Transcript Relevance of in vitro dissolution testing for evaluating

Application of Dissolution Testing in
Industrial Product Development
“The Third International Workshop: Drug Development and Registration”
First Moscow State Medical University and Ministry of Healthcare in Russia
October 28-29, Moscow, Russia
Contents
• Relevance of dissolution testing in pharmaceutical industry
• Case studies:
• Influence of stability testing on dissolution
• Special dosage form (ODT)
• Extended release formulation
• Copraecipitate formulation
• Fixe dose combination
• Conclusion
page 2 •
Relevance of dissolution testing in pharmaceutical
industry
Aims of method development
A robust dissolution method, that provides rugged,
reproducible and reliable data !
 Appropriately discriminating, but not over discriminating !
 „Quality indicating“ with regard to:
 Stability effects
 Failures during manufacturing process
 Changes in composition
 Capable of being transferred between laboratories !
 Suitable to show changes affecting in-vivo performance !
page 3 •
Relevance of dissolution testing in pharmaceutical
industry
Dissolution testing is involved throughout the entire products life cycle

Formulation development and finding
 important tool for formulation development in order to
find the best candidate to fit the medical/kinetic requirements

Monitoring of clinical trials during phase 1, 2 and 3
 release testing

Stability studies
 to define shelf life

Challenge scale up und process validation
 to ascertain conformity of lab- and production scale
page 4 •
Relevance of dissolution testing in pharmaceutical
industry

Submission

Quality control of market products and during phase 4
 release testing and as critical quality control tool for
investigations on uniformity of product quality within the technical range of
manufacturing processes

Post Approval Changes (SUPAC)
 to prove similarity of pre - and postchange quality

Biowaiver, IVIVC (In-Vitro In-Vivo Correlation)
 to avoid redundant clinical bioequivalence studies

Line Extensions
 to support formulation development
page 5 •
Case study 1.1: Stability effects on the formulation
Stability effects of a new tablet formulation within 1 month storage
120,00
dissolution [% of labelled amount]
100,00
single value curves
80,00
40°C/75 rh, alu/alu blister
60,00
40°C/75 rh, PP blister
40,00
20,00
0,00
0
10
20
30
40
50
60
time [ min ]
Conclusion:
water permeation though the PP blister occurs  clear influence of humidity
on the tablet  can be avoided by using suitable packaging material !
page 6 •
Case study 1.2: Stability effects on the formulation
Stability effects of a new formulation within 3 month storage at accelerated test
conditions: 40°C/75 rh
120
start
dissolution [% of labelled amount]
100
1 month
OOS !
3 months
80
60
HDPE bottle  water permeation
non-protective packaging material
40
20
mean value curves
0
0
5
Conclusion:
10
15
20
time [ h ]
• only dissolution is affected (assay and degradation in spec)
• clear influence of temperature and humidity
• in vivo relevance
page 7 •
Case study 1.2: Stability effects on the formulation
Stability effects of a new formulation within 3 month storage at accelerated test
conditions: 40°C/75 rh
120
start
dissolution [% of labelled amount]
100
1 month
3 months
80
60
HDPE bottle with dessicant 
non-protective packaging material
40
OOS !
20
mean value curves
0
0
5
10
15
20
time [ h ]
Conclusion:
• Dissolution profiles now the other way round
 decreasing instead of increasing !
page 8 •
Case study 1.2: Stability effects on the formulation
Stability effects of a new formulation within 3 month storage at accelerated test
conditions: 40°C/75 rh
120
start
dissolution [% of labelled amount]
100
1 month
3 months
80
60
40
alu alu blisters 
protective packaging material
20
mean value curves
0
0
5
10
15
20
time [ h ]
Conclusion:
• selecting a suitable packing material based on dissolution tests is possible
• material provides an appropriate protection of the product
page 9 •
Case study 1.3: Stability effects on the formulation
Stability effects of a new capsule formulation within 12 months storage
120
start
dissolution [% of labelled amount]
100
Q=75 %; t=45 min
80
3 month
6 months
12 months
60
40
OOS !
20
cross-linking !
mean value curves
0
0
10
20
30
40
50
60
hart
gelatine
capsules
30°C/75 rh
time [ min ]
Conclusion:
 clear influence of temperature and humidity on the capsules requires a
storage and transport advice for the product
page 10 •
Case study 2: ODT as Line Extension
ODT as a Line Extension of a standard IR tablet
Orally Disintegrating Tablet (USA) / Orodispersible Tablet (EU):
 a solid dosage form containing medical substances which
disintegrates rapidly, usually within a matter of seconds, when
placed upon the tongue.
API is highly soluble in 0.1M HCl (pH 1), acetate-buffer pH 4.5
and dem. water (sink-conditions !)
API is slightly soluble in phosphate-buffer pH 6,8
 addition of 0.1% SDS required to reach sink-conditions
“Official” method for IR tablet uses 0.1 M HCl as dissolution medium
Aim:
page 11 •
discriminating dissolution method for development purposes in
order to find the fastest disintegrant !
Case study 2: ODT as Line Extension
• Starting point: dissolution profiles of IR tablets obtained in different media
(pH 1, pH 4.5, dem. water, pH 6.8 + 0.1% SDS) at 50 rpm
 rapidly dissolving at all pH-values
120
d is s o lu tio n / % o f la b le d a m o u n t
100
80
pH 1
•
pH 4.5
•
dem. water
•
pH 6.8 + 0.1%
SDS
V e sse l 1
V e sse l 2
60
V e sse l 3
V e sse l 4
40
V e sse l 5
V e sse l 6
20
0
0
15
30
tim e [m in ]
page 12 •
•
45
60
Case study 2: ODT as Line Extension
• Problem solving: evaluation of the characteristics of the API and the
discriminatory power of the dissolution method
 shorter sample drawing times under non sink-cond. (pH 6.8 without SDS)
• Submission: replacement of dissolution by disintegration acc. ICH QA6
d is s o lu tio n / % o f la b le d a m o u n t
120
100
80
clear differentiation
of the formulations
is feasible !
60
40
20
0
0
15
30
45
60
tim e [m in ]
page 13 •
D is in te g ra n t A
D is in te g ra n t B
D is in te g ra n t C
D is in te g ra n t D
Case study 3: Development of a GIT System
1 - orifice GITS (Gastro Intestinal Therapeutic System)
• Modified release formulation based on an osmotic principle (OROS
technology)
• SPM: semipermeable membrane  diffusion of water
• Drug layer: API homogeneously dispersed in a polymer matrix
• Push layer: diffusion of water  swelling  osmotic pressure  pushing out
the API through the orifice
page 14 •
Case study 3: Development of a GIT System
• Starting point: 1. formulation approach: 1 - orifice GITS
 advantage: dissolution profiles are not affected by pH-changes and/or
mechanical stress (rotation speed)
• Zero order kinetic  low batch intravariability  RSD < 2%
d is s o lu tio n / % o f la b le d a m o u n t
120
100
80
60
40
20
0
0
page 15 •
120
240
360
480
600
720
tim e [m in ]
840
960
1080
1200
1320
1440
Case study 3: Development of a GIT System
• Problem during release testing of clinical batch: OOS in dissolution !
• All other release parameter comply to the specification  Reason ?
d is s o lu tio n / % o f la b le d a m o u n t
120
100
80
60
40
20
0
0
120
240
360
480
600
720
tim e [m in ]
page 16 •
840
960
1080
1200
1320
1440
Case study 3: Development of a GIT System
page 17 •
Case study 3: Development of a GIT System
Formulation after 24 hours of dissolution testing:
 formulation bursts due to high osmotic pressure !
Formulation optimization
via a discriminating
dissolution testing method !
page 18 •
Case study 3: Development of a GIT System
• Problem solving: 2 - orifices reduce pressure in the formulation !
 homogeneous profiles with low scatter and intra-batch variability
d is s o lu tio n / % o f la b le d a m o u n t
120
100
80
60
40
20
0
0
120
240
360
480
600
720
tim e [m in ]
page 19 •
840
960
1080
1200
1320
1440
Case study 4: Copraecipitate formulation
• Crystalline drug substance (two main modifications) is insoluble in aqueous
media over the physiological pH range
• Addition of various surfactants do not provide sink conditions (40 mg dosage)
• Solubility data of crystalline substance at 37 °C:
medium
acetate buffer
pH 4.5
SDS conc. [%]
0
0.5
1.0
1.5
solubility [mg/900 mL]
after 24 h
0.03
23
34
36
Problem solving:
• Drug product is formulated as a solid solution !
 amorphous form increases solubility and therefore
enhanced bioavailability dramatically !
page 20 •
no sink-conditions with
SDS achievable
Case study 4: Copraecipitate formulation
Crystalline API:
amorphization
is lying on the aqueous
surface due to high surface
tension  no dissolution
page 21 •
Copraecipitate:
fast dissolution
 high bioavailability
Case study 4: Copraecipitate formulation
Monitoring the amorphous state of the API in the drug product is absolutely
mandatory  potential recristallisation directly influences bioavailability
1. Quantitative characterization by X-ray powder diffraction (XRPD)
50 %
20 %
10 %
5%
mod I
mod I
mod I
mod I
signals of different amounts
of crystalline ‘mod I’,
insoluble in aqueous media
Problem:
• XRPD measurement time > 24 h
• method precision not acceptable: +/ - 10%
page 22 •
Case study 4: Copraecipitate formulation
Options for monitoring the amorphous state of the API in the drug product
2. Quantitative characterization by in vitro dissolution testing using fibre optic
technique
120
solid solution
dissolution [% of labelled amount]
100
80
100 %
5%
10 %
10 %
20 %
amorphous
mod I
mod I
monohydrate
mod I
50 %
mod I
60
40
20
mean values of n=6 tablets
Method:
USP 2 apparatus, 75 rpm
acetate buffer pH 4.5 + 0.1 % SDS
0
0
10
20
30
time [ min ]
page 23 •
40
50
60
20 mg tablets
crystalline
amounts
Case study 4: Copraecipitate formulation
Conclusion:
• Quantitative characterization of crystalline amounts and monitoring of a
potential re-crystallization of the API into the insoluble form is possible
by in vitro dissolution testing via fibre optic
• Method precision +/- 3%
• Short measurement time of 60 minutes compared to 24 h
• Robust technique and automation with RoboDis1 is feasible, in particular for
conducting a broad range of stability tests (e.g. packaging material tests)
page 24 •
Case study 5: Innovative fixe dose combination
Fixe dose combination with 2 different APIs:
Modified release formulation combined with an IR formulation
• MR part: consists of a GIT system containing the first API,
constant drug release over 24 hours
• IR part: coating of the MR part containing the 2 API,
complete dissolution within 1 hour
Optimal way:
• development of one automated dissolution procedure for routine
analyses with regard to apparatus, dissolution medium, rotation speed
and sampling time points including
• including one analytical method for the quantification of both API
 both APIs can be analyzed in 1 tablet in parallel !
page 25 •
Case study : Innovative fixe dose combination
• Challenges with regard to dissolution method:
IR
MR
Dissolution apparatus
Paddle
Paddle
Dissolution medium
pH 6.8 + 1 % SDS
pH 4.5 + 0.3% Brij
Rotation speed
100 rpm
75 rpm
Filtration
25 µm
0,45 µm
Analytical method
Offline quantification
Online quantification
page 26 •
Case study 5: Innovative fixe dose combination
• Result:
• Determination of both APIs in different dissolution tests
 Prerequisite: batch to batch consistency !
• 2 Dissolution systems
 online measurement for the MR part using RoboDis 1
(fully automated)
 fraction collection for the IR part selecting Sotax AT 70 smart
(semi-automated)
 two analytical methods (online and offline quantification)
page 27 •
Case study 5: Innovative fixe dose combination
IR part: dissolution profiles in buffer pH 4.5 containing 0.3% Brij
page 28 •
Case study 5: Innovative fixe dose combination
Semi-automated dissolution system – Sotax AT70 smart®
page 29 •
Case study 5: Innovative fixe dose combination
MR part: dissolution profiles (n=6) in buffer pH 6.5 containing 0.5% SLS
page 30 •
Case study 5: Innovative fixe dose combination
Fully automated dissolution system – RoboDis 1®
page 31 •
Conclusion
In Industrial product development…
• … high flexibility is mandatory !
• … willingness to unusual approaches !
• … acceptance of increased effort !
Prerequisite: qualified personnel !
Courage for discussions with colleagues and authorities !
But always keep in mind: submission is priority 1 !
page 32 •
Thank you for your attention!