USP diltiazem (ER) monograph describes 15 sets of tolerances or, by definition, “the permitted variation in the results (link)”; four sets for 12-hour and eleven sets for 24-hours products. Figures 1 and 2 present these tolerances in a profile format by using the average values of the ranges described. The first and last tolerances, where ranges are often described as NMT (not more than) or NLT (not less than) respectively, averages are calculated using zero and NMT values and NLT values and 110 (highest expected percent dissolved from the CU requirement).

In short, these profiles represent acceptable variation in dissolution characteristics for presumably good quality (without a clinical concern) diltiazem products that are permissible for sale. In addition, although the monograph describes the tolerances for 12- and 24-h products separately, in most cases, these tolerances appear to overlap, as shown in Figure 3. Therefore, it would be safe to assume that, from the pharmacopeial perspective (in vitro testing), both of these types of products will show similar dissolution characteristics!

In most cases, tolerances are based on separate dissolution test conditions. Therefore, it is impossible to ascertain whether the dissolution characteristics reflect a product characteristic or because of the experimental conditions used. Therefore, it may not be possible to establish the quality of the product.

On the other hand, if such variations in drug dissolution (release) results are acceptable, the tolerances can be simplified by representing these only with one set of tolerances (upper and lower limit profiles) as shown in Figure 4. This would avoid the current complex and resource-intensive practices of setting individual tolerances with no apparent advantage. In addition, it will also help in establishing underlying expected variability in dissolution results.

In general, an apparatus means a machine having a specific function. In our case, a dissolution apparatus means “a machine which may be used to determine dissolution characteristics (function) of a drug product such as a tablet or capsule”. This function (dissolution) can only be achieved if the machine is able to provide thorough but gentle (low rpm) stirring and mixing within a vessel. Another way of saying the same thing is that the machine should provide thorough but gentle product/solvent interaction at low rpms, i.e., less than 100.

The reason the machines shown above may not be considered dissolution apparatuses is that they do not provide appropriate and required product/solvent interactions, thus drug dissolution. All these machines required very high speed (RPMs) for mixing. At lower RPMs, the test products often lie around stagnant, thus incorrectly indicating limited or no dissolution.

 A critical requirement for a dissolution apparatus is that it should be capable of providing stirring and mixing at low RPMs and it must also avoid stagnation of the test product.

Method development and validation are critical parts of drug dissolution testing and are required for an appropriate product evaluation. However, it is a common practice and often time confusing and frustrating exercise. In addition, these exercises are often described by different names such as developing QC/QA, bio-(relevant) and/or discriminatory methods. In addition, these method development exercises are further complicated by requiring different types for each drug and product. A single type of product of the same drug, in particular ER, can have multiple methods.

On the other hand, however, if the methods described in the literature are critically evaluated, it would be quite obvious that there are not significant differences in these methods. The majority of the methods described in the literature are based on USP apparatus 1 (Basket) or 2 (Paddle) set mostly at 100/75/50 rpm with water or some form of buffer, having a pH in the range of 5-7 as a medium. Usual method validation steps follow this experimental part. Confusion and frustration arise from the question of how to select a particular set of experimental conditions (apparatus, rpm, and medium). Unfortunately, there is no rationale or scientifically valid approach available for selecting the required set of experimental conditions. Formulators or analysts are often expected to make their own judgment calls, which causes the confusion and frustration.

Although complex and difficult as this situation may be, one should be able to address this problem by simplifying and breaking down into parts the method development and validation exercises. In this regard, one can break this down into four distinct parts: (1) Apparatus containing medium; (2) Sampling or cleanup step; (3) Quantitation and; (4) Data analysis (or validation). 

  • An apparatus is a vessel with a stirrer containing some volume of water or buffer, representing the physiological environment within the GI tract, particularly of the small intestine. It is fairly easy to assume and construct such an environment. For most purposes, a one-liter vessel with a stirring rod containing water (with or without a solubilizing agent) serves well and has been in use for a long time. Let us assume that this arrangement reflects the required GI tract environment appropriately. If so, then one has already simplified the method development step because now all products should be tested using this environment and as the physiological environment does not change with the drugs and/or products, neither should be the apparatus and experimental conditions. For a more thorough discussion on this aspect, please see link .
  • Data analysis (Method Validation) is basically an exercise of determining values of precision and accuracy parameters from the data/results. This is also common for all drugs and products.
  • Quantitation: This is dependent on the drug and mostly represents the choice of a wavelength. This is often available from the literature or can easily be determined by a UV scan. However, it is important to note that it is not a dissolution issue as dissolution is conducted for a product while wavelength is a drug characteristic and is often known prior to the product development stage.
  • Sampling or clean-up step. This clearly depends on the product in particular its excipients. This is where the expertise of an analyst is required to establish if the dissolution samples can be quantified as such or would require a clean-up step to remove interference if observed. Clean-up step may be off-line (simple liquid-liquid extraction) and/or on-line (chromatographic).

An important conclusion from the above discussion is that three are already set or fixed out of the four steps, and an analyst/chemist does not have to be concerned about them. It appears that dissolution method development and validation exercises boil down to step number two, i.e., determining an appropriate dissolution sample-clean up procedure.

The main reason for the confusion in the method development exercise is that analysts often work with step one, i.e., the apparatus part. They seek an appropriate apparatus with associated experimental conditions to evaluate their products. However, realistically this practice is incorrect, as it assumes that the GI tract environment will be different or linked to their product. The fact is that the GI tract remains the same and is not product-dependent.

On the other hand, if the intent is to develop a new apparatus and/or its associated experimental conditions, or improve upon a currently employed approach, then this practice should be considered as an apparatus and/or experimental conditions development step, not a “method” development step. Apparatus/experimental conditions development is very different and requires an analyst to demonstrate that the suggested apparatus and associated test conditions do reflect an improved GI tract environment. In addition, such development will require a “product” with known and well-recognized dissolution characteristics. Such an approach cannot be used for product characterization or evaluation.

Therefore, in short, the current practice of “method development” only requires development and validation of the sample prep step. Changing the apparatus and/or associated experimental conditions for a product under development would invalidate a dissolution method and its results.

It often puzzles people as to how one should select one approach over the other. It is often considered that for quality control (QC) purposes, one may use a single-point approach, while during product and/or method development stages, one may use a multi-point sampling approach. The single-point approach is often derived from multi-point sampling used during the product development stage. It is important to note that for ER products, usually there are no single-point tolerances, even for QC purposes. Should or do these approaches provide different outcomes? For example, with the multi-point sampling approach, dissolution may be measured at 5, 10, 15, 20, 30, 45, and 60 minutes, and for QC purposes, a single sampling time of say 30 minutes may be chosen. The dissolution results at 30 minutes should exactly be the same whether one uses a multi-point or single-point approach as dissolution is the property of the product that remained the same.

For selecting an approach (multiple or single), one may use the following rationale:

It appears that the confusion arises from the division of the tests as either drug dissolution or drug release tests. People often consider that if the test is a dissolution test, one may use single-point sampling, while for a release test, one should consider multi-point sampling. However, in reality, dissolution and release tests are the same things. If fact, one should consider the test as a drug release-based dissolution test. Therefore, it is very important to note that whether it is a QC test or a test for product/method development for an IR or ER product, it is a release-based dissolution test. One monitor (establishes) release characteristics of a drug from a product by measuring the content (dissolution) of the drug in the medium. It does not matter if one takes a sample at 5 minutes or 24 hours, if the drug is released, one needs to take a sample to measure the drug in the medium (dissolution). Therefore, for drug release/dissolution purposes, one sample should be sufficient, whether at 5 minutes or 24 hours, to establish whether the drug is releasable from the product or not.

 On the other hand, if one were to consider that in addition to the extent of drug release, its rate of release is important, then one has to measure dissolution at multiple sampling times. It is not a matter of preference, choice, or issues related to the type of product (IR or ER). It is the need to establish the rate of drug release/dissolution for a particular product. For example, if it is required for a product to release/dissolve a drug quickly for prompt/immediate action such as painkillers, then there is no point in monitoring the rate. One should decide how fast drug release/dissolution is required and then sample at that time to establish the required dissolution. It is generally assumed that if a drug is released within an hour or so the body may not recognize the differences in the rates, so there may not be a need for going for the extra step. On the other hand, if it is shown that the drug is to be released at a certain rate to complete dissolution even for an IR product, then multi-point sampling becomes a need and has to be monitored at different sampling times. Monitoring of the rate of release/dissolution for ER products is critical, to avoid any potential adverse effect (dose dumping or abrupt release) or lack of efficacy (slower than expected).

An important conclusion from the preceding discussion is that the type of sampling approach depends on the expected requirement of drug release/dissolution for the product action. A formulator/analyst is expected to fulfill this requirement.

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.

fig2-3

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.