cone effect

[JSantamaria]

Could anybody tell me: How I can eliminate "cone effect"?, obviously remaining inside USP recomendations

Thanks.

[harthur]

Could anybody tell me: How I can eliminate "cone effect"?, obviously remaining inside USP recomendations

Thanks.

I will assume you are using paddles - cone formation is pretty common when using paddles. Have you tried using the peaked vessels? Or possibly switching to baskets?

[JSantamaria]

Thanks harthur:

Yes, we are using paddles. With baskets, the dissolution reach almost 100%, but, with paddles it is only 75% ( aproximattely ). Nevertheless, the USP stablish paddles for that product.
I don't think that peaked vessel are officials. Do you have any information about it?

Thanks again.

[kgauger]

The only luck that I have had in overcoming coning has been to increase the RPMs, which if you are following a monograph, is also not allowed.

[JSantamaria]

Thanks Kgauger, I´ll really appreciate your help. According our last investigations we think that exist some class of interaction between the drug ( from an specifical source ) and crosscarmellose sodium or PVP CL, that produce adhesion and therefore cone efect, because the same formulations with drug from another manufacturer pass the dissolution test whitout any trouble.
Have you ear something like this?

[Matteo]

can you explain me what you mean with cone effect?

thanks

[Moderator]

can you explain me what you mean with cone effect?

thanks
http://www.dissolution.com/images/coning.jpg

[JSantamaria]

Thanks Moderator:

One image is better than thousands words.
I just only would like add, that we can call cone effect to the accumulation of tablet residues, forming a cone by the action of hydrodinamical forces, that diminish the ability of the formulation to release druf from its excipient matrix. Obviously not all accumulations produce low dissolution, we suspect that the physico-chemical properties of the formulation has an important role.
Are you agree with that ?

[qureshi]

Thanks Moderator:

Obviously not all accumulations produce low dissolution, we suspect that the physico-chemical properties of the formulation has an important role.
Are you agree with that ?

Moderator excellent picture. Thanks.

This (cone formation) is the biggest problem is drug dissolution testing, which causes high variability is results, failure in apparatus calibration (USP system suitability test) and one of the main reasons of lack of bio-relevancy of results (as body does not accumulate material like this, material is constantly in motion and mixing state). This accumulation of the material is an inherent problem of geometry of the apparatus (round bottom shape vessel and paddle combination). Please keep the USP and other regulatory bodies informed about this situation/drawback so that need for improved dissolution testing be recognised.

Please refer to my other post in this regard e.g. http://www.dissolution.com/vbulletin/showthread.php?p=3400#post3400

Saeed

[JSantamaria]

Dear all:
The USP methodology to evaluate the dissolution of an oral solid form has been very usefull, and it will be in the future. But at least that this in vitro assay has been correlated with an in vivo study, we can´t say that it represents the behavior inside the body. We have reach this agreement based on several studies. But no more. So, I´m agree with qureshi in the sense that some modifications in the method are needed.
By the other hand, to get an equipment that resembles exactly hydrodinamical behavior of the body it will be not only expensive but may be unneceesary. It could be enough changing the shape of the bottom of the vessel, and even, being a little dreamer, designing an paddle with a three dimensional caotic movement, because the tortuous gastrointestinal tract, doesn´t produce an laminar circular flow.
Any way, until we can use this or another technical solutions, we must solve the problems like "cone effect "with the actual apparatus.
By the other hand, except the fact that the apparatus 2 is stablished in USP for our product, we can´t see a good reason for not use the basket apparatus in a formulation that we are pretty sure that won´t accumulate in a cone inside the body.
I am waiting your views.

[qureshi]

Saying, "… until we can use this or another technical solutions, we must solve the problems like "cone effect" with the actual apparatus.". My view is that it is not possible to eliminate cone effect without changing the spindle (Paddle) and/or the vessel. For addressing the problem, something has to be changed.

Saying "to get an equipment that resembles exactly hydrodinamical behavior of the body it will be not only expensive but may be unneceesary." I am of the view that, we need to SIMULATE not DIPLUTICATE GI tract environment or physiology. Hydrodynamics of GI is such that products move and get stirred with reasonable force. We need to simulate that effect. Unfortunately, Paddles provide just the opposite phenomenon. Thus relevancy of in vitro results to in vivo results, even if they appear related, has to be questionable.

To address these issues we have proposed a modified spindle (http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12885394&dopt=Abstract), which seems to address the concerns of current dissolution apparatus well. Please review it and, if possible, provide us your comments. Thanks.

Saeed

[kgauger]

Dr. Qureshi,

I like the idea of a better bio-indicative apparatus 2 than we currently have. I was reading the abstract you posted and I didn’t see any testing of non-bioequivalent formulations with the new paddle design. Has any work been done with formulations that are not expected to match?

[qureshi]

Thanks for your kind words about our work.

Showing relevant dissolution results with non-bioequivalent products is the next step for which we do not have data yet. For us it will be very expensive to conduct such studies ourselves. In fact, we are seeking collaboration in this regard. I have a few ideas, if some is interested in collaborating with us. Hopefully we will conduct such studies soon. Saeed

[Krishnakant7]

I am facing the same problem , i am getting low disoslution with appt 2 50rpm and better results using appt 1 50rpm. can I go ahead with Appt 1 50rpm to avaoid the cone effect.

pl reply at the earliest.

Regards
K.T.GANDHI

[qureshi]

Cone effect may be considered as a reflection of a broader problem associated with the use of USP Paddle and Basket apparatuses. The problem in using these apparatuses comes from the settling effect of drug products or disintegrated particle at the bottom of the vessels. This settling effect, which is more pronounced with USP 2 (Paddle) with certain products and known as cone formation, but is always present with apparatuses 1 and 2.

The result of this cone formation or settling effect is that it hinders in proper drug/product interaction with dissolution medium. Thus results not only be unpredictable, but also testing will lack proper evaluation of drug release characteristics of a product.

Often, it is suggested that increasing the rotation speed of spindles may alleviate the problem. However, one does get higher results because of higher erosion on the surface with higher rpms, but lack of efficient product-medium interaction remains. Therefore, possible solution to addressing the problem would be an approach which provides efficient product-medium interaction. In this regard, we have proposed a new spindle (********-shaped) which appears to work very well in addressing the problem.

Hope this clarifies the problem, cause of it, and a potential solution to address the problem.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[moff]

To eliminate the effect of coning, you might also want to try the Peak vessel. It has a small peak in the bottom of the vessel where the area of low hydronymics/coning occurs. This can often lead to getting rid of the coning artifact, and acheive more discriminative profiles than traditional vessel methods at a higher RPM.

The Peak vessel isn't in any official USP monographs as of yet that I'm aware of, but there have been some methods using the Peak vessel which have been accepted by regulatory agencies.

[qureshi]

I agree with Moff that Peak vessels may also, to some extent, address the cone problem by pushing the product off-centre. However, the problem of poor product-medium interaction, thus lack of predictability and bio-relevance, would remain the same as with regular vessels.

The reason that Peak vessels use has not caught up or accepted, in my view, is that like the use of higher speed (rpm), use of Peak vessels also targets to achieve higher results. This conceptually does not fit well with dissolution testing. For proper dissolution testing it is the medium-product interaction which is necessary. Therefore, my view has been, that if one uses a technique which does not provide intimate interaction of product and medium, then the dissolution results will be of limited value. Keep this thought in mind in choosing proper dissolution testing approach/technique.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[moff]

Qureshi,
Thanks for your post. I just wanted to say that the goal of peak vessels is to increase discriminatory power, not increase % dissolved. Generally, when one is using peak vessels you would also decrease RPM significantly at the same time. The % dissolved by doing this may stay at the same benchmark, but the artifact of the coning effect is removed.

By removing the cone, and having a lower RPM speed one would have a dissolution based more on a media - dosage form interaction and less on hydrodynamic forces, etc.

I believe the peak vessel acheives some of the same goals as you are looking to acheive with the ******** brush.

[qureshi]

Moff: Thanks for your post. However, unfortunately, your views do not make sense.

Peak vessel has nothing to do with discriminatory aspect (power). As I said, it just pushes the product off center, thus somewhat higher dissolution results, nothing more. However, if you will reduce the rpm that will be a different issue, perhaps dissolution rate may decrease or may not.

Hydrodynamic within the vessel (Peak) remains the same (Laminar, which is the problem).

Use of Peak vessel does not at all achieve the same results as that of using ********-shaped spindle. In one of our earliest publications, I have clearly showed that use of Peak vessel does not provide efficient product-medium interaction.

********-shaped spindle provides intimate product-medium interaction, Peak vessel does not.

Hope this clarifies.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[moff]

Qureshi,
There have been articles written describing the effect of the peak vessels on dissolution results and that it can produce more discriminative data. Use of a peak vessel where coning is present in a standard vessel can allow you to remove the cone effect at a lower RPM than with a standard vessel. For example, a formulation may need to be at 75 rpm in a standard vessel to break up the cone and with the peak it may only need to be at 50 or 60 rpm. The reduction in RPM decreases the effect of shear forces on the disintegration and dissolution of the dosage form.

See: http://www.dissolutiontech.com/DTresour/200502Articles/DT200502_A02.pdf
which states "...at higher agitation rates the method tends to become less discriminating."

I did not say that the peak vessel and ******** brush provide the same agitation or give the same results, only that the peak vessel acts to remove some of the artifacts of dissolution testing for some products, as you are trying to remove artifacts with the ******** brush.

[qureshi]

Moff: I will greatly appreciate references to some of the publications you are referring to where Peak vessels have been shown to be more discriminatory than the USP vessels, as I am not aware of those.

With regard to the reference you mentioned, the following is the observation noted in the publication.

“There was no significant difference in the dissolution rates obtained using the USP and flat bottom vessels for either the low and or high solubility drug formulations. The dissolution rate for both formulations was significantly higher in the Peak vessel and was comparable to the results obtained at higher rotation speeds of 60 rpm and 75 rpm in the USP vessels”

There is no indication or mention of improved discrimination. My interpretation would be higher results lower discrimination, if there is one, or shown to be otherwise.

Saeed

Disclaimer: Views expressed here are for scientific discussion puposes only and may not be reflective of opinions and policies of my employer.

[Murthy]

Did you ever try with a Sinker?? I think a Sinker at the bottom of the vessel may disturb the cone. And the usage of Sinkers is acceptable to the Pharmacopoeia.

[qureshi]

I agree with you Murthy, that perhaps sinker might help in pushing the product and disintegrated material off centre, thus higher dissolution results. However, I would not bet on it, as I have seen cases otherwise, in which results appears to be lower with the use of sinkers. The reason being, the product becomes encaged and the product-medium interaction further reduces. Therefore, use of sinker may or may not help.

However, my main concern is not the use of Peak vessel, sinker, metal striped/band (as we have published), these are not solutions, but in fact demonstration of the problems (flaws) of current apparatuses/practices. By using any of the approaches described, one is not monitoring the dissolution results, but observing flaws of vessel/Paddle use by different approaches.

Let me explain it further, suppose for a product one gets dissolution results of 60%, 70%, 80% and 90% at a fixed time (say 30 minutes) using regular vessels, with metal strip, sinker and Peak vessel respectively. Question is which answer is right, or what is the actual dissolution characteristics of the product? Answer is perhaps NONE of the above. By the way, if someone put the product in a blender and shows 100% dissolution in 30 seconds, would that be also considered as dissolution characteristics of the product? If not, then why not?

The testing approach must have a link to some reference. In our case, link to bio-behaviour of the product. As all the approaches mentioned above do not provide link to bio-behaviour, thus results would be of limited use.

Recent studies show that use of ********-shaped spindle provides this link and appears to provide relevant results or at least provides a lead in the right direction. Some thoughts for consideration.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[rc_12321]

Saeed, there are other alternative apparatus as well which can provide maximum medium-product interaction.Apparatus 3 and others do not have an issue like cone effect.Have you ever tried with them in matching bio-results?


You have referred one thing in above post, bio-behaviour of the product.Perhaps you have seen it from one angle i.e medium-product interaction and trying to match in vitro and in vivo results.But there are other areas as well which needs maximum consideration .If new design simulates bio-behaviour of the drug product ,it must equally give odd results for bio-faling batches .But i am not aware of any data available in support of this aspect.One must see in this direction also.


As for as cone effect which is caused by the accumulation of particulate matter in the dead zone of vessel is not the problem posed by the apparatus alone .Cone effect, most of the times ,depends on the density of the particles of particular formulation .Formulations that contain ingredients which have lesser density than the media do not suffer from this issue. . Hence the issue needs to be addressed from this angle also.

[qureshi]

RC: I thought you were going to provide references to some studies/publications where, in your view, it has been shown that Peak vessels provide discriminatory results. Obviously there are none.

With regard to other apparatuses, e.g. USP 3, I am not aware of reports of discriminatory studies using this apparatus as well. In my view, if an apparatus is listed in USP does not mean that it should be accepted as such that it is/will provide expected or more accurate/relevant/discriminatory results. I am not aware of any monographs which utilizes the USP 3 or 4. To me it is a strong evidence, that use of these apparatuses has not validated or useful.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[rc_12321]

Saeed ,here is an artcle that describes how the peak vessels proide improved environment of hydridynamics over USP-2.The concluding remarks of the paper pointed that the peak vessels reduce the variability typically observed for conventional usp apparatus.
http://www.dissolutiontech.com/DTresour/1998Articles/DT199805_A03.pdf

[qureshi]

RC: My post was referring to discriminatory ability not high results and less variability. High results with less variability is no brainer. If I use a blender which results in 100% in 30 second, variability (%STD) will be zero.

Objective for dissolution results should be to differentiate between good and bad batches/products, in reference to bio. High results/low (or different) results are immaterial. Use of ********-shaped spindle has clearly demonstrated to achieve such bio-relevant results (Please see latest issue of Dissolution Technologies).

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may be reflective of opinions and policies of my employer.

[moff]

The peak vessel articles do show higher discrimatory power for coning dosage forms. I explained this in a previous post in this thread.

At the same RPM, a peak vessel will yield higher % dissolved than a traditional vessel. Howeever, a peak vessel is able to be run at LOWER rpm than the traditional vessel. Thus, the overall dissolution rate can remain about the same between a tradition vessel at something like 75 rpm and a peak vessel at 50 rpm. The peak vessel could give the benefit of better discriminatory power and lower RSD in formulations with coning.

As far as the ********-shaped spindle goes, the latest issue of dissolution technologies discusses both the Peak vessel and the ******** spindle brush. The Your brush was talked about as promising, but still having flaws which would need to be addressed in further development, whereas the Peak vessel is farther along in acceptance and data. From the article you mention:

"Additionally, the acceptance of the ********-shaped spindle by the USP for routine dissolution testing would require improvements in the robustness of the ********-shaped paddles curvature, reproducable positioning in the vessel, maintainance of bristles, and acceptable calibration in order to reduce variability in measurements and allow for consistant comparisons. Since the Peak vessel, which satisfies the aforementioned criteria, still has not gained world-wide acceptance, the ********-shaped spindle will face many of the same challenges."

[qureshi]

Moff: Thanks for your post and feedback on the recent publication regarding the use of ********-shaped spindle.

With regard to the use of Peak vessel, there is no problem if you are convinced that Peak vessel is equal or better in merit with ********-shaped spindle, there should not be any hesitation in using it. However, in my opinion, there has not been any study reported in the literature in which application of Peak vessel has been shown to relate to bio-results. ********-shaped has been shown to be discriminatory based on bio-studies (my studies and now from Merck Frost).

There is a misconception that if a test shows differences in dissolution results, then the test be considered discriminatory. This is not accurate. Such results are just different but NOT discriminating. For differences to become discriminating, bio-link is a must.

Another thing, in your post you are saying that Peak vessel at 50 rpm gives the same or similar results as with regular vessel at 75. Then I do not understand, if the results are the same then how they are different as well at the same to become so-called discriminating.

With regard to the comments you noted in your post which described in the publication “As far as the ********-shaped spindle goes, the latest issue of dissolution technologies discusses both the Peak vessel and the ******** spindle brush. The Your brush was talked about as promising, but still having flaws which would need to be addressed in further development”

I agree with those comments and it should be like this. These are mechanical and operational aspects. These are to be addressed and will be addressed. These are minor issues. I think we have pretty good handle on these. Focus of the work was to validate the concept with bio-studies and other pharmaceutical attributes. I believe they have done a tremendous job in this regard and have validated the concept very well. Such validation has not been done or shown with any of the current apparatuses.

In the end I like to say another thing that if without standardization, use of ********-shaped spindle can provide such fantastic discriminating and bio-relevant results, just imagine what will happen when operation will be standardized!!!

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[moff]

Qureshi,
I am aware of bio-results compared to the Peak vessel which were promising, however, I don't know if these have been published.

I do not believe that the ******** shaped spindle and peak vessel can really be compared apples to apples to say one is better or worse. I think when the ******** spindle is refined it will have applications which it is well suited for as the Peak vessel also has applications it is well suited for.

To clarify my comment on Peak vs. standard vessels, the point I was trying to make is that one could see the final % dissolved between a peak at 50 and standard at 75 be similar. That the final % dissolved is the same does not mean that the curve to that point is the same or state what the RSD would be.

I don't know if I would call any of the data for ********-shaped spindles "fantastic". Promising yes, fantastic no. Let's not make the DDG a ********-shaped spindle infomercial.

[gdeedee]

Is there a precise USP (or other) definition of what constitutes "discriminating power" of a dissolution apparatus ?

[qureshi]

... Let's not make the DDG a ********-shaped spindle infomercial.

Moff: As I have developed and proposing the use of ********-shaped spindle as a more appropriate option than the others such as Paddle and Basket, therefore, it may be said that I am doing “infomercial”. Unfortunately, I have to live with such comments/remarks. However, I do have to say that such comments/remarks are neither accurate nor help others in critically evaluating new proposals/suggestions.

Let me say it another way, the publication from Merck Frosst described four cases and in one case, in a small side experiment, they show ********-shaped spindle does help addressing the artifact of cone formation just like Peak vessel. You only picked this small part and ignored the main part of publication including IVIVC part which consist two studies out of four. Should I say that you are doing “negative infomercial”. No, you like to discuss one part, I and others may like to discuss others as well. That is perfectly alright. That is why participation in the forum.

With regard to the comparison of ********-shaped spindles with others including Peak vessels. I agree with your example that ********-shaped and Peak vessel is not comparing apples vs apples. However, in your opinion, ********-shaped spindle may be good for some situations, so does Peaks vessel. And if I may add further, with due respect, perhaps blender can also be used for some situations. Question is what situations would those be? This is where my difference of opinion, i.e. a dissolution test has to provide results relevant to bio. Therefore, choice should be made for an equipment and device which is shown to reflect of bio-relevant results as in the case of ********-shaped. Therefore, use of ********-shaped spindle should be considered appropriate for dissolution testing. It is not that I do not believe you and any one else, I have not seen results which have shown as bio-relevant using any other of the choices including Peak vessel.

Further, I will go one step further, as I have stated many times, to have bio-relevant results, test environments must be bio-relevant as well. One of the major discrepancies between current choices and the ********-shaped with the physiological relevance is the (mis)match of stirring and mixing aspect. Therefore, even if I will see bio-relevant results from the current apparatuses, I have to know and question how these provide bio-relevant results when they should not? There must be a rational for a spindle/vessel to be able to provide bio-relevant results.

Hope this clarify the position.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[moff]

Qureshi,

I am not ignoring the IVIVC portion of the article, the data is promising. I'm also not willing to jump to the conclusion that the ******** spindle brush is an improvement in IVIVC development, the population of data is just too small at this point in my opinion.

To your last comment:

"Further, I will go one step further, as I have stated many times, to have bio-relevant results, test environments must be bio-relevant as well. One of the major discrepancies between current choices and the ********-shaped with the physiological relevance is the (mis)match of stirring and mixing aspect. Therefore, even if I will see bio-relevant results from the current apparatuses, I have to know and question how these provide bio-relevant results when they should not? There must be a rational for a spindle/vessel to be able to provide bio-relevant results."

1) How is a test tube brush any more biorelevant than a paddle or basket?
2) If IVIVC results are obtained using an apparatus other than ********-shaped spindle you will question it, however if it is acheived with the ********-spindle brush you don't question it?

At this time, the ********-shaped spindle is not an acceptable route for method development for industry. Once the design challenges have been met which were addressed in the article you cite, and a reproducable design has been acheived, then this may become an option.

Other options for development which remove the coning artifact (such as Peak) have been defined precisely and have had accepted methods into the FDA. I imagine that once the patents for the drugs with accepted Peak methods lapse, we will see IVIVC literature appear on the subject as well as USP monographs.

[moff]

Gdeedee,
This is a pretty good explanation:
A dissolution test measures the rate of release of the drug. The objective is to develop a discriminatory method that is sensitive to variables that affect the dissolution rate. Such variables may include characteristics of the active pharmaceutical ingredient (API) (e.g., particle size, crystal form, bulk density), drug product composition (e.g., drug loading, and the identity, type, and levels of excipients), the drug product manufacturing process (e.g., compression forces, equipment), and the effects of stability storage conditions (e.g., temperature, humidity).

from:
http://www.findarticles.com/p/articles/mi_m0EEH/is_12_28/ai_n8704569/pg_1

[qureshi]

Qureshi,

I am not ignoring the IVIVC portion of the article, the data is promising. I'm also not willing to jump to the conclusion (fair enough) that the ******** spindle brush is an improvement in IVIVC development, the population of data is just too small at this point in my opinion, (It is lot more than available for any other approaches)

To your last comment:

"Further, I will go one step further, as I have stated many times, to have bio-relevant results, test environments must be bio-relevant as well. One of the major discrepancies between current choices and the ********-shaped with the physiological relevance is the (mis)match of stirring and mixing aspect. Therefore, even if I will see bio-relevant results from the current apparatuses, I have to know and question how these provide bio-relevant results when they should not? There must be a rational for a spindle/vessel to be able to provide bio-relevant results."

1) How is a test tube brush any more biorelevant than a paddle or basket? Because ********-shaped spindle provides stirring and mixing, as in the GI tract. No other approach provides stirring and mixing, therefore cannot provide bio-relevant environment and results.
2) If IVIVC results are obtained using an apparatus other than ********-shaped spindle you will question it, however if it is acheived with the ********-spindle brush you don't question it? The results can only be bio-relevant, or IVIVC, if in vitro-in vivo environment match, otherwise no. See above under 1.

At this time, the ********-shaped spindle is not an acceptable route for method development for industry. Once the design challenges have been met which were addressed in the article you cite, and a reproducable design has been acheived, then this may become an option. In one sense I agree with you about standardization. However, standardization is good for routine use, not for establishing relevance, as stated in the publiaction as well. I believe you will accept that Paddle and Basket are standardized to the extreme, do these provide any relevant results? Not to my knowledge and these should not, as the environment they create is not relevant.

Other options for development which remove the coning artifact (such as Peak) have been defined precisely (How high and wide the Peak should be and with what tolerance? Have the peak dimensions are validated and how?) and have had accepted methods into the FDA (I am not aware of that, so I cannot discuss for which supporting results are not available). I imagine that once the patents for the drugs with accepted Peak methods lapse, we will see IVIVC literature appear on the subject as well as USP monographs. (In my view, product dependent testing will be history by then, because, product dependent (any) testing of any type is not accurate).

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies on my employer.

[moff]

1) There is no statement anywhere that Mixing + Stirring = IVIVC. If you want to come up with a situation most like a biological condition, I feel that is the Apparatus 3.
A blender can stir and mix (as well as puree, dice, mince, etc.) and it isn't IVIVC.
Furthermore, I would argue that a paddle at 250RPM would also stir and mix and also wouldn't be biorelevant.

2) The results can only be bio-relevant, or IVIVC, if in vitro-in vivo environment match, otherwise no. See above under 1.
There is nothing stating that in vivo-in vitro conditions must match for IVIVC to be relevant (similar media is definitely advised though)
There is nothing stating that mixing + stirring = biological conditions.
There is also not a brush, paddle, basket, rotating cylinder, reciprocating disk, etc. in the human body. Any device is going to be a very rough translation of the human body (with the exception of on-going work with multi-chamber testers which are being designed to mimic all the bodily processes).

3) In one sense I agree with you about standardization. However, standardization is good for routine use, not for establishing relevance, as stated in the publiaction as well. I believe you will accept that Paddle and Basket are standardized to the extreme, do these provide any relevant results? Not to my knowledge and these should not, as the environment they create is not relevant.
The reason I made this comment is because you are championing the ******** spindle on the forum for people looking for routine use. As of now, advising someone that they can overcome a coning issue on their product with a ********-spindle is not helpful. When it is standardized and has met some acceptance, then things will be different.
I am not saying your spindle does not provide relevant or promising results, all I am saying is that it is not acceptable for use at this time in routine testing.

4) (How high and wide the Peak should be and with what tolerance? Have the peak dimensions are validated and how?)
There are specific parameters with tolerances associated with the vessel. If you contact the manufacturer, they can provide that info to you.
As the FDA accepted methods with the Peak are proprietary, we can't really address that here.

[qureshi]

Moff: Now I think I have to stop this discussion here, as it is not making any sense. You also appears to need sometime to think it through, as your arguments are pretty bizarre and are not related to dissolution testing at all. Sorry.

Saeed

[rc_12321]

Saeed , I think you are strongly insisting that good mixing and stirring is the ONLY FACTOR that decides the bio-relevancy of the instrument .That is why i brought into the picture the USP-3 , which do provide maximum stirring and mixing environment .But you cannot deny this thing just by saying that literature is not available in support of USP-3.

I do not think that only good mixing and stirring alone will provide bio-relevant environment.If it were the case , dissolution system would have been as simple as any flask and stirrer apparatus.Just a mere matching of results by changing the design of apparatus is not welcome ,rather one has to try to improve the bio-descriminatory power of the testing apparatus .
When a good mixing and stirring alone constitutes a bio-relevant environment , the new design which is based on the above concept, must and should exhibit results accordingly for both for bio-passed and bio-failed batches.I think the second criteria is not met by the new design ,which is a clear indication that GOOD MIXING AND STIRRING alone is not sufficient to address the problem of IVIVC and IVIVR.

I have gone through the article that has some evidence in support of your work.But you have to accept the concluding remarks of the article , which explicitly states that .....peak vessel satisfied a forementioned criteria .......It is left to you only.

[moff]

RC,
I think that was an excellent summary of the discussion at hand. Nicely put.

[qureshi]

... When a good mixing and stirring alone constitutes a bio-relevant environment , the new design which is based on the above concept, must and should exhibit results accordingly for both for bio-passed and bio-failed batches.I think the second criteria is not met by the new design ...

RC:

I think you should read the publication from Merck Frosst bit more carefully, it contains answer to your question. The study did show VERY CLEARLY that the use of ********-shaped spindle provides similar results corresponding to similar bio-results (case 1) and DISsimilar results for bio-DISsimilar results (case 2). Hope this will help.

My objective of participation on the board is to provide opinion with logic and facts obtained from experimental studies for general good. Not to respond to prediction/interpretation of some people’s dreams or illusions. Talking about JUST goods/bads about apparatuses or techniques may not be useful. If you are convinced that the use of USP 3 or any other addresses the issues, you should use these and propose your ideas to USP and other regulatory agencies. Let them decide merits of your ideas and logic and supporting evidence.

My view is that the drug dissolution testing is a simple solubility determination technique, for that appropriate stirring and mixing environment is needed to the extent that results make sense from bio perspective. In my view, current apparatuses, in particular USP 1 and 2, lack that aspect along with other artefacts, so I proposed another one. My proposal showed clear evidence of superiority based on experimental studies including one now from Merck Frosst.

If you think literature is full of experimental studies showing bio-relevancy of other apparatuses, please make use of those and if possible share your observations or from literature with others. Otherwise, think about your logic and arguments. Just keep on arguing is not useful and, in future, I will also restrict myself not to respond to those comments which are not supported with facts or logic.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may not be reflective of opinions and policies of my employer.

[rc_12321]

Saeed, if you want to be reserved yourself , that is your choice only.You have a mind set where you always keep telling that other's suggestions ,predictions,comments interpretations etc are not accurate but mere imaginations.Let me tell you one thing .No body including Moff & My self is against your work nor do we cast any dispersion about your experiments.We do not have our own laboratories to do experiments .We try to apply logic ,reasoning from what we have learnt .

I would like to say that your work is still in development process only.But you are saying that your work is fantastic .How can one infer the data generated by the equiment which is still under development or trails?
In fact the thread was started with cone issue .The thread initiator perhaps want to know about the concept ,its impact on the test and some suggestions to circumvent the problems.Is it really useful to say that i have done a fantastic job in over coming this issue.....? Just dragging the discussion off the track and trying to make your work hub of the discussion will not solve the problems associated with the technique.If your work is worthy ,it will have its own place in the industry.Hope you will undestand .
If you want us not to comment on your work , i have no problems to keep off the topic .

[qureshi]

RC: I do not think it is necessary to respond to this post as it does not appear to relate to dissolution testing or enhance any knowledge in the area. This post is regarding individual styles of responding/posting, mine or yours is as good as anyone’s.


However, I was anticipating a response from you about the following comment.


RC: I think you should read the publication from Merck Frosst bit more carefully, it contains answer to your question. The study did show VERY CLEARLY that the use of ********-shaped spindle provides similar results corresponding to similar bio-results (case 1) and DISsimilar results for bio-DISsimilar results (case 2).

That is, have you re-read the paper from Merck Frosst and found answer to your question that ********-shaped spindle did provide corresponding results for bio- similar and bio-dissimilar products. That is all.

Saeed

Disclaimer: Views expressed here are for scientific discussion purposes only and may be related to opinion and policies of my employer.

[moff]

From the FDA - Guidance for Industry - Analytical Procedures and Methods Validation Chemistry, Manufacturing, and Controls Determination

"The FDA encourages the development and use of the most appropriate instrumentation. However, the use of rare or exotic systems not only place undue burden on the regulatory laboratory, but also may delay the validation process."

In other words, for the dissolution chemist in industry looking to have methods approved by the FDA, compendial systems should be used - and if compendial systems cannot be used then commercially available solutions should be used - only once compendial and commercially available options have been explored would exotic systems be an option for the dissolution chemist.

[Moderator]

I think this thread has run its course.