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畢業(yè)設(shè)計（論文）
外文翻譯
學(xué)生姓名
班 級
學(xué) 號
學(xué)院名稱
專業(yè)名稱
指導(dǎo)教師
年
5月
26日
asian?journal?of?pharmaceutical?sciences?12?(2017)?412–417
Available?online?at?www.sciencedirect.com
ScienceDirect
journal?homepage:?www.elsevier.com/locate/ajps
Original?Research?Paper
Prediction?of?effects?of?punch?shapes?on
tableting?failure?by?using?a?multi-functional
single-punch?tablet?press
Takashi?Osamura?a,b,?Yoshiko?Takeuchi?a,?Risako?Onodera?a,?Masahiro?Kitamura?b,
Yoshiteru?Takahashi?b,?Kohei?Tahara?a,?Hirofumi?Takeuchi?a,*
a
b
Laboratory?of?Pharmaceutical?Engineering,?Gifu?Pharmaceutical?University,?1-25-4?Daigaku-Nishi,?Gifu?501-1196,?Japan
Pharmaceutical?Technology?Department,?Sawai?Pharmaceutical?Co.?Ltd,?12-34,?Hiroshibacho,?Suita-Shi,?Osaka?564-0052,?Japan
A?R?T?I?C?L?E
I?N?F?O
A?B?S?T?R?A?C?T
Article?history:
Received?11?April?2017
Accepted?4?May?2017
Available?online?17?May?2017
Keywords:
Tableting
Formulation?design
Lubricant
Punch?shape
Single-punch?tablet?press
Losartan?potassium
We?previously?determined?“Tableting?properties”?by?using?a?multi-functional?single-punch
tablet?press?(GTP-1).?We?proposed?plotting?“Compactability”?on?the?x-axis?against
“Manufacturability”?on?the?y-axis?to?allow?visual?evaluation?of?“Tableting?properties”.?Various
types?of?tableting?failure?occur?in?commercial?drug?production?and?are?in?uenced?by?the
amount?of?lubricant?used?and?the?shape?of?the?punch.?We?used?the?GTP-1?to?measure
“Tableting?properties”?with?different?amounts?of?lubricant?and?compared?the?results?with
those?of?tableting?on?a?commercial?rotary?tableting?machine.?Tablets?compressed?with?a?small
amount?of?lubricant?showed?bad?“Manufacturability”,?leading?to?sticking?of?powder?on?punches.
We?also?tested?various?punch?shapes.The?GTP-1?correctly?predicted?the?actual?tableting?results
for?all?punch?shapes.?With?punches?that?were?more?likely?to?cause?tableting?failure,?our?system
predicted?the?effects?of?lubricant?quantity?in?the?tablet?formulation?and?the?occurrence?of
sticking?in?the?rotary?tableting?machine.
??2017?Production?and?hosting?by?Elsevier?B.V.?on?behalf?of?Shenyang?Pharmaceutical
University.?This?is?an?open?access?article?under?the?CC?BY-NC-ND?license?(http://
creativecommons.org/licenses/by-nc-nd/4.0/).
1.
Introduction
powders?have?been?investigated?by?using?the?equations?of
Kawakita?and?Ludde?[1],?Heckel?[2,3],?and?Klevan?et?al.?[4].?Some
constants?in?these?equations?are?frequently?used?as?indica-
In?developing?a?tablet?formulation,?it?is?necessary?to?under-
stand?“Tableting?properties”?and?to?determine?the?optimum
type,?grade,?and?amount?of?ingredients.?“Compressibility”?is
evaluated?by?loading?pressure?onto?a?powder?bed?while?mea-
suring?the?bulk?density?of?the?bed.?The?properties?of?formulated
tors?of?“Compressibility”.?“Compactability”?is?typically?evaluated
by?measuring?the?tensile?fracture?stress?(TFS)?of?tablets?as?a
function?of?compaction?pressure?[5,6].?“Manufacturability”?con-
cerns?tableting?failure?(e.g.,?sticking,?capping,?and?binding).
Sugimori?et?al.?proposed?that?capping?could?be?predicted?from
*?Corresponding?author.?Gifu?Pharmaceutical?University,?1-25-4?Daigaku-nishi,?Gifu?501-1196,?Japan.?Tel.:?+81?58?230?8100.
E-mail?address:?takeuchi@gifu-pu.ac.jp?(H.?Takeuchi).
Peer?review?under?responsibility?of?Shenyang?Pharmaceutical?University.
http://dx.doi.org/10.1016/j.ajps.2017.05.001
1818-0876/??2017?Production?and?hosting?by?Elsevier?B.V.?on?behalf?of?Shenyang?Pharmaceutical?University.?This?is?an?open?access
article?under?the?CC?BY-NC-ND?license?(http://creativecommons.org/licenses/by-nc-nd/4.0/).
asian?journal?of?pharmaceutical?sciences?12?(2017)?412–417
413
residual?die?wall?pressure?[7].?Urabe?et?al.?suggested?that?es-
timation?of?general?tableting?properties?and?failures?was?possible
by?using?a?micro-powder?characterizer?with?in?nitesimal?quan-
tities?of?powder?sample?[8,9].
2.
2.1.
Materials?and?methods
Materials
Combining?these?separate?tests,?the?Gamlen?Tablet?Press
(GTP-1;?Gamlen?Tableting?Ltd.,?Nottingham,?UK),?a?benchtop
single-punch?tablet?press,?measures?pressure?and?displace-
ment?during?compression,?the?friction?between?die?and?tablet
during?ejection?(ejection?stress),?and?the?strength?of?the?tablet
(TFS)?in?a?single?device.?In?our?previous?study,?we?suggested
the?use?of?TFS?as?an?indicator?of?“Compactability”?and?ejec-
We?purchased?granulated?lactose?(Dilactose?R;?Freund?Corpo-
ration,?Japan),?microcrystalline?cellulose?(MCC:?Ceolus?PH302,
Asahi?Kasei?Chemicals,?Japan),?partly?pregelatinized?starch
(Starch?1500;?Nippon?Calorcon,?Japan),?magnesium?stearate
(MgSt;?Taihei?Chemical,?Japan),?and?losartan?potassium?(LP;
Kolon,?Korea).
tion?stress?as?an?indicator?of?“Manufacturability”,?as?die?wall
friction?can?be?problematic?when?the?tablet?is?ejected?from
2.2.
Methods
the?die?[10].?We?evaluated?“Compressibility”,?“Compactability”,
and?“Manufacturability”?with?a?GTP-1?and?plotted?TFS?(i.e.,
“Compactability”)?on?the?x-axis?against?ejection?stress?(i.e.,
“Manufacturability”)?on?the?y-axis?to?allow?visual?evaluation
of?the?quantitative?“Tableting?properties”?of?formulations.?This
method?makes?it?possible?to?reach?an?optimum?tablet?formu-
lation?quickly.?We?demonstrated?the?usefulness?of?the?method
by?using?losartan?potassium?as?an?active?pharmaceutical?in-
gredient,?microcrystalline?cellulose?as?an?excipient,?and
magnesium?stearate?(MgSt)?as?a?lubricant?in?a?model?formu-
lation.?We?con?rmed?quantitatively?that?the?microcrystalline
cellulose?increased?the?“Compactability”,?and?that?the?amount
of?MgSt?and?mixing?time?affected?both?“Compactability”?and
“Manufacturability”.
Commercial?drug?production?uses?rotary?tableting?ma-
chines?with?much?more?dynamic?tableting?conditions?than?the
GTP-1.?We?therefore?need?to?determine?the?relationship?between
the?results?obtained?with?each?apparatus.?Pitt?et?al.?reported
that?“Compactability”?determined?by?the?GTP-1?agreed?with?that
produced?by?an?industrial?tableting?machine?(Fette;?Fette?Com-
pacting,?Germany)?[11].?They?found?that?measurement?of?the
ejection?stress?using?the?GTP-1?was?useful?in?predicting?the
occurrence?of?capping?during?commercial-scale?tableting?of?for-
mulations?with?different?levels?of?microcrystalline?cellulose.
In?general,?tableting?failures?are?strongly?affected?by?the?amount
of?lubricant?in?the?formulation?and?the?shape?of?the?tablet?(i.e.,
the?punch?shape).?A?lack?of?lubricant?lowers?“Manufacturability”
and?leads?to?tableting?failure?[12,13].?On?the?other?hand,?too
much?lubricant?reduces?“Compactability”?and?thus?tablet
strength?[14].?In?addition,?some?punch?shapes?are?more?prone
to?tableting?failure,?notably?punches?that?have?secant?lines,?em-
bossed?marks,?and?large?curves?on?their?surfaces?[15,16].?When
these?types?of?punches?are?used,?more?lubricant?is?needed?in
the?formulation?to?prevent?tableting?failure.?When?predicting
“Tableting?properties”?at?the?production?scale?by?using?the
GTP-1,?both?“Compactability”?and?“Manufacturability”?need?to
be?satisfactory,?and?the?shape?of?the?punch?must?be?chosen
to?minimize?tableting?failure.
Here,?we?prepared?four?formulations?with?different
amounts?of?lubricant.?We?measured?the?“Compactability”?and
2.2.1.? Sample?preparation
Tablets?with?the?formulations?listed?in?Table?1?were?prepared
by?direct?compression.?In?all?cases?the?quantity?was?450?g,?which
is?enough?to?make?3000?tablets?of?150?mg?each?at?the?manu-
facturing?scale.?LP,?Dilactose?R,?MCC,?and?Starch?1500?were?mixed
in?a?plastic?bag?and?sieved?through?a?12-mesh?sieve.?The?sieved
powder?was?mixed?for?10?min?at?10?rpm?in?a?rotary?mixer?(CB1-
5/10;?10?L;?Picks?Technica,?Japan).?MgSt?was?added?to?the?mixture
at?0,?0.5,?1,?or?3?mg?per?tablet?(Table?1)?and?then?samples?B?(MgSt
0.5),?C?(MgSt?1),?and?D?(MgSt?3)?were?mixed?for?a?further?60?min.
2.2.2.? Evaluation?of?formulations?on?the?GTP-1
The?GTP-1?measures?the?upper?punch?pressure?and?displace-
ment?during?compression,?the?ejection?force?(the?friction
between?the?die?wall?and?the?tablet?during?ejection),?and?the
strength?of?the?tablet?(TFS)?after?ejection.?To?make?a?tablet,
100?mg?of?powder?is?placed?in?the?die?of?the?GTP-1?and?com-
pressed?at?4.9?kN?by?the?upper?punch?(a??at?punch?6?mm?in
diameter)?at?a??xed?30?mm/min.?All?formulations?were?pressed
and?measured?three?times.The?methods?of?calculation?and?plot-
ting?are?described?in?our?previous?report?[10].
2.2.3.? Evaluation?of?formulations?on?the?rotary?tableting
machine
Four?types?of?formulation?(A?to?D,?Table?1)?with?various?amounts
of?lubricant?were?compressed?on?a?rotary?tableting?machine
(Virgo-512,?Kikusui?Seisakusho,?Japan).?About?600?tablets?(150?mg
each,?90?g?total)?were?continuously?compressed?at?around?6.0
kN?and?30?rpm.?Four?different?types?of?punch?were?used:
Type?1,??at?punch?with?a?secant?line;?Type?2,?convex?cup?punch
(R?[major?cup?radius]?=?11?mm);?Type?3,?compound?cup?punch
(R?=?9?mm,?r?[minor?cup?radius]?=?3?mm);?and?Type?4,?convex
cup?punch?with?a?secant?line?and?embossed?marks?(R?=?9)?mm
(??7.5?mm?each;?Fig.?1).?The?cup?radius?was?taken?as?a?single
arc?generated?from?the?tablet’s?centerline?(midpoint)?across?the
tablet’s?diameter,?minor?axis,?or?major?axis.?In?Types?2?and?4,
Table?1?–?Formulations.
“Manufacturability”?of?these?formulations?with?the?GTP-1,
plotted?the?results,?and?compared?them?with?the?results?of
production-scale?tableting.?We?also?compared?“Tableting?prop-
erties”?using?punches?of?various?shapes.?The?aim?of?this?study
was?to?examine?the?usefulness?of?measuring?“Tableting?prop-
erties”?with?the?GTP-1?for?the?development?of?formulations?in
commercial?drug?production.
Sample
Losartan?potassium?(LP)?(mg)
Dilactose?R?(mg)
Ceolus?PH302?(MCC)?(mg)
Starch?1500?(mg)
Magnesium?stearate?(MgSt)?(mg)
Total
A
50
26
59
15
0
150
B
50
25.5
59
15
0.5
150
C
50
25
59
15
1
150
D
50
23
59
15
3
150
414
asian?journal?of?pharmaceutical?sciences?12?(2017)?412–417
Upper?punch
Lower?punch
Upper?punch
Lower?punch
Type?1:?flat?punch?with?secant?line
Type?2:?convex?cup?punch?(R?=?11)
Upper?punch
Lower?punch
Upper?punch
Lower?punch
Type?3:?compound?cup?punch?(R?=?9,?r?=?3)
Type?4:?convex?cup?punch?with?secant?line
and?embossed?marks?(R?=?9)
Fig.?1?–?Four?types?of?punches?tested.
the?convex?cup?punches?had?a?single?radius,?whereas?in?Type
3,?the?convex?cup?punch?had?two?radii.?The?surface?of?every
tablet?was?visually?inspected.?Tableting?was?terminated?when
failure?occurred.?Tablet?hardness?was?measured??ve?times?with
a?hardness?tester?(Portable?Checker?PC-30,?Okada?Seiko,?Japan).
placement?of?samples?B?and?C?in?range?(I)?indicated?no?prob-
lems?with?“Compactability”?or?“Manufacturability”.?In?contrast,
the?placement?of?sample?A?in?range?(III)?indicated?problems
with?“Manufacturability”?(sticking?and?binding);?and?the?place-
ment?of?sample?D?in?range?(II)?indicated?potentially?low?tablet
hardness.?Optimization?of?formulations?so?that?the?data?fall
in?range?(I)?will?achieve?durable?physical?properties?during
3.
Results?and?discussion
distribution?and?use?[17,18].
3.1. “Tableting?properties”?of?model?formulations?with
different?amounts?of?lubricant
Our?method?for?visually?assessing?“Tableting?properties”
plots?TFS?(hardness)?on?the?x-axis?and?ejection?stress
(“Manufacturability”)?on?the?y-axis?[10].?The?graph?is?divided
into?four?ranges?(Fig.?2).?If?a?point?is?plotted?in?range?(I)?(lower
right),?the?formulation?has?superior?“Compactability”?and
“Manufacturability”.?Conversely,?if?a?point?is?plotted?in
3.2.? Comparison?of?“tableting?properties”?predicted?by
using?each?apparatus
We?tested?the?ability?of?the?method?described?in?section?3.1
to?predict?the?results?of?tableting?on?a?commercial?rotary
“Manufacturability”10
Ejection?stress
(MPa)
range?(IV)?(upper?left),?the?tablet?is?soft?and?die?wall?friction
is?high,?indicating?problems?with?both?“Compactability”?and
“Manufacturability”.
Four?types?of?formulation?(samples?A?to?D?in?Table?1)?with
IV
A(MgSt?0?)
different?levels?of?lubricant?were?prepared,?and?then?com-
pressed?by?using?the?GTP-1?(Table?2).?Sample?A?(MgSt?0)?had
“Compactability”
TFS?(MPa)
good?“Compactability”?(TFS?≥?2?MPa),?but?bad?“Manufacturability”
(ejection?stress?≥?5?MPa),?and?so?was?plotted?in?range?(III).
0
1
5
2
3
4
5
Samples?B?and?C,?with?increasing?amounts?of?MgSt,?were?plotted
in?range?(I),?indicating?much?better?“Manufacturability”.?Samples
with?insuf?cient?lubricant,?which?lowers?“Manufacturability”,
are?plotted?in?range?(III)?or?(IV)?[12,13].
Sample?D?(MgSt?3)?had?reduced?“Compactability”
(TFS?=?1.83?MPa),?but?good?“Manufacturability”?(ejection
II
B?(MgSt?0.5)
C?(MgSt?1)
D?(MgSt?3)
I
stress?=?1.01?MPa),?and?was?plotted?in?range?(II).?Too?much?lu-
bricant?decreases?“Compactability”?and?thus?tablet?hardness
(Shah?and?Mlodozeniec,?1977).?This?corresponds?to?plotting?in
range?(II)?or?(IV).?Our?method?makes?it?possible?to?visualize?the
effects?of?lubricant?quantity?on?“Tableting?properties”.?The
0
Fig.?2?–?“Tableting?properties”?of?four?formulations
evaluated?by?using?the?benchtop?single-punch?tablet?press
(means,?n?=?3).
asian?journal?of?pharmaceutical?sciences?12?(2017)?412–417
415
Table?2?–?“Tableting?properties”?of?model?formulations?with?different?amounts?of?lubricant?evaluated?with?the?benchtop
single-punch?tablet?press.
Sample
A?(MgSt?0)
B?(MgSt?0.5)
C?(MgSt?1)
D?(MgSt?3)
“Compactability”:
TFS?(MPa)
2.88?±?0.10
2.66?±?0.16
2.27?±?0.07
1.83?±?0.04
“Manufacturability”:
ejection?stress?(MPa)
8.21?±?0.78
3.25?±?0.77
1.54?±?0.00
1.01?±?0.09
“Compressibility”:
elastic?recovery?(%)
32.97?±?0.56
35.03?±?1.03
36.64?±?0.26
38.78?±?0.38
Plot?range
III
I
I
II
tableting?machine?using?a?Type?1?punch?(?at?punch?with?a
secant?line;?Fig.?3A).?Samples?B?(MgSt?0.5),?C?(MgSt?1),?and?D
(MgSt?3)?were?tableted?without?any?problems.?Sample?A?(MgSt
0)?left?materials?stuck?to?the?surface?of?the?punch?(Fig.?3B),?which
interfered?with?the?tableting?process?after?130?to?140?presses
(Fig.?3;?Table?3).?This?result?was?consistent?with?the?plotting
of?sample?A?in?range?(III)?in?section?3.1.?The?prediction?for
sample?D?(MgSt?3)?placed?it?in?range?(II),?indicating?poor
“Compactability”,?because?tablet?hardness?decreases?as?the
amount?of?lubricant?is?increased.?As?predicted,?the?tablet
(A)
Initial
hardness?of?sample?D?was?lower?than?those?of?samples?A,?B,
and?C?(Table?4,?Type?1).
3.3.? Evaluation?of?“tableting?properties”?on?the?rotary
Upper?punch
Lower?punch
tableting?machine?with?various?punches
(B)
After?130–140?presses
The?results?in?section?3.2?agreed?with?those?in?section?3.1?when
a??at?punch?with?a?secant?line?was?used.?We?also?tested?dif-
ferent?punches?with?curved?surfaces?(with?different?curvatures),
secant?lines,?and?embossed?marks?(Fig.?1).?When?a?Type?3?com-
pound?cup?punch?was?used,?the?particles?at?the?center?of?the
tablet?did?not?deform?as?much?as?those?at?the?periphery?(Fig.?4).
Upper?punch
Lower?punch
This?difference?indicates?that?use?of?a?compound?cup?punch
may?make?it?dif?cult?to?compress?tablets?evenly?across?the
Fig.?3?–?Sticking?of?powder?to??at?punch?surfaces?(Type?1).
(A)?Before?tableting;?(B)?after?130?to?140?presses.?Sample?A
(50%?active?pharmaceutical?ingredient,?50%?excipients,?no
magnesium?stearate).
surface.?On?the?other?hand,?the?use?of?a??at?punch?is?not?prone
to?sticking?on?the?punch?surfaces.?Therefore,?punches?with?a
suitable?shape?have?to?be?chosen?carefully,?depending?on?the
powder?formulation.
Table?3?–?Numbers?of?tablets?successfully?produced?with?punches?of?each?type?in?GTP-1.
Sample
A?(MgSt?0)
B?(MgSt?0.5)
C?(MgSt?1)
D?(MgSt?3)
Plot?range
III
I
I
II
“Manufacturability”
Bad
Good
Good
Good
Type?1
130–140
600a
600a
600a
Type?2
165–175
600a
600a
600a
Type?3
5–15
5–15
105–115
600a
Type?4
20–30
95–105
600a
600a
Type?1:??at?punch?with?a?secant?line;?Type?2:?convex?cup?punch?(R?=?11);?Type?3:?compound?cup?punch?(R?=?9,?r?=?3);?Type?4:?convex?cup?punch
with?a?secant?line?and?embossed?marks?(R?=?9).
a
The?tablets?were?manufactured?without?any?failure?using?the?total?amount?of?formulated?powders.
Table?4?–?Hardness?(N)?of?tablets?manufactured?on?a?rotary?tableting?machine.
Sample
A?(MgSt?0)
B?(MgSt?0.5)
C?(MgSt?1)
D?(MgSt?3)
Plot?range
III
I
I
II
“Compactability”
Good
Good
Good
Bad
Type?1
61.0?±?2.3
53.2?±?3.3
49.2?±?4.7
34.6?±?1.8
Type?2
54.2?±?5.4
44.4?±?2.9
42.6?±?4.3
29.8?±?1.6
Type?3
42.0?±?2.6a
35.8?±?2.0a
35.6?±?2.5
28.0?±?0.7
Type?4
51.4?±?4.8a
39.0?±?2.2
35.8?±?1.9
26.8?±?1.3
Type?1:??at?punch?with?a?secant?line;?Type?2:?convex?cup?punch?(R?=?11);?Type?3:?compound?cup?punch?(R?=?9,?r?=?3);?Type?4:?convex?cup?punch
with?a?secant?line?and?embossed?marks?(R?=?9).
a
Tablets?could?not?be?formed?with?these?formulations.?Therefore,?the?surface?of?the?punches?was?lubricated?with?magnesium?stearate?and
tableting?was?performed?again.
416
asian?journal?of?pharmaceutical?sciences?12?(2017)?412–417
Fig.?4?–?Electron?micrographs?of?a?tablet?compressed?with?a?compound?cup?punch.
When?theType?2?convex?cup?punch?(R?=?11)?was?used,?samples
B?(MgSt?0.5),?C?(MgSt?1),?and?D?(MgSt?3)?were?tableted?without
any?failures?(Table?3).?However,?after?only?165?to?175?tablets?were
compressed,?tablets?of?sample?A?(MgSt?0)?would?not?separate
from?the?surface?of?the?punch?and?were?caught?on?the?scraper
and?broke?apart.?The?surface?of?the?punch?was?covered?with
powder.?This?result?corresponded?with?the?plotting?of?sample
A?in?range?(III)?(Fig.?2),?indicating?poor?“Manufacturability”.
When?the?Type?3?compound?cup?punch?(R?=?9,?r?=?3)?was?used,
sample?D?(MgSt?3)?was?tableted?without?any?failures?(Table?3).
In?contrast,?sample?A?(MgSt?0)?adhered?to?the?punch?imme-
diately,?and?the?cup?began?to??ll?with?powder.?Sample?B?(MgSt
0.5)?covered?the?surface?of?the?punch?as?soon?as?compression
began:?only?5?to?15?tablets?were?pressed?before?the?tablets
became?dif?cult?to?separate?from?the?punch?and?broke?apart.
Sample?C?(MgSt?1)?began?to?adhere?to?the?center?of?the?cup
after?105?to?115?tablets?had?been?pressed,?and?a?dimple-like
indentation?appeared?in?the?center?of?the?tablet.?Ejection?stress
(on?the?y-axis),?which?was?associated?with?the?occurrence?of
tableting?failure,?increased?in?the?order?of?samples?D?
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