Agilent Dissolution Seminar Series · Agilent Dissolution Seminar Series © -2013 All Rights Reserved 2 The Dissolution Test Measure and carefully introduce dissolution media to the

Agilent Dissolution Seminar Series

1© - 2013 All Rights Reserved

DISSOLUTION TECHNIQUE

The Dissolution Test

The analyst is responsible for verification of the physical parameters.

Verify that the equipment is clean.


Prepare dissolution media and properly deaerate.

USP Method: Heat media to 41°C, vacuum filter through 0.45µm filter, continue to pull vacuum for 5 additional minutes.


Care must be taken in measuring the dissolution media to maintain the volumetric accuracy at ±1%.

Volumetric accuracy is based on dissolution media measured at room temperature.


Alternatively, dissolution media may be weighed.




Measure and carefully introduce dissolution media to the vessel.

Have materials ready for the test including all sampling equipment.


Allow media in each vessel to reach 37 °C ± 0.5 °C and use immediately.


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


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.


Have analyst notebook or dissolution worksheets for recording information. All information must be recorded directly into analyst notebooks or official batch record worksheets.


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.




Prepare calibrated timer.

Record times as tablets are dropped.


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.


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.


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.




Once the sample has been filtered the second phase of the testing begins to determine the analytical concentration of the sample.

Analytical concentration is generally determined through UV-Vis spectroscopy or HPLC analysis. HPLC is primarily used for drug products

containing multiple active components or for stability testing.

The responses from the analytical finish will be used to calculate the amount

of sample released from the dosage form within the specific time interval.

Calculation

The sample concentration will be calculated against a reference standard of known concentration. The result in % label claim will be compared to

acceptable ranges stated in the dissolution method or monograph.

The following calculation provides results in % label claim (%LC)

100(mg) Claim Label

(mL) Vol. Sample

(mL) Vol. Standard

(mg) Wt.Standard

Abs. Standard

Abs. Sample×××

What is Q?

Q, as it relates to dissolution is commonly used in the USP for immediate release and delayed release dosage forms.

The quantity of Q is the amount of dissolved active ingredient specified in the individual monograph expressed as a percentage of the labeled content.

Immediate Release Forms – Acceptance Table USP <711>

Stage Number Tested Acceptance Criteria

S1 6 Each unit is ≥ Q + 5%.

S2 6 Average of 12 units (S1 + S2) is ≥ Q and no unit is < Q – 15%.

S3 12 Average of 24 units (S1 + S2 + S3) 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 S1 or S2, proceed to the next stage and test

the number of units indicated.

Delayed Release Forms – Acid Stage USP <711>

•USP Delayed Release Dosage Forms – Method A:

•Media is 750 mL of 0.1N HCl

•Samples are removed for analysis after 2 hours ± 2%.

Delayed Release Forms – Acid Stage Acceptance Table USP <711>

Stage Number Tested

Acceptance Criteria

A1 6 No individual value exceeds 10% dissolved.

A2 6 Average of 12 units (A1 + A2) is no more than 10% dissolved and no single

unit is greater than 25% dissolved.

A3 12 Average of 24 units (A1 + A2 + A3) is not more than 10% dissolved and no single

unit is more than 25% dissolved.

If a sample fails either Stage A1 or A2, proceed to the next stage

and test the number of units indicated.



Delayed Release Forms - Buffer Stage

•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

USP Apparatus 4 is called the Flow-Through Cell



USP APPARATUS 3THE RECIPROCATING CYLINDER

USP Apparatus 3

General Apparatus 3 Description

Reciprocating cylinder

Vessels

Current physical parameters

USP calibration requirements

Typical products tested

Non-Compendial variations

USP Apparatus 3


A presentation at the 1980 Federation Internationale Pharmaceutique (FIP)

drew attention to acute problems associated with USP Apparatus 1 and 2 dissolution results. The conference inspired the concept for the USP

Apparatus 3.

USP Apparatus 3


The USP Apparatus 3 (Bio-Dis) is an excellent apparatus for developing

controlled release products because it can quickly and easily expose products to mechanical and physiochemical conditions which may influence

the release of the products in the GI tract.

USP Apparatus 3


The Bio-Dis Extended Release Tester was designed to test the dissolution

rates of extended release products or any dosage form requiring release profiling at multiple pH levels.

The ability to transfer the product from one pH to another makes it an

excellent candidate for delayed release products.

Compendial Dissolution Apparatus

USP <711> Apparatus 3

• 300 mL Vessel

• Normally 200 mL to 275 mL vessel

volume

• Operational minimum – 150 mL

vessel volume

• Extended release tablets, capsules, beads



USP Apparatus 3


The reciprocating cylinder apparatus consists of sets of cylindrical, flat

bottom glass vessels with corresponding sets of reciprocating cylinders.

USP Apparatus 3


A motor and drive assembly reciprocate the cylinders vertically inside the vessels.

The cylinders are allowed to move from row to row to expose the undissolved drug product to various pH levels.

USP Apparatus 3

Reciprocating Cylinders

The reciprocating cylinders are glass tubes fitted with top and bottom caps containing screens designed to contain the product under evaluation.

USP Apparatus 3

Reciprocating Cylinders

As the cylinder reciprocated vertically the drug product is constantly exposed to media contained in the vessel.

USP Apparatus 3

Vessels

This picture shows the Apparatus 3 with automatic sampling.

The last position on each row contains a blank and standard tube to be sampled for automated analysis.



USP Apparatus 3

Current Physical Parameters and Tolerances

Temperature 37 ± 0.5 °C

Dip rate (DPM) ± 5% of set speed

Stroke Distance 10.0 ± 0.1 cm

Bottom screen Per method

Top screen Per method (optional)

Timepoints ± 2% of specified time

USP PVT Chlorpheniramine Maleate – No longer required per USP 2012. USP working to replace the PVT since it is no longer available.

USP Apparatus 3

USP Calibration Requirements

Originally, Apparatus Suitability was demonstrated with USP

Chlorpheniramine Maleate tablets

This test was withdrawn from 1st February 2012

USP APPARATUS 4THE FLOW-THROUGH CELL

USP Apparatus 4

General apparatus description

Flow-through cell

Current physical parameters

Typical products tested

USP Apparatus 4

General Apparatus Description

The flow-through cell was developed for lipophilic solid dosage forms such as

suppositories and soft capsules. It is made up of three transparent parts which fit into each other.

The lower part consists of two adjacent chambers connected to an overflow

device.

USP Apparatus 4


The dissolution media passes into the lower part of the chamber then flows

upward to an exit in the upper chamber which leads to a filter assembly.

The middle part of the cell has a cavity and holder designed to contain the dosage unit.



USP Apparatus 4


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


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


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.


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

possible.



USP Apparatus 5 USP Apparatus 5


Dimensions per USP

Paddle Height 25mm ± 2 mm from disk

Centering ± 2 mm center line

Speed ± 4% of set speed

Vessel Temp. 32 ± 0.5°C

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.

USP Apparatus 6



USP Apparatus 6


Dimensions per USP

Height 25 mm ± 2 mm

Centering ± 2 mm center line

Speed ± 4% of set speed

Vessel Temp. 32 ± 0.5°C

Timepoints ± 2% or ± 15 minutes of specified time (lesser)

USP Apparatus 6

Typical Test System Preparation

Remove the system from the package.

Remove the protective liner from the system.

Place the adhesive side on a piece of Cuprophan that is not less than 1 cm

larger on all sides of the system perimeter.

USP Apparatus 6

USP Apparatus 6

Place the system on a clean surface with the Cuprophan side down.

Apply a suitable adhesive to the exposed Cuprophan borders, and back if

necessary (Dow Corning , 355 medical adhesive 18.5% in Freon 113, or equivalent).

USP Apparatus 6

Carefully apply the adhesive-coated side of the system to the

exterior of the cylinder with the

long axis of the system fitting around the circumference of the

cylinder.



USP Apparatus 6

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

dosage forms

USP Apparatus 7


Temperature 32±0.5°C

Dip rate 30 DPM

Stroke Distance 2 cm

Holder Per USP

Timepoints ± 2% of specified time



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.



Challenges with Traditional Apparatus 7

• Instrument was not originally designed for extremely low volumes.

• Evaporation control was difficult due to reciprocating rod (which held the

dosage form/device). Many methods allowed for media addition (“top up”)

prior to analysis.

• Initial design was difficult to automate The smaller volume tubes had

smaller diameter openings; as a result, clearance was tight for sample and return lines.

• The requirement for testing 12 stents at a time lead to the development of a 12 place collector.

Early DevelopmentProof of Concept Unit

The intent was to develop a prototype inexpensively in order to test:

1) theory of operation

2) conformance with USP specifications and

3) eliminate problems associated with past units.

Utilized existing hardware with modified firmware.

The unit was built for manual testing, sampling and media changes where done by hand

Proof of ConceptApparatus 7 with Magnetic Drive

How did it work?

• Each rack was designed for a specific size stent/tube

• The rack reciprocated the USP specified 2 cm distance

• Each rack had a magnetic plate which drove the stent holder within each tube

Design Advantages

• Matched USP specifications for Apparatus 7

• Able to handle small volumes (5 -

50mls)

• Inert materials used in design

allowed solvents to be used

• Able to change DPM to more

closely match in-vivo release

• Provided a tool for IVIVC work as

well as accelerated QC release testing

• High throughput in a single tester (customize the number of available

rows)

• Excellent temperature control, allows elevated temperatures

• Sealed system; essentially no evaporation

• Disposable tubes (no dead volume or cleaning issues to contend with)

Small Volume Drug Release Apparatus Prototype to Commercial Product

Agilent 400-DS

• Parent module has the ability to test 13 samples and incorporates the ability to access up to four types of media.

• Sample collection is built into each module.

• Additional modules, each capable of testing 13 samples, can be added to the parent module to extend testing capacity to 52 samples.

• Each unit is individually operated and controlled via the software provided.



400-DS: Dissolution Cell Design

Dissolution Cell

Heater

Jacket

Temperature

Probe

Media / Sample

Port

• A glass tube (dissolution cell), open at both ends, is placed atop a base seal

• A heating jacket fits around each tube (no water bath is used)

• The sample holder is inserted and the tube is capped

• All media fill and sampling is done via the bottom of the tube via the media/sample port

• Media temperature is recorded and controlled through the built-in temperature probe

• Dissolution cells are disposable and can be readily replaced when necessary

400-DS Temperature Control

• External jacket designed to provide uniform heating of the test media

• Temperature feedback provided by internal temperature probe in the base of each chamber

• No water bath!

Dissolution cells -5 mL and 10 mL

Heater jackets surround the dissolution cells

Temperature probe and sampling port at bottom of the dissolution cells

Reciprocating holder for drug-eluting stents of various lengths

400-DS – Improved Test Performance

The 400-DS successfully addresses the many challenges associated with the testing of combination products:

• Small Volume

• Low Evaporative Loss

• Use of organic solvent media

• Automated Sampling and Media Replacement

• Bathless

• Regulatory Compliance

• Small footprint

400-DS Reciprocating Holder Options

400-DS Contact Lens Holder

Documents

Agilent Dissolution Seminar Series · Agilent Dissolution Seminar Series © -2013 All Rights Reserved 2 The Dissolution Test Measure and carefully introduce dissolution media to the