Author: Dr. Saeed Qureshi, Ph.D.

While surfing the net, I came across a response to a query published in Dissolution Technologies (see issue of February 2011 Volume 18 Issue 1, Question & Answer Section) regarding product-specific dissolution testing. It is quite disturbing to read that such poor and irrational scientific reasoning can be provided, for multiple and product-dependent, dissolution tests in the pharmacopeia. The suggested reasons are scientifically invalid and provide a strong case for removing the tests and standards from the compendia, which by definition is expected to set unbiased and independent product standards. For example:

It is stated that “We may find tempting the notion that because products may have similar doses and dosing intervals, they should have the same dissolution test. In the present state of the art, that is simply not the case for extended-release products.” On the other hand, such a practice is valid for immediate-release (IR) products because the same dissolution tests are recommended for IR products (e.g., generics) having similar doses and dosing intervals. It is unclear how a dissolution tester and/or test will differentiate between IR and extended-release (ER) products and will start behaving differently by providing unacceptable results for ER products only.

It is stated that “While bioequivalence is used to establish generic status, the release mechanisms of reference listed drugs and generics may not produce adequately similar profiles in the dissolution test conditions to satisfy one quality control performance test.” A “generic status” means that drug release characteristics of the reference and generic products are the same. The composition, manufacturing and/or mechanism attributes of the reference and generic products are always different. That is why bioavailability/bioequivalence studies are required and conducted to establish that given the differences in products, their drug release characteristics MUST be the same. So, if products are bio-equivalent, i.e., having the same drug dissolution/release profiles in vivo, and another test, in vivo or in vitro, shows differences in drug release, how relevant or useful would such a test be? The responder, in fact, appears to be arguing for developing an irrelevant dissolution test, for ER products, which would show differences in vitro dissolution/release profiles for products having the same or similar in vivo profiles.

It is further stated that “Depending on your use of the dissolution test, you may need to develop a test specifically for the product in hand.” What should be the basis (or criteria) for developing the test for products having similar in vivo dissolution profiles if that is the case? If it is accepted that dissolution tests are to be developed as product dependent and not necessarily linked to in vivo characteristics of the product, then a test having the attributes of 80% drug dissolved in 45 minutes using water with 50% alcohol as the dissolution medium with the paddle (250 rpm) has to be considered satisfactory. Otherwise, current pharmacopeial drug dissolution testing requirements may be considered based on the principle of “follow the instructions” and not science and/or logical reasoning.

It appears that the responder has provided a strong case for the discontinuation of the pharmacopeial dissolution standards and/or requirements, at least for the ER products. This may be explained as follows: (1) if the tests and tolerances are linked to a specific product as suggested, then such standards may become proprietary and may be difficult for others to meet and/or duplicate; (2) if the reported tests or standards in the pharmacopeia are not required or expected to be met then why are these in the pharmacopeia; (3) in the absence of such requirements, obviously one is free to develop any tests and/or tolerances, with or without the relevance to in vivo drug release. The question is, then again, what is the use of setting public standards?

In short, it may be argued that the current practices of setting multiple and product-dependent dissolution tests are scientifically invalid and provide no useful purpose; thus should be discontinued.

The Figure is a simple schematic representation for explaining the solubility of drugs for absorption purposes in the human GI tract for drugs that are weak acids or bases. These drugs dissociate into ions in equilibrium with the undissociated molecules (drugs) in the solution.

The undissociated drugs get absorbed, which disturbs the equilibrium with the corresponding ions. To maintain the equilibrium, the drug moves from the solid to the dissolved (undissociated) form, which gets extracted/absorbed. This cycle continues until the entire drug gets absorbed. The important thing to note here is that for complete absorption, drugs are neither required to be highly soluble nor need a large volume of solvent. It is this continuous extraction/absorption step that makes drug absorption possible and efficient.

For further discussion on the topic, please see the following links: (1, 2, 3, 4)

Dissolution tests are conducted for solid oral products such as tablets/capsules to simulate/evaluate in vivo drug dissolution required for the absorption of drugs from the GI tract to exert their therapeutic effects. Therefore, for appropriate absorption, drugs should dissolve in the liquid present in the GI tract. The liquid present in the GI tract is simulated in vitro with water or aqueous buffers having a pH in the range of 1 to 7.

Commonly in literature, three pH values are suggested, which are 1, 4.5, and 6.8 to cover the range of pH of the GI tract. It is possible, in fact quite common, that a drug may be freely soluble at one pH but not the other. For example, acidic drugs such as NSAIDs (e.g., ibuprofen) would practically be insoluble in a solution having a pH of 1 but will be freely soluble at pH 7. So, how should one decide, for dissolution testing purposes, whether such drugs are of high or low solubility characteristics, and how should they be tested? Please click here for the complete article

To avoid potential frustrations and unnecessary workloads, when conducting dissolution tests one should be watchful of the following limitations of the currently suggested practices and requirements (please follow the links provided within brackets for further details on the topic).

  • Mechanical qualification and performance verification testing of apparatuses (paddle/basket) are made up of compliance requirements that do not establish that the apparatuses are dissolution testers or capable of providing dissolution characteristics of products (Links: 1, 2, 3).
  • Conducting a dissolution test as a QC test or for checking lot-to-lot consistency of products is also a made-up requirement or practice and of limited value. Such tests, as conducted presently, are not linked to any of the product quality characteristics (Links: 1, 2, 3).
  • Currently used dissolution testers, in particular the paddle and basket, are not qualified and/or validated for dissolution testing purposes (Links: 1, 2).
  • As currently described in the literature, drugs and product-specific tests are scientifically invalid (Links: 1, 2).
  • Similarly, developing a drug and/or product-specific dissolution test is a scientifically invalid practice and should be avoided. The practices of developing product-specific dissolution methods and/or using such developed methods are pretty much a waste of time and resources.  Following such practices, scientists/analysts will never know the dissolution characteristics but determine experimental conditions to achieve desired dissolution results (Links: 1, 2).
  • Developing discriminatory tests for detecting formulation and/or manufacturing differences has no meaning or practical use, as products having such differences (e.g., generics) can be bioequivalent and of perfectly acceptable qualities (Links: 1, 2, 3, 4).
  • Experimental conditions such as de-aeration, vibration-free environment, use of sinkers etc., can make a dissolution test potentially invalid as these test conditions are not physiologically relevant (Links: 1, 2).
  • Developing an in vitro-in vivo correlation (IVIVC) is futile because dissolution tests are conducted based on the principle that IVIVC always exists (Links: 1, 2, 3).
  • Plasma drug levels from dissolution results can only be predicted/estimated using the convolution-based technique. The IVIVC and/or de-convolution techniques cannot be applied/used for such purposes (Links: 1, 2).
  • Predicting/estimating plasma drug levels from dissolution results must be ascertained that results are bio-relevant and obtained using physiologically relevant experimental conditions (Link: 1).
  • The biopharmaceutic Classification System (BCS) is based on drug characteristics and not that of the products. Therefore, its use for products evaluation/development may be of limited relevance or use (Link: 1).
  • Bio-waivers require that dissolution results must be obtained using bio- or physiologically relevant dissolution tests. However, as currently described, methods are generally not bio- or physiologically relevant. Therefore, bio-waivers using such methods should be considered a scientifically weak case (Link: 1).

For assessing the potential absorption behavior of drugs from the GI tract, the following points may be helpful:

  1. Drugs are preferentially absorbed as non-ionized (un-dissociated or un-protonated) drug species. Therefore, solubility/concentration of the non-ionized species at the site of absorption is to be considered and not that of the ionized (protonated or salt) form. For example, drugs such as diltiazem, metoprolol, and propranolol are considered highly water-soluble. However, in reality, these are low solubility drugs. This discrepancy is because these drugs are available and administered as hydrochloride salts, which make them appear highly water-soluble. However, following administration in humans, drugs are dissociated from the salt forms depending on the pH of the surrounding environment. They behave according to their native (intrinsic) basic forms, which usually have low aqueous solubilities. In vitro (e.g., for dissolution testing), these drugs may freely dissolve as salt, but in vivo, these will behave as native (basic) low solubility drugs. Therefore, in reality, in the terminology of BCS, such drugs should belong to Class II and not Class I, as they are commonly referred to.
  2. Similarly, an acidic drug such as a propionic acid-based NSAID e.g., naproxen as a sodium salt, may provide high in vitro aqueous solubility but would remain a low solubility drug as a native acid just like others such as ibuprofen and diclofenac.

Please click here for the complete article

In an earlier article (link) the mechanism of drug absorption was described considering ionization characteristics of drugs and the differences between the surface areas of the stomach and intestine. The purpose of the article was to explain and highlight how ionization of both an acidic and basic drug will provide undissociated drug molecules both in the stomach and intestine. It is important to note that the undissociated drug molecules in the solution form are responsible and required for drug absorption.

The low (acidic) pH of the stomach would favor high undissociated concentrations of acidic drugs compared to high (neutral or basic) pH of the intestine, which will favor higher dissociated (ionized) concentrations. The opposite is true for basic drugs where the stomach’s low (acidic) pH will result in higher concentrations of ionized or protonated basic drugs in the stomach compared to higher concentrations of undissociated drugs in the intestine. Thus, the pH of the environments (stomach and intestine) explains only the ionization of drugs (acidic or basic), i.e., comparative availability of undissociated drug molecules in solution form but NOT the EXPECTED absorption of the drugs from these sites. However, the absorption of drugs can only be explained based on the available surface areas of the stomach and intestine. As the intestine provides a much larger and efficient (permeable) surface compared to the stomach, thus it provides far superior and efficient drug absorption, as explained in the previous article.

It is sometimes assumed that as acidic drugs are more readily available in the undissociated form in the stomach (low pH), they will preferentially be absorbed from the stomach. The basic drugs will be more readily available in the undissociated form in the intestine (neutral or higher pH) thus will preferentially be absorbed from the intestine. This assumption is inaccurate, as such a simplistic approach ignores the absorption capacity and differences of surface areas of the stomach and intestine sites. Furthermore, such an assumption i.e. absorption based on pH consideration only contradicts the observations reported extensively in the literature. For example:

  1. “The stomach is primarily a processing organ and not an absorptive organ …”. Washington, N., Washington, C., and Wilson, C. Physiological pharmaceutics: Barriers to drug absorption, 2nd ed. CRC Press, 2001. (p. 82)
  2. “The experimental data available from classical work of Brodie (1964) and more recent studies (Prescott and Nimmo, 1981) are all consistent with the following conclusion: the nonionized form of a drug will be absorbed more rapidly than the ionized form at any particular site in the gastrointestinal tract. However, the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predominantly ionized in the intestine and largely nonionized in the stomach.” Goodman, L., Gilman, A., and Gilman, A. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. New York: Macmillan, 1985. p. 7.
  3. “Theoretically, weakly acidic drugs (eg, aspirin) are more readily absorbed from an acid medium (stomach) than are weakly basic drugs (eg, quinidine). However, whether a drug is acidic or basic, most absorption occurs in the small intestine because the surface area is larger and membranes are more permeable.” (Merck Manual)
  4. “The scintigraphy studies suggest that a sustained release ibuprofen formulation is absorbed throughout the entire GI tract and that the large bowel is the site that demonstrates the greatest proportion of ibuprofen absorption.” Davies N.M. “Clinical Pharmacokinetics of Ibuprofen: The First 30 Years.” Clinical Pharmacokinetics. 1998: 101–154.
  5. “Ketoprofen, like many other drugs, is mainly absorbed in the small intestine”. Shohin et al. “Biowaiver Monographs for Immediate-release Solid Oral Dosage Forms: Ketoprofen.” Journal of Pharmaceutical Sciences. 2012: 3593–3603.

An important implication of such a physiological process (i.e. drugs absorption from the intestine) is that a dissolution test should also be conducted simulating the intestinal environment, e.g., using a dissolution medium having a pH in the range of 5 to 7. Conducting the tests using acidic pH (simulating the stomach environment) may not be appropriate when the dissolution results are related to physiological outcomes such as plasma drug levels.

This article provides an overview of the mechanism of drug absorption from the GI tract based on solubility/dissolution and dissociation/pH characteristics of a drug. It is argued that although pH values of the environment (stomach and intestine) may play a role, it is the availability of the large surface area of the intestine which predominantly is responsible for the drug absorption for both acidic and basic drugs. Furthermore, in the GI tract, drugs exist in three forms, i.e., solid (outside solvent/solution) and solid and ions in solution which are in equilibrium with one another. However, it is only the drug in a solution form which is relevant for the absorption purpose. The interactions between drug (solid), drug/ions in solution, and the surface areas are discussed in providing efficient drug absorption. Considering the absorption mechanism, the role of in vitro drug dissolution testing is also highlighted. Please click here for the complete article

The similarity Factor or F2 is a parameter commonly used to show the similarity or equivalence of two dissolution profiles. The F2-value is often calculated using the formula described here (link)—the values of F2 range from 0 to 100. Commonly, a value between 50 and 100 is considered to reflect the similarity of two dissolution profiles, which implies that the products will have similar in vivo drug release characteristics (please click here for complete post).