Dissolution Test

- A qualitative tool that can provide valuable information about the biological activity of a drug as well as batch-batch consistency. - Simple and inexpensive indicator of a products physical consistency.

Used depends on intention

1. Quality Control - examining batch to batch homogeneity - examining batch to batch conformity - examining stability 2. Research and Development - examining drug release behavior of pre-formulations - in-vitro simulation of the gastrointestinal passage 3. IVIVC (in vitro-in vivo correlation)

General factors that may affect the reliability of the test

1. Proper alignment/geometry of dissolution apparatus -dimensions of vessels, paddles, baskets and cylinders -height, centering and wobble 2. Proper conditions during dissolution test - temperature - agitation speed - degassing - sampling (sampling zone, timing, filtration, dilution) - vibration (common variable introduce in the dissolution system) - torsional vibration (disturbance in rotational devices, resulting in periodic vibrations in rpm - points to consider to avoid undesirable effects of vibration: - dissolution equipment should be placed on a plane area - bench/table should be stable - drive chain or belt should free of tension and/or dirt - torn parts of the dissolution apparatus (if there are any) replaced - correctly functional gear plates - individual spindles are not surging - no sources of vibration nearby 3. Proper validation of analytical method

Specifications
1. Eccentricity of the stirring device - the stirring shaft must rotate smoothly without significant wobble - eccentricity can be measured with a machinists indicator. It is measured in terms of total indicator reading (TIR), which determines the sum of the distance on both sides of the axis rotation. 2. Guiding the shaft - An eccentricity of 0.005 in. (0.11mm) at a distance of 1in. (25mm) from the chuck will barely be perceptible, but at 6 in. it will amount to 0.30 in. (0.75mm), which is the maximum that can be tolerated. 3. Speed of rotational device selected by official compendium: 50rpm or 100rpm - Other speeds specified for certain drugs.

4. Alignment of the stirring element - Two important factors to consider: a. Tilt b. Agitation intensity 5. Temperature - drug solubility is temperature-dependent - generally a temperature of 37C (+0.5C) is always maintained 6. Dissolution Medium -pH of the dissolution medium -surface tension of the dissolution medium (surfactants and wetting agents lower the contact angle and improve penetration by the dissolution medium) -viscosity of the dissolution medium (dissolution rate decreases with an increase in viscosity)

Types of Dissolution Apparatus

Apparatus 1 Rotating Basket Apparatus 2 Rotating Paddle Apparatus 3 Reciprocating Cylinder Apparatus 4 Flow Through Cell Apparatus 5 Paddle over Disk Apparatus 6 Rotating Cylinder Apparatus 7 Reciprocating Holder Apparatus 8 Vertical Diffusion Cell (non-compendial)

Apparatus 1
- consists of a 1-inch diameter x 13/8in-high stainless steel 40-mesh wire basket - rotated at a constant speed ranging between 25 and 150rpm (100 rpm common) - immersed in 900mL of dissolution medium in a vessel of 1000mL capacity - the medium in the vessel maintained at 37C (+0.5C)by means of suitable water bath - shaft should be positioned so that its axis is NMT 2mm at any point from the vertical axis of the vessel and rotates smoothly without significant wobble. - the dosage unit is placed in a dry basket at the beginning of each test - distance between inside bottom of the vessel and the basket is maintained at 25 + 2mm during the test. - useful for non-disintegrating dosage forms (SUPERIOR to Apparatus 2) - performs well for floating dosage forms - INFERIOR for testing dosage forms which contains gums due to the clogging of screen matrix - Useful for capsules, beads, delayed release/ enteric coated dosage forms and floating dosage forms

Advantages:
- breadth of experience (more than 200 monographs) - full pH change during the test - can be easily automated which is important for routine investigations

Disadvantages:
- disintegration-dissolution interaction - hydrodynamic dead zone under the basket - degassing is particularly important

Apparatus 2
- method of choice for immediate release dosage forms - most commonly used media includes: water, 0.1N HCl buffer solution, water or buffer with surfactant and low content alcoholic aqueous solution - the medium in the vessel maintained at 37C ( +0.5C) by means of suitable water bath - metallic or suitably inert, rigid blade and shaft comprise a single entity - paddle and blade shaft can be coated with suitable inert coating (Teflon) - the dosage form is allowed to sink to the bottom of the vessel before rotation of the blade is started. - for disintegrating and non-disintegrating dosage form at 50rpm (common) - USP/NF permits variation in the paddle method in the use of a helix of a non-reactive material as sinker for floating dosage form - Useful for tablets, capsules, beads, immediate release and delayed release/enteric coated dosage forms

Advantages:
- easy to use, easily standardized, simple - robust - can be easily adapted to apparatus 5 - long experience - can be easily automated which is important for routine investigations

Disadvantages:
- pH/media change is often difficult - hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking, floating) and therefore may significantly affect drug dissolution CONING

Apparatus 3
- Composed of cylindrical, flat bottomed glass vessel - a set of glass reciprocating cylinders - stainless steel fittings and screen (should be made of suitable non-sorbing and non-reactive material and should fit the top and bottoms of the reciprocating cylinders) - motor and drive assembly to reciprocate the cylinders vertically inside the vessels and if desired, index the reciprocating cylinders horizontally to a different row of vessels The vessels are immersed in suitable water bath at any size that permits holding the temperature at 37C (+0.5C)during the test - Useful for tablets, beads and controlled release formulations - First line of apparatus in the product development of CR preparations - Standard volume 200-250mL per station

Advantages:
- gastrointestinal tract conditions can be easily simulated, as it is easy to make time dependent pH changes - most suitable for extended or delayed release (enteric coated) dosage forms - hydrodynamics can be directly influenced by varying the dip rate

Disadvantages:
- small volume (max. 250mL) - little experience - limited data

Apparatus 4
-Composed of a reservoir and a pump for dissolution medium, a flow through cell, a water bath that maintains dissolution medium at 37C (+0.5C) -the pump forces the dissolution medium upwards through the flow through cell -the pump has delivery range between 240 and 960mL/hr and deliver constant flow of 4,8 and 16mL/min. - must be volumetric to deliver constant flow independent to flow resistance in the filter device -Useful for low solubility drugs, semi-solid dosage forms, micro-particulates, powders, granules, implants, suppositories and controlled release formulations. -has 6 most common types of cells - Tablet cell (12mm, 22.6mm) - Cell for powder and granulates - Cell for implants - Cell for suppositories and soft gelatin capsules - Cell for ointments and creams

Variations:
- Open loop system (with fraction collector) - Closed loop system (with UV/VIS Spectrometer)

Advantages:
- ability to test drugs of very low aqueous solubility in the open loop mode - ability to change the pH conveniently - sink conditions - different mode

Disadvantages:
- operational difficulties of preparing large volumes of medium - labor intensive - deaeration necessary

Apparatus 5
-used with the addition of a stainless steel disk assembly designed for holding the transdermal system at the bottom of the vessel -temperature is maintained at 32C (+0.5C) -A distance of 25 + 2mm between the paddle and blade and the surface of the disk assembly is maintained during the test -The vessel may be covered during the test to minimized evaporation -Disk assembly for holding the transdermal system is desi ned to minimi ed any dead volume. -USP 30 footnote: a suitable device is the watchglass-patch-polytef mesh sandwich assembly available as the Transdermal Sandwich (accepted by FDA)

Advantage:
-standard equipment (paddle) can be used, only add a stainless steel disk assembly

Disadvantage:
-disk assembly restricts patch size (upto 90mm)

Apparatus 6
-The vessel assembly used is same as Apparatus 1, except the basket and the shaft is replaced with a stainless steel cylinder stirrin element to maintain a temperature of 32C (+0.5C) -The shaft and cylinder components of the stirring element are fabricated of stainless steel to the specifications (100rpm common) -dosage units are placed on the cylinder at the beginning of each test -A distance between the inside bottom of the cylinder is maintained at 25 + 2mm during the test

Advantages:
-standard apparatus can be used -variable volumes -larger patch size can be tested

Disadvantages:
-patch is difficult to fix in place -little experience

Apparatus 7
-a set of volumetrically calibrated and tared solution containers (made of glass or other suitable inert material) -a motor and drive assembly to reciprocate the system vertically and to index the system horizontally to a different row of vessels automatically if desired -a set of suitable sample holders - Acrylic rod (ER tablets, osmotic devices) - Angled disk (transdermal systems) - Teflon cylinder (transdermal systems) - Spring holder (ER tablets) - Reciprocating disk (transdermal systems) - introduced in the USP as a small-volume option for transdermal patches -formerly known as Reciprocating Disk and later renamed with the adoption of 4 additional holders -agitation rate: typically 30 cycles per minute at an amplitude of 2cm - can accommodate dissolution as low as 5mL -the vessels are partially immersed in a suitable water bath that permits maintaining the temperature at 32C (+0.5C) (transdermal systems) and 37C (+0.5C) (tablets) -a device allows the reciprocation rate to be selected and maintained at the specified dip rate, within + 5% - Cuprophan (cellophane paper) is used for holding of semi-solid dosage forms - Useful for -transdermal patches -ER products -osmotic pump delivery system -ointments -non-disintegrating oral MR dosage forms -gels -emulsions

Advantages:
-small volume possible -selection of holder types -pH can be easily changed