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“The Third International Workshop: Drug Development and Registration”
First Moscow State Medical University and Ministry of Healthcare in Russia
October 28-29, Moscow, Russia
Application of Dissolution Testing in Industrial Product Development
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 •
page 3 •
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 !
Relevance of dissolution testing in pharmaceutical industry
page 4 •
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 5 •
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
Stability effects of a new tablet formulation within 1 month storage
Conclusion:
water permeation though the PP blister occurs clear influence of humidity on the tablet can be avoided by using suitable packaging material !
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Case study 1.1: Stability effects on the formulation
40°C/75 rh, PP blister
40°C/75 rh, alu/alu blister
single value curves
page 6 •
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Stability effects of a new formulation within 3 month storage at accelerated testconditions: 40°C/75 rh
OOS !
Conclusion:
• only dissolution is affected (assay and degradation in spec)
• clear influence of temperature and humidity
• in vivo relevance
start
1 month
3 months
HDPE bottle water permeationnon-protective packaging material
mean value curves
Case study 1.2: Stability effects on the formulation
page 7 •
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Stability effects of a new formulation within 3 month storage at accelerated testconditions: 40°C/75 rh
OOS !
Conclusion:
• Dissolution profiles now the other way round decreasing instead of increasing !
start
1 month
3 months
mean value curves
Case study 1.2: Stability effects on the formulation
HDPE bottle with dessicant non-protective packaging material
page 8 •
Stability effects of a new formulation within 3 month storage at accelerated testconditions: 40°C/75 rh
Conclusion:
• selecting a suitable packing material based on dissolution tests is possible
• material provides an appropriate protection of the product
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mean value curves
Case study 1.2: Stability effects on the formulation
alu alu blisters protective packaging material
page 9 •
Stability effects of a new capsule formulation within 12 months storage
Conclusion:
clear influence of temperature and humidity on the capsules requires a storage and transport advice for the product
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Case study 1.3: Stability effects on the formulation
mean value curves
start
3 month
6 months
12 months
OOS !
cross-linking !
Q=75 %; t=45 min
hart gelatine capsules
30°C/75 rh
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: discriminating dissolution method for development purposes in order to find the fastest disintegrant !
page 11 •
Case study 2: ODT as Line Extension
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Vessel 1
Vessel 2
Vessel 3
Vessel 4
Vessel 5
Vessel 6
• 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
page 12 •
• pH 1
• pH 4.5
• dem. water
• pH 6.8 + 0.1% SDS
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
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Disintegrant A Disintegrant B Disintegrant C Disintegrant Dpage 13 •
clear differentiation of the formulationsis feasible !
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%
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page 15 •
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 ?
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page 16 •
Case study 3: Development of a GIT System
page 17 •
Case study 3: Development of a GIT System
Formulation optimization via a discriminating dissolution testing method !
Formulation after 24 hours of dissolution testing: formulation bursts due to high osmotic pressure !
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
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page 19 •
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:
Problem solving:
• Drug product is formulated as a solid solution !
amorphous form increases solubility and therefore enhanced bioavailability dramatically !
solubility [mg/900 mL]after 24 h
acetate buffer 0 0.03pH 4.5 0.5 23
1.0 341.5 36
medium SDS conc. [%]
no sink-conditions with SDS achievable
page 20 •
Case study 4: Copraecipitate formulation
Crystalline API:is lying on the aqueous surface due to high surface tension no dissolution
amorphization Copraecipitate:
fast dissolution high bioavailability
page 21 •
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)
signals of different amounts of crystalline ‘mod I’, insoluble in aqueous media
Problem:
• XRPD measurement time > 24 h
• method precision not acceptable: +/ - 10%
50 % mod I20 % mod I10 % mod I5 % mod I
page 22 •
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50 % mod I
Method:USP 2 apparatus, 75 rpmacetate buffer pH 4.5 + 0.1 % SDS
20 mg tablets
Case study 4: Copraecipitate formulation
crystalline amounts
mean values of n=6 tablets
solid solution
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
page 23 •
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)
Case study 4: Copraecipitate formulation
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:
page 26 •
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
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
page 28 •
IR part: dissolution profiles in buffer pH 4.5 containing 0.3% Brij
Case study 5: Innovative fixe dose combination
page 29 •
Semi-automated dissolution system – Sotax AT70 smart®
Case study 5: Innovative fixe dose combination
page 30 •
MR part: dissolution profiles (n=6) in buffer pH 6.5 containing 0.5% SLS
Case study 5: Innovative fixe dose combination
page 31 •
Fully automated dissolution system – RoboDis 1®
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!
