BIOANALYTICX

It is often assumed that if a test provides faster dissolution, its discriminatory ability may be diminished or compromised. Unfortunately, this is an incorrect view. In this regard, it is invariably assumed that the slower results obtained using Paddle/Basket apparatuses are the reference, or the most discriminatory, and any increase in dissolution rate should by default be considered as less discriminatory. 

However, before one considers this comparison, it may be important to decide which results are the correct ones, the slower one obtained using Paddle/Basket or faster ones using any other approach (higher rpm, different apparatus etc.). Looking at Figure 1, let us assume that the lower profile is obtained using the Paddle apparatus and the upper using some other experimental condition. Should the method which produced the upper profile be considered less discriminatory or less desirable? The upper curve may be a more accurate representation of the product’s characteristics than the lower one. If so, then the results obtained using Paddle, even slower, should be considered as a false representation of the product.

This is, in fact, the case here. The profiles shown here are of 60 mg diltiazem IR tablet products using Paddle (75 rpm, lower curve) and crescent-shape spindle (25 rpm, upper curve). The reason for the slow rate of drug release from tablets using Paddle, even at 75 rpm, is that the tablets are stagnant at the base of the vessel (Figure 2), and there is no, or limited, tablet-medium interaction or drug dissolution from the bottom of the tablet.

On the other hand, as the tablet moves with a crescent-shaped spindle, the tablet-medium interaction is from all sides of the tablet and thus faster dissolution with corresponding higher results (Figure 3). Similar behavior was observed with beads from a capsule product. In this case, a 120 mg ER diltiazem capsule product was analyzed (Figure 4). Again, lower (slower) drug release was observed using Paddle at 75 (Figure 5), while higher drug release was observed using the crescent-shaped spindle (Figure 6). It can, therefore, be concluded that a lower dissolution rate using Paddle may not reflect a better discriminatory ability but is a poor reflection of product-medium interaction, thus false dissolution characteristics of a product. For further discussion on the subject of poor product-medium interaction and poor dissolution using Paddle apparatus, please see the publication (link).

Developing a dissolution method requires an apparatus with associated experimental conditions capable of providing an expected outcome, in this case, dissolution characteristics of a reference product. The dissolution characteristics of the reference product must be known and established independently. As, at present, there is no reference product available with known or accepted drug release characteristics, one cannot develop a dissolution method in the true sense of the concept and/or practice of analytical chemistry.

However, this limitation may be addressed by using the concept of relative dissolution. i.e., developing a method (apparatus and associated experimental conditions) that will differentiate dissolution characteristics of approved IR and ER products of the same drug. Also, this differentiation in dissolution results should be achieved within the dosing interval of these (IR and ER) products. The practice of such an exercise will be called “dissolution method development,” which should be used to determine the dissolution characteristics of a test product. As a rule, an appropriate dissolution method has to be product-independent.

It is important to note that a dissolution method cannot be developed using a product that is being developed. Therefore, one should be careful in reading and interpreting the literature in this regard.

It is often described in the literature that method developments for poorly/sparingly soluble drugs pose special challenges, thus, may require a more careful and elaborate approach. Such views do not appear to be convincing.

First, a dissolution test is conducted for a product (tablet/capsule), not for a drug. Therefore, if the product (formulation/manufacturing) remains the same, containing either a freely or sparingly soluble drug, the same method should perform well. However, the difference will be in the monitoring (quantitation). If an appropriate medium is not used, quantitation would be either erratic or not possible for low solubility drugs.

On the other hand, quantitation often does not cause problems. As a fundamental requirement, a dissolution test should only be conducted under a sink condition, i.e., the expected amount of drug from the product must be freely soluble in the medium. This “sink” condition is established before method development. Therefore, it is important to note that high or low solubility relates to the general aqueous solubilities of drugs, not to dissolution medium or testing. For a dissolution test, a drug must be freely soluble. Therefore, both (high and low solubility drugs) are equivalent for dissolution testing.

The question is then, why do the products of these two types of drugs often behave differently in dissolution testing so that they require a different classification or different approaches. It is because of the poor interaction between the product (disintegrated) content and the dissolution medium. Due to poor hydrodynamics within dissolution vessels, paddle and basket, the product contents tend to accumulate at the bottom. This accumulation is known as “cone” formation (as shown in the picture). Often such pronounced “cones” are not observed with the basket apparatus, but similar accumulation/settling of the product contents at the vessel’s bottom is present. Depending on the “cone” size, the release of the drug from the “cone” will be different, mostly slower and erratic than expected. The size and shape of the “cone” will depend on the excipients (nature and amount). Bulkier and larger amounts of excipients would have a greater impact. In short, it is not a problem because of the low aqueous solubility of a drug or the product itself, but poor hydrodynamic (stirring and mixing) in a dissolution vessel, whether it is paddle or basket apparatus. Unfortunately, this is an inherent weakness of the paddle and basket stirrers and cannot be resolved.

In conclusion, the classification of high (freely) or low (sparingly) solubility drugs does not appear relevant for drug dissolution test purposes.

A commonly asked question is how one should choose between Paddle and Basket apparatuses when selecting an apparatus? In short, there is no clear-cut answer, in particular, based on scientific merit or reasoning.

It is important to note that both of these apparatuses have been shown to provide highly variable and unpredictable results. Furthermore, the results obtained using these apparatuses often lack a link to the test products’ physiological or in vivo characteristics. These apparatuses usually provide two different sets of results for the same product under similar operating conditions. Thus, it would be impossible to know which one reflects the product’s actual/true dissolution behavior. Between the two, the Basket apparatus appears to provide more variable results than the Paddle apparatus.

It appears that traditional practices/views, rather than scientific merit, are used in selecting the apparatuses. For example, it is commonly suggested that the Basket apparatus may be preferred for products that may float in the dissolution vessels. On the other hand, such floatation may be controlled using a “sinker” if one prefers to use a Paddle apparatus. Eventually, it boils down to the personal preference of an analyst, as to what his or her expectations are for the dissolution behavior of the test product.

In short, current practices are to choose an apparatus that would provide desired dissolution results (behavior) of the test product. How useful or relevant would such results be? This remains an open and debatable question

Drug dissolution testing is often described as a quality control tool for assessing pharmaceutical products, such as tablets and capsules, by establishing batch-to-batch consistency in their production (see). The question is, what quality and consistency here one refers to? Saying it in another way, if an analyst conducts a dissolution experiment and obtains certain results, how these results are linked to the quality of the test products. If establishing repeatability/reproducibility/consistency of a product and/or results is the objective, then why can this be achieved ONLY by conducting a dissolution test, when other tests can also be done, e.g., disintegration or grinding (to achieve consistent fine powder). If a product disintegrates or is ground to a fine powder, then expected batch-to-batch consistency is established. There is actually no need to conduct a dissolution test for such a purpose. Manufacturers and regulators have to consider this aspect carefully as to why a dissolution test is necessary to establish batch-to-batch consistency.

On the other hand, if a dissolution test as a solution formation test is needed, then perhaps one can do a test using a 50/50 solution of water and ethanol with stirring for half an hour at an rpm of 150 for all products. It is not necessary that the entire drug has to be released or dissolved as long as the results are consistent and reproducible. Such a test can also meet the requirement of a consistency test.

Moreover, a dissolution test is suggested as a consistency test. However, there appears to be nothing consistent about the test itself. For example, one may use any apparatuses (mostly paddle or basket), with any rpm (mostly 50, 75 or 100) using any volume of medium (mostly 250, 500, 900 mL or 1L) having any pH (mostly 1, 4.5, 6.8) of any strength (mostly 0.01 to 0.1M) and having any solubilizing agent (mostly SLS). Further, a dissolution test can be run for any duration of time from 15 minutes to 24 hours. There are no criteria in choosing a consistent experimental condition other than choices based on the discretion of a formulator/analyst to achieve certain DESIRED dissolution characteristics of the product.

In short, a dissolution test as it is conducted or suggested currently does not appear to provide scientific or logical support. It can be considered a test to monitor batch-to-batch consistency of pharmaceutical products.

So why is a dissolution test conducted? The only reason the test is to be conducted is to assess in vivo dissolution characteristics of a product. This is a very important concept/requirement which somehow has been overlooked and requires urgent attention.

IVIVC is commonly referred to as having an in vitro dissolution method which can relate to dissolution or absorption properties of a drug in vivo, mostly in humans. It is further assumed that an analyst will use a paddle or basket apparatus to develop such IVIVC. On the other hand, it is interesting to note that the use of paddle and basket apparatuses has never been validated for establishing IVIVC i.e., whether or not these apparatuses are capable of providing relevant in vivo results. Successful examples of such IVIVC are rare if any. More recent literature highlights that lack of an appropriate stirring/mixing environment within dissolution vessels for these apparatuses may NOT properly reflect in vivo (or bio-relevant) environment, thus demonstrating their inability to provide IVIVC.

Therefore, when considering developing IVIVC or evaluating published literature/studies in this regard, one should be cautious because the conclusions drawn could be misleading and/or erroneous.

I often receive comments and queries regarding one of my publications on the subject of IVIVC and determining C-t profiles. The method for establishing C-t (blood conc.-time) profiles described in the publication [Link] appears to be quite popular and acceptable. However, readers are missing a critical aspect of the publication, i.e., the use of the crescent-shaped spindle for obtaining the dissolution data used for calculating the C-t profiles.

For successful C-t profiles development, it is critical that the in vitro dissolution test method employed must be capable of producing in vivo relevant or bio-relevant dissolution results. Unfortunately, as paddle and basket apparatuses cannot provide bio-relevant results, the methodology described in my publication may be of limited use or help for the data generated with paddle and basket apparatuses.

Therefore, please make sure that when you determine the C-t profiles, you are using a bio-relevant dissolution tester, and the associated experimental conditions, to generate in vitro dissolution results.

It is common understanding and practice that an appropriate dissolution test is to be developed for a particular drug product when the product itself is being developed. The rationale is that the product development stage provides a sufficient variety of formulation/manufacturing differences and in vivo (bioavailability/bioequivalence) data to establish the relevance and validity of the proposed dissolution test. The choice of experimental conditions (such as apparatus, rpm, medium, pH, etc.) which fit the product’s behavior be chosen as the best or most appropriate dissolution test for future use. If one method may not fulfill the need or requirement, as commonly happens, then two or more methods for the same product may be suggested such that one (simpler) would be used as a QC test and the other (somewhat complex) as bio-relevant. In short, while products are developed, dissolution test(s) are being developed for the product evaluation.

On the other hand, one of the main uses of a dissolution test often described is to facilitate product development by establishing its drug release or dissolution characteristics. It is interesting to note that as described in the previous paragraph where a dissolution test is being chosen, the same process is also concurrently considered as the use of dissolution testing for product development. Both product and method developments are interdependent or they use each other to establish each other’s use and credibility. It is exactly like measuring something while establishing the “scale” for measuring by using the object to be measured. This practice is not only scientifically invalid but based on flawed logic as well.

Dissolution method development and product development steps must be treated as two separate steps. A dissolution method should not be used for product development until and unless it has been clearly shown independently, prior to its use, the method can determine drug dissolution (or release). A biopharmaceutic laboratory should require from an analytical chemistry laboratory or a vendor of the dissolution testers evidence that a dissolution tester (apparatus and associated experimental conditions) can determine the drug dissolution properties of products. Determining drug dissolution characteristics does not mean determining drug concentrations in different solutions at different times using multiple stirring speeds. Determining drug dissolution characteristics means that as the products are developed for human use, a formulator likes to know from an analytical laboratory how the drug is going to be released/behaved in humans. Therefore, a MANDATORY requirement for a dissolution tester is to demonstrate that it is capable of evaluating drug dissolution in humans. Unfortunately, at present, formulators/analysts both consider a dissolution tester as a validated tester if it is listed in a compendium and/or available from a vendor rather than based on its required capability of measuring drug dissolution. At present, available apparatuses lack evidence to show that they can provide drug dissolution characteristics of products.

The question is what evidence one would need to establish the validity of a tester as a dissolution tester. There are two requirements for this:(1) the tester must be capable of providing dissolution results of a product, established independently such as from pharmacokinetic studies; (2) the tester/method must be capable of differentiating dissolution characteristics of products (e.g. IR vs ER) as one would see in humans. In addition, as dissolution testing is linked to human physiology, which remains constant from product to product, these two testing conditions/criteria must be met using constant experimental conditions. Suppose a tester is not capable of providing expected/known dissolution results and not capable of differentiating products having different dissolution characteristics using common experimental conditions. In that case, the tester/method is NOT a dissolution tester/method and cannot and should not be used for product development.

At present, none of the apparatuses with associated experimental conditions appears to meet the fundamental requirement of a dissolution tester/method; thus, unfortunately, none of these testers may be used for product development and/or their evaluations. The formulators and analysts should be aware of this limitation and deficiency. On the other hand, formulators and analysts are expected to use “whatever is available”, which results in confusion and a large array of bizarre dissolution practices under different names and terminology, as shown here (Link). A huge amount of work/resources have gone into the practice of drug dissolution testing, which understandably is often rationalized with vigor, but the fact remains that these practices have been of limited or no use in determining dissolution characteristics of products. An even more frustrating aspect of the current practices of dissolution testing is that analysts and formulators are expected to develop IVIVC using testers that have never been shown for their in vivo relevance. In short, therefore, a new approach is needed to fulfill this gap of providing an appropriate dissolution tester/method.

One option is to use a vessel-based dissolution tester with a modified stirrer known as “Crescent-Shaped Spindle” which has been designed by considering the deficiencies of the current practices. The spindle description and its use have been described in the literature and on this site; for example, see links [1, 2, 3].

Dissolution profiles were generated using the USP vessel apparatus with crescent-shaped spindles set at a rotation speed of 25 rpm in all cases. The media used was 900 mL water for diltiazem and 900 mL water containing 0.5% sodium lauryl suphate (SLS) for carbamazepine products, respectively. The SLS was added to provide the needed sink condition. Using the suggested experimental conditions, all one has to do is to provide an appropriate dissolution medium (water with or without a solubilising agent e.g. SLS) so that the expected amount of drug is soluble in the medium. This single method/approach was employed for analyzing different types of products: tablets, capsules, IR and ER products having high water solubility (diltiazem) and low solubility (carbamazepine). As these experimental conditions are commonly used and simple, the method may easily be transferred to a QC test along with bio-relevant support of the testing environment. For further explanation and discussion on this topic please refer to the publication (link).