UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Tablets & tableting
Jukka Rantanen
&
Holger Grohganz
Dias 1
UNIVERSITY
OF
COPENHAGEN
university of copenhagen
Department
Pharmacy
Department
of of
Pharmacy
Intended learning outcomes
After this lecture the students should be able to
• Identify the key excipients in a tablet product
• Understand the influence of bulk properties on
tableting process
• Explain the difference between compressibility
and compactability
• Discuss the functionality of the various excipient
types
• Describe standard tabletting machines
• Discuss the interplay between process
parameters and tablet properties
Dias 2
UNIVERSITY
OF
Dias 3
COPENHAGEN
Department of Pharmacy
UNIVERSITY
OF
Tabletter
Dias 4
Department of Pharmacy
COPENHAGEN
Piller
UNIVERSITY
OF
COPENHAGEN
Pills and tablets
Dias 5
Department of Pharmacy
X
X
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Tabletmaskiner
Dias 6
UNIVERSITY
OF
COPENHAGEN
Overstempel, understempel og matrice
Dias 7
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
EKSCENTERTABLETMASKINE
Dias 8
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
EKSCENTERTABLETMASKINE
komprimeringscyklus
Dias 9
Department of Pharmacy
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
ROTATIONSTABLETMASKINE
Stempler: 100
Stemplehastighed: 100 km/t
Tabletter pr. time: 1.000.000
Vægt: 4 ton
Dias 10
UNIVERSITY
OF
COPENHAGEN
ROTATIONSTABLETMASKINE
komprimeringscyklus
Dias 11
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Høj komprimeringshastighed på
ROTATIONSTABLETMASKINER medfører
•
øgede krav til komprimeringsevne
 anvend egnede råvare
•
øgede krav til udluftning
 forkomprimering
•
øgede krav til flydeegenskaber
 brug af tvangsføder
Dias 12
Department of Pharmacy
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
KONSTRUKTIONSFORSKELLE
ekscenter- & rotationstabletmaskine
Ekscenter-tabletmaskine
Matrice
Doseringsprincip
Trykpåvirkning
Antal stempler
Rotationstabletmaskine
Fastsiddende
Bevægelig
Bevægelig
Fastsiddende
Ensidigt gen.
overstempel
1
Dobbeltsidigt (bedre
trykfordeling)
Mange
(6-120)
UNIVERSITY
OF
COPENHAGEN
university of copenhagen
From particle to powders
and finally, a TABLET
Dias 14
Department
Pharmacy
Department
of of
Pharmacy
UNIVERSITY
OF
COPENHAGEN
Tablets on the Danish market
What is out there? medicin.dk
Dias 15
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Tablets on the Danish market
What is out there? produktresume.dk
Department of Pharmacy
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Tablets on the Danish market
What is out there? produktresume.dk
DATA science approach:
WEB SCRAPING from produktresumer.dk
SuperTab® 11SD
120 Sheffield™ 80M
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Eksempel:
Naproxen tabletter 250 mg, 300.000 stk
Forskrift:
Naproxen Ph.Eur.
I Cellulose, mikrocrystallinsk Ph.Eur.
Calciumhydrogenphosfat dihydrat Ph.Eur.
75 kg
55 kg
33,5 kg
Silica, kolloid vandfri Ph.Eur.
900g
Magnesiumsterat Ph.Eur.
300g
II
Tabletbruttomasse: 549 mg
45,5% heraf er lægemiddelstof
Dias 18
UNIVERSITY
OF
Dias 19
COPENHAGEN
Department of Pharmacy
UNIVERSITY
OF
Dias 20
COPENHAGEN
Department of Pharmacy
UNIVERSITY
OF
Dias 21
COPENHAGEN
Department of Pharmacy
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Hjælpestoffer
Handelsnavn
Farmakopénavn
Middelpartikel
størr.
Avicel®
PH102
Cellulose, mikrocrystallinsk
fylde- og
100 µm sprængem.
-
Emcompress®
Calciumhydrogenphosfatdihydrat
fylde100 µm
middel.
-
Aerosil®
Silica, kolloid
vandfri (SiO2)
MgStearat
Magnesiumstearat
15 µm
Hjælpestof
gruppe
glittem.
flydefrem.
frikt.nedsæt.
5 µm
antiadhæsion
Specifik
overflade
200
m2/g
5 m2/g
UNIVERSITY
OF
Dias 23
COPENHAGEN
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Procesdiagram
Naproxen tabletter
Dias 24
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Naproxen tabletter 250 mg, 300.000 stk
Forskrift:
Naproxen Ph.Eur.
I
Avicel®PH102
Emcompress®
II
Aerosil®
Magnesiumstearat Ph.Eur.
Tabletbruttomasse: 549 mg
45.5% heraf er lægemiddelstof
Dias 25
75 kg
55 kg
33.5 kg
900 g
300 g
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
BULKEGENSKABER
• er egenskaber af en samling enkeltpartikler
• har stor indflydelse på produktionsprocessen
bulk
→ noun
1 [mass noun] the mass or size of something large: residents jump up and down on their rubbish
to reduce its bulk.
• large size or shape: he moved quickly in spite of his bulk.
• [count noun] a large mass or shape.
• [as modifier] large in quantity: bulk orders of over 100 copies.
• cargo in an unpackaged mass such as grain or oil.
– PHRASES
in bulk
1 (of goods) in large quantities and generally at a reduced price: retail multiples buy in bulk.
2 (of a cargo or commodity) not packaged; loose.
– ORIGIN Middle English: the senses ‘cargo as a whole‘ and ‘heap, large quantity‘ (the earliest
recorded) are probably from Old Norse búlki ‘cargo‘;
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
BULKEGENSKABER
er egenskaber af en samling enkeltpartikler
Bulkdensitet
rB =
Vo
m
VL
Vo
Bulkporøsitet
e= V
rB
e = 1- r
VL
o
UNIVERSITY
OF
COPENHAGEN
Stampevolumeter
250 stamp pr minut
”Faldhøjde”: 3 mm
Dias 28
Department of Pharmacy
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
BULKEGENSKABER
er egenskaber af en samling enkeltpartikler
Bulkvolumen
Dias 29
Vo
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
BULKEGENSKABER
Kompressibilitetsindekset, K
K=
Vo- Vk
Vo
* 100%
Vo
Letflydende pulvere, K<15%
Kohæsive pulvere, K>25%
Dias
30
Vk
UNIVERSITY
OF
COPENHAGEN
BULKEGENSKABER
Flydeegenskaber betingede af:
1. Partiklernes
• Størrelse
• Form
• Densitet
• Overflade
2. Ydre påvirkninger
• Pakning, Fluidisering
• Fugt
• Elektrostatisk opladning
Dias 31
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
KOHÆSIVITET
• Afhænger af partikelstørrelse og partikelform.
• Medfører sammenklumpning.
• Kohæsive pulvere kan være svære at håndtere.
Dias 32
UNIVERSITY
OF
a.
Dias 33
Department of Pharmacy
COPENHAGEN
b.
UNIVERSITY
OF
COPENHAGEN
FORBEDRING AF FLYDEEGENSKABERNE
•
Maskinel
•
Variation af råvarens egenskaber
•
Formuleringsmæssige tiltag
Dias 34
Department of Pharmacy
Dias 35
Tvangsføder
Dias 36
UNIVERSITY
OF
COPENHAGEN
Variation af råvarens egenskaber
Modificering af partikelstørrelsen
 granulering
Modificering af partikelformen
 spraytørring
 omkrystallisering
Dias 37
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Formuleringsmæssige tiltag:
tilsætning af glittemiddel
Glittemiddeltyper:
•
Flydefremmende glittemidler (”glidant”)
(eks. talkum, kolloid silica)
•
Friktionsnedsættende glittemidler (”lubricant”)
(eks. talkum, Ca- & Mg-stearat)
•
Antiadhæsions-glittemidler (”antiadherent”)
(eks. Ca- & Mg-stearat, hærdede olier)
Dias 38
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Fraktionering, vibrering
Udgangstilstand
Mellemtilstand


fuldstændig
god
adskilt
blandingstilstand
Dias 39
Sluttilstand

fuldstændig
fraktionering
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Fraktionering, udhældning
ophobning af små
partikler
ophobning af store
partikler
Dias 40
UNIVERSITY
OF
Dias 41
COPENHAGEN
Department of Pharmacy
UNIVERSITY
OF
Dias 42
COPENHAGEN
Department of Pharmacy
UNIVERSITY
OF
Dias 43
COPENHAGEN
https://www.youtube.com/watch?v=MdFyqF-rwRw
Department of Pharmacy
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Opgave 1
Blanding
nr.
Flydehastighed Vo,
ml
sek./100g
Vk,
ml
1
5.1
144 129
2
8.5
147 121
3
6.0
166 150
Kompressibilitetsindeks, %
Dias 45
Prepare to vote
Internet
1 Go to sendsteps.me
This presentation
has
loaded without the Sendsteps add-in.
2 Log
in been
with science4233
Want to download the add-in for free? Go to
https://dashboard.sendsteps.com/.
TXT
1 Text to 4199 2016
2 Type science4233 <space> your choice
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Opgave 1: Den bedste blanding er...
A.
B.
C.
1
2
3
Blanding nr.
Flydehastighed
sek./100g
Vo, ml
Vk, ml
1
5.1
144
129
2
8.5
147
121
3
6.0
166
150
The question will open when you
start your session and slideshow.
Closed
This
presentation has been loaded without the Sendsteps add-in.
"Description of message sending methods"
Want to download the add-in for free? Go to 0
"It will be inserted after you've started a session"
https://dashboard.sendsteps.com/.
Internet
TXT
0
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Opgave 1: Den bedste blanding er...
A.
1
B.
2
C.
3
28.9%
7.2%
63.9%
Closed
This
presentation has been loaded without the Sendsteps add-in.
"Description of message sending methods"
Want to download the add-in for free? Go to
"It will be inserted after you've started a session"
https://dashboard.sendsteps.com/.
Internet
TXT
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Opgave 1
Blanding
nr.
Flydehastighed Vo,
ml
sek./100g
Vk,
ml
1
5.1
144 129
2
8.5
147 121
3
6.0
166 150
Kompressibilitetsindeks, %
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Opgave 1
Blanding
nr.
Flydehastighed Vo,
ml
sek./100g
Vk,
ml
Kompressibilitetsindeks, %
1
1. 5.1
144 129
2. 10.4
2
3. 8.5
147 121
3. 17.7
3
2. 6.0
166 150
1. 9.6
UNIVERSITY
OF
COPENHAGEN
Komprimeringsprocessen
Dias 50
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Komprimeringsprocessen
Dias 51
Tryk (MPa)
Densitet (g/cm3)
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Bindingsmekanismer
Hvad holder en tablet sammen?
To faktorer er mest relevante
• Dominerende bindingsmekanisme.
• Kontaktfladen hvor bindingerne er aktive.
De vigtigste bindingsmekanismekræfter for tabletter
• Intermolekylære kræfter(hovedsageligt van-der
Waals kræfter, men også: elektrostatiske kræfter
og hydrogenbindinger)
• Faste broer (kontakt på atomart niveau mellem to
overlader; smeltning eller sammensintring)
• Mekanisk fastlåsning af uregelmæssige krogede
partikler
• (Fugt)
Dias 52
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Komprimeringsegenskaber
Kompressibilitet
• partikelsystemets evne til at deformere eller
formindske volumen under kraftpåvirkning
Kompaktibilitet
• partikelsystemets evne til at danne en
sammenhængende masse under
kraftpåvirkning
Dias 53
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Komprimeringsegenskaber
elastisk
plastisk
Kompaktering
skørt
Forøgelse af bindingsareal
Fordelagtigt mht. flydegenskaber :
Store partikler
Glatte overflader
Sfæriske partikler
Dias 54
Problem: Mindre bindingsareal
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Compaction simulator
Gamlen
compaction simulator
Fordele:
- Materialebesparende
- Registrering af kraft/vej diagram
- Kontrol af komprimeringskraft, -hastighed og –tid.
- Vurdering af udstødningskraft, glittemiddeleffekt.
Dias 55
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Kraftdiagramme
A2
A
Dias 56
A1
B
overstempelkraft
overstempelkraft
B
A2
A
C
A1
C
overstempelbevægelse
overstempelbevægelse
a.
b.
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Kompressibilitet
Ascorbinsyre
1
𝑙𝑛 ln(1/
)
1 − 𝐷𝑟𝑒𝑙
2
1
Mikrokrystallinsk cellulose
0
0
50
100
Overstempeltryk (MPa)
Dias 57
150
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Kompaktabilitet
800
Tabl etbrudstyrke (N)
Mikrokrystallinsk cellulose
600
400
200
Sorbitol
0
0
50
100
150
200
Maksimalt komprimeringstryk (MPa)
Dias 58
250
UNIVERSITY
OF
COPENHAGEN
Hyppige problemer ved komprimering
• Vedhæng (sticking)
• Lågdannelse (capping)
• Ændring i bruttomasse
Dias 59
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Opgave 2
•
I forbindelse med opskalering fra ekscentertabletmaskine til
rotationstabletmaskine af komprimeringsprocessen for
Naproxen tabletter 250 mg er effekten af komprimeringskraft
og rotationshastighed på egenskaberne af tabletter fremstillet
på rotationstabletmaskinen undersøgt ved tre forskellige
komprimeringskræfter og tre forskellige rotationshastigheder.
•
Der er undersøgt følgende tabletegenskaber:
Massevariation, srel %
Trykbrudstyrke, N
Lågdannelsesfrekvens, %
Henfaldstid, min./sek.
•
De opnåede resultater er anført i nedenstående tabel, hvor
tabletegenskaberne er angivet i oven-nævnte rækkefølge.
Dias 60
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
OPGAVE 2
Relativ spr. masse, %
Lågdannelsesfrekvens, %
Brudstyrke, N
Henfaldstid, min
Rotationshastighed
Trykkraft
30.000
40.000
50.000
15 KN
0,82%
37,6 N
0%
2’51’’
0,75%
34,9 N
0%
2’31’’
2,13%
31,2 N
1%
1’15’’
20 KN
0,89%
72,3 N
0%
7’22’’
0,94%
70,4 N
0%
5’27’’
2,64%
52,3 N
2%
3’05’’
25 KN
0,87%
87,1 N
0%
12’38’’
1,20%
76,8 N
3%
11’40’’
3,34%
74,1 N
8%
9’13’’
Dias 61
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Hvilke procesparametre vælges?
(trykkraft, rotationshastighed)
A.
B.
C.
D.
E.
F.
G.
H.
I.
15
15
15
20
20
20
25
25
25
kN,
kN,
kN,
kN,
kN,
kN,
kN,
kN,
kN,
30.000
40.000
50.000
30.000
40.000
50.000
30.000
40.000
50.000
Rotationshastighed
Trykkraft
30.000
40.000
50.000
15 KN
0,82%
37,6 N
0%
2’51’’
0,75%
34,9 N
0%
2’31’’
2,13%
31,2 N
1%
1’15’’
20 KN
0,89%
72,3 N
0%
7’22’’
0,94%
70,4 N
0%
5’27’’
2,64%
52,3 N
2%
3’05’’
25 KN
0,87%
1,20%
3,34%
87,1 N
76,8 N
74,1 N
0%
3%
8 %you
The question
will open when
12’38’’
9’13’’
start your 11’40’’
session and slideshow.
Closed
This
presentation has been loaded without the Sendsteps add-in.
"Description of message sending methods"
Want to download the add-in for free? Go to 0
"It will be inserted after you've started a session"
https://dashboard.sendsteps.com/.
Internet
TXT
0
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Hvilke procesparametre vælges?
(trykkraft, rotationshastighed)
2.8%
A.
15 kN, 30.000
B.
15 kN, 40.000
C.
15 kN, 50.000
D.
20 kN, 30.000
E.
20 kN, 40.000
F.
20 kN, 50.000
G.
25 kN, 30.000
H.
25 kN, 40.000
0.0%
I.
25 kN, 50.000
0.0%
14.1%
1.4%
15.5%
60.6%
1.4%
4.2%
Closed
This
presentation has been loaded without the Sendsteps add-in.
"Description of message sending methods"
Want to download the add-in for free? Go to
"It will be inserted after you've started a session"
https://dashboard.sendsteps.com/.
Internet
TXT
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
OPGAVE 2
Relativ spr. masse, %
Lågdannelsesfrekvens, %
Brudstyrke, N
Henfaldstid, min
Rotationshastighed
Trykkraft
30.000
40.000
50.000
15 KN
0,82%
37,6 N
0%
2’51’’
0,75%
34,9 N
0%
2’31’’
2,13%
31,2 N
1%
1’15’’
20 KN
0,89%
72,3 N
0%
7’22’’
0,94%
70,4 N
0%
5’27’’
2,64%
52,3 N
2%
3’05’’
25 KN
0,87%
87,1 N
0%
12’38’’
1,20%
76,8 N
3%
11’40’’
3,34%
74,1 N
8%
9’13’’
Dias 64
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Instrumentering
Dias 65
UNIVERSITY
OF
COPENHAGEN
ROTATIONSTABLETMASKINE
Dias 66
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Instrumentering af tabletmaskiner
Produktion:
Proceskontrol,sammenhæng tryk/vægt
Problem:
Aktion
Massevariation
sortering
Defekte stempler
stop
Bruttovægt
regulering
Udvikling, kvalitetssikring:
Udstødningskraft, glitning
Komprimeringsegenskaber
Dias 67
Department of Pharmacy
UNIVERSITY
OF
COPENHAGEN
Department of Pharmacy
Stempel nr 40
Rotationstabletmaskine med 60 stempler
Dias 68
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Stempelkraft (kN)
7
6
5
4
3
280
290
300
310
Tabletmasse (mg)
Dias 69
320
330
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Stempelkraft (kN)
7
6
5
4
3
280
290
300
310
Tabletmasse (mg)
Dias 70
320
330
UNIVERSITY
OF
Department of Pharmacy
COPENHAGEN
Sammenfatning
• Direkte komprimering stiller store krav til
stoffernes flyde- og komprimeringsegenskaber
• I proceskontrollen kan komprimeringstrykket
anvendes som et indirekte mål for tabletternes masse.
• Bulk- og stampevolumen giver et bedre udtryk for
bulkegenskaber end måling af flydeevne
DET HEDDER IKKE PILLER!
Dias 71