Powder Technology 207 (2011) 407–413

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Influence of needle-shaped drug particles on the solid lipid extrusion process

Rieke Witzleb a, Venkata-Rangarao Kanikanti b, Hans-Jürgen Hamann b, Peter Kleinebudde a,⁎a Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, 40225 Duesseldorf, Germanyb Bayer Animal Health GmbH, 51368 Leverkusen, Germany

⁎ Corresponding author.E-mail address: kleinebudde@uni-duesseldorf.de (P.

0032-5910/$ – see front matter © 2010 Elsevier B.V. Aldoi:10.1016/j.powtec.2010.11.027

a b s t r a c t

a r t i c l e i n f o

Article history:Received 22 June 2010Received in revised form 9 November 2010Accepted 20 November 2010Available online 27 November 2010

Keywords:Die diameterMillingNeedleParticle shapeScrew setupSolid lipid extrusion

It has been shown previously that solid lipid extrusion with several drugs is uncomplicated and robust. In thiswork it has been shown for the first time that needle shaped drugs cause problems during solid lipid extrusionand sometimes such drugs cannot be processed. Extrusion performance could not be improved by i: changingthe screw configuration or the die geometry by increasing the die diameter, ii: changing the type of lipid or iii:additives or iv: decreasing the drug load. In contrast milling the needle-shaped crystals before extrusion inorder to obtain more isometric particles led to smooth reproducible processes.Praziquantel, mesalazine and caffeine were milled. Then both milled and unmilled powders were extrudedusing the same excipients and process parameters. The processing performance was compared, the surfacetexture of the extrudates was analysed and the drug crystals were investigated regarding their particle sizeand shape before and after milling and extrusion, respectively. The effect of milling on the process wassignificant for praziquantel and caffeine, whereas needle-shaped mesalazine crystals were broken downduring extrusion and caused less problems during the process.

Kleinebudde).

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© 2010 Elsevier B.V. All rights reserved.

1. Introduction

It is generally known that the particle shape of a powder has animpact on its bulk properties such as flowability and bulk density.Spherical particles show ideal flow properties and high bulk density,whereas long fine needles practically do not flow and form felted,fluffy bulks [1,2]. Also the influence of particle shape on thetabletability of a powder has been reported. The needle-shape of adrug cannot only lead to dosing problems due to poor flowability andcohesiveness of a powder, but can also cause sticking to punches andcapping during compaction. In previous studies paracetamol hasshown problems like capping and lamination. It has been demon-strated that its needle-shaped particle shape was the reason. Bettercompactibility was achieved using paracetamol in isometric particleshape, that was obtained by milling of the drug powder [3,4].Ibuprofen consists of needle-shaped particles as well and has beenshown to cause difficulties during compression. With granulation orrecrystallisation into isometric forms its tabletability could beimproved [1,5]. Further, the needle-shaped drug celecoxib showedimproved flowability and compactibility after recrystallisation [6].Also, a negative impact of the needle-shape of particles on the processof microencapsulation was demonstrated previously. During micro-encapsulation of needle-shaped praziquantel particles, agglomerationinhibited a quantitative processing, whereas milled praziquantel was

encapsulated smoothly [7]. Recently, a negative impact of the needle-shape of a drug on a wet-extrusion process has been reported [8]. Inproduction of glass-ceramics needle-shaped apatite crystals havebeen hot melt extruded while they were embedded in molten glass. Ithas been shown that the crystals orientate themselves in direction ofextrusion. Viscosity and extent of orientation depended on temper-ature and shear rate. A suspension effect was suggested, where theneedle-shaped crystals behaved like fibrous particles in a solvent [9].

Lipid-based formulations have spread in their importance inpharmaceutical drug development in the last years. They areincreasingly used to enhance the oral bioavailability of poorlywater-soluble drugs [10]. In addition, lipids are used for taste maskingof bitter drug substances, especially developed for children andanimals [11–13]. Furthermore, lipids are used for oral and parenteralcontrolled release systems and for dosage forms with water-sensitivesubstances by protecting them from hydrolysis [14–16].

In solid lipid extrusion a powdered lipid is mixed with a drug andextruded below themelting range of the lipid. The drug is dispersed inthe lipid matrix and the lipid does not completely melt but it softens.Previous studies of solid lipid extrusion with 1 mm die diameter usingseveral drugs in different lipids have demonstrated that the process isuncomplicated and robust [13–15]. Accordingly, extrusion with diediameters smaller than 0.5 mm was recently introduced for tastemasking purposes with the drug enrofloxacin [12]. The objective ofthis study was firstly to develop a robust solid lipid extrusion processwith die diameters smaller than 0.5 mm with the bitter tasting andneedle-shaped anthelminthic praziquantel. Secondly the aim of thiswork was to investigate the influence of drug particle shape on the

Fig. 1. Investigated screw setups containing kneading elements with 30°, 60° and 90°advance angle (black) and conveying elements with 20 mm pitch (dark grey), 30 mmpitch (light grey) and 40 mm pitch (white). Process direction is from right to left.

Table 1Measures of die plates. Cylindrical dies (white), stepped die (grey), see the schematicdrawing in Fig. 2.

Die diameter/mm 0.3 0.3 0.5 0.7 1.0

Total number of dies 33 67 87 45 23Die length/mm 0.75 (5.0) 2.5 1.25 1.75 2.5Die length/die diameter 2.5 8.3 2.6 2.5 2.5

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solid lipid extrusion process. Knowledge of the behaviour of a drugduring the process is of high value for formulation development,especially if it enables prediction of the processing performance ofdifferent drug qualities.

Therefore, in addition to praziquantel two other needle-shapeddrugs were used as model drugs: mesalazine, an anti-inflammatoryused to treat inflammatory bowel disease and the stimulant caffeine.The three drugs were milled in order to break the needles. Then bothmilled and unmilled powderswere extrudedwith the same excipientsand process parameters. The processing performance was compared,the surface texture of the extrudates was analysed and the drugcrystals were investigated regarding their particle size and shapebefore and after milling and extrusion, respectively. In Sections 2.2and 3.1 the development of a solid lipid extrusion process withpraziquantel is described. The investigation of the impact of drugparticle shape on the process is depicted in Sections 2.3 and 3.2.

2. Experimental part

2.1. Materials

Praziquantel was obtained from Bayer HealthCare (Leverkusen,Germany), caffeine was donated by BASF (Ludwigshafen, Germany)and mesalazine was provided by Ferring (Copenhagen, Denmark).

The following powdered lipids were received from Sasol (Witten,Germany): glyceryl trimyristate (Dynasan® 114), glyceryl tripalmitate(Dynasan® 116) and glyceryl tristearate (Dynasan® 118) as mono-acidic glycerides with an average of 98% pure triglycerides, glycerylstearate with 40–55% monostearate (Imwitor® 900 K) and hydroge-nated glyceryl cocoate (Witocan® 42/44). Powdered glyceryl dibehe-nate (Compritol® 888 ATO) was obtained from Gattefossé (Weil amRhein, Germany).

Polyethylene glycol (PEG) was used in molecular weights 1500,3350 and 6000 and was received from Clariant (Sulzbach, Germany).Polyvinylpyrrolidone K-17 (PVP) was purchased from ISP (Cologne,Germany), polyvinyl acetate (PVA) was obtained from WackerPolymers (Burghausen, Germany), hydroxypropyl methylcellulose(HPMC) was received from Shin-Etsu (Tokyo, Japan) and colloidalsilicium dioxide (Aerosil® 200) was acquired from Degussa (Essen,Germany).

2.2. Solid lipid extrusion with praziquantel

Praziquantel was mixed with the excipients in a laboratory scaleblender LM 20 (Bohle, Ennigerloh, Germany) at 40 rpm for 15 min.Batch size was either 1 or 1.5 kg. The powder mixture wasgravimetrically fed by a dosing device KT20 (K-Tron Soder, Lenzhard,Switzerland) into the barrel of the co-rotating twin-screw extruderMikro 27GL-28D (Leistritz, Nürnberg, Germany).

Four different screw setups, as shown in Fig. 1, with conveying andkneading elements in varying order were used. Die plates with diediameters of 0.3 mm, 0.5 mm, 0.7 mm and 1 mmwere investigated asdescribed in Table 1. Powder feed rates of 5 to 80 g/min and screwspeeds from 5 to 100 rpm were tested. Different lipids were used forextrusion. The barrel temperature was varied from the melting rangeof the respective lipid down to 20 °C below. The loading ofpraziquantel was varied between 10% and 50%.

2.3. Impact of drug particle shape

2.3.1. MillingThe drug powders were milled twice each. For praziquantel an

8 in. air jet mill (Bayer CropScience, Leverkusen, Germany) was used.The operating parameters were 5.5 bar injection and milling gaspressure each. Mesalazine and caffeine were ground in a spiral jet millAlpine 50AS (HosokawaMicron, Osaka, Japan) equippedwith a feeder

DR 100 (Retsch, Haan, Germany). The operating parameters were6 bar injection gas pressure and 2 bar milling gas pressure.

2.3.2. ExtrusionPraziquantel, caffeine and mesalazine, respectively, were mixed

with 49% glyceryl dibehenate and 1% colloidal silicium dioxide and fedinto the extruder as described above. Since the melting range ofglyceryl dibehenate is 69 to 74 °C, the temperature of the extruderbarrel was adjusted to 68 °C. A constant screw speed of 60 rpm andpowder feed rate of 30 g/min were used. Screw setup A, as shown inFig. 1, and the die plate with 0.3 mm die diameter and 67 cylindricaldies were used in all experiments. The pressure in the extruder barrelwas measured next to the die plate with a pressure gauge M30-6-M-B35D-1-A-0 XM 281 (Gefran, Provaglio d'Iseo, Italy).

2.3.3. Image analysisThe drugs were analysed regarding their particle size and shape

with the image analysis system Sysmex FPIA 3000 (MalvernInstruments, Worcestershire, United Kingdom). Dilute aqueoussuspensions of drug particles were ultrasound pretreated for betterdisagglomeration. Samples were then passed through a measurementcell where images of the particles were captured using a CCD camera.Particle flow through the measurement cell ensured that all particleswere orientated with their largest area facing the camera. For eachsample more than 7500 particles were extracted and quantified.The particle size was measured as length, expressed as 90% quantile(l(0.9)) of a particle length distribution. The particle shape wasevaluated as aspect ratio, which is the minimum distance of a particledivided by maximum distance, expressed as 90% quantile (ar(0.9)).

2.3.4. Optical microscopyThe drug powders were viewed by the optical microscope DMLB

(LeicaMicrosystems,Wetzlar, Germany) and CCD camera D300 (Nikon,

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Tokyo, Japan) with polarised light. The drug crystals in extrudates werevisualized by hot stage microscopy at 100 °C, where the lipids weremolten and the drug crystals were still solid. The extrudates weremolten on a stage THMS 600with TMS 94 temperature control (LinkamScientific Instruments, Tadworth, Surrey, United Kingdom).

2.3.5. Scanning electron microscopyThe extrudates were broken into pieces after cooling in liquid

nitrogen and visualized by the scanning electronmicroscope Leo 1430VP (Leo Electron Microscopy, Cambridge, UK). The samples were goldsputtered by the Agar Manual Sputter Coater B7340 (Agar Scientific,Stansted, UK) prior to electron microscopic investigations.

3. Results and discussion

3.1. Solid lipid extrusion with praziquantel

3.1.1. The processIt has been shown previously that solid lipid extrusion with drug

material is straightforward and robust, even with small die diameters[12–15]. However, extrusion of the needle-shaped drug praziquanteltogether with lipophilic materials was found to be difficult. Indica-tions of these problemswere blocked dies due to accumulatedmass inthe extruder barrel next to the die plate. Furthermore, due to poorflowability of the powder mixture it was not possible to maintain aconstant dosing at high feed rates, even the powder down pipe wasblocked occasionally.

Extrusion is a continuous process and all material that is dosed intothe extruder must leave the barrel through the dies. If blocking occursat any stage of the process, extrusion has to be stopped. Blocking ofthe extrusion process can be measured with a pressure gauge in thebarrel next to the die plate. During lipid extrusion with praziquantelgradually increasing pressure was measured due to blocked dies.

3.1.2. FormulationIn order to overcome these difficulties to extrude praziquantel

with lipophilic materials, several approaches were taken. Using die

Table 2Open dies during extrusion depending on die plate and formulation, expressed as percenta

Die diameter/mm

Praziquantel Glyceryl... S

50% ...trimyristate 49% 150% ...tripalmitate 49% 150% ...dibehenate 49% 150% ...monostearate 49% 150% ...cocoate 49% 150% ...tripalmitate 44% PVP 5% 150% ...dibehenate 44% PVP 5% 150% ...monostearate 44% PVP 5% 150% ...tripalmitate 44% PVA 5% 150% ...tripalmitate 44% HPMC 5% 150% ...dibehenate 44% HPMC 5% 150% ...monostearate 44% HPMC 5% 150% ...trimyristate 44% PEG 1500 5% 150% ...tripalmitate 44% PEG 3350 5% 150% ...tripalmitate 46% PEG 3350 3% 150% ...tristearate 42% PEG 6000 7% 150% ...tristearate 34% PEG 6000 15% 150% ...dibehenate 44% PEG 6000 5% 150% ...monostearate 44% PEG 3350 5% 130% ...trimyristate 69% 130% ...tripalmitate 69% 130% ...dibehenate 69% 120% ...tristearate 64% PEG 6000 15% 110% ...trimyristate 84% PEG 1500 5% 110% ...tripalmitate 84% PEG 3350 5% 110% ...tripalmitate 74% PEG 3350 15% 110% ...tristearate 74% PEG 6000 15% 1

plates with 0.3 and 1 mm die diameter, the formulation was changedat first regarding the type of lipid. Pure monoacid triglycerides showexcellent stability of the dosage form [14,15], but they are brittle andhave a narrowmelting range. Therefore, they are difficult to handle ina solid lipid extrusion process. On the other hand diglycerides,monoglycerides and multiacid glyceride mixtures have a smoothconsistency and a broader melting range, resulting in robust and lesscomplicated extrusion processes. For comparison of the extrudabilityof different formulations the fraction of open dies during the processwas used as evaluation parameter. Table 2 shows the fraction of opendies, depending on formulation and die plate, expressed as percentageof all dies belonging to the respective plate. On looking at the trialswith different lipids, it becomes clear that during extrusion ofdiglycerides, monoglycerides and multiacid glyceride mixtures thefraction of open dies is increased compared to monoacid triglycerides.It can be concluded that mixed lipids with smooth consistency areeasier to handle.

The second approach to change the formulation was adding up to15% of different pore formers. The presence of PVP, PVA and HPMC inthe formulation did not have any influence on the extrusion process. Incontrast, the addition of PEG led to a certain increase of open dies. Thetype of PEG was chosen depending on the melting range of the lipid inorder to achieve simultaneous softening and melting of the twoexcipients. The addition of 5% PEG 3350 to the glyceryl tripalmitateformulation led to an increase of open dies from 0 to 15%. Furthermore,an increase from 0 to 30% was achieved using 5% PEG 6000 in theglyceryl dibehenate formulation (Table 2). These results indicate thatPEG has a certain positive effect on the processability of praziquantel.

Finally, the praziquantel load was reduced to 10% using the dieplate with 0.3 mm die diameter. Comparing the results in Table 2, adecrease of praziquantel load was accompanied with an increase inopen dies indicating a concentration dependent effect. But even with10% praziquantel the process did not run with 100% open dies. Inother words praziquantel itself was likely the reason for thedifficulties during the process, particularly as lipid extrusion with50% enrofloxacin and 0.3 mm die diameter could be done withoutdifficulty [12].

ge of all dies belonging to one plate.

0.3 0.5 0.7 1.0

ilicium-dioxide

% 58% 0 9% 3 100% 4 100% 3% 0 22% 0 100% 100% 0 13% 0 26% 100% 7 100% 15 1 71% 15 17% 9 1 49% 24 1 29% 13% 30 100% 100% 22% 10% 81% 19% 13% 54% 60% 67

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3.1.3. Extruder configurationSince no formulation based approach succeeded in extruding

praziquantel with lipids, the extruder configuration was addressed.Die plates with diameters of 0.3 mm, 0.5 mm, 0.7 mm and 1 mmwereinvestigated (Table 2). All formulations tested with differentdiameters showed an increased number of open dies with increaseddie diameter. Using the die plate with 1 mm diameter severalformulations were extruded with 100% open dies. These resultsconfirm that the process becomes more sensitive using small diediameters.

Since the objective was to develop a robust process with small diediameters, different die channel geometries were tested next. Theinvestigated die plate designs are depicted schematically in Fig. 2. Alldie plates described above consisted of dies with cylindrical channels,which are shown exemplarily for the die plate with 0.3 mm diameterin Fig. 2A. Additionally, a plate with shorter die length of 0.75 mmwasused (Table 1). A die plate of this thickness would not endureextrusion because of the high pressure inside the barrel. Therefore,the plate itself was designed 5 mm thick, resulting in a larger part ofthe dies with an outer diameter of 1.8 mm and a length of 4.25 mm(Fig. 2B). The advantage of a shorter die length is a smaller inner diesurface and thus a decrease of friction during the process. At screwspeeds above 15 rpm, which is far below a reasonable productionspeed, the mass accumulated in the 1.8 mm wide part of the diechannel, and the resulting diameter of the extrudates was 1.8 mminstead of 0.3 mm. It can be concluded that extrusion with this diedesign was not advantageous compared to cylindrical dies.

Therefore, the influence of screw setup on the extrusion processwas investigated. With a modular design it is possible to adapt theextrusion screws to the requirements of the excipients and thedesired properties of the product. This process engineering approachis common in the plastic industry and was recently used oncontinuous granulation with a twin-screw extruder [17]. Conveyingelements in general are used to convey material forward in theextruder barrel. A high pitch conveying element has the ability totransport large material quantities and low pitch elements are used topressurize the die. Kneading elements put shear forces on thematerialby acting as a barrier in the barrel. Usually kneading elements withadvance angles of 30°, 60° and 90° are used, wherein the applied shearforce increases and the conveying ability decreases with increasingadvance angle. Elements with advance angle 90° push materialneither forward nor backward [18].

Fig. 1 shows the investigated screw setups. Configuration Acontained less low pitch conveying elements next to the die platecompared to the other setups. Additionally, the kneading block was

Fig. 2. Schematic drawing of investigated die plates, extrusion in direction of narrow.A: cylindrical die, B: stepped die.

positioned close to the die plate and applied shear forces on materialthat was already softened. Both resulted in reduced pressure on thedies. Screw setups B and C contained long low pitch forwarding zonesthat pressurized the die. The kneading block in configuration C wasmuch more powerful because of an additional 90° element, as usuallyused in melt extrusion processes. Configuration D contained nokneading elements at all, thus no shear forces but high forwarding andpressurizing power was applied.

During all experiments that were described so far screw setup Bwas used. The application of configurations A, C and D did not improvethe process with 50% praziquantel and glyceryl tripalmitate. In allcases the number of open dies was below 5%. Therefore, the screwsetups were evaluated with pure glyceryl dibehenate and 0.3 mmdiameter die plate. The results are shown as percentage of all diesbelonging to one plate, according to process performance in ascendingorder: D (30%)bC (52%)bB (60%)bA (100%). Obviously, a reducedpressure on the dies and shear forces applied late in the process wereadvantageous, whereas extrusion without shear forces but with highforwarding and pressurizing power led to the worst results. Screwconfiguration A was used for further experiments.

3.2. Impact of drug particle shape

Since neither formulation nor instrumentation based approachesessentially improved the process, and because other drugs were easyto extrude with lipophilic materials [12–15], praziquantel itself wassuspected of causing the problems. Therefore, its particle shape wasgiven attention to. Micrograph pictures of praziquantel powder(Fig. 3) showed that the crystals were fine and needle-shaped. Ithas been demonstrated previously that the particle shape of powderscan impact its bulk properties and tabletability [1–7]. Hence it washypothesised that the needle-shape of praziquantel caused theproblems during extrusion, although the particles were more than10 times smaller than the die diameter. Praziquantel was milled inorder to break the needles and to obtain more isometric particles.Indeed, extrusion with milled praziquantel led to smooth reproduc-ible processes. Even with a small die diameter of 0.3 mm and 50%praziquantel load the extrusion process ran with 100% open dies.

For further investigation of the impact of drug particle shape onthe process, beside praziquantel two other needle-shaped modeldrugs were studied: the stimulant caffeine and mesalazine, an anti-inflammatory used to treat inflammatory bowel disease. The first twohave fine needle-shaped crystals with a length of up to 7.2 and 8.2 μm,respectively. Mesalazine crystals on the other hand consist of longerneedles with a length of up to 68.8 μm. Detailed results of particle sizeand shape analysis of praziquantel, caffeine and mesalazine beforeand after milling are given in Table 3.

The three drugs were air jet milled in order to obtain moreisometric particles. The results of milling were verified by imageanalysis of unmilled and milled powders. The particle shape wasevaluated as aspect ratio, i.e. an ideal isometric particle has a value ofone, and the aspect ratio decreases towards zero the more needlelikethe particle is. The aspect ratio of all three drug powders increasedthrough milling, and the length of the needle-shaped crystalsdecreased. Obviously, through milling the needles were brokendown to smaller more isometric particles. Fig. 3 shows micrographpictures of unmilled andmilled powders, where the described effect isclearly visible.

For comparative extrusion of needle-shaped and milled drugsglyceryl dibehenate was used as matrix former. Pure glyceryldibehenate can be extruded smoothly and reproducible with 100%open dies, as described in Section 3.1.2, which is important in order toensure that the observed effects were caused by the drugs and not bythe excipient. Extrusion experiments were performed with 50% drugload, 0.3 mm cylindrical die plate and screw configuration A (Fig. 1).

Fig. 3. Micrograph pictures of milled and unmilled drug crystals before and after extrusion.

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Pressure profiles measured during extrusion of praziquantel(Fig. 4A) and caffeine (Fig. 5A) demonstrate the extent of blockagein the extruder barrel. Using unmilled drug material, mass accumu-lated next to the die plate, hence pressure increased rapidly up to35 bar and the process was stopped after 16 and 8 min, respectively.With praziquantel only 3% of the dies were open. During extrusion ofcaffeine all dies blocked at once, even though the pressure profileshows a pressure increase up to 8 min due to accumulating mass inthe extruder barrel. Finally after 8 min the process was stopped.

Using milled drug material the mass, instead of accumulating,flowed smoothly through all dies. The pressure remained constantand below 10 bar (Figs. 4A, 5A). Pictures of the die plate duringextrusion of praziquantel (Fig. 4B) and caffeine (Fig. 5B) show on theleft needle-shaped and on the right milled drug material. Obviously,the mass with unmilled material blocked the die plate in contrast tothe smoothly running process with isometric drug particles. Duringextrusion of unmilled caffeine pure lipid, that was molten due to

high pressure, was squeezed out (Fig. 5B) when the drug materialremained in the barrel.

Yue et al. [9] reported that needle-shaped particles of 1 μmdiameter and 10–12 μm length in a glass melt orientate themselvesparallel to the direction of extrusion through a die of 5 mm diameter,especially at higher extrusion velocity. A piston extruder with apressing ratio of 18.5 was used. It seems likely that needles in softenedlipid, instead of arranging themselves, felt and stuck together. Thismight be due to the solid character of the lipid mass compared to amolten glass and to the small die diameter of 0.3 mm to 1 mm.

With scanning electron microscopy it was not possible to visualizefelting of needles in lipid mass or orientation of needles in theextrudate. Pictures of extrudates with needle-shaped and milledpraziquantel demonstrate that the surface of extrudates withunmilled drug was covered with a smooth lipid layer (Fig. 6A), unlikethe extrudates with milled material. During processing of needle-shaped praziquantel the mass left the extruder with increased speed

Table 3Particle size and shape of drug crystals, measured by image analysis. Size measured aslength (l) in μm, shape evaluated as aspect ratio (ar).

Unmilled Milled

Praziquantel ar(0.1) 0.3 0.5ar(0.5) 0.6 0.7ar(0.9) 0.9 1.0

Caffeine ar(0.1) 0.3 0.4ar(0.5) 0.5 0.6ar(0.9) 0.7 0.9

Mesalazine ar(0.1) 0.1 0.2ar(0.5) 0.2 0.5ar(0.9) 0.5 0.9

Praziquantel l(0.1) 0.9 0.9l(0.5) 2.7 1.7l(0.9) 7.2 4.1

Caffeine l(0.1) 0.9 0.9l(0.5) 2.7 1.9l(0.9) 8.2 4.6

Mesalazine l(0.1) 6.9 1.4l(0.5) 28.3 5.1l(0.9) 68.8 14.1

Fig. 5. A: Pressure profiles measured in the extruder barrel during extrusion withunmilled andmilled caffeine. B: Pictures of the die plate during extrusion with unmilled(left) and milled (right) caffeine.

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due to high pressure. Consequently, increased frictional forces in thedie channel led to melting of lipid on the extrudates surface. Withmilled praziquantel the die passing velocity was much slower,consequently the entire extrudate contained drug, dispersed in lipidmatrix, even on the surface (Fig. 6B).

For mesalazine the problems during extrusion were not as forpraziquantel and caffeine. Mesalazine has much larger and longerneedles, some crystals were only 3 times smaller than the diediameter (Fig. 3). If needles felt and stick together in a bulk inside theextruder barrel and squeeze out lipid, longer needles would probablycause even more problems during extrusion. On the contrary, theprocess with unmilled mesalazine was easier than with praziquanteland caffeine. Fig. 7A shows pressure profiles measured during

Fig. 4. A: Pressure profiles measured in the extruder barrel during extrusion withunmilled and milled praziquantel. B: Pictures of the die plate during extrusion withunmilled (left) and milled (right) praziquantel.

extrusion of needle-shaped and milled mesalazine. Obviously, withboth powders the pressure stayed constant some minutes, only thepressure level was higher for unmilledmesalazine. Also pictures of the

Fig. 6. A: SEM picture of extrudate cross-section with 50% unmilled praziquantel/49%glyceryl dibehenate/1% silicium dioxide. B: SEM picture of extrudate cross-section with50% milled praziquantel/49% glyceryl dibehenate/1% silicium dioxide.

Fig. 7. A: Pressure profiles measured in the extruder barrel during extrusion withunmilled and milled mesalazine. B: Pictures of the die plate during extrusion withunmilled (left) and milled (right) mesalazine.

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die plate (Fig. 7B) show that extrusion with unmilled material,although 75% of the dies blocked, was easier compared to praziquan-tel and caffeine. During extrusion of milled mesalazine the massflowed smoothly through all dies and no blocking occurred.

These findings can be explained by comparing the particle shapesof the drugs before and after extrusion, what has been done by hotstage microscopy of the extrudates (Fig. 3). The majority of the longmesalazine needles was broken down to more isometric particlesduring extrusion, whereas with praziquantel and caffeine only a fewparticles were broken to a small extent. Therefore, the mesalazineparticles that reached the die plate were not as clearly needle-shapedas praziquantel and caffeine and consequently showed less felting andblocking in the extruder barrel. Studies with dicalcium phosphateshowed that effective crushing of particles is possible in a twin-screwextruder, but kneading elements are necessary in a screw setup toapply sufficient shear forces [19]. Possibly for shorter needles likepraziquantel and caffeine the leverage effect at the kneading elementswas too small to break the crystals.

4. Conclusion

It was shown that the crystal shape of a material has a dramaticimpact on its extrusion processing performance, even if the crystalsare more than 10 times smaller than the die diameter. Mainly during

extrusion with die diameters below 0.5 mm, needle-shaped materialfelts in the extruder barrel and blocks the process, whereas theextrusion of isometric shaped crystals is smooth and uncomplicated.In the future it is possible to solve problems during extrusion ofneedle-shaped drugs by using isometric shaped drug material thatcan, for instance, be obtained by milling.

Acknowledgements

The authors would like to thank the companies Sasol andGattefossé for providing the lipids. Dr Jürgen Lühmann (MalvernInstruments) is gratefully acknowledged for his assistance duringimage analysis.

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