DESC:
FIELD OF DISCLOSURE
[0001] The present disclosure relates to the field of dissolution testing. In particular, it pertains to dissolution testing apparatus that are employed during pharmaceutical development phase involving in-vitro analyses of different dosage forms.

BACKGROUND
[0002] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Dissolution apparatuses are employed widely to assess and study, in controlled conditions, the dissolution characteristics of different drug formulations for their suitability for in-vivo applications on entering bloodstream of a subject. Pharmaceutical development phase of most dosage forms requires determination of impact of factors such as manufacturing process, physical parameters of active pharmaceutical ingredient (API), excipients in formulation and changes in physiochemical characteristics of API in formulation and accordingly, to determine the relevance of dissolution tests to in-vivo behavior of such dosage forms. Further, various regulatory and performance parameters too require proper dissolution testing before any drug is marketed to its end users. For similar reasons, dissolution apparatus of various types are employed depending upon their in-vitro testing capabilities, which are acceptable indicators and thereby predictors of in-vivo performance of drug formulations.
[0004] However, there are common problems associated with dissolution apparatuses mainly due to absence of uniform hydrodynamics that leads to cone formation and dosage sticking at bottom of the apparatus and undesired forced breakage of particles, among other issues known in the art. More often than not, these issues are found to have a direct relation on the presence of hard and/or solid surfaces in such apparatuses, wherein said surfaces interfere with proper dissolution that would have been desired and lead to limitations in one form or the other.
[0005] These problems, among many other obvious shortcomings, make a case for further improvement in the design of conventional dissolution apparatuses or any component related thereto, as currently is use, to assist in dealing with common limitations involved with their operation. Further, any uneven dissolution leads to uncertainties in determination of actual drug release from any dosage form.
[0006] There is therefore, a need in the art for a dissolving means that obviates deficiencies of the known configurations so that it is simple and appropriate in design for testing purposes. It would be an additional benefit in case the proposed dissolving means provides an option of varying hydrodynamic that can be readily customized depending upon testing need.
[0007] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0008] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0009] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00010] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00011] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

OBJECTIVES OF THE INVENTION
[00012] A general object of the present disclosure is to provide a dissolution testing apparatus for a reliable assessment in respect of dissolution behavior of a product that can be used for reliable prediction of in-vivo behavior of the same.
[00013] An object of the present disclosure is to provide a dissolution testing apparatus that does not cause breakage of the product.
[00014] Another object of the present disclosure is to provide a dissolution testing apparatus that does not cause sticking of the drug particles to bottom of container.
[00015] Yet another object of the present disclosure is to provide a dissolution testing apparatus that provides uniform hydrodynamics that prevents cone formation.

SUMMARY
[00016] Aspects of the present disclosure relate to a dissolution apparatus of certain types that employ a “stirring means” attached to a shaft to achieve desired agitating action. In particular, the present disclosure pertains to improvement to the stirring means used in dissolution testing apparatus such as, but not limited to, USP type II (or type II), which are employed during pharmaceutical development phase involving in-vitro analysis of different dosage forms.
[00017] In an aspect, the proposed stirring means prevents breakage of the drug form or sticking of the drug form to bottom of container and provides uniform hydrodynamics that prevents cone formation. Thus, the disclosed apparatus with proposed “stirring means” of suitable shape and structure can be readily utilized to overcome deficiencies of the known apparatuses.
[00018] In an aspect, the disclosed stirring means comprise at least one paddle/baffle attached to a shaft to provide required agitation to a dissolving media that may be contained in a container, wherein at least one paddle/baffle is characterized by a mesh/web structure.
[00019] In an aspect, paddle/baffle can be removably attached to bottom end of the primary shaft.
[00020] In an aspect, mesh/web structure of the paddle/baffle can have plurality of holes through the paddle/baffle, and size of the plurality of holes on the paddle/baffle can allow the drug particle that is being dissolved in the media, to pass through the holes.
[00021] In an aspect, paddle/baffle of the stirring means can be of elliptical or trapezoidal in shape.
[00022] In an aspect, the disclosed stirring means further include one or more additional baffles positioned on the shaft at a suitable height above the at least one paddle/baffle.
[00023] In an aspect, one or more additional baffles can be solid or of mesh structure.
[00024] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.

BRIEF DESCRIPTION OF THE DRAWINGS
[00025] The accompanying drawings are included to provide a further understanding of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure.
[00026] The diagrams are for illustration only, which thus is not a limitation of the present disclosure, and wherein:
[00027] FIG. 1 illustrates exemplary view of solid paddle of conventional USP Type II apparatus.
[00028] FIG. 2 illustrates exemplary front view of elliptical baffle attached to shaft contained in an apparatus in accordance with an exemplary embodiment of the present disclosure.
[00029] FIG. 3 illustrates exemplary front view of trapezoidal paddle attached to shaft contained in an apparatus in accordance with an exemplary embodiment of the present disclosure.
[00030] FIG. 4 illustrates exemplary front view of trapezoidal paddle as well as additional baffle with both attached to shaft contained in an apparatus in accordance with an exemplary embodiment of the present disclosure.

DETAILED DESCRIPTION
[00031] The following is a detailed description of embodiments of the disclosure depicted in the accompanying drawings. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00032] Each of the appended claims defines a separate invention, which for infringement purposes is recognized as including equivalents to the various elements or limitations specified in the claims. Depending on the context, all references below to the "invention" may in some cases refer to certain specific embodiments only. In other cases, it will be recognized that references to the "invention" will refer to subject matter recited in one or more, but not necessarily all, of the claims.
[00033] Various terms as used herein are given below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00034] As used herein, a person skilled in the relevant art would appreciate that terms “product” or “dosage form” or “tablets” or “drug” or “capsules” can be solids (monodisperse, polydisperse) drug products that are commonly tested with dissolution apparatus such as USP Type II. Such terms have been used interchangeably hereinafter throughout the present disclosure with reference to different aspects and figures related thereto.
[00035] As used herein term “Stirring means” signifies an attachment to a shaft, rotation or movement of which causes agitation or movement of liquid/media or dosage form in a dissolution apparatus. Stirring means can be of any shape and design. Preferably, it is paddle or baffle.
[00036] Embodiments of the present disclosure generally relate to dissolution apparatus of certain types that employ a “stirring means” attached to a shaft to achieve desired agitating action. In particular, it pertains to improvement to dissolution testing apparatus such as, but not limited to, USP Type II, which are employed during pharmaceutical development phase involving in-vitro analysis of different dosage forms. Thus, the disclosed apparatus with proposed “stirring means” of suitable shape and structure can be readily utilized to overcome deficiencies of the known apparatuses.
[00037] FIG. 1 illustrates view 100 of solid paddle 102 of conventional USP Type II apparatus (whole apparatus not shown here and in general implementation includes a beaker, among other components, to contain any media say a liquid). As shown herein, the solid paddle 102 is attached to primary shaft 104 that provides the agitation movement to any media contained in the apparatus. Movement of the paddle 102, at a pre-defined rotation per minute (rpm), produces hydrodynamic movement to dissolve any dosage form (not shown here); However, in its implementation, solid nature of paddle 102 (of FIG. 1) leads to certain limitations that prevent proper utilization of USP Type II apparatus (alternatively, Type II). While working, dosage form at times has uneven dissolution due to forced size reduction when the dosage form comes in dynamic contact with the paddle 102 while it is in motion. There is also non-uniform hydrodynamics due to presence of solid surface that is not ideal for free and uniform movement of media. Low rpm and thereby low shear hydrodynamics at bottom of the apparatus (or below the paddle 102) leads to cone formation or sticking of dosage forms particularly tablets. To get around this problem in case rpm is increased beyond a certain threshold, it was seen that the media lost its discriminatory power. Thus, there is a need to employ more ingenious solutions so as to perform proper dissolution testing without a need to largely manipulate any basic parameter of the apparatus; wherein the dosage form can be freely placed in the apparatus to let dissolution testing to happen without restricting movement of the dosage form while hydrodynamic force acts on it, as would act in case of in-vivo conditions.
[00038] In an aspect, the present disclosure provides an improved dissolution apparatus that incorporates mesh/screen/lattice/web structured “stirring means”. Preferably “stirring means” is paddle or baffle.
[00039] In an aspect, presence of mesh/screen/lattice/web structure of “stirring means” serves the purposes of preventing forced size reduction of large disintegrated particles of drug forms due to unwanted impact; minimum impact of baffle/paddle over drug release; more uniform hydrodynamics inside apparatus essentiality preventing cone formation at apparatus bottom; retention of discriminatory tool property for testing purposes.
[00040] The dimensions, shape of “stirring means”, more particularly paddle102 can be decided based upon dosage form parameters and testing time involved therewith.
[00041] FIG. 2 illustrates view 200 of elliptical baffle 202 as “stirring means” attached to shaft 104 contained in an apparatus 204 in accordance with an exemplary embodiment of the present disclosure. The view 200 shows details of the elliptical baffle 202 to bring their shape and structure in focus. As shown, the baffle 202 has mesh like structure so as to allow more uniform flow of media (generally a liquid as solvent) contained in the apparatus 204.
[00042] In an aspect, baffle can be of any shape known in the art so as to cater to requirements of dissolution testing of selected drug formulation. Such shape may depend more so, but need not necessarily, upon constraints related to size/type of shaft/apparatus/drug among other similar factors.
[00043] In an aspect, baffle 202 can replace paddle 102 (of existing apparatuses) in order to improve hydrodynamic properties of Type II apparatus. The baffle 202 preferably has mesh/screen/lattice/web like structure mainly to readily allow flow in and out of it. This free flow of media allows uniformity in flow inside apparatus 204and thereby obviates shortcomings such as undesired forced breakage of particles as found in case of the existing apparatuses.
[00044] In an aspect, mesh like structure of baffle 202 also checks forced reduction of dosage form particles, wherein such structure of the baffle 202 permits uninterrupted flow of the particles of dosage form. This ensures more certainty in dissolution testing as compared to cases in which solid paddle was used like in earlier cases.
[00045] In an aspect, there may be one or more arms of baffles 202 (FIG. 2 shows two such arms) depending upon underlying factors that may vary based upon nature/type/size of dosage form, apparatus, shape and the like. Variations in number of arms of the baffles 202 may be required for obtaining modified agitating action or due to any space constraint or any other specific need for desired dissolution test.
[00046] In an aspect, as usually happens in case of invariably high rpm, increase in rpm of shaft 104 beyond a certain threshold may stymie the ability of USP Type II apparatus to serve as discriminatory tool. For similar reasons, it may be preferable to vary the number of arms or dimensions of elliptical baffle 202 rather than crossing a threshold of rpm and as a result disrupting discriminatory testing prospects of the apparatus.
[00047] In some aspects, pore206 (alternatively, hole) size of mesh/screen/lattice/web of elliptical baffle 202 (or even any other baffle of appropriate shape in some exemplary embodiments) can be varied based on dissolution testing parameters. Factors such as nature of dosage form, testing time, rpm of shaft etc. may be considered while settling for any pore/hole 206 size of mesh/screen/lattice/web as it largely decides hydrodynamic forces inside Type II apparatus. In an aspect, employment of higher pore/hole size of mesh/screen/lattice/web of “stirring means” is utilized to prevent forced size reduction of large disintegrated particles of dosage forms. This necessarily reduces undue interference between the dosage form and the baffle. This hindrance may some time lead to unit-to-unit variation when dosage units have long disintegration time.
[00048] FIG. 3 illustrates view 300 of trapezoidal paddle302 as “stirring means”, attached to shaft 104 contained in apparatus 204 in accordance with an exemplary embodiment of the present disclosure. Here, the trapezoidal paddle302comprises mesh like structure which leads to less interference over drug release due to prevention of size reduction of large disintegrated particles of said drugs. Replacement of solid paddle with mesh like structure can improve prospects of dissolution testing with more agitation (or hydrodynamics) throughout the apparatus 204.
[00049] In an aspect, paddle can be of any shape known in the art so as to cater to requirements of dissolution testing of selected drug formulation. Such shape may depend more so, but need not necessarily, upon constraints related to size/type of shaft/apparatus/drug among other similar factors.
[00050] In an aspect, paddle 302 is of trapezoidal shape of suitable dimensions keeping in mind requirements of dissolution testing. Further, number of arm of trapezoidal paddle 302may be one or more, even or odd, symmetrical or unsymmetrical as per desired dosage form to be tested, among other requirements.
[00051] FIG. 4 illustrates view400 of trapezoidal paddle 302 as well as additional baffle402, as “stirring means”, with both attached to shaft 104 contained in an apparatus 204 in accordance with an exemplary embodiment of the present disclosure. As shown, the additional baffle 402 is of solid cover shape and attached at a suitable height above the trapezoidal paddle 302 to the shaft 104. Presence of the additional baffle 402 provides additional agitation inside the apparatus 204 along with other related benefits.
[00052] It is to be appreciated that though exemplary illustration of FIG. 4 shows additional baffle 402 in combination with trapezoidal paddle 302, it is possible to have the additional baffle 402 on the disclosed stirring means having one or more elliptical shaped baffles such as baffle 202/206, or with baffle of any other shape.
[00053] In an aspect, additional baffle 402 finds more prominence in case of apparatus having more height among any other constraint or factor faced by person having knowledge in the art. This not only supplements hydrodynamic force from bottom “stirring means”(trapezoidal or elliptical of foretold aspects) but also ensures discriminatory testing by the apparatus. In an embodiment, additional baffle 402 can also be having mesh like structure for purpose as decided depending upon suitability for dissolution testing. Further, number of additional baffle 402, may be one or more, even or odd, symmetrical or unsymmetrical as per desired dosage form to be tested, among other requirements.
[00054] In an aspect, rotation of shaft 104 (along with attached “stirring means “of elliptical or trapezoidal or other similar shape as required) can be as shown in the figures with a solid arrow in clockwise direction (or even in anti-clockwise direction).
[00055] In an aspect, baffle/paddle, whether elliptical or trapezoidal, maybe removably attached to the bottom of shaft 104 to ensure easy replacement of the “stirring means” for any other “stirring means” of choice. In an aspect, pore/hole 206 (as shown in FIG. 2) serves for exemplary purposes only. Mesh like paddle/baffle of other figures may have similar or different pore/hole as decided while taking into account underlying factors of dissolution testing among any other factors.
[00056] In an aspect, although different aspects and drawings have been explained taking reference to USP Type II apparatus in general, any “stirring means” paddle or baffle, elliptical or trapezoidal, with or without additional paddle/baffle, can be readily used with other dissolution apparatus, and all such modifications are well within the scope of the present disclosure.
[00057] Thus, the present disclosure provides for an improved dissolution (USP Type II) apparatus that overcomes deficiencies of the existing arrangements with ingenious improvements to paddle and/or any auxiliary component attached thereto. Additionally, it provides an option to achieve variations in hydrodynamics with auxiliary components that can be readily used with or without proposed modifications.
EXAMPLE
[00058] In an exemplary experiment Ticagrelor which is a low soluble drug was chosen for discrimination to achieve target profile and define the batch to batch variation. The formulation was subjected to dissolution in both a conventional dissolution apparatus type II as well as a modified dissolution apparatus type II (in accordance with the present disclosure) for comparative evaluation of the proposed design. In both cases paddle was rotated at speed of 50 RPM in a volume of 900 ml. of media.
Dissolution percentage
Time in min. 5 10 15 20 30 45 60 75
Normal paddle 30.5 51.6 64.7 73.9 73.9 91.4 94.2 96
Modified paddle 28.8 42.5 54.9 63.4 73.3 78.9 82.2 83
Table1: Dissolution results of USP II with and without modified paddle.
[00059] From above dissolution results it can be concluded that rate of dissolution is slower with modified paddle. This is attributed to reduced hindrance and impact of paddle on tablet.
[00060] Thus the disclosed dissolution apparatus incorporating modified paddle helps to prevent non-uniform dissolution of drug forms by preventing hindrance and impact of paddle on tablet.
[00061] While the foregoing describes various embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention.

ADVANTAGES OF THE INVENTION
[00062] The present disclosure provides a dissolution testing apparatus for a reliable assessment in respect of dissolution behavior of a product that can be used for reliable prediction of in-vivo behavior of the same.
[00063] The present disclosure provides a dissolution testing apparatus that does not cause forced size reduction of the dosage form.
[00064] The present disclosure provides a dissolution testing apparatus that does not cause sticking of the drug particles to bottom of container.
[00065] The present disclosure provides a dissolution testing apparatus that provides uniform hydrodynamics that prevents cone formation.
,CLAIMS:

1. A dissolution apparatus for dissolving a dosage form, the dissolution apparatus comprising:
a container for holding a dissolving media; and
a stirring means comprising at least onepaddle/baffle attached to a shaft to provide required agitation to the media;
wherein the at least one paddle/baffle is characterized by a mesh/web structure.

2. The dissolution apparatus of claim 1, wherein the mesh/web structure is characterized by presence of plurality of holes through the at least one paddle/baffle.

3. The dissolution apparatus of claim 2, wherein the plurality of holes on the at least one paddle/baffle are sized to allow the dose form being dissolved in the media to pass through.

4. The dissolution apparatus of claim 1, wherein the at least onepaddle/baffle is of elliptical shape.

5. The dissolution apparatus of claim 1, wherein the at least one paddle/baffle is of trapezoidal shape.

6. The dissolution apparatus of claim 1 wherein the at least one paddle/baffle is removably attached to bottom end of the shaft.

7. The dissolution apparatus of claim 1 wherein the stirring means further include one or more additional baffles positioned on the shaft at a suitable height above the at least one paddle/baffle.

8. The dissolution apparatus of claim 7, wherein the one or more additional baffles are solid.

9. The dissolution apparatus of claim 7, wherein the one or more additional baffles are of mesh structure.