Dissolution Testing andAcceptance Criteria for
Immediate-Release Solid Oral
Dosage Form Drug ProductsContaining High Solubility
Drug Substances
Guidance for Industry

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2018
Biopharmaceutics

1074043 FNL
08/09/18

Dissolution Testing andAcceptance Criteria for
Immediate-Release Solid Oral
Dosage Form Drug ProductsContaining High Solubility
Drug Substances
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2018
Biopharmaceutics

Contains Nonbinding Recommendations
TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 2

III.

ELIGIBLE DRUG PRODUCTS ..................................................................................... 2A.

Dosage Form ................................................................................................................................... 3

B.

Solubility ......................................................................................................................................... 3

C.

Therapeutic Index .......................................................................................................................... 3D.

Time to Maximum Plasma Concentration................................................................................... 4

E.

Manufacturing and Testing History............................................................................................. 4

F.

Excipients ........................................................................................................................................ 4

IV.

STANDARD DISSOLUTION TESTING CONDITIONS ............................................ 4A.

Basket Method (USP apparatus 1) ............................................................................................... 5

B.

Paddle Method (USP apparatus 2) ............................................................................................... 5V.

DISSOLUTION ACCEPTANCE CRITERIA ............................................................... 5
VI. POSTAPPROVAL CONSIDERATIONS.................................................................................... 5i

Contains Nonbinding Recommendations

Dissolution Testing and Acceptance Criteria for Immediate-Release
Solid Oral Dosage Form Drug Products Containing
High Solubility Drug Substances
Guidance for Industry 1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on thetitle page.

I.

INTRODUCTION

This guidance is developed to provide manufacturers with recommendations for submission of
new drug applications (NDAs), investigational new drug applications (INDs), or abbreviatednew drug applications (ANDAs), as appropriate, for orally administered immediate-release (IR)drug products that contain highly soluble drug substances. 2 The guidance is intended to describe
when a standard release test and criteria may be used in lieu of extensive method development
and acceptance criteria-setting exercises. This guidance finalizes the guidance for industry on
Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms
Containing Biopharmaceutics Classification System Class 1 and 3 Drugs (August 2015). 3 The
revised title of this guidance better reflects its focus on the solubility of the drug substance in the
drug product. Therefore, a direct reference to biopharmaceutics classification system (BCS)
class 1 and class 3 is not necessary because permeability requirements are not within the focus of
this guidance. The recommendations in this guidance clarify the recommendations in theguidance for industry on Dissolution Testing of Immediate Release Solid Oral Dosage Forms(August 1997) for high solubility drug substances in IR drug products 4 that meet the conditions
described in section III in this guidance. For drug substances that do not meet the conditions inthis guidance, sponsors/applicants should follow the recommendations provided in the August
1997 guidance mentioned above.

1

This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation andResearch (CDER) at the Food and Drug Administration.
2
Drug substance is an active ingredient that is intended to furnish pharmacological activity or other direct effect inthe diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of thehuman body, but does not include intermediates used in the synthesis of such ingredient. 21 CFR 314.3(b).
3
We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
Drugs guidance web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
4Drug product is a finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally,
but not necessarily, in association with one or more other ingredients. 21 CFR 314.3(b).

1Contains Nonbinding Recommendations
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II.

BACKGROUND

Drug absorption from a solid dosage form after oral administration depends on the release of the
drug substance from the drug product, the dissolution or solubilization of the drug substanceunder physiological conditions, and the permeation across the gastrointestinal membrane. 5,6
NDAs and ANDAs submitted to FDA contain bioavailability (BA) or bioequivalence (BE) dataand in vitro dissolution data that, together with chemistry, manufacturing, and controls (CMC)
data, characterize the quality and performance of the drug product. In vitro dissolution data are
generally obtained from: (1) batches used in pivotal clinical and/or BA/BE studies, (2) batches
used as stability registration batches, and (3) batches used in other human studies conductedduring product development. In general, knowledge about the solubility, permeability,
dissolution, and pharmacokinetics of a drug substance and drug product are considered whendefining dissolution acceptance criteria as part of the drug approval process.
Immediate-release solid oral dosage form drug products containing high solubility drug
substances are considered to be relatively low risk regarding the impact of dissolution on in vivo
performance, provided the in vitro performance meets or exceeds the recommendations
discussed herein.
This guidance establishes standard dissolution methodology and acceptance criteria that areappropriate for highly soluble drug substances that are formulated in IR dosage forms. The
availability of these standards will facilitate the rapid development of dissolution methodology
and related acceptance criteria with no requirement to show discriminatory ability of the
dissolution method for these products during drug product development. In addition, thesestandards will facilitate FDA’s evaluation of the data submitted in the application.
III.

ELIGIBLE DRUG PRODUCTS

In addition to being an IR dosage form, the drug product should meet all of the following
conditions in order for the dissolution standards in this guidance to apply. The FDA’s
Biopharmaceutics Classification System (BCS) guidance should be followed to establish that the
drug product contains highly soluble drug substance. 7 Sponsors/applicants may contact FDA for
5

Amidon GL, Lennernas H, Shah VP, and Crison JR, 1995, A Theoretical Basis for a Biopharmaceutic DrugClassification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res,
12(3):413-420.
6
Amidon GL, Lennernas H, Shah VP, and Crison JR, 2014, A Theoretical Basis for a Biopharmaceutic DrugClassification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res 12,
413-420, 1995-Backstory of BCS, The AAPS Journal, 16(5):894-898.
7
See guidance for industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.

2

Contains Nonbinding Recommendations
assistance in applying the BCS guidance or in determining whether a particular drug productmeets any of the particular conditions listed below. 8,9A.

Dosage Form

This guidance applies to solid orally-administered IR drug products, such as tablets and capsules,
that are meant to be swallowed. This guidance does not apply to orally disintegrating tablets(ODT). 10 However, if absorption from the oral cavity can be ruled out for the ODT, then the
dissolution of the ODT may fall under this guidance. This guidance also does not apply to
sublingual dosage forms which can be ODTs as well, as the scientific principles upon which thisguidance is premised do not apply to the sublingual route of delivery, since sublingual dosage
forms are intended for absorption in the oral cavity. This guidance may apply to chewable
tablets 11 if the dissolution studies are conducted on the intact tablets and the product meets theconditions described in this guidance.
B.

Solubility

To be considered a highly soluble drug product, the drug substance should be considered highly
soluble with the highest drug product’s strength12 soluble in 250 mL or less of aqueous media
over the pH range of 1 to 6.8 at 37°C ± 1°C. In other words, the highest strength divided by 250
should be less than or equal to the lowest solubility observed over the entire pH range of 1 - 6.8.
For drug products where the highest single dose administered is higher than the highest strength,
additional information may be necessary. The drug substance should be chemically stable atleast up to the last dissolution time point in the specified dissolution media for the drug product,plus the interval of the longest analysis time including sample preparation and chromatography
run times. Additional details regarding solubility testing methods can be found in the BCS
guidance.
C.

Therapeutic Index

This guidance does not apply to narrow therapeutic index (NTI) drug products because of thecritical relationship between the bioavailable dose and clinical performance. NTI drug productspose higher therapeutic risks owing to their associated smaller differences between
8

For drug products to which the criteria in this guidance apply, the current methods listed in the FDA’s Dissolution
Methods Database will be replaced by the dissolution methods recommended in this guidance, on a case-by-casebasis, upon submission of supplements in the corresponding NDA or ANDA submission. For products where thedissolution method described in a United States Pharmacopeia (USP) drug product monograph differs from therecommendations of this guidance, ANDA applicants may propose to use the approaches in this guidance as an
updated method and seek revision of the relevant monograph.
9
When the submission is for an NDA, contact the specific drug product’s review division with questions. When thesubmission is for an ANDA, submit a Controlled Correspondence via email to GenericDrugs@fda.hhs.gov. For thedefinition of a controlled correspondence as well as the process to submit a controlled correspondence, see theguidance for industry Controlled Correspondence Related to Generic Drug Development.
10
See guidance for industry Orally Disintegrating Tablets.
11
See draft guidance for industry Quality Attribute Considerations for Chewable Tablets. When final, this guidance
will represent the FDA’s current thinking on this topic.
12
For ANDAs, the highest strength for which approval is sought.

3

Contains Nonbinding Recommendations
effective/ineffective and/or toxic/safe doses. The streamlined approach described in theguidance might not be able to detect the batch-to-batch difference(s) that might impact NTI
performance with respect to safety or efficacy. 13
D.

Time to Maximum Plasma Concentration

If the time to maximum plasma concentration is critical to the intended use, this guidance does
not apply. For example, labeling claims of early or rapid onset of action (e.g., rapid analgesia,
rescue medications) exclude the drug product from adoption of the dissolution standard proposed
herein.
E.

Manufacturing and Testing History

Manufacturing and testing history, including stability testing throughout its shelf-life, should
demonstrate that the drug product will meet the acceptance criteria in this guidance when using
the standard dissolution testing conditions described herein.
F.

Excipients

Excipients chosen for drug product formulation should be consistent with the design of IR drug
products. Excipients should be included in quantities that are consistent with the excipients’labeled function and the target population. Excessive quantities of excipients, such as certain
sweeteners and surfactants that can impact the drug absorption, may be problematic. For
example, mannitol induces a dose proportional decrease in small intestinal transit time. 14 When
this is a factor, we encourage sponsors/applicants to contact FDA9 for guidance on a specificdrug product.
IV.

STANDARD DISSOLUTION TESTING CONDITIONS

If a drug product meets the eligibility requirements described in section III for a standard
dissolution method and acceptance criterion, one of the following methods may be used. 15
Information on apparatus and number of units to test can be found in the USP General Chapter<711> Dissolution. The apparatus should be calibrated before use. 16

13

The current approach to establish bioequivalence of NTI drugs is described here: Yu LX, Jiang W, Zhang X,
Lionberger R, Makhlouf F, Schuirmann DJ, Muldowney L, Chen M‐L, Davit B, Conner D, Woodcock J, 2015,
Novel Bioequivalence Approach for Narrow Therapeutic Index Drugs, Clinical Pharmacology & Therapeutics,
97(3):286-291.
14
Adkin, D.A., Davis, S.S., Sparrow, R.A., Huckle, P.D., Phillips, A.J., Wilding, I.R., 1995, The effect of different
concentrations of mannitol in solution on small intestinal transit—implications for drug absorption, Pharm. Res., 12:
393–396.
15
Shah V, Gurbarg M, Noory A, Dighe S, Skelly J, 1992, Influence of Higher Rates of Agitation on Release
Patterns of Immediate-Release Drug Products, J Pharm Sci, 81(6): 500-503.
16
See guidance for industry The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 – Current Good
Manufacturing Practice (CGMP).
4

Contains Nonbinding Recommendations
A.

Basket Method (USP apparatus 1)

•
•
•
•

Stirring rate = 100 RPM
500 mL of 0.1N HCl in aqueous medium
No surfactant in medium
37±0.5°C

B.

Paddle Method (USP apparatus 2)

•
•
•
•

Stirring rate = 50 RPM
500 mL of 0.1N HCl in aqueous medium
No surfactant in medium
37±0.5°C

Although the hydrodynamics of the gastrointestinal tract are complicated and cannot be
reproduced by the USP basket or paddle apparatus, a rotation speed of 100 RPM has been foundto be discriminatory for the basket method. For the paddle method, 50 RPM (or 75 RPM withappropriate justification) can be discriminating while minimizing coning effects seen with lower
stirring rates.15 For the paddle method (USP apparatus 2), it is acceptable to add a few turns of awire helix to ensure that capsule dosage forms are fully immersed in the dissolution bath. The
acid conditions of the media reflect the conditions of the stomach whose volume is estimated at
250 mL when a glass of water is co-ingested with the oral dosage form. This volume is too low
to use with the current basket and paddle apparatus; however, 500 mL of medium is commonlyused and is an appropriate volume of medium for a highly soluble, rapidly dissolving drug
substance. The 500 mL dissolution medium should be an appropriate volume to provide sinkconditions for dissolution of the high soluble drug. Proper justification should be provided if 900
mL volume of the medium is used. Besides the recommended 0.1N HCl in aqueous medium,other dissolution media within the physiological pH range may be acceptable if appropriate
justification is provided.
V.

DISSOLUTION ACCEPTANCE CRITERIA

The drug product dissolution acceptance criterion is based on the high solubility of the drug
substance. If an alternate acceptance criterion is proposed, the sponsor/applicant should provide
additional data to support the proposed acceptance criterion. Additional supportive information
could include appropriate in silico modeling in addition to dissolution performance data. For
immediate release solid oral drug products containing a high solubility drug substance (asdefined herein), the dissolution criterion is Q=80% in 30 minutes.
VI.

POSTAPPROVAL CONSIDERATIONSIn regard to post-approval changes, with respect to the dissolution documentation that is needed
to support the proposed change(s), the recommendations provided in the SUPAC-IR Guidance 17
should be followed.
17

See guidance for industry Immediate Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation.
5