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Guidance for Industry
Dissolution Testing of Immediate
Release Solid Oral Dosage Forms
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 1997
Guidance for Industry
Dissolution Testing of Immediate
Release Solid Oral Dosage Forms
(Internet) http://www.fda.gov/cder/guidance.htm U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 1997
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 BIOPHARMACEUTICS CLASSIFICATION SYSTEM . . . . . . . . . . . . . . . . . . . . . . . 2 SETTING DISSOLUTION SPECIFICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3A.
Approaches for Setting Dissolution Specifications for a New Chemical Entity . . . 4 Approaches for Setting Dissolution Specifications for Generic Products . . . . . . . 5 Special Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Mapping or Response Surface Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 In Vivo-In Vitro Correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Validation and Verification of Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 DISSOLUTION PROFILE COMPARISONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8A.
Model Independent Approach Using a Similarity Factor . . . . . . . . . . . . . . . . . . . 8 Model Independent Multivariate Confidence Region Procedure . . . . . . . . . . . . 10 Model Dependent Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 DISSOLUTION AND SUPAC-IR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 BIOWAIVERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-1 GUIDANCE FOR INDUSTRY1
Dissolution Testing of Immediate Release
Solid Oral Dosage Forms
INTRODUCTION
This guidance is developed for immediate release (IR) dosage forms and is intended to provide (1) general recommendations for dissolution testing; (2) approaches for setting dissolutionspecifications related to the biopharmaceutic characteristics of the drug substance; (3) statisticalmethods for comparing dissolution profiles; and (4) a process to help determine when dissolutiontesting is sufficient to grant a waiver for an in vivo bioequivalence study. This document alsoprovides recommendations for dissolution tests to help ensure continuous drug product qualityand performance after certain postapproval manufacturing changes. Summary information ondissolution methodology, apparatus, and operating conditions for dissolution testing of IRproducts is provided in summary form in Appendix A. This guidance is intended to complementthe SUPAC - IR guidance for industry: Immediate Release Solid Oral Dosage Forms: Scale-upand Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro DissolutionTesting, and In Vivo Bioequivalence Documentation, with specific reference to the generation ofdissolution profiles for comparative purposes.
BACKGROUND
Drug absorption from a solid dosage form after oral administration depends on the release of thedrug substance from the drug product, the dissolution or solubilization of the drug underphysiological conditions, and the permeability across the gastrointestinal tract. Because of thecritical nature of the first two of these steps, in vitro dissolution may be relevant to the predictionof in vivo performance. Based on this general consideration, in vitro dissolution tests forimmediate release solid oral dosage forms, such as tablets and capsules, are used to (1) assess thelot-to-lot quality of a drug product; (2) guide development of new formulations; This guidance has been prepared by the Immediate Release Expert Working Group of the Biopharmaceutics Coordinating Committee in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. This guidance document represents the Agency’s current thinking on the dissolution testing of immediate release solidoral dosage forms. It does not create or confer any rights for or on any person and does not operate to bind FDA or thepublic. An alternative approach may be used if such approach satisfies the requirements of the applicable statute,regulations, or both.
and (3) ensure continuing product quality and performance after certain changes, such as changesin the formulation, the manufacturing process, the site of manufacture, and the scale-up of themanufacturing process.
Current knowledge about the solubility, permeability, dissolution, and pharmacokinetics of a drugproduct should be considered in defining dissolution test specifications for the drug approvalprocess. This knowledge should also be used to ensure continued equivalence of the product, aswell as to ensure the product's sameness under certain scale-up and postapproval changes. New drug applications (NDAs) submitted to the Food and Drug Administration (FDA) containbioavailability data and in vitro dissolution data, that, together with chemistry, manufacturing, andcontrols (CMC) data, characterize the quality and performance of the drug product. In vitrodissolution data are generally obtained from batches that have been used in pivotal clinical and/orbioavailability studies and from other human studies conducted during product development. Acceptable bioequivalence data and comparable in vitro dissolution and CMC data are requiredfor approval of abbreviated new drug applications (ANDAs) (21 CFR 314.94). The in vitrospecifications for generic products should be established based on a dissolution profile. For newdrug applications, as well as generic drug applications, the dissolution specifications should bebased on acceptable clinical, bioavailability, and/or bioequivalence batches.
Once the specifications are established in an NDA, the dissolution specifications for batch-to-batch quality assurance are published in the United States Pharmacopeia (USP) as compendialstandards, which become the official specifications for all subsequent IR products with the sameactive ingredients. In general, these compendial dissolution standards are single-point dissolutiontests, not profiles.
BIOPHARMACEUTICS CLASSIFICATION SYSTEM
Based on drug solubility and permeability, the following Biopharmaceutics Classification System(BCS) is recommended in the literature (Amidon 1995): High Solubility - High Permeability Drugs This classification can be used as a basis for setting in vitro dissolution specifications and can alsoprovide a basis for predicting the likelihood of achieving a successful in vivo-in vitro correlation(IVIVC). The solubility of a drug is determined by dissolving the highest unit dose of the drug in250 mL of buffer adjusted between pH 1.0 and 8.0. A drug substance is considered highly solublewhen the dose/solubility volume of solution are less than or equal to 250 mL. High-permeabilitydrugs are generally those with an extent of absorption that is greater than 90% in the absence of documented instability in the gastrointestinal tract or those whose permeability has beendetermined experimentally. The BCS suggests that for high solubility, high permeability (case 1)drugs and in some instances for high solubility, low permeability (case 3) drugs, 85% dissolutionin 0.1N HCl in 15 minutes can ensure that the bioavailability of the drug is not limited bydissolution. In these cases, the rate limiting step for drug absorption is gastric emptying. The mean T50% gastric residence (emptying) time is 15-20 minutes under fasting conditions. Based on this information, a conservative conclusion is that a drug product undergoing 85%dissolution in 15 minutes under mild dissolution test conditions in 0.1N HCl behaves like a solution and generally should not have any bioavailability problems. If the dissolution is slowerthan gastric emptying, a dissolution profile with multiple time points in multimedia isrecommended.
In the case of low solubility/high permeability drugs (case 2), drug dissolution may be the ratelimiting step for drug absorption and an IVIVC may be expected. A dissolution profile in multiplemedia is recommended for drug products in this category. In the case of high solubility/lowpermeability drugs (case 3), permeability is the rate controlling step and a limited IVIVC may bepossible, depending on the relative rates of dissolution and intestinal transit. Drugs in case 4 (i.e.,low solubility/low permeability drugs) present significant problems for oral drug delivery.
SETTING DISSOLUTION SPECIFICATIONS
In vitro dissolution specifications are established to ensure batch-to-batch consistency and tosignal potential problems with in vivo bioavailability. For NDAs, the dissolution specificationsshould be based on acceptable clinical, pivotal bioavailability, and/or bioequivalence batches. ForANDAs/AADAs, the dissolution specifications should be based on the performance of acceptablebioequivalence batches of the drug product. The NDA dissolution specifications should be basedon experience gained during the drug development process and the in vitro performance ofappropriate test batches. In the case of a generic drug product, the dissolution specifications aregenerally the same as the reference listed drug (RLD). The specifications are confirmed by testingthe dissolution performance of the generic drug product from an acceptable bioequivalence study. If the dissolution of the generic product is substantially different compared to that of the referencelisted drug and the in vivo data remain acceptable, a different dissolution specification for thegeneric product may be set. Once a dissolution specification is set, the drug product shouldcomply with that specification throughout its shelf life.
The International Conference on Harmonisation (ICH) Q1A guideline (Stability Testing of NewDrug Substances and Drug Products) has recommended that for an NDA, three batches (twopilot and one smaller scale) be placed into stability testing. These batches also may be used to setdissolution specifications when a suitable bioequivalence relationship exists between these batchesand both the pivotal clinical trial batch and the drug product intended for the market.
Three catagories of dissolution test specifications for immediate release drug products aredescribed in the guidance.
As a routine quality control test. (For highly soluble and rapidly dissolving drugproducts.) For characterizing the quality of the drug product.
As a routine quality control test for certain types of drug products (e.g., slow dissolving or poorly water soluble drug product like carbamazepine).
For accepting product sameness under SUPAC-related changes.
To waive bioequivalence requirements for lower strengths of a dosage form.
To support waivers for other bioequivalence requirements.
In the future, a two-time point approach may be useful, both to characterize a drug product andto serve as quality control specification.
Approaches for Setting Dissolution Specifications for a New Chemical Entity
Dissolution methodology and specifications developed by a sponsor are presented in thebiopharmaceutics section (21 CFR 320.24(b)(5)), and the chemistry, manufacturing, andcontrols section (21 CFR 314.50(d)(1)(ii)(a)) of an NDA. The dissolution characteristicsof the drug product should be developed based on consideration of the pH solubilityprofile and pKa of the drug substance. The drug permeability or octanol/water partitioncoefficient measurement may be useful in selecting the dissolution methodology andspecifications. The dissolution specifications are established in consultation withbiopharmaceutics and CMC review staff in the Office of Pharmaceutical Science (OPS). For NDAs, the specifications should be based on the dissolution characteristics of batchesused in pivotal clinical trials and/or in confirmatory bioavailability studies. If theformulation intended for marketing differs significantly from the drug product used inpivotal clinical trials, dissolution and bioequivalence testing between the two formulationsare recommended.
Dissolution testing should be carried out under mild test conditions, basket method at50/100 rpm or paddle method at 50/75 rpm, at 15-minute intervals, to generate adissolution profile. For rapidly dissolving products, generation of an adequate profilesampling at 5- or 10-minute intervals may be necessary. For highly soluble and rapidlydissolving drug products (BCS classes 1 and 3), a single-point dissolution testspecification of NLT 85% (Q=80%) in 60 minutes or less is sufficient as a routine qualitycontrol test for batch-to-batch uniformity. For slowly dissolving or poorly water solubledrugs (BCS class 2), a two-point dissolution specification, one at 15 minutes to include adissolution range (a dissolution window) and the other at a later point (30, 45, or 60minutes) to ensure 85% dissolution, is recommended to characterize the quality of theproduct. The product is expected to comply with dissolution specifications throughout itsshelf life. If the dissolution characteristics of the drug product change with time, whetheror not the specifications should be altered will depend on demonstrating bioequivalence ofthe changed product to the original biobatch or pivotal batch. To ensure continuousbatch-to-batch equivalence of the product after scale-up and postapproval changes in themarketplace, dissolution profiles should remain comparable to those of the approvedbiobatch or pivotal clinical trial batch(es). Approaches for Setting Dissolution Specifications for Generic Products
The approaches for setting dissolution specifications for generic products fall into threecategories, depending on whether an official compendial test for the drug product existsand on the nature of the dissolution test employed for the reference listed drug. Allapproved new drug products should meet current USP dissolution test requirements, ifthey exist. The three categories are: USP Drug Product Dissolution Test Available In this instance, the quality control dissolution test is the test described in the USP. The Division of Bioequivalence, Office of Generic Drugs, also recommends takinga dissolution profile at 15-minute intervals or less using the USP method for testand reference products (12 units each). The Division of Bioequivalence may alsorecommend submitting additional dissolution data when scientifically justified. Examples of this include (1) cases in which USP does not specify a dissolution testfor all active drug substances of a combination product and (2) cases in which USPspecifies use of disintegration apparatus.
USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Publicly Available In this instance, a dissolution profile at 15-minute intervals of test and referenceproducts (12 units each) using the method approved for the reference listedproduct is recommended. The Division of Bioequivalence may also request submission of additional dissolution testing data as a condition of approval, whenscientifically justified. USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Not Publicly Available In this instance, comparative dissolution testing using test and reference productsunder a variety of test conditions is recommended. The test conditions mayinclude different dissolution media (pH 1 to 6.8), addition of surfactant, and use ofapparatus 1 and 2 with varying agitation. In all cases, profiles should be generatedas previously recommended. The dissolution specifications are set based on theavailable bioequivalence and other data. Special Cases
For poorly water soluble drug products (e.g., carbamazapine), dissolution testingat more than one time point for routine quality control is recommended to ensurein vivo product performance. Alternatively, a dissolution profile may be used forpurposes of quality control.
To more accurately reflect the physiologic conditions of the gastrointestinal tract,two-tiered dissolution testing in simulated gastric fluid (SGF) with and withoutpepsin or simulated intestinal fluid (SIF) with and without pancreatin may beemployed to assess batch-to-batch product quality provided the bioequivalence ismaintained. Recent examples involving soft and hard gelatin capsules show a decrease in thedissolution profile over time either in SGF or in SIF without enzymes. This hasbeen attributed to pellicle formation. When the dissolution of aged or slowerreleasing capsules was carried out in the presence of an enzyme (pepsin in SGF orpancreatin in SIF), a significant increase in the dissolution was observed. In thissetting, multiple dissolution media may be necessary to adequately assess productquality.
Mapping or Response Surface Methodology
Mapping is defined as a process for determining the relationship between criticalmanufacturing variables (CMV) and a response surface derived from an in vitrodissolution profile and an in vivo bioavailability data set. The CMV include changes in the formulation, process, equipment, materials, and methods for the drug product that cansignificantly affect in vitro dissolution (Skelly 1990, Shah 1992). The goal is to developproduct specifications that will ensure bioequivalence of future batches prepared withinthe limits of acceptable dissolution specifications. Several experimental designs areavailable to study the influence of CMV on product performance. One approach to studyand evaluate the mapping process includes (1) prepare two or more dosage formulationsusing CMV to study their in vitro dissolution characteristics; (2) test the products withfastest and slowest dissolution characteristics along with the standard or the to bemarketed dosage form in small groups (e.g., n> 12) of human subjects; and (3) determinethe bioavailability of the products and in vitro-in vivo relationship. The products withextreme dissolution characteristics are also referred to as side batches (Siewert 1995). Ifthe products with the extreme range of dissolution characteristics are found to bebioequivalent to the standard or the to be marketed dosage form, future batches withdissolution characteristics between these ranges should be equivalent to one another. Thisapproach can be viewed as verifying the limits of the dissolution specifications. Productdissolution specifications established using a mapping approach will provide maximumlikelihood of ensuring stable quality and product performance. Depending on the numberof products evaluated, the mapping study can provide information on in vitro-in vivocorrelations and/or a rank order relationship between in vivo and in vitro data.
In Vivo-In Vitro Correlations
For highly water soluble (BCS classes 1 and 3) immediate release products using currentlyavailable excipients and manufacturing technology, an IVIVC may not be possible. Forpoorly water soluble products, BCS class 2, an IVIVC may be possible.
The value of dissolution as a quality control tool for predicting in vivo performance of adrug product is significantly enhanced if an in vitro-in vivo relationship (correlation orassociation) is established. The in vitro test serves as a tool to distinguish betweenacceptable and unacceptable drug products. Acceptable products are bioequivalent, interms of in vivo performance, whereas unacceptable products are not. To achieve an invitro-in vivo correlation, at least three batches that differ in the in vivo as well as the invitro performance should be available. If the batches show differences in in vivoperformance, then in vitro test conditions can be modified to correspond with the in vivodata to achieve an in vitro-in vivo correlation. If no difference is found in the in vivoperformance of the batches and if the in vitro performance is different, it may be possibleto modify test conditions to achieve the same dissolution performance of the batchesstudied in vivo. Very often, the in vitro dissolution test is found to be more sensitive anddiscriminating than the in vivo test. From a quality assurance point of view, a morediscriminative dissolution method is preferred, because the test will indicate possiblechanges in the quality of the product before in vivo performance is affected.
Validation and Verification of Specifications
Confirmation by in vivo studies may be needed for validation of an in vitro system. In thissituation, the same formulation should be used but nonformulation CMV should be varied. Two batches with different in vitro profiles should be prepared (mapping approach). These products should then be tested in vivo. If the two products show different in vivocharacteristics, then the system is validated. In contrast, if there is no difference in the invivo performance, the results can be interpreted as verifying the dissolution specificationlimits as discussed under mapping. Thus, either validation or verification of dissolutionspecifications should be confirmed.
DISSOLUTION PROFILE COMPARISONS
Until recently, single-point dissolution tests and specifications have been employed in evaluatingscale-up and postapproval changes, such as (1) scale-up, (2) manufacturing site changes, (3)component and composition changes, and (4) equipment and process changes. A changedproduct may also be a lower strength of a previously approved drug product. In the presence ofcertain minor changes, the single-point dissolution test may be adequate to ensure unchangedproduct quality and performance. For more major changes, a dissolution profile comparisonperformed under identical conditions for the product before and after the change(s) isrecommended (see SUPAC-IR). Dissolution profiles may be considered similar by virtue of (1)overall profile similarity and (2) similarity at every dissolution sample time point. The dissolutionprofile comparison may be carried out using model independent or model dependent methods.
Model Independent Approach Using a Similarity Factor
A simple model independent approach uses a difference factor (f ) and a similarity factor (f ) to compare dissolution profiles (Moore 1996). The difference factor (f ) calculates the percent (%) difference between the two curves at each time point and is a measurement ofthe relative error between the two curves: where n is the number of time points, R is the dissolution value of the reference (prechange) batch at time t, and T is the dissolution value of the test (postchange) batch The similarity factor (f ) is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolutionbetween the two curves.
A specific procedure to determine difference and similarity factors is as follows: Determine the dissolution profile of two products (12 units each) of the test (postchange) and reference (prechange) products.
Using the mean dissolution values from both curves at each time interval, calculate the difference factor (f ) and similarity factor (f ) using the above For curves to be considered similar, f values should be close to 0, and f values should be close to 100. Generally, f values up to 15 (0-15) and f values greater than 50 (50-100) ensure sameness or equivalence of the two curves and,thus, of the performance of the test (postchange) and reference (prechange)products.
This model independent method is most suitable for dissolution profile comparisonwhen three to four or more dissolution time points are available. As furthersuggestions for the general approach, the following recommendations should alsobe considered: The dissolution measurements of the test and reference batches should bemade under exactly the same conditions. The dissolution time points forboth the profiles should be the same (e.g., 15, 30, 45, 60 minutes). Thereference batch used should be the most recently manufactured prechangeproduct.
Only one measurement should be considered after 85% dissolution of boththe products.
To allow use of mean data, the percent coefficient of variation at the earliertime points (e.g., 15 minutes) should not be more than 20%, and at othertime points should not be more than 10%.
The mean dissolution values for R can be derived either from (1) last prechange (reference) batch or (2) last two or more consecutivelymanufactured prechange batches.
Model Independent Multivariate Confidence Region Procedure
In instances where within batch variation is more than 15% CV, a multivariate modelindependent procedure is more suitable for dissolution profile comparison. The followingsteps are suggested: Determine the similarity limits in terms of multivariate statistical distance (MSD) based on interbatch differences in dissolution from reference(standard approved) batches.
Estimate the MSD between the test and reference mean dissolutions.
Estimate 90% confidence interval of true MSD between test and reference Compare the upper limit of the confidence interval with the similarity limit. The test batch is considered similar to the reference batch if the upper limit of theconfidence interval is less than or equal to the similarity limit.
Model Dependent Approaches
Several mathematical models have been described in the literature to fit dissolutionprofiles. To allow application of these models to comparison of dissolution profiles, thefollowing procedures are suggested: Select the most appropriate model for the dissolution profiles from the standard, prechange, approved batches. A model with no more than threeparameters (such as linear, quadratic, logistic, probit, and Weibull models) isrecommended.
Using data for the profile generated for each unit, fit the data to the most A similarity region is set based on variation of parameters of the fitted model for test units (e.g., capsules or tablets) from the standard approved batches.
Calculate the MSD in model parameters between test and reference Estimate the 90% confidence region of the true difference between the two Compare the limits of the confidence region with the similarity region. If the confidence region is within the limits of the similarity region, the test batch isconsidered to have a similar dissolution profile to the reference batch.
DISSOLUTION AND SUPAC-IR
The SUPAC-IR guidance defines the levels of changes, recommended tests, and filingdocumentation to ensure product quality and performance of reference (prechange product) withpostapproval changes in (1) components and composition, (2) site of manufacturing, (3) the scaleof manufacturing, and (4) process and equipment changes in the manufacturing of immediaterelease products (FDA 1995). Depending on the level of change and the biopharmaceuticsclassification system of the active drug substance, the SUPAC-IR guidance recommends differentlevels of in vitro dissolution test and/or in vivo bioequivalence studies. Tests vary depending ontherapeutic range and solubility and permeability factors of the drug substance. For formulationchanges beyond those listed in the guidance, additional dissolution profile determinations inseveral media are recommended. For manufacturing site changes, scale-up equipment changes,and minor process changes, only dissolution testing should be sufficient to ensure unchangedproduct quality and performance. The SUPAC-IR guidance recommends dissolution profilecomparisons for approving different levels of changes and documenting product samenessbetween the test (postchange) and reference (prechange) product. It recommends dissolutionprofile comparisons using a model independent approach and the similarity factor (f ).
BIOWAIVERS
In addition to routine quality control tests, comparative dissolution tests have been used to waivebioequivalence requirements (biowaivers) for lower strengths of a dosage form. For biowaivers, adissolution profile should be generated and evaluated using one of the methods described underSection V in this guidance, "Dissolution Profile Comparisons." Biowaivers are generally providedfor multiple strengths after approval of a bioequivalence study performed on one strength, usingthe following criteria: For multiple strengths of IR products with linear kinetics, the bioequivalence study may beperformed at the highest strength and waivers of in vivo studies may be granted on lowerstrengths, based on an adequate dissolution test, provided the lower strengths are proportionatelysimilar in composition (21 CFR 320.22(d)(2)). Similar may also be interpreted to mean that thedifferent strengths of the products are within the scope of changes permitted under the category"Components and Composition," discussed in the SUPAC-IR guidance. In all cases, the approvalof additional strengths is based on dissolution profile comparisons between these additionalstrengths and the strength of the batch used in the pivotal bioequivalence study.
Appendix A
Dissolution Testing Conditions
Apparatus
The most commonly employed dissolution test methods are (1) the basket method (Apparatus 1)and (2) the paddle method (Apparatus 2) (Shah 1989). The basket and the paddle methods aresimple, robust, well standardized, and used worldwide. These methods are flexible enough toallow dissolution testing for a variety of drug products. For this reason, the official in vitrodissolution methods described in U.S. Pharmacopeia (USP), Apparatus 1 and Apparatus 2 shouldbe used unless shown to be unsatisfactory. The in vitro dissolution procedures, such as thereciprocating cylinder (Apparatus 3) and a flow-through cell system (Apparatus 4) described inthe USP, may be considered if needed. These methodologies or other alternatives/modificationsshould be considered on the basis of their proven superiority for a particular product. Because ofthe diversity of biological and formulation variables and the evolving nature of understanding inthis area, different experimental modifications may need to be carried out to obtain a suitable invivo correlation with in vitro release data. Dissolution methodologies and apparatus described inthe USP can generally be used either with manual sampling or with automated procedures.
Dissolution Medium
Dissolution testing should be carried out under physiological conditions, if possible. This allowsinterpretation of dissolution data with regard to in vivo performance of the product. However,strict adherence to the gastrointestinal environment need not be used in routine dissolutiontesting. The testing conditions should be based on physicochemical characteristics of the drugsubstance and the environmental conditions the dosage form might be exposed to after oraladministration.
The volume of the dissolution medium is generally 500, 900, or 1000 mL. Sink conditions aredesirable but not mandatory. An aqueous medium with pH range 1.2 to 6.8 (ionic strength ofbuffers the same as in USP) should be used. To simulate intestinal fluid (SIF), a dissolutionmedium of pH 6.8 should be employed. A higher pH should be justified on a case-by-case basisand, in general, should not exceed pH 8.0. To simulate gastric fluid (SGF), a dissolution mediumof pH 1.2 should be employed without enzymes. The need for enzymes in SGF and SIF should beevaluated on a case-by-case basis and should be justified. Recent experience with gelatin capsuleproducts indicates the possible need for enzymes (pepsin with SGF and pancreatin with SIF) todissolve pellicles, if formed, to permit the dissolution of the drug. Use of water as a dissolutionmedium also is discouraged because test conditions such as pH and surface tension can varydepending on the source of water and may change during the dissolution test itself, due to theinfluence of the active and inactive ingredients. For water insoluble or sparingly water solubledrug products, use of a surfactant such as sodium lauryl sulfate is recommended (Shah 1989,1995). The need for and the amount of the surfactant should be justified. Use of a hydroalcoholic medium is discouraged. All dissolution tests for IR dosage forms should be conducted at 37±0.5°C. The basket andpaddle method can be used for performing dissolution tests under multimedia conditions (e.g., theinitial dissolution test can be carried out at pH 1.2, and, after a suitable time interval, a smallamount of buffer can be added to raise pH to 6.8). Alternatively, if addition of an enzyme isdesired, it can be added after initial studies (without enzymes). Use of Apparatus 3 allows easychange of the medium. Apparatus 4 can also be adopted for a change in dissolution mediumduring the dissolution run.
Certain drug products and formulations are sensitive to dissolved air in the dissolution mediumand will need deaeration. In general, capsule dosage forms tend to float during dissolution testingwith the paddle method. In such cases, it is recommended that a few turns of a wire helix (USP)around the capsule be used.
The apparatus suitability tests should be carried out with a performance standard (i.e., calibrators)at least twice a year and after any significant equipment change or movement. However, a changefrom basket to paddle or vice versa may need recalibration. The equipment and dissolutionmethodology should include the product related operating instructions such as deaeration of thedissolution medium and use of a wire helix for capsules. Validation of automated procedurescompared to the manual procedures should be well documented. Validation of determinativesteps in the dissolution testing process should comply with the set standards for analyticalmethodology.
Agitation
In general, mild agitation conditions should be maintained during dissolution testing to allowmaximum discriminating power and to detect products with poor in vivo performance. Using thebasket method, the common agitation (or stirring speed) is 50-100 rpm; with the paddle method,it is 50-75 rpm (Shah et al., 1992). Apparatus 3 and 4 are seldom used to assess the dissolutionof immediate release drug products.
Validation
Validation of the dissolution apparatus/methodology should include (1) the system suitability testusing calibrators; (2) deaeration, if necessary; (3) validation between manual and automatedprocedures; and (4) validation of a determinative step (i.e., analytical methods employed inquantitative analysis of dissolution samples). This should include all appropriate steps andprocedures of analytical methods validation.
REFERENCES
Amidon, G. L., H. Lennernas, V. P. Shah, and J. R. Crison, 1995, "A Theoretical Basis For a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug ProductDissolution and In Vivo Bioavailability," Pharmaceutical Research, 12:413-420.
FDA, 1995, Center for Drug Evaluation and Research, Guidance for Industry: Immediate Release Solid Oral Dosage Forms. Scale-up and Post-Approval Changes: Chemistry,Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo BioequivalenceDocumentation [SUPAC-IR], November 1995.
Meyer, M. C., A. B. Straughn, E. J. Jarvi, G. C. Wood, F. R. Pelsor, and V. P. Shah, 1992, "The Bioequivalence of Carbamazepine Tablets with a History of Clinical Failures,"Pharmaceutical Research, 9:1612-1616.
Moore, J. W. and H. H. Flanner, 1996, "Mathematical Comparison of Dissolution Profiles," Pharmaceutical Technology, 20 (6):64-74.
Shah, V. P., et al., 1989, "In Vitro Dissolution Profile of Water Insoluble Drug Dosage Forms inthe Presence of Surfactants," Pharmaceutical Research, 6:612-618.
Shah, V. P., et al., 1992, "Influence of Higher Rate of Agitation on Release Patterns of ImmediateRelease Drug Products," Journal of Pharmaceutical Science, 81:500-503.
Shah, V. P., J. P. Skelly, W. H. Barr, H. Malinowski, and G. L. Amidon, 1992, "Scale-up of Controlled Release Products - Preliminary Considerations," PharmaceuticalTechnology, 16(5):35-40.
Shah, V. P., et al., 1995, "In Vivo Dissolution of Sparingly Water Soluble Drug Dosage Forms,"International Journal of Pharmaceutics, 125:99-106. Siewert, M., 1995, "FIP Guidelines for Dissolution Testing of Solid Oral Products," Pharm. Skelly, J. P., G. L. Amidon, W. H. Barr, L. Z. Benet, J. E. Carter, J. R. Robinson, V. P. Shah, andA. Yacobi, 1990, "In Vitro and In Vivo Testing and Correlation for Oral Controlled/Modified-Release Dosage Forms," Pharmaceutical Research, 7:975-982.
United States Pharmacopeia (USP), U.S. Pharmacopeial Convention, Inc. Rockville, MD.

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