A suggested definition of “quality” for QbD purposes is described. It is hoped that the article will help in highlighting the underlying scientific issues and deficiencies which will prevent in achieving the intended objectives of the suggested “QbD based ANDA example documents”. It is argued that the documents are based on invalid analytical (dissolution) methodologies, which makes the suggestions/recommendations invalid as well. Suggestions for improvement are provided.Please click here for complete article

A method based on convolution technique has been described earlier to predict plasma drug concentration time (C-t) profiles. This article describes further refinement of the method for a more realistic representation of a human bioavailability study outcome by including variabilities in stomach emptying time and bioavailability factor (F). The advantages of such refinement are discussed including setting physiologically relevant specifications for dissolution testing.Please click here for complete article

PS: Please note that an error in the text was detected on page 2, column 2 and paragraph 2, which has been corrected. The revision reads as follows: “For this particular example it is assumed that the filter will release (not adsorb) on average 44%±10(±SD) of the drug, representing average F (bioavailability) and variation in the F for diltiazem.”  My apologies for the oversight and any inconvenience it may have caused. Saeed (July 27, 2012).

This article summarizes the principles of drug dissolution testing with an emphasis on the underlying scientific assumptions that are often not clearly described, or understood. It should be noted that the technique itself is extremely simple to use, however, current practices of selecting experimental conditions and the interpretation of dissolution results are seriously misunderstood, and require attention. To address these deficiencies, analysts should seek essential training in the areas of relevant physiology and pharmacokinetics. In the absence of such required training and knowledge of the subjects, it is highly unlikely that an analytical laboratory can generate relevant and accurate dissolution data, thus will fail in meeting the products development and evaluation objectives. Links to some articles on the subjects are provided which may help the analysts in improving their overall skills in these areas. Please click here for complete article

Recently a question was asked as to whether my suggested approach of IVIVP for predicting plasma drug levels, based on convolution technique, is applicable for evaluating the stability samples as well. The answer is yes, an explanation follows:

It appears that this question originates from the current thinking and belief that dissolution methods depend on the nature and source of a product. For example: it is quite common that different products such as IR and ER are often analyzed using different dissolution methods. Similarly, often dissolution methods for QC purposes and for product development are different. Unfortunately, this current thinking i.e. product dependent dissolution testing, is not correct.

Appropriate prediction of plasma drug levels requires that dissolution results should be obtained using physiologically relevant experimental conditions. As the physiological (GI tract) condition or environment is independent of the nature or source of the product one, therefore, requires the use of product independent dissolution testing as well.

The artefact of the poor stirring and mixing within dissolution vessels dictates that the tests using paddle and basket apparatuses should be conducted using product dependent experiment conditions. Therefore, results obtained using these apparatuses cannot be considered as physiologically relevant. The predicting of plasma drug levels to evaluate products using these apparatuses obviously becomes a futile exercise. Continue reading →

As a part of ongoing discussion on the LinkedIn Network group (Quality-by-Design), I posted the following response. For the interest of people who do not participate in the LinkedIn Network or the particular group, I am posting the response on the blog as well. I hope that you will find the post useful.

Bill:

With all due respect and with all my humbleness, I say that your post in response to my question about a fairy tale, itself is a fairy tale. Do this or do that and fire some people, who file papers/data which were created by others, you know who, but keeping the lobbyists should hardly be considered as defining and describing the problem and let alone solving it.

Let me go one step further, in my view, a bigger and juicier fairy tale is QbD itself. It is an adult version of children fairy tales, only it cost a lot more than children versions. Let me explain:

In our area (related to drug product quality), the quality of products, in particular oral products such as tablets and capsules, is determined by plasma levels of the drug. However, in most cases, the quality after initial stages of product development is established based on in vitro methods. The leading test in this regard is a drug dissolution test. People, who are not familiar with this area/subject, can take my words for it (considering my 25+ years of experience in all aspect of such testing) that it is the most simple test one can have in the entire science area perhaps after the procedure for taking body temperature. The idea behind this test is that if the drug dissolves (which we measure by this test) the drug will be absorbed in the body and will provide its intended efficacious effect. It is part of all GMP requirements and all national and international guidances and standards. Continue reading →

There is no doubt that drug dissolution evaluation is a very important and critical step for the development and assessment of products and will remain so in the future. However, dissolution testing itself will change significantly and dramatically.

The simplification will be reflected by the availability of a very small number of methods, if not only one or two, even for QC purposes. It is important to note that the currently described methods, which are in the hundreds, if not in thousands, will be discontinued as they will not be considered as dissolution methods. These will, in fact, be considered as sets of experimental conditions to show presumed or pre-set dissolution results which will be of limited use. For an appropriate dissolution characterisation of a product the test must be product independent, which is currently not the case.

The test procedures and the apparatuses mostly used, in particular, paddle and basket, are not validated and qualified for their intended use. It is surprising that these apparatuses have been in use for such a long time, however, this practice cannot continue further in a modern and highly regulated and standardized industry such as pharmaceutical, in particular for QC purposes.

It is to be noted that these apparatuses (paddle/basket) cannot be qualified and validated: (1) these apparatuses are inherently flawed because of the poor hydrodynamics within the dissolution vessels hence cannot provide the required repeatability and reproducibility for testing; (2) the stirring/mixing environment within the vessels is such that they cannot simulate the required GI tract physiology appropriately, thus they will never provide physiologically relevant results. Therefore, the use of these apparatuses will be discontinued.

In addition, it should be noted that as the results and conclusions drawn from many years of work are based on the use of these flawed apparatuses, all the observations and claims will require reconsideration.

Considering the above described facts, it should be prudent that one should start preparing for this eventuality of discontinuation of paddle/basket apparatuses.

The good news, however, is that the dissolution characteristics, including the prediction of the plasma drug levels, can easily be determined using a modified approach of Assay and CU determination. For further discussion in this regard, please see the selected links below:

http://www.drug-dissolution-testing.com/?p=1349
http://www.drug-dissolution-testing.com/?p=1328
http://www.drug-dissolution-testing.com/?p=1214
http://www.drug-dissolution-testing.com/?p=1183

The present day confusion regarding IVIVC comes from a poor understanding of the concept and its presentation in the literature. The commonly presented description of the IVIVC concept in literature is the development of the relationships, or lines, between in vitro (dissolution profiles) and in vivo (dissolution or plasma profiles) results, as described earlier (see link).  The confusion comes from both aspects i.e. theoretical, along with its associated mathematical procedures, and the experimental.  Please click here for complete article

The development of IVIVC is often described as follows: In vitro in vivo correlation (IVIVC) is an important concept and a tool in the development and evaluation of pharmaceutical dosage forms, especially modified release dosage forms. The objective of developing an IVIVC is to establish a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. Please click here for complete article

There is a common belief within the dissolution community that not only should the stirring within a dissolution vessel should be very gentle but the product should also be not in contact with the rotating spindle/paddle. Touching or moving of the product by the spindle is considered to be a harsh and undesirable testing environment that may result in loss of the discriminatory ability of the dissolution test. On the other hand, there are no standards or requirements describing such gentleness or softness of the stirring, other than the belief that the softer the environment/stirring is, the better it will be. Such a belief has resulted in the practice of the other extreme i.e. the commonly recommended stirring (e.g. 50 rpm) in fact provides no, or extremely limited, stirring which in reality makes the current practices of dissolution testing meaningless. please click here for complete article

It is a well established fact that the currently used dissolution testers, in particular the paddle and basket, are not qualified and validated apparatuses, thus cannot be used for appropriate and accurate evaluation of dissolution characteristics of the products. To address these deficiencies a new spindle, known as the crescent shape spindle, has been suggested as a substitute for the paddle and basket in the vessel based apparatuses. This substitution not only addresses the flaws of the paddle and basket apparatuses, as described below, but also provides a number of additional advantages for easier, scientifically valid and superior product evaluation. For example: please click here for complete article

I’ll be giving two talks on drug dissolution testing at the Informa Conference on Bioavailability / Bioequivalence, Dissolution and Biowaivers, 23 – 24 May 2012, Continental Zara Hotel, Budapest, Hungary.  http://www.informaglobalevents.com/event/beba12

If you are attending the conference, I will be very happy to discuss topics of your interest before or after the presentations. Please, let me know by sending an email to moderator@drug-dissolution-testing.com

Considering the flaws of poor hydrodynamics of the most commonly used apparatuses, paddle and basket, it is very well established that these apparatuses are not qualified and validated to provide relevant and reproducible dissolution results. Therefore, it is natural that people are seeking alternatives. The vessel based apparatuses using the crescent shape spindle provides such an alternative. The next obvious question would be, are such apparatuses qualified to be used as dissolution testers? Also, have these been standardized? The answer to both questions is yes, as explained below. please click here for complete article

The purpose of a dissolution tester is to test a tablet/capsule product for its potential dissolution characteristics in the human GI tract. In general, it is now well recognized that the currently used dissolution testers, in particular paddle and basket, do not provide such dissolution characteristics. In fact, they cannot provide dissolution characteristics because of the flaws of poor product/medium interaction within the apparatuses. Therefore, these apparatuses cannot be qualified and/or validated as dissolution testers and thus cannot be used for the development and evaluation of the products.

The practices of the past many years have been to keep using these apparatuses for product development and evaluation (isn’t this bizarre?) with a change/twist in the objective of dissolution testing by calling it a quality control test. However, how does one link the dissolution test to the quality of the product, when it will require its link to the dissolution characteristics in vivo, i.e., human GI tract? Oops, there is no link here, as stated in the paragraph above. Continue reading →

These apparatuses:

1. Lack scientific merit and support. Experimental studies have shown that they will provide highly variable and unpredictable results because of poor product/medium interaction.




2. Cannot be qualified/validated using commonly used industry wide practices of qualifications for analytical instruments. In particular, they do not meet the requirements of design qualification (not fit for intended use) and operation qualification (cannot be qualified using a reference product).




3. Require meeting undefined and unqualified requirements such as de-aeration of the medium and control of vibration in and around the equipment.




4. Require drug and/or product dependent experimental conditions. Therefore, it will not be possible to know whether dissolution characteristics are a reflection of the products or of the experimental conditions used.




5. Do not differentiate between IR and ER products. The analyst must first know what type of release/dissolution to expect from the product and then use the experimental conditions design to provide the presumed released/dissolution characteristics.




6. Are routinely used for evaluating drug products for human use (e.g. pharmacopeial testing). However, they have never been validated to demonstrate that they can provide bio- or physiologically relevant results.




7. Are often used for quality control, and to check lot-to-lot consistency, purposes. However, a link of these apparatuses, and associated experimental conditions, to the quality of a product, and consistency thereof, is unknown or undefined. The only criterion used for this purpose is that the dissolution results must meet some arbitrary standards/tolerances. If the criterion is not met, it is assumed that the products may be of substandard attributes.




8. Are expected to provide discriminatory tests which should be capable of showing formulation/manufacturing differences among products and/or batches. On the other hand, it is a well known fact that these apparatuses frequently provide discriminatory results lacking any physiological significance or consequence.




9. Do not simulate in vivo or physiological environment (stirring and mixing) thus one cannot develop bio-relevant tests.




10.   Require tolerances be set lower than potency and content uniformity values, thus, results will reflect inaccurate and inappropriate quality of perfectly acceptable products.

Considering the above mentioned deficiencies, results obtained using these apparatuses can easily be questioned/challenged for their validity and relevance.

It is a well established fact, and often a regulatory requirement, that one has to demonstrate that an apparatus is capable of providing the intended and expected outcome. A simple and common example of this requirement is calibration of a laboratory weighing scale or balance. Initially when a balance is purchased, and then occasionally thereafter, it must be calibrated against reference weights to show that the balance can provide accurate weights of the references. If the balance does not perform as expected then it has to be adjusted accordingly. please click here for complete article

It is quite often asked which approach should one choose and why, i.e., is there a reason for the preference for one over the other?

Such a question has two components; (1) scientific or logical (2) required standards. Generally, the required standards component is based on the first one, i.e. science and logic. Unfortunately, in case of the current practices of dissolution testing, scientific principles are completely absent from the standardization. That is why there is so much difficulty, along with the associated frustrations.

I provide suggestions based on underlying scientific principles, which often do not fit well with the current practices, because, as I stated above, the current practices lack scientific reasoning and logic. People say that both MQ and PVT are good and valid, which is correct, and an analyst can choose either. However, the next question is, which one is better and why. That is where the difficulty is. If one likes to know which one is better, then one has to know the reason behind conducting these tests to start with, which will help in deciding and rationalizing the preferred one.

So, the question is why are these MQ and PVT done? The answer is, to establish that the apparatuses are fit for their intended purpose, i.e. apparatuses can be used to evaluate dissolution characteristics of a product for human use. The next question is, or at least should be, that if one meets the requirements of MQ/PVT, will the apparatuses be considered fit for the evaluation of the product for human use. The answer is clearly no, because both MQ/PVT lack the critical link between apparatuses and the evaluation of dissolution characteristics of a drug product (please use the link to read the article for further discussion). Therefore, in general, MQ and PVT are not useful practices and requirements, and are unnecessary burdens on the pharmaceutical industry.

Now if the testing (MQ/PVT) lacks any real benefit, but has to be performed to meet the requirement, then, I would prefer the MQ. The MQ takes the responsibility away from the analysts and transfers it to the vendors of the dissolution testers. They can provide certification that the testers meet the specifications, which they usually provide when one purchases an apparatus and may provide later as well. In addition, the beauty of MQ is that no one can question that an apparatus does not work/perform as expected, because there is no way to prove that it does not work, as performance of the apparatuses is not associated with the MQ requirements. So, my dear analysts, go with the MQ and say good bye to the PVT and its so called “best practices”.

This article provides a discussion based on data presented in literature that a direct comparison of dissolution results (profile) with blood levels (C-t profiles) can lead to misleading interpretation. For a more appropriate comparison dissolution results should first be converted to C-t (plasma drug conc.-time) profiles. Examples are provided for converting dissolution profiles, using convolution techniques, to C-t profiles which provide improved evaluation of dissolution results. The article also presents an argument, that for proper reflection of bio-relevancy of dissolution results, the tests require higher agitation (or product/medium interaction) relative to what is provided by the paddle apparatus at 50 and 75 rpm. please click here for complete article

The prediction of drug concentration-time (C-t) profiles in humans is highly desirable and needed for appropriate development of products and to establish their quality during production. A simple method to predict or estimate the C-t profiles, based on the convolution approach, has been suggested [link].

This article provides an application of the approach for the evaluation of metoprolol tartrate tablet products. Furthermore, it also demonstrates that the approach can be used to predict the C-t profiles for a sub-population as well. please click here for complete post

A commonly asked question is how one should select a dissolution apparatus. It may be of interest to know that, such a question is often asked when a dissolution analyst gets frustrated with the unexpected or unanticipated dissolution behavior of a test product. Such a question is seldom asked at the beginning of the project as it is always understood or assumed that one will most likely use a paddle apparatus. Furthermore, the analyst will try some variations of rpm (50, 75 or 100) or medium (different buffers and pHs). If this does not work, then perhaps the basket apparatus will be tried with similar variations in rpms and buffers. In the end, the analyst usually settles with a test which will provide the anticipated/expected characteristics of the test product. .(please click here for complete post)

It appears that there is confusion in the description of these terminologies. In reality, these are one and the same thing. Let me explain:

A bio-relevant dissolution test is a test, which should be able to differentiate (discriminate) between the in vivo behaviour of two or more products. The in vivo behaviour means bioequivalency or bio-in-equivalency of the tested products. Therefore, by its very nature a bio-relevant test becomes a discriminatory test as well.

So, why are these two terminologies often referred to as different or separate? It is due to the fact that in the dissolution testing area, a discriminatory test is also described as, wrongly, an in vitro dissolution test, which may show formulation/manufacturing differences without their in vivo relevance or consequence. Such tests are often described as QC or consistency-check tests (e.g., in pharmacopeias). It is important to note that these tests do not relate to the in vivo characteristics of products, however, they are still expected to reflect quality of the products for humans use. How? It is not clear and is the most confusing part of current dissolution practices! In my opinion, these tests (QC or in vitro discriminatory), and their requirements, are not very useful and are conducted as a “tradition”. Continue reading →

It is often noted that drug dissolution results fail to reflect the in vivo behaviour of a product, i.e., lack of relationship to bioequivalence of two test products. Therefore, it is usually inquired as to how one should explain the lack of relevance and/or how to address this issue.

There could be a number of potential causes for such a problem (lack of bio-relevance). In addition, the problem could only be related to the specific product. In such cases, it is difficult for others to provide suggestions without knowing the details about the formulation of the product, which are often not available because of the proprietary nature of the information. Therefore, it is almost impossible that one can obtain a direct and/or a correct suggestion to address the problem. The formulator should be aware that he/she might obtain completely un-related suggestions which may end up wasting a lot of time. Keeping these thoughts in mind, a few very general suggestions are provided here which may be helpful in such situations.

There are usually two potential outcomes in such situations (lack of bio-relevance): (1) in vitro dissolution tests show different (the so called “discriminatory”) results, but the in vivo results are similar; (2) in vitro dissolution test show similar results, but the in vivo results are not similar i.e. bio-in-equivalent.

In the first scenario, the most likely cause is that the test may have been conducted using much softer conditions (in particular, related to stirring/mixing) under the “requirements” of obtaining “discriminatory” results. For example, if the formulations of the two products are such that one hides the drug (API) better than the other at the bottom of the vessel then one will observe different in vitro dissolution results, but most likely similar in vivo results. Drugs with low aqueous solubility and/or of low content would show such a problem. This is the most commonly observed issue with the use of paddle/basket apparatuses as these provide poor, and/or lack of, stirring and mixing required. Commonly such tests are referred to as “overly discriminatory”, however, in reality these tests are incorrect tests, mostly because of the incorrect choice of a dissolution apparatus.

In the second scenario, the most likely cause would be of chemical nature, such as an interaction between a drug and an excipient. It is possible that during dissolution testing a complex has been formed, or dissociated, with much higher solubility, which may not be the case in vivo. The likely suspect in this case may be the pH of the medium. One should make sure that the pH of the medium has not been inadvertently increased as this will certainly cause this problem (use of larger amounts of SLS may be a prime suspect here). Some focus on the chemistry aspect of the product (drug excipient interaction) would be very helpful.

The next consideration should be given to the use of the paddle/basket apparatuses themselves. If possible, avoid using these apparatuses as these can be the main cause of the problem. Even if you are going to try the suggestions provided above, the use of paddle/basket may hinder in establishing cause of the problem. Consider using an apparatus which will provide efficient and reproducible mixing and stirring.

As described, in one of my earlier posts, one can easily perform an analytical method validation by spiking the dissolution medium using solution of a drug (API, link). The suggested approach is scientifically correct and valid, however, I do see where dissolution scientists in general will face difficulties. Let me explain:

Suppose an analyst follows the suggestion made, and obtains a %RSD of “X” for the method (say less than 5) and the analyst is happy with it. Now the analyst proceeds to the next step and tests the tablets and gets a %RSD of “Y”.  Under normal circumstances, this will reflect the %RSD of the product which will include %RSD of the method as well. Usually there are no concerns as most often this value of “Y” comes out acceptable, between 5 and 10.

However, dissolution testing, in particular using paddle/basket, faces a unique problem, that it introduces one additional variability component which is very well documented in literature. This is because of the positioning effect of the tablet/capsule i.e., where it settles at the bottom of the vessel (link1, link2, link3). Unfortunately, people do not realise how such a minor variation can cause a big problem, but it does. As one cannot control this positioning effect, therefore, one cannot control variability due to this effect as well. It is totally random. The contribution from this random effect is reported to produce very high RSD, up to 37% (link). So, when it is asked what should be the expected variability for drug dissolution testing of a product, a safe bet/estimate is 37%. A product may have excellent repeatability/reproducibility of its drug dissolution characteristics (with extremely low %RSD), however, dissolution results may or may not reflect this low variability.

It is just like any other biased, but random phenomenon, where one may or may not succeed, however, one always sees advertisements of some examples of big winnings/successes. In dissolution terminology, one may observe some low %RSD values, at random, but overall variability using paddle/basket apparatuses will always be high. There are number of publications available describing this high variability aspect, which may be useful. In addition, some posts may also be useful in this regard e.g. see link.

If you are re-visiting this post, please make sure that you read the correction at the end of this post.

It appears that there is confusion that to develop IVIVC one is required first to de-convolute a plasma drug concentration-time (C-t) profile to obtain a so called “weighting function or factor” and then this function should be used to predict C-t profiles. The confusion appears to come from the way the concept and practice of IVIVC have been presented in literature.

As described in some earlier posts (link1, link2, link3, link4), and a publication (link), to develop or evaluate products one does not require IVIVC. The IVIVC is a step to relate in vitro dissolution to in vivo dissolution/absorption this is why one requires a de-convolution step to obtain in vivo dissolution from a C-t profile. However, it is very important to note that during the product development and evaluation stage one does not have C-t profiles, and the formulator is required to predict/estimate C-t profiles using experimentally observed in vitro dissolution results of test products. Therefore, at this stage the formulator cannot use the de-convolution step.

On the other hand, as stated above, at the product development stage, one needs to predict C-t profiles, for this purpose the only option is to use the convolution method. Mathematically to use the convolution method one would require a “weighting function or factor”, which in reality is the drug elimination rate equation, following drug administration using IV bolus. This weighting function or elimination rate equation can be obtained from literature. For most drugs, the elimination rate equation can easily be derived using the elimination half lives. Thus, there is no reason to conduct a bio-study to obtain this weighting function or elimination rate equation, as literature often suggests.

To conclude, for predicting C-t profiles one only requires a one step convolution method. The convolution method requires the use of a weighting function, which in reality is the elimination rate equation of the drugs, which can be obtained from literature. Combining the dissolution results with the elimination rate equation (weighting function) along with the volume of distribution and bioavailability values of the drug, also obtained from literature, and using the suggested spreadsheet software provide the required C-t profiles.

Note: Earlier it was stated that one obtains the “input function” from the deconvolution step. However, it was meant to be the “weighting function or factor” which one obtains from the deconvolution step. Therefore, accordingly, the wordings have been changed in the post. My apologies for this oversight (March 18, 2012).

It is commonly suggested that a dissolution medium should be de-aerated or de-gassed which presumably helps in reducing the variability in dissolution results. It is to be noted that it is not the presence of air, or gas, in the medium which causes the problem. It is the formation of the bubbles from these gases which may cause the problem. The question is why and how these bubbles are formed. If the source of bubble formation is established and then removed, only then this problem can be addressed.

The source of the bubble formation may be explained as follows: Drug dissolution tests are conducted using media maintained at 37 °C, however, media used are generally stored at room temperature which is lower than 37 °C commonly around 20 °C. Therefore, when a medium is transferred to dissolution vessels/baths and heated up to 37 °C, there is a change in solubility of the dissolved gasses, which are from the air thus de-aeration terminology, from higher to lower solubility. The decrease in solubility of the gasses at higher temperatures causes the dissolved gasses to come out of the medium in the form of tiny bubbles which tend to stick at random to the vessel and spindle surface, and may be to the product itself. However, once the medium is equilibrated at 37 °C the formation of the bubbles stops. Therefore, the answer to the question of why and how the bubbles are formed, is because of a transitory stage during the heating process of the dissolution medium. A simple solution to avoid this problem is to remove the temperature gradient effect, i.e., avoid transferring low temperature medium directly into the dissolution vessels. Therefore, the analysts should heat the medium to 37 °C out side the dissolution vessel or give sufficient time for the medium to equilibrate in a dissolution vessel at 37 °C with moderate stirring.

However, unfortunately, a practice of de-aeration or de-gassing has been introduced to address this problem of bubble formation. It is a practice which does not appear to be well thought out. The practice not only has its practical limitations, but also makes the drug dissolution testing irrelevant and unpredictable. For example:

1. Physiological environment does not require a de-aerated medium. Obviously, if the results obtained using a de-aerated medium they will not relate well with the physiological characteristics of the product.
2. The commonly suggested procedure of de-aerating, which is based on heating/vacuum steps, is without a measurable endpoint. Therefore, the de-aerating step will always be variable and unpredictable, thus it will introduce variability in testing.
3. In addition, no matter how reproducible one tries to be with the de-aeration step, after de-aeration the medium will quickly start equilibrating itself with the atmospheric gasses. Therefore, until this equilibrium is reached, the system will remain unstable and unreliable.
4. Often media containing detergents such as SLS are difficult, if not impossible, to de-aerate due to excessive foam formation. Therefore, one may not be able to work with de-aerated medium using SLS.

On the other hand, the medium equilibrated at 37 °C within a dissolution apparatus, or external to it such as by keeping in a water bath, provides a simple, stable, reproducible and physiologically relevant alternative.

One of the requirements to conduct an appropriate drug dissolution test is to use a sufficient volume of dissolution medium, which should be able to dissolve the expected amount of drug released from a product. This ability of the medium to dissolve the expected amount of drug is known as a “sink condition”. It is important to note that a dissolution test should not be conducted in a volume of the medium which would not dissolve the expected amount of the drug completely and freely. This is because of the obvious reasons that even if a product contains and releases 100% of the drug as expected, one cannot measure (quantify) it because for quantitation/sampling  the drug has to be in the solution. Therefore, it should be noted that this requirement of “freely soluble” or “sink condition” is the requirement for the quantitation (analytical chemistry) and has nothing to do with the physiological aspect. Considering that often times limited volume is available for in vitro dissolution testing such as with the vessel based apparatuses, one is required to add some solubilising agent (e.g., SLS) to create the sink condition for quantitation of the drug.

It is to be noted that a physiological environment deals with the availability of limited volume in a completely different manner. Here, the drug is continuously absorbed into blood, metabolised and eliminated, which provides a very efficient mechanism for providing a high solubility equivalent. Continue reading →