Rationale for dissolution testing - NHS Wales Testing of... · Dissolution testing of non- ... • A dissolution method developed solely for QC for ... • General principles of dissolution

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