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In this article, experts discuss the fundamentals of dissolution testing and highlight the challenges that are surfacing as a result of the increasing numbers of poorly soluble molecules entering the development pipeline.
Because oral solid dosage forms are still the most common way in which drugs are administered, dissolution of the dosage form after it is swallowed, namely the rate at which the active ingredient is released into the body, is a critical facet of drug development. “Dissolution testing is an essential analytical procedure that’s required as part of the final release investigation for solid oral dosage forms to control product quality, stability, and batch-to-batch consistency,” confirms Meike Eckert, head of Dissolution Laboratories, Evonik Health Care. “As the rate of dissolution can significantly affect bioavailability, the goal of dissolution tests and associated acceptance criteria should be to identify batches with unacceptable bioavailability.”
The primary functions of a dissolution test during early stages of development are to characterize therapeutic efficacy, bioequivalence, and bioavailability of API. During later stages of the development process, dissolution testing is also used for quality control (QC) purposes. “The type of dissolution testing performed along with the information required from the testing will change as the molecule progresses from the early stages of development to later in clinical development and towards product registration,” says Charlotte Clay, head of Analytical Development, Pharmaceutical Analysis, Quotient Sciences.
“At the initial stages of characterizing and selecting the API, in-vitro dissolution testing can be performed to aid determination of the Developability Classification System (DCS) classification of an API, and in turn provide useful guidance on the best formulation development strategy for a molecule,” Clay continues. “In later stages of development, dissolution testing is used as a QC procedure to detect the influence of critical manufacturing variables on a drug product.”
During early drug development stages, it is possible to use a biorelevant dissolution method to determine how a formulation may react in media, such as fasted simulated gastric fluid (FaSSGF) and fasted simulated intestinal fluid (FaSSIF), that closely mimics conditions found inside the human body, Clay explains. “This methodology provides a prediction of how a formulation will behave within the body and ensure that the most appropriate formulations are taken forward into clinical trials,” she says.
After the optimal formulation has been chosen to progress, dissolution methods specifically aimed at assessing quality and stability are developed. “These methods may not be biorelevant (standard acidic and phosphate buffered medias are typically used), but they are able to distinguish batch-to-batch variability as well as any changes in the formulations’ dissolution performance that could affect product stability,” Clay confirms.
Once pharmacokinetic (PK) data have started to be collected from clinical trials of the chosen formulation, it is appropriate to develop a biopredictive dissolution method. When used in combination with PK data, it is possible for developers to set up in-vitro–in-vivo correlations (IVIVC), which can be used to optimize formulations and determine equivalence for generic or modified versions of originator drug products, states Eckert.
“By following a quality-by-design (QbD) approach, risk assessments and definitions for quality target product profiles can be used throughout the clinical development and commercial lifecycle to identify potentially high-risk formulation and process variables,” summarizes Eckert. “Dissolution testing can also achieve an improved product and process understanding to develop an appropriate control strategy.”
Of paramount importance for dissolution testing is the assurance that the conditions used for testing are appropriate and correct for the product that is being tested, as well as for the information that is hoped to be gained from the test, stresses Clay. “There are many variables when it comes to dissolution testing from the type of apparatus and the dissolution media used, through to the small but important decisions on parameters, such as paddle/basket rotation speed, the use of sinkers, and the number of sampling time points, to name but a few,” she explains. “Small changes to these variables can have a big impact on the data generated; for example, the sinker mesh size used can have a direct impact on the release rate of the formulation, so it is therefore important to control these parameters and specify them in the analytical test method.”
Additionally, Clay emphasizes that as a result of an increasing number of poorly soluble molecules entering the development pipeline, the number of ingredients falling into a DCS class II or IV are also rising. “As such, choosing the correct dissolution media where sink conditions can be achieved is becoming more of a challenge when developing dissolution methods,” she says.
In agreement, Eckert highlights that it can often be necessary to add solubilizers, such as sodium lauryl sulfate, at an appropriate concentration to achieve meaningful dissolution results when dealing with poorly soluble ingredients. “During the formulation development process, it can be challenging to identify the right dissolution test methods to predict how the target formulation will perform in-vivo to reduce risk during future clinical studies,” she continues. “Based upon the physicochemical characteristics of the API and the type of formulation, the use of media with different rates of complexity can be employed. These media options can range from plain buffers up to biorelevant media and the potential addition of digestion enzymes.”
Currently, there are seven different types of dissolution apparatus defined in the United States Pharmacopeia (USP)-basket type, paddle type, reciprocating cylinder, flow through cell, paddle over disc, rotating cylinder, and reciprocating disc. Of the seven apparatus, basket type (apparatus I) and paddle type (apparatus II) are most commonly used for oral solid dosage forms but many different product types, from capsules to creams, can be testing using the apparatus defined in the USP.
“USP Apparatus I and II are the most commonly used dissolution apparatus for solid oral dosage forms and are versatile in enabling the development of many types of dissolution methods, from those for formulation development purposes to those used for QC testing of commercial batches,” confirms Clay. “There are also a number of more bespoke dissolution apparatus/techniques being developed and used as drug products become more complex and the search for a more biopredictive technique continues.”
In concurrence, Eckert notes that development of newer in-vitro tools has occurred as a result of the rising number of APIs with more complex physicochemical characteristics and the more stringent regulatory requirements being demanded for the prediction of in-vivo behavior. “In addition to Apparatus III and IV (reciprocating cylinder and flow through cell), which are candidates for the prediction of detailed gastrointestinal transit with multiple test media or bioequivalent volumes, there is a growing toolbox of other emerging systems that are now offered by university spin-offs, such as Physiolution or other specialized companies for certain specific challenges,” she says.
Giving an example, Eckert explains that multiple providers now offer services to combine dissolution testing with simulated mechanical stress. “These combination tests offer additional benefits for dosage forms that are sensitive to mechanical stress, such as delayed release capsules,” she adds. “They can also be useful in the development of generic products to compare eroding and non-eroding matrices.”
Volumes can be problematic when determining the most appropriate dissolution test to use, stresses Eckert. The commonly used apparatus are limited for use with media volumes of between 500 mL and 1000 mL, which can restrict the physiological relevance. However, using high volumes for dissolution testing can lead to an overestimation of in-vivo performance. “To better reflect conditions within the human gastrointestinal tract, the use of mini-paddles combined with smaller vessels can sometimes be advantageous,” Eckert says. “However, this method is not yet considered by the pharmacopeias.”
Clay continues by highlighting the fact that there has been an escalating use of modified and non-compendial apparatus in the field of dissolution testing over recent years. “These apparatuses are being utilized to offer novel perspectives on different dosage types, delivery devices, and formulations, with the goal being to make dissolution results more biorelevant,” she states. “As a result, previous ‘fringe’ techniques such as intrinsic dissolution, small-volume dissolution, and dissolutions using enhancer, immersion, or extraction cells are becoming more widely adopted.”
Furthermore, advancements in detection techniques are also enabling testing, either online or in real-time, of more complex, multi-component formulations, Clay confirms. With the added capabilities afforded by these new detection techniques, developers can achieve a comprehensive data set, which provides a better understanding of the interactions of APIs and excipients in product formulations.
Globally, various pharmacopeias provide clear outlines for apparatus, procedures, and evaluations that will help developers to fulfill the dissolution testing criteria of regulatory bodies. For example, USP has several chapters, including 711, 1092, and 1225, detailing preliminary assessments, method development, analysis, automation, validation, and acceptance criteria (1–3). In European Pharmacopoeia section 2.9.3 (4), developers can find information on apparatus, procedures, and evaluations for acceptance criteria also.
“Since 2014, Europe has also started following the USP approach of publishing individual formulation monographs containing dissolution methods and acceptance criteria,” adds Eckert. “In the US, additional information is also publicly available in the dissolution methods database (5) of FDA.”
Further information can also be found on the physical operating conditions of the dissolution testers, confirms Clay, with guidelines covering dissolution testing for immediate release, delayed release, and extended release drug formulation types. “However, given the complexities of the human body, physiology, and chemical/biological interactions that take place, it can be difficult to solely rely on the dissolution test as a way of predicting how a drug formulation may perform in vivo,” she stresses. “The use of biorelevant media can aid such assessments, but there is no way of understanding how closely the dissolution test may predict in-vivo performance without performing clinical studies.”
The European Medicines Agency (EMA) also provides guidelines on the investigation of bioequivalence, reveals Eckert. “These guidelines describe the use of dissolution studies to waive a bioequivalence study in applicable cases and the evaluation of similarity of dissolution profiles,” she says. “The use of dissolution data in IVIVC approaches is also explained in EMA’s guideline (6) on the pharmacokinetic and clinical evaluation of modified release dosage forms.”
Because dissolution testing is fundamental for the assessment of the performance of oral formulations and is widely used around the world, much work has been done to create a globally uniform approach. The International Council for Harmonization (ICH) has worked with various pharmacopeias to harmonize many of the dissolution testing methodologies (specifically USP I and II Apparatus) so that they are standardized across many different regions, Clay iterates.
“Dissolution is a harmonized technique across many pharmacopeias in which dimensions of the equipment used and operating parameters are clearly defined and documented,” Clay continues. “Thanks to this harmonization, successful transfer of validated dissolution methods from one laboratory to another is made to be relatively straightforward.”
1. USP, USP–NF <711>, “Dissolution” (US Pharmacopeial Convention, Rockville, MD, 2011).
2. USP, USP 35 <1092>, “The Dissolution Procedure: Development and Validation” (US Pharmacopeial Convention, Rockville, MD, 2012).
3. USP, USP 36 <1225>, “Validation of Compendial Procedures” (US Pharmacopeial Convention, Rockville, MD, 2012).
4. European Pharmacopoeia, Ph. Eur. 2.9.3. “Dissolution Test for Solid Dosage Forms” (European Medicines Agency, London, UK, 2008).
5. FDA, “Drug Databases: Dissolution Testing,” [accessed Sep. 18, 2019].
6. EMA, Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms (Brussels, Nov. 20, 2014).
Vol. 43, No. 10
When referring to this article, please cite it as F. Thomas, “The Fundamentals of Dissolution Testing,” Pharmaceutical Technology 43 (10) 2019.