dissolution tools for api characterization. -...

Dissolution Tools

for API

Characterization.

Tablet Compression Workshop

25 - 26 January 2017 | Department of OrganicTechnology, UTC

Iva Martincová | [email protected]

Petr Zámostný | [email protected]

Samir Haddouchi | [email protected]

SOTAX Group

SPS Pharma Services

CRO offering all analytical services (founded in 2005)

The only company in the world specialized in R&D for

dissolution and release testing

Located in Orleans, France

Facility fully cGMP-compliant, US FDA-inspected,

regularly subject to audits

Key Portfolio:

R&D Services

Routine Analytical Services (GMP)

Support Services

2

Privately owned, independent, globally active

Corporate headquarter in Switzerland with a strong presence in

Asia and the America

Direct sales channels / own subsidiaries with distributor channel

SPS Pharma – 2005

Zymark – 2008

Pharma Dr. Schleuniger - 2013 Since 1973.

SOTAX Group

Dissolution Tools for API

Characterization.

Introduction on Dissolution

API Characterization

Intrinsic Dissolution Rate

Apparent Dissolution

Case Studies: Paracetamol

Case Studies: IR Tablets

Conclusion

4

Introduction on Dissolution.

Time

Pla

sm

a C

on

ce

ntr

atio

n

Cmax

Tmax

AUC

Adapted from Prof. Cardot & Prof. Beyssac

(Université d’Auvergne)

Release

Absorption

Distribution

Metabolisation

Elimination

Effect

Dosage

form

API

released

API

dissolved

API

absorbed

Distribution

Elimination

Efficacy

Safety

API in

blood

API in

tissues

5


dW/dt = dissolution rate

D = diffusion coefficient

h = thickness of the stagnant layer surrounding the dissolving particle

S = the surface area of the solid

Cs = the concentration of a saturated solution

Cb = the concentration at any given time of the bulk solution

)CS(Ch

D

dt

dWbs

6

Introduction on Dissolution –USP 1, 2 ,4

USP 1: Rotating Basket

Temperature inside the vessel

at 37 ± 0.5 °C

Shaft with a cylindrical basket

Problem with homogeneity of mixing

Difficulty to monitor the dosage form

Problem of corrosion

Problem of polymers/gelatin and mesh

Bubbles on the mesh (degassing)

Cleaning process may be tedious

Sensitivity to environmental conditions

7

Introduction on Dissolution –USP 1, 2, 4

USP 2: Rotating Paddle

Temperature inside the vessel at 37 ± 0.5 °C

Shaft with a paddle placed at 25 mm from bottom

Problem with light formulation

Use of sinkers

Insoluble excipients

Coning effect

Sensitivity to environmental conditions

8

Introduction on Dissolution –USP 1, 2, 4

USP 4: Flow-Through Cell

Flexibility:

from very small volumes to infinite

Monitoring the release and not the

dissolution properties

Allowing control of the dosage form

positioning

No sensitivity to environmental

conditions

9

../200806 Actelion/USP4 capsules.AVI

USP 4 - Dosage Form Challenges

• MR, CR, SR and ER tablets

• pH change• Poorly soluble

• API’s• Powders• Granules

• Low dose• Hydrodynamic

control

• Capsules• Pellets

• Floating• Capsule

interference

• Medical devices• Drug-eluting beads

& stents• Implants• Coated ocular

implants & lenses

• Low dose

• Suppositories• Soft-gelatin

capsules

• Lipid interference

• Parenterals• Emulsions• Suspensions• Microspheres• Semi-solids

• Low dose• Small particles• Dialysis often

required

CHA

LLE

NG

ED

OS

AG

E

FO

RM

USP 4 - Specific cells for all dosage forms

small tablets large tablets different adapters for semi-solids, contact

lenses, dialysis bags, etc.

powder suppositories implants large stents small stents or products with

adsorption problems


Importance of all steps in a dissolution test interpretation

Disintegration cohesive properties of the formulation

Release type and proportion of excipients

Dissolution of the drug API characteristics

Dosage

Form

Disinte-

grationRelease

Dissolu-

tion

Dissolved

Drug

12


Characterization.







Conclusion

13

Intrinsic Dissolution. (1)

)CS(Ch

D

dt

dWtsat

Eur. Ph. § 2.9.29

USP <1087>

The intrinsic dissolution rate is the rate of dissolution of pure pharmaceutical ingredients

when conditions such as volume, agitation, pH and ionic strength of the dissolution medium

and surface area are held constant .

Physical properties’ effects are minimized or eliminated.

Determination of the constant k

Use of a tablet of pure drug

Expressed as mg/min/cm2

14


15


16


17


y = 0.275x - 0.2133R² = 0.9998

0

2

4

6

8

10

12

14

16

18

20

0 10 20 30 40 50 60

Am

ou

nt

dis

so

lve

d(m

g/c

m2)

Time (min)

18

Intrinsic Dissolution: Comparison.

0

5

10

15

20

25

0 10 20 30 40 50 60 70 80 90

Am

ou

nt

dis

so

lve

d(m

g/c

m2)

Time (min)

19


Characterization.







Conclusion

20

Apparent Dissolution. (1)

When applied to powders, dissolution studies allow:

To optimize formulation variables, including particle size.

To compare batches of active ingredient having different

physical properties:

Surface area and particle size distribution.

The comparison of various polymorphic forms of drug substances

can show identical or very different biopharmaceutical properties.

21

The Flow-Through Cell.

The test sample is located in a small

volume cell through which solvent passes

The eluate is filtered upon leaving the cell

The eluate is analyzed directly (on-line)

with a spectrophotometer and/or collected

in a fraction collector (off-line)

22

../200806 Actelion/USP4 capsules.AVI

Open System with pH Change.

Cell

Pump

Waste

Fraction Collection

Splitter

Media

Selector

C

t

differential

23

Closed Loop System.

Cell

Pump

Magnetic

stirrer

UV-Vis

Photometer

Fraction

Collection

C

t

cumulative

24

Why Choose USP 4?

USP 4 is the method of choice for poorly soluble compounds in order to maintain sink conditions

USP 4 is a method for low volume dissolution media

Specific cells for special / novel dosage forms are available

Automated pH changes can be easily achieved for IVIVC studies

Solves many challenges of USP 2 such as floating or sticking products, and inherent sampling issues

USP 4 method is increasingly used for measuring API characterization (apparent dissolution in Eur. Ph. § 2.9.43)

USP 4 is a recomended method for injectable suspensions

25

Powder cell for apparent dissolution can also be used for pellets and granules.

Dissolution results depend on physical properties of powder.

Advantages:

No floating, no sticking

Powder / API is not

compressed

Powder is wet

immediately

APIs: Apparent Dissolution

3-stage filtration

Dispersion disk(sieve + blocker)

Sieves + filter to support powder

Mobile sieve (450 µm)

Fixed sieve (450 µm)

Filter (2.7 µm)



Filter (2.7 µm)



Pre-filter (2.7 µm)

Filter (0.7 µm)


Eur. Ph. § 2.9.43

27


28


Characterization.





Case Studies 1: VSCHT – Effect of maize starch

properties on drug dissolution rate

Case Studies 2: VSCHT – Doc. Zámostný - Dissolution

Rate of Agglomerates, QbD Approach To formulation

Conclusion

29

Effect of maize

starch properties

on drug

dissolution rate

Case study 1

Aim of the work

„Pregelatinized maize starch contributes to retardation of both soluble and slightly

soluble drugs compared to microcrystalline cellulose or spray-dried lactose“Levina M, Rajabi-Siahboomi AR. The influence of excipients on drug release from hydroxypropyl methylcellulose matrices. J

Pharm Sci 2004;93:2746-54.

„Different cross-linking in starch samples causes substantial differences in release“Onofre F, Wang Y-J, Mauromoustakos A. Effects of structure and modification on sustained release properties of starches.

Carbohydr Polym 2009;76:541-7.

Our objective

compare API release from different starch matrices

describe release rate by mathematical model

correlate release parameters to functional properties

Experimental

5 different pregelatinized starch samples (courtesy of Zentiva company)

Characterization

SEM, XRD, DSC, PM

functional characteristics

Preparation of API/starch mixtures 1 : 4

SEM images of maize starch

Pregelatinized Native

Starch ID A B C D E

V/V0 4.9 4.4 5.7 8.1 7.7

wH2O, % 8 8 8 7 7

wdis,20°C, % 10.3 6.4 10.9 8.9 6.8

wdis,35°C, % 12.2 13.4 13.5 10.6 8.0

Maize starch functional properties

0 5 10

A

B

C

D

E

V/V0

0 5 10 15

A

B

C

D

E

wdis,35°C, %

Apparent intrinsic dissolution

Fill mixture

to

dissolution

die

Compress

a compact

in die and

place in

IDR

time

amount

released

Apparent IDR

IDR

Dissolution results

0,0

0,2

0,1

c, g.l-1

0 6030 t, min

111

1

11

1

1

1

1

1

1

1

1

11

11

1

2

22

22

2

2

2

2

2

2

2

2

2

2

2

2

2

2

333

33

3

3

3

3

3

3

3

3

3

3

33

33

0,0

0,2

0,1

c, g.l-1

0 6030 t, min

API1 API2

Cumulative dissolution profiles of caffeine released from caffeine-starch matrix comprising different

pregelatinized maize starch samples (A, B, C, D, E) measured in standard IDR apparatus (900 ml

0,1M HCl, 50 rpm)

Mathematical model

Noyes-Whitney

„Sink“ conditions + resistance

due to swollen layer

Swollen layer thickness

ef API,API

HL

*

APIAPI 1

d

d

DD

V

wAc

t

c

API

*

API ccKAr

HL

ST*

STST

ef CAF,CAF

HL*

CAFCAF

11

d

d

Dc

DD

ct

caffeine leaching starch

matrix

decay

Regression results - caffeine

0,0

0,2

0,1

c, g.l-1

0 6030 t, min

API1

Starch ID A B C D E

DAPI,

cm2.s−14.20 × 10−6

Def/DAPI180 181 135 30 25

RST,dis, cm.s-

1 (×103)0.09 0.61 < 0.01 1.38 1.34

Correlation analysis

0

100

200

3 5 7 9

Def/DCAFF

V/V0

0

1

2

7 11 15

RST, dis

cm2.s-1

wdis,(35 °C), %

0

100

200

4,0 5,0 6,0

Def/DCAFF

V/V00

1

11,0 15,0

RST, dis

cm2.s-1

wdis,(35 °C), %

API1

API2

starch, used in drug formulations, can significantly alter the active ingredient release profile

different maize starches within the pharmacopeial requirements can exhibit substantial differences in their effect on drug dissolution

retardation effect of starch on the release rate is determined

by the effective diffusivity of active ingredient within the swollen starch layer

by the rate of starch layer decay

effective diffusivity – strong function of swelling capacity

starch matrix decay

not simple function of starch solubility

can depend on API/mixture properties


Characterization.





Case Studies 1: VSCHT – Doc. Zámostný-Effect of maize

starch properties on drug dissolution rate



Conclusion

40

Dissolution Rate

of Agglomerates

- QbD Approach

To formulation

Case study 2

Aim of the work

The overall rate of the API release depends on arrangement and interactions of

APIs and excipients in dosage forms

Affected by dosage form processing history

Evaluate the API release rate from granules prepared by different granulation

methods and understand the effects

Setup

Powdered API

API/excipients granulated by wet-granulation

Compacted API/excipients

Fractions of particle size 75 – 125 μm and 425 – 1000 μm

Dissolution test:

USP 4: 0.1N HCl, 37 °C, open-loop arrangement

Dissolution cell for powders and granulate

Release rate from different agglomerates

powdered API (black)

wet granulate (green)

dry granulate (red)

425 – 1000 μm (filled

markers)

75-125 μm (empty

markers)

Release rate from different agglomerates

S

HL

CAD

dt

dm

Noyes-WhitneyResistance to

diffusion- binder

Adsorption- MCC

Wetting

m

m

mK

mKk

D

dd

D

CA

dt

dm

Ads

Ads

Ads

ef

ppHL

s

11

2

0

The data analysis allows us to determine the cause of possible

dissolution problems at the design stage


Characterization.





Case Studies 1: VSCHT – Doc. Zámostný - Effect of

maize starch properties on drug dissolution rate



Conclusion

46

Take-home Message.

API biopharmaceutical characterization may be considered as time consuming but…

In-vitro testing is not expensive compared to in-vivo studies.

It can guide and facilitate formulation development.

These are good tools to de-risk biostudies.

Different approaches can be used:

XRPD, DSC, particle morphology

Intrinsic / apparent dissolution

Evaluation of different dissolution methods than USP 1 & 2

Use of different pHs / media

Finally, development time can be shortened.

47

Thank you for cooperation.

Petr Zámostný, VSCHT

Samir Haddouchi, SPS Pharma

www.vscht.cz

www.sotax.com

www.sps-pharma.com

dissolution tools for api characterization. -...

Documents