Dissolution testing of non-
conventional dosage forms
Prof Barbara Conway
Annual Symposium for Technical Services
27th Sept 2011
Rationale for dissolution testing
• Purpose of dissolution
test
– Product development
• Investigational
formulations testing (QC)
– Product evaluation
• Stability program (QC)
• Establishment of
product’s shelf life
• Release of commercial
batches (QC)
– SUPAC changes
• IVIVC development
• A dissolution method
developed solely for QC for
manufacturing without
bearing on patient safety or
product efficacy has limited
use
Dissolution for IVIVC
• Establishment of IVIVC and its ability to
discriminate requires good design
• Reproduce conditions in GI after dosage form
administered as closely as possible
• Very often, the in vitro dissolution test is found
to be more sensitive and discriminating than the
in vivo test
Practicality of testing
• Balance between conditions allowing for release over appropriate timeframe (for QC applications)
• General principles of dissolution tests for conventional oral dosage forms also apply to the in vitro release tests for alternative dosage forms– not possible to have a single test system that
could be used to evaluate the release characteristics of all novel products
– Need to look at requirements on individual and possibly case-by-case basis
BP 2011
• Dissolution Apparatus 1 – Basket
• Dissolution Apparatus 2 - Paddle
• Dissolution Apparatus 3 - Reciprocating Cylinder
• Dissolution Apparatus 4 - Flow-Through Cell
Apparatus 3
• Reciprocating cylinder
• Useful for modified release dosage forms
• Can change dissolution medium to simulate changes in environment through GI tract
Flow-through cell– Disk assembly method
– Cell method
– Rotating cylinder method
• USP 5,6&7 Paddle over disk, cylinder
method, reciprocating disk
The disc comprises a 35 mm o.d. sieve having a pore size of 125 microns mounted in a stainless steel holder having a diameter of 41.2 mm and is designed to hold the transdermal patch at thebottom of the vessel.
Paddle over diskSimple, easy to reproduce
Transdermal patch testing
• Fentanyl formulations
• Fentalis®, Matrifen®, Mezolar®, Osmanil®, Tilofyl®, Victanyl®
• Media pH-5 to 6
• Media Temperature-32 ºC
• Paddle Speed : 100 rpm
• 6-12 samples
Patch formulation
• Rate-limiting step for matrix patches is
normally the skin
• More likely to get relevant IVIVC data for
reservoir
Franz diffusion cell
Karpanen et al., Antimicrobial activity of a chlorhexidine intravascular catheter site gel dressing. JAC, 2011, 66, (8), 1777-1784
Media composition
FaSSGF
Sodium taurocholate
(µM)
80
Lecithin (µM) 20
Pepsin (mg/mL) 0.4
Sodium chloride (mM) 34.2
HCl (q.s.) pH 1.6
FeSSGF (middle)
Sodium chloride (mM) 237.02
Acetic acid (mM) 17.12
Sodium acetate (mM) 29.75
Milk/buffer 1:1
HCl (q.s.) pH 5
Jantratid E, Dressman J. Biorelevant Dissolution Media, Dissolution Technologies, August 2009
Simulated fluid
FaSSIF-V2 (mM)
Sodium taurocholate 3
Lecithin 0.2
Maleic acid 19.12
Sodium hydroxide 34.8
Sodium chloride 66.82
pH 6.5
FeSSIF-V2 (mM)
Sodium taurocholate 10
Lecithin 2
Glycerol monooleate 5
Sodium oleate 0.8
Maleic acid 55.02
Sodium hydroxide 81.65
Sodium chloride 125.5
pH 5.8
Duration of dissolution study
• Drug absorbed from upper SI, administered in
fasted state- duration of 30 minutes
• Drug absorbed throughout SI and LI,
administered with food-duration of 10 hours
• More usual
– gastric conditions: 15-30 mins
– SI conditions: 1h
Fibre optic dissolution
• Direct measurement of
dissolved drug in the
dissolution vessel via an
individual probe for each
dosage unit tested
– In situ measurements
– profiles are calculated in
real time
• More samples can be
taken in shorter time
– Useful for fast
dissolving formulations
Manual vs. fibre optic
Apparatus used for special dosage forms
Type of dosage form
Oral suspensions paddle
Orally disintegrating tablets Paddle and disintegration
Chewable tablets Basket, paddle, reciprocating cylinder
Aerosols Cascade impactor
Thin dissolvable films Basket and disintegration
Dermal delivery-patchesTopical-semisolids
Paddle over diskFranz diffusion cell
Suppositories Paddle, modified basket, dual chamber flow-through
Powders and granules Flow-through cell
Microparticulates Modified flow-through cell
Implants Modified flow-through cell
Chewing gum Special apparatus (Ph. Eur)
Method development
• Avoid unnecessary proliferation of test
equipment
– First approach should use compendial equipment
• Well developed for suspensions, chewable
tablets, suppositories, topicals etc
• Some dosage forms, such as chewing gums,
powders, and parenterals, further method
development and refinement is needed
Dosage forms for oral cavity
• Local, sublingual or buccal
– convenient, accessible, and generally well
accepted
• Can avoid first pass metabolism and
presystemic metabolism
• Can have rapid onset
• Active is dissolved in saliva and either
swallowed or absorbed buccally
Sub-lingual tablets
Rachid et al., 2011. Dissolution Testing of Sublingual Tablets: A Novel In Vitro Method . AAPS PharmSCiTech, 12 (2) 544-552.
Medicated chewing gums
• Medicinal chewing gums have been
available since the late 1920s
(Aspergum®)
• Nicotine Chewing Gums
– Nicotine Polacrilex USP. The nicotine is
loaded to around 18% w/w on an ion
exchange resin (Amberlite™ IRP64)
– include water-soluble buffering agents such
as alkali carbonates to increase the salivary
pH and thereby increase bioavailability.
Advantages of chewing gum-based drug delivery
• Convenient and discreet
• Widely acceptable
• Fast acting
• Suitable for prolonged-
release applications
• Suitable for local and
systemic applications
• Typical gum formulation
– Gum base 29%
• elastomer, plasticiser, texture
agent, wax, lipid, emulsifier,
colorant, antioxidant
– Sorbitol 43%
– Sorbitol solution 21%
– Glycerin 5%
– Peppermint flavour 1%
– Lecithin 0.5%
– Aspartame 0.33%
Manufacture of chewing gums• use conventional gum processes
• The gum base is softened or melted
and placed in a kettle mixer where
sweeteners, syrups, active ingredients
and other excipients are added at a
defined time
• The gum is then sent to a series of
rollers that form it into a thin, wide
ribbon.
• Coated with an anti-sticking agent can
be added (e.g. magnesium stearate,
calcium carbonate, or finely
powdered sugar or sugar substitute)
• Finally, the gum is cut to the desired
size and cooled at a carefully
controlled temperature and humidity.
Chewing gum formulations
• The mechanism and kinetics of release not yet been
completely understood due to the complex nature
of the formulation
• Release conventionally measured by chew-out
studies
– Need to control how gum is chewed
– Process is destructive at each timepoint, cannot sample
• Need for a in vitro test apparatus
Chewing gum apparatus
• Chewing apparatus adopted by EP in 2000
chewing pistons
base of chewing chamber
tongue
chewing chamber
Chewing gum apparatus
The chewing machine
• Temperature-controlled chewing chamber
– the gum piece is chewed by two electronically-controlled horizontal
pistons driven by compressed air
• Pistons transmit twisting and pressing forces to the gum whilst, a
third vertical piston, (“tongue”) operates alternately to the two
horizontal pistons to ensure that the gum stays in the appropriate
position
• Temperature can be maintained at 37°C±0.5°C and the chew rate
varied
• Other adjustable settings include the volume of the medium,
distance between the jaws and the twisting movement
• The EP recommends using 20 mL of unspecified buffer (with a pH
close to 6) in a chewing chamber of 40 mL and a chew rate of 60
strokes per minute
Selection of dissolution medium
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
0 5 10 15 20 25 30 35
Time (minutes)
% N
icot
ine
Rel
ease
Real salivaArtificial saliva (1)Artificial Saliva (2)
Artificial saliva
Components of artificial saliva
Quantity (mmol L-1)
KH2PO4 2.5
Na2PHO4 2.4
KHCO3 15.0
NaCl 10.0
MgCl2 1.5
CaCl2 1.5
Citric acid 0.15
pH adjusted to 6.7 with NaOH or HCl
Release from commercial products
0
20
40
60
80
100
0 10 20 30 40Time (min)
% D
rug
Rel
ease
4mg gum 2mg gum
0
20
40
60
80
100
0 5 10 15 20 25 30 35 40 45
Time (mins)
% R
elea
se o
f Nic
otin
e
2mg gum 4mg gum
Directly compressible gumbases
• As the heating process involved in conventional
methods may limit the applicability of the process for
formulation of thermally labile drugs, directly
compressible, free-flowing powdered gums have been
developed to simplify the process
• Mixtures of polyol(s) and/or sugars with a gum base
• These formulations can be compacted into a gum tablet
using a conventional tablet press, thus enabling rapid
and cheap development of a gum delivery system
Directly compressible bases
0
20
40
60
80
100
0 5 10 15 20 25 30Time (min)
(%) D
rug
rele
ase
Pharmagum M
Pharmagum S
Nicorette
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
0 10 20 30 40
Time (min)
Ave
rage
% N
icot
ine
Rel
ease
20mL 40mL 80mL
Process parameters
0.0
20.0
40.0
60.0
80.0
100.0
120.0
140.0
0 10 20 30 40
Time (min)
Ave
rage
% N
icot
ine Relea
se
23°C 37°C 53°C 26ºC
Influence of chew rate on commercial 2 mg gum
0.0
10.0
20.0
30.0
40.0
50.0
60.0
0 5 10 15 20 25 30 35 40
Time (min)
Ave
rage
% N
icot
ine
Rel
ease
82 Chew/min 60 Chew/min 42 Chew/min 22 Chew/min 12 Chew/min
6 Chew/min 4 Chew/min
General conclusions
• As a general rule, under sink conditions,
the rate at which the drug is released is
directly proportional to the chewing
frequency and aqueous solubility of drug
substance and is indirectly proportional to
the mass of the gum base
• Order of addition of excipients and mixing
efficiency have impact on release
In vitro chew rate study (4 mg)
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
0 5 10 15 20 25 30 35
Time (minutes)
% R
ele
ase
chew rate 82 chew rate 60 chew rate 40 chew rate 20 Chew rate 30
chew rate 10 chew rate 5
Chew out study
• Single-centre, open-label, four-phase cross-
over design with a minimum interval of 24
hours between each phase.
• 4 mg branded gum using a standard chewing
protocol for the prescribed time period of 2,
5, 7, 10, 15, 20, 25 and 30 minutes
• The gum was chewed once every 4 seconds,
accompanied by an audible sound
Chew out study methodology
• Chewed for 30 seconds on one side of the mouth and
then moved the gum to the other side of the mouth,
alternating the side of the mouth every 30 seconds
• Subjects were instructed to swallow at verbal command
every 30 seconds
• At the end of the chew interval, each chewed gum piece
was collected and analysed for any residual nicotine.
Correlations
IVIVC (in vitro & in vivo release)
0
20
40
60
80
100
0 20 40 60 80 100
% Dose Released (Chewing Machine)
% D
ose
Rel
ease
d (C
hew
Out
)5 Chew/min
10 Chew/min
20 Chew/min
30 Chew/min
40 Chew/min
60 Chew/min
82 Chew/min
IVIVC (in vitro & in vivo release)
0
20
40
60
80
100
0 20 40 60 80 100
% Dose Released (Chewing Machine)
% D
ose
Rel
ease
d (C
hew
Out
)5 Chew/min
10 Chew/min
20 Chew/min
30 Chew/min
40 Chew/min
60 Chew/min
82 Chew/min
5 Chew/min
10 Chew/min
20 Chew/min
30 Chew/min
40 Chew/min
60 Chew/min
82 Chew/min
In Vitro and In Vivo Release
0
10
20
3040
50
60
70
80
90
100
0 10 20 30Time
% D
ose
Rel
ease
d
Chew out
82 Chew/min
60 Chew/min
40 Chew/min
30 Chew/min
20 Chew/min
10 Chew/min
5 Chew/min
Time Conversion Chart
0
30
60
90
120
150
180
0 20 40 60
In Vitro Time
Co
rres
po
nd
ing
In V
ivo
Tim
e
82 Chew/min 60 Chew/min
40 Chew/min 30 Chew/min
20 Chew/min 10 Chew/min
5 Chew/min
Time Conversion Chart
0
30
60
90
120
150
180
0 20 40 60
In Vitro Time
Co
rres
po
nd
ing
In V
ivo
Tim
e
82 Chew/min 60 Chew/min
40 Chew/min 30 Chew/min
20 Chew/min 10 Chew/min
5 Chew/min
Summary
• Need a range of different dissolution apparatus
for testing of novel dosage forms
– shows promise for other dosage forms, such as
chewable tablets, suspensions, and suppositories.
• For others, need to consider the application
– Potential to provide information regarding the in
vivo release
– Need further development and refinement for
routine QC applications
• Have defined relationship with in vivo data for
chewing apparatus