WO2011081857A1

WO2011081857A1 - Container and device for dissolution testing

Info

Publication number: WO2011081857A1
Application number: PCT/US2010/059993
Authority: WO
Inventors: Charles E. Colson; Leslie L. Graham; Kenneth C. Hartner
Original assignee: Cephalon, Inc.
Priority date: 2009-12-14
Filing date: 2010-12-13
Publication date: 2011-07-07

Abstract

A device for dissolution testing of a solid dosage form has a container with a non-woven sidewall surrounding a central space and first and second panels attached at opposite ends of the sidewall. Rims at the ends of the sidewall facilitate attachment of the panels to the sidewall to form a top and a bottom. At least the sidewall has a multiplicity of apertures therethrough. The apertures are sized and spaced to simulate a sieve having the characteristics of standard mesh sizes used in pharmaceutical analysis. The device includes a vessel for holding the liquid solvent in which the container is immersed for testing. An agitator in the vessel is used to mix the solvent. A method of positioning the container relative to the agitator uses a spacer with a precise thickness positioned between two fittings or between a fitting and a lid of the device.

Description

CONTAINER AND DEVICE FOR DISSOLUTION TESTING

Field of the Invention

This invention relates to a container for dissolution testing of pharmaceutical solid oral dosage forms, and to a dissolution testing device using the container. Background

Certain pharmaceutical related solid oral dosage forms, for example, those which do not have a disintegrant, such as crospovidone or sodium starch glycolate as part of their formulation, do not readily dissolve in a liquid test medium. Such dosage forms present a challenge in characterizing their dissolution rates through known methods of dissolution testing with prior art apparatus. Prior art dissolution testing methods involve holding the solid oral dosage form in a basket made of woven stainless steel wire gauze, and positioning the basket in a vessel containing the liquid test medium. The liquid test medium within the vessel is constantly agitated, for example, by a rotating paddle agitator, and samples of the liquid test medium are periodically withdrawn and analyzed by a suitable chromatographic or spectrophotometric technique to measure the concentration of the compound, whose dissolution rate is to be determined, as a function of time. Standard protocols for dissolution testing may be found in US Pharmacoepia.

Inconsistency of test results is one problem which plagues dissolution testing of difficult to dissolve solid oral dosage forms. This is believed to be due, in part, to the physical characteristics and positioning of the baskets in which the solid dosage form is held within the test apparatus. There is clearly a need for a dissolution apparatus which can provide consistent test results for difficult to dissolve solid oral dosage forms. Summary

The invention concerns a container for dissolution testing of a solid dosage form. The container comprises a non-woven sidewall surrounding a central space. The sidewall has first and second oppositely disposed ends and a multiplicity of apertures therethrough. A first panel is attached to the first end of the sidewall and is positioned covering the central space. A second panel is attached to the second end of the sidewall and is positioned covering the central space. The second panel is removably attached to the sidewall to facilitate positioning of the solid dosage form within the central space. First and second rims surround each end of the sidewall.

In one embodiment the first panel is also non- woven and comprises a multiplicity of apertures therethrough. The sidewall as well as the first panel may form a mesh equivalent to US Standard Mesh sizes from 4 to 20, 7 to 10, as well as US Standard Mesh size 8.

In one embodiment the apertures have a square shape having dimensions from about 0.2 inches by 0.2 inches to about 0.03 inches by 0.03 inches. Alternately, the apertures may have a square shape having dimensions from about 0.1 inches by 0.1 inches to about 0.07 inches by 0.07 inches. Additionally, the apertures may have a square shape having dimensions at least about 0.09 inches by 0.09 inches.

The apertures may have any shape and have an area of about 0.04 square inches to about 0.0009 square inches. Alternately, the apertures may have an area of about 0.01 square inches to about 0.0049 square inches, or in another embodiment, the apertures may have an area of at least about 0.009 square inches. The container has a distribution of the apertures of about 7 per linear inch to about 10 per linear inch. Alternately, the distribution of the apertures is about 8 per linear inch.

In one embodiment, the sidewall forms a circular cross section.

The invention also encompasses a device for performing dissolution testing of a solid dosage form in a liquid. The device comprises a vessel having an interior space and an open top. The vessel holds the liquid in the interior space. A lid is positioned overlying the open top to enclose the interior space. An agitator is positioned within the interior space and is movable therein to agitate the liquid. The container as described above is positioned with the interior space to hold the solid dosage form immersed within the liquid. The container includes a second panel attached to the second end of the sidewall. The second panel is positioned covering the central space. The second panel is removably attached to the sidewall to facilitate positioning of the solid dosage form within the central space. A rod has a first portion attached to the lid and a second portion attached to the second panel for suspending the container within the interior space. The invention further encompasses a method for positioning a container relatively to an agitator positioned within a vessel having a lid. The method comprises:

(a) suspending the container within the vessel in contact with the agitator on a rigid rod;

(b) placing a first fitting on the lid and in engagement with the rod; (c) fixing the position of the first fitting on the rod;

(d) drawing the rod upwardly, thereby moving the first fitting away from the lid; (e) positioning a spacer between the lid and the first fitting; and

(f) lowering the first fitting into contact with the spacer. The method may further include:

(g) positioning a second fitting on the lid between the first fitting and the lid and in engagement with the rod;

(h) positioning the spacer on the second fitting; and

(i) fixing the position of the second fitting relative to the rod.

Brief Description of the Drawings

Figure 1 is an isometric view of a device and a container for dissolution testing according to the invention;

Figure 2 is an isometric view of the container for dissolution testing shown in Figure 1;

Figure 3 is a cross sectional view of the container for dissolution testing taken at line 3-3 of Figure 1; Figure 4 is a cross sectional view of the container for dissolution testing taken at line 4-4 of Figure 2;

Figure 5 is a partial longitudinal sectional view of the container for dissolution testing taken at line 5-5 of Figure 3;

Figure 6 is an exploded isometric view of a portion of a positioning apparatus taken at line 6-6 of Figure 1; and Figure 7 is a flow diagram illustrating a method according to the invention.

Detailed Description of Embodiments

Figure 1 illustrates an embodiment of a device 10 for dissolution testing according to the invention. Device 10 comprises a vessel 12 having an interior space 14 and an open top 16. Vessel 12 is preferably made of an inert material such as glass, stainless steel, plastic or polytetrafluoroethylene which will not adversely affect the dissolution test results. A lid 18 is positionable overlying the open top 16 to enclose the interior space 14 and mitigate evaporation of liquid 20 held in vessel 12. Liquid 20 is the solvent in which dissolution testing is performed. Example liquids 20 suitable for dissolution testing include water, dilute hydrochloric acid and dilute aqueous buffers such as phosphate buffered saline, all with or with out a surfactant wetting agent. Device 10 also has an agitator 22 to mix the liquid 20 as required according to test protocols. In this example the agitator is a rotatable paddle 24 which is mounted on a shaft 26 and rotates about the longitudinal axis of the shaft as indicated by arrow 28. A container 30 is positioned within the interior space 14 of vessel 12. The container holds the solid dosage form 32 whose dissolution rate is to be ascertained using device 10. As shown in Figure 2, container 30 comprises a non- woven sidewall 34 which surrounds a central space 36. In this example the sidewall 34 forms a circular cross section and has a multiplicity of apertures 38 therethrough to promote flow of the liquid 20 through the container during dissolution testing. The apertures 38 in sidewall 34 may be formed by various techniques such as by punching, etching and plasma cutting. Using a non- woven sidewall provides a robust design which will tolerate rough handling without significant deformation and is expected to yield more consistent test results among different containers having the same characteristics and used under the same test conditions. It is understood that the sidewall may have a cross sectional shape other than round, and that the apertures may have a shape other than square as shown in the example container 30. As shown in Figures 2 and 4, the container has a panel 40 attached to one end 42 of the sidewall 34 which forms a bottom to support the solid dosage form 32 (see Figure 1). In this example panel 40 is also non- woven and has a multiplicity of apertures 38 to further promote flow of liquid 20 through the container. A rim 44 surrounds end 42 of the sidewall 34 and provides a structure which enables the panel 40 to be attached to the sidewall 34. The rim also increases the robustness of the design.

As shown in Figures 1 and 2, a second panel 46 is removably attached to the opposite end 48 of sidewall 34. Removable attachment is conveniently effected by flexible, resilient clips 50 (see also Figures 3 and 5) which extend from the panel 46 and engage a second rim 52 which is attached to the sidewall 34 at end 48. Removable attachment of the panel 46 facilitates placement of the solid dosage form within the container 30. As shown in Figures 1 and 2, a rod 54 is also attached to the panel 46. The rod is also attachable to the lid 18 of the vessel 12 for suspending the container within the interior space 14.

Consistency of test results is also affected by the position of the container 30 relatively to the agitator 22 within the vessel 12. The rod 54 is therefore adjustably movable relative to the lid 18 to allow positioning of the container 30 at a desired position relative to the agitator 22. For consistent results it is necessary to position the container 30 at the same height above the agitator for each test. The invention provides both an apparatus and a method to easily and reliably ensure that the required relative positional relationship between the container and the agitator are consistently achieved for any test. The positioning apparatus 56 is shown in Figures 1 and 6, and comprises a lower fitting 58, a spacer 60, and an upper fitting 62. In use, the lower fitting 58 is positioned on the top of lid 18, the spacer 60 rests on top of the lower fitting, and the upper fitting 62 rests on top of the spacer.

As shown in detail in Figure 6, lower fitting 58 has an opening 64 through which rod 54 passes. A set screw 66 is threadedly engaged with the lower fitting and extends into the opening 64 so as to engage and fix the relative position between the rod and the lower fitting when the set screw is tightened. Loosening the set screw 66 allows the rod 54 and lower fitting 58 to move relatively to one another. Similarly, upper fitting 62 has an opening 68 which permit the rod 54 to pass through. A clamping screw 70 is threadedly engaged between opposing jaws 72 comprising the upper fitting 62. The jaws 72 are engageable with the rod 54 such that tightening the clamping screw 70 resiliently deforms the jaws so that they clamp down on the rod and fix the position of the rod relatively to the upper fitting 62. Loosening the clamping screw 70 allows relative motion between the rod 54 and the upper fitting 62. The spacer 60 has a precisely measured thickness and a U-shaped opening 74 which allows the spacer to be inserted between the upper and lower fittings 62 and 58 or the upper fitting and the lid 18 without access to a free end of rod 54. This allows the spacing between the container 30 and the agitator 22 to be precisely established as described below in the positioning method according to the invention.

As described at 80 and 82 in the flow diagram of Figure 7, the positioning method begins with the container 30 positioned within the vessel 12, the rod 54 extending through the lid 18, through the lower fitting 58 (if present) positioned on the lid 18, and through the upper fitting 62 resting on the lower fitting. To set the container 30 in its desired location relatively to the agitator 22 both the set screw 66 and the clamping screw 70 are loosened to allow the rod 54 to move vertically with respect to both fittings and the agitator 22. Container 30 is then lowered by moving rod 54 so that the container rests on the top edge of a paddle 24. As noted at 84, the clamping screw 70 is then tightened, fixing the position of the upper fitting on the rod and thereby preventing motion between the rod 54 and the upper fitting 62. Next, as indicated at 86, the container 30 is raised by drawing the rod 54 upwardly, moving the upper fitting 62 away from the lid or the second fitting if present. As noted at 88, the spacer 60 is then positioned on the lower fitting 58 if present, or on the lid 18, but between the upper fitting and the lid. The container 30 is next lowered by moving the rod 54 downwardly until the upper fitting 62 (which moves with the rod) rests on the spacer 60 as indicated at 90, the spacer 60 resting on the lower fitting if present, or on the lid 18. The set screw 66 of the lower fitting 58 is then tightened, fixing the relative position of the lower fitting to the rod (see 92), and also fixing the height of the container 30 above the agitator 22, that height being equal to the thickness of the spacer 60. The container can now be moved up and down, for example, to conveniently load solid dosage forms, by loosening the set screw 66, which permits the rod to slide though the lower fitting 58. The desired position of the container 30 relative to the agitator however, can be readily and precisely reestablished simply by sliding the rod 54 downwardly until the upper fitting 62 contacts the spacer 60.

The container 30 and the rod 54 are advantageously formed of inert but inherently strong materials such as stainless steel to provide a robust design which will not affect the test results. Other materials may also be used, such as polytetrafluoroethylene, known by its tradename Teflon, and polyoxymethylene plastic, known by its tradename Delrin.

To meet the required protocols necessary for dissolution testing, the apertures 38 in the sidewall 34 and panel 40 are sized and spaced relative to one another to form a sieve which has characteristics equivalent to known standard mesh sizes used in the

pharmaceutical industry. For example, it is possible to simulate the characteristics of any mesh, such as US Standard Mesh sizes from 4 to 20, including US Standard Mesh sizes from 7 to 10, and also including Standard Mesh size 8. To achieve the equivalent of these mesh sizes, apertures having a square shape as shown in the example container have dimensions from about 0.2 inches by 0.2 inches to about 0.03 inches by 0.3 inches, about 0.1 inches by 0.1 inches to about 0.07 inches by about 0.07 inches, or at least about 0.09 inches by about 0.09 inches. As noted above, the apertures need not be square. Therefore, one may alternately specify the approximate area of the apertures, which may range, for example, from about 0.04 square inches to about 0.0009 square inches, from about 0.01 square inches to about 0.0049 square inches, or an area of at least about 0.009 square inches. Furthermore, the apertures may be spaced from about 7 apertures per linear inch to about 10 apertures per linear inch, as well as about 8 apertures per linear inch. The overall size of the container may, of course, be varied to accommodate dosage forms of different sizes.

Containers according to the invention and devices using containers according to the invention for dissolution testing are expected to yield improved consistency of results for different containers having the same characteristics (for example, overall size, shape and mesh simulation) when used under the same test conditions.

Claims

What is claimed is:

1. A container for dissolution testing of a solid dosage form, said container comprising: a non-woven sidewall surrounding a central space and having first and second oppositely disposed ends, said sidewall having a multiplicity of apertures therethrough; a first panel attached to said first end of said sidewall and positioned covering said central space.

2. The container according to Claim 1, wherein said first panel is non- woven and comprises a multiplicity of apertures therethrough.

3. The container according to Claim 1, further comprising a rim surrounding said first end of said sidewall.

4. The container according to Claim 1, further comprising a second panel removably attached to said second end of said sidewall to facilitate positioning of said solid dosage form within said central space.

5. The container according to Claim 1, further comprising a rim surrounding said second end of said sidewall.

6. The container according to Claim 2, wherein said sidewall and said first panel form a mesh equivalent to US Standard Mesh sizes from 4 to 20.

7. The container according to Claim 2, wherein said sidewall and said first panel form a mesh equivalent to US Standard Mesh sizes from 7 to 10.

8. The container according to Claim 2, wherein said sidewall and said first panel form a mesh equivalent to US Standard Mesh size 8.

9. The container according to Claim 2, wherein said apertures have a square shape having dimensions from about 0.2 inches by 0.2 inches to about 0.03 inches by 0.03 inches.

10. The container according to Claim 2, wherein said apertures have a square shape having dimensions from about 0.1 inches by 0.1 inches to about 0.07 inches by 0.07 inches.

11. The container according to Claim 2, wherein said apertures have a square shape having dimensions at least about 0.09 inches by 0.09 inches.

12. The container according to Claim 2, wherein said apertures have an area of about 0.04 square inches to about 0.0009 square inches.

13. The container according to Claim 2, wherein said apertures have an area of about 0.01 square inches to about 0.0049 square inches.

14. The container according to Claim 2, wherein said apertures have an area of at least about 0.009 square inches.

15. The container according to Claim 2, having a distribution of said apertures of about 7 per linear inch to about 10 per linear inch.

16. The container according to Claim 2, having a distribution of said apertures of about 8 per linear inch.

17. The container according to Claim 1, wherein said sidewall forms a circular cross section.

18. A device for performing dissolution testing of a solid dosage form in a liquid, said device comprising: a vessel having an interior space and an open top, said vessel holding said liquid in said interior space; a lid positioned overlying said open top to enclose said interior space; an agitator positioned within said interior space and movable therein to agitate said liquid; a container positioned with said interior space to hold said solid dosage form immersed within said liquid, said container comprising: a non-woven sidewall surrounding a central space and having first and second oppositely disposed ends, said sidewall having a multiplicity of apertures therethrough; a first panel attached to said first end of said sidewall and positioned covering said central space; a second panel attached to said second end of said sidewall and positioned covering said central space, said second panel being removably attached to said sidewall to facilitate positioning of said solid dosage form within said central space; a rod having a first portion attached to said lid and a second portion attached to said second panel for suspending said container within said interior space.

19. The device according to Claim 18, wherein said first panel is non- woven and comprises a multiplicity of apertures therethrough.

20. The device according to Claim 18, further comprising a first rim surrounding said first end of said sidewall.

21. The container according to Claim 20, further comprising a second rim surrounding said second end of said sidewall.

22. The device according to Claim 19, wherein said apertures have a square shape having dimensions from about 0.2 inches by 0.2 inches to about 0.03 inches by 0.03 inches.

23. The device according to Claim 19, wherein said apertures have a square shape having dimensions from about 0.1 inches by 0.1 inches to about 0.07 inches by 0.07 inches.

24. The device according to Claim 19, wherein said apertures have a square shape having dimensions at least about 0.09 inches by 0.09 inches.

25. The device according to Claim 19, wherein said apertures have an area of about 0.04 square inches to about 0.0009 square inches.

26. The device according to Claim 19, wherein said apertures have an area of about 0.01 square inches to about 0.0049 square inches.

27. The device according to Claim 19, wherein said apertures have an area of at least about 0.009 square inches.

28. The device according to Claim 19, having a distribution of said apertures of about 7 per linear inch to about 10 per linear inch.

29. The device according to Claim 19, having a distribution of said apertures of about 8 per linear inch.

30. The device according to Claim 18, wherein said sidewall forms a circular cross section.

31. The device according to Claim 18, wherein said agitator comprises a rotatable paddle.

32. A method for positioning a container relatively to an agitator positioned within a vessel having a lid, the method comprising: suspending the container within the vessel in contact with the agitator on a rigid rod; placing a first fitting on the lid and in engagement with the rod; fixing the position of the first fitting on the rod; drawing the rod upwardly, thereby moving the first fitting away from the lid; positioning a spacer on the lid between the lid and the first fitting; and lowering the first fitting into contact with the spacer.

33. The method according to Claim 32, further comprising: positioning a second fitting on the lid between the first fitting and the lid and in engagement with the rod;

positioning the spacer on the second fitting; and

fixing the position of the second fitting relative to the rod.