It is generally accepted that for a drug to be absorbed from the human gastrointestinal (GI) tract, it should be in solution form which is established based on solubility/dissolution characteristics of the drug. This in vivo dissolution is determined using in vitro drug dissolution tests.

It is also generally accepted that higher the solubility of the drug, the higher the dissolution and absorption, and their corresponding rates, will be.  In addition, it is also a well established fact that absorption preferentially occurs from the non-polar or undissociated form of a drug. On the other hand, the undissociated, or non-polar moiety, of a drug often shows lesser aqueous solubility compared to its polar version.

For example, propranolol is a drug which is basic in nature with a pKa value of 9.42 and its aqueous solubility is of 61.7 mg/L or 1 part in ~16,000 (link). Therefore, propranolol should be considered to be a low solubility drug. However, its products are usually manufactured using the drug in its hydrochloride salt form i.e. propranolol·HCl which is freely or highly soluble in water. In water it would exist in its ionic/protonated form, which would be less absorbable than the native propranolol. On the other hand, propranolol is known to be highly absorbable/permeable (bioavailability higher than 90%), which suggests that in reality the body sees propranolol as non-polar/undissociated moiety. Therefore, for in vivo dissolution/absorption purposes the solubility of native propranolol should be considered, not of its salt form. This means that in reality propranolol (and other similar drugs) is a BCS class II drug and not the class I drug, as commonly considered.

In conclusion, for drug dissolution and absorption evaluation purposes, one should consider solubility characteristics of a drug in its native form and not that of its salt form. For further discussion on the topic, the following links would be useful (1, 2, 3, and 4).

Drug dissolution tests are routinely conducted to evaluate drug release characteristics of pharmaceutical products such as tablets and capsules. It is highly desirable that these tests should be conducted to reflect in vivo drug release which in turn is reflected by the observed plasma drug conc.-time (C-t) profiles in humans.

In this regard, a simple convolution based method using spreadsheet software has been suggested to convert dissolution results into C-t profiles (link1, link2). This article provides another example describing estimation of plasma drug levels from OROS-based nifedipine products using the suggested convolution approach.

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There are about 500+ dissolution methods listed in the FDA database and about 600+ methods (monographs) in the USP. In addition to these, there are many more, perhaps in the hundreds, dissolution methods described in literature. Moreover, as part of new product development exercises, it is a common and expected practice to develop additional new or revised methods.

It may be interesting to note that the objective of drug dissolution testing has never been to develop methods, but to determine/estimate drug dissolution/release characteristics of products. By developing drug and/or product specific dissolution tests, one in fact would never know or determine the actual dissolution characteristics of any product. The current practices of method development simply defeat the purpose of products evaluation.

For products evaluation, one requires a test/method which is independently developed and established. Therefore, current practices of method developments are not only scientifically invalid and useless but also a waste of time and resources.

The use of the crescent shape spindle, with a common set of experimental conditions, is suggested to address the current difficulties. The suggested approach not only practically eliminates the need for method developments, in particular product dependent, but also provide a scientifically sound and valid drug dissolution testing and product evaluation approach (e.g. see link, link2).

The following links may be useful for further information regarding the difficulties of the current practices: Continue reading →

Developing an IVIVC and its applications are often described in literature as follows (e.g. see link):

“In vitro – in vivo correlation (IVIVC) allows prediction of the in vivo performance of a drug based on the in vitro drug release profiles. To develop an effective IVIVC, the physicochemical and biopharmaceutical properties of the drug as well as the physiological environment in the body must be taken into consideration. Key factors include drug solubility, pKa, drug permeability, octanol-water partition coefficient and pH of environment.”

There are number of deficiencies in the above mentioned description. For example:

• “in vivo performance of drug”, IVIVC studies are commonly conducted for products (such as tablets and capsules) and not for drugs.
• An IVIVC does not allow prediction of in vivo performances from in vitro results. In vitro studies (testing) are conducted based on the assumption that the IVIVC already exits.
• Furthermore, considering the existence of IVIVC, in vitro (dissolution) results are used to reflect or predict expected plasma drug concentration-time profiles.
• The mathematical approach used for the prediction of plasma concentration-time profiles is not the IVIVC but the convolution technique. This (convolution) is the only technique which can be used or applied for the prediction of plasma drug profiles of products.
• The parameters mentioned above such as, drug solubility, pKa, drug permeability, and octanol-water partition coefficient, are all drug characteristics, and not those of the products for which dissolution tests are conducted. Therefore, these parameters often remain constant, or are kept constant, to evaluate the impact of formulation and/or manufacturing attributes on release/dissolution characteristics of a product.
• Regarding the “pH of environment”, this is linked to GI tract physiology and is independent of the drugs and products, thus for drug dissolution testing the environment must also remain constant and independent of products and/or drugs.

Therefore, the IVIVCs as currently conducted or promoted are not of any practical use and can easily be ignored or avoided.