Dissolution Testing: A Vital Drug Development Phase
Oral dosage forms represent one of the most flexible and effective treatments available to the patient.
All solid oral dosage products must undergo dissolution testing throughout their development and as part of QC release testing. Such tests are vital and carried out to expose any changes that may occur with respect to the active pharmaceutical ingredient or to the actual overall dosage form that may impact upon the drug delivery charateristics. Ultimately, it is dissolution testing that, from early in the drug development process, helps lay the path towards a successful, safe and efficacious finished product.
If they are to be effective in the patient, orally-administered drugs need to be capable of dissolving in the gastrointestinal tract fluids, prior to absorption. Therefore, derivation of suitable dissolution methods is key to formulating oral dosage forms.
A major issue for drug developers is achieving the best possible drug release level in relation to the therapeutic effect sought. Both insufficient bioavailability – leading to insufficient efficacy – and overabundant bioavailability – resulting in potentially adverse side effects – could result if the optimisation isn’t performed appropriately
Dissolution testing is the standard approach taken with respect to drug release characteristics. However, the main requirements of such testing are often not fully appreciated. The testing procedure must be solid, replicable and involve mechanisms that enable any significant changes pertaining to product performance to be observed. Two factors – dosage form features and intended administration route – influence the precise dissolution testing route followed. USP (United States Pharmacopoeia) Apparatus 1 (‘basket’) and 2 (‘paddle’) are the two main techniques utilized for dissolution evaluation. Standard dissolution baths plus USP 2 paddles are typically used to test immediate, modified or extended release products, while oral dosage forms that tend to float are usually USP 2 (basket)-tested.
USP 3-to-7 (reciprocating cylinders, flow-through-cell, paddle-over-disc, cylinder and reciprocating holders, respectively) are among the other dissolution technique options, however this article focuses on the first two. Included is a summary of the parameters that need considering during dissolution method assessment
Crucial to efficacious dosage forms are both extraction and absorption of the API (Active Pharmaceutical Ingredient). It is essential that the mechanics behind this process are well understood, if successful in-vitro method development is to take place.
What is Dissolution?
Dissolution involves API extraction from a solid dosage form into solution.
Fig 1: Dissolution of a solid oral dosage form
Absorption occurs once the API is in the solution. This sees the drug substance move into the circulatory system from the gastrointestinal lumen. Thereafter, it can migrate in the blood stream to the appropriate receptor sites.
When performed in vitro, dissolution is used to assess the API extraction process. It can indicate the API’s likely in vivo dissolution behaviour but not necessarily how effectively how it will be absorbed. The latter would tend to be evaluated by scrutiny of a pharmacokinetic data.
Appropriate in vitro condition selection and evaluation methods can both help establish optimal IVIVC (In Vitro-In Vivo Correlation) or, at the very least, an interlinking relationship.
Notably, optimal dissolution parameters for quality control might not align with those needed for IVIVC, so it might be that two dissolution methods are required.
A logical and systematic approach to dissolution method development is needed, with consideration given to both scientific and regulatory principles. Significant interferences (such as matrix effects arising from excipients) should be minimized but a suitable profile capable of discriminating between different batches/formulations should be targeted.
Having identified an appropriate medium and apparatus additional method optimization (to assess the medium’s ionic strength, rate of agitation and surfactant concentration, should be evaluated. The final method should be capable of discriminating between a range of different formulations/batches but not at the expense of stability or precision. In terms of precision, <20% and <10% RSD are typically considered for early and later time-points, respectively.
Fig 2: Typical Dissolution Bath Apparatus
Sink conditions is defined as ‘the solution concentration corresponding to typically 5-10 times the nominal working concentration of the API in the dissolution medium’. In terms of a suitable dissolution method, achievement of sink conditions is vital. Failure to do this may lead to inconsistent and/or inaccurate dissolution measurements.
Potential media screening should begin with aqueous material that sits within the 1.2-6.8 pH range. When examining APIs that have low solubilities under aqueous conditions across the pH spectrum, it’s recommended that a surfactant is incorporated, although be mindful to keep levels to a minimum
The dosage form’s inherent properties – type (whether tablet, capsule, etc.), strength, release type (immediate, sustained or delayed), excipients, surface coatings and stability data – all need consideration during the method development phase. Furthermore, manufacturing variables can significantly alter the API release characteristics. If the dissolution method has been well-developed, then these characteristics should be easily discernible.
When a dissolution is being carried out, sampling should be performed at set intervals and calculation of amount of drug dissolved versus time plotted.
Fig 3: Dissolution profile showing discrimination between different formulations
It is essential to perform regular visual observations throughout the dissolution analysis process as a means of obtaining supplementary data to support any numeric variance in the analytical results. It is also necessary to establish the analytical finish. To keep things efficient, where possible, a straightforward UV finish should be considered, assuming there’s an appropriate chromophore in place and acceptable specificity can be demonstrated.
Typically, quantitation would be undertaken using HPLC-UV. This is frequently favoured as a means of minimizing or wholly removing interferences that could otherwise adversely affect a UV method used in isolation. Also, it is highly probable than an existing HPLC assay method may be optimised for the dissolution samples by curtailing the run-time and thus enabling the high sample throughput needed for dissolution. HPLC additionally offers versatility in injection volume to facilitate the use of a single analytical method for a range of product strengths.
Times will arise when elemental components screening might be a more viable approach. That could be the case if dealing with an inorganic salt: in scenarios where conventional detection proves tricky, then monitoring calcium, sodium or some other counter ion might be an option.
Numerous elemental spectroscopy techniques could be considered. The type of instrument to be used is dependant upon the particular analyte required and the anticipated concentration of the solution(s). For example, the profile for a potassium bromide tablet dissolution could be achieved in one of two ways: FAAS (Flame Atomic Absorption Spectrometry), to measure the potassium level, or ICP-MS (Inductively Coupled Plasma – Mass Spectrometry) to establish bromide concentration (i.e. elemental bromine). ICP-OES (Inductively Coupled Plasma – Optical Emission Spectroscopy) is another potential option, permitting the iron content of solutions taken from a ferrous fumarate tablet dissolution to be deduced.
Overall, there are many parameters to consider when developing an efficient dissolution procedure. Dissolution testing done in vitro should ideally yield a body of data robust enough to guarantee the product’s quality and performance. It is important to keep the in vitro dissolution comparable to in vivo conditions at all stages of the process. Effective dissolution method design will ultimately speed up drug development and potentially reduce the need for human studies.
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