This course is designed to provide: (1) clear understandings of the principles, uses and practices of dissolution testing; (2) suggestions for improving and simplifying the testing by addressing the limitations of current practices; (3) demonstration and availability info for the crescent-shaped spindle. For information on future courses, please email: (contact)

Summary:

Using a recently suggested approach, based on IVIVC principles, C-t profiles (or blood levels) are determined for different strengths and release types (IR and ER) of carbamazepine products from in vitro drug dissolution results. Drug dissolution tests were conducted using the crescent-shaped spindle (25 rpm) with 900 mL of water containing 0.5% of SLS as the dissolution medium. Predicted blood levels along with the derived pharmacokinetic parameters (Tmax, Cmax, and AUC) compare remarkably well with the corresponding human in vivo values reported in the literature. It appears that the approach described previously, and further detailed here, provides a powerful analytical technique for predicting blood levels and then evaluating product quality by establishing their equivalencies. (Link to complete article)

Often analysts face a dilemma as how to approach the above mentioned situations, which appear to be quite common in the industry. Such situations arise because of the current practices of developing and using product specific experimental conditions such as apparatuses, rpm, media etc. The experimental conditions are set by obtaining desired or expected drug release characteristics of the test product which are associated with that test product only. If the expectation of dissolution results are changed or change is made to the product (formulation/manufacturing), the test would require different set experimental conditions, reflecting new expectations. In short, the current practices do not provide true dissolution characteristics of products.

To avoid such a situation, or developing a modified method, one should develop a product independent method based on a physiologically relevant environment which does not change from product to product. The physiologically relevant method not only provides appropriate and unbiased dissolution characteristics of the products, but also frees the analyst from a constant struggle of looking into altering and selecting experimental conditions.

There are suggestions in the literature (1, 2, 3) for conducting physiologically relevant tests independent of products, which may provide answers to the above mentioned situations and significantly simplify dissolution testing in general.

The terminology of “developing IVIVC” is often used in the area of drug dissolution testing which reflects developing a relationship between in vitro (dissolution) and in vivo (bioavailability) results.  However, in reality, the statement and view appear redundant, as this relationship always exists between in vitro and in vivo results. In fact, existence of this relationship (IVIVC) forms the basis of dissolution testing practice. 

So, then the question is, why are these IVIVC development studies frequently conducted and described in the literature? The reason may be explained as follows:
 
The apparatuses commonly used for dissolution testing, in particular paddle and basket, do not provide relevant dissolution results as they do not appropriately simulate an in vivo environment. So, instead of using apparatuses which would appropriately simulate an in vivo environment, studies are conducted to find or to “develop” experimental conditions to obtain in vitro results which would match the in vivo results. Thus this practice of developing product specific experimental conditions (apparatus, medium, rpm etc) has become known as “developing IVIVC”. This practice of IVIVC does not serve any useful purpose for predicting in vivo results, relating in vitro results to in vivo outcome or assessing drug release characteristics of the product.

Having said that, question then becomes, what is the intended purpose of IVIVC development?  The purpose is not to develop IVIVC, as stated above this relationship always exist, but determining/predicting the drug concentrations in blood utilizing the IVIVC concept. Thus, the practices of IVIVC and dissolution testing are in fact for establishing (calculating/predicting) drug concentration-time (C-t) profiles in humans. For a more detailed discussion on this subject alongwith 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 very important that one keeps this understanding in mind, otherwise conducting a dissolution test and the results obtained from the testing would be of limited or no value.

European Medicines Agency (July 14, 2010): Concept paper on the revision of the note for guidance on quality of modified release oral dosage forms and transdermal dosage forms: Section I (quality).

… The main topics to be discussed during the revision of the guideline in the context of modified release oral dosage forms are: … (Link)

USP provides Reference Standards (Abbreviated by RS symbol) for drug substances. In practical terms their purpose is to provide a goal post or reference against which purity (quality) of drug substances, and then drug products, be established. An RS comes with its own purity certificate, established independently by different analytical tests. These RS compounds are used extensively for qualification, development and then validation of analytical methods such as chromatographic or spectrophotometric. In addition, for cost/expense savings, often these standards are used as primary standards for developing in house secondary standards. Continue reading →