Dissolution Solutions Network

News, Stories and Commentary from the Pharma Lab

PVT

Mechanical

Prednisone

Salicylic Acid

Currently there are no specified calibration intervals in the USP. Several studies are under way to investigate need and effectiveness of the parameters of calibration. Calibration is currently done by verifying 9 physical parameters and testing two types of tablets. Each of which is shown to be very sensitive to out of specification parameters, defects, or irregularities. This is expected to change very soon. Keep in touch for upcoming modifications to the PVT.

Several proposed changes in calibration or being investigated, such as defining time of calibration, increasing mechanical calibration, quantifying mechanical calibrations, and decreasing chemical calibrations. There are many differing opinions as to changes in dissolution calibration. I find that the chemical calibrator tablets provide me with a wealth of information that the mechanical calibration can not even quantify.

Problem areas

Weaknesses of Paddle Method

  • Problems with floating dosage units products.
  • Use of spiral for holding capsules is subject to variability with operators.
  • The phenomenon of cone formation that results from nondispersion of disintegrated tablets can lead to nonreproducibility of test.

Weaknesses of Basket Method

  • Poor mechanical stability.
  • Hindered visual inspection.
  • Disintegration-dissolution interaction (slower disintegration keeps the dosage unit in a site of higher agitation, thus increasing dissolution).
  • Poor homogeneity of the bulk fluid due to insufficient stirring or agitation.
  • Sensitivity against external vibration, eccentricity, and the presence of baffles such as thermometer or sampling tube.
  • Inconvenience for cleaning the set-up after testing.

Drug Information Journal, Vol. 30, pp. 1045?1054, 1996 0092-8615/96

Calibration Troubleshooting Tips

There are many factors that will cause a dissolution analysis to give incorrect or errant results. Most dissolution apparatus will not pass calibration unless all conditions are optimal in the apparatus, the standards, the media, and the calibrator tablets. Therefore, it is possible to narrow down all possible causes of failure to calibrate to only a few conditions.

1. Deaeration of medium

Improper deaeration is the most common problem in dissolution analysis. Heat the media to 41C. Vacuum filter through a 0.45-um filter into a 4 liter vacuum flask, stirring with a magnetic stirrer. Continue to draw a vacuum and stir for an additional 5 minutes. When done properly, this process will eliminate almost all dissolution problems. Media should be deaerated immediately before use. Gently transfer the medium directly to the vessel. Do not introduce air into the medium. Reaeration occurs within 30 minutes. However, excess air only occurs after 20-24 hours.

2. Vibration and mechanical problems

Vibration of the system while appearing insignificant can affect such factors as shaft perpendicularity, head coplanarity, and tension on the drive belt, centering and operation condition of the gear plates. To minimize vibration effects, the dissolution equipment should be on a stable bench or table. Other mechanical equipment using fans, pumps or other vibration sources should be removed from the area or isolated in some other way. The Bulldozer effect has been shown to give higher results in prednisone. Trains, air conditioning, pumps can cause vibration,

3. Tablets

The calibrator tablets should be stored in the original containers in a dry place. Avoid excess humidity. Use the tablets immediately on removal from the container. Do not put the tablets out while waiting to start the test.

4. Reference Standard

Use the current lot of USP reference standard and follow any drying instructions on the label.

5. Filtering

Do not centrifuge sample. A separate clean dry filter should be use for each sample and the standard.

Here are the results of some past variability studies done on excess in dissolution on calibrator tablets.

Variable

Maximum Allowable*

Effects of excess

Method of control

Wobble

1.0 mm

(4-6%)

replace shafts

Vibration

0.1 mil. displacement @ vessel

5-10%

Eliminate source

Alignment

1.5Degr. to perpendicular

2-25%

Adjust alignment

Centering

2mm

(2-13%)

Adjust centering

Agitation Rate

4%

Linear

belts, gears

Dissolved Gas

Deaerated

+/-50%

deaerate media

Media pH

varies (usually +/-0.05pH)

10%

check buffers, pH meter

Evaporation

none

Linear

use evaporation covers

Temperature

+/-0.5C

Linear

Monitor temperature

Flow

no interference

?

remove resident probes

*Not all of these are compendial requirements.
Reference: Hanson’s Handbook of Dissolution testing: 2nd edition
Pharmacopeial Forum: Volume 20, Number 6

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