For a more detailed discussion on this subject along with a description of a simple method for determining C-t profiles, please see the article (The Open Drug Delivery Journal, 2010, 4, 38-47. (Link).
For a more detailed discussion on this subject along with a description of a simple method for determining C-t profiles, please see the article (The Open Drug Delivery Journal, 2010, 4, 38-47. (Link)
It is often suggested that as drug release mechanisms may differ from product to product dissolution tests, conditions/methods should also be product-dependent to reflect these differences in drug release mechanisms. Often, such reasoning is provided for extended-release products and, strangely enough, not for immediate-release products. For example, recently (Link, Feb. 2011 issue, Q&A section), such an opinion is provided for nifedipine extended-release tablet products. In reality, however, it is not a correct view and is scientifically invalid as well.
A drug dissolution test does not have a link to the mechanism of drug release of a product. Thus it would not be able to differentiate the mechanism. A dissolution test only measures the amount of drug present in solution form at a specific sampling time. Perhaps the following analogy may explain it better. Monitoring (measuring) the speed of a moving vehicle using a speed gun (radar) does not depend on the type of engine (V4, V6, or V8) or size (car, van, bus, or truck) of the vehicle or type of the fuel (petrol or diesel) the vehicle uses. A speed gun works on the principle of monitoring change in distance per unit time. It is immaterial whether the change in distance is produced by different engine types or vehicle types (car or bus). Similarly, a dissolution test measures drug concentration in a dissolution medium with time, irrespective of the mechanism of drug release such as osmotic-based, diffusion-based or any other type. A dissolution test only reflects the drug in solution at a given sampling time.
On the physiological side, absorption is also independent of the drug release mechanism of a product. Drug absorption, or levels in the blood, depends on the drug in solution form in the GI tract, not how (a mechanism) it is delivered. If a drug is released slowly from the product, then dissolution will be slowed thus, absorption will be slow, irrespective of the release mechanism and vice versa.
Furthermore, the dissolution test conditions (medium, temperature, mixing) mimic the GI tract (intestinal) environment, not the product type or its delivery mechanism. As the GI tract environment remains constant from product to product, dissolution testing environments must also remain constant, otherwise a dissolution test should be considered void.
It is to be noted that the use of product-dependent experimental conditions are employed to accommodate the use of paddle and basket apparatuses which are known to be flawed because of their poor mixing and stirring characteristics. These apparatuses are not capable of providing the required product independent dissolution testing. As a result, product-dependent dissolution testing is a practice that produces useless dissolution data and puts an enormous and unnecessary burden on the pharmaceutical industry and regulatory agencies.
It is hoped that standard-setting organizations will discourage and/or consider discontinuing the current practices of product-dependent dissolution testing.
All dissolution apparatuses, or perhaps more accurately dissolution testing in general, have serious problems regarding the lack of appropriate and standardized agitation (stirring and mixing) value. Analysts do not know what should be an appropriate rpm (in the case of Apparatuses 1 and 2), flow rate (in the case of Apparatus 4), and dip rate (in the case of Apparatus 3). This is a big problem. Every analyst sets this (e.g., rpm) based on his or her preference to achieve some desired dissolution characteristics. Thus the test loses its usefulness.
Considering the deficiency, a common agitation speed has been suggested using a new spindle (crescent-shaped). It is to be noted that the crescent-shaped spindle was chosen for this purpose because Paddle/Basket would not provide appropriate stirring and mixing. These apparatuses have a design/operation problem, which is very well and extensively documented in the literature. I am of the opinion that if one could make a slight adjustment to Apparatus 1 and 2 by using a crescent-shaped spindle, then the current problems in dissolution testing can easily and economically be resolved.
Title: Limitations of Some Commonly Described Practices in Drug Dissolution Testing and Suggestions to Address These.
… In conclusion, it may be argued that most of the deficiencies/problems of current practices of dissolution may be related to poor hydrodynamics within the paddle and basket apparatuses, which also lack relevance to the physiological environment. The dissolution testing may significantly be improved if its role may clearly and objectively be established that the tests are to be conducted only to reflect in vivo dissolution characteristics of a product. This clarity of objective will provide an improved basis for selecting appropriate apparatuses and associated experimental conditions. In addition, such an objective will also reduce the significant workload by eliminating repeated IVIVC developments and other physiologically nonrelevant testing requirements. American Pharmaceutical Review, Jan/Feb. 2011. (link)
Current practices of dissolution testing invariably use paddle and basket apparatuses. In fact, describing a dissolution test almost always assumes that the tests been conducted are using these apparatuses.
The main objective of a dissolution test is to evaluate or predict dissolution characteristics of a product in vivo, mostly in humans. This link, or predictability aspect, is often referred to as in vitro-in vivo co-relationship (IVIVC).
On the other hand, a supporter of this test often propagate (market) it as a means to facilitate the development of products and later as a quality control test for monitoring batch-to-batch consistency in the production of pharmaceutical products for human use.
In reality, the test is a variation of a simple extraction-based analytical test, but its applications are large and powerful. The test is considered to provide an in vitro simulation of the release and dissolution of the drug in the human GI tract. Therefore, the first and foremost requirement for conducting this test is to make sure (validate) that the extraction process simulates the GI tract environment as closely as possible. In addition, like any other analytical test, the dissolution test should also have an acceptable level of repeatability and reproducibility.
These extraction tests, known as drug dissolution tests, are mostly conducted using paddle and basket apparatuses. These apparatuses have been in use for a long time. However, their relevance to simulate the required GI tract environment and reproducibility aspect appears to have never been established. In other words, these apparatuses have never been validated for their intended use, in particular using pharmaceutical products for human use. For any analytical chemistry test, including a dissolution test, to be acceptable for general use its appropriate validation is essential. Without the validation, the results obtained from the tests or apparatuses may be of limited value or use.
It is often debated as to which approach is better or more appropriate for calibration or standardization of the apparatuses. It appears that calibration may not be a critical or important step at present. The reason being, even if the apparatuses (paddle and basket) are adequately calibrated using any of the two approaches, they still would show a lack of relevance of results and provide very high variability in dissolution results.
It has been shown from experimental studies and computer simulation modeling that paddle and basket apparatuses provide poor hydrodynamics. Thus results obtained from these apparatuses would be of limited value and use. As a result, the calibration aspect becomes secondary.
It is often claimed that drug dissolution testing is a useful technique during the product development stage. Does this claim have merit? Let us explore.
A formulator prepares two or more formulations/products having different dissolution rates using commonly described dissolution test conditions. How would the formulator decide which product can be tested in humans? For this purpose, the formulator needs to have some confidence in the predictability of the dissolution test for the behaviour of a product in humans. It is well known that current practices of dissolution testing do not provide such predictability. Thus the testing cannot be used for product development. There are examples that products having differences in vitro results provide overlapping in vivo results.
Then why do people suggest the use of dissolution testing for product development? Apparently, the suggestion is correct but not its interpretation. In principle, it is correct that dissolution tests should be reflective of in vivo results. However, success will depend on how a dissolution test is conducted and what type of instrument/apparatus is used. Presently, people invariably assume that dissolution testing means conducting a test using paddle and basket apparatus. The missing link here is that these apparatuses have never been validated to provide relevant in vivo conditions (environment) to predict in vivo results? Obviously, these apparatuses cannot provide relevant in vivo results. It is like saying that can a distance from point A to B, 1000 miles apart, be travelled in an hour by road? Of course, yes, but we need a car that would run at a speed of 1000 miles/hour. The objective is fine, but the practicality of achieving the objective is not. This is exactly what is happening with the current practices of drug dissolution testing, i.e., the objective is fine, but means (paddle and basket apparatuses) to achieve the objective is not.
The other day someone indicated that even products of drugs from BCS class II (low solubility and high permeability) had not shown successful IVIVC. These drugs, at least in theory, provide the best-case scenario for successful IVIVCs. The question was then asked what may be the reason for such a general lack of success.
For any successful IVIVC, one needs to conduct dissolution tests by mimicking the in vivo environment as closely as possible. This is usually done by conducting a dissolution test using water or aqueous buffers having pH in the range of 5 to 7 maintained at 37C. These conditions represent the GI tract (intestinal) environment.
On the other hand, the tests are conducted mostly using paddle and basket apparatuses to simulate mixing and stirring environment. Unfortunately, the stirring and mixing environment of these apparatuses lack simulation of the in vivo environment. In fact, these apparatuses almost provide no stirring and mixing. Therefore, because of this mismatch, one should not expect successful IVIVC. For successful IVIVC, one requires an efficient (gentle but thorough) stirring environment. One such possibility to address this issue may be the use of a crescent-shaped spindle. For further discussion on the use of a crescent-shaped spindle, one may search this site or literature in general.
In short, one should not expect success in developing IVIVC using paddle and basket apparatuses.
The primary purpose of the dissolution test is to distinguish between acceptable and unacceptable batches of a product for human use. However, it is now widely recognized that current practices of dissolution testing may not be used for such purposes, i.e., for bio-relevancy purposes.
Therefore, rather than addressing the underlying deficiencies and improving upon these, the test now commonly propagated as a measure/monitor of batch-to-batch consistency. It is not clear which element(s) of the manufacturing process(es) the test is linked to and how such a link has been established. In addition, there is a lack of validation of an appropriate link of dissolution to manufacturing. In the absence of such validation, it is impossible to describe this test as performance or quality control/assurance.
The current practice of dissolution testing as a QC test may be equated to installing a sophisticated digital camera to take a picture of every finished car coming out on an assembly line. As long as the pictures are consistent from car to car, a car’s performance and quality may be assumed ”assured.” However, as the picture and performance are not linked, there is no guaranty that an acceptable picture, in reality, will reflect an acceptable performance of the car and vise versa.
Similarly, as a dissolution test is not linked to the performance of a product, acceptable dissolution results may not reflect the acceptable performance of the product and vice versa.