Fig 1: Dissolution of a solid oral dosage form

Once the API is in solution, the process of absorption can take place, whereby the drug substance is passed from the gastrointestinal lumen into the circulatory system where it can then travel to the relevant receptor sites to exert a biological response.

Dissolution is an in-vitro​ test that evaluates how an API is extracted from a solid dosage form. It can provide an indication of the efficiency of in-vivo​ dissolution but by no means provides any data on drug substance absorption. In order to assess the latter, pharmacokinetic data would need to be generated and used to supplement the dissolution work.

If appropriate in-vitro​ conditions are selected and appropriately evaluated (to simulate in-vivo​ conditions), it can aid in determining successful in vitro-in vivo​ correlation (IVIVC), or, worst case, a relationship between the two. It should be noted that dissolution parameters that are optimal for QC purposes may not be suitable for establishing IVIVC, so two dissolution tests may well be required to satisfy both development and regulatory needs.

When developing a dissolution method, it is important to take a logical, systematic approach to the process, and ensure that both the scientific and regulatory principles are borne in mind. A robust dissolution method should be free of significant interferences (e.g. matrix effects due to excipients), give low variability (precision) and produce a good profile shape.  The method should also be challenged to discriminate between batches of material with different quality attributes. Once the process of identifying suitable medium and apparatus are complete, further optimisation of the method would be required to evaluate ionic strength of the medium, agitation rate and, if required, surfactant concentration. The final developed method should have the ability to discriminate between different formulations/batches, but still maintain acceptable precision and robustness.  With regards to precision, typical limits for early and later time-points would be <20% and <10% RSD respectively.

fig 2

Fig 2: Typical dissolution bath apparatus

Sink conditions    

Sink conditions are defined as ‘the solution concentration corresponding to typically 5-10 times the nominal working concentration of the API in the dissolution medium’.  Confirmation of achievement of sink is critical in establishing a suitable dissolution method.  If these are not able to be achieved (and hence the media reaches saturation point), the dissolution rate cannot be consistently measured. It is important that when conducting dissolution testing, the only influences on the result should be the agitation rate and solubility of the product.

Media

The initial focus when screening potential media is to start with those which are aqueous based, within the pH range of 1.2-6.8 at the recommended ionic strength (as per USP/EP).  When assessing APIs that display low solubilities in aqueous media throughout the pH range, incorporation of a surfactant is advisable, although the levels used should be as low as possible.

Dosage form 

The fundamental characteristics of the dosage form type (capsule, tablet etc.), strength, excipients, release type (immediate, sustained, delayed), stability data and surface coatings, should all be considered during the method development phase. Additionally, manufacturing variables can also be pivotal in evaluating differences in API release between different formulations. A well-developed dissolution method should allow discrimination of the various product attributes.

When performing a dissolution, samples would be removed at set time-points, and the percent dissolved against time plotted (as demonstrated in figure 3 below):

fig 3

Fig 3: Dissolution profile showing discrimination between different formulations

Throughout the duration of the dissolution analysis, it is critical to ensure visual observations are maintained. This can provide additional data to support any quantitative differences in the analytical results.

The analytical finish for the dissolution needs to be established. Where possible, in order to maintain simplicity and efficiency (and assuming the presence of a suitable chromophore), a simple UV finish could be employed; this would also require suitable specificity to be obtained to ensure that the absorbance of the active is not compromised by any other interferences.

More often than not, quantitation would be performed using HPLC-UV. This can often be favoured in order to reduce/eliminate interferences that may otherwise compromise a stand-alone UV method. Additionally, it is very likely that a previous HPLC assay method can be adapted for the dissolution samples by curtailing the run-time to allow the high sample throughput required for dissolution analysis. HPLC also provides flexibility in adjustment of injection volume to accommodate variations in sample concentration that are likely to be needed for different product strengths.

There are occasions where it maybe a practical alternative to screen for elemental components of the material, for example for a product where the active material is an inorganic salt, or in situations where traditional detection is problematic, then it may be possible to monitor a counter ion such as sodium or calcium instead.

There are a variety of elemental spectroscopy techniques that can be employed for this purpose. The choice of instrument is dependent of the analyte required and the expected concentration in the solutions.

For example, a potassium bromide tablet dissolution profile could be obtained by use of either flame atomic absorption spectrometry (FAAS) to measure the level of potassium or alternatively the concentration of bromide (measured as elemental bromine) could be measured by inductively coupled plasma – mass spectrometry (ICP-MS). Another application may be the use of inductively coupled plasma – optical emission spectroscopy (ICP-OES) to ascertain the content of iron in solutions drawn from a ferrous fumarate tablet dissolution

In summary, the design of a suitable dissolution procedure must take into consideration many parameters spanning the API, formulation and analytical method. In-vitro​ dissolution testing should provide a robust body of data in order to assure product performance and quality. Throughout the process it is important to ensure that the in-vitro​ dissolution resembles in-vivo​ conditions. If the dissolution procedure is designed effectively, it will accelerate drug development, and ideally reduce the need for human studies.HPLC-UV. This can often be favoured in order to reduce/eliminate interferences that may otherwise compromise a stand-alone UV method. Additionally, it is very likely that a previous HPLC assay method can be adapted for the dissolution samples by curtailing the run-time to allow the high sample throughput required for dissolution analysis. HPLC also provides flexibility in adjustment of injection volume to accommodate variations in sample concentration that are likely to be needed for different product strengths.