusion, disintegration and combinations of those modalities.
Perhaps the primary reason for undertaking dissolution testing in the pharmaceutical industry is to measure the performance of a particular product. This is particularly important for oral solid dose forms of pharmaceuticals, but is not limited to oral dose forms, since release of the active ingredient(s) from the solid dose after oral administration is a prerequisite for absorption and bioavailability. Dissolution properties become even more significant if the solid dose form is of a sustained-release formulation, since dissolution is a key property of such a product.
Dissolution testing is also used as a key tool in research and development of new drugs since it can provide considerable information in the selection of an appropriate formulation for a proposed pharmaceutical. It also enables a manufacturer to accurately gauge the stability of a pharmaceutical to determine if it maintains its dissolution characteristics from the time of its manufacture to its expiry date.
In view of the above, and for other reasons as well, dissolution testing is now deemed of such importance that it is a mandatory United States pharmacopeial requirement. For example, the United States Pharmacopeial Convention presently identifies seven USP approved types of dissolution equipment for dissolution testing of solid dosage forms. Those types are referred to as USP I, USP II, USP III, USP IV, USP V, USP VI, and USP VII.
As is known USP I equipment is characterized by use of a rotating basket in which the solid dosage form of the pharmaceutical to be tested is held and immersed in a dissolution liquid in a flask or other concave bottom chamber. The flask or chamber typically has a volume of from 100 to 4000 ml. The basket is made up of a wire mesh of any mesh size, e.g., from USP mesh 10 to USP mesh 100. The basket is arranged to rotated about a vertical central axis at any suitable speed, e.g., from 50 to 125 rpm, within the dissolution liquid to enable the dissolution liquid to gain access to the solid dosage form to cause it to dissolve. With USP I equipment the dissolution liquid is sampled at a sampling point within the chamber, but outside the basket. The sample is provided to spectrophotometric, high performance liquid chromatographic or other suitable analyzer equipment for analysis.
While USP I apparatus may be generally suitable for their purposes, they nevertheless suffer from various significant disadvantages. One of the most significant disadvantages is the non-uniformity of the dissolution liquid in the chamber due to the production of poor eddy currents or inadequate stirring. Thus, within the chamber there are areas of the more concentrated dissolution liquid (so-called “hot spots”) and areas of less concentrated liquid (so-called “blind spots”). In addition, the baskets of USP I equipment are relative fragile and can be bent or otherwise deformed, whereupon their rotation in a bent or deformed state-may result in uneven stirring of the dissolution liquid. Another significant disadvantage of this USP I equipment is that the baskets may become clogged, thereby impeding the access of the dissolution liquid to the dosage form. Lastly, USP I apparatus is not particularly suitable for testing the dissolution of a solid dosage form under changing pH conditions, e.g., conditions where pH increases, such as occurs when the dosage form is taken orally by a patient.
USP II equipment is similar to USP I equipment, except that the solid dosage form is placed at the bottom of the chamber and a paddle is used to stir the dissolution liquid in the chamber. In some applications a stainless steel or glass helix or another holder (sometimes referred to as a “lobster pot”) may be used to encircle the solid dosage form and hold it slightly above the concave bottom surface of the chamber. The chamber typically has a volume of from 100 to 4000 ml. The paddle is disposed above the dosage form and is arranged to rotated about a vertical central axis at any suitable speeds, e.g., from 50 to 150 rpm to enable the dissolution liquid to have access to the dosage form to cause it to dissolve. The dissolution liquid is sampled within the chamber, but above the paddle and is provided to the same type of analysis equipment mentioned above for analysis.
While USP II apparatus may also be generally suitable for their purposes they also suffer from various drawbacks. One drawback is the non-uniformity of the dissolution liquid in the chamber due to the creation of a conical “blind-spot” of less concentrated dissolution liquid directly under the paddle. Another drawback is that the dosage form is susceptible to floating, if not held in position by a helix or lobster pot, thereby interfering with its even dissolution. Moreover, since the dosage form is exposed, it can be struck by the paddle, possibly breaking the dosage form and thus interfering with its normal dissolution properties. Further still the dosage form may rest on or stick to the inner surface of the chamber, thereby reducing the surface area of the dosage form so that an accurate reading of its dissolution properties is compromised. The use of a helix, lobster pot or other device to surround the dosage form to lift it off the surface of the chamber may eliminate that problem, but is not conducive for use with dosage formulations that swell, e.g., hydrogels. Moreover, like USP I apparatus, USP II apparatus is not particularly suitable for testing the dissolution of a solid dosage form under changing pH conditions
USP III equipment is sometimes referred to as a “reciprocating cylinder” and is particularly suited for extended release products. USP III equipment basically comprises an array of plural rows of individual flat bottomed glass vessels or chambers for holding the dissolution liquid. The vessels are typically of a volume of 200 ml. A plurality of reciprocating cylinders having mesh tops and bottoms into which respective ones of solid dosage forms of the pharmaceutical are located are disposed over the array of vessels for reciprocation and immersion in selected rows of the array of vessels. For example, the reciprocating cylinders may be reciprocated into the first row of the array of vessels to immerse the dosage forms into the dissolution liquid in those vessels. Thereafter the row of cylinders can be reciprocated out of the first row of vessels and indexed to the next successive row of vessels to immerse the dosage forms into the dissolution liquid in the second row of vessels. This operation can continue until all of the rows of vessels have been used. The advantage of this type of equipment is that each row of vessels may include dissolution liquid of the same pH or of increasing pH. Moreover, the fact that this type of apparatus uses plural vessels into which each dosage form is immersed enables the apparatus to be used to test poorly soluble active ingredients, since there will be more dissolution liquid available to dissolve such formulations than exists in either USP I or USP II equipment. Notwithstanding these advantages, the USP III apparatus still suffer from various disadvantages. For example, poorly soluble formulations which disintegrate could experience a loss of sink conditions if disintegration occurs in one sample 250 ml tube. Moreover, the apparatus is difficult to use with a surfactant based dissolution liquid, as frothing of the liquid severely limits the sample holder reciprocation rate. Further still, clogging of the sample holder mesh is possible, thus obstructing the free flow of dissolution liquid past the sample formulation.
USP IV equipment is sometimes referred to as a “flow through cell” and is particularly suitable for testing poorly soluble drugs and for extended release products. Moreover, UPS IV apparatus is suitable for testing active substances, granulated substances and formulated dosages in the same equipment. To that end USP IV equipment basically comprises a reservoir and a pump for the dissolution liquid, a flow-through-cell and a water bath for maintaining the temperature of the dissolution liquid. The cell is a hollow cylinder having a conical bottom wall with a central opening forming the inlet to the cell. The dosage form to be tested is disposed in the center of the cell. The top end of the cell is in the form of a filter or sieve. The dissolution liquid is pumped into the bottom of the cell so that it flows past the dosage form to cause it to dissolve. The dissolution liquid exits through the filter at the top of the cell. Since this equipment exposes the dosage form to a flow of the dissolution liquid past it, the dosage form is always subjected to fresh dissolution liquid, making the equipment particularly suitable for low solubility drugs. Moreover, this equipment enables one to precisely change the pH of dissolution liquid and avoids the hot spots and blind spots that are inherent in USP I and USP II equipment. Notwithstanding these advantages, USP IV equipment still suffers from its own disadvantages, e.g., it requires large volumes of dissolution liquid, calibration tests are unavailable, and validation of the flow rate is difficult.
USP V equipment is sometimes referred to as a “paddle over disk apparatus.” It basically comprises the USP II equipment with the inclusion of a stainless steel disk located at the bottom of the chamber. The disk is arranged to hold a transdermal dosage form. While USP V equipment offers advantage over USP II equipment for transdermal dosage forms, it never the less suffers from the same disadvantages of that equipment insofar as the non-uniformity of the dissolution liquid in the chamber is concerned.
Other USP approved equipment is USP VI equipment (sometimes referred to as a “cylinder” apparatus), and USP VII equipment (sometimes referred to as a “reciprocating holder” or “reciprocating disk” apparatus). As is known USP VI apparatus basically comprises the USP I equipment, except that the mesh basket is replaced with a stainless steel cylinder stirring element. USP VII equipment is sometimes referred to as a “reciprocating holder” or “reciprocating disk” apparatus and basically comprises a set of volumetrically calibrated glass cylinders.
The patent literature also discloses various devices for testing the dissolution of solid dosage forms. See, for example, U.S. Pat. No. 4,855,821 (Swon et al.), U.S. Pat. No. 4,856,909 (Mehta et al.), U.S. Pat. No. 5,127,278 (Benz), U.S. Pat. No. 5,142,920 (Bart et al.), U.S. Pat. No. 5,412,979 (Fassihi), U.S. Pat. No. 5,469,752 (Kitamura et al.), U.S. Pat. No. 5,816,701 (Martin et al.), U.S. Pat. No. 5,827,984 (Sinnreich et al.), U.S. Pat. No. 5,908,995 (Pauchon et al.), U.S. Pat. No. 6,076,411 (Horvath), U.S. Pat. No. 6,163,149 (Löfler), U.S. Pat. No. 6,170,980 (Martin) and U.S. Pat. No. 6,174,497 (Roinestad et al.) and Japanese Abstract JP05184579A2.
The patent to Martin et al. discloses an automated tablet dissolution apparatus that includes a camera under computer control for viewing the contents through the bottom of a dissolution vessel. A tablet to be tested is located with a basket disposed in the dissolution vessel and is exposed to a heated dissolution media the vessel. The camera is used to determine if the tablet was dropped into the dissolution vessel properly or has dissolved properly or to enable the contents of the vessel to be visually inspected. This testing of a sample of the dissolution media over a period of time is achieved in this patent by various techniques, e.g., spectrophotometry, high performance liquid chromatography, etc.
The patent, to Swon et al. (U.S. Pat. No. 4,855,821) discloses an apparatus for dissolution testing solid dosage forms, e.g., tablets, including one or more video cameras for the surveillance of a plurality of separate tablet containing vessels to record the dissolution of the tablets in a liquid dissolution media. Plural tablets are held on a wire mesh or screen.
The patent to Löfler (U.S. Pat. No. 6,163,149) discloses an apparatus for dissolution testing of medicaments in pressed form, such as tablets, pills, or capsules, and makes use of a basket-like frame supporting plural glass tubes, each of which is adapted to hold the medicament.
The patent to Martin (U.S. Pat. No. 6,170,780) is similar to U.S. Pat. No. 5,816,701 which was discussed above.
While all of the above identified apparatus and methods of use may be suitable for their intended purposes they still leave much to be desired from the standpoint that the information about the dissolution properties of the solid dosage forms that can be determined by their use is somewhat limited. In this regard prior art apparatus and techniques may enable one to determine the rate at which a particular solid dosage form dissolves (i.e., its so-called “dissolution profile”), but they do not provide accurate information about the mechanism of how the dosage form actually dissolved, e.g., by erosion, disintegration, diffusion and/or combinations of those actions. Moreover, while some prior art dissolution testing systems may have included utilizing a visualization device, e.g., a camera to record selected images of the dosage forms during their process of dissolving, such techniques have been very limited in the quality of the images provided, particularly where the dosage forms are susceptible to movement and displacement in the apparatus as they dissolve. For example, as is known the rotating paddles of USP II devices tend to cause the dosage forms to shift around and move in the dissolution vessel, thereby making sustained, accurate imaging difficult. Moreover, the stirring of the dissolution liquid causes surface turbulence, rendering image acquisition through the surface difficult. The rotating basket of USP I apparatus also presents an imaging problem since the basket in which the dosage form is located is moving and a relatively high speed, thereby tending to blur or otherwise obscure the dosage form during the dissolution process. Further still, where the dosage form is a sustained or timed release medication, e.g., a capsule with a large plurality of polymer coated active ingredient beads, with some of the beads having thicker coatings than others to enable the timed release of their active ingredient(s), the prior art systems have proved wanting to provide high quality images of the entire dissolution process from which accurate information about the manner and rate of release of the active ingredient(s) can be determined.