Compilation of FDA Guidance and Resources for in vitro Dissolution Testing of Immediate Release Solid Oral Dosage Forms
The purpose of this webpage is to provide a centralized location for accessing information and references to relevant FDA Guidance and USP Chapters for in vitro dissolution testing of immediate release solid oral dosage forms. Within the context of this webpage, in vitro dissolution testing is considered from the perspective of its use in formulation evaluation during product development and the establishment of quality control (QC) specifications. Therefore, the regulatory information compiled on this webpage provides an overview of this topic, including: defining the purpose of in vitro dissolution testing, establishing dissolution test conditions, validating dissolution test methods, setting in vitro specifications, and submitting information for regulatory consideration [chemistry, manufacturing, and controls (CMC) documentation]. These concepts may also be applied to dissolution methods used to support bioequivalence. The compiled information and references can be viewed by expanding the headings below.
The objective of in vitro dissolution testing is to evaluate the variables that effect the rate and extent of release of a drug substance from the finished dosage form, and in turn, the in vivo performance of the drug product. When this objective is met, a comparison of product in vitro dissolution profiles or adherence to the product release specification ensures that the product or batch being evaluated will have consistent quality and performance.
Establishing Test Conditions
Dissolution tests for immediate release dosage forms should be conducted at 37±0.5°C. Proposals to increase media temperature to model physiologic temperatures should be discussed with CVM for concurrence.
For additional considerations and information refer to: USP <711> Dissolution, USP <1092> The Dissolution Procedure: Development and Validation, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
There are seven types of USP apparatuses that can be used within a regulatory environment to evaluate the release of drug substance from a finished dosage form (for additional information regarding the different types of apparatuses and their uses, refer to USP <711> Dissolution). Two of these (USP Apparatus 1, basket, and USP Apparatus 2, paddle) are more commonly used when evaluating the in vitro dissolution of immediate release solid oral dosage forms.
Table 1. Comparison of USP Dissolution Apparatuses.
| USP Apparatus | Apparatus Name | Agitation* | Dosage Form |
|---|---|---|---|
| I | Basket Method | 50-100 rpm | Solid oral dosage forms like capsules or tablets |
| II | Paddle Method | 50-75 rpm 25-50 rpm |
Solid oral dosage forms like capsules or tablets Suspensions |
*Agitation speeds included here are recommendations as per USP and the appropriateness of the agitation speed should be evaluated for each drug product formulation as part of method development. Excessive agitation rate can lead to foaming, which may cause failure to discriminate between inequivalent formulations.
For additional considerations and information refer to: USP <711> Dissolution, USP <724> Drug Release, USP <1711> Oral Dosage Forms – Performance tests, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Selection of timepoints should adequately reflect the shape (e.g. the ascending and plateau phases, as well as possible curvature in the dissolution versus time profile) and duration of the dissolution curve. The sampling volume and information regarding the method for media replacement and calculations should be documented as part of the dissolution method.
For additional considerations and information refer to: USP <711> Dissolution, USP <1092> The Dissolution Procedure: Development and Validation, USP <1711> Oral Dosage Forms – Performance Tests, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Media Composition
In general, media selection should be based on formulation properties, solubility of the drug substance(s), and the stability of the drug substance(s) during the dissolution testing. The media used in dissolution studies can include acidic or basic solutions, buffers, surfactants, and surfactants with acid or buffers. Use of species-appropriate biorelevant media should be discussed with CVM and will be considered on a case-by-case basis. Use of a hydroalcoholic medium is discouraged. When using USP Apparatus 3, the media and sequence of media composition changes, should be justified.
The selection of the buffer should be based upon its ability to maintain a constant pH throughout the duration of the dissolution evaluation. Also, for drug substances that are weak acids and bases, the pH of the media can change as the drug substance dissolves, constraining further dissolution as the pH approaches the drug pKa. Therefore, attention is needed not only to the type of buffer but also to the amount of buffer to ensure the necessary buffer capacity throughout the dissolution test procedure. Furthermore, the use of purified water is discouraged as the water quality can vary as a function of the source, and the pH can vary day to day and during the dissolution run depending on the drug substance and excipients.
For additional considerations and information refer to: USP <1092> The Dissolution Procedure: Development and Validation, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Media Volume
In general, the volume of solvent used when conducting in vitro dissolution testing is determined by the equilibrium solubility of the drug substance and the fluid volume needed to maintain sink conditions. Typical media volumes are 500, 900, or 1000 mL for USP Apparatus 1 and Apparatus 2. Justification should be provided if volumes fall outside of this typical range or if there is a change in volume across the various tablet strengths within a product line.
For additional considerations and information refer to: USP <1092> The Dissolution Procedure: Development and Validation, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Sink Conditions
Sink conditions are defined as the volume of fluid needed to fully dissolve three times the targeted amount of drug substance in the dosage form. The use of sink conditions ensures that the shape of the dissolution profile is influenced primarily by product formulation rather than by drug substance solubility. If, because multiple strength tablets, sink conditions are met for the lower but not for the highest strengths, sponsors should discuss their proposal for dissolution volumes with CVM.
For additional considerations and information refer to: USP <1092> The Dissolution Procedure: Development and Validation, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
pH
The following points should be considered when selecting the pH of the dissolution medium:
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For drug substances that are weak acids, the dissolution rate increases with an increase in pH whereas for drug substances that are weak bases, dissolution rate increases with a decrease in pH.
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When possible, the pH selected should provide sink conditions and minimize the need to add a surfactant or solvent. The selection of the pH of the dissolution media should take into consideration whether the drug substance is a weak acid or base and its corresponding pKa. However, if the drug substance is a weak acid whose pKa exceeds a physiologically-relevant pH, it may be appropriate to use a media titrated to a physiologically-relevant pH and to add a surfactant to enhance drug solubility.
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The buffer capacity of the system should maintain a constant pH throughout the dissolution test.
For additional considerations and information refer to: USP <711> Dissolution, USP <1092> The Dissolution Procedure: Development and Validation, USP <1711> Oral Dosage Forms – Performance Tests, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Surfactant
In the presence of solubility constraints, there may be a need to employ surfactants. Surfactants are wetting agents that act by lowering the surface tension between the solid particle and the solvent, thereby improving the solubility or wettability of a drug. The use of surfactants may be appropriate when the drug substance is relatively insoluble, irrespective of pH, or when solubilization of the drug substance occurs at a non-physiological (not biologically relevant) pH. If a surfactant is needed to maintain sink conditions, its selection should be based on the characteristics of the drug substance (for example, it is not appropriate to use anionic surfactants, such as sodium laurel sulfate (SLS), with a cationic drug substance).
For additional considerations and information refer to: USP <711> Dissolution, USP <1092> The Dissolution Procedure: Development and Validation, USP <1236> Solubility Measurements, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Common-Ion Effect
Media selection should ensure absence of a common-ion (the same counter-ion as the salt form of the drug substance) that can affect the ionization and solubilization of the drug substance. In the case of a charged/ionizable drug substance, the solubilization can be affected based on the presence of a common-ion.
For additional considerations and information refer to: USP <1092> The Dissolution Procedure: Development and Validation, and USP <1236> Solubility Measurements.
Drug Substance Solubility and Stability
The solubility and stability of the drug substance in the proposed dissolution media should be evaluated. The influence of buffers, pH, temperature, and surfactants on the solubility and stability of the drug substance is important when selecting the proper dissolution media.
For additional considerations and information refer to: USP <1092> The Dissolution Procedure: Development and Validation and USP <1236> Solubility Measurements.
Deaeration
Air bubbles can adversely affect the dissolution and therefore the reliability of the test results (for additional details and information see USP <1092>). A method for deaeration is described in USP <711> and the typical steps include heating, filtering, and drawing a vacuum for a period of time. Other validated deaeration techniques are available and can be used. Once a suitable process is identified, it should be documented as part of the dissolution procedure. Media containing surfactants are not usually deaerated after the surfactant has been added to the medium due to excessive foaming.
For additional considerations and information refer to: USP <711> Dissolution, USP <1092> The Dissolution Procedure: Development and Validation, and USP <1711> Oral Dosage Forms – Performance Tests
Power of Discrimination
Optimum dissolution conditions need to be developed to ensure that the method can discriminate between changes to the drug product formulation and manufacturing process, thereby distinguishing between an acceptable and unacceptable batch. There are many ways to challenge the sensitivity of the method; and, as per USP <1092>, one option is to compare dissolution profiles of formulations that are intentionally manufactured with meaningful variations for the most relevant critical manufacturing variable (±10%–20% change to the range of the variables). To demonstrate discriminatory power, the calculated similarity factor (f2) for the altered batches should be <50 when compared to the bio-, pivotal, or clinical batches.
For additional considerations and information refer to: USP <1090> Assessment of Solid Oral Drug Product Performance and Interchangeability, Bioavailability, Bioequivalence, and Dissolution, USP <1092> The Dissolution Procedure: Development and Validation, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Dissolution method validation encompasses both the dissolution step (release of the drug substance from the drug product formulation in the dissolution medium) and the analytical finish (the sample handling and analytical method that are used to determine the amount of drug substance dissolved during the dissolution step). The precision and robustness of the dissolution step should typically be evaluated. The analytical method should be demonstrated to be scientifically sound by evaluating all typical validation parameters for the type of method being used (e.g., UV or HPLC). Additionally, the dissolution method should be demonstrated to be discriminatory (i.e. capable of distinguishing between and acceptable and unacceptable batch).
For additional considerations and information please see: USP <1092> The Dissolution Procedure: Development and Validation, USP <1224> Transfer of Analytical Procedures, USP <1225> Validation of Compendial Procedures, CVM GFI #63 (VICH GL1) – Validation of Analytical Procedures: Definition and Terminology, CVM GFI #64 (VICH GL2) – Validation of Analytical Procedures: Methodology: Final Guidance, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Setting in vitro Specifications
- Dissolution specifications should be able to characterize the quality and performance of the product, sensitive to changes in the rate-limiting factor controlling the rate and extent of the drug release from the drug product in question, and be driven by regulatory and compendial expectations, for the reason of quality control and for ensuring batch-to-batch consistency.
- Dissolution specifications should assure that products meet clinical performance and that manufacturing processes are performing as expected.
For additional considerations and information refer to: CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
When used for quality control and batch release, the acceptance criterion for the percent of drug substance dissolved is recommended to be set based on the dissolution data (release and stability) generated from the bio-, pivotal, or clinical batches.
The general categories of dissolution test specifications are described in CDER’s 1997 Dissolution Guidance and include:
- Single-point specifications: As a routine quality control test. (For highly soluble and rapidly dissolving drug products)
- Two-point specifications: As a routine quality control test for certain types of drugs products (e.g., slow dissolving or poorly water soluble drug product). This approach may be useful to characterize a drug product and serve as a quality control specification.
Unless otherwise specified in the individual monograph, the acceptance criteria are met if the quantities of active ingredient released from the dosage units tested conform to the appropriate Acceptance Table in USP <711>.
For additional considerations and information refer to: USP <711> Dissolution, USP <1092> The Dissolution Procedure: Development and Validation, and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
Over a drug product’s lifecycle, it is expected that manufactured batches conform to appropriate dissolution specifications to both ensure consistency between manufactured batches and evaluate the product’s stability throughout the shelf life. To this end, dissolution characteristics should be continually monitored over the life of the product to ensure the CQAs are the same and the specifications remain effective.
To ensure continuous batch-to-batch equivalence of the product after scale-up and post-approval changes in the marketplace, dissolution profiles should remain comparable to those generated for the batches used to support bioequivalence or pivotal clinical trials. Typically, dissolution profile comparisons are carried out using the similarity factor (f2) as described in Section V.A. Of CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms. Ideally, to avoid situations where the product markedly deviates from the in vivo characteristics associated with the lots used to support the original product approval, all changes subsequent to approval should be compared to the lot(s) for which there are clinical safety and effectiveness or bioequivalence data. [For additional details on the requirements for scale-up and post-approval changes (SUPAC) refer to CDER's 1995 Guidance for Industry SUPAC-IR]. When in vitro methods are to be submitted in support of either product bioequivalence or the acceptability of a SUPAC change requiring a bioequivalence study, sponsors are advised to contact the target animal division for product-specific advice and considerations.
For additional considerations and information refer to: CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms, and SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation.
For generic products, the dissolution specifications should be based on the observed data, taking into account the dissolution profiles of the batches of the drug product that showed acceptable performance in vivo (i.e. those batches used in the in vivo bioequivalence studies). Once a dissolution specification is set for the generic product based upon the batch used in the in vivo bioequivalence trial, the generic product should comply with that specification throughout its shelf life.
For additional information refer to: USP <711> Dissolution, USP <1092> The Dissolution Procedure: Development and Validation and CDER’s 1997 Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms.
The dissolution method should be developed and validated in accordance with USP <711> and <1092>. It is recommended that the following data be provided for regulatory consideration:
- Apparatus used
- Solubility data showing sink conditions are met (for the entire range of strengths, if applicable)
- Drug substance stability data in the dissolution medium
- Agitation speed, with justifications for higher than recommended agitation speeds
- Temperature 37 ± 0.5o C
- Media components and composition, including pH
- Media volume, with justifications for using more or less than the recommended volume
- Sampling volume should be indicated and information regarding the method for media displacement should be provided
- Filter compatibility studies
- Number of units tested
- Timepoints sampled and percent of the drug substance released at each timepoint for each sample
- Dissolution protocol and procedure, which should include details regarding how the test and reference products were handled prior to and during testing.
- Lot numbers and formulation of the products tested
- Data demonstrating discriminatory power of the method
- Method validation information and data. The method validation for the dissolution step and analytical methods should be performed per USP <1092> and <1225>. If applicable, method transfers should be performed per USP <1224>.
Post-approval changes for immediate release solid oral dosage forms that affect components and composition, scale-up, site changes, and manufacturing process or equipment changes are recommended to be submitted for regulatory consideration as per SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation. This guidance defines the levels of change, recommended CMC tests for each level of change, in vitro dissolution tests and/or in vivo bioequivalences tests, and documentation that should support the change.
For additional considerations and information refer to: SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation.
When in vitro methods are to be submitted in support of either product bioequivalence, biowaiver of additional strength(s), or the acceptability of a SUPAC change requiring a bioequivalence study, sponsors are advised to contact the target animal division for product-specific advice and considerations.