Question and Answer Section — February 2015

William Brown and Margareth Marques
The following questions have been submitted by readers of Dissolution Technologies. Margareth Marques, Ph. D. and Will Brown, United States Phamacopeia, authored responses to each of the questions.
*Note: These are opinions and interpretations of the authors, and are not necessarily the official viewpoints of the USP

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Q How should repeatability and intermediate precision be evaluated for dissolution procedures? In the case of repeatability, should I evaluate if my sample is meeting the acceptance criteria or should I calculate the relative standard deviation between the samples? In the case of intermediate precision, should the variability between the analysts be not more than 5%?

Repeatability is evaluated by calculating the relative standard deviation of multiple determinations by the same analyst. It has no relationship with the samples meeting the acceptance criteria. Intermediate precision is evaluated using at least two analysts, running the dissolution profiles in different days, using different equipment, if possible. The results will be evaluated using an appropriate statistical test, and the acceptance criteria may be product specific. See more information in the USP General Chapter <1092> The Dissolution Procedure: Development and Validation, published in Pharmacopeial Forum 40(1) (available free of charge at ) that will be official in the First Supplement of USP 38.

Q We are developing a new dissolution procedure for a fixed combination product. We determined the solubility of both active substances in the physiological pH range, and we selected 0.001 M HCl as the most appropriate dissolution medium. When we started running the dissolution test, we found that there is a big change in pH during the test. Initially the pH is around 3.0, and after the dissolution test it reaches pH 7.4. Is there an acceptable range for pH change during dissolution testing?

You need to determine the solubility of both drug substances in dissolution media with a pH at and around 7.4. As the formulation disintegrates and the components solubilize, the dissolution medium may reach a pH value where the drug substance has low solubility. Why was the 0.001 M HCl medium chosen? One liter of that medium will only have 0.001 equivalent of acid. For a basic drug, that acts as a strong base; assuming a molecular weight of 300, the acid would be neutralized by the dissolution of only 0.3 mg in a liter. To solve or minimize this problem, you need to increase the buffering capacity of the dissolution medium or switch to a pH range where the reaction of the drug is not an issue as far as adversely affecting dissolution. This assessment needs to be done in a case-by-case approach as each formulation will behave in a different way in any one dissolution medium.

Q We have a dissolution procedure for a product in gelatin capsules where the dissolution medium is 900 mL of pH 7.5 buffer containing 2% of Triton X100. How should we proceed in the case of crosslinking in the gelatin capsules? Should we use 450 mL of the medium with pancreatin and then 450 mL with the surfactant? Should we prepare the first 450 mL with 3500 units of pancreatin to have 1750 units when we add the medium containing the surfactant?

As surfactants may inhibit or degrade the enzyme, it is advisable to do a pretreatment of the cross-linked capsules with exactly the same dissolution medium stated in the method without the surfactant and with the enzyme. It needs to be a smaller volume of medium than the one specified in the dissolution procedure because at the end of the pretreatment period, you will add the medium containing the surfactant in such a concentration that when mixed with the medium already in the vessel you reach the surfactant concentration specified in the procedure. The enzyme is added only to the pretreatment step medium in the concentration prescribed in the USP General Chapter <711> Dissolution. The volume for the pretreatment step needs to be determined in a case-bycase approach. The recommended time period for the pretreatment step is not more than 15 min. This time is included in the total time of the test. If the time specified in the dissolution procedure is 30 min and you use 15 min in the pretreatment step, you have only 15 min more with the medium containing surfactant. See more details in the revision to the USP General Chapter <711> Dissolution published in Pharmacopeial Forum 40(6) (available free of charge at and in the paper “Use of Enzymes in the Dissolution Testing of Gelatin Capsules and Gelatin-Coated Tablets-Revisions to Dissolution <711> and Disintegration and Dissolution of Dietary Supplements <2040>” published in Dissolution Technol. 21(4).

Q We would like to know the correct way of evaluating the stability of a drug substance in the dissolution medium during the development of the dissolution procedure.

Most labs prepare the solution of the drug substance in dissolution medium and quantify the active ingredient as soon as the solution is prepared. Then, they store it at room temperature (and at any other appropriate temperature) and perform the quantitative determination over a period of time, such as over 24 h. Ideally the stability should allow for completion of the analysis of the samples. Information on the expiration date of any solutions should be included in the final version of the dissolution procedure.

Q What is the maximum acceptable relative standard deviation in the evaluation of intermediate precision in the validation of dissolution procedures?

There are no commonly agreed limits for the immediate precision of dissolution procedures. The variability has at least two components coming from the manufacturing process and from the dissolution procedure. Consequently, the variability you will see when running the dissolution test will be different for each product. USP General Chapter <1092> gives advice on ruggedness for the dissolution procedure. You need to try to reduce any variability from the analytical procedure as much as you can. When the variability of product dissolution is high, a review of the manufacturing process may be appropriate.

Q During dissolution testing for extended-release tablets, many times the tablets tend to stick to the vessel wall. Can appropriate sinkers be used in the case of tablets that tend to stick to the vessel?

Yes, sinkers are an option if the tablet sticks to the vessel walls. The choice of sinker design is determined by the product being tested. You need to select the sinker type that is the most appropriate for your formulation.

Q We are developing a dissolution procedure for a depot formulation. It is an extended-release injectable suspension in three different strengths prefilled in syringes. Can we perform the dissolution test as for a cream or gel formulation where a specified quantity of the sample is weighed and transferred to the dissolution vessel or should we transfer the complete contents of one syringe to each vessel?

You need to transfer to the apparatus an amount of product equivalent to the highest dose that can be administered at one time. You will need to verify the best way to transfer the dose to the equipment and decide if it should be by volume or by weight. Also, depending on the equipment you are using, you need to evaluate the most appropriate way of introducing the sample in the equipment. It is not advisable to use the procedure recommended for semisolid dosage forms because in most cases they do not have a prescribed dose, whereas your product has.

Q Our team is validating an in-house dissolution method, and as part of the validation, we need to perform a method comparison with Dissolution Test 2 in the USP monograph. This test uses an autosampler that is kept at 5 °C. As we do not have this equipment, can we perform the test at room temperature?

Although you may have other reasons for doing so, you may not need to determine equivalence of your inhouse dissolution procedure with the procedure in the USP monograph. You need to demonstrate that your in-house method is discriminative to the critical quality attributes of your product and that the USP procedure is not suitable for your formulation. You will also need to do a complete validation of your dissolution procedure. See the draft FDA Guidance for Industry—Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA, available at ucm377465.pdf.

Q What is the acceptable variability for the release results during stability studies for a semisolid formulation?

There is no official range or limit for this variability. The test conditions and equipment used in the drug release testing for semisolid dosage forms are not yet well standardized. Also, the results are sensitive to intermediate precision factors. If the test conditions are not well controlled and if the analyst is not well trained, the repeatability standard deviation can be as high as 35%. See the USP General Chapter <1724> Semisolid Drug Products—Performance Tests. There are several papers published that discuss the issues associated with this test and how to minimize the test variability.

Q What are the statistical evaluations that should be done when validating linearity for a dissolution procedure? Can I evaluate only the correlation coefficient and the sum of residuals?

Simple linear regression analysis will generate a correlation coefficient and the y-intercept. See the revision to the USP General Chapter <1092> The Dissolution Procedure: Development and Validation published in Pharmacopeial Forum 40(1) that will be official in the First Supplement of USP 39.

Q Can I apply the same dissolution parameters and media used for dissolution of immediaterelease dosage forms to evaluate dissolution of the suppository form containing the same ingredient?

The principles for developing a dissolution test for suppositories are the same as for the dissolution test of any other dosage form. In the case of suppositories with a lipophilic base, the release of the drug will happen only after the dosage form has melted. Depending on the characteristics of the base (hydrophilic or lipophilic) of your suppository, you may need to use a special basket, known as Palmieri basket, or a special cell for USP Apparatus 4 (see USP General Chapter <2040> Disintegration and Dissolution of Dietary Supplements).

Q I think that calcium carbonate tablets when labeled as an antacid are subject to the dissolution requirements in the USP monograph. However, it is unclear to me if the requirement applies to both chewable and swallowable tablets. Does the dissolution requirement apply to chewable calcium carbonate tablets?

Chewable tablets in general require a dissolution test, regardless if they are a new product, generic product, dietary supplement, or OTC. The dissolution test has the same conditions and requirements as for any immediate-release tablets and is done with the intact tablet. The test needs to be developed in conjunction with the formulation group because sometimes the tablet is so hard that it does not readily disintegrate. You can find more information at and at the FDA database for dissolution methods.

The USP monograph for Calcium Carbonate Tablets was developed several years ago when dissolution tests were not required for this type of dosage form. Therefore, the product that originated the USP monograph was approved without a dissolution test. This is the reason for not having a dissolution test for this specific tablet. If a new version of this product is approved by FDA with a dissolution test, the test can be included in the USP monograph.

Q We are developing a dissolution test for extended-release tablets, and we would like to know if there is any FDA guidance that says how many time points need to be in the acceptance criteria. At how many timepoints should the amount released be determined during the dissolution test of this type of dosage form? How can the acceptance criteria be defined?

See the FDA Guidance for Industry—Extended Release Oral Dosage Forms: Development, Evaluation, and Applications of In Vitro/In Vivo Correlations available at ucm070239.pdf. This guidance recommends a minimum of three time points. These time points should cover the early, middle, and late stages of the dissolution profile. Most companies select four to five time points to better control the product. This guidance also gives some recommendations on how to define the acceptance criteria for this type of dosage form. Please keep in mind that you need to evaluate the dissolution profiles of all samples tested during product development, samples that were submitted to any in vivo evaluation (even when the results were not good), and samples under stability studies.

Q When should sink conditions be evaluated or defined? Which is the ideal sink condition for a tablet containing 100 mg of a drug substance?

Solubility is essential information in dissolution testing. Sink conditions are defined as not more than 1/3 of the saturation concentration for the dose dissolved in the volume of dissolution medium. In the example using 900 mL, the solubility should be greater than 0.33 mg/mL.

Q We performed a dissolution profile with sampling at 5, 10, 15, 30, and 60 min. At 60 min the release was 94% of the product label claim. After that, we did an evaluation of dissolution at the infinity point, setting the agitation to 150 rpm and collecting the sample after 60 min for a total time 120 min. The amount released at the infinity point was 102%. Is there any acceptance criterion for the infinity point? Is this difference of 8% acceptable?

Dissolution at infinity point is used just to give you an idea about the total amount of drug present in the dosage form. The aggressive stirring is intended to dissolve any drug remaining after the first 60 min of test. Therefore, you should not be surprised to find a difference in the amount recovered.