DESC:
FIELD OF DISCLOSURE
[0001] The present disclosure relates to the field of apparatuses for pharmaceutical testing. In particular, it pertains to a dissolution testing apparatus that is employed during pharmaceutical development phase of different pharmaceutical 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] During development of pharmaceutical formulations, it is essential to establish a relationship between in vitro characterization of a dosage form and its in vivo performance. Several experimentations have shown existence of significant likelihood that the rate of in vitro dissolution of a pharmaceutical product or dosage form is a significant indicator of the in vivo activity of said dosage form after it enters the bloodstream of the subject. Accordingly, during pharmaceutical development dissolution testing is a requisite for all solid oral dosage forms in which absorption of the drug is required to result in a desired therapeutic effect.
[0004] The dissolution test also enables to study impact of various factors such as process of manufacturing, physical parameters of Active Pharmaceutical Ingredient (API), excipients in formulation and changes in physiochemical characteristics of API in formulation. Further, regulatory and variousperformance parameters too require proper dissolution testing before any drug is marketed to its end users.
[0005] 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. Several type of dissolution apparatuses exist and are used in the industry. In United States Pharmacopeia (USP) four dissolution apparatuses are standardized and specified They are: (a) USP Dissolution Apparatus 1 - Basket (37°C), (b) USP Dissolution Apparatus 2 - Paddle (37°C), (c) USP Dissolution Apparatus 3 - Reciprocating Cylinder (37°C), and USP Dissolution Apparatus 4 - Flow-Through Cell (37°C).
[0006] However, there are problems associated with known dissolution apparatuses mainly due to absence of uniform hydrodynamics that leads to cone formation, 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 absence of sufficient hydrodynamics at the bottom, or other distantlow-agitated areas, of the apparatus. Without binding to any theory, such low-agitated areas are probably formed on account of inability of conventional setups, due to practical limits of currently employed stirring means, to uniformly reach every corner of the dissolution apparatus. These shortcomings affect ability of conventional dissolution apparatus to act as a discriminatory tool, which in turn affects in vitro-in vivo correlations (IVIVC) of a dosage form being tested.
[0007] There is therefore, a need in the art for a dissolving apparatus that obviates deficiencies of the known configurations and that is simple in design for testing purposes. It would be an additional benefit in case the proposed dissolving apparatus provides an option of varying hydrodynamic that can be readily customized depending upon testing need.
[0008] 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.
[0009] 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.
[00010] 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.
[00011] 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.
[00012] 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
[00013] 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 drug form that can be used for reliable prediction of in-vivo behavior of the same.
[00014] An object of the present disclosure is to provide a dissolution testing apparatus that does not experience wobbling/swaying that prevent proper utilization of the apparatus.
[00015] Another object of the present disclosure is to provide a dissolution testing apparatus that avoids non-uniform hydrodynamics thus providing ideal free and uniform movement of media.
[00016] Another object of the present disclosure is to provide a dissolution testing apparatus that allows rotation of the apparatus at speeds that do not cause the apparatus to lose its discriminatory power and yet prevent other drawbacks.
[00017] Another object of the present disclosure is to provide a dissolution testing apparatus that allows rotation of the apparatus at relatively higher speed without creating non-uniform movement of media.
[00018] Yet another object of the present disclosure is to provide a dissolution testing apparatus that provides adequate low shear hydrodynamics at bottom of apparatus to prevent sticking of dosage forms especially tablets at bottom.

SUMMARY
[00019] 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 I (or type I), which are employed during pharmaceutical development phase involving in-vitro analysis of different dosage forms.
[00020] In an aspect, the present disclosure provides an improved dissolution apparatus that incorporates stirring means attached at basket bottom. In an aspect, the stirring means can provide better hydrodynamics in the apparatus, preferably at the bottom of the basket. Thus, the disclosed apparatus with proposed stirring means of suitable shape, orientation or length can overcome deficiencies of the known apparatuses.
[00021] The disclosed dissolution apparatus comprises a basket made of mesh to allow free flow of a media in which the basket is dipped, there through; anda primary shaft attached to the basket to provide required rotational movement to the basket for agitating the media. In an aspect of the present disclosure, the apparatus further includes additional stirring means that are attached to bottom of the basket.
[00022] In an aspect, the additional stirring means can be one or more stirring rods attached along circumference of bottom of basket of the disclosed dissolution apparatus.
[00023] In an aspect, one or more stirring rods can be attached pointing downwards spreading outwardly.
[00024] In an aspect, one or more stirring rods can be equi-spaced along the circumference.
[00025] In an aspect, additional stirring means can alternatively be one or more paddles attached to the bottom of the basket through a shaft.
In an aspect, one or more paddles can be disc shaped and of solid construction.

BRIEF DESCRIPTION OF THE DRAWINGS
[00026] 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.
[00027] The diagrams are for illustration only, which thus is not a limitation of the present disclosure, and wherein:
[00028] FIG. 1 illustrates a typical view of basket of a conventional USP Type I apparatus.
[00029] FIG. 2 illustrates an exemplary front view of stirring rods attached to basket of dissolving apparatus in accordance with an embodiment of the present disclosure.
[00030] FIG. 3 illustrates an exemplary front view of shaft with bottom paddle attached to basket of dissolving apparatus in accordance with an 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 shown 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 “dosage form” or “tablets” or “drug” or “capsules” can be solids (monodisperse or polydisperse) drug products that are commonly tested with dissolution apparatus such as USP Type I. 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 basket, rotation or movement of which causes agitation or movement of liquid/media or dosage form in an dissolution apparatus. Stirring means can be of any shape, design, length and width. Preferably, it is stirring rod or paddle.
[00036] Embodiments of the present disclosure generally relate to a dissolution apparatus that employ a basket, particularly with screen mesh along its curved surface, attached to a shaft (also referred to as primary shaft) to impart a desired agitating action such as rotation to the basket within a media where the basket is dipped during testing. In particular, it pertains to dissolution testing apparatus such as, but not limited to, USP Type I, which are employed during pharmaceutical development phase involving in-vitro analysis of different dosage forms.
[00037] FIG. 1 illustrates a typical view of a basket 102 of a conventional USP Type I dissolving apparatus 100. As shown, body of the basket 102 is made of mesh 106, to allow free flow of media therethrough, and is typically attached to a primary shaft 104 that provides required rotational movement to the basket 102 for agitating media(generally a liquid as solvent) in which the basket is dipped. The basket 102 with the dosage form placed within the basket 102, and the primary shaft 104 are used in combination with a container such as a beaker (not shown here) that holdsthe media which generally is a liquid solvent. Notably, movement of the basket 102, at a pre-defined rotation per minute (rpm), produces the required hydrodynamic movement to dissolve any dosage form.
[00038] In its implementation, high rpm of basket 102 (of FIG. 1) can lead to wobbling/swaying and thereby create certain limitations that prevent proper utilization of USP Type I apparatus 100. Such limitations can be non-uniform hydrodynamics due to presence of wobbling motion that is not ideal for free and uniform movement of media. On the other hand, low rpm of basket 102 (of FIG. 1) can lead to reduced movement of the basket and hence, low shear hydrodynamics at bottom of the apparatus 100. The low shear hydrodynamics at bottom of apparatus 100 can also lead to sticking of dosage forms especially tablets to bottom of container. Further large pore size of bottom screen can cause settling of disintegrated mass leading to cone formation near bottom center of the 102 basket.
[00039] Increase or decrease of rpm beyond a certain threshold to overcome the draw backscan result in the apparatus losing 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.
[00040] In an aspect, the present disclosure provides an improved dissolution apparatus that incorporates stirring means attached at basket bottom. In an aspect, the stirring means can provide better hydrodynamics in the apparatus, preferably at the bottom of the basket. Thus, the disclosed apparatus with proposed stirring means of suitable shape, orientationor length can overcome deficiencies of the known apparatuses.
[00041] FIG. 2 illustrates an exemplary view of the proposed dissolution apparatus 200 that incorporates stirring rods 202 (shown four in number in present figure) attached to basket 102 of dissolving apparatus 200 in accordance with an embodiment of the present disclosure. As shown, the stirring rods 202 can be fixed to bottom of the basket 102 along outer its circumference, at an angle spreading outwardly so as to act as stirrers and allow more uniform flow of media contained in container such as a beaker 204 where media is placed.
[00042] In an aspect, stirring rods 202 can be attached around the circumference of bottom of the basket 102 and can project downward in order to stir the media below the bottom of the basket 102 to improve hydrodynamic properties of Type I apparatus. The stirring rods 202 preferably have linear rod-like structure which readily allows enhanced agitation of media in container 204 and particularly at bottom of the container 204 below the basket 102. Free flow of media allows uniformity in flow inside the container 204 and thereby obviates shortcomings such as cone formation, dosage sticking as observed with conventional dissolution apparatuses without stirring means.
[00043] In an aspect, stirring rods 202 can be equi-spaced and attached symmetrically along circumference of bottom of the basket 102 as shown in front and bottom views of FIG. 2. In implementation, number of the stirring rods 202 or their angle of attachment to basket 102 their dimensions (i.e. length and/or thickness) can be varied to cater to hydrodynamic requirements for desired dissolution testing.
[00044] In an aspect, presence of stirring rods 202 ensures stable motion (as compared to wobbling encountered in conventional apparatuses) of basket 102 ensuring more uniformity and certainty in dissolution testing.
[00045] In an aspect, there can be any number of stirring rods 202 attached to basket 102 depending up underlying factors that can vary based upon nature/type/size of dosage form, container and the like. Variations in number of arms/rods of the stirring rods 202 may be required for obtaining modified agitating action or on account of space constraint or any other specific need for desired dissolution test.
[00046] In some aspects, shape or point of attachment of stirring rods 202 (or even any other additional stirring means in some exemplary embodiments) can be decided by those skilled in the art after taking into account dissolution testing parameters. Factors such as nature of dosage form, testing time, rpm of shaft etc. may be considered while settling for any shape of the stirring rods 202 as it largely decides hydrodynamic forces inside Type I apparatus.
[00047] In an aspect, the stirring means,instead of having linear rod-like configuration, can be implemented in different shapes, positionsor lengths. For example it can be paddle 304 fitted to a shaft302 disposed at center of basket bottom as shown in FIG. 3. Here, the bottom shaft 302 with suitable length that allows the basket 102 to be immersed in the media contained in the container 204 can be fixed to bottom of the basket 102 along the axis of primary shaft 104. The paddle 304 can be of size and dimensions so as to provide adequate stirring movement to the media as the basket 102 is rotated.
[00048] In an aspect, paddle 304 can be of any shape such as, but not limited to, circular, trapezoidalor any other shape with three or more sides (regular or irregular), depending upon dissolution requirements. Further it can be solid or perforated to provide varying degree of stirring action; preferably it is solid.
[00049] In an aspect, basket 102 can be solid or has meshed structure or half of the basket can be solid and half of the basket can have meshed structure.

EXAMPLES
[00050] In an exemplary experiment Cinacalcet 90 MG tablets were chosen as the model dosage unit for dissolution in 900mL of 0.05N HCl constituting as media. The basket was rotated at constant speed of 50rpm.

Dissolution percentage and Standard Deviation (SD)
Time(min) 0 5 10 15 20 30 45 60 90 120
Basket 0 29.55 39.65 40.7 42.05 44.2 47.55 50.45 54.2 57.05
SD 0.0 2.9 8.0 7.9 8.1 7.8 8.7 9.4 8.9 8.6
Basket modified with rods 0.0 51.7 64.1 70.3 74.2 84.0 89.8 92.4 92.9 92.0
SD 0.0 1.0 3.0 3.3 2.4 0.5 1.6 3.7 6.6 8.8
Basket modified with disc 0.0 73.5 88.0 91.9 92.1 90.4 92.4 91.3 93.5 92.5
SD 0.00 0.42 0.28 0.92 0.64 0.99 0.85 1.13 2.76 1.56
Table1:Dissolution results of USP I Basket modified with rods and disc.
[00051] From above dissolution results following inferences were drawn:
a) While using unmodified basket, only a maximum of 57.05% drug was found released at the end of 2hours. Settling of disintegrated mass was observed at the bottom of container.
b) No such disintegrated mass was observed at the bottom of container with modified baskets.
c) Unit to unit variation was found to be relatively greater with unmodified basket as compared to the modified baskets.
d) Steady hydrodynamics due to stirring rods facilitated uniform and faster release of drug in media (92% at the end of 2h).
e) Steady hydrodynamics due to disc facilitated uniform and faster release (92.5% at the end of 2h) of drug in media.
[00052] Thus the disclosed dissolution apparatus incorporatingstirring meansin form of one or more rodsat suitable position with or without paddle helps to prevent non-uniform dissolution of drug forms by obviating undue settling of disintegrated particles; create more uniform hydrodynamics inside apparatus essentiality preventing cone formation/dosage sticking at apparatus bottom and thereby retainsits property as a discriminatory tool for testing purposes.
[00053] 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 when combined with information and knowledge available to the person having ordinary skill in the art.

ADVANTAGES OF THE INVENTION
[00054] The present disclosure provides a dissolution testing apparatus for a reliable assessment in respect of dissolution behavior of a drug form that can be used for reliable prediction of in-vivo behavior of the same.
[00055] The present disclosure provides a dissolution testing apparatus that does not experience wobbling/swaying that prevent proper utilization of the apparatus.
[00056] The present disclosure provides a dissolution testing apparatus that avoids non-uniform hydrodynamics thus providing ideal free and uniform movement of media.
[00057] The present disclosure provides a dissolution testing apparatus that allows rotation of the apparatus at speeds that do not cause the apparatus to lose its discriminatory power and yet prevent other drawbacks.
[00058] The present disclosure provides a dissolution testing apparatus that allows rotation of the apparatus at relatively higher speed without creating non-uniform movement of media.
[00059] The present disclosure provides a dissolution testing apparatus that provides adequate low shear hydrodynamics at bottom of apparatus to prevent sticking of dosage forms especially tablets at bottom.

,CLAIMS:
1. A dissolution apparatus comprising:
a basket made of mesh to allow free flow of a media in which the basket is dipped, there through; and
a primary shaft attached to the basket to provide required rotational movement to the basket for agitating the media;
wherein the dissolution apparatus further comprises additional stirring means that are attached to bottom of the basket.

2. The dissolution apparatus of claim 1, wherein the additional stirring means are one or more stirring rods attached along circumference of bottom of the basket.

3. The dissolution apparatus of claim 2, wherein the one or more stirring rods are attached pointing downwards spreading outwardly.

4. The dissolution apparatus of claim 2, wherein the one or more stirring rods are equi-spaced along the circumference.

5. The dissolution apparatus of claim 1, wherein the additional stirring means are one or more paddles attached to the bottom of the basket through a shaft.

6. The dissolution apparatus of claim 5, wherein one or more paddles are disc shaped and are solid.