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畢業(yè)設計（論文） 外文翻譯 學生姓名 班 級 學 號 學院名稱 專業(yè)名稱 指導教師 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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