DISSOLUTION TESTING

MEI ANGELICA M. DE LOS REYES

DISSOLUTION

 Defined as a physical test to predict drug delivery to a target area in the

proper amount at the right time
 More than simple measurement of the rate of solubility
IMPORTANCE OF DISSOLUTION TESTING

 To meet legal requirements for compendial drugs.

 As quality control tool for drug product manufacturing.
 As dosage formulations optimization tool.
 For stability – bioavailability of drug over shelf life.
DISSOLUTION VS DISINTEGRATION
DISSOLUTION RATE

 the amount of active ingredient in a solid dosage form dissolved in unit

time under standardized conditions of liquid/solid interface, interface and
media composition
 Noyes-Whitney Equation – the traditional mathematical expression for
dissolution rate
NOYES-WHITNEY EQUATION

𝑑𝑤
= 𝐾𝑆 𝐶𝑠𝑎𝑡 − 𝐶𝑠𝑜𝑙
𝑑𝑡
Where:
dw/dt or
w or m = weight or mass (kg)
dm/dt = dissolution rate (kg•s-1)
t = time (s)
K = dissolution constant (m•s )-1

S = surface area of the solid (m2)

Csat = concentration of the saturated solution (moles/L or M)
Csol = concentration at any given time (moles/L or M)
DISSOLUTION PROCESS OF SOLID DOSAGE FORMS
USEFUL THEORETICAL CONCEPTS

 Rate Limiting – Each process in the transfer of a solid active ingredient

from its delivery system (disintegration, deaggregation, dissolution) may
take a different percentage of total time required for the active
ingredient to be dissolved and any of those process may be rate limiting.
 Bioavailability – Drug’s availability in the body compartment correlates
well with dissolution rate only when dissolution time is longer than
assimilation time, that is, when dissolution is rate limiting for the
absorption system.
USEFUL THEORETICAL CONCEPTS

 Rate Limiting – Each process in the transfer of a solid active ingredient

from its delivery system (disintegration, deaggregation, dissolution) may
take a different percentage of total time required for the active
ingredient to be dissolved and any of those process may be rate limiting.
 Bioavailability – Drug’s availability in the body compartment correlates
well with dissolution rate only when dissolution time is longer than
assimilation time, that is, when dissolution is rate limiting for the
absorption system.
 Higher Dissolution Rate = Higher Absorption Rate
DISSOLUTION STANDARDS

 Apparatus Suitability
 Media Selection (USP Guidelines)
 Controlling Variables
 USP Specifications
APPARATUS CLASSIFICATION IN USP

 Apparatus 1 (Rotating Basket)

 Apparatus 2 (Paddle Assembly)
 Apparatus 3 (Reciprocating Cylinder)
 Apparatus 4 (Flow-through Cell)
 Apparatus 5 (Paddle Over Disk)
 Apparatus 6 (Cylinder)
 Apparatus 7 (Reciprocating Holder)
APPARATUS FOR CONTROLLED-RELEASE DRUG
FORMS AND SUSPENSIONS
APPARATUS 1 (ROTATING BASKET)
 The assembly consists of the
following :
 A covered vessel
 Transparent material
 A motor
 A metallic drive shaft
 A cylindrical basket
 The water bath permits the holding of
temp inside vessel at 37±0.5 ̊C
 The vessel is a cylindrical with
hemispherical bottom
APPARATUS 1 (ROTATING BASKET)

 The shaft is positioned so that its axis is

not more than 2mm at any point from the
vertical axis of the vessel and rotates
smoothly and with out significant wobble.  Drug product:
 Solids (mostly floating)
 Use 40mm mesh cloth.
 Monodisperse (tablets)
 A basket having a gold coating 0.0001 inch
thick may be used.  Polydisperse (encapsulated beads)
 The dosage unit is place in a dry basket at  Disadvantage:
the beginning of each test.  Formulation may clog to 40 mesh screen
 The distance between the inside bottom of
the vessel and the basket is maintained at
25± 2m.
APPARATUS 2 (PADDLE ASSEMBLY)
 The assembly from apparatus 1, except
paddle formed from a blade.
 A shaft is used as the stirring element
 The vertical center line of the blade is flush
with the bottom of the shaft.
 The distance of 25±2 mm between the
blade and the inside bottom of the vessel.
 The paddle, blade and shaft may be coated
with a suitably inert coating.
 The dosage unit is allowed to sink to the
bottom of the vessel before rotation of the
blade.
 A small, loose piece of nonreactive material
such as wire helix may be attached to
dosage units in order to prevent floating.
 Standard volume: 900/1000 ml
 Advantages:
 Easy to use and robust
 pH change possible
 Can be easily adapted to apparatus 1
 Disadvantages:
 Floating dosage forms require sinker
 Positioning of tablet
APPARATUS 2 (PADDLE ASSEMBLY)
LIMITATIONS OF USP APPARATUS 1 AND 2

 Apparatus has plenty of HYDRODYNAMICS.

 Complicated 3-dimensional flow generated by the paddle.
 Significant impact of convective transport – Conditions used (50 – 100
rpm) highly exaggerates flow in the GI.
 Use of solvents and surfactants non-native to GI.
APPARATUS 3 (RECIPROCATING CYLINDER)
 The assembly consists of:
 A set of cylindrical, flat-bottomed glass
vessels
 A set of glass reciprocating cylindrical
 Stainless steel fitting
 Screen
 A motor and drive.
 The vessel is immersed in water bath
holding temp at 37± 0.5 ̊
APPARATUS 3 (RECIPROCATING CYLINDER)
 Useful for:
 Tablets
 Beads
 Controlled-release formulations
 Standard volume: 200-250 ml/station
 Advantages:
 Easy to change the pH-profiles
 Hydrodynamics can be directly influenced by
varying the dip rate.
 Disadvantages:
 Small volume (max. 250 ml)
 Limited data
APPARATUS FOR SUPPOSITORIES
APPARATUS 4 (FLOW-THROUGH CELL)
 The assembly consists of:
 A reservoir and a pump for the
dissolution medium
 A flow-through cell
 A water bath.
 The pump forces the dissolution medium
upwards through the flow-through cell.
 The pump has a delivery range between
240 and 960 mL per hour, with standard
flow rates of 4, 8, and 16 mL per minutes.
APPARATUS 4 (FLOW-THROUGH CELL)
 The cell is immersed in a water bath
and the temperature is maintained  Advantages:
at 37 + 0.5°  Easy to change media pH
 The apparatus uses a clamp  PH-profile possible
mechanism and two O-rings for the  Sink conditions
fixation of the cell assembly.
 Disadvantages:
 Useful for:
 Deaeration necessary
 Low solubility drugs
 High volumes of media
 Micro particulates
 Labor intensive
 Implants
 Suppositories
APPARATUS FOR TRANSDERMAL AND TOPICAL
DOSAGE FORMS
APPARATUS 5 (PADDLE OVER DISK)
 The paddle and vessel assembly from
apparatus 2 with the addition of stainless
steel disk assembly.
 The temperature is maintained at 32 +
0.5°C
 A distance of 25 + 2 mm between the
paddle blade and the surface the disk
assembly is maintained during the test.
 The disk assembly is designed to minimize
any dead volume between the disk
assembly and the bottom of the vessel.
APPARATUS 5 (PADDLE OVER DISK)

 Standard volume: 900 ml

 Disadvantages: • Disk assembly restricts
the patch size.
APPARATUS 6 (CYLINDER)
 The vessel assembly from apparatus 1
except to replace the basket and shaft
with a stainless steel cylinder stirring
element and to maintain the
temperature at 32 + 0.05°C
 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.
APPARATUS 6 (CYLINDER)
APPARATUS 7 (RECIPROCATING HOLDER)
 The assembly consists of:
 A set of volumetrically calibrated or
tared solution containers.
 A motor and drive assembly to
reciprocate the system vertically
 A set of suitable sample holders.
 The solution containers are partially
immersed in a suitable water bath,
inside the temperature of the
containers at 32 + 0.5°C USP
APPARATUS 7 (RECIPROCATING HOLDER)
MEDIA SELECTION (USP GUIDELINES)

 Distilled water is the preferred medium.

 If deemed necessary because of the nature of the drug, buffered aqueous
solution having a pH between 4.0 – 8.0 should be used. Where its use
can be justified, dilute acid may be selected.
 No enzymes should be incorporated.
 Quantity should not be less than three times that required to form a
saturated solution of the drug substance present in the drug unit.
MEDIA SELECTION (USP GUIDELINES)
MEDIA SELECTION (USP GUIDELINES)

 Depends upon following parameters.

 Type of formulation (Immediate or modified release).
 Solubility characteristics of active component.
 Type formulation design, e. g. Soft gel capsule, Hard gel capsule, Tablets,
Suspension, powder etc.
MEDIA SELECTION (USP GUIDELINES)
 COMPENDIAL DISSOLUTION MEDIA:
 Simulated Gastric Fluid
 Water
 Simulated Intestinal Fluid
 BIORELEVENT MEDIA:
 Fasted State Gastric Conditions (FaSSGF)
 Fasted State Small Intestinal Conditions (FaSSIF)
 Fed State Gastric Conditions
CONTROLLING VARIABLES

 For capsules (both soft gel and hard

 SELECTION OF RPM
 The selection of RPM depends
upon:
 Type of formulation
 Solubility characteristics of active
substances
 Apparatus used for dissolution study.
gel), USP-I i. e. Basket apparatus is
recommended, rotation speed for
basket shall be 50 to 75 RPM.
 For tablets, USP-II i. e. paddle apparatus
is recommended, rotation speed for
paddle shall be 75 to 100 RPM.
 Any change in apparatus and RPM
other than recommended parameters
should be justified.
CONTROLLING VARIABLES
 SELECTION OF DISSOLUTION TIME INTERVAL
 Dissolution time is defined as the time in minutes at which maximum
amount of drug is dissolved.
 For immediate release dosage forms, dissolution time from 30min. to 60min.
 In some cases dissolution time may be higher i. e. up to 90min. to l20min.
 For modified release formulations (delayed release, enteric coated and
sustained release), time depends upon design of formulation, site of action
and therapeutic use. Time for such formulations may be from about 6 hrs.
to 24 hrs. or may be higher.
CONTROLLING VARIABLES
 SELECTION OF OTHER PARAMETERS LIKE, MEDIA VOLUME,
TEMP., ETC.
 The volume of dissolution media is ideally 900ml, however if label
claim is less than 5mg and if active substances has less absorbance at
selected wavelength, then in that case dissolution volume can be
reduced to 500ml.
 Usual volume of medium: 500 to 1000ml greater volumes (up to
2000ml) allowed for drugs with limited solubility.
 The dissolution media temperature is fixed: 37.0 (±0.5)ºC
USP SPECIFICATIONS
 1st Case:
 All tablets and capsules are subject to a general dissolution standard of not
less than 75% of the labeled content is dissolved in not more than 45
minutes in 900ml of H2O using the apparatus, procedures and
interpretations provided in the USP.
 2nd Case:
 If the chemistry of the drug or properties of the formulation do not allow
workable application in the first case, and no medically significant
bioavailability problem is documented, then the monograph sets out details
of a specific dissolution test and specification.