Powder Technology - Labmaq do Brasil b… · Coating and granulation of pharmaceutical solid dosage forms are important operations in the pharmaceutical industry for improving the

Powder Technology 270 (2015) 453–460

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Granulation of indomethacin and a hydrophilic carrier by fluidized hotmelt method: The drug solubility enhancement

Toni C. Andrade, Rodrigo M. Martins, Luis Alexandre P. Freitas ⁎Núcleo de Apoio à Pesquisa em Medicamentos Naturais Sintético, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil

⁎ Corresponding author at: Via do Café, s/n, 14040-903,16 36024225; fax: +55 16 3602 4879.

E-mail address: [email protected] (L.A.P. Freitas).

http://dx.doi.org/10.1016/j.powtec.2014.07.0300032-5910/© 2014 Elsevier B.V. All rights reserved.

a b s t r a c t
a r t i c l e i n f o
Available online 30 July 2014

Keywords:Factorial designGranulesAngle of reposeSize distribution

Fluidized bed hot melt granulation is an interesting alternative for preparing pharmaceutical solid dosage formswith functional properties such as sustained release and enhanced solubility. The aim of this work was to studyindomethacin granulation by the FBHMG process. Fifteen granulates were prepared using indomethacin as amodel drug, polyethylene glycol 4000 as a hydrophilic carrier, and spray-dried lactose as a fluidising substrate.The binder used for spray granulation in the FBHMG technique was a mixture of molten PEG 4,000 and indo-methacin. The effects of the nozzle airflowrate, the binderflow rate and theweight of the binder usedwere stud-ied using a Box–Behnken design. The dependent variables studiedwere themean particle size (D50) and the flowproperties, whichwere determined from the angle of repose. The D50 values ranged from 479 to 824 μm, and theanalysis of variance by a response surface methodology showed that the granule size was affected by the nozzleair flow rate at a significance level of 5%. The D50 value was also affected by the weight of binder/drug usedand the interaction between the binder/drug flow rate and the weight of binder/drug used at a significancelevel of 10%. The angle of repose was not affected by the factors studied. Lower spray nozzle air flow rates(45 to 25 L/min) produced granules with excellent flow properties. The granule properties and the drug/binder/substrate interactionswere comprehensively characterized using differential scanning calorimetry, scan-ning electron microscopy, Fourier transform infrared spectroscopy, X-ray powder diffraction and in vitro drugdissolution. Thermal and infrared spectroscopy analyses showed that there was no drug interaction during theprocess. The X-ray diffraction and scanning electron microscopy results showed that indomethacin crystalswere present on the surface of the granules. Granulation enhanced the dissolution profile of indomethacin re-markably. Unprocessed indomethacin released only 45% of the drug in 120 min, whereas the granule released100% of the drug in 20 min in a phosphate buffer media (pH 7.2). Therefore, the results confirmed the high po-tential of the FBHMG technique to produce granules with enhanced drug solubility and release rates.

© 2014 Elsevier B.V. All rights reserved.

1. Introduction

Coating and granulation of pharmaceutical solid dosage forms areimportant operations in the pharmaceutical industry for improvingthe mechanical, chemical and biological properties of the final product[1]. The key characteristics of granulates and coated forms include thesize, density, flowability, compactability, and capability for slow orpH-dependent release [2]. Granulates containing active ingredients areusually prepared by successive operations of blending, drying, and siev-ing, which are each carried out using a different piece of equipment [3],thereby increasing the process time and the risk of contamination. Flu-idized beds are an effective alternative for pharmaceutical granulation,because some of these operations, such as blending and drying, maybe carried out simultaneously during fluidisation [4]. However, the

Ribeirão Preto, Brazil. Tel.: +55

conventional method of fluidized bed granulation involves the sprayingof a binder solution. Recent regulatory restrictions on organic solventshave limited the use of conventional granulation in which solvents areused to prepare binder solutions [2]. However, aqueous solutions alsopresent the risk of microbial contamination, drug hydrolysis and otherdifficulties that are related to residual moisture [2].

Recently, fluidized bed hot melt granulation (FBHMG) has receivedattention as a technique for processing pharmaceutical powders. Theprimary advantage of the hot melt method is that solvent use is elimi-nated [5–8]. The process of FBHMG, has been previously used to prepareacetaminophengranuleswith polyethylene glycol [9],white beeswaxmi-crocapsules containing potassium chloride [10], theophylline granuleswith Compritol® 888 Ato [11], chlorpheniramine maleate microparticleswith beeswax [12], propanolol hydrochloride using Gelucire® 50/02 andPrecirol® ATO5 [13].

Although FBHMG has been most commonly used for sustained re-lease formulations [9–12], it has also an served as an alternativemeans of enhancing the solubility of weakly water soluble drugs [13]in spray freeze drying [14], spray congealing [15,16], supercritical fluids

Fig. 1. Fluidized bed FBD 3.0 with 3-kg capacity (reproduced with permission of Labmaqdo Brasil Ltda, Ribeirão Preto, SP, Brazil).

454 T.C. Andrade et al. / Powder Technology 270 (2015) 453–460

[17] and spray drying [18–20]. The solubility of drugs inwater is directlyrelated to their bioavailability and has recently received attention be-cause of the increasing number of low-solubility active pharmaceuticalingredients, APIs, [13].

Indomethacin, IND, is an example of a drug with low water solubili-ty. IND is a non-steroidal anti-inflammatory drug thatwas discovered in1963 and inhibits the production of prostaglandins. Following its ap-proval by Food and Drug Administration (U.S.A) in 1965, IND has beenused to treat pain, fever, swelling and stiffness [21]. Despite its lowwater solubility, IND is classified as a class II drug in the Biopharmaceu-tical Classification System, BCS [22], because of its high permeabilitythrough the intestinal membrane. Consequently, many efforts havebeen made to increase the solubility of IND in aqueous media to im-prove its bioavailability. One option is to prepare a solid dispersion con-taining IND using a hydrophilic carrier. A solid dispersion is a usefulmeans of dispersing drugs at the molecular level using a hydrophiliccarrier.

The aim of this work was to study the fluidized bed granulation ofIND by the hot melt method using a mixture of molten PEG 4000 andIND as a binder and spray-dried lactose as a substrate. The key FBHMGfactors that were investigated included the nozzle air flow rate, thebinder/drug atomisation rate and the total weight of the binder/drugapplied to the substrate. A fractional factorial design of the Box–Behnken type was used in the experimental study. Box–Behnken facto-rial design is a tool that reduces the number of experimental runs byavoiding the execution of unnecessary experiments under extreme con-ditions. This design also enables first-order, second-order, and interac-tion coefficients to be efficiently estimated to characterize and/oroptimize a process [23]. The granule quality was evaluated from thesize distribution and the flow properties. The granule properties andthe drug/carrier/substrate interactions were also comprehensivelycharacterized using differential scanning calorimetry (DSC), scanningelectron microscopy (SEM), Fourier transform infrared spectroscopy(FT-IR), X-ray powder diffraction (XRPD), and in vitro drug dissolution.

2. Material and methods

2.1. Materials

The substrate used in the granulation experiments was spray-driedlactose DCL-11 (Selectchemie, Brazil), which was supplied bySelectchemie Ltda (São Paulo, Brazil). Indomethacin was purchasedfrom Henrifarma Ltda (São Paulo, Brazil), and the hydrophilic carrierwas polyethylene glycol 4000, which was supplied by Vtech Ltda (SãoPaulo, Brazil).

2.2. Fluidized bed granulation

The equipment usedwas afluidized bed,model LMFBD3.0 (Labmaqdo Brasil Ltda, Ribeirão Preto, SP, Brazil) that consisted of three stainlesssteel parts: a cylindrical column that was 35 cm in diameter and 25 cmin height, which was coupled with a conical base with a 60° includedangle that was 35 cm in height and a top section that was 35 cm in di-ameter and 15 cm in height. The air inlet had a diameter of 9.5 cm anda stainless steel screen mesh of 270. Fluidising air was supplied by a 2-HP radial compressor, for which the mass flow rate was measured bya Pitot probe and calibrated with a turbine anemometer model MDA11 (Minipa Ltda, Manaus, AM, Brazil). The pneumatic spray nozzlewas centered at the top of the cylindrical column on an assembly thatallowed the vertical position to be varied. A bagfilterwith an automatedpneumatic self-cleaning systemwas also installed at the top of the cylin-drical body to retain and return elutriated fines to the chamber. A PIDcontroller and an electrical heater were used to set the process temper-ature. The air temperature and the humidity at the outlet were mea-sured using a thermo hygrometer, model MTH 1380 (Minipa Ltda,Manaus, AM, Brazil). The spray nozzle consisted of a double fluid with

external mixing and a liquid outlet orifice with a 1-mm diameter(Labmaq do Brasil Ltda., Ribeirão Preto, SP, Brazil). The spray nozzlewas connected to a jacketed extensor that allowed a heating fluid tobe circulated at 110 °C to prevent the solidification of IND/PEG 4000.The fluidized bed is shown Fig. 1.

Three hundred and forty grams of spray-dried lactose was weighedand loaded into the chamber; the minimum fluidisation air flow ratewas checked and then adjusted according to the experimental design.When the set temperature was stable, the mixture of molten PEG4000 and IND was atomized at predetermined spraying conditions.The following conditions were maintained constant for all of the exper-iments: the spray nozzle air temperature and pressure were 80 °C and4 bar, respectively; the spray nozzle was located at a vertical distanceof 55 cm from the bottom of the bed, the temperature of binder/drugfeed was 110 °C, the pump head and the tubing temperature were80 °C, and the self-cleaning filter purging interval was 30 s. Thefluidisation air velocity was varied linearly to maintain the solid motionat 10% above the minimum spouting velocity, in accordance with themethodology developed by Mathur and Epstein [24]. The IND contentinmolten PEG 4000 (binder/drug) was 25% (w/w) for all of the granula-tion experiments. After completion of the experiments, the granuleswere collected for characterization.

The experiments followed a Box–Behnken design [25]with 3 factorsand 3 levels. The factors chosen were the spray nozzle air flow rate(QNA), the binder/drug feed flow rate (QMD) and the total weight ofbinder/drug (WMD) applied to the substrate. The levels and factors stud-ied are presented in Table 1, which shows the coded and non-codedvalues of the factors. The formula applied to decode the factor levels isgiven by Eq. (1).

Xi ¼value−0:5� high � valueþ low � valueð Þð Þ

0:5� high � value−low � valueð Þ ð1Þ

An analysis of variance on experimental data was performed using asurface response methodology with the Visual General Linear Model(VGLM) module from the software Statistica 7 (Statsoft Inc., Tulsa,

Table 1Box–Behnken experimental designwith real and coded levels of factors; results of depen-dent variables studied with predicted and actual response showing values of D50, angle ofrepose (Φ), Hausner factor (HF) and Carr index (CI).

Experiments Factors Results of dependentvariables considered

QNA

(L/min)QMD

(mL/min)WMD

(g)D50

(mm)ϕ(°)

HF CI(%)

1 −1 (25) −1 (3.7) 0 (136) 0.778 35.80 1.13 11.882 +1 (45) −1 (3.7) 0 (136) 0.575 37.23 1.12 10.503 −1 (25) +1 (11.1) 0 (136) 0.806 37.23 1.08 7.744 +1 (45) +1 (11.1) 0 (136) 0.673 38.66 1.17 14.675 −1 (25) 0 (7.4) −1 (102) 0.683 40.69 1.12 11.176 +1(45) 0 (7.4) −1 (102) 0.602 38.66 1.12 10.987 −1 (25) 0 (7.4) +1 (170) 0.824 37.95 1.09 8.028 +1 (45) 0 (7.4) +1 (170) 0.723 38.66 1.16 13.709 0 (35) −1 (3.7) −1 (102) 0.598 38.66 1.16 13.5210 0 (35) +1 (11.1) −1 (102) 0.542 37.95 1.13 11.5011 0 (35) −1 (3.7) +1 (170) 0.54 42.61 1.16 13.5112 0 (35) +1 (11.1) +1 (170) 0.719 41.35 1.17 11.9913 0 (35) 0 (7.4) 0 (136) 0.614 39.35 1.12 10.4714 0 (35) 0 (7.4) 0 (136) 0.479 38.66 1.14 11.9815 0 (35) 0 (7.4) 0 (136) 0.589 38.66 1.14 12.43

Note: QNA—nozzle air flow rate, QMD—binder/drug flow rate and WMD—weight of binder/drug applied.

Table 2Analysis of variance of D50 data.

Factors SS DF MS F P

QNA 0.033541 1 0.033541 10.5883 0.022596⁎

QNA2 0.060298 1 0.060298 19.0354 0.007270⁎

QMD 0.007750 1 0.007750 2.4466 0.178547QMD2 0.001410 1 0.001410 0.4451 0.534210

WMD 0.018145 1 0.018145 5.7282 0.062128⁎⁎

WMD2 0.001410 1 0.001410 0.4451 0.534210

QNA × QMD 0.001225 1 0.001225 0.3867 0.561284QNA × WMD 0.000100 1 0.000100 0.0316 0.865951QMD × WMD 0.013806 1 0.013806 4.3585 0.091166⁎⁎

Error 0.015838 5 0.003168

⁎p b 0.05; ⁎⁎p b 0.1.

455T.C. Andrade et al. / Powder Technology 270 (2015) 453–460

USA). The multiple linear equation given by Eq. (2) was used for the re-sponse function:

Yi ¼ A0 þ A1X1 þ A2X2 þ A3X3 þ A4X1X2 þ A5X1X3

þ A6X2X3 þ A7X12 þ A8X2

2 þ A9X32 ð2Þ

where Yi = dependent variables: mean particle size (D50) and angle ofrepose (Φ); X1 (QNA), X2 (QMD) and X3 (WMD) = factors studied; X1X2;X1X3 and X2X3 = interaction terms; Xi2 = quadratic terms; and Ai =polynomial coefficients.

The ranges of the QNA and QMD rates were chosen based on a previ-ous study on the atomization quality [26]. The resulting experimentaldesign is shown in Table 1. The effects of the factors were consideredto be significant for p-values below 0.1.

2.3. Granule characterization

The granule size distribution was determined using a sieve shaker(Bertel Ltda, São Paulo, Brazil) with stainless steel screen meshes of170, 60, 40, 30, 20, 18, 14 and 12. Three hundred-and-fifty-gram sam-ples were shaken at frequency level 5 for 5 min. The weight fractionswere transformed into percentages and plotted versus the particlesize. Cumulative distribution plots were also constructed to obtain theD50 values.

The bulk and tapped densities were used to calculate the Carr Indexand Hausner ratio, and the angles of repose were measured using thetechnique developed in [9]. The bulk and tapped densities were obtain-ed by precisely weighing the granule sample in a 10-mL glass flask be-fore and after the sample was subjected to a controlled vibration (inthe sieve shaker) until a constant volume was obtained. The bulk andtapped densities were calculated using the initial and final sample vol-umes. The reported results corresponded to the mean of five measure-ments. The values of these two densities were used to calculate theCarr index and the Hausner factor. The angle of repose of the granuleswas determined using the funnel method [23]. Thus, 5.0 g of each sam-ple was allowed to flow down through a glass funnel with a flat circularbase and a known diameter. The height of the cone formed by the sam-plewasmeasuredwith a caliper, and the angle of reposewas calculated.Five measurements were made on each sample.

The DSCmeasurements were performed using a DSC-50 (ShimadzuCo., Kyoto, Japan), and 5 mg of each sample was placed into aluminumpans under a nitrogen flow rate of 50 mL/min. These sampleswere then

heated from 22 to 300 °C at a scanning rate of 10 °C/min. The KBrmeth-od was used to prepare the samples used for the spectral measure-ments. A Nicolet Protégé 450 FT-IR (Nicolet Inst. Inc., Madison, WI,USA) spectrophotometer was operated over a scan range of 4000 to500 cm−1. Samples were analyzed by the XRPD technique using aD5005 Bruker-Siemens diffractometer (Siemens AG Co., Munich,Germany) with CuKα radiation (λ = 1.5418 Å). The scanning angleranged from 2° to 50° in 2θ steps of 0.2° and a delay time of 2 s/step.The current and voltage applied were 30 mA and 40 kV, respectively.The morphological characteristics of the microparticles were observedby SEM using a Jeol JSM 5200 microscope (JEOL Inc., Peabody, MA,USA). The samples were coated with gold/palladium under an argon at-mosphere using a sputter coater Bal-Tec SCD 005 (Leica MicrosystemsCo.,Wetzlar, Germany). Photomicrographswere then taken at an accel-eration voltage of 25 kV.

The dissolution rates of the IND and the granule sampleswere deter-mined using the basketmethod (apparatus 1, USP XXX) at a stirring rateof 75 rpm and 37 ± 1○C in a NE 330-8 dissolutor (Nova Ética, Ltda, SP,Brazil). The dissolution media were a HCl solution (0.1 N) and a phos-phate buffer pH 7.2 (500mL), and the sampleswere filled to correspondto 40mgof IND. Aliquots (2mL)werewithdrawn after 10, 15, 20, 30, 45,60, 90 and 120min. The aliquots were then filtered (0.22 μm), and theirIND contents were determined by spectrophotometry at 318 nm. Eachsample was assayed in sextuplicate.

3. Results and discussion

3.1. Study of dependent variables

Hot melt granulation using a fluidized bed was found to be a simpleand quick method for producing IND granules. The apparatus used wasadequate and demonstrated that the FBHMG is a reliable process whenthe temperature of molten binder/drug can be controlled in all parts ofthe equipment, such as the heating bath, the pump, the tubing and thespray nozzle. The process times varied from 9.0 to 46min depending onthe binder/drug feed rate.

The granule sizes were calculated as D50, which corresponded to theexact size for a 50% weight from the cumulative size distribution curve.The D50 values varied from 0.540 to 0.834 mm (Table 1), which was anadequate size for the compression of tablets with a 4.7-mm diameter.The specification of the granule size for tableting in rotary machines de-pends on the punch size, because larger granules are needed for largerpunches [3].

The analysis of variance (ANOVA) given in Table 2 shows that thelinear and squared terms of QNA significantly affected the D50 values at5 and 1%, respectively. In addition, the linear term ofWMD and the inter-action between QMD and WMD significantly affected the D50 values at10%. Nevertheless, the probability values above 10% in this ANOVAshowed that while the aforementioned factors were not significantover the range of values studied, these factors could be significantover different ranges. In addition to the droplet size, other parameters


and phenomena affected the granulation process and the final value ofD50.

The surface in Fig. 2A shows that D50 increased with decreasing QNA

and increasing WMD. This behavior was expected, because data has al-ready been presented in the literature indicating that the atomizationquality may influence the final granule size [8,9]. Increasing the airflow through the spray nozzle increases the difference between the liq-uid and air velocities, which is an important parameter for pneumaticatomizers [27,28]. During the hot melt process in fluidized beds, parti-cles may be preferentially coated rather than granulated depending onthe size of the atomized droplets [8]. When the atomized droplets arelarger than the substrate, the agglomeration rate increases, and granula-tion is favored over coating [8,9]. This phenomenon is similar for bothconventional methods (with solvents) and hot melt (solvent-free)methods [9]. Using a spray with finer droplets produces smaller gran-ules because of the kinetics of growth and breakage during the granula-tion process. Finer droplets create thinner liquid bridges betweenparticles that are easier to break with the mechanical stresses inducedby particle–particle and particle–wall collisions that typically occur influidisation [9,29,30]. Fig. 2B shows the effect of the binder/drug feedrate, QMD, and the weight of the binder/drug applied, WMD. The granulesize increased because of the large amount of molten mixture that wassprayed onto the substrate. The slope of the flat surface indicated thatthe mean granule size increased with the liquid feed rates, which mayalso have been related to the changes in the droplet sizes. In this case,increasing the liquid feed increased the droplet size, producing coarsergranules. Fig. 3A and B show representative granule size distributionsthat were obtained in this study.

Fig. 3A shows the cumulative particle size distribution for experi-ment 3 (Table 1), where QNA = 25 L/min, QMD = 11.1 mL/min andWMD = 136 g. The initial size of the substrate, spray-dried lactose,ranged from 0.03 to 0.20mm, with amean D50 of 0.053mm. Examiningthe particle size distribution in Fig. 3A shows that the granule sizes var-ied from 0.173 to 1.550 mm, but the primary fractions corresponded tosizes above 0.725 mm. This result shows that particle granulation wasfavored over coating [8,9] and that the granules were substantially larg-er than the initial substrate.

Fig. 3B presents the granule size distribution thatwas obtained in ex-periment 4 (Table 1), where QNA = 45 L/min, QMD = 11.1 mL/min andWMD = 136 g. The size distribution in Fig. 3B was obtained using an airflow rate in the spray nozzle, QNA (from 25 to 45 L/min) that was higherthan that used to obtain the data in Fig. 3A. Themean particle sizes, D50,for both experimentswere 0.806and 0.673mm for Fig. 3A andB, respec-tively. However, these distributions indicated a large polydispersity.

Fig. 2. Response surface of D50 as a function of QNA and WMD (A) a

Experiment 2 (Table 1) shows a smaller D50with a narrower polydisper-sity, which could be attributed to the higher air flow rate, QNA.

The surface response methodology was used to obtain an equationcorrelating the mean granule mean, D50, with the factors with signifi-cance levels higher than 10%. Eq. (3) had a correlation coefficient ofR = 0.707.

D50 ¼ 0:56−0:06QNA−35

10

� �þ 0:13

QNA−3510

� �2

þ 0:05WMD−132

34

� �þ 0:02

QMD−7:43:7

� �WMD−132

34

� �ð3Þ

This result indicates that for FBHMG, a negative correlation was ob-tained between the factor QNA and D50, and a positive correlation wasobtained among the factorsWMD and QMD and D50, which could be use-ful for determining the exact condition for producing a specified granulesize.

The flow properties of granules are also important for their pharma-ceutical application. In the pharmaceutical field, flow properties areusually measured in terms of the angle of repose, the Carr index or theHausner factor [1]. In the results reported here, all of these threephysical parameters were used as measures of the flowability of thegranules. The bulk densities of the granules ranged from 0.326 to0.430 g/mL, and their tapped densities ranged from 0.378 to0.480 g/mL. These results show that there was a small variation inthese densities under the FBHMG conditions, and the analysis of vari-ance proved that none of these effects were significant. However, thedifferences between the bulk and tapped densities were significant.The calculated Carr indexes varied from 7.74 to 14.67%. These valueswere used to classify the granule flow as good to excellent [1]. TheHausner factor ranged from 1.08 to 1.17, which corroborated the classi-fication using the Carr index [1]. The analysis of variance by the re-sponse surface methodology showed that the significant factors forboth the Carr index and the Hausner factor were the spray air flowrate, QNA (1% significance level), the interaction of QNA and the binder/drug feed rate QMD (1% level) and the interaction of QNA and theweightof the binder/drugWMD (5% level). Both the Carr index and theHausnerfactor aremeasures of the granule consolidation or compaction capacity[1] rather than the flow properties of the granules. These consolidationproperties are very important because they represent the capacity ofthe solids to quickly accommodate or compact under minimum poros-ity conditions. This behavior is important for the quick and effective fill-ing of dies in rotary compression machines [1]. The granules obtainedhere, under all of the conditions investigated, exhibited good to

nd response surface of D50 as a function of WMD and QMD (B).

Fig. 3. Granule size distribution for experiment 3 (A) and granule size distribution for experiment 4 (B).

IND

PEG

LAC

Exp. 74000 3500 3000 2500 2000 1500 1000 900 800 700 600 500

Wavenumbers cm-1

Fig. 4. FT-IR profiles for (IND) indomethacin, (PEG) polyethylene glycol 4000, LAC (lactose) and granules from experiment 7 (Exp. 7) for scan range from 4000 to 500 cm-1.


20 60 100 150 200 3000

Hea

t flo

w e

ndo

dow

nIND

PEG

EXP. 7

EXP. 6

LAC

Fig. 5. DSC traces for (IND) indomethacin, (PEG) polyethylene glycol 4000, LAC (lactose)and granules for (EXP. 6) experiment 6 and (EXP. 7) experiment 7.


excellent consolidation properties, demonstrating their viability in fur-ther compression for tablet preparation.

The angle of repose,Φ, ranged from35.80 to 42.62°. According to [1],pharmaceutical powders exhibit good flowability for 25° b Φ b 30°, ac-ceptable flowability for 30° b Φ b 40°, and poor flowability for Φ N 40°.Only three experimental conditions resulted in angles of repose above40°, showing that the prepared granules exhibited acceptable flowproperties. Adequate flow properties are an essential requirement forpharmaceutical granules to control uniformfilling and the consolidationspeed inside the punches of tableting machines. However, unlike theCarr index and the Hausner factor, the ANOVA showed that none ofthe factors studied affected the angle of repose, Φ, even at the signifi-cance level of 10% that was considered in this study.

3.2. Physicochemical characterisation

The granules obtained in experiments 6 and 7were chosen for phys-icochemical characterisation because these granules exhibited distinctsize distributions. Approximately 46% of the granules in experiment 6ranged from 0.6 to 0.8 mm in size, whereas the same percentage ofthe granules in experiment 7 ranged from 1.2 to 1.4 mm in size. There-fore, therewas a difference in the granule size between the experimentsthat could have affected the specific characteristics of the granules, suchas the dissolution profile.

10 15 20 25 30 35 402θ

IND

EXP 6

EXP 7

PEG

LAC

5

Fig. 6. XRPD patterns for indomethacin (IND, (PEG) polyethylene glycol 4000, (LAC) lac-tose, and granules for experiment 6 (Exp. 6) and experiment 7 (Exp. 7).

The FT-IR analysis of the granules in experiment 7 is shown in Fig. 4.The spectroscopic data was compared to the FT-IR spectra of rawIND, PEG 4,000 and spray-dried lactose. The FT-IR spectra of INDcorresponded with the previously reported spectra for polymorphicform II [31]. Characteristic bands of IND form II were found at 1716and 1692 cm−1, corresponding to the acid carbonyl and benzoyl groups,respectively. The spectra of these granules exhibited no new bands andwere similar to the IND spectrum, although the intensity of the granules'spectra was not the same as the intensity of the pure IND spectra, prob-ably because a smaller amount of drug was used to prepare the gran-ules. In the 4000 to 2400 cm−1 range, no changes in the bands orpotential interactions were observed, and the prevailing characteristicbands were those of the lactose that was used as the substrate. This re-sult shows that the spray-dried lactose could serve as an effective adju-vant in the granulation of weakly soluble drugs.

The thermograms of IND, PEG, spray-dried lactose and granules(Exps. 6 and 7) are shown in Fig. 5. The IND thermogram exhibited acharacteristic endothermic peak at 157.9 °C, which was related to themelting of the drug [32]. The PEG thermogram exhibited a single endo-thermic peak relative to the melting point of the drug at 61.4 °C [33].The spray-dried lactose (LAC) exhibited two endothermic peaks duringthe analysis: an endotherm at 210.1 °C, corresponding to themelting ofalpha form, and another endotherm at 216.0 °C, corresponding to thebeta form [34]. The DSC curves of the granules were similar when com-paredwith each other and exhibited only two endothermic peaks at thetemperature related to the melting of the carrier of approximately61.4 °C, and two other endothermic peaks at 210 °C and 216 °C thatwere associated with the lactose melting point. The IND endothermicpeak in the granules disappeared relative to the IND peak. The IND peakprobably vanished because of the dissolution of the drug in the meltedcarrier during the gradual heating of the samples in the DSC process [15].

Fig. 6 shows the XRPD results for IND, PEG, spray-dried lactose andthe granules (Exps. 6 and 7). The IND was in crystalline form with in-tense diffraction peaks at 10.3°, 11.8°, 17.2°, 19.6°, 21.9°, 24.1°, 26.7°,27.6° and 29.5° of 2θ, which corresponded to the γ-form [28]. The PEGdiffractogram exhibited peaks at 19.0°, 23.2°, 26.8°, and 36.0° of 2θ.The XRPD results for LAC exhibited peaks at 12.7°, 16.6°, 20.2°, 23.9°,25.8° and 37.8° of 2θ. The diffractograms of the granules (Exps. 6 and7) exhibited the characteristic peaks associated with IND, LAC andPEG, but with a lower intensity, showing that there were no solidstate changes.

Scanning electron microscopy (SEM) is a technique that providesthree-dimensional morphological information and can be used to iden-tify the chemical elements of solid samples. SEM images of granules pro-vide information on the surface morphology of the granules and can beused to identify the presence and distribution of a drug in crystallineform on a granule surface [35].

Fig. 7 shows the SEM photomicrographs of the granules. Fig. 7A andA1 show the spray-dried lactose particles used in this study. Analysis ofthe photomicrographs of granules in Fig. 7B and C showed that that thespray-dried lactose particles underwent agglomeration that was pro-moted by the aggregating agent IND/PEG because of the formation ofthin layers on the lactose particles, thereby confirming the particlesize distribution results. Another interesting result was the presence ofIND crystals on the surface of the granules, as indicated by arrows inFig. 7B1 and C1, which supported the FT-IR and XRPD results.

Therefore, the FBHMG process did not promote solid state changesor chemical interactions between the functional groups of IND and theother compounds (PEG and LAC) studied.

3.3. In vitro drug release

The dissolution profile determines the characteristics of the rate ofdissolution of a drug in a solid dosage form. Dissolution studies are gen-erally performed to detect differences in manufacturing for the soliddosage form to ensure uniformity during the production of each batch.

A A1

B1

C1C

B

Fig. 7. Scanning electronmicrographs of granules: (A) Lactose 75×; (A1) Lactose 350×; (B) Exp. 6 100×; (B1) Exp. 6 500×; (C) Exp. 7 50×; (C1) Exp. 7 500×; arrows indicate indometh-acin crystals on surface of granules.


In this study, the dissolution rate of IND for the granules was evaluatedand compared with that of pure IND [36]. Fig. 8 shows the in vitro re-lease profile of pure IND and the granules (Exps. 6 and Exp. 7) in acidand alkalinemediums. Fig. 8A shows the IND dissolution rate in an alka-line medium, where pure IND was released at only 40% at 60 and120 min. However, the IND dissolution rate for the granules was 100%at 20min. The INDwas almost insoluble in the acid medium. Therefore,increasing the IND dissolution rate in this medium is critical for therapid action of this anti-inflammatory agent. Fig. 8B shows that bothgranules increased IND release in the acid medium up to 28% of theIND released, whereas pure IND released only 2%. These valuescorresponded to an approximately 14-fold increase in the IND solubilityin the acid medium. The increase in the IND released in both mediums

IND

rele

ased

(%)

Time (minutes)

020

100

60

0 50 100 12525 75 150

Exp. 6Exp. 7IND

A

Fig. 8. Comparison of in vitro dissolution profiles for pure IND and granules (Exps. 6 and 7) in(0.1 N) at pH 1.0.

probably occurred because of the presence of polyethylene glycol4000. PEG is a highly hydrophilic carrier. In addition, PEG is widelyused because of its low melting point, low toxicity, and high viscosity,as well as because it is inert and easily available [37].

Note that in Exp. 7, a higher amount of IND was released in a lowertime than in Exp. 6, independent of the pH. In a basic medium, 100% ofthe INDwas released in 15min in Exp. 7, whereas only 65% of drug wasreleased in the same time in Exp. 6. Relative to the results obtained inthe acid medium, 28% of IND was released in Exp. 7, and only 14% wasreleased in Exp. 6. The granules only differed in size, where the size inExp. 7 was approximately 50% that in Exp. 6; thus, this size differencewas probably responsible for promoting the increased release of IND as-sociated with the presence of higher amounts of PEG. As shown above,

IND

rele

ased

(%)

Time (minutes)

80

60

40

20

00 50 100 12525 75 150

Exp. 6Exp. 7IND

B

two different dissolution mediums: (A) phosphate buffer at pH 7.2 and (B) HCl solution


the granules were produced because of the formation of thin layers onthe particles of spray-dried lactose that was promoted by the aggregat-ing agent IND/PEG. The larger granules corresponded to a greater pro-portion of the lactose particles being coated with IND/PEG. This resultpromoted the rapid release of small particles in the medium. Thesesmaller particles resulted in a higher surface area that promoted an in-crease in the drug solubility [38].

4. Conclusions

The granulation of IND by a fluidized bed hotmelt process using poly-ethylene glycol as a molten carrier and spray-dried lactose as a substratewas demonstrated to be an effect alternative for pharmaceutical applica-tion. In general, the process proved to be rapid and reliable, but specialcare was required tomaintain themolten feed at a reproducible temper-ature. The granule size depended on nebulising the primary air flow rate,thereby making it easier to produce particles with a specified size. Also,the granules exhibited acceptable flow properties that did not dependon the spray nozzle air flow rate, the molten liquid flow rate or thetotal weight of polyethylene glycol and indomethacin used. The meansize and flowability of the granules were adequate for further tableting.The DSC and FT-IR analysis showed that there was no drug interactionduring the process. The results of the XRPD and SEM analyses showedthe presence of indomethacin crystals on the granules. The dissolutionprofile of indomethacinwas remarkably enhancedby granulation. There-fore, the results confirmed the high potential of the FHMG technique toproduce granules with enhanced drug solubility and release rates.

List of symbols

Ai polynomial coefficients in Eq. (2)CD Carr indexDF degree of freedom in ANOVAD50 mean diameter based on 50% fraction, mmF f numberHF Hausner factorMS mean squaresp probabilityQNA atomising air flow rate, (L/min)QMD molten mixture feed rate, (mL/min)SS sum of squaresWMD weight of molten liquid applied, (g)X1 coded PEG feed rateX2 coded atomising air pressureX3 coded spray nozzle positionYi dependent variableϕ angle of repose, degrees

Acknowledgments

We are grateful to FAPESP (05/05191-2) and CNPq (PQ-2) for finan-cial support.

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