University of Szeged Faculty of Pharmacy Department of Pharmaceutical Technology Head: Prof. Dr. Habil. Piroska Szabó-Révész DSc. and Gedeon Richter Plc. Doctoral dissertation COMPARISON OF THE EFFECT OF GRANULATION AND DRYING TECHNIQUES ON THE QUALITY OF A PHARMACEUTICAL PRODUCT WITH A HIGH ACTIVE INGREDIENT CONTENT By Ágota Hegedűs Pharmacist Supervisor: Prof. Dr. Habil. Klára Pintye-Hódi DSc. Szeged 2007
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University of Szeged
Faculty of Pharmacy
Department of Pharmaceutical Technology
Head: Prof. Dr. Habil. Piroska Szabó-Révész DSc.
and
Gedeon Richter Plc.
Doctoral dissertation
COMPARISON OF THE EFFECT OF GRANULATION AND DRYING
TECHNIQUES ON THE QUALITY OF A PHARMACEUTICAL PRODUCT
WITH A HIGH ACTIVE INGREDIENT CONTENT
By
Ágota Hegedűs
Pharmacist
Supervisor:
Prof. Dr. Habil. Klára Pintye-Hódi DSc.
Szeged
2007
Publications
I. Kelen Á., Hegedűs Á., Nagy T., Máthé Z., Hódi K.: A mikrohullám alkalmazásának
R. C. Dicalcium phosphate dihydrate for direct compression: Characterisation and
intermanufacturer variability, Int. J. Pharm. 1994, 109, 1-8
114 Johansson, B.; Alderborn, G. The effect of shape and porosity ont he compression
behavior and tablet forming ability of granular materials formed from microcrystalline
cellulose, Eur. J. Pharm. and Biopharm. 2001, 52, 347–357
Acknowledgements
I am very grateful to my supervisor
Professor Dr. Klára Pintye-Hódi DSc.
for her support. I greatly appreciate her continuous help during the preparation of my thesis.
I owe my warm gratitude to her for her criticism, encouragement and numerous discussions
during my Ph. D. work.
My warmest thanks go to
Dr. Attila Bódis
Head of the Pharmaceutical Technology Department, for his help, encouragement and invaluable
advice.
I would like to thank
Professor Dr. István Erős DSc.
Head of the Ph.D. programme Pharmaceutical Technology
and
Professor Dr. Piroska Szabó-Révész DSc.
present Head of Department of Pharmaceutical Technology,
for providing me with the possibility to complete my work.
I express my grateful thanks to
Mátyás Koncz
Head of the Solid Dosage Forms Plant
and
Gábor Toma
Deputy-head of the Solid Dosage Forms Plant
for providing possibility for me to carry out scientific research in the Plant.
I thank all members of the Gedeon Richter Plc. for their collaboration in this work.
ANNEX
Related articles
I.
II.
III.
S114 Posters / European Journal of Pharmaceutical Sciences 25S1 (2005) S1–S226
P-45
The effects of different drying techniques on the porosityparameters of granules at production scale
A. Hegedusa, A. Kelena, K. Pintye-HodibaGedeon Richter Ltd., H-1475 Budapest, P.O. Box 27.,Hungary; bDepartment of Pharmaceutical Technology,University of Szeged H-6720 Szeged, E¨otvos Str. 6., Hungary
1. Introduction
There are two known closed-system wet granulation pro-cedures: high-shear granulation and fluid-bed granulation.These techniques differ in the modes of agitation of the solidparticles, and for this reason there are also differences ingranule growth.
In the course of fluid-bed granulation, the powder bed iskept in motion by specially treated (filtered, temperature andhumidity-controlled) air, which is introduced through a sieveplate in the base of the granulator.
In high-shear granulation, an impeller is used to agitate thesolid particles within an enclosed space. The binding agentis added or sprayed in from above. The mixing, densificationand agglomeration of the wet material is performed by theimpeller through the exertion of shearing and compactingforces.
Originally, high-shear granulators did not have a dryingcapability, which means that the wet granules produced inthese machines had to be dried in a separate machine, suchas a fluid-bed drier. Later, these granulators were further de-veloped into what are termed “single-pot” systems, whichare capable of performing all the processes of mixing, gran-ulation, drying and mixing. The possible drying methods arevacuum, vacuum-microwave and gas-vacuum methods, all ofwhich can be combined with side-wall heating [1–3].
Our objective was to compare the porosities of granulesthat were all produced using a traditional high-shear granu-lation, but were dried using either a fluid-bed dryer (GlattWSG 200), or vacuum-drying technology (Collette UltimaPro 600).
2. Materials and Methods
The given tablets contained 50% w/w active ingredient.The binding solution was an aqueous solution of PVP K-30(4.5% w/w). The other excipients were corn starch (30% w/w)as diluent; colloidal anhydrous silica (4% w/w) and glycerine(1.5% w/w) as moisture regulator; and microcrystalline cel-lulose (7.9% w/w), talc (1.6% w/w) and magnesium stearate(0.5% w/w) to improve tablet formation. We used the samecomposition and batch size (150 kg) in both sets of equip-ment.
In both cases we performed the granulation in a ColletteUltima Pro 600 single-pot machine, while the drying wascarried out in either a Glatt WSG 200 fluid bed granulator
and drier or a Collette Ultima Pro 600 single-pot granulator.The two machines are shown in Figs. 1 and 2.
The properties of granules and tablets are also influencedby the porosity of the granules. Porosity can be definedthrough the relationship between the true (�true) and tapped(�tapp) densities, using the following equation[4] :(
1 − ρtapp
ρtrue
)× 100
The true density (�true) was determined using Stereopyc-nometer SPY-5 (Quantachrome Corp.). The pycnometric truedensity is determined by measuring the volume occupied bya known mass of powder which is equivalent to the volumeof helium gas displaced. The true density was calculated thefollowing equation:
ρtrue = w
v
where w = weight of samples, v = true volume of samples.
3. Results and Discussion
We know from the specialist literature that the porosity ofgranules is affected considerably by the impeller speed andthe wet massing time [5]. However, less research has beenconducted into the extent to which the porosity of granulesprepared using the same granulation technology is influencedby the subsequent use of different drying methods.
Posters / European Journal of Pharmaceutical Sciences 25S1 (2005) S1–S226 S115
Table 1
Porosity of granules subjected to different drying techniques
Glatt WSG 200 Collette Ultima Pro 600
Porosity� (%) 73.9 63.1
The data in Table 1 show that granules dried in a vacuumchamber are more porous than those dried using a fluid-bedprocess, although the drying process is slower. This is dueto the mechanism by which the moisture is forced out of thegranule’s capillaries under sub-atmospheric pressure, whichresults in the formation of “channels” in the granule’s interioras the moisture leaves the granule. In the course of fluid-bed drying, which takes places at atmospheric pressure, thegranules dry from their surface inwards, which results in alower level of porosity.
A reduction in porosity generally leads to a deteriorationin compressibility. In the case of the systems examined byus, this took the form of a shift in the range of pressing forcerequired in order to produce a tablet of the same hardness.
Besides the porosity test, our findings are also corrobo-rated by the SEM (Scanning Electron Microscopy) imagesshown in Figs. 3 and 4.
The granules dried in a vacuum chamber are moregeometrically regular, and spherical, and thus they havea different external physical structure than that of thegranules dried using fluid-bed technology. In terms of theirtablet-forming properties, these granules fill the die moreevenly.
4. Conclusion
Granules produced in a traditional high-shear granulatorand dried in a vacuum chamber are more porous, due to thespecial characteristics of the drying process; and, in contrastto granules dried using fluid-bed technology, they retain theirspherical shape. The porosity test shows the ratio of the totalvolume of the pores in the granules to the total volume of thegranules, thereby making it suitable for a more discriminativeexamination of the differences between the granules, and en-abling us to draw conclusions regarding their tablet-formingproperties.
References
[1] Parikh, D., 1997. Handbook of Pharmaceutical Granu-lation Technology; Drugs and Pharmaceutical Sciences,Marcel Dekker Inc. New York, USA, p. 81, p. 151–204.
[2] Stahl, H., 2000. Pharm. Technol. Eur. 12, 192–201.[3] Stahl, H., 2004. Pharm. Technol. Eur. 16, 23–33.[4] Kumar, V., Reus-Medina, M. L., Yang, D., 2002. Int. J.
Pharm. 235, 129–140.[5] Badawy, S, I. F., Menning, M. M., Gorko, M. A, Gilbert
D. L., 2000. Int. J. Pharm. 198, 51–61.
P-46
Preparation and evaluation of ketoprofen loaded self-microemulsifying systems
M. Homara, M. Markocicb, M. GasperlinbaLek Pharmaceuticals d.d., Research and Development,SI-1526 Ljubljana, Verovˇskova Str. 57., Slovenia;bFacultyof Pharmacy, University of Ljubljana, SI-1000 Ljubljana,Askerceva Str. 7., Slovenia
1. Introduction
In recent years more and more ingredients are known thatare active but exhibit low bioavailability due to their low sol-ubility. Formulation of emulsions and microemulsions (ME)can greatly enhance the bioavailability of many such sub-stances. The main advantages of ME are thermodynamicstability, spontaneous formation, increased drug solubilityand permeability enhancement. Self-emulsifying (SES) andself-microemulsifying (SMES) drug delivery systems, whichform emulsions and ME on gentle agitation in aqueous media,offer additional advantages, the most important being theirgreater stability, compared to emulsions or even microemul-sions, and greater drug loading capacity [1,2]. Ketoprofenwas used as a model drug.
International Journal of Pharmaceutics 330 (2007) 99–104
Comparison of the effects of different drying techniques on properties ofgranules and tablets made on a production scale
Agota Hegedus a, Klara Pintye-Hodi b,∗a Gedeon Richter Ltd., H-1475 Budapest 10, PO Box 27, Hungary
b Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Eotvos u. 6, Hungary
Received 24 April 2006; received in revised form 21 August 2006; accepted 6 September 2006Available online 10 September 2006
bstract
The aims of this study were to compare the properties of granules prepared in a high-shear granulator and dried by using different methodsfluid-bed and microwave-vacuum drying) and to compare the properties of tablets pressed from such granules. Experiments on a production scaleere performed with Collette Ultima Pro 600 single-pot processing equipment and a Glatt WSG 200 fluid-bed granulator and drier. The particles
ranulated in the traditional high-shear granulator and dried in a vacuum chamber had a higher porosity and higher bulk and tapped densities, asconsequence of the special characteristics of the drying process. They retained their spherical form, in contrast with the particles dried via theuid-bed technology. The two types of granules required different compressing forces for tabletting.2006 Elsevier B.V. All rights reserved.
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eywords: Single-pot processing equipment; Fluid-bed drier; Production scale
. Introduction
Granulation is a size-enlargement process in the course ofhich small particles are formed into larger, physically strong
gglomerates in which the original particles can still be identi-ed. The agglomeration of solid particles renders them moreuitable for further processing, such as tablet formation. Itmproves the flowability, ensures optimal particle size distri-ution and better homogenization of the active ingredient, andllows control of the granules, making them suitable for com-ression. In the wet-granulating process, a granulating liquids used to facilitate the agglomeration process, and the moistranules are then dried (Parikh, 1997).
Drying involves the removal of liquid from solid material thatontains moisture, through a process of evaporation resultingrom the application of heat. Thermal energy can be applied tohe granules by convection, conduction or vacuum drying (Fox,
005).
1.1. Convection is achieved by means of a flowing gaseousedium, in which the gaseous particles transmit heat while
cle size distribution; Bulk and tapped densities; Porosity; SEM
hanging place. Fluid-bed drying is an example of a convectiverying method. In the process of fluid-bed drying, the granuleso be dried are placed in a device fitted with a perforated screenr sieve, and air is circulated through this layer at a rate sufficiento lift and separate the granules, which are set in motion and taken what is termed a fluidized state. The drying occurs as a resultf the consequent intensive contact between the granules andhe gaseous drying medium.
1.2. Conduction can be attained by heat exchange betweendjacent particles of matter, heat transfer through a jacked bowlall and vacuum drying.1.3. In the process of vacuum drying, the material is placed
n a vacuum chamber, and the heat necessary to remove theoisture is applied directly to the solid material.The process of pure vacuum drying requires a longer drying
ime, but its undisputed advantage over other methods is that therying takes place at a lower temperature, which could be impor-ant when heat-sensitive materials are to be dried (Fox, 2005;tahl, 2004). Gas-assisted vacuum drying, and more commonlyicrowave-vacuum drying, allow quicker drying in a single-pot
rocessor, used consecutively or simultaneously (Fox and Bohle,001; McMinn et al., 2005).
In production-scale pharmaceutical manufacturing, the meth-ds most commonly used to produce granules are fluid-bed
ranulation and drying, or a combination of high-shear granu-ation and fluid-bed drying. In recent years, however, single-potechnology has grown in popularity, partly because the trans-er of the moist granules from the high-shear granulator to theuid-bed drier is critical. The single-pot equipment has taken
he form of a mixer/granulator retrofitted with a drying unitStahl, 2000). The drying unit is capable of pure vacuum dry-ng, microwave-vacuum drying, gas-assisted vacuum drying, orcombination of microwave and gas-assisted vacuum drying.icrowaves are waves of electromagnetic radiation, generated
y magnetrons under the combined action of electric and mag-etic forces. Microwave drying is based on the absorption oflectromagnetic radiation by dielectric materials. The dielec-ric material is placed in an electromagnetic field, when the
aterial becomes polarized and stores electrical energy througholarization. The level of polarization depends on the state andomposition of the material and the frequency of the appliedlectric field. For pharmaceutical-industry drying, microwavesith a frequency of 2450 MHz (wavelength 12.2 cm) are used.he microwaves are not forms of heat, but rather forms of energy
hat are manifested as heat through their interaction with materi-ls. The permittivity (ε) of materials sensitive to microwaves isomplex and comprises two parts, the first corresponding to theeal part or relative dielectric constant, and the second represent-ng the imaginary part or loss factor. The dielectric loss factorf a material is a measure of how much heat is generated insidematerial per unit time when an electric field is applied, when
ubjected to microwave heating (McLoughlin et al., 2003). Mostf the materials commonly used in the pharmaceutical industryave a relatively low loss factor and absorb microwave powernly at high field strengths. By comparison, granulation liquidswater or organic solvents) have high loss factors relative tohe dry materials used (Fox and Bohle, 2001; Pere and Rodier,002).
The purpose of this study was to compare the properties ofranules produced in the same manner, through high-shear gran-lation, but dried by using two different techniques (fluid-bednd microwave-vacuum drying).
. Materials and equipment
.1. Materials
The given tablets contained 50% (w/w) active ingredient.he binding solution was an aqueous solution of PVP K-30
4.5%, w/w). The other excipients were corn starch (30%, w/w)s diluent; colloidal anhydrous silica (4%, w/w) and glycerine1.5%, w/w) as moisture regulators; and microcrystalline cel-ulose (7.9%, w/w), talc (1.6%, w/w) and magnesium stearate0.5%, w/w) to improve tablet formation. We used the sameomposition and batch size (150 kg) in both sets of equipment.
.2. Equipment
In both cases, we performed the granulation in a Colletteltima Pro 600 single-pot processor (Fig. 1). The drying was
arried out in a Glatt WSG 200 fluid-bed granulator and drier
aTtw
Fig. 1. Photograph of Collette Ultima Pro 600 single-pot equipment.
Fig. 2) and in Collette Ultima Pro 600 single-pot processingquipment.
.2.1. Collette Ultima Pro 600This is a closed, single-pot system, which means that the
ntire granulation process can be performed in the one device.he bowl has a jacket wall to allow the circulation of hot or coldater, in order to regulate the temperature of the product. Both
he impeller and the chopper are positioned vertically, and pro-rude into the machine from above. The speeds of the impellernd the chopper are adjustable within a given range. The liq-id binder addition is regulated, and the machine is suitableor the spraying of binder solution with high or low viscosity.
number of parameters can be used to set up the end-point ofranulation: the processing time, the torque, the product temper-ture, etc., or a combination of these. The granules can be driedy vacuum and microwave energy, which can be combined withide-wall heating. The drying cycle of this machine is there-ore more energy-efficient than other drying processes. Therere three possible drying methods: vacuum, vacuum-trans flownd vacuum-microwave. The machine is suitable for computer-ontrolled, automated manufacturing.
.2.2. Glatt WSG 200This is also a single-pot system which is suitable for gran-
lation and drying process in the one device. There is an inlet
ir handling unit fit for air filtering, air heating, and air cooling.he air must be introduced at the bottom of the product con-
ainer through the perforated air distributor plate (screen type)hich is important to fluidize and mix material in the container.
A. Hegedus, K. Pintye-Hodi / International Jour
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he spraying head with three or six nozzles can be set in threeifferent positions over the distribution plate. Within the expan-ion chamber, granules are formed. There are bag filters withinhe machine which retain the particles. The filter bag is made ofolyester-lined material which is of a certain mesh size. Safetyir filters are built in the outlet air product. Main processes suchs air flow and spraying rate are controlled. The machine isquipped with a data acquisition system.
. Methods
.1. Preparation of granules and tablets
We performed the granulation in the Collette Ultima Pro 600rocessing equipment. The active ingredient, the corn starchnd the colloidal anhydrous silica were homogenized (impellerpeed: 65 rpm, process time: 6 min). The liquid binder was addedo the powder mixture (impeller speed: 95 rpm, chopper speed:00 rpm, liquid binder flow rate: 7 kg/min, process time: approx-mately 4 min). After addition of the liquid binder, mixing wasontinued to the torque value (wet massing—impeller speed:5 rpm, chopper speed: 2700 rpm, torque value: 6.5 kW).
The granules were dried to the prescribed value of the lossn drying by using two different methods.
In one case, we removed the wet granules from the Colletteltima Pro 600 equipment, loaded them into the Glatt WSG 200
uid-bed drier and performed the drying at 60 ◦C (process time:5 min, maximum product temperature: 35.5 ◦C).
In the other case, drying was carried out in the Colletteltima Pro 600 equipment by microwave-vacuum drying. The
3
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nal of Pharmaceutics 330 (2007) 99–104 101
im was to achieve the shortest possible drying time, and weherefore used the maximum forward energy (vacuum: 50 mbar,
After drying, the granules were sized in a 1.5 mm sieve (rota-ion speed: 500 rpm), and next homogenized for 2 min with theabletting excipients (microcrystalline cellulose, talc) and thenmin (magnesium stearate) in a container blender.
Fig. 3 shows the detailed flowcharts of the manufacturingrocesses.
We determined the size distribution of the granules, theirapped and bulk densities, porosity and moisture content, andook SEM photographs. The individual and average masses,eights and hardnesses of the tablets were examined.
.2. Testing of granules and tablets
.2.1. Particle size analysisWe determined the particle size distribution of an approx-
mately 25 g sample of the final granules, using a Hosokawalpine 200 LS air jet sieve with an array of five sieves.
.2.2. Bulk and tapped densitiesHundred millilitres of granules was poured into a 250 ml
raduated tared measuring cylinder, and the granules were theneighed and their bulk density, ρT, was determined in g/100 ml.The density of 100 ml of granules of known weight was
easured with a Stampfvolumeter 2003 (J. Engelsmann Appa-atebau, Ludwigshafen, Germany). After 200–300 taps (whenconstant value had been achieved), the volume of the tapped
olumn of granules was read off, and the density, ρT, was deter-ined in g/100 ml.
.2.3. PorosityThe properties of granules and tablets are influenced by the
orosity of the granules. Porosity can be defined through theelationship between the particle (ρpart) and tapped (ρT) densi-ies, using the following equation (Kumar et al., 2002):
=(
1 − ρT
ρpart
)× 100
The particle density (ρpart) was determined with a Stere-pycnometer SPY-5 (Quantachrome Corp.). The pycnometricarticle density was determined by measuring the volume occu-ied by a known mass of powder, which is equivalent to theolume of helium gas displaced. The particle density was cal-ulated via the following equation:
part = w
v
here w is the weight of sample and v is the volume of samples.
.2.4. Moisture determinationThe loss on drying of 2 g of granules (homogenized with the
xternal phase) to mass constancy at 70 ◦C was determined, withMettler Toledo HR 73 halogen moisture analyser. The loss on
102 A. Hegedus, K. Pintye-Hodi / International Journal of Pharmaceutics 330 (2007) 99–104
in tw
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iisnpvcpwit is therefore not necessary to ensure a low loss on drying whenthe granules are dried (Table 1), in which case fluid-bed dryingwould be preferable. For this reason, with these products we hadthe opportunity to perform a comparative granulometric analysis
Table 1Granule properties of batches dried in the Collette Ultima Pro 600 and in theGlatt WSG 200
Glatt WSG 200 Collette Ultima Pro 600
Bulk density (g/100 ml) 68.49–71.43 79.37–83.30Tapped density (g/100 ml) 80.55–84.29 94.53–104.17
Fig. 3. Flow sheet of granulation
rying of the granules must be within the range 2.5–4.5%, thisange being suitable for the tabletting of this product.
.2.5. Scanning electron microscopy (SEM)The morphological properties of the granules prepared in
oth sets of equipment were examined with a JEOL JSM-600LV scanning electron microscope fitted with an energyispersive X-ray spectrometer. A Polaron sputter coating appa-atus was applied to induce electric conductivity on the surfacef the sample. The air pressure was 1.3–13 mPa.
.2.6. Tablet evaluationThe granules were pressed into 500 mg tablets by using a
ourtoy R190 Ft tablet press with 36 punches. The rotationalpeed of the press was 65 rpm. We measured the average andndividual masses, the thickness, the hardness (Pharma Test
HT-2ME) and the disintegration (Pharma Test PTZ-E) fiveimes in the course of the tablet-formation process. The relativetandard deviation (R.S.D.) of the mass of the individual tabletsas determined by measuring 20 tablets.
. Results and discussion
Depending on the composition of the material system and theolvents used (organic or water), and their quantities, preference
LFDP
o types of dryer and tabletting.
s given to different drying techniques (e.g. fluid-bed or vacuum)n the pharmaceutical industry. However, for certain materialystems, the differences between the drying technologies areot marked enough to make one or the other unambiguouslyreferable. The products under study do not contain organic sol-ents or materials that are sensitive to heat or oxygen, or whichontain toxic or potent compounds, in which cases the single-ot technology would be clearly preferable. On the other hand,e are not using a liquid binder with a high water content, and
oss on drying (%) 2.70–3.45 3.07–4.08ine particles (%) <21 <23
50 (�m) 310–370 360–420orosity, ε (%) 73.9 63.1
A. Hegedus, K. Pintye-Hodi / International Journal of Pharmaceutics 330 (2007) 99–104 103
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Fig. 4. SEM photographs of granules dried in Glatt WSG 200.
f different techniques used for drying wet granules preparedy using the same method. The advantage of fluid-bed dryings the short drying time, in contrast with pure vacuum drying,hich entails a long processing time. Accordingly, we com-ined vacuum drying with microwave drying, since the durationf processing is an important consideration in the pharmaceu-ical industry. In the drying process, the primary goal was tohorten the processing time. In the experiments, the differenceetween the maximum product temperatures attained with thewo drying techniques (35.5 ◦C and 43 ◦C) had no impact on theroduct quality.
Granule size increase is influenced by the impeller speed, theet massing time and the amount of liquid in the case of high-
hear granulation. In this study, the granules were granulated byeans of the same technology, but dried with different methods.he powder fraction was relatively high for both vacuum anduid-bed drying, at <21% and <23%, respectively, as shown inable 1, but a significant difference in the powder fraction wasot detected (Vromans et al., 1999). As conserns the composi-ion under study, the mean particle size (D50) was larger for theranules dried by using microwaves than for the fluid-bed dried
ample. This is because the granules collide with each other andhe wall of the equipment during the fluid-bed drying process.articles therefore constantly break off and are eroded.
Fig. 5. SEM photographs of granules dried in Collette Ultima Pro 600.
icpt
Ft
ig. 6. Drying curves of the vacuum-microwave (- - -) and fluid-bed (—) dryingechnology.
Besides D50, our findings were also corroborated by the SEMmages shown in Figs. 4 and 5. The granules dried in the vacuumhamber were more geometrically regular and spherical, andhus had a different external physical structure from that of theranules dried with the fluid-bed technology.
The physical differences between the granules could resultartly from the drying time, and partly from the nature of therying curves (Fig. 6). In order for a material system with theame moisture content to develop by the end of the drying pro-ess, approximately 1.5 times the drying time is necessary inhe case of vacuum drying than in the case of fluid-bed drying.n other words, the expulsion of moisture is slower, gentler andore even, with the result that the primary physical structure of
he granules remains more intact. In the case of fluid-bed drying,he raggedness and erosion of the granules arise not only fromhe impact, but also as a result of the sudden temperature change,wing to the rapid expulsion of moisture. This rapid evaporationnflicts more intensive damage on the granules.
It is known from the literature that the porosity of granules isffected considerably by the impeller speed and the wet mass-ng time (Badawy et al., 2000). However, less research has been
onducted into the extent to which the porosity of granules pre-ared by using the same granulation technology is influenced byhe subsequent use of different drying methods.
ig. 7. Correlation between hardness and pressing power. Vacuum-microwaveechnology (×), fluid-bed dried granules (�).
104 A. Hegedus, K. Pintye-Hodi / International Jour
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ig. 8. Correlation between hardness and thickness. (�) Tablets pressed fromranules dried in Collette Ultima Pro 600. (�) Tablets pressed from granulesried in Glatt WSG 200.
The data in Table 1 show that the granules dried in the vacuumhamber had a lower level of porosity than those dried by usinghe fluid-bed process, although the drying process was slower.his is due to the mechanism by which the moisture is forced outf the capillaries in the granules under sub-atmospheric pressure,hich results in the formation of “channels” in the interior of
he granules as the moisture leaves the granules. In the coursef fluid-bed drying, which takes place at atmospheric pressure,he granules dry from their surface inwards, which results in aigher level of porosity.
The lower porosity values entail higher bulk and tapped den-ity values, as shown in Table 1.
A reduction in porosity generally leads to a deterioration inompressibility. In the systems we examined, this took the formf a shift in the range of compressing force required to producetablet of the same hardness.
The correlation between compressing force and hardness ishown in Fig. 7. The granules prepared by using microwave-acuum drying are denser, with the result that the tablets areower and easily compressible, but a higher pressure force muste applied than in the case of the granules dried with the fluid-ed technology. The correlation between hardness and heights shown in Fig. 8. The height of the compressed tablets fromhe granules dried with the microwave-vacuum technology wasower than that of the tablets compressed from granules of theame hardness, dried with the fluid-bed technology. The dif-
erences in compressibility can be attributed to the differencesetween the structures of the granules, caused by the differ-ng drying technologies. As can be seen in Table 2, the use ofhe different drying techniques had no effect on the individual
able 2roperties of tablets pressed from granules dried in the Collette Ultima Pro 600nd the Glatt WSG 200
Glatt WSG200
Collette UltimaPro 600
elative standard deviation (R.S.D.) ofindividual mass from average mass (%)
ass distribution or disintegration time of the tablets; they hadrelatively low mass distribution and short disintegration time
<1 min) in both cases.
. Conclusions
Following the wet massing process, the drying technologiespplied in the pharmaceutical industry were selected on the basisf a number of criteria, such as the properties of the active ingre-ient, the type of solvent, the processing time, etc. The choicef the most suitable technology for the given purpose requiresareful consideration and testing. Two drying techniques, basedn differing principles (fluid-bed and microwave-vacuum) wereelected for the purposes of the present research, and the prop-rties of the granules produced by using these methods wereompared.
The granules produced in the traditional high-shear gran-lator and dried in a vacuum chamber had a lower level oforosity, and higher bulk and tapped densities, owing to thepecial characteristics of the drying process. They retained theirpherical form, in contrast with the granules dried by using theuid-bed technology. These characteristics of the granules alsoetermined the properties of the tablets pressed from them, andade it necessary to apply a greater compressing force in the
ase of the granules prepared by using the microwave-vacuumrying process. At the same time, the mass distribution and dis-ntegration time were not affected.
Despite the measurable physical differences arising from theiffering principles of the two drying methods, both dryingechnologies proved highly suitable for production-scale manu-acturing of the compositions under study.
eferences
adawy, S.I.F., Menning, M.M., Gorko, M.A., Gilbert, D.L., 2000. Effect ofprocess parameters on compressibility of granulation manufactured in ahigh-shear mixer. Int. J. Pharm. 198, 51–61.
arikh, D., 1997. Handbook of Pharmaceutical Granulation Technology; Drugsand Pharmaceutical Sciences, vol. 81. Marcel Dekker Inc., New York, pp.151–204.
ere, C., Rodier, E., 2002. Microwave-vacuum drying of porous media: experi-mental study and qualitative considerations of internal transfers. Chem. Eng.Process. 41, 427–436.
tahl, H., 2000. Single-pot system for drying pharmaceutical granules. Pharm.Technol. Eur. 12, 192–201.
Chemical Engineering and Processing 46 (2007) 1012–1019
Influence of the type of the high-shear granulatoron the physico-chemical properties of granules
Agota Hegedus a,∗, Klara Pintye-Hodi b
a Gedeon Richter Ltd., H-1475 Budapest 10, P.O.B. 27, Hungaryb Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged,
Eotvos str. 6, Hungary
Received 23 May 2006; received in revised form 19 April 2007; accepted 17 May 2007Available online 20 June 2007
bstract
The purpose of this experiment was to compare the results of the granulation that can be achieved in different production-scale high-shearranulator models, and the characteristics and tablet-forming properties of the granules produced, in the case of a product with a high activengredient content. We studied granules prepared in Diosna P400 and Collette Ultima Pro 600 industrial high-shear granulators. The main differencesetween the two machines relate to the geometry of the bowl and the positioning of the chopper and impeller. The granules produced in theseachines (which have identical manufacturing capacity) have different macroscopic and microscopic structures. The aim was to create, optimize
nd reproduce a robust technology that furnishes granules (and the tablets formed from them) with similar physical properties in both sets of
quipment. With the currently studied product, it was possible to establish the optimal ranges of the impeller and chopper speeds, the water contentf the binder solution, the liquid binder flow rate, the wet massing time and the torque, thereby rendering the manufacturing process controllablend reproducible.
2007 Elsevier B.V. All rights reserved.
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eywords: High-shear granulator; Production scale; Particle size distribution; B
. Introduction
Wet granulation is a technique whereby a liquid is usedo transform small solid particles into clusters of larger ones,hrough a process of agglomeration. In pharmaceutical tablet
anufacturing, the agglomeration of solid particles renders themore suitable for tablet formation. It improves the flowability,
nsures optimal particle size distribution and a better homog-nization of the active ingredient, and allows control of theranules, making them suitable for compression.
There are two known closed-system wet granulation proce-ures: high-shear granulation and fluid-bed granulation. Theseechniques differ in the modes of agitation of the solid particles,
nd for this reason there are also differences in granule growth.
In the course of fluid-bed granulation, the powder bed isept in motion by specially treated (filtered, temperature and
umidity-controlled) air, which is introduced through a sievelate in the base of the granulator. The binder solution is sprayednto the fluidized powder bed. The granules are created dur-ng the wetting of the powder bed, through the adhesion ofolid particles as the drops of liquid reach the powder bed. Thegglomeration of the powder takes place during the wetting pro-ess and, once the process of spraying the adhesive onto theowder bed has been completed, the granules are dried throughhe use of warm air [1].
In high-shear granulation, an impeller is used to agitate theolid particles within a closed space. The binder solution is addedr sprayed in from above. The mixing, densification and agglom-ration of the wet material are performed by the impeller throughhe exertion of shearing and compacting forces. The process isnded before the granules begin to grow uncontrollably, whichould result in the phenomenon known as “ball growth”.
High-shear granulators have long been used in the pharma-
eutical industry, both for mixing and for granulating. Originally,igh-shear granulators did not have drying capability, whicheans that the wet granules produced in these machines had
T(a(lulose (7.9%, w/w), talc (1.6%, w/w) and magnesium stearate
A. Hegedus, K. Pintye-Hodi / Chemical En
o be dried by using another machine, such as a fluid-bed drier.ater, these granulators were further developed into what are
ermed “single-pot” systems, which are capable of performingll of the processes of mixing, granulation, drying and blending.he possible drying methods are vacuum, vacuum-microwavend gas-vacuum methods [2], all of which can be combined withide-wall heating [3–5].
Pharmaceutical companies often find that they have to presentcientific evidence to justify the replacement or modernizationf equipment that could be up to one or two decades old. Phar-aceutical companies endeavour to achieve more cost-effective
nd better-regulated processes, in line with the standards of Goodanufacturing Practice (GMP). The advantages of single-pot
igh-shear granulators include the facts that the entire processakes place in one set of equipment, GMP requirements are met,he processing time is reduced, cleaning is simplified throughhe use of integrated, programmed cleaning systems, and theranulators are equipped with the appropriate safety systems4,5].
Our objective was to adapt the production-scale granula-
ion process, previously performed with a traditional high-shearranulator (Diosna P400) and a fluid-bed drier (Glatt WSG-200),o that it could be carried out in a single-pot high-shear gran-lator (Collette Ultima Pro 600). In view of the considerable
Fig. 1. Photographs of the Diosna P400 mixer granulator.
(c
F
ing and Processing 46 (2007) 1012–1019 1013
ifferences between the two machines, the fact that our experi-ents were not preceded by laboratory and pilot tests, and the
act that we were working on a production scale, we decidedo adapt the processes in two stages: first the granulation step,nd then the overall process, including the drying step. We alsoet out to compare the granulation process of a specific compo-ition in two sets of equipment, which, although identical withespect to capacity and operating principles, differ in many otherespects.
. Materials and equipment
.1. Materials
The given tablets contained 50% (w/w) active ingredient.he binder solution was an aqueous solution of PVP K-30
4.5%, w/w). The other excipients were cornstarch (30%, w/w)s diluent; colloidal anhydrous silica (4%, w/w) and glycerine1.5%, w/w) as moisture regulators; and microcrystalline cel-
0.5%, w/w) to improve tablet formation. We used the sameomposition and batch size (150 kg) in both sets of equipment.
ig. 2. Photographs of the Collette Ultima Pro 600 single-pot equipment.
1014 A. Hegedus, K. Pintye-Hodi / Chemical Engineer
Table 1Technical data of the Diosna P400 and the Collette Ultima Pro 600
Diosna P400 Collette Ultima Pro 600
Bowl capacity (l) 385 400Impeller speed (rpm) 64 or 129 From 14 to 135Chopper speed (rpm) 1450 or 2930 From 600 to 2700
We performed the granulation in a Diosna P400 (Fig. 1)onventional mixer-granulator (without drying facility) and aollette Ultima Pro 600 single-pot equipment (Fig. 2). Techni-al data on the two types of equipment can be seen in Table 13,6]. In both cases, drying was carried out in a Glatt WSG 200uid-bed granulator and drier.
The main differences between the two granulators are asollows.
.2.1. Diosna P400It has a single-walled design. Neither the side-walls nor the
id of the device can be temperature-controlled. The machine isone-shaped, with the impeller positioned vertically, and thehopper horizontally. The impeller protrudes into the devicerom below. The impeller blades and the special shape of the
codu
ig. 3. Flow sheet of the granulation in two types of high-shear granulator and in a flnd Collette Ultima Pro 600.
ing and Processing 46 (2007) 1012–1019
achine ensure effective mixing. Both the impeller and thehopper have two speed settings, with no fine adjustment. Thempeller and the chopper are fitted with a time switch, whichs the only means of setting an end-point. (There is no mea-urement of torque or power consumption.) It is not possible toegulate the application of the binder solution. The quality ofhe granules depends largely on the skill and experience of theersonnel carrying out the production.
.2.2. Collette Ultima Pro 600This is a closed, single-pot system, which means that the
ntire granulation process can be performed in the one device.he bowl has a jacket wall to allow the circulation of hot orold water, in order to regulate the temperature of the prod-ct. Both the impeller and the chopper are positioned vertically,nd protrude into the machine from above. The speeds of thempeller and the chopper are adjustable within a given range.he liquid binder addition is regulated, and the machine is suit-ble for the spraying of the binder solution with high or lowiscosity. A number of parameters can be used to set up thend-point of granulation: the processing time, the torque, theroduct temperature, etc., or a combination of these. The gran-les can be dried by vacuum and microwave energy, which
an be combined with side-wall heating. The drying cyclef this machine is therefore more energy-efficient than otherrying processes. There are three possible drying methods: vac-um, vacuum-trans flow and vacuum-microwave. The machine
uid-bed granulator and dryer. Setting ranges of the parameters in Diosna P400
gineering and Processing 46 (2007) 1012–1019 1015
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s suitable for computer-controlled, automated manufacturing2,6,7].
. Methods
.1. Manufacturing process
Fig. 3 shows the flowcharts of the manufacturing processesn the Diosna P400 and the Collette Ultima Pro 600.
In the Diosna P400, the binder solution is poured onto theowder during the second step, and the addition of the binderolution is therefore not regulated. In the Collette Ultima Pro00, in the course of liquid binder addition and wet massing,e varied five parameters that could affect the characteristics of
he granules [8]. We then compared the granules thus produced,nd the granulating processes used. Table 2 details 11 differentombinations of the following five parameters [9,10]:
1) impeller speed,2) chopper speed,3) water content of the binder solution,4) liquid binder flow rate,5) wet massing time.
At the beginning of our experiments, we adapted the machineettings (the impeller and chopper speeds, and the water contentf the binder solution) to correspond to those of the Diosna00 (Table 2, setting 0). With setting 0, we were unable to pro-uce granules in the Collette Ultima Pro 600. We observed thathe product manufacturing processes are not always transferablewith identical technological parameters) between granulatorsith the same production capacity, but different geometric
haracteristics. Through our experiments, we determined theorque values representing the granulation end-points at variousmpeller speeds [11]. These values are shown in Fig. 4. In ourxperiment, at the torque value associated with an impeller speedf 65 rpm (530 Nm), aggregation did not occur, and no gran-les were formed. The explanation for this is that the motions
f the materials differed because of the geometrical differ-nces (with respect to both the shape and the positioning ofhe impeller and the chopper) between the two machines, withhe result that the different systems required different impeller
m
wr
able 2etting parameters of the Collette Ultima Pro 600
un Impeller speed (rpm) Chopper speed (rpm) Water content of the binde
ig. 4. Relationship between the torque value and impeller speed at the granu-ation end-points by Collette Ultima Pro 600.
peeds to achieve the same degree of granulation formation12,13].
In both cases, the granules were dried as follows.We discharged the wet granules from the high-shear granula-
or equipment and loaded them into the Glatt WSG 200 fluid-bedryer and performed the drying at 60 ◦C, temperature at the endf the drying: 34 ◦C. After first drying, the granules were sized in1.5 mm sieve, and then followed the drying step at 60 ◦C to thealue of the loss on drying. Dried granules were homogenizedor 2 and 5 min with the tabletting excipients (microcrys-alline cellulose, talc and magnesium stearate) in a containerlender.
.2. Testing of granule characteristics
.2.1. Particle size analysisWe determined the particle size distribution of an approx-
mately 25 g sample of the final granules, using a Hosokawalpine 200 LS air jet sieve with an array of five sieves.
.2.2. Bulk and tapped densitiesWe poured 100 ml of granules into a 250 ml graduated tared
easuring cylinder, and then weighed the granules and deter-
ined their bulk density, ρt, in g/100 ml.We measured the density of 100 ml of granules of known
eight with a Stampfvolumeter 2003 (J. Engelsmann Appa-atebau, Ludwigshafen, Germany). After 200–300 taps (when a
r solution (kg) Liquid binder flow rate (kg/min) Wet massing time (min)
7 127 27 57 47 57 27 27 43 2
12 47 4
1 gineering and Processing 46 (2007) 1012–1019
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Table 3Active ingredient physical properties
Particle size analysis (�m)D10 25D50 125D90 300
Carr compressibility index (%) 21.70BT
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016 A. Hegedus, K. Pintye-Hodi / Chemical En
onstant value had been achieved), we read off the volume of theapped column of granules, and the density, ρT, was determinedn g/100 ml [14].
.2.3. Carr compressibility indexThe flow properties of the granules can be determined through
ompaction, and the extent of the compaction can be definedhrough the relationship between the bulk and tapped densities,hich can be expressed with the Carr compressibility index [15],sing the following equation:
arr compressibility (%) = ρT − ρt
ρT× 100
here ρT is the tapped density and ρt is the bulk density.
.2.4. Moisture determinationWe determined the loss on drying to mass constancy of 2 g of
ranules (homogenized with the external phase) at 70 ◦C, usingMettler Toledo HR 73 halogen moisture analyser. The loss onrying of the granules must be within the range 2.5–4.5%. Thisange is suitable for the tabletting of this product.
.2.5. Scanning electron microscopyWe examined the morphological properties of the granules
repared in both sets of equipment, using a JEOL JSM-5600LVcanning electron microscope (SEM) fitted with an energy dis-ersive X-ray spectrometer. A Polaron sputter coating apparatusas applied to induce electric conductivity on the surface of the
ample. The air pressure was 1.3–13 mPa.
. Result and discussion
Table 3 shows the active ingredient’s physical properties.
.1. Particle size analysis
The rate of granule growth is influenced by the speed of thempeller, the wet massing time and the amount of binder [16].
e carried out our experiments on a production scale.In the Collette Ultima 600 machine, the end-point of granu-
ation was the torque necessary for the given impeller speed (inrder to avoid possible variations between the different batches
flbea
able 4ranules properties in the Collette Ultima Pro 600 of the different setting parameters
1 2 3 4
ulk density (g/100 ml) 69.44 68.49 75.76 70.42apped density (g/100 ml) 84.72 76.71 84.85 80.28arr compressibility index 18.04 10.72 10.71 12.28oss on drying (%) 3.44 2.90 3.15 3.06
article size analysis (%)<0.090 mm 18.7 18.6 17.6 21.00.090–0.180 mm 7.5 35.2 16.2 17.30.180–0.355 mm 15.8 26.7 29.5 23.50.355–0.710 mm 33.7 18.3 24.9 29.90.710–1.000 mm 17.9 1.2 8.9 7.0>1.000 mm 6.4 0 3.2 1.3
ulk density (g/100 ml) 71.50apped density (g/100 ml) 91.30
f active ingredient, which, for a product containing 50% activengredient, could result in a substantial divergence). Even withelatively short wet massing periods, for preparations that granu-ated well, only small differences were detected, even at a varietyf impeller speeds. This means that these two parameters areot of great importance as factors influencing the particle sizeistribution in the composition studied.
The most important factor influencing the particle size distri-ution of the granules proved to be the amount of liquid binder,s may be seen in Table 4. In experiment 1, in which the greatestuantity of liquid was used, the highest proportions were thosef the largest particles, i.e. >1000 �m (6.4%), and of particles355 �m (58%). In experiment 2, where the lowest quantity ofinder liquid was used, the proportion of particles <180 �m was53.8%).
In comparison, the granules prepared in the Diosna P400ranulator displayed a considerable variance in their particle sizeistribution, as is to be seen in Table 4. The proportion of parti-les >1000 �m was between 0.9% and 14.8%, while the fraction180 �m varied between 24.0% and 60.5%. These differencesould have been caused by the initial uneven distribution of mois-ure, and the subjectivity involved in determining the end-pointf granulation.
.2. Bulk and tapped densities and Carr compressibilityndex
The Carr compressibility index is widely used to analyse the
ow properties of granules. If the Carr compressibility index isetween 5 and 10, then the granules have excellent flow prop-rties, whiles values of 12–16 indicate good, 18–21 acceptable,nd 23–28 poor flowability. In this case the Carr compressibility
Table 6Granules properties of reproduction batches in the Collette Ultima Pro 600
R/1 R/2 R/3 R/4 R/5 R/6
Bulk density (g/100 ml) 68.49 69.44 69.44 69.44 71.43 69.44Tapped density (g/100 ml) 80.82 82.64 81.94 80.55 84.29 81.94Carr compressibility index 15.26 15.97 15.26 13.79 15.26 15.26Loss on drying (%) 3.00 2.96 3.45 3.42 3.35 2.70
Particle size analysis (%)<0.090 mm 19.7 16.2 20.6 20.2 18.9 19.70.090–0.180 mm 20.4 15.6 19.2 15.9 15.7 14.70.180–0.355 mm 26.7 27.0 25.4 24.7 24.8 21.90.355–0.710 mm 24.9 28.4 28.2 29.8 29.9 32.1
tr
up(10.80%) for the D batches than the R batches (4.74%). Thebulk and tapped densities varied within a wider range andhigher relative standard deviation for the D batches (bulkdensity: 68.49–75.76 g/100 ml, R.S.D.: 4.34%; tapped density:
A. Hegedus, K. Pintye-Hodi / Chemical En
ndex indicate weakly or poorly flowing granules, as the Carrompressibility index was 18.04. This result can be consid-red acceptable. The Carr compressibility index, with a valuef 7.40, showed that the granules produced in experiment 7 (aedium quantity of binder solution: 26 kg, a medium flow rate:kg/min, a medium impeller speed: 95 rpm, and a low chopper
peed: 1500 rpm) had excellent flow properties. The granulesrepared in experiments 2 (Carr compressibility index 10.72)nd 3 (10.71) were similarly good. The bulk and tapped densi-ies of the granules produced in experiments 2 and 7 were low.or compositions with a high active ingredient content, relativelyigh bulk and tapped densities are favourable from the point ofiew of tablet formation, since the volume of die filling is pro-ortionally reduced [17]. With respect to the flow properties ofhe granules, the settings used in experiment 3 (a medium quan-ity of binder solution: 26 kg, a medium flow rate: 7 kg/min, aow impeller speed: 80 rpm, and a low chopper speed: 1500 rpm)ielded the best results.
In comparison, there were no significant differences in thearr compressibility index values of the granules prepared in
he Diosna P400, given in Table 5. The best Carr compressibilityndex was 11.51, but all the granules had good flow properties,ith values ranging between 11.51 and 15.97. The bulk density
anged between 68.49 and 75.76, while the tapped density variedrom 78.47 to 87.50.
.3. Reproduction
We performed our experiments with production-scaleachinery. Reproducibility is important, and a prerequisite for
alidation in the pharmaceutical industry. For this reason, setting0 was selected as medium value to manufacture a further fiveatches in the Collette Ultima Pro 600 (the results are shownn Table 6), and the granules with those prepared in the Diosna400 were compared.
With respect to the particle size distribution, for all the repro-uction (R) batches, the fraction of particles >1000 �m was3%, but for D/2 and D/3 (14.8% and 10.8%) it exceeded
his value. In all cases, the fraction of the particles <90 �mn the R batches < 20%, but for D/4 and D/5 it was 20.8%nd 25.5%. For the R batches, the majority of the granules>50%) fell into the fraction 180–710 �m, in contrast with
able 5ranules properties in the Diosna P400
D/1 D/2 D/3 D/4 D/5 D/6
ulk density (g/100 ml) 73.53 74.63 75.76 69.44 68.49 69.44apped density (g/100 ml) 87.50 86.57 87.88 79.86 80.14 78.47arr compressibility index 15.97 13.79 13.79 13.05 14.54 11.51oss on drying (%) 3.06 3.10 3.11 3.09 3.04 3.50
article size analysis (%)<0.090 mm 11.7 16.0 15.7 19.1 20.8 25.50.090–0.180 mm 18.8 8.0 9.7 29.8 39.7 16.20.180–0.355 mm 32.6 14.9 26.2 28.2 18.7 24.60.355–0.710 mm 16.2 27.5 23.2 15.8 13.7 22.30.710–1.000 mm 11.6 18.8 14.4 6.2 5.9 8.5>1.000 mm 9.1 14.8 10.8 0.9 1.2 2.9
0.710–1.000 mm 6.8 10.4 5.8 8.3 9.2 11.6>1.000 mm 1.5 2.4 0.8 1.1 1.5 0
hose produced in the Diosna P400, none of which were in thisange.
The Carr compressibility index demonstrated that the gran-les prepared in both sets of equipment had good flowroperties, but relative standard deviation (R.S.D.) is higher
Fig. 5. SEM pictures of granules prepared in the Diosna P400.
1018 A. Hegedus, K. Pintye-Hodi / Chemical Engineer
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ig. 6. SEM pictures of granules prepared in the Collette Ultima Pro 600.
9.86–87.88 g/100 ml, R.S.D.: 5.21%) than for the R batchesbulk density: 68.49–71.43 g/100 ml, R.S.D.: 1.39%; tappedensity: 80.55–84.29 g/100 ml, R.S.D.: 1.65%).
Fig. 5 shows SEM pictures of granules prepared in the Diosna400. The particles making up the granules prepared in theiosna P400 were dense and relatively large. The spherical
tructure was retained during the fluid-bed drying process thatollowed the granulation. The surfaces of the granules displayedittle wear.
Fig. 6 presents SEM pictures of granules prepared in the Col-ette Ultima 600. These granules had a looser structure, were lesspherical and smaller, and cracked during drying. Any irregularrotrusions of the particles broke away from the granules.
In both cases, the starch particles (which have a dense texture)ould be easily differentiated from the active ingredient crystalsnd excipients.
The differences in the texture of the granules could be causedy the differing geometries of the two machines as concerns thehape and positions of the impeller and chopper blades. Becausef these factors, the materials exhibit completely different typesf motion during granulation, with the Collette Ultima 600 pro-
ucing an “undulating” effect, and the Diosna P400 granulatormploying a “folding” action. This difference can be made evenore distinct by varying the settable parameters.
ing and Processing 46 (2007) 1012–1019
The result homogeneity study (Blend Uniformity Analysis)emonstrated a mean value of 99.1 ± 0.4% for the active ingre-ient content with the relative standard deviation less than 1.5%n both case.
.4. Tablet evaluation
We pressed the granules into 500 mg tablets by using a Cour-oy R190 Ft tablet press with 36 punches. The rotational speedf the press was 65 rpm, and the main pressure applied was6 ± 1 kN. We measured the average and individual masses,he thickness and the hardness (Pharmatest WHT-2ME), the fri-bility (Pharmatest PT-TD) and the disintegration (PharmatestTZ-E) five times in the course of the tablet-formation pro-ess. We determined the R.S.D. of the weight of the individualablets by measurements of 20 tablets. The tablet parametersere satisfactory in both batches. The friability was <0.33%,
he thickness was between 4.00 and 4.19 mm, the disintegrationime was <2 min for all batches, and the average hardness wasetween 51 and 66 N. The weight variation of the tablets was.60–1.00% for the experimental batches, 1.01–1.12% for the Datches, and 0.57–0.7% for the R batches.
. Conclusion
For two high-shear granulators with different constructions,e established the ranges of parameter settings which ensure
he safe transference of the technologies for a preparation withhigh content of active ingredient.
We determined the optimal setting ranges for mass productionimpeller speed: 80–135 rpm; ideal torque associated with thempeller speed: 560–800 Nm; chopper speed: 600–2700 rpm;deal water content of the binder solution: 26 kg; liquid binderow rate: 3–12 kg/min; massing time: 2–6 min), within whicharameter ranges a satisfactory product could be manufacturedn a manner such that the drying stage took place within theame fluid-bed drying equipment. The experiment demonstratedhat, although the two technological devices perform granulationccording to similar principles of operation, their different geo-etric properties require different technical settings in order for
he end-products to have the same physical characteristics.The textures of the granules prepared in the two types of
achine differed considerably, but the differences between theeasured physical parameters were not as great. The granulation
rocess was highly controllable, the product was suitably robustnd the results were easy to reproduce in the Collette Ultima00 granulator, which allowed elimination of the inconsistenciesesulting from the use of the Diosna P 400.
eferences
[1] B. Fox, True grit: granulation & drying of delicate products, Chem. Eng.115 (2005) 35–38.
[2] C. Pere, E. Rodier, Microwave vacuum drying of porous media: experimen-
Process. 41 (2002) 427–436.[3] D. Parikh, Handbook of Pharmaceutical Granulation Technology, 81, Drugs
and Pharmaceutical Sciences, Marcel Dekker Inc., New York, 1997, pp.151–204.
gineer
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A. Hegedus, K. Pintye-Hodi / Chemical En
[4] H. Stahl, Single-pot system for drying pharmaceutical granules, Pharm.Technol. Eur. 12 (5) (2000) 192–201.
[5] H. Stahl, Comparing different granulation techniques, Pharm. Technol. Eur.16 (11) (2004) 23–33.
[6] A. Faure, I.M. Grimsey, R.C. Rowe, P. York, M.J. Cliff, Applicability of ascale-up methodology for wet granulation processes in Collette Gral highshear mixer-granulators, Eur. J. Pharm. Sci. 8 (1999) 85–93.
[7] A. Faure, P. York, R.C. Rowe, Process control and scale-up of pharma-ceutical wet granulation process: a review, Eur. J. Pharm. Sci. 52 (2001)269–277.
[8] P.C. Knight, A. Johansen, H.G. Kristensen, T. Schaefer, J.P.K. Seville, Aninvestigation of the effect on the agglomeration of the changing the speedof a mechanical mixer, Powder Technol. 110 (2000) 204–209.
[9] K. Saleh, L. Vialatte, P. Guigon, Wet granulation in a batch high shear
mixer, Chem. Eng. Sci. 60 (2005) 3763–3775.
10] A. Devay, K. Mayer, Sz. Pal, I. Antal, Investigation on drug dissolutionand particle characteristics of pellets related to manufacturing process vari-ables of high-shear granulation, J. Biochem. Biophys. Methods 69 (2006)197–205.
[
ing and Processing 46 (2007) 1012–1019 1019
11] G. Betz, P.J. Burgin, H. Leuenberer, Power consumption measurementand temperature recording during granulation, Int. J. Pharm. 272 (2004)137–149.
12] P. Holm, T. Schaefer, H.G. Kristensen, Granulation in high-speed mixers.Part. VI. Effects of process condition on power consumption and granulegrowth, Powder Technol. 43 (1985) 225–233.
13] P. Holm, T. Schaefer, C. Larsen, End-point detection in a wet granulationprocess, Pharm. Dev. Technol. 6 (2) (2001) 181–192.
14] A. Schussele, A. Bauer-Brandl, Note on the measurement of flowabil-ity according to the European Pharmacopoeia, Int. J. Pharm. 257 (2003)301–304.
16] S.I.F. Badawy, M.M. Menning, M.A. Gorko, D.L. Gilbert, Effect of process
parameters on compressibility of granulation manufactured in a high-shearmixer, Int. J. Pharm. 198 (2000) 51–61.
17] V. Kumar, M.L. Reus-Medina, D. Yang, Preparation characterization, andtabletting properties of a new cellulose-based pharmaceutical aid, Int. J.Pharm. 235 (2002) 129–140.