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Measure and carefully introduce dissolution media to the vessel.
Have materials ready for the test including all sampling equipment.
The Dissolution Test
Allow media in each vessel to reach 37 °C ± 0.5 °C and use immediately.
The Dissolution Test
Always handle dosage units with gloves (not cotton), forceps or tweezers which will not scratch or damage the surface of the dosage unit.
Examine the six dosage units. Do not use chipped, cracked or capped tablets
The Dissolution Test
Option: Record the dosage unit weights? Weight is for information and investigation purposes only.
Dosage units are to be chosen at random and may not be selected or discarded based on weight.
The Dissolution Test
Have analyst notebook or dissolution worksheets for recording information. All information must be recorded directly into analyst notebooks or official batch record worksheets.
The Dissolution Test
Prepare to drop tablets. Lower paddles to proper height, or suspend baskets until ready to begin the test.
Note: Apparatus 1 baskets should be tested immediately after placing the tablet inside and clipping to the shaft. Exposure to humidity can alter test results.
For the paddle apparatus, drop the dosage units into non-rotating medium. They must settle to the bottom of the vessel before rotation of the shaft
begins. Then start rotation.
Visually inspect the dosage forms for air bubbles immediately after dropping.
For the basket apparatus, lower the baskets into non-rotating medium.
When at the correct height, immediately start rotation.
Record any unusual observations.
The Dissolution Test
Most immediate release tablets disintegrate very rapidly and will reaggregate in the form of a cone on the bottom of the vessel.
As the active drug goes into solution during the dissolution process, some excipient material may be visible on the bottom of the vessel at the end of the test.
The Dissolution Test
Withdraw sample at the proper time ± 2% (a 30 minute sample must be pulled within ± 36 seconds) and filter immediately.
Temperature must be taken a second time at least, generally after the last sample is pulled and before the shaft has stopped
The samples are withdrawn at a depth halfway between the top of the paddle (or basket) and the top of the medium and not less than 1cm from the wall of the vessel.
The Dissolution Test The Dissolution Test
Filtration stops the dissolution process and defines the end of the first phase of the test which is basically a sample preparation period executed under strictly controlled physical parameters.
•Within 5 minutes of withdrawing the acid stage sample aliquots, add 250 mL of 0.20-M tribasic sodium phosphate, adjusting to pH + 0.05 at 37 °C while stirring at the specified rate.
•Dissolution continues for 0.75 h (or per monograph) or less.
•Sample aliquots are then analyzed with Q being the total % dissolved for both acid and buffer stages.
Delayed Release Forms - Buffer Stage Acceptance Table USP <711>
Stage Number Tested
Acceptance Criteria
B1 6 Each unit is ≥ Q + 5%.
B2 6 Average of 12 units (B1 + B2) is ≥ Q and no unit is < Q – 15%.
B3 12 Average of 24 units (B1 + B2 + B3) is ≥Q, not more than 2 units are < Q –
15% and no single unit is less than Q –
25%.
If a sample fails either Stage B1 or B2, proceed to the next stage
and test the number of units indicated.
Delayed Release Forms – Acid StageUSP <711>
•USP Delayed Release Dosage Forms – Method B:
•Media is 1000 mL of 0.1N HCl
•Samples are removed for analysis after 2 hours ± 2%.
Delayed Release Forms – Buffer StageUSP <711>
•USP Delayed Release Dosage Forms – Method B:
•Drain the acid from the original vessel and replace with
1000mL pH6.8 phosphate buffer pre equilibrated at 37°C
•or switch the dosage form to a second vessel containing the
phosphate buffer
USP APPARATUS 3 AND 4FLOW-THROUGH APPARATUS
USP Apparatus 3 & 4
USP Apparatus 3 & 4 are now found in USP General Chapter <711> Dissolution
USP Apparatus 3 is called the Reciprocating Cylinder Apparatus
Initially designed for poorly soluble extended release compounds
Typical flow rates from 4 mL per minute up to 16 mL per minute
A closed system with a small media reservoir could reduce volume to 100 mL
Extended release tablets, beads, suppositories and implants
USP Apparatus 4
General Apparatus Description
With a flow through system the specimen is placed in a small column which is continuously flushed with a stream of fluid, simultaneously providing the medium and the mechanical agitation for dissolution of the drug substance.
USP Apparatus 4 can be run as an open or closed system. The open system provides a large volume of multiple solvents as needed.
USP Apparatus 4
Current Physical Parameters and Tolerances
Temperature 37 ± 0.5 °C
Pump rate 240 - 960 mL/hour
Std flow rates 4,8,16 mL/minute
Flow rate accuracy ± 5%
Pulsation 120 ± 10 pulses/min
Cell Diameters 12 and 22.6mm
USP APPARATUS 5, 6, AND 7PADDLE OVER DISK, ROTATING CYLINDER, RECIPROCATING HOLDER
USP Apparatus 5, 6 and 7
These apparatus are primarily used for the analysis of transdermal systems and are decscribed in the USP general chapter <724> Drug Release.
The transdermal systems are typically run at 32 °C, similar to the temperature of the skin.
Transdermal Delivery
Prior to the 1980s, the skin was seldom regarded as a suitable route for administration of drugs to systemic circulation.
However, the transdermal route offered several potential advantages for the systemic delivery of drugs.
Drugs with narrow therapeutic indices can be good candidates for transdermal route because of the absence of the peak and valley feature
common to conventional oral dosage forms.
Transdermal systems provide controlled blood levels of potent drugs.
Transdermal Delivery
Lastly, because of its noninvasive delivery, transdermal patches may be removed easily if toxicity or side effects begin to appear, an advantage over
both the oral and the parenteral routes.
Transdermal Advantages
The employment of the skin as a portal of drug entry into the systemic circulation provides a convenient route for the sustained administration of
a premeasured amount of drug.
Because of the long-acting feature, the patient is always protected,
especially during sleep.
Transdermal Advantages
Because the drug reaches the blood circulation directly, it does not have to travel through the gastrointestinal tract, where it can degrade, suffer from
poor absorption or cause distress.
Drugs avoid the first pass effect, common to the oral route, where some
drugs are metabolized partially by the liver before reaching systemic
circulation.
USP APPARATUS 5PADDLE OVER DISK
USP Apparatus 5
The apparatus is used as described under <711> Dissolution apparatus 2 paddle with the exception of a stainless steel disk holder placed in the bottom
of the vessel.
The transdermal patch is attached to a disk, composed of a stainless steel
support screen, metal ring and Teflon ring.
This system ensures that the release surface of the system is as flat as
Timepoints ± 2% or ± 15 minutes of specified time (lesser)
USP APPARATUS 6ROTATING CYLINDER
USP Apparatus 6
Use the vessel assembly from Apparatus 1 and 2 as described under <711> Dissolution, except to replace the shaft with a stainless steel cylinder stirring
element and to maintain the temperature at 32 ± 0.5°C.
USP Apparatus 6
The dosage unit is placed on the cylinder at the beginning of each test.
The distance between the inside bottom of the vessel and the cylinder is maintained at 25 ± 2 mm during the test.
Press the Cuprophan covering to remove trapped air bubbles.
Place the cylinder in the dissolution apparatus, lower into
the media and immediately rotate
at the specified speed.
USP APPARATUS 7RECIPROCATING CYLINDER
USP Apparatus 7
Also known as the “Alza apparatus” USP apparatus 7 has evolved to handle not only transdermal apparatus but other sustained release products.
The apparatus utilizes sets of volumetrically or gravimetrically calibrated tubes and a mechanical device capable of reciprocating the specific holders
vertically in the tubes containing dissolution medium.
Compendial Dissolution Apparatus
USP <724> Apparatus 7
• Typical 40 mL – 50 mL
• Operational minimum around 25 mL
• Modifications have been made to accommodate 300 mL vessels
• Extended release tablets, capsules,
beads, implants, transdermals, osmotic pumps, and other novel
MODIFICATION OF USP APPARATUS 7 FOR DRUG ELUTING STENTS
What is a Stent
A stent is a wire metal mesh tube used to prop open an artery during angioplasty.
The stent is collapsed to a small diameter on a balloon catheter. It is then moved into the area of blockage, When the balloon is inflated, the stent expands, locks in place as a scaffold. This holds the artery open.
The stent stays in the artery permanently, holds it open, improves the blood flow and relieves the symptoms
Angioplasty
A tiny balloon that presses the plaque blockage against the artery so that
blood may flow more freely through
the vessel
Stenting
A stent is inserted into an artery after angioplasty to help ensure that blood continues to flow freely through the vessel and to reduce the chance that plaque will block the artery again.
Development of Coated and Drug-Eluting Stents
Physicians and companies began testing a variety of drugs that were
known to interrupt the biological
processes that caused restenosis. Stents were coated with these drugs,
sometimes imbedded in a thin
polymer for time-release, and clinical trials were begun.
Case StudyDrug Eluting Stents
• Initially, most drug eluting stent manufacturers utilized a rocking “incubator,” shaker tables or USP Apparatus 4 or 7 as their instruments of choice.
• Modifications to App 7 allowed smaller volumes and automated sampling.
• Custom holders had been designed for various stents and other medical devices.