Crospovidone as a dry binder in roll

compaction and direct compression

Dr. Verena Geiselhart

Pharma Ingredients & Services, BASF SE
1
 • Introduction
Part 1

• Benchmark studies dry binders

Part 2

• Benchmark study disintegrants

Part 3

• Crospovidone as complexing agent

Part 4
Granulation – Overview
Comparison of different granulation methods
Direct Compression

API (s) Excipients

Mixing

Compression

Tablets
3
Direct compression
Important requirements

 No de-mixing of powder mixture

 Similar densities required
 Suitable particle shapes/surfaces
 => Content uniformity!
 Good flowability of powder mixture
 Good compressibility

4
Granulation – Overview
Comparison of different granulation methods

API (s) Excipients

Mixing

GRANULATION STEP

Compression

Tablets
5
Granulation – Overview
Comparison of different granulation methods

API (s) Excipients

Mixing

Addition of
GRANULATION STEP Binder Solution
or solvent
Dry granulation, e.g. Thermal granulation,
Roll Compaction e.g. Melt Granulation, Wet Granulation
HME
Drying

Compression

Tablets
6
The equipment – Roll compactor
Source: Gerteis

7
The equipment – Roll compactor
Source: Gerteis

Breaker

Feeding auger

Tamping auger
Compaction rolls

Scraper

Granulation unit

8
The equipment – Granulator
Why bimodal particle size distribution?

Granulation

11
Roll compaction - Advantages

 Continuous process

 No water needed

 No expensive drying equipment

 Easy parameter to control

 High throughput

 Easy to scale-up

13
Roll compaction - Disadvantages
 High amount of fines
 Reduction of tensile strength of tablets (MCC 101)

11
tensile strength [N/mm²]

10

5
0 2 4 6 8 10 12
spec. compaction force [kN/cm]
Herting, Kleinebudde, Eur. J. Pharm. Biopharm. 70/1 (2008) 14
 • Introduction
Part 1

• Benchmark studies dry binders

Part 2

• Benchmark study disintegrants

Part 3

• Crospovidone as complexing agent

Part 4
Binders for direct compression &
dry granulation
Natural polymers Synthetic polymers

Cellulose derivatives Polyvinyl pyrrolidone derivatives

➢ Powder Cellulose ➢ Copovidone (VA 64)
➢ Microcrystalline Cellulose ➢ Crospovidone (crosslinked PVP)
➢ Hydroxypropyl methylcellulose
(HPMC)
➢ Hydroxypropyl cellulose (HPC)
Starch derivatives
➢ Pregelatinized starch

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Binders for direct compression &
dry granulation

Kollidon VA64 Fine

Vinylpyrrolidone / vinylacetate copolymer Copovidone
Copovidone
Kollidon VA64 (BASF SE)

Chemical Structure

CH CH2 CH CH2 Kollidon VA64

N Copovidone
O O O

m CH3 n

Mr= (111.1)m x (86.1)n 6+4

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Binders for direct compression &
dry granulation
Crosslinked PVP
Crospovidone Kollidon CL-M
Kollidon CL (BASF SE) Crospovidone

Kollidon CL-SF
 Insolubility mainly caused by physical Crospovidone
cross-linking ( chain entanglement)

 Chemical cross-linking contributes only to

a minor extend
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SEM pictures of the different binders

Kollidon VA64 Fine Kollidon CL-M

Copovidone Crospovidone

Kollidon VA64 Kollidon CL-SF

Copovidone Crospovidone

22
SEM pictures of the different binders

MCC L-HPC

HPMC 2910

23
Benchmark study dry binders

24
Benchmark study dry binders I
Formulation

Tablet Formulation I Fraction [%]

Binder 9
Dicalciumphosphate 91

Herting, Kleinebudde, Pharm Dev Tech, 12/5 (2007) 25

Benchmark study dry binders I
Experimental setup

Filler Binder Kollidon VA64

Kollidon VA64 Fine
Kollidon CL-M
Mixing Kollidon CL-SF
MCC
HPMC
Powder mixture L-HPC

Roll compaction In gap porosity [%]: 45,25

Granules

Compression Force level [kN]: 10, 18, 25

Tablets

Herting, Kleinebudde, Pharm Dev Tech, 12/5 (2007) 26

Benchmark Study dry binders I
Tensile strength of tablets obtained by DC

10 kN 18 kN 25 kN
[N/mm²]
strength [N/mm²]

2.0
2,0
Druckfestigkeit

1.0
1,0
tensile

0
0,0
ne

C
64

PC
M

10
S

PM
CL
Fi

CL

H
A

CC
V
64

H
M
A

Mean ± CI (n = 10, α = 0.05)

V

Herting, Kleinebudde, Pharm Dev Tech, 12/5 (2007) 27

Benchmark Study dry binders I
Tensile strength of tablets obtained by roll
compaction followed by compression

10kN 18kN 25kN

[N/mm²]
strength [N/mm²]

2.0
2,0
Druckfestigkeit

1.0
1,0
tensile

0,00
ne

C
64

PC
M

10
S

PM
CL
Fi

CL

H
A

CC
V
64

H
M
A

Mean ± CI (n = 10, α = 0.05)

V

Herting, Kleinebudde, Pharm Dev Tech, 12/5 (2007) 28

Influence of the particle size on the
number of particle contacts

Filler or active Filler or active

Dry binder Dry binder

29
Benchmark Study dry binders I
Tensile strengths of tablets made from granules
vs. d50 granules
1.2
1,2
[N/mm²]
strength[N/mm²]

1.0
1,0
VA 64 Fine
Druckfestigkeit

VA 64
CLM
0.8
tensile

0,8 CLSF
MCC
HPMC
HPC
0.6
0,6
0 100 200 300 400 500
dd50 Granulate[µm]
50 granules [µm]
Mean ± CI (n = 10, α = 0.05)
Herting, Kleinebudde, Pharm Dev Tech, 12/5 (2007) 31
 • Introduction
Part 1

• Benchmark studies dry binders

Part 2

• Benchmark study disintegrants

Part 3

• Crospovidone as complexing agent

Part 4
Disintegrants
Function & Requirements
Function:
 Accelerate disintegration of tablet

Requirements:
 Hydrophilic
 Water insoluble
 In solution no increase of viscosity
 Good flowability
 High compressibility
Disintegrants
Mechanism of action

Crospovidone Starch Cellulose Ion exchanger

swelling deformation wicking repulsion

swelling
Disintegrants
Particle size distribution

Measurement via laser diffraction (Malvern)

%
10 100
Mean
Particle size Kollidon CL-M Kollidon CL-SF Competiitor B 90
Span
D_[4,3]
80
[µm]
Kollidon CL-F 70
Kollidon CL 118 2,0
Kollidon CL -M 5 1,6 60
Kollidon CL
Kollidon CL -F 29 2,9 50
Kollidon CL -SF 17 2,4
40
Competitor A 145 2,7
Competitor B 27 1,8 Competitor A 30
L

Ac-Di-Sol 20
49 2,4
(Na-CMC)
10
Primojel
41 1,1 0 0
(Na-starch glycolat e) 1.0 10.0 100.0 1000.0

Particle Diameter (µm.)

The disintegrant – a crucial building block
Kollidon® CL disintegrants

 Kollidon® CL – BASF crospovidone grades

Specific
Ph. PSD Bulk Tapped Hydration
surface
Eur. malvern density density capacity
area
Type [m] [g/ml] [g/ml] [g/g]
[m2/g]

Kollidon® CL A standard 110-130 0.30–0.40 0.40–0.50 3.5–5.5 <1

Kollidon® CL-F A fine 20-40 0.18–0.28 0.25–0.35 5.5–6.6 ~1.5

Kollidon® CL-SF B super fine 10-30 0.10–0.16 0.18–0.25 7.0–8.5 ~3

Kollidon® CL-M B micronized 3-10 0.15–0.25 0.25–0.35 3.0–4.5 >6

Kollidon® CL is available in four grades with different characteristic properties

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Disintegrants
Ethanol uptake capacity of different disintegrants
15 g disintegrants in 45 ml ethanol

Kollidon CL-M Kollidon CL Competitor A Competitor B

Kollidon CL-F Kollidon CL-SF Ac-Di-Sol Primojel

The disintegrant – a crucial building block
Kollidon® CL disintegrants

 BASF crospovidone grades

50 m

Kollidon® CL Kollidon® CL-F Kollidon® CL-SF Kollidon® CL-M

10 m

The Kollidon® CL grades differ in particle size distribution and surface structure
46
Benchmark study disintegrants

48
Disintegrants
DC-placebo formulation with different disintegrants

Composition of placebo tablet:

Ludipress LCE* 467,50 mg

Disintegrant 30,00 mg
Mg-stearate 2,50 mg
______________________________________________________________

Tablet weight 500,00 mg

All components were sieved and tumbeled in a turbula mixer for 10 min
.
* Ludipress LCE does not contain disintegrants.
Disintegrants
Disintegration of placebo tablets

480
433
disintegration time [s]

420

360

300
250
240

180
116 129 120
120 93 81
69 73
60

0
Disintegrants
Influence of disintegrants on tablet hardness

Hardness as a function of compression force (formulation - Ludipress LCE)

Kollidon CL Competitor B
Competitor A Kollidon CL-F
240
Kollidon CL-SF Kollidon CL-M
Ac-Di-Sol Primojel

200
hardness [N]

160

120

80

40

0
0 5 10 15 20 25 30

compression force [kN]

Disintegrants
Influence of tablet hardness on disintegration time

Disintegration time as a function of hardness (formulation - Ludipress LCE)

Kollidon CL Competitor B
Competitor A Kollidon CL-F
Kollidon CL-SF Kollidon CL-M
360
Ac-Di-Sol Primojel

300
disintegration time [s]

240

180

120

60

0
0 50 100 150 200 250

hardness [N]
 • Introduction
Part 1

• Benchmark studies dry binders

Part 2

• Benchmark study disintegrants

Part 3

• Crospovidone as complexing agent

Part 4
Kollidon®
Dissolution of Indomethacin after mixing with PVP/Crospovidone

Dissolved indomethacin [%]

100
90
+ Kollidon CL-M 1+2
80
70
60 + Kollidon 30 1+2

50
40
30
20
Indomethacin alone
10
0
0 30 60 90 120
Time [min]
56
Kollidon® CL grades
Comparison of Disintegrants: Formulation with APIs

Formulation 2:
ASS-powder 250,00mg
Acetaminophen cryst. 250,00mg
Caffeine gran. 0,2-0,5 50,00mg
Kollidon 30 27,50mg
Disintegrant 16,00mg
Mg-stearate 5,00mg
Tablet weight 598,50mg

This mixture was granulated in the DIOSNA-mixer at stage 2 (with chopper)

for 2 minutes and sieved in the Alexanderwerk (vertical sieve).
For drying the granules were spread on a tray, stored for 2 days at ambient
conditions and sieved again in the Alexanderwerk (horizontal sieve).

57
Kollidon® CL grades
Comparison of Disintegrants: Dissolution of Acteaminophen

 Dissolution of acetaminophen tablets

(Ludipress® LCE + 2.7% disintegrant; wet granulation; 18 kN compression force)

100
dissolved drug [%]

90 Kollidon® CL
80 Kollidon® CL-F
70 Kollidon® CL-SF
60 Crospov. Compet. A (100–130 µm)
50 Crospov. Compet. A (30–50 µm)
40 Croscarmellose-sodium
30
20 Sodium starch glycolate
10
0
0 10 2 30 40 50 60 70 80 90 100 110 120 method: paddle 100 rpm; 37 °C
0 time [min]

Dissolution profiles can differ in dependency of type of crospovidone applied

58
Kollidon® CL grades
Guideline

Performance Demands
Good Improved
Water Smooth
Fast Dis- mouthfeel Hard drug
uptake tablet
integration (e.g. for tablets solubility/
capacity surface*
ODTs) dissolution

Kollidon® CL

Kollidon® CL-F

Kollidon® CL-SF

Kollidon® CL-M Mainly used as suspension stabilizer (but also good dry binder)
* When stored in multi-dose container

The four Kollidon® CL types are tailored to optimize different tablet properties
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 Instant & Modified Release Platform
Decision tree for Binders

Functions:
Binders - Improve of mechanical stability of tablet (packaging, coating)
- Improve tabletting properties of powder blend/granules (e.g. flowability)

Direct Granulation
compression
High performance Dry* Wet
Kollidon VA64 Fine
High performance
Kollidon CL-M
Kollidon VA64 Fine
Economy Aqueous Solvent- Low volume, Hydrophobic
Kollidon CL-M Peroxide based high efficiency
Kollidon VA64
Economy protection
Kollidon CL-SF P
Kollidon VA64 Good VA64 VA64 Kollidon 90 F P Kollicoat SR 30D
▪ 2 in 1 = dry binder +
disintegrant Kollidon CL-SF P Extended K25 / K30 P K25 / K30 P

▪ 2 in 1 = dry binder + K30 LP P K30 LP P

Ludipress
disintegrant
Best Kollicoat IR (Kollicoat IR)

P Peroxeal packaging
* e.g. roll compaction Ready-to-use 60
Instant & Modified Release Platform
Decision tree for Disintegrants

P Peroxeal packaging
Function:
Disintegration - Fast disintegration of tablet for fast API
Ready-to-use

release.

coarse Particle size fine

Kollidon® CL P Kollidon® CL-F P Kollidon® CL-SF P Kollidon® CL-M

▪ Max disintegration ▪ Strong disintegration ▪ Good disintegration For small tablets

▪ For standard to big ▪ For wide range of ▪ Best mouthfeel Strong dry binder!
tablets tablet sizes ▪ Optimal for ODTs
▪ Coarse particles ▪ Dry binder!

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Instant & Modified Release Platform
Decision tree for Lubricants

Common option
Function:
Lubricants - reduction of friction forces, mechanical &
currently not in
our portfolio
thermal stress

Lipophilic lubricant Hydrophilic / watersoluble lubricants

Sensitive API Non-sensitive API Kolliphor P188 micro

Kolliphor P407 micro

Acidic API Alkaline API Kolliphor SLS Fine

Kolliwax SA Mg Stearate Mg Stearate

Kolliwax S Fine Remark:
Kolliwax HCO Usually the best lubricant is Mg Stearate
Glyceryl Dibehenate (not BASF portfolio).
Sodium Stearyl Fumarate Reasons for other lubricants:
- Incompatibilities with Mg Stearate
- Water-soluble lubricant needed (e.g.
effervescents)

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Thank you for your attention! Questions?

www.pharma-solutions.basf.com

65