Question and Answer Section - August 2012

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

Email for correspondence: web@usp.org

Q We have a product that is a suspension with two active substances, one of which has high solubility in water. For the manufacturing of this product, a solution of the highly soluble drug is prepared first, and then the poorly soluble active is added followed by all the other excipients, resulting in a suspension. Is it necessary to develop a dissolution test for both active substances or only for the poorly soluble one?
A You will need to verify experimentally how the highly soluble drug substance is affected by the formulation by do-ing a dissolution profile along with the other drug substance. Depending on the behavior of the two active substances in the dissolution test, you will decide if you are going to control the dissolution of both of them or only the poorly soluble one.

Q We are running the dissolution test for an ex-tended-release tablet, and the acceptance criteria at the first time point is not more than 25% of the drug substance dissolved. How should the level L2 from Acceptance Table 2 in the USP General Chapter <711> Dissolution be applied for this time point?
A To apply the levels L2 and L3 of the Acceptance Table 2, you need a range. In the case of the example mentioned, the range will be 0—25%. For the level L2, the new range will be from (0% of the label claim minus 10% of the label claim) to (25% of the label claim plus 10% of the label claim) resulting in a new range of -10—35%. As dissolution results cannot be negative, the new acceptance criterion will be from 0% to 35% of the label claim. The same logic should be applied to the other time points and to level L3.

Q Are there any guidelines on the use of peak vessels?
A Peak vessels are not described in the dissolution general chapter in part because their geometry has not been stan-dardized. They can only be used with appropriate justifica-tion. One commonly used justification is the elimination of variability due to the formation of a cone of sediment at the bottom of the vessel during paddle dissolution testing. In most cases, the problem of formation of a cone of material at the bottom of the vessel can be eliminated or reduced by increasing the speed of the paddle. If peak vessels are going to be used, it is necessary to demonstrate that they bring an advantage to the method that cannot be achieved with the standard apparatus. In the USP, there are only two mono-graphs where peak vessels are used, Galantamine Tablets, Dissolution Test 3, and Praziquantel Tablets, veterinary use.

Q What are the differences and advantages of USP Apparatus 3 and USP Apparatus 4?
A Apparatus 3 provides a high turbulence that may be useful with dosage forms such as liquid-filled capsules with lipophilic filling. It has a limitation that not more than 250 mL of dissolution medium can be used in each tube, but allows testing over six tubes. The medium can be modified in each tube. If testing in multiple tubes is done, the dosage form should be contained within the mesh at the bottom. For this reason, granules, pellets, and matrix or layered tablets are typical samples.

Apparatus 4 allows a broad range of volumes. In the closed-loop configuration, a minimal amount of medium can be used. The open-loop configuration allows the use of an unlimited volume of fresh medium. With modern pumps, flows from 1 to 2 mL/min to as much as 50 mL/min can be achieved. By switching reservoirs, the medium composition can be changed. The large volume available in the open-loop configuration makes this apparatus useful in testing extend-ed-release implants or products with poorly soluble drugs.

Q The regulatory agency asked our company to develop a dissolution test for a product that contains an active substance that is nearly insoluble in water. It has local action on the GI and negligible systemic availability. Why should a dissolution method be developed? How should a dissolution method be developed for this kind of product?
A The drug will likely have to be in solution to provide pharmacological action even though it is not absorbed into the systemic circulation. That being the case, it should have some solubility within the physiologic pH range, roughly pH 1—7.6. Start by evaluating the solubility over that range. From that data, you might discover a possible dissolution medium. The use of basket or paddle apparatus and 900—1000 mL are typical and would be a good starting point. If dissolution at a reasonable level cannot be achieved, then it is possible that the addition of a surfactant to the medium may be needed. Some drugs rely on naturally occurring surfactants to dissolve in the GI tract. At the end of the process with dissolution data in hand, you will still need to justify the conditions chosen. Some level of physiological relevance as well as discriminatory power are important aspects of a dissolu-tion method.

Q One compendial monograph has a dissolution test with a tolerance of NLT 75% (Q) of the label claim dissolved in a certain time. However, in USP General Chapter <711> Dissolution, the acceptance criterion is Q + 5%. Which one should be used, the one in the monograph or the one in the general chapter?
A In dissolution tests found in USPmonographs, the tolerances are typically presented in the format ìnot less than X% (Q)î. The Qvalue is a variable that is substituted into the acceptance criterion given in Acceptance Table 1. Acceptance Table 1 allows the test to stop after the first stage (six units tested) if all results are not less than Qplus 5%. In your example, that would be 80%. However, for the later stages of the test, the average of the units tested must not be less than Q.

Q We are developing a new product that contains an active substance in the hydrochloride form that is not soluble and forms a precipitate in basic pH. We are conducting some evaluations using fasted-state simulated intestinal fluid (pH 6.5) and fed-state simulated intestinal fluid (pH 5.5), and the drug substance precipitates immediately in both media. Do you have any suggestions?
A The use of dissolution media that simulate biological fluids is a useful tool to gather more information about how the dosage form could perform in vivo. The use of these types of dissolution media is not mandatory and does not have application in routine quality control. The information obtained with dissolution testing using simulated biological fluids should be shared with the formulation development team to help them seek formulation alternatives to prevent or minimize the precipitation that may occur in vivo.

Q Can Acceptance Table 3 from the USP General Chapter <711> Dissolution be used for the in-pro-cess dissolution testing of delayed-release pellets? They are filled into capsules at the clientís facility.
A The USPGeneral Chapter <711> Dissolution is silent on the dissolution testing for in-process controls. The acceptance tables are not product specific. Acceptance Table 3 gives general criteria for acid resistance testing. The instructions stated in the chapter can be adapted for this particular application. Typically, an amount of pellets equivalent to the target capsule contents will be tested.

Q In some disintegration procedures for delayed-release capsules, the use of disks is recommended. We are developing a new disintegration method for this type of dosage form, and we would like to know if we should use disks or if we can use sinkers to prevent the capsules from getting out of the tubes.
A The use of sinkers is not part of disintegration testing. If necessary and with justification, the disks described in the USPGeneral Chapter <701> Disintegration can be used. The description of the setup of the disintegration test, if followed, will prevent the immersion of the tops of the tubes. Therefore, floating capsules should not be able to escape.

Q What are the effects on the results when the dos-age form does not drop to the center of the vessel in the paddle apparatus?
A There is no general answer to this type of question. The hydrodynamics within the paddle apparatus has been described in the literature. Shear is at a minimal level in the region below the tip of the paddle shaft. Experimental results have shown that tablets falling to rest away from the vessel center may have higher dissolution results than tablets at the vessel center. Every attempt should be made to initiate the test in a standard fashion. Therefore, the dosage form should fall to rest at the center of the vessel bottom. Sinkers have been used to facilitate positioning the dosage form at the bottom of the vessel.

Q According to the certificate that accompanies USP Prednisone Tablets RS, if the equipment has fewer than 12 positions, step 1 should be repeated with an additional set of tablets. If dissolution apparatus with six and eight vessels are being evaluated, should the test be carried out with two different sets of tablets?
A The Performance Verification Test (PVT) using USP Prednisone Tablets RS, lot P1, for test assemblies with not more than eight vessel positions can be performed either as a two-stage or a single-stage procedure. The choice of using the single- or two-stage procedure must be made in advance of the test. Both procedures can use as many as 2X tablets, where X is the number of positions. For a six-position test assembly, 2X would be 12 tablets tested. The two-stage procedure allows a stop at only 1X if the criteria are met. For the six-position assembly, that would be after only six tablets are tested (one tablet in each vessel). For the two-stage procedure, if the criteria after stage 1 are not met, six additional tablets are tested.