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Continuous twin screw granulation Influence of process variables on granule and tablet quality

Continuous twin screw granulation Influence of process variables on granule and tablet quality
Continuous twin screw granulation Influence of process variables on granule and tablet quality

Research paper

Continuous twin screw granulation:In?uence of process variables on granule and tablet quality

J.Vercruysse a ,D.Córdoba Díaz b ,E.Peeters a ,M.Fonteyne c ,U.Delaet d ,I.Van Assche d ,T.De Beer c ,J.P.Remon a ,C.Vervaet a ,?

a

Laboratory of Pharmaceutical Technology,Ghent University,Ghent,Belgium

b

Department of Pharmacy and Pharmaceutical Technology,Complutense University of Madrid,Madrid,Spain c

Laboratory of Pharmaceutical Process Analytical Technology,Ghent University,Ghent,Belgium d

Department of Pharmaceutical Development,Johnson &Johnson Pharmaceutical Research and Development,Janssen Pharmaceutica,Beerse,Belgium

a r t i c l e i n f o Article history:

Received 13February 2012

Accepted in revised form 21May 2012Available online 9June 2012Keywords:

Continuous wet granulation Twin screw granulation Process variables

Granule and tablet quality Experimental design

a b s t r a c t

The aim of the current study was to screen theophylline (125mg)tablets manufactured via twin screw granulation in order to improve process understanding and knowledge of process variables that deter-mine granule and tablet quality.A premix of theophylline anhydrate,a -lactose monohydrate and PVP (ratio:30/67.5/2.5,w/w)was granulated with demineralized water.Experiments were done using the high-shear wet granulation module (based on twin screw granulation)of the ConsiGma?-25unit (a con-tinuous tablet manufacturing system)for particle size enlargement.After drying,granules were com-pressed using a MODUL?P tablet press (compression force:10kN,tablet diameter:12mm).Using a D-optimal experimental design,the effect of several process variables (throughput (10–25kg/h),screw speed (600–950rpm),screw con?guration (number (2,4,6and 12)and angle (30°,60°and 90°)of knead-ing elements),barrel temperature (25–40°C)and method of binder addition (dry versus wet))on the granulation process (torque and temperature increase in barrel wall),granule (particle size distribution,friability and ?owability)and tablet (tensile strength,porosity,friability,disintegration time and disso-lution)quality was evaluated.The results showed that the quality of granules and tablets can be opti-mized by adjusting speci?c process variables (number of kneading elements,barrel temperature and binder addition method)during a granulation process using a continuous twin screw granulator.

ó2012Elsevier B.V.All rights reserved.

1.Introduction

In contrast to other industries (plastics,food,chemistry),the pharmaceutical industry has been reluctant to move from batch processing toward continuous processing for several reasons (e.g.,high pro?t margins,stringent regulatory constraints,limited material volume)[1–3].However,as many patents of drug mole-cules recently expired or expire in the near future and due to an increasing demand for solid dosage forms,it is expected that the importance of the concept of continuous production will increase over the coming years [4,5].

As wet granulation is the most popular method to improve material properties (?ow,homogeneity,compressibility)prior to tableting,it is obvious that a continuous wet granulation process is of high importance for a manufacturer of solid dosage forms.Several continuous wet granulation techniques were developed,which have been reviewed by Vervaet and Remon [1,4].Keleb et al.[6]described the use of a laboratory scale co-rotating twin screw extruder without a die block in order to avoid excessive material densi?cation inside the barrel.In this way,wet granules could be obtained in a continuous manner.Based on this research work [6–9],a twin screw granulator was implemented as the high-shear granulation unit in the commercially available industrial scale ConsiGma?-system (GEA Pharma Systems,Collette?,Wommelgem,Belgium).This system consists of three modules,as already described by Fonteyne et al.[10]and Chablani et al.[11]:a wet high-shear granulation module,a segmented dryer module and an evaluation module.

Wet granulation via twin screw granulation is an attractive technology for the continuous processing of pharmaceuticals.Twin screw granulators are very ?exible in terms of use,offering multi-ple variables (e.g.,screw design,the placement of auxiliary units like feeders and pumps)[12].Besides,Van Melkebeke et al.[13]successfully demonstrated the possibility to perform melt granula-tion using the same equipment.However,up-to-now,process knowledge (certainly toward speci?c pharmaceutical formula-tions)about this innovative manufacturing technique is almost

0939-6411/$-see front matter ó2012Elsevier B.V.All rights reserved.https://www.doczj.com/doc/d312872763.html,/10.1016/j.ejpb.2012.05.010

?Corresponding https://www.doczj.com/doc/d312872763.html,boratory of Pharmaceutical Technology,Ghent University,Harelbekestraat 72,9000Ghent,Belgium.Tel.:+3292648069;fax:+3292228236.

E-mail address:Chris.Vervaet@UGent.be (C.Vervaet).

non-existing within the pharmaceutical

process understanding,optimize granule process yield,knowledge about the

ables that determine granule quality is made a?rst attempt to modify the screw ing discharge elements with conveying pitch,the compression of the granules amount of lumps was generated.Shah[14] tion with only conveying and chopping order to improve the output and avoid wet mass as it exited the extruder.Van ported that implementing an extra kneading block improved the granulation oversized agglomerates.Djuric and

son and Sun[12]evaluated the impact of on continuous granulation with a twin

that granule and tablet properties could be ferent designs of screw elements.Dhenge in?uence of screw speed,powder feed rate on the granule properties.In this paper,

at a time for each experiment(COST alteration in these process variables had the residence time and the average torque process,yielding granules with different to-solid ratio was recognized as the most ing the granule quality.Djuric and

that for scale-up of continuous twin screw the material throughput could not be optimization of process variables was these results,Dhenge et al.[18]reported feed rate leads to changes in the size, strength and dissolution time of the

a full-factorial experimental design to describe the effect of granu-lation liquid composition,injection rate and screw speed on extru-der power consumption,granule and tablet properties.

In the current study,an experimental design approach was used to screen theophylline(125mg)tablets manufactured via twin screw granulation.Design of experiments was used to identify the critical process variables and to study their impact on the gran-ulation process,granule and tablet quality attributes.

2.Materials and methods

2.1.Materials

Theophylline anhydrate was purchased from Farma-Química Sur (Malaga,Spain).a-lactose monohydrate200M(Caldic,Hemiksem, Belgium)was used as?ller for granulation and polyvinylpyrroli-done(PVP)(Kollidonò30,BASF,Ludwigshafen,Germany)as binder. If PVP was added to the dry premix,distilled water was used as granulation liquid.Magnesium stearate(Fagron,Waregem, Belgium)was applied as lubricant during tableting.

2.2.Preparation of granules

Granulation experiments were performed using a high-shear co-rotating twin screw granulator without die plate,being the granulation unit of the ConsiGma?-25unit(Fig.1).The length-to-diameter ratio was25:1.In the ConsiGma?-25unit,the granu-lation unit is directly linked to a six-segmented?uid bed dryer.As the aim of the current study was to improve process understanding of the granulation step,the?uid bed dryer was not used in order to avoid the impact of dynamic drying on the product properties.The barrel of the continuous granulator can be divided into two segments:a feed segment,where powder enters the barrel and consisting of conveying elements to transport the material through the barrel;and a work segment,where the powder is intensively mixed with the granulation liquid by kneading elements[10].To evaluate the in?uence of process variables on the granulation pro-cess,the torque and temperature of the barrel wall at the work seg-ment of the granulator were recorded.The equipment has an in-built torque gauge.The torque values obtained after equilibration of the process were averaged to give the overall torque during each run.At the work segment,the temperature of the barrel wall was controlled by a Pt100temperature sensor.As the barrel jacket was not divided into different temperature zones,the full length of the barrel was preheated to equal temperature.During process-ing,the powder premix was gravimetrically dosed by a twin screw feeder(KT20,K-Tron Soder,Niederlenz,Switserland).Granulation liquid was gravimetrically pumped into the screw chamber using two peristaltic pumps(Watson Marlow,Comwall,UK)and silicon tubing(internal and external diameter of1.6and4.8mm,respec-tively)connected to a1.6-mm nozzle.Liquid was added in front of the?rst kneading element.PVP was used as a binder,2.5%(w/w)in granules,based on dry mass.To evaluate the dissolution proper-ties,theophylline anhydrate(30%)was added as a model drug to the formulation.The water concentration(9%,calculated on wet mass)was kept constant for all experiments.For each run,after equilibration of the system,800g of wet granules was collected at the outlet of the granulator,spread on a tray and oven-dried at40°C during24h.After drying,the total granule batch was di-vided into two parts of400g.One part was analyzed for particle size distribution as such,and the other part was milled through a 1400l m screen at800rpm using a Quadro comil U10(Quadro Engineering,Ontario,Canada),which is part of the evaluation mod-ule of the ConsiGma?-25system.The response parameters when investigating the in?uence of process variables on granule quality were the following:particle size distributions before and after milling,and friability and?owability of the milled granules.

Consigma?-25granulation unit:high-shear twin screw granulator(a)

K-Tron KT20loss-in-weight feeder(b)and gravimetric liquid addition on screws(c).(For the interpretation of the references to color in this?gure legend, reader is referred to the web version of this article.)

206J.Vercruysse et

2.3.Preparation of tablets

Tablets were made using the milled granulation product.Before tableting,the granules were blended with0.5%(w/w)magnesium stearate in a tumbling mixer(W.A.Bachofen,Basel,Switserland). Tablets(417mg)were prepared using a MODUL?P tablet press (GEA Pharma Systems,Courtoy?,Halle,Belgium)equipped with a round concave(radius:24mm)Euro B punch of12mm diameter at a compression force of10kN per tablet.Tensile strength,poros-ity,friability,disintegration time and dissolution of the tablets were tested.

2.4.Design of experiments

Preliminary experiments were carried out to determine the experimental ranges for the DOE factors throughput,screw speed and barrel temperature at different number and angle of kneading elements.When12kneading elements were used,two kneading zones each consisting of6kneading elements had to be used (Fig.2).Both kneading zones were separated by a conveying ele-ment having the same length as one kneading zone.In this way, accumulation of material due to the retaining character of the kneading elements could be limited.An extra conveying element was implemented after the second kneading block in order to re-duce the amount of oversized agglomerates,as reported by Van Melkebeke et al.[7].Nevertheless,as the use of12kneading ele-ments at an angle of90°at different process settings resulted in excessive formation of lumps or even blockage of the system due to excessive friction,this combination of factor levels had to be ex-cluded from the design.For all experiments,the distance between liquid addition and?rst kneading element was kept constant.An 18-experiment D-optimal design was used to evaluate the in?u-ence of six process variables on the granulation process,granule and tablet properties:total throughput(10–25kg/h),screw speed (600–900rpm),screw con?guration(number(2,4,6and12)and angle(30°,60°and90°)of kneading elements),barrel temperature (25–40°C)and method of binder addition(dry versus wet)).D-optimal designs are used for screening and optimization instead of the classical factorial designs when the experimental space is irregular and/or when several(multilevel)qualitative factors are examined,as is the case for this study[20].Three replicates of the design center point were run.The different factor settings for each run are listed in Table1.The results were evaluated with MODDE9.0software(Umetrics,Ume?,Sweden).

2.5.Evaluation of granules

2.5.1.Particle size analysis

Sieve analysis was performed using a Retsch VE1000sieve sha-ker(Haan,Germany).Granules were placed on the shaker during 5min at an amplitude of2mm using a series of sieves(150,250, 500,710,1000,1400and2000l m).The amount of granules re-tained on each sieve was determined.All granule batches were measured in duplicate.The amount of?nes and oversized agglom-erates was de?ned as the fractions<150and>1400l m,respec-tively.After milling,the amount of coarse granules was de?ned as the fraction between710and1400l m.The yield of the granu-lation process was de?ned as the fraction between150and 1400l m.

2.5.2.Friability of granules

The granule friability was determined(n=3)using a friabilator (PTF E Pharma Test,Hainburg,Germany)at a speed of25rpm for 10min,by subjecting10g(I wt)of milled granules together with 200glass beads(mean diameter4mm)to falling shocks.Prior to determination,the granule fraction<250l m was removed to as-sure the same starting conditions.Afterward,the glass beads were removed and the weight retained on a250l m sieve(F wt)was determined.The friability was calculated as((I wtàF wt)/I wt)?100.

2.5.

3.Flowability

The bulk volume(V0)of30g milled granules was recorded in a 100ml measuring cylinder as well as the volume after1250taps (V1250)in a tapping machine(J.Englesman,Ludwigshafen, Germany)(n=3).Bulk and tapped densities were calculated as 30g/V0and30g/V1250,respectively.The compressibility index (C%)was calculated from the bulk and tapped density using the fol-lowing equation:

C%?feq fàq iT=q f g?100

where q i is the bulk density and q f is the tapped density.

2.6.Tablet evaluation

The hardness,thickness and diameter of tablets(n=10)were determined(Sotax HT10,Basel,Switserland)after a24-h storage period at21°C and30%RH.The tablet tensile strength T was cal-culated using the equation described by Fell and Newton[21]:

T?2F=p dt

where F,d and t denote the diametral crushing force,the tablet diameter and the tablet thickness,respectively.Tablet porosity was calculated(n=3)using tablet apparent density and the helium density of the former granules.

The tablet friability was determined(n=3)using a friabilator described in Eur.Ph.(PTF E Pharma Test,Hainburg,Germany),at a speed of25rpm for4min.The percentage weight loss was expressed as the tablet friability.

The disintegration time was determined(n=6)using the appa-ratus described in Eur.Ph.(PTZ-E Pharma Test,Hainburg,Ger-many).Tests were performed in distilled water at37±0.5°C using disks.

Dissolution tests were performed(n=3)in900ml demineral-ized water(pH=5)using the paddle method(VK7010,Vankel, Cary,NC,USA).The temperature of the dissolution medium was maintained at37±0.5°C,while the rotation speed was set at 50rpm.5ml samples were withdrawn at5,10,15,20,30,45 and60min after starting the dissolution.The drug content was determined at272nm using an UV-1650PC double-beam spectro-photometer(Shimadzu Benelux,Antwerp,Belgium).

3.Results and discussion

3.1.Evaluation of granulation process

Generally,conveying elements are used in a screw design to move material with minimal mechanical energy imparted,while kneading elements intensively mix solid and liquid components

b

a c

J.Vercruysse et al./European Journal of Pharmaceutics and Biopharmaceutics82(2012)205–211207

during continuous wet granulation.Kneading elements operate fully?lled with material and may be partially or fully dependent on pressure-driven?ow,as described by Thompson and Sun[12]. Because of their retaining character for the mass?ow through the barrel,increasing the number of kneading elements led to more friction inside the barrel and consequently higher torque val-ues(Fig.3).As the granulation process generates friction and heat, the temperature of the barrel wall at the work segment of the gran-ulator was monitored during each https://www.doczj.com/doc/d312872763.html,ing more kneading ele-ments caused a higher temperature increase at the barrel wall (0.0–21.5°C)(Table2)as a result of the higher amount of heat gen-erated by friction.If the level of barrel temperature was low(25°C) and a higher number of kneading elements were used,the contri-bution of the heat generated by friction to the temperature of the differences in extent of shear and compaction forces experienced by the material inside the barrel were observed.Changing the an-gle of kneading elements or the binder addition method had no sig-ni?cant effect on torque.As described above,the combination of12 kneading elements at an angle of90°was excluded from the design due to the formation of lumps or even blockage of the system.It seems that the angle of kneading elements only becomes an important factor when a higher amount of kneading elements is used.

During start-up of each run,the torque and temperature of the barrel wall increased until equilibrium was reached.This can be explained by the gradual layering of the barrel wall at the work segment with wet mass during this phase.The time needed for the torque and temperature of barrel wall to equilibrate gives a good indication of the time needed for the granulation process to reach steady-state conditions.It was found that when a higher number of kneading elements were used,the time to reach equilib-rium was higher(0–9min)(Table2).Using a feedback control sys-tem,material loss during start-up can be minimized.This system regulates the temperature of the barrel jacket during the granula-tion process in order to compensate for the temperature increase in the barrel wall due to friction.

3.2.In?uence of process variables on granule quality

Particle size distributions of granules before and after milling were determined.A signi?cant relationship between amount of ?nes and amount of oversized agglomerates and three process variables was detected:number of kneading elements,barrel tem-perature and binder addition method(Fig.4a and b).By increasing the number of kneading elements,the powder was more inten-sively mixed with the granulation liquid,yielding less?nes (0.9–20.2%<150l m)and more oversized agglomerates(19.5–82.3%>1400l m)(Table2).This was also described by Thompson and Sun[12]and Djuric and Kleinebudde[15].The same effects on particle size distribution were observed at a higher barrel temper-ature due to an increased solubility rate of the powder mixture in the granulation liquid.Because of the low residence time during twin screw granulation,the binder was more effective when it was already dissolved in the granulation liquid.Although changing the throughput led to different degrees of barrel?lling and torque values,no signi?cant impact on the particle size distribution was detected.No signi?cant effect for angle of kneading elements and screw speed on particle size distribution was found.According to

Table1

Overview of factor settings from the experimental design.

Run Throughput(kg/h)Screw speed(rpm)Kneading elements Barrel T(°C)Binder addition

Number Angle(°)

117.577546032.5Wet 22560029025Wet 32595023040Dry 410600123040Dry 525600123040Wet 62595023025Wet 725600126025Dry 825950123025Dry 92560029040Dry 101060023025Dry 111095029025Dry 122595069040Wet 1310950123025Wet 1417.577546032.5Wet 1517.577546032.5Wet 161095023040Wet 171060069040Wet 1810950126040Dry

Fig.3.Contour plot for torque as a function of throughput(kg/h)and number of

kneading elements.(For the interpretation of the references to color in this?gure

legend,the reader is referred to the web version of this article.)

208J.Vercruysse et al./European Journal of Pharmaceutics and Biopharmaceutics82(2012)205–211

Table2

Characterization of granulation process and granules from the experimental design.

Run Process Unmilled granules Milled granules

Torque (Nm)Barrel T

increase(°C)

Time to steady

state(sec)

<150l m

(%)

150–

1400l m

(%)

>1400l m

(%)

<150l m

(%)

710–

1400l m

(%)

150–

1400l m

(%)

Friability

(%)

Compressibility

(%)

1 1.50.0250 6.651.142.229.318.570.78±08±1

2 2.20.010020.248.830.945.013.055.010±110±1

3 2.10.02510.855.833.335.215.064.87±012±1

4 4.010.0350 1.341.357.515.730.984.33±010±3

57.310.33350.933.765.415.333.284.73±08±1

6 2.40.416511.347.141.533.920.166.19±17±1

7 5.612.528511.260.028.829.319.170.72±08±0

8 6.621.5535 1.843.654.617.928.182.19±19±1

9 1.90.03516.551.432.136.616.863.411±19±1

10 1.30.36014.657.727.734.118.265.99±010±0

110.90.14519.061.519.537.615.662.49±09±1

12 4.9 6.2250 1.016.782.318.228.681.81±09±0

13 4.520.2335 2.446.251.419.528.180.54±07±1

14 1.70.12158.751.839.531.117.668.97±110±1

15 1.40.027511.054.434.633.317.066.77±09±1

16 1.30.02007.653.938.527.420.072.65±010±1

17 4.4 6.0300 1.652.446.117.227.782.83±07±2

18 2.88.5385 2.453.444.217.926.782.13±09±0

J.Vercruysse et al./European Journal of Pharmaceutics and Biopharmaceutics82(2012)205–211209

elements signi?cantly affected granule bulk and tapped density.Increasing the number of kneading elements resulted in higher bulk and tapped densities.When a higher number of kneading ele-ments were used,more irregular-shaped coarse granules were formed,in agreement with Thompson and Sun [12],leading to a better packing of the granules when poured into the cylinder.The compressibility index was used to describe the ?owability of the https://www.doczj.com/doc/d312872763.html,pressibility indices marginally differed from each other and did not exceed 15%,indicating a good ?owability of the granules [22].No signi?cant relationships between the ?ow prop-erties and any of the process variables were detected.

3.3.In?uence of process variables on tablet quality

Tablets were made from the milled fraction of the granules.No extragranular disintegrant was added to the formulation in order to avoid the loss of signi?cant relationships between process variables and tablet properties.In accordance with Djuric and Kleinebudde [15],shortening of the kneading section during twin screw granulation yielded granules with a lower https://www.doczj.com/doc/d312872763.html,pres-sion of these granules resulted in tablets with a higher tensile strength (1.24–1.78MPa)(Table 3)due to the lower resistance toward deformation during compression.

For all tablets,the friability was low (0.17–0.30%).However,barrel temperature had statistically signi?cant impact on the tablet friability.A higher barrel temperature during granulation resulted in tablets with a lower friability.Regarding the porosity of the tab-lets (19.1–24.8%),no signi?cant process variables were detected.The use of more kneading elements during granulation created granules with a higher density [15].Because of the increased density,the percolation of liquids inside these granules is ham-pered,resulting in tablets with a higher disintegration time (470–1256s).Besides,elongation of the kneading zone during granulation decreased the amount of ?nes,which are important for disintegration.

Next to the disintegration time,it was investigated whether process variables could signi?cantly in?uence the drug release pro-?le,as this is the most important characteristic for tablets.As the aim of this study was to compare drug release pro?les of tablets made from granules produced with different process settings,no disintegrant was added to the formulation.Again,the number of kneading elements showed a signi?cant impact on the dissolution results (Fig.8).Similar to the disintegration results,tablets made from denser granules (i.e.,higher number of kneading elements)showed a slower drug release pro?le (69.8–86.6%released after 45min).These results were in agreement with the

conclusions

Fig. 6.Surface plot for friability of milled granules as a function of barrel temperature (°C)and number of kneading elements.(For the interpretation of the references to color in this ?gure legend,the reader is referred to the web version of this article.)

Table 3

Characterization of tablets from the experimental design.Run

Tensile strength (MPa)Porosity (%)Friability (%)Disintegration time (s)%release after 45min 1 1.78±0.0419.0±2.10.25772±8073.8±3.12 1.48±0.0615.2±1.90.30730±6676.8±4.33 1.57±0.0917.9±0.50.26828±2573.7±5.64 1.32±0.0516.0±1.90.24927±4972.2±2.15 1.36±0.0519.4±1.00.23649±4571.1±2.26 1.43±0.0619.0±0.80.26605±7573.9±1.97 1.45±0.0416.1±1.10.27774±4474.0±2.08 1.24±0.0616.9±1.10.23766±5777.8±5.59 1.52±0.0617.2±1.20.22834±5973.4±4.810 1.52±0.0815.7±1.00.27470±5082.1±6.011 1.61±0.0618.8±0.20.26529±5977.4±1.412 1.54±0.0717.5±0.30.19825±10871.9±4.413 1.27±0.0816.6±0.60.23938±7870.9±3.514 1.52±0.0420.1±0.70.21536±4381.7±1.715 1.51±0.0519.6±0.90.19557±3776.5±1.316 1.63±0.0719.9±1.10.21485±6286.6±3.417 1.35±0.0917.9±0.90.19765±6173.1±6.018

1.44±0.08

18.4±0.4

0.17

1256±49

69.8±

3.7

g /m l

and Biopharmaceutics 82(2012)205–211

made by Dhenge et al.[18].In this paper,it was noticed that at in-creased powder feed rate,denser granules were produced that took longer time to release the salt embedded in them.

4.Conclusions

This study was designed to screen theophylline(125mg)tab-lets manufactured via twin screw https://www.doczj.com/doc/d312872763.html,ing a D-optimal experimental design,the effect of several process variables on the granulation process,granule and tablet quality was evaluated. No signi?cant relationships for angle of kneading elements and screw speed were found.Increased throughput and number of kneading elements resulted in higher torque values during granu-lation.More friction due to elongation of the kneading zone re-sulted in a higher temperature increase in the barrel wall.A higher number of kneading elements and barrel temperature re-sulted in less?nes,more oversized agglomerates and less friable granules.As barrel temperature had an important effect on the granule properties,this parameter should be carefully controlled, especially when using good water-soluble components,for exam-ple lactose.Because of the short residence time during twin screw granulation,the binder was more effective when it was already dissolved in the granulation liquid.The tensile strength,disintegra-tion time and dissolution pro?le of tablets depended on the num-ber of kneading elements.Increasing the number of kneading elements yielded denser granules that were less deformable during compression.Percolation of liquids inside these granules is ham-pered,resulting in tablets with a longer disintegration time and a slower drug release.The results showed that the quality of gran-ules and tablets can be optimized by adjusting speci?c process variables(number of kneading elements,barrel temperature and binder addition method)during a granulation process using a con-tinuous twin screw granulator.

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[10]M.Fonteyne,J.Vercruysse,D.C.Díaz,D.Gildemyn,C.Vervaet,J.P.Remon,T.D.

Beer,Real-time assessment of critical quality attributes of a continuous granulation process,Pharmaceutical Development and Technology(2011). [11]L.Chablani,M.K.Taylor,A.Mehrotra,P.Rameas,W.C.Stagner,Inline real-time

near-infrared granule moisture measurements of a continuous granulation–drying–milling process,AAPS PharmSciTech12(2011)1050–1055.

[12]M.R.Thompson,J.Sun,Wet granulation in a twin-screw extruder:implications

of screw design,Journal of Pharmaceutical Sciences99(2010)2090–2103.

[13]B.Van Melkebeke,B.Vermeulen,C.Vervaet,J.P.Remon,Melt granulation using

a twin-screw extruder:a case study,International Journal of Pharmaceutics

326(2006)89–93.

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tablet dosage form,Pharmaceutical Technology6(2005)52–66.

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with a twin-screw extruder,Journal of Pharmaceutical Sciences97(2008) 4934–4942.

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标示牌技术规范标准说明

* 标示牌 、分类及使用范围 安全标志分为警告标志、指令标志、提示标志、禁止标志和其他标志五大类型。见表1。

* 表1安全标示牌分类及使用范围 退运设备标志:运行场所中已退出运行而未及 拆除的设备。 安全距离标志:适用于对正常活动范围内工作 人员与带电设备需要保持安全距离的场所。 警示色标志:适用于公路旁有可能被车辆碰撞 的杆塔。 类型 使用范围 基本形式 图例 警告 标志 用于可能发生危险的环境。如: “止步高压危 险”、“当心触电”、“当心坑洞”、“当心滑跌” 禁止 标志 用于禁止人员不安全行为。如“禁止攀登 高压 危 险”、“禁止合闸 有人工作”、“禁止跨越”、 “未经许可 不得入内”等。 提示 标志 用于向人员提供某种信息,如标明安全设施或 场所。如“在此工作”、“从此上下” 用于强制人员必须做出某种动作或采取防范措 指令 一 施。如“必须戴安全帽”、必须系安全带“、必 标志 须戴防护手套”等。 其他 标志 限速标志:在变电站场所内限制交通运输车辆 的速度。 限高标志:在车辆行驶高度受限的地方。 退运 曇导向标志:电缆线路隧道内指示岀口的方向。

* 二、技术要求 1、安全标示牌应有衬边。除警告标示牌边框用黄色勾边外,其余全部用白色将边框勾一窄边,即为安全 退运设备标志的衬边,衬边宽度为标志边长或直径的0.025倍。印 刷技术选用:丝网印刷技术、打印机打印。 2、材质要求: 标志一般选用不锈钢板、铝合金板、塑料等耐久性材料,亦可选用 透明材料和 0.8mm以上厚的铝板, 覆白底反光膜,或聚乙烯反光胶带。。 有触电危险的作业场所应使用绝缘材料。 对防火有要求的采用不燃材料,否则应在其外面加设玻璃或其他不燃透明材料制成的保护罩。 特殊场合使用的标示材料应符合有关规定。 3、颜色要求 安全标示牌所用的颜色应符合表2标准色的要求。 表2 标准色 类型标准色要求图例字体颜色

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技术规格书格式

第一节一般要求 1. 工程说明 1.1 工程概况 1.1.1 本工程基本情况如下: 。 1.1.2 本工程施工场地(现场)具体地理位置如下: 。 1.2 现场条件和周围环境 1.2.1 本工程施工场地(现场)已经具备施工条件。施工场地(现场)临时水源接口位置、临时电源接口位置、临时排污口位置、建筑红线位置、道路交通和出入口、以及施工场地(现场)和周围环境等情况见本章附件A:施工场地(现场)现状平面图。 1.2.2 施工场地(现场)临时供水管径。 施工场地(现场)临时排污管径。 施工场地(现场)临时雨水管径。 施工现场临时供电容量(变压器输出功率)。 1.2.3 现场条件和周围环境的其他资料和信息数据如下: 。 1.2.4 承包人被认为已在本工程投标阶段踏勘现场时充分了解本工程现场条件和周围环境,并已在其投标时就此给予了充分的考虑。 1.3 地质及水文资料 1.3.1 现场地质及水文资料和信息数据如下: 。 1.4 资料和信息的使用 1.4.1 合同文件中载明的涉及本工程现场条件、周围环境、地质及水文等情况的资料和信

息数据,是发包人现有的和客观的,发包人保证有关资料和信息数据的真实、准确。但承包人据此作出的推论、判断和决策,由承包人自行负责。 2.承包范围 2.1 承包范围(如分标段,须按标段分别描述,并明确界面责任分工) 2.1.1 承包人自行施工范围 本工程承包人自行施工的工程范围如下: 。 各标段界面责任分工如下: 。 2.1.2 承包范围内的暂估价项目 2.1.2.1 承包范围内以暂估价形式实施的专业工程见第五章“工程量清单”表 4.10-3“专业工程暂估价表”。 2.1.2.2 承包范围内以暂估价形式实施的材料和工程设备见第五章“工程量清单”表4.10-2“材料和工程设备暂估价表”。 2.1.2.3 上述暂估价项目与本节第2.1.1项承包人自行施工范围的工作界面划分如下: 。 2.1.3 承包范围内的暂列金额项目 2.1. 3.1 承包范围内以暂列金额(包括计日工)方式实施的项目见第五章“工程量清单”表 4.10-1“暂列金额明细表”(不包括计日工)和表 4.10-4“计日工表”,其中计日工金额为承包人在其投标报价中按表 4.10-4“计日工表”所列计日工子目、数量和相应规定填报的金额。 2.1. 3.2 暂列金额明细表中每笔暂列金额所对应的子目,包括计日工,均只是可能发生的子目。承包人应当充分认识到,合同履行过程中所列暂列金额可能不发生,也可能部分发生。即便发生,监理人按照合同约定发出的使用暂列金额的指示也不限于只能用于表中所列子目。 2.1. 3.3 暂列金额是否实际发生、其再分和合并等均不应成为承包人要求任何追加费用和

技术规格书规范

项目名称:XX市轨道交通XX线AFC系统 文档编号:xxx XX轨道交通XX线 XXX技术规格书 方正国际软件(北京)有限公司 XX年X月

北京市轨道交通亦庄线xxx 技术规格说明书 第1页 ? 2009, Copyright by FOUNDER Group 文档编号:xxx 序号 版本 时间 修订说明 修改人 1 (手动填写) 00.00.00.00 YYYY/MM/DD NNN 2 3 4 5

XX 市轨道交通XX 线xxx 技术规格说明书 第2页 ? 2009,Copyright by FOUNDER Group 文档编号:xxx 目 录 图 表 表 格

第3页 ? 2009, Copyright by FOUNDER Group 文档编号:xxx (从此处开始正文) 样式说明 (除“样式与格式”中所列格式外,其它格式一律不得使用,方案完成过程中首先消除原文档中不符合要求的格式!) 1 标题1 只用“正文首行缩进” 1.1 标题2 1. 列表编号2 1). 列表编号3 a. 列表编号4 b. 列表编号4 2). 列表编号3 2. 列表编号2 1.1.1 标题3 列表1 (此 可在各列表编号下使用,但不能作为列表编号) 列表2 列表3

第 4页 ? 2009,Copyright by FOUNDER Group 文档编号:xxx 1.1.1.1 标题4 图表 1 图形居中请选择“图形居中”的样式(编号1的后面加一空格) 1.1.1.1.1 标题5 序号 内容 1 (手动填写,没必要时可以不填) 2 3 4 5 1.1.1.1.1.1 标题6 1. 列表编号2 2. 列表编号2 2 标题1 此段为新增内容,除正常刷格式,再选择该段内容,刷“新增内容”的样式。可在确认后,直接删除样式“新增内容”即可,对原样式和结果没有影响。 请从下页开始插入正文内容。

产品技术规格书

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控中心传输相关的报警信息。 5)实时数据、历史数据的通过曲线或数据列表的形式显示。根据需要 可进行图表的打印。 6)各种监测参数的量程、报警值、相关换算系数及其他设置内容(如 下位机的系列号,用于通讯的相关设置等)。 7)反向控制在现场仪器仪表提供相应功能和协议的条件下,可实现对 仪器仪表的反向控制,如自动清洗,量程校正、分瓶采样、视频控 制等。 8)数采仪要求视频接入模块(支持电信“全球眼”视频叠加技术)。 9)企业端2路视频数据可保留一周以上,支持智能存储/删除。 10)支持浙江省污染源在线监控系统使用。 11)提供多种通讯接口(4-20Ma、RS232、RS485等)。 12)支持间歇性排放标准的企业的监控控制,实现通过流量来控制仪器 的做样。 13)数采仪要求视频接入模块。 (二)PH分析仪 pH测量范围0.00 to 14.00 pH 分辨率0.01 pH 准确度± 0.01 pH 温度测量范围- 9.9 to + 125.0 °C 分辨率0.1 °C 相对准确度± 0.5 °C 传感器Pt 100 /Pt 1000 (连线端子选择) 温度补偿方式自动/ 手动 (参照 25.0 °C) 设定点和控制器功能 功能(可转换的) 设定点控制器 控制器特性极限控制器 加速 /减慢继电器0 to 2000 秒. pH 迟滞宽度0.1 to 1 pH 工作电压最大 250 VAC 工作电流最大. 3A 功耗最大 600 VA 电参数和连接 电源110 / 220 VAC (短路子选择) 频率48 to 62 Hz 输出信号 4 to 20 mA, 电隔离

螺纹连接和螺旋传动练习题

第五章 螺纹联接及螺旋传动 一、选择题 5-1 在常用的螺旋传动中,传动效率最高的螺纹是__________。 (1)三角形螺纹 (2)梯形螺纹 (3)锯齿形螺纹 (4)矩形螺纹 5-2 在常用的螺纹联接中,自锁性能最好的螺纹是__________。 (1)三角形螺纹 (2)梯形螺纹 (3)锯齿形螺纹 (4)矩形螺纹 5-3 当两个被联接件不太厚时,宜采用__________。 (1)双头螺柱联接 (2)螺栓联接 (3)螺钉联接 (4)紧定螺钉联接 5-4 当两个被联接件之一太厚,不宜制成通孔,且需要经常拆装时,往往采用__________。 (1)螺栓联接 (2)螺钉联接 (3)双头螺柱联接 (4)紧定螺钉联接 ? 5-5 当两个被联接件之一太厚,不宜制成通孔,且联接不需要经常拆装时,往往采用__________。 (1)螺栓联接 (2)螺钉联接 (3)双头螺柱联接 (4)紧定螺钉联接 5-6 普通螺纹的牙型角α为60o ,当摩擦系数μ=时,则该螺纹副的当量摩擦系数μv =__________。 (1) (2) (3) (4) 5-7 在拧紧螺栓联接时,控制拧紧力矩有很大方法,例如__________。 (1)增加拧紧力 (2)增加扳手力臂 (3)使用测力矩扳手或定力矩扳手 5-8 螺纹联接防松的根本问题在于__________。 (1)增加螺纹联接的轴向力 (2)增加螺纹联接的横向力 (3)防止螺纹副的相对转动 (4)增加螺纹联接的刚度 5-9 螺纹联接预紧的目的之一是__________。 # (1)增强联接的可靠性和紧密性 (2)增加被联接件的刚性(3)减小螺栓的刚性 5-10 承受预紧力F ′的紧螺栓联接在受工作拉力F 时,剩余预紧力为 F ″,其螺栓所受的总拉力F 0为__________。 (1)'+=F F F 0 (2)"+=F F F 0 (3)"'=F F F +0 (4)F C C C F F m b b ++ =0 5-11 承受预紧力和轴向变载荷的紧螺栓联接,当其螺栓的总拉力F 0的最大值和被联接件的刚度C m 不变时,螺栓的刚度C b 愈小,则__________。 (1)螺栓中总拉力的变化幅度愈大 (2)螺栓中总拉力的变化幅度愈小 (3)螺栓中总拉力的变化幅度不变 (4)螺栓中的疲劳强度降低 5-12 承受预紧力和轴向变载荷的紧螺栓联接,当其螺栓的总拉力F 0的最大值和螺栓的刚度C b 不变时,被联接件的刚度C m 愈小,则__________。

机械设计—螺纹联接与螺旋传动计算题

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技术规格书模板

中国石油大庆炼化公司 技术规格书 (物资名称:) 编制人:(专业厂或业务管理部门签字)年月日 审核人:(专业厂单位领导签字)年月日 审批人:(业务管理部门领导签字)年月日

目录 1.总则 2. 执行标准 3. 主要技术要求 4. 检验和试验 5. 包装及运输 6. 资料交付 7. 技术服务及售后保证 8. 其它 附件供货范围

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了。 A.不致损伤螺栓头和螺母 B.增大接触面积,不易松脱 C.防止产生附加偏心载荷 D.便于装配 7、设计螺栓组时常把螺栓布置成轴对称的均匀的几何形状,这主要是为 了。 A.美观 B.受力最小 C.联接方便 D.接合面受力较均匀 8、单向受力的螺旋传动机构广泛采用() A、三角螺纹 B、梯形螺纹 C、矩形螺纹 D、锯齿螺纹 9、螺纹传动机构() A、结构复杂 B、传动效率高 C、承载能力高 D、传动精度低 10、防松方法简单方便,但只能用于不甚重要的连接和载荷平稳的场合。 A、机械 B、摩擦 C、破坏螺纹副关系 11、防松适用于受冲击、振动的场合和重要的连接。 A、机械 B、摩擦 C、破坏螺纹副关系 12、防松常用于装配后不再拆卸的场合。 A、机械 B、摩擦 C、破坏螺纹副关系 三.判断题 1.普通螺纹的公称直径是指螺纹中径的基本尺寸。( ) 2.焊接防松属于摩擦防松。( ) 3.对同一螺栓组,通常采用相同的螺栓材料、直径和长度。( ) 4.螺栓联接通常用于被联接件之一较厚且不经常装拆的场合。( ) 5.设计螺栓组时常把螺栓布置成轴对称的简单几何形状,从而使接合面受力较均 匀。( ) 6.螺钉联接通常用于被联接件之一较厚且经常装拆的场合。( ) 7.常用的防松方法有磨擦防松、锁住防松和不可拆卸防松。( ) 8、为增强联接的紧密度,联接螺纹大多数采用多线三角螺纹。() 9、两个相互配合的螺纹,其旋向相同。() 10、M24表明螺纹的大径是24mm. () 11、差动螺旋传动可以产生极小的位移,可方便地实现微量调节。() 12、螺栓连接的结构特点是被连接件上有孔,螺栓穿过通孔,螺栓与孔之间没有间隙。()

技术参数说明(精)

技术参数说明: 一控制台: 1.4米钢控制桌(可参照:博慧电子(悉备)[与中控一体]二、多媒体备课室(多媒体计算机):所有品牌都必须有厂家的本项目的授权,并加盖鲜章)(三种方案均可) 第一方案 产品描述: 1.主板INTEL G41高速芯片组(带ICH7) 2.CPU酷睿E7500 (2.93GHZ/1066FSB/3M) 3.内存2G NECC DDR3 1066MHz 最大可升级到8G 4.光驱16X DVD SA TA接口 5.显卡512 MB ATI?RADEON?HD 3450 6.声卡集成HD高性能声卡 7.网卡集成1000M网卡 8.硬盘320G SA TA硬盘可设置硬盘保护密码/硬盘免回收服务 9.机箱BTX高效散热静音设计,立卧两用,带有安全锁孔,免工具开箱,带有系统状态诊断指示装置且前置。机箱前面板全黑。10%的废品材料可回收,帮助降低对环境的影响。包装可回收率高达89% 10.扩展/接口2个PCI,1个PCI-E×16, 一个PCI-E×1,串口,并口,8个USB且2个前置 11.电源255瓦标准PSU或可选效率为88%的255瓦PSU;符合能源之星5.0规范 12.显示器20寸16:9宽1600*900高清分辩率VGA/DVI接口 13.服务三年完全免费的原厂商售后服务:包括原厂商(800)电话支持、所有部件(包括键盘鼠标显示器在内)的原厂商备件、不晚于第二工作日原厂商售后服务工程师上门,安全、可靠。如主要配件在

三年保修期内更换后,更换的主要配件的三年保修期应从更换之日重新计算。 14,环境标准(生态标签): 能源之星? 5.0(精选配置)、EPEAT Gold(精选配置)、CECP、TCO 05、WEEE、日本能源法、CES、日本绿色PC、FEMP、韩国生态标签、欧盟RoHS、中国RoHS 其他环境选项: 智能节能设置;碳中和;系统回收(资产恢复服务) 15,安全性 支持机箱锁插槽和锁环 可选机箱防盗开关 设置/BIOS密码 I/O接口安全性 BIOS支持可选Computrace? 16,系统管理选项 免费的系统管理控制台;允许您在整个组织内部署、管理客户机系统以及对其进行故障排除。 17,其他选项 多媒体教室计算机教室每室配能保证学生上课时约70平方米的教室使用的音响设备一套,每台计算机配耳机。 备课室每台计算机都配耳机。 每台计算机必须有正版Windows XP(专业版)操作系统,并附有安装光盘。每台计算机必须能硬件支持升级到Windows 7(专业版)操作系统。 必须有正版的Microsoft Office 2003,并附有安装光盘。 必须有微软公司的使用授权书。 第二方案 产品描述: 1.主板INTEL G41告诉芯片组(带ICH7) 2.CPU 酷睿E7500 (2.93GHZ/1066FSB/3M) 3.内存2G NECC DDR3 1066MHz 最大可升级到8G 4.光驱16X DVD SATA接口 5.显卡256 MB ATI? RADEON? HD 3450 6.声卡集成HD高性能声卡 7.网卡集成1000M网卡

项目说明及技术规格要求

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4.整个项目实施周期不超过30工作日,培训周期一周。 二、区域化集中消毒供应追溯系统功能需求(包括但不局限于以下功能) 1.清洗、消毒、包装、灭菌过程记录: ①记录物品回收、清洗、消毒、包装、灭菌、发放全过程。 ②*记录物品的清洗全过程,包括清洗机和批次、清洗篮网标牌(金属激光)绑定方式、人员和时间。清洗开始、结束时间不可手动输入,每一清洗审核批次必须和机器清洗码一致,此功能请截图并告知在使用此模块本省用户名单,招标时请带篮网标牌。 ③支持手工清洗过程的记录。 ④实时记录包装人员、包装日期和时间。 ⑤支持打包物品图片显示:应显示该诊疗包中应包含的物品种类、数量、器械图片。 ⑥自动打印条形码标签,包含物品名称规格、包装人员、灭菌日期、有效日期。 ⑦*在硬件设备开放端口前提下,实时记录灭菌时间、灭菌温度、灭菌压力、灭菌人员、治疗包等信息。灭菌开始、结束时间不可手动输入,每一灭菌审核批次必须和灭菌机唯一生成码一致,此功能请截图并告知在本省使用此模块用户名单。 ⑧消毒物品的发放,可记录发放人员、领用科室信息,发放时系统可自动校对数量和有效日期。 ⑨支持物品包的回收,部分贵重器械回收,外来器械的登记,无条码包的回收登记,丢失器械的登记以及回收数据采集。支持回收任务列表展示;支持回收查询。 2.物品请领: ①*区域化各院请领物品,支持申请模式。实现无纸化申领机制。可实现对无菌包发放信息的记录,可按时间段按科室统计发放情况。

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