Pharmaceutical Dissolution Method Development & Troubleshooting
Dissolution testing at Avivia is closely integrated with pharmaceutical formulation development and analytical development. Our dissolution scientists do not simply generate a dissolution profile and return the results to a separate development team. The formulation, analytical method and dissolution behaviour are evaluated together throughout drug product development.
This close interaction allows us to extract more information from a dissolution experiment than the release profile alone. We know the formulation being tested, understand the purpose of the experiment and can focus on observations that may explain the measured behaviour. Wetting, disintegration, swelling, erosion, floating, sticking, cone formation and other physical changes can therefore be evaluated alongside the quantitative dissolution data.
Results and observations are discussed directly with the formulation scientists. Where appropriate, the formulation or process is adapted, new prototypes are prepared and dissolution testing is repeated. In this way, dissolution becomes an active development tool rather than an isolated analytical test.
Avivia is an independent pharmaceutical development contracting organization in the Netherlands offering a unique, complementary range of pharmaceutical services in the areas of:
Dissolution as Part of Drug Product Development
At Avivia, dissolution method development takes place in close cooperation between Pharmaceutical R&D and Analytical R&D. The objective is not only to measure how much drug is released, but to understand why a formulation behaves as it does and how its performance can be improved.
During formulation development, dissolution results can therefore immediately lead to discussions about API properties, excipient selection and levels, manufacturing parameters, tablet properties, coating, disintegration and release mechanisms. This interaction allows hypotheses generated during dissolution testing to be tested directly in subsequent formulation experiments.
The development process may therefore follow an iterative cycle:
formulate → test → observe → interpret → discuss → adapt formulation or method → test again
This integrated approach is particularly valuable when differences between formulations are subtle or when a conventional dissolution profile alone does not explain the observed product behaviour.
Looking Beyond the Dissolution Profile
A dissolution profile provides quantitative information about drug release, but the physical behavior of the dosage form during the experiment can provide equally important information during development.
Avivia therefore records relevant observations during dissolution testing and evaluates these together with the release profile. Depending on the dosage form, this may include:
- wetting and initial hydration;
- disintegration behaviour;
- swelling or gel formation;
- erosion;
- floating or movement of the dosage form;
- sticking to the vessel;
- cone formation;
- coating rupture;
- formation of particles or agglomerates;
- appearance of the remaining dosage form during the test.
These observations can help distinguish between, for example, a solubility limitation, delayed disintegration, matrix-controlled release, hydrodynamic effects or formulation-related behaviour.
When Can Dissolution Method Development or Troubleshooting Help?
Avivia can support dissolution development and troubleshooting when:
- a formulation does not achieve the intended release profile;
- dissolution results are variable or difficult to explain;
- an existing or compendial method does not discriminate sufficiently between formulations;
- differences between prototype formulations need to be understood;
- a generic or hybrid formulation needs to be compared with a reference product;
- a poorly soluble API creates challenges with sink conditions or release testing;
- excipient, supplier, grade or process changes may affect drug release;
- modified-, delayed- or controlled-release behaviour needs to be characterized;
- physiologically relevant changes in pH or hydrodynamics need to be incorporated into the test;
- an advanced R&D method needs to be translated into a robust routine dissolution method.
Dissolution Method Development: Developing a Meaningful and Discriminatory Method
Method development therefore starts with an assessment of the API, its physicochemical and biopharmaceutical properties, the formulation and dosage-form design, relevant manufacturing variables and, where available, pharmacokinetic or clinical information. These factors help determine which aspects of drug release are critical and which experimental conditions are most appropriate to investigate them.
Depending on the development question, Avivia can investigate parameters such as dissolution apparatus, medium composition and pH, medium volume, agitation or flow rate, sink conditions, surfactant concentration, sampling and filtration conditions and sequential changes in the dissolution environment.
Because the dissolution scientists work closely with the formulation team, the method can also be challenged using deliberately modified formulations or process conditions. This helps determine whether the method is sufficiently sensitive to changes that may be relevant to drug product performance.
Depending on the project, information considered during dissolution method development may include:
Active pharmaceutical ingredient (API): dose, solid-state and morphological form, particle size, wetting, intrinsic and pH-dependent solubility, pKa, hydrophobicity and potential precipitation. These properties are considered in relation to the required sink conditions, etc.
Excipients: function, properties, type, grade, particle size, etc.
Pharmaceutical process type: blending, granulation, drying, tableting, coating, etc.
Process variables: adding, speed, time, temperature, solvent, compression force, spraying time, etc.
Time release technology: delayed release, extended release, immediate release, timed release, etc.
Route of administration: oral, buccal, sublingual, rectal, injection, etc.
Pharmacokinetic properties: absorption, distribution, metabolism, excretion
Clinical study program: fasted, fed, timing, volumes, etc.
Combining this information, identifying the critical parameters and translating them into a meaningful in-vitro test requires expertise across formulation, analytical development and dissolution. Experience and the close interaction between these disciplines within Avivia enables dissolution methods to be developed in the context of the drug product rather than as isolated analytical procedures. Where appropriate, dissolution conditions are varied systematically to determine which experimental parameters are responsible for observed differences and which conditions provide the most meaningful discrimination between formulations.
Dissolution Troubleshooting
Unexpected dissolution results can originate from the formulation, the dissolution conditions or the analytical procedure used to quantify drug release. Troubleshooting therefore requires evaluation of the complete experiment.
Avivia can investigate potential causes including dosage-form behaviour, disintegration, API solubility, hydrodynamics, sink conditions, sampling position, filtration, adsorption, sample stability and the analytical method.
Troubleshooting can therefore extend beyond the dissolution vessel to the complete sample and analytical pathway, including sampling devices, filters, sample containers and interactions that may occur between sampling and analysis.
Where conventional USP Apparatus I or II testing does not adequately explain the observed behaviour, alternative techniques such as USP Apparatus III or IV can be used as complementary development tools to investigate the influence of hydrodynamics, changing medium conditions or sink limitations.
Because Analytical R&D and Pharmaceutical R&D work together, an unusual dissolution profile is not simply reported as a result. Observations and analytical data are discussed in the context of the formulation, hypotheses are generated and targeted experiments can be designed to distinguish between analytical, method-related and formulation-related causes.
Biorelevant Dissolution Method Development
During development, standard compendial conditions may not always provide sufficient insight into how a formulation behaves under physiological conditions. Where relevant, biorelevant method development may include sequential changes in medium composition and pH, different hydrodynamic conditions and consideration of fasted or fed gastrointestinal conditions. Available preclinical, clinical or pharmacokinetic data can be evaluated alongside the in-vitro results and, where informative, used to further refine the dissolution method.
Available information about gastrointestinal conditions, food effects, API properties and, where appropriate, preclinical or clinical performance can be used to design experiments that provide greater insight into in-vivo product behaviour.
The objective is not necessarily to reproduce the gastrointestinal tract in every detail, but to develop an in-vitro experiment that helps answer the relevant formulation or product-performance question.
Dissolution in Generic and Hybrid Drug Product Development
Dissolution testing can play a central role in generic and hybrid drug product development by comparing prototype formulations with the reference product and identifying formulation variables responsible for differences in release behaviour.
At Avivia, dissolution can be combined with formulation development, analytical development and, where required, Excipia deformulation and excipient characterization. This allows reference-product composition, excipient properties and dissolution performance to be evaluated as part of one integrated development strategy.
Selecting the Appropriate Dissolution Technique
The Avivia dissolution laboratory is equipped with several complementary dissolution technologies. The dissolution apparatus is selected based on the drug product, API properties and the development question. API solubility and stability, formulation concept, release mechanism, required sink conditions and relevant hydrodynamic conditions are considered when selecting the experimental approach. Avivia has access to USP Apparatus I, II, III and IV as well as the Pion µDiss Profiler, allowing the technique to be selected according to the information required rather than being limited to a single standard apparatus.
• USP apparatus 1 / Basket dissolution apparatus
• USP apparatus 2 / Paddle dissolution apparatus
• USP apparatus 3 / Reciprocating cylinder dissolution apparatus / BioDis
• USP apparatus 4 / Flow through cell dissolution apparatus
• Pion µDiss Profiler (low volume in situ fiber optic UV monitoring dissolution and solubility system)
We know from experience what the strengths are of each technique, and how we can best apply them to highlight and optimize the most relevant properties of each formulation.
If desired, other less common or more academic dissolution testing techniques are accessible in our network, or we design a tailor-made dissolution setup with, for example, glass fiber optic probes and semi permeable membranes.
From Development Method to Routine Dissolution Testing
During formulation development, one or more dissolution methods may be developed as biorelevant models to better understand formulation behaviour and its potential relationship with in-vivo product performance. These methods are designed using product prototypes with variations in formulation-specific critical parameters, and preferably optimized using data from pilot clinical studies. The predictive dissolution methods used in the development stage may require the use of advanced dissolution testers such as USP apparatus III or IV and complex dissolution media.
For routine quality control, however, a simpler and more robust method is generally preferable. Once the critical product and method variables have been understood, Avivia can investigate whether the discriminatory characteristics of the development method can be translated into a simpler USP I or II method suitable for subsequent routine use and transfer to a GMP laboratory.
Avivia has experience in converting complex R&D dissolution methods to more QC friendly product release dissolution methods that uses USP apparatus I or II.
Frequently Asked Questions About Dissolution Method Development
What makes a dissolution method discriminatory?
A discriminatory dissolution method is sensitive to formulation or process changes that may affect drug product performance. During development, Avivia evaluates which product attributes are most relevant and selects dissolution conditions that can reveal meaningful differences between formulations. Depending on the product, this may involve changes in medium composition, pH, agitation, flow rate, sink conditions or apparatus. Where appropriate, deliberately modified formulations can be used to challenge the method and assess whether it responds to relevant changes.
Why can two formulations give different dissolution profiles?
Differences in dissolution behaviour can result from many factors, including API solubility and particle properties, excipient type or grade, disintegration behaviour, matrix formation, coating properties, tablet hardness, manufacturing process and hydrodynamic conditions during testing. At Avivia, dissolution results are therefore interpreted together with formulation knowledge and physical observations during the test rather than considering the release profile in isolation.
What can cause variable or unexpected dissolution results?
Unexpected dissolution results do not always originate from the formulation itself. Variability can also arise from apparatus conditions, hydrodynamics, sampling, filtration, adsorption, sample stability or the analytical method used to determine drug concentration. Because Avivia combines dissolution expertise with analytical and pharmaceutical development, these potential causes can be investigated together to distinguish analytical or method-related effects from genuine formulation behaviour.
When should USP Apparatus III or IV be considered?
USP Apparatus III can be useful when a dosage form needs to be exposed to sequential media or changing hydrodynamic conditions, for example during development of modified-release products or biorelevant methods. USP Apparatus IV can be useful for poorly soluble compounds and products where controlled flow conditions provide advantages over conventional vessel-based methods. The choice of apparatus depends on the dosage form and the specific development question rather than on a fixed preference for one technique.
Can dissolution testing support generic and reference-product development?
Yes. Dissolution testing can be used to compare reference products with prototype formulations, investigate differences in release behaviour and guide formulation optimization. At Avivia, this can be combined with formulation development, analytical development and, where needed, Excipia deformulation and excipient characterization to evaluate composition and product performance together.