The following questions have been submitted by readers of Dissolution Technologies. Tahseen Mirza, Ph.D.*, United States Pharmacopeia, authored the reponses to each of the questions.

Q We have been consistently getting low results for USP Prednisone calibrator tablets (Lot M) using Paddles @ 50rpm. The average % release is usually 32%. The results range from 29% to 34%, which are at the low end of the acceptance range of 28% to 42%. Sometimes one or two values are slightly below the lower limit of 28%, thus failing the test. Can you suggest the reasons for low results in case of Prednisone calibrator tablets?

A Low results for USP Prednisone Tablets (Dissolution Calibrator, Disintegrating, Lot M) may be attributed to the following causes:
· Adsorption of the drug on to the dissolution vessel
· Adsorption of the drug on to the filter paper
· Improper degassing
· Improper paddle height adjustment or centering
· Systematic error such as calculation error, error in standard preparation etc.

To solve this problem of low Prednisone results, I recommend the following remedies:
· Clean the dissolution vessels thoroughly- concentrated acid, methanol, soap and de-ionized water
· Make sure that the vessel walls are not scratched
· Conduct a filtration study to determine if there is adsorption on the filter membrane
· Use the degassing procedure described in the USP, do not let the medium sit too long prior to dropping the tablets and do not stir the paddles to accelerate temperature equilibration
· Check the paddle height and centering before and after the test
· Check calculations and make sure that the standard is being prepared properly

Degassing: The Lot M Prednisone calibrator tablets are extremely sensitive to the amount of dissolved gases in the medium. Helium degassing is known to cause failures for Prednisone calibrator tablets. We recommend that you use USP degassing technique that is described in the USP General Chapter <711>. Our laboratory has demonstrated that the amount of Prednisone release has almost a linear relationship with the amount of dissolved gases. Therefore, it is quite possible that if you use a degassing technique, which results in the amount of dissolved gases at lower end of the curve, you may get results lower than the acceptance ranges.

In our laboratory, slightly lower than 100-millibar vacuum is applied during the filtration of the medium and once filtration is over, it is left under 50 to 60-millibar vacuum for additional five minutes. At approximately 60 millibar, you can clearly observe the dissolved gases escaping out of the medium. Please do not degas for more than five minutes. We get results right in the middle of the acceptance ranges by using the procedure described above.
Note: Remember the dissolution volume is 500 mL for this lot of tablets and not 900 mL as was the case in previous lots. Check to make sure that you are using 500 mL and not 900 mL in your calculations.

Q In our recent calibration of dissolution apparatus using Salicylic Acid Calibrator Tablets, Lot N, we had failing results in two vessels. Upon investigation we found out that the tablets were taken from a bottle that was opened more than year ago. We got passing results when tablets from a fresh bottle were used. My question is, even though the tablets are from the current lot, how long are the tablets stable after opening the bottle? Is there an expiration date for opened bottles?

A TheUSP Salicylic Acid Tablets (Dissolution Calibrator, Non-disintegrating, Lot N) contain only salicylic acid. The tablets are manufactured using a very simple process and do not contain any excipients. Salicylic acid sublimes out of the tablets when stored under hot and humid conditions. When the bottles are improperly stored, you can find the salicylic acid residue on the tablets and on the inside walls of the bottle. If stored properly in a desiccant at room temperature, the sublimation process can be contained to an acceptable level. I do not have data to suggest an expiration period after the opening of the bottle. I am not aware of any stability studies that have been conducted specifically using opened bottles. All stability studies are conducted with closed bottles only. Therefore, I suggest that you store the opened bottles in a desiccant at room temperature or use only fresh bottles.

Q Do you have a procedure for calibration of a dissolution unit with 3-L capacity vessels?

A It is important for me to point out that the 3-L dissolution vessels are not officially recognized by the USP. In the Dissolution General Chapter <711>, only 1-, 2- and 4-L vessels are recognized and their detailed dimensions are given. Therefore, I cannot support the use of 3-L dissolution vessels. If possible, try to use the 2- or 4-L vessels. Another point that needs clarification is that the calibrator tablets are designed to test the entire system that comprises of the analyst, apparatus and the analytical instrument /procedure. The vessels are a component of the apparatus and hence a part of the system. When the system passes the test, it is an assurance that all the components including the vessels are in working condition. The Dissolution Apparatus is calibrated using only 1-L flasks. It is not necessary to repeat the calibration with the larger volume vessels. If you must use 3-L vessels and cannot use the other USP recognized vessels; you can apply a similar approach and calibrate the Apparatus with 1-L flasks. However, you have to bear in mind that it is your responsibility to justify the use of the non-USP compliant vessels.

Q Is there a USP Dissolution test for beta-Carotene? If not, is USP planning on coming up with a Dissolution standard in future?

AThe current USP 24/NF 19 does not have Dissolution standards for oil-soluble vitamins. Only Disintegration as described in USP General Chapter <2040> is necessary to demonstrate the release of the vitamins from the dosage form. In the future, USP may consider Dissolution requirements for oil-soluble vitamins. A new USP subcommittee (Bioavailability and Nutrient Absorption) was recently formed and will be responsible for dealing with this issue. Please check the Pharmacopeial Forum regularly to find out what actions, if any, the subcommittee will be taking on this issue.

*Note: These are opinions and interpretations of the author, Tahseen Mirza, Ph.D., and are not necessarily the official viewpoints of the USP.

Answers provided by: Tahseen Mirza, Ph.D., M.B.A.
Pharmaceutics Section Leader
USP Research and Development Laboratory and
Liaison to the USP Subcommittee on
Dissolution and Bioavailability