Dissolution testing has always been important for both gathering data about your form and also as part of product quality control. Dissolved drug products will vary in how quickly they release their active ingredient, so doing a dissolution test means you’ll understand how that form will affect the body after you take it. Many governments (U.S. FDA and EMA) examine how quickly a drug can dissolve since dissolved drugs have a direct effect on how well that drug can get absorbed (bioavailability) and work effectively (therapeutic use).
Conventional dissolution testing also has a number of shortcomings that make it less predictive, than it once did. Recently new ways of developing tests have emerged to make testing more automated, easier to conduct and more biorelevant.
This article will describe both the shortfalls of traditional dissolution test methods and also the progression of new methods that are changing how dissolution is measured and perceived in contemporary pharmaceutical science.
Some common dissolution testing equipment includes:
Examples of biorelevant dissolution media:
- FaSSIF (Fast State Simulated Intestinal Fluid)
- FeSSIF (Fed State Simulated Intestinal Fluid)
- FaSSGF (Fast State Simulated Gastric Fluid)
These new formulations better model bile salt composition, lecithin content and changes in pH seen in the GI tract and will improve the predictive ability of the in vitro–in vivo correlation (IVIVC) of drugs with low solubility.
Benefits of biorelevant dissolution media
- Increased ability to predict the extent of drug absorption
- Improved understanding of how food impacts drug dissolution
A. USP Apparatus III (Reciprocating Cylinder) - Simulates pH change that occurs within the GI tract after first meal of modified release drug.
B. USP Apparatus IV (Flow-Through Cell) - Continuous flow of media for poorly soluble and extended release drugs.
C. Miniaturized Dissolution Systems - Use smaller sample sizes and are intended for early-stage screening of formulations.
Advantages: Improved reliability, ability to perform dissolution studies at more realistic dynamic flow conditions.
Today's dissolution testing systems incorporate online, real-time monitoring and automated sampling techniques:
- Using automated sampling methods limits the chance of variation during collection.
- Employing online UV spectrophotometry with fibre optic sensors or raman spectroscopy allows for measurement of drug solubility at any moment.
- Utilizing methods that can monitor the media temperature and media used allows for continuously closed-loop testing.
The benefits are:
- The improved accuracy and reproducibility of the test results.
- The reduction in time for collectors and the speed with which information can be processed.
By allowing a consistent ongoing collection of dissolution data, continuous process monitoring is available through this system.
IVIVC modelling correlates dissolution and absorption kinetics in order to produce plasma concentration-time profiles. These correlations can help reduce the number of in vivo bioequivalence studies required.
Tools used to conduct IVIVC modelling include:
- The GastroPlus, Simcyp and PK-Sim software packages.
- Mechanistic models of absorption (MAM) which predict drug behavior while inside the gastrointestinal (GI) tract.
Advantages of using IVIVC modelling include:
- Formulation support for product optimization.
- It accelerates the submission of bioequivalent formulations to regulatory agencies.
- It creates the opportunity for conducting virtual bioequivalence assessments.
A. Dissolution Imaging: Visualization of how tablets disintegrate and how they diffuse through a dissolution medium in real-time using cameras and spectroscopic devices
B. Microfluidic dissolution systems: To create low-volume fluid dynamics comparable to a human GI tract.
These two new technologies (dissolution imaging and microfluidics) will allow for greater understanding of the mechanisms of drug dissolution, how drug particles behave during dissolution and how excipients interact with one another.
When PBPK data are integrated into the prediction of in vivo performance based on in vitro dissolution data, it has several potential benefits:
- Enable improved prediction (to a greater degree) of the bioavailability of a drug.
- Provide data to assist in optimizing a formulation prior to FDA approval.
- Reduce the amount of clinical trials for formulation changes.
The FDA and EMA, as well as some other regulatory agencies, encourage the use of PBPK modeling as an additional tool in the development of biowaivers and formulation.
This development will include the use of automated high throughput dissolution systems in combination with imaging and modeling tools to facilitate the efficient evaluation of 3D printed and individualized drug delivery systems.
Examples of anticipated trends include:
- The integration of Artificial Intelligence (AI) to assist in predicting dissolution profiles based on manufacturing formulation information.
- The implementation of automated high throughput systems for rapid screening of formulations.
- The linkage of dissolution testing with continuous processing systems for the purpose of implementing real-time release testing (RTRT).
As the pharmaceutical industry evolves toward Quality by Design (QbD) and continuous processing, dissolution testing will become an increasingly dynamic element of quality assurance instead of being confined to the role of a regulatory requirement.
Dissolution Testing has been traditionally accepted as a key aspect of Pharmaceutical Quality Assurance because it relates the way the drug is formulated to how well it will perform therapeutically. Nonetheless, traditional methods’ limitations stem from the low physiological relevance and limited predictive abilities utilized to perform this type of testing.
Recent innovations, such as biorelevant test media, automated testing methods, enhanced testing apparatus designs and computer-modelled testing procedures have been fundamental in changing the manner in which dissolution testing assists both formulation development and regulatory approvals.
With the inclusion of recent advancements, the pharmaceutical industry is gradually moving to a more productive, scientifically-driven and patient-centred drug product development strategy. Dissolution testing is evolving from a method of simply confirming the manufacturer's quality to also being a predictive tool for clinical success.
1) Traditional Dissolution tests have poor physiological relevance
2) They have severely limited predictive value,
3) Their results are operator dependent.
This article will describe both the shortfalls of traditional dissolution test methods and also the progression of new methods that are changing how dissolution is measured and perceived in contemporary pharmaceutical science.
Understanding Dissolution Testing
Dissolution testing is a laboratory test performed to establish the rate and extent at which a dosage form (tablet, capsule or liquid) will dissolve in an aqueous solution under standard conditions. This test allows for the:- Assessment of the consistency of drug product manufacture between batches.
- Relationship to the biological activity of the drug (the bioavailability of the drug).
- Assistance with formulation development and evaluation of product stability.
Some common dissolution testing equipment includes:
- USP Apparatus I (Basket) - for capsules and floating tablets;
- USP Apparatus II (Paddle) - for tablets and liquid suspensions; and
- USP Apparatus III-VII - for modified release and specialized formulations.
Limitations of Traditional Dissolution Testing
Traditional dissolution testing may provide an accurate performance of drug products in vitro. There are many limitations associated with the traditional dissolution testing as it relates to performance of a drug product in the human body.1. Physiological Relevance
The media used for dissolution testing in both the United States Pharmacopeia and European Pharmacopeia are very simple (i.e., 0.1 N HCl and buffer solution) and the stirring conditions used in dissolution testing in both the United States and the European Pharmacopeia are constant. The Gastrointestinal Tract (GI Tract) is a very dynamic environment.- The pH of the GI Tract is not constant but it is constantly changing.
- Bile salts and digestive enzymes have a direct effect on drug solubility.
- The variation in time it takes to transport drug products throughout the GI tract has a direct effect on when the drug is released.
2. Limited Predictive Power (Poor IVIVC)
In Vitro In Vivo Correlation (IVIVC) is critical for predicting the oral bioavailability of drug products. Traditional dissolution testing does not provide an accurate assessment of the drug products that would occur upon ingestion of the drug and the subsequent use of the gastrointestinal (GI) tract for absorption.3. Incomplete Simulation of Modified-Release Formulations
Sustained-release and enteric-coated products release drugs over time, under complex, time-dependent conditions. For example, there are several pH changes that are present at different stages of the GI tract, as well as variations in the motility of the GI tract.4. Variability and Reproducibility Problems
The handling of samples, equipment vibrations and techniques for taking samples all introduce variability. Furthermore, very small deviations in stirring speed and/or temperature from the recommended values have a significant impact on the results of the testing and, therefore, limit the ability to reproduce the results in different labs.5. Not Appropriate for Poor Soluble Drugs
As the number of BCS Class II & IV drugs (low solubility) increases, traditional testing methods are not able to provide a reasonable representation of the actual physiological process that takes place after a drug has been ingested. This makes these methods less useful for improving formulations.6. Availability of Regulatory Changes
Once the dissolution method has received regulatory approval for use with a marketed product, the ability to change that approved method is limited due to regulatory restrictions. This creates a disincentive for the adoption of improved and biorelevant methodologies after an approved product is marketed.Advances in Dissolution Testing
Continuously advancing technologies and methodologies have been introduced to pharmaceutical science to help overcome these limitations of dissolution testing by creating more predictive, automated and biorelevant tools for dissolution testing.1. Biorelevant Dissolution Media
Biorelevant dissolution media have become popular as a more closely representative of the conditions in the gastrointestinal tract than traditional dissolution media.Examples of biorelevant dissolution media:
- FaSSIF (Fast State Simulated Intestinal Fluid)
- FeSSIF (Fed State Simulated Intestinal Fluid)
- FaSSGF (Fast State Simulated Gastric Fluid)
These new formulations better model bile salt composition, lecithin content and changes in pH seen in the GI tract and will improve the predictive ability of the in vitro–in vivo correlation (IVIVC) of drugs with low solubility.
Benefits of biorelevant dissolution media
- Increased ability to predict the extent of drug absorption
- Improved understanding of how food impacts drug dissolution
2. Advanced Design of Dissolution Apparatuses
To overcome limitations of hydrodynamic influence on dissolution, researchers and agencies have developed new dissolution apparatus designs which more accurately model in vivo conditions. Examples of these new designs include:A. USP Apparatus III (Reciprocating Cylinder) - Simulates pH change that occurs within the GI tract after first meal of modified release drug.
B. USP Apparatus IV (Flow-Through Cell) - Continuous flow of media for poorly soluble and extended release drugs.
C. Miniaturized Dissolution Systems - Use smaller sample sizes and are intended for early-stage screening of formulations.
Advantages: Improved reliability, ability to perform dissolution studies at more realistic dynamic flow conditions.
3. Online Monitoring and Automation
Manual sampling and offline analytic testing methods, including UV and high-pressure liquid chromatography (HPLC), has been consistently used to monitor dissolution test results in a time-consuming and human error prone approach.Today's dissolution testing systems incorporate online, real-time monitoring and automated sampling techniques:
- Using automated sampling methods limits the chance of variation during collection.
- Employing online UV spectrophotometry with fibre optic sensors or raman spectroscopy allows for measurement of drug solubility at any moment.
- Utilizing methods that can monitor the media temperature and media used allows for continuously closed-loop testing.
The benefits are:
- The improved accuracy and reproducibility of the test results.
- The reduction in time for collectors and the speed with which information can be processed.
By allowing a consistent ongoing collection of dissolution data, continuous process monitoring is available through this system.
4. In Vitro–In Vivo Correlation (IVIVC) Modelling
Computer modelling is an integral component of the relationship between dissolution data and pharmacokinetic performance.IVIVC modelling correlates dissolution and absorption kinetics in order to produce plasma concentration-time profiles. These correlations can help reduce the number of in vivo bioequivalence studies required.
Tools used to conduct IVIVC modelling include:
- The GastroPlus, Simcyp and PK-Sim software packages.
- Mechanistic models of absorption (MAM) which predict drug behavior while inside the gastrointestinal (GI) tract.
Advantages of using IVIVC modelling include:
- Formulation support for product optimization.
- It accelerates the submission of bioequivalent formulations to regulatory agencies.
- It creates the opportunity for conducting virtual bioequivalence assessments.
5. Drug Dissolution Imaging and Microfluidics Technology
With the advent of new technology, visualization and micro-studies of how drugs dissociate and dissolve are possible.A. Dissolution Imaging: Visualization of how tablets disintegrate and how they diffuse through a dissolution medium in real-time using cameras and spectroscopic devices
B. Microfluidic dissolution systems: To create low-volume fluid dynamics comparable to a human GI tract.
These two new technologies (dissolution imaging and microfluidics) will allow for greater understanding of the mechanisms of drug dissolution, how drug particles behave during dissolution and how excipients interact with one another.
6. The Use of Physiologically Based Pharmacokinetic (PBPK) Models
PBPK models are an amalgamation of physiological parameters (GI pH, GI motility and GI enzyme activity) with the physical characteristics of a formulation in order to predict in vivo performance based on in vitro dissolution data.When PBPK data are integrated into the prediction of in vivo performance based on in vitro dissolution data, it has several potential benefits:
- Enable improved prediction (to a greater degree) of the bioavailability of a drug.
- Provide data to assist in optimizing a formulation prior to FDA approval.
- Reduce the amount of clinical trials for formulation changes.
The FDA and EMA, as well as some other regulatory agencies, encourage the use of PBPK modeling as an additional tool in the development of biowaivers and formulation.
7. 3D Printing and Novel Formulation Testing
In the development of 3D printed pharmaceuticals, new methods for the evaluation of dissolution characteristics and customization will need to be developed.This development will include the use of automated high throughput dissolution systems in combination with imaging and modeling tools to facilitate the efficient evaluation of 3D printed and individualized drug delivery systems.
Future Directions
The future of dissolution testing is in increasing the degree of integration and automation. Combining the use of both in vitro and in silico techniques will continue to increase the predictive value of dissolution study results.Examples of anticipated trends include:
- The integration of Artificial Intelligence (AI) to assist in predicting dissolution profiles based on manufacturing formulation information.
- The implementation of automated high throughput systems for rapid screening of formulations.
- The linkage of dissolution testing with continuous processing systems for the purpose of implementing real-time release testing (RTRT).
As the pharmaceutical industry evolves toward Quality by Design (QbD) and continuous processing, dissolution testing will become an increasingly dynamic element of quality assurance instead of being confined to the role of a regulatory requirement.
Dissolution Testing has been traditionally accepted as a key aspect of Pharmaceutical Quality Assurance because it relates the way the drug is formulated to how well it will perform therapeutically. Nonetheless, traditional methods’ limitations stem from the low physiological relevance and limited predictive abilities utilized to perform this type of testing.
Recent innovations, such as biorelevant test media, automated testing methods, enhanced testing apparatus designs and computer-modelled testing procedures have been fundamental in changing the manner in which dissolution testing assists both formulation development and regulatory approvals.
With the inclusion of recent advancements, the pharmaceutical industry is gradually moving to a more productive, scientifically-driven and patient-centred drug product development strategy. Dissolution testing is evolving from a method of simply confirming the manufacturer's quality to also being a predictive tool for clinical success.
Frequently Asked Questions (FAQs) on Dissolution Testing
Q1. Why do we do dissolution testing?
Answer: We do dissolution testing to know how well a drug releases from a dosage form when subjected to standard test conditions.Q2. Why is dissolution testing relevant?
Answer: Performing dissolution testing provides a way to ensure each dose of a drug will perform the same, enable evaluations of drugs with similar pharmacokinetic profiles (bioequivalence) and maintain regulatory requirements as a manufacturer.Q3. What are the significant limitations of traditional dissolution tests?
Answer:1) Traditional Dissolution tests have poor physiological relevance
2) They have severely limited predictive value,
3) Their results are operator dependent.
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