Effects of moisture content and compression pressure of various deforming granules on the physical properties of tablets

Powder Technology 310 (2017) 92–102

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Effects of moisture content and compression pressure of various deforming granules on the physical properties of tablets Prakash Thapa a, Ah Ram Lee b, Du Hyung Choi c,⁎, Seong Hoon Jeong a,⁎⁎ a b c

College of Pharmacy, Dongguk University-Seoul, Gyeonggi 410-820, Republic of Korea School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea Department of Pharmaceutical Engineering, Inje University, Gyeongnam 621-749, Republic of Korea

a r t i c l e

i n f o

Article history: Received 15 May 2016 Received in revised form 2 October 2016 Accepted 6 January 2017 Available online 10 January 2017 Keywords: Moisture content Ejection force Porosity Tensile strength Compression pressure High-shear granulation

a b s t r a c t The main purpose of this study was to investigate the effects of moisture content (MC) of different deformation granules (brittle, plastic, and elastic) and compression pressure (CP) on the physical properties of tablets. A general full factorial design was used with three blocks (deformation property of excipient) and two control factors: MC and CP. Lactose monohydrate (LM), microcrystalline cellulose (MCC), and corn starch (CS) were selected as brittle, plastic, and elastic materials, respectively. The granules were prepared with a high-shear granulator having a capacity of 0.9 L by adding water using a peristaltic pump. This high-shear granulator allows recording of real-time impeller torque values with 1-s intervals. The torque curves can facilitate determination of the transition between saturation stages of a system. Analysis of variance was performed to determine the significance of each factor and their interactions with response variables. All control factors and deformation properties of excipient showed significant effects on the properties of tablets, including ejection force, tensile strength, and porosity (p b 0.05). However, their mutual interaction was not significant on the response variables (p N 0.05). Analysis of the relationship between ejection work and peak force (Fmax) demonstrated that the ejection work profiles were associated with the deformation properties of the excipient. Moreover, tablet strength was dependent on the control factors and the deformation nature of excipient. As these factors significantly influenced the physical properties of tablets, achieving high-quality tablets would require comprehensive information on the excipient properties while considering the compression process. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Among the various pharmaceutical dosage forms, tablet is the most commonly used solid dosage form, offering several advantages in terms of manufacturing and use, such as a high production rate, low cost, ease of administration, and high patient compliance. Tablet production involves several manufacturing steps, among which the granulation and compression stages have dramatic effects on the finished product. Granulation is a process of particle size enlargement, converting fine powders into granules. It offers several advantages including improvement of dosage uniformity, densification of materials, improvement of volumetric dispensing, reduction of dustiness, reduction of segregation in downstream processes, and improvement of mechanical properties [1–4]. Granulation can be classified broadly as dry or wet granulation. Dry granulation is preferable when the active

⁎ Correspondence to: D.H. Choi, Department of Pharmaceutical Engineering, Inje University, Gimhae-si, Gyeongnam 621-749, Republic of Korea. ⁎⁎ Correspondence to: S.H. Jeong, College of Pharmacy, Dongguk University-Seoul, Goyang, Gyeonggi 410-820, Republic of Korea. E-mail addresses: [email protected] (D.H. Choi), [email protected] (S.H. Jeong).

http://dx.doi.org/10.1016/j.powtec.2017.01.021 0032-5910/© 2017 Elsevier B.V. All rights reserved.

ingredient is heat and moisture sensitive as a liquid binder is not necessary. The major limitation is the generation of a large amount of fines [5], which, as well as non-compacted powder, can cause capping and hardness issue in tablets, leading to compromised product quality and production yield. Moreover, not all excipients have good compaction properties and hence a wet granulation process is often preferred. Wet granulation is classified into three types: low-shear, high-shear, and fluidized-bed granulation. Among them, high-shear granulation is the most commonly used manufacturing process as it generates small, uniform, and dense granules suitable for tableting [2]. The process can be separated into three stages: mixing of materials, addition of binder solution, and wet massing [1]. The amount of liquid solution used in granulation is dependent on the amount and types of excipients in a formulation, due to variations in their water-holding capacity. For example, microcrystalline cellulose has high water-holding capacity and takes up more water, whereas lactose has a low capacity and takes up less water. Moreover, various formulation and process variables could affect granule and tablet properties, including impeller speed, amount of binder, wet massing time, and liquid addition rate [2,6–9]. Compression is a pharmaceutical unit operation used for densification of granules or powder by applying pressure between two punches

P. Thapa et al. / Powder Technology 310 (2017) 92–102

in a die. During compression, granules initially undergo rearrangement and then densification due to solid bridges, mechanical interlocking, and van der Waals force [10]. There are various process and formulation variables, including the moisture content (MC) of granules, deforming nature of excipients, and compression pressure (CP). The deforming nature of the excipient can affect tablet porosity. Granules produced from brittle excipients form less porous tablets, whereas elastic-deforming excipients form porous tablets. Therefore, for successful compaction of pharmaceutical granules, knowledge of the deformation nature and physicochemical and mechanical properties of excipients is required [11,12]. Similarly, the deforming nature of excipients may have a role in determining the tablet ejection force after compression, and moisture present in pharmaceutical excipients/granules has a considerable impact on the physical properties of the granules, such as their compression characteristics, and the mechanical strength of the resulting tablets [13,14]. As the MC increases, bonding between the particles increases [15]. Moreover, moisture present in granules could affect the tablet ejection force because of its lubricating properties. The effects of MC on tablet porosity have been reported previously [12,16–18]. CP is another critical parameter that may affect tablet porosity and ejection force. As the CP increases, the porosity of the tablet is expected to decrease, while the ejection force is expected to increase because powder/granules are consolidated at high CPs. Moreover, increased CP increases radial die wall pressure. However, CP should not be too high because this creates excessive friction, which may damage the tablet and reduce tooling life due to wear [19]. Few studies have reported the effects of moisture of granules, CP, and the deforming nature of excipients on the ejection force and compression properties of tablets. In the present study, three different types of granule; i.e., lactose granules as fragmented [11], microcrystalline cellulose (MCC) granules as plastic deforming [11], and corn starch (CS) granules as elastic deforming [20] were prepared using a highshear granulator; all other process and formulation variables were maintained constant. Then, the effects of MC present in granules, CP, and excipient type were investigated on tablet ejection force, tablet porosity, and tensile strength using a general full factorial design of experiment. 2. Materials and methods 2.1. Materials Lactose monohydrate (Pharmatose 200M, DFE Pharma, Goch, Germany), microcrystalline cellulose (Heweton 102, JRS Pharma GmbH & Co., Rosenberg, Germany), and corn starch (Powdered NF Corn starches, Roquette Pharma, Lestrem, France) were selected to represent brittle, plastic, and elastic materials, respectively. Polyvinyl pyrrolidone (Kollidon 30, BASF, Ludwigshafen, Germany) was used as a binding agent. All other chemicals were of analytical grade and used without further purification. 2.2. Experimental design A factorial design might produce an appropriate mathematical model with the minimum number of experiments for the evaluation of factors that influence responses. This design allows all factors to be varied simultaneously; hence, it may be able to evaluate the effects of each variable at each level, together with their mutual interactions. The responses are measured for each experiment and then a simple linear, interactive, or empirical model is generated by carrying out multiple regression analysis and F-statistics to identify statistically significant terms [21]. As shown in Table 1, a general full factorial design was used with three blocks (deformation properties of excipient) and two control factors: MC (x1) and CP (x2), which had four and three levels, respectively. Each formulation contains a variable excipient (95%, w/w) and a fixed

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Table 1 Experimental design with three blocks and two control factors for wet granulation process and resulting responses including ejection force, tablet porosity, and tablet tensile strength. Run order

Block

Control factors

Responses

Excipient

x1 Moisture content (%)

x2 Compression pressure (MPa)

y1 Ejection force (N)

y2 Porosity (%)

y3 Tensile strength (N/cm2)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

MCC MCC MCC MCC MCC MCC MCC MCC MCC MCC MCC MCC LM LM LM LM LM LM LM LM LM LM LM LM CS CS CS CS CS CS CS CS CS CS CS CS

2.5 7.5 2.5 10.0 7.5 7.5 10.0 5.0 5.0 5.0 2.5 10.0 10.0 2.5 10.0 5.0 7.5 7.5 2.5 7.5 10.0 5.0 2.5 5.0 2.5 5.0 7.5 7.5 2.5 10.0 5.0 2.5 7.5 10.0 10.0 5.0

150 100 200 150 200 150 100 150 100 200 100 200 150 150 100 150 200 100 200 150 200 200 100 100 150 100 200 150 200 200 150 100 100 150 100 200

63.91 54.09 109.27 74.60 103.91 82.57 58.43 82.13 49.07 116.21 27.05 76.66 18.41 53.23 11.99 24.86 27.18 13.69 56.44 27.18 12.39 45.21 40.93 16.89 102.81 58.91 43.61 45.09 124.50 25.26 86.93 61.86 35.81 28.19 30.88 99.73

41.88 41.55 36.88 33.06 30.93 37.06 39.45 38.58 43.14 35.13 41.88 26.92 9.52 22.85 11.96 14.50 7.25 11.33 19.94 10.10 7.07 9.52 27.84 15.47 36.70 38.42 19.54 25.89 31.02 15.53 32.86 42.25 33.03 20.40 28.04 27.42

18.67 33.73 32.87 201.14 144.81 66.98 102.99 22.04 13.46 49.24 12.34 383.16 202.73 628.05 205.29 755.27 410.24 288.03 869.73 351.69 182.38 1038.80 420.84 561.50 377.90 329.58 2350.64 1327.52 1020.60 2585.61 801.59 137.52 772.40 1763.19 1270.30 1540.91

amount of Kollidon 30 (5%, w/w). Tablet ejection force (y1), tablet porosity (y2), and tablet tensile strength (y3) were selected as the responses of the experimental design that were processed by the Design-Expert® software (version 10; Stat-Ease, Inc., MN, USA). Analysis of variance (ANOVA) was performed to determine the significance of each factor and their mutual interactions on the response variables. The level of significance was taken as p b 0.05. The best-fit empirical model was generated on the basis of the comparison of statistical parameters such as the multiple correlation coefficient (R2), adjusted multiple correlation coefficient (adjusted R2), and the high value of adequate precision (Adeq. Precision). The 3-D response surface was generated using the same software. 2.3. Preparation of granules Before the granulation process, all materials were passed through a #30 mesh sieve to remove any aggregates and then mixed for 3 min at 200 rpm. The batch size of powder mixture for each experiment was 180 g. The granulation was carried out in a high-shear granulator (ProCepT, Zelzate, Belgium) having a capacity of 0.9 L by adding water using a peristaltic pump. The impeller and chopper speed were set at 800 rpm and 3000 rpm, respectively, and the granulation time was approximately 8–12 min. This high-shear granulator allows recording of real-time impeller torque values with 1-s intervals. The torque curves can facilitate determination of the transition between saturation stages of a system [2]. Power consumption is a process analytical tool

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(b)

400

600

Impeller torque (mNm)

Impeller torque (mNm)

(a)

300 200 100

400

200

0

0 0

5

10

0

15

10

Liquid/Solid ratio (%) [w/w]

20

30

40

Liquid/Solid ratio (%) [w/w]

(c) Impeller torque (mNm)

400 300 200

100 0

0

10

20

30

40

Liquid/Solid ratio (%) [w/w] Fig. 1. Impeller torque profiles plotted versus the liquid/solid ratio during the high-shear granulation; (a) LM granules, (b) MCC granules, and (c) CS granules. The torque curves can be used to determine the transition between saturation stages of the system.

developed for monitoring high-shear granulation, which can be determined by measuring the electrical power consumed or the torque of the agitator. Early studies showed that the power exerted by the impeller changes as the granules grow and consolidate, and the overall trend can be related to the stages of granulation [2,22,23].

compression, room temperature was maintained at temperature and relative humidity of 21 °C and 60% respectively. The percent moisture content was calculated using Eq. (1).

2.4. Analysis of moisture content

where Wi and Wf are the initial and final weights of the granules, respectively.

After granulation, the granules were sieved with a #16 mesh sieve to remove any aggregates. Sieved granules were divided into four equal parts in aluminum plates and dried in an oven at 50 °C until the designated MC was achieved. The MC was analyzed using a moisture analyzer (Sartorius AG, Germany). Granules with four moisture levels (i.e., 2.5%, 5.0%, 7.5%, and 10.0%) were collected according to the experimental design. The granules were tightly packed in a plastic container and subsequently sealed in air-tight container, placed in dry chamber and compression was then completed with a minimum delay. During

(a)

(b)

Moisture Content ¼

W i −W f  100% Wi

ð1Þ

2.5. Measurement of granule density The true density of each granule was determined using a helium pycnometer (AccuPyc 1330; Micromeritics Instrument Co., GA, USA). The accuracy of the pycnometer was evaluated using a standard steel sphere before measurements. The experimental sample was accurately weighed and loaded into the sample cell. The sample volume was calculated by measuring pressure by filling the sample chamber with high-

(c)

Fig. 2. SEM images of granules in size range of 600–710 μm at the impeller speed of 800 rpm. (a) LM granules, (b) MCC granules, and (c) CS granules. All the granules were observed to be nearly spherical. However, MCC and CS granules have smooth surface morphology compared to LM granules.

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Table 2 The initial moisture content of granules depending on granule type before drying and their moisture content of granules controlled according to the experimental design (n = 3). Granule type

Moisture content (%, n = 3)

LM granules MCC granules CS granules

Before drying mean ± SD

10.0%, mean ± SD

7.5%, mean ± SD

5.0%, mean ± SD

2.5%, mean ± SD

13.67 ± 0.46 53.78 ± 0.68 33.5 ± 0.9

9.66 ± 0.39 10.04 ± 0.22 10.09 ± 0.10

7.49 ± 0.08 7.65 ± 0.10 7.47 ± 0.27

5.10 ± 0.06 4.96 ± 0.13 4.97 ± 0.25

2.49 ± 0.17 2.68 ± 0.13 2.59 ± 0.07

Table 3 Carr's Index, Hausner ratio, and true density of granules prepared using the various deforming excipients. Granule type

Carr's Index (%)

Hausner ratio

True density (g/cm3)

LM granules MCC granules CS granules

10.20 12.25 10.89

1.11 1.14 1.12

1.5506 1.5117 1.5043

purity helium gas followed by discharging the gas into a second empty chamber. The measurements were repeated for five cycles. The bulk and tap density of the granules were determined using an MT-1000 instrument (Seishin Enterprise Co., Tokyo, Japan). Bulk density was determined after dropping powder in a 100 mL mass cylinder. The tap density was determined after 2000 taps. Each analysis was repeated three times.

The increase in bulk density of a powder is related to the cohesiveness of the powder. Ratios of the poured bulk to tapped densities are expressed in two ways to give indices of flowability; i.e., the Carr's compressibility index and Hausner ratio, as determined by Eqs. (2) and (3), respectively. Carr 0 s Index ¼

DT −DB  100% DT

ð2Þ

where DB and DT are the bulk density and tap density of the granules, respectively. Hausner ratio ¼

DT DB

ð3Þ

The Hausner ratio varies from about 1.2 for a free-flowing powder to 1.6 for cohesive powder. The Carr's Index classifications are listed as

Fig. 3. Residual plots for (a) tablet ejection force, (b) tablet porosity, and (c) tablet tensile strength.

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Table 4 Analysis of variance (ANOVA) of the dependent variables using the experimental design. Responses

Source

Sum of square

Mean square

F value

p value

R squared

Adjusted R squared

Adeq. precision

y1

Model x1 x2 Blcok x1 x2 Residual Cor total Model x1 x2 Block Residual Cor total Model x1 x2 Block Residual Cor total

34229.98 6199.66 6041.07 13387.00 2144.19 2007.63 36237.61 4688.00 745.14 478.92 3354.44 121.71 4809.71 1.45 × 107 6.44 × 105 1.74 × 106 7.43 × 106 5.53 × 105 1.51 × 107

3803.33 6199.66 6041.07 6693.50 2144.19 77.22

49.26 80.29 78.24 86.68 27.77

b0.0001 b0.0001 b0.0001 b0.0001 b0.0001

0.9446

0.9254

25.518

586.00 745.14 478.92 1677.22 4.51

130.00 165.30 106.24 372.08

b0.0001 b0.0001 b0.0001 b0.0001

0.9747

0.9672

41.629

1.81 × 106 6.44 × 105 1.74 × 106 3.71 × 106 20476.04

88.58 31.46 84.95 181.41

b0.0001 b0.0001 b0.0001 b0.0001

0.9633

0.9524

31.826

y2

y3

5–12% (free flow), 12–16% (good flow), 18–21% (fair flow), 23–35% (poor flow), 33–38% (very poor flow), and above 40% (extremely poor flow) [24].

dimension and thickness were measured using a digital slide caliper (Mitutoyo Co., Kawasaki, Japan) (n = 5). The tablets were then evaluated in terms of ejection force, tablet porosity, and tablet tensile strength.

2.6. Tablet preparation

2.7. Measurement of ejection force, tablet tensile strength, and tablet porosity

Granules (400 mg) were weighed, inserted into a die, and compressed on a single punch Carver Laboratory Press (Carver, Inc., Wabash, IN, USA) using 9 mm flat faced punch at three different compression pressures (Table 1). Each compact was weighed accurately, and its

The crushing strength was determined by compressing a compact diametrically on a texture analyzer (TA.XT plus, Stable Micro Systems Ltd., UK). The radial tensile strength of the compact was calculated

Fig. 4. Three-dimensional plots of the effects of CP and MC on the ejection force of granules based on the factorial design. (a) LM granules, (b) MCC granules, and (c) CS granules. The dots on the surface represent the experimental points based on the factorial design. Colors correspond to the values for the ejection force according to the color scale shown beside the plots.

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Fig. 5. Ejection force profile after compression of LM granules based on the factorial design with different MCs: (a) 2.5%, (b) 5.0%, (c) 7.5%, and (d) 10.0%. Black, blue, and red lines represent compression pressures of 101, 152, and 207 MPa, respectively.

from the compact crushing strength and compact thickness in accordance with Fell and Newton's method (Habib et al., 1996), in which the radial tensile strength σx is given in Eq. (4) as follows:

where ε, Dtablet, and Dtrue are the tablet porosity, tablet density, and true density of granules, respectively. 3. Results and discussion

2x σx ¼ πdt

ð4Þ

where σx is the tensile strength (MPa), x is the force required to cause failure in tension (N), d is the diameter of the compact (mm), and t is the thickness of the compact (mm). The use of tensile strength allows the dimensions of the compact to be taken into account, which is in contrast to the use of crushing strength. The force leading to failure in tension was used for the calculation of tensile strength. Tablet ejection force was measured using the texture analyzer after compression with a 9 mm flat faced punch. After the compression, the die contained the compressed tablet was immediately placed on a sample holder and a 4 mm cylindrical probe was adjusted in center of the die. The probe was advanced into the die at test speed of 10 mm/s until a triggering force of 0.1 N. When a trigger force reached 0.1 N, the signal began to be recorded and the probe was consistently advanced at test speed of 4 mm/s. When the tablet was released from the die, the test was stopped. The ejection force was determined by the total probe displacement value (D) and the force applied (F), according to Eq. (5): Z Tablet ejection force ¼

FdD:

ð5Þ

Tablet dimensions were measured using a micrometer caliper with a precision of 0.01 mm (Mitutoyo, Japan). The porosity of tablets, ε, was calculated using Eq. (6): ε ¼ 1−

Dtablet Dtrue

ð6Þ

3.1. Granulation and granule properties The amount of water as a binder solution required for granulation was dependent on the type of excipients, likely due to the variations in the water absorption capacity of excipients. The end-point of granulation was determined based on an impeller torque curve depending on the liquid/solid ratio (%) (Fig. 1). The impeller torque gradually increased and then reached a peak, which might suggest the end point. If more water was added, the torque would begin to decrease as a result of over-wetting [25]. MCC granules required more water and higher impeller torque to reach the end-point, while lactose granules required less water consumption and lower torque to reach the end-point because of high wettability of lactose. Fig. 2 shows the scanning electron microscopy (SEM, Model S-4700, Hitachi, Japan) images of dried LM, MCC, and CS granules in size range of 600–710 μm. All the granules were nearly spherical shape due to the effect of high impeller speed. However, MCC and CS granules have smooth surface morphology, but LM granules have rough texture. This might suggest that the granule formation is mainly governed by various mechanisms depending on the deformation nature of excipients. The granule formation of LM might be mainly dependent on collision mechanism. However, both layering and collision mechanisms might influence the granule formation of MCC and CS, that have plastic and elastic deformation properties, respectively. Table 2 shows the initial moisture contents after granulation. The four different moisture contents were controlled according to the experimental design. The MC in the granules could exist in at least three

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Fig. 6. Ejection force profile after compression of MCC granules based on the factorial design with different MCs: (a) 2.5%, (b) 5.0%, (c) 7.5%, and (d) 10.0%. Black, blue, and red lines represent compression pressures of 101, 152, and 207 MPa, respectively.

states: tightly bound to anhydrous units, less tightly bound, and bulk water [12]. Increased tensile strength with increasing MC can be explained by the following mechanisms: absorbed water could lead to an increased amount of solid bridges as the surface restructuring medium, and immobile water layers absorbed at particle surfaces could enhance the particle-particle interactions [26]. However, bulk water in granules could cause the formation of multiple layers of water at the particle surface, decreasing the tensile strength of the tablet since the layers may disturb or reduce intermolecular attraction forces and thereby reduce the tablet strength [27]. Therefore, the MC needs to be controlled to achieve optimal tablet strength. In this study, the MC was controlled (2.5–10.0% w/w in granules) based on the factorial design to investigate its effects on the physicochemical/mechanical properties of resulting tablets. Table 3 shows the Carr's Index, Hausner ratio, and true density values of the granules. The granules with low moisture level (2.5%) were used to measure the parameters. The Carr's Indices of powder before granulation were 41.2 (LM), 39.33 (MCC), and 31.3 (CS) (data not shown). After granulation, all of the granules exhibited sharp decreases in Carr's Index. Granulation is the process of agglomerating fine powders using a liquid binder to give large granules and controls the shape of granules by sieving. This may result in improved flowability of powders. In particular, LM granules have the greatest increase in flowability. Lactose can be classified as a brittle material and the force used in granulation may produce fragments of lactose, which can allow for shaping with better flowability. 3.2. Effects of moisture content and compression pressure on ejection force The experimental results are presented in Table 1. The random behavior of the residuals was evaluated with the residual analysis. The

normal probability plots were prepared for residual errors of the response variables (Fig. 3a). The plot showed normal distribution and located on straight lines. As shown in Table 4, a p value b 0.05 for any factor in analysis of variance represents an effect of the ejection force of tablets (y1). It can indicate that all control factors (p b 0.0001), the mutual interactions of the control factors (p b 0.0001), and deformation nature of excipients (p b 0.0001) had significant effects on the ejection force. The actual model R2 is 0.9446 and adjusted R2 is 0.9254. The high value of adequate precision (25.518) indicates adequate model discrimination. Fig. 4 shows three-dimensional plots of the effects of CP and MC on the ejection force of granules based on the factorial design. The ejection force under the same conditions decreased in the following order: CS granules ≥ MCC granules N LM granules. These data suggested that elastic- and plastic-type granules exhibited stronger binding with the die than brittle-type granules. The empirical model equations in coded terms for ejection force are provided in Eqs. (7)–(9): yL1 ¼ 13:36−0:71x1 þ 0:29x2 −0:02x1 x2

ð7Þ

yM 1 ¼ 46:94−3:20x1 þ 0:85x2 −0:09x1 x2

ð8Þ

yC1 ¼ −86:98 þ 12:84x1 þ 1:06x2 −0:08x1 x2

ð9Þ

C where yL1, yM 1 , and y1 indicate the ejection force of LM granules, MCC granules, and CS granules, respectively. Based on the Eq. (7) for LM granules, MC had a negative effect on the ejection force, while CP had a positive effect on the ejection force. As shown in Fig. 4a, the highest ejection force was located between the highest CP and the lowest MC. Fig. 5 shows the ejection force profiles after compression of LM granules. The ejection force increased immediately after the beginning of compression and then sharply decreased

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Fig. 7. Ejection force profile after compression of CS granules based on the factorial design. with different MCs: (a) 2.5%, (b) 5.0%, (c) 7.5%, and (d) 10.0%. Black, blue, and red lines represent compression pressures of 101, 152, and 207 MPa, respectively.

after the maximum force was reached (Fmax). Up to 5.0% MC, CP increased with increasing ejection force (Fig. 5a and b). However, the tendency was different at 7.5% and 10.0% MC (Fig. 5c and d). These data suggested that the surface of LM granules was dissolved in water (LM has a solubility of approximately 21.6 g/100 mL in water) and the surface had viscoelastic properties [28], which would be expected to result in strong bonding between LM granules and the die at the initial stage of the ejection profile. When compressed in the die, LM granules were tightly attached on the surface of the die since the surface of LM granules was partially solved, which served as a binder. Additionally, the ejection force decreased sharply after the initial movement, indicating that the absorbed water in the granules decreased the particle surface energy and the adhesion of the tablet to the die wall [12]. In contrast, the ejection force increased with an increase in CP because the LM granules underwent greater consolidation with increasing CP. Similarly, the Eq. (8) for MCC granules showed that MC and CP had negative effect and positive effect on tablet ejection force, respectively. As shown in Fig. 3b, the ejection force decreased with increasing MC and decreasing CP. Fig. 6 shows the ejection force profile of MCC granules based on the factorial design. The results might be explained by the water lubrication effect. MCC is generally insoluble in water; thus, water in MCC granules may have a strong lubrication effect. However, the ejection force increased with increasing CP, indicating that the plastic nature could result in plastic deformation, which occurs when a material is stressed above its elastic limit. After this limit, the resulting plastic deformation cannot be recovered by simply removing the stress that caused the deformation [29–32]. In the compression process, the force applied to the upper punch is usually expressed as the total applied CP, which is expressed as the sum of the force transmitted to the lower punch and the reaction at the die wall owing to friction at the surface after the plastic deformation. The reaction at the die wall due to

friction at the surface may be higher than the force transmitted to the lower punch, as the ejection force of MCC granules increased with increasing CP. The equation for CS granules (Eq. (9)), Figs. 4c and 7 show that the CP and the MC had a positive effect on the tablet ejection force. This may indicate that CS granules can hold a lot of water in the porous space of granules and the surface of granules. In addition, the water in granules and on the surface could not migrate into the granule particles because CS is insoluble in water [33]. The water in

Fig. 8. Relationship between the total ejection work and peak force (Fmax) on the ejection profile. The dotted lines represent the best linear fit. Circle, square, and triangle represent LM granules, MCC granules, and CS granules with the best-fitted equation of y = 1.0029x + 0.697, y = 2.5163x + 0.697, and y = 2.433x − 2.338, respectively.

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Fig. 9. Three-dimensional plots of the effects of CP and MC on the porosity of granules based on the factorial design. (a) LM granules, (b) MCC granules, and (c) CS granules. The dots on the surface represent the experimental points based on the factorial design. Colors correspond to the values for the ejection force according to the color scale shown beside the plots.

granules may serve as a strong binder between the granules and the die. Therefore, the ejection force of CS granules increased with increasing moisture content. Based on the ejection force profiles, the total ejection work and Fmax were in good agreement, as illustrated in Fig. 8. This was confirmed by the similar correlation coefficients (r = 0.99, 0.99, and 0.83 for MCC granules, CS granules, and LM granules, respectively). Notably, the deformation nature of excipients can influence the ejection force profiles, together with moisture content and compression force.

after compression than brittle-type granules since the fragments produced after the compression of brittle-type granules filled the inter-granular space within the tablets. The reduced empirical model equations in coded terms for ejection force are provided in Eqs. (10)–(12): yL2 ¼ 33:92−1:83x1 −0:06x2

ð10Þ

yM 2 ¼ 60:53−2:11x1 −0:12x2

ð11Þ

yC2 ¼ 56:21−0:95x1 −0:09x2

ð12Þ

3.3. Effects of moisture content and compression pressure on tablet porosity Tablet porosity as a response based on the factorial design is presented in Table 1. Fig. 3b shows that the normal probability plots were prepared for residual errors of the response variables, which showed normal distribution and located on straight lines. As shown in Table 4, a p value b 0.05 for any factor in analysis of variance represents an effect on the tablet porosity (y2). It can indicate that all control factors (p b 0.0001) and deformation nature of excipients (p b 0.0001) had significant effects on tablet porosity. However, the mutual interactions of the control factors (p N 0.05) was not significant on the response. The actual model R2 was 0.9747 and adjusted R2 was 0.9672. The high value of adequate precision (41.629) indicates adequate model discrimination. Three-dimensional plots for the effects of control factors on tablet porosity are illustrated in Fig. 9. Tablet porosity decreased in the following order: CS granules ≥ MCC granules N LM granules. The data suggested that elastic- and plastic-type granules might have larger porous space

C where yL2 , yM 2 , and y 2 represent the tablet porosity of LM granules, MCC granules, and CS granules, respectively. The estimated coefficients for all factors were negative, indicating that the tablet porosity decreased with increases in the MC and the CP. The tablet pores for LM granules may be filled with lactose dissolved in water, originating from the surface of lactose, suggesting the importance of MC for the tablet porosity of LM granules. Additionally, an increase in CP may yield fragments of LM granules due to the brittle nature of lactose; these fragments can fill the pores of the tablets. Thus, the tablet porosity of LM granules was lower than that of the other granules. The tablet porosity of MCC granules was influenced by MC and CP, which had negative effects on the porosity. The water in MCC granules may serve as a binder in the evaluation of MC; thus, interactions among the granules would be increased. Due to the strong interaction

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Fig. 10. Three-dimensional plots of the effects of CP and MC on the tensile strength of tablets based on the factorial design. (a) LM granules, (b) MCC granules, and (c) CS granules. The dots on the surface represent the experimental points based on the factorial design. Colors correspond to the values for the ejection force according to the color scale shown beside the plots.

between granules, the distance between granules may be decreased, resulting in decreased porosity. In addition, since the plastic nature of MCC granules resulted in good compressibility, the volume of MCC tablets decreased sharply as the CP increased. Notably, the tablet porosity of CS granules was affected mainly by the MC and CP. During the compression of elastic material, the tablets tended to recover their original position after release of stress owing to the high elastic modulus. However, reduction of the volume of the tablet may only occur in the context of high compression pressure; i.e., a value higher than the yield pressure applied to the tablet. At this point, the tablet porosity of CS granules was higher than that of the other granules, and this effect was due mainly to the CP. 3.4. Effects of moisture content and compression pressure on tablet tensile strength Tablet tensile strength as a response based on the factorial design is presented in Table 1. Fig. 3c shows that the normal probability plots were prepared for residual errors of the response variables, which showed normal distribution and located on straight lines. As shown in Table 4, a p value b 0.05 for any factor in analysis of variance represents an effect on the tablet tensile strength (y3). It can indicate that all control factors (p b 0.0001) and deformation nature of excipients (p b 0.0001) had significant effects on tablet tensile strength. However, the mutual interactions of the control factors (p N 0.05) was not significant on the response. The actual model R 2 was 0.9633 and adjusted R2 was 0.9524. The high value of adequate precision (31.826) indicates adequate model discrimination. Threedimensional plots for the effects of control factors on tablet tensile strength are illustrated in Fig. 10. Tablet tensile strength decreased in the following order: MCC granules ≥ LM granules ≥ CS granules.

Based on the above results, brittle- and plastic-type granules may exhibit stronger interactions between granules after compression, whereas the interactions between granules of an elastic nature may be weakened owing to the reduced volume after the release of stress. The reduced empirical model equations in coded terms for ejection force are provided in Eqs. (13)–(15): yL3 ¼ 549:2−70:54x1 þ 2:56x2

ð13Þ

yM 3 ¼ −1850 þ 187x1 þ 12:47x2

ð14Þ

yC3 ¼ −241:6 þ 27:08x1 þ 1:06x2

ð15Þ

C where yL3, yM 3 , and y3 represent the tablet tensile strength of LM granules, MCC granules, and CS granules, respectively. The estimated coefficients for CP were positively effective on tablet tensile strength, whereas MC was negative on tablet tensile strength of LM granules. As shown in Fig. 10a, the tablet tensile strength of LM granules generally increased as the MC decreased and the CP increased. At low moisture contents in LM granules, water may dissolve the surface of granules, and the surface surrounded by the water film may have viscoelastic properties. This causes strong interactions between granules; thus, the tablet tensile strength of LM granules was high at low MC. However, as the MC in LM granules increased, the water began to form multiple layers on the surface of granules. The thickness of these layers may increase as the MC increases, potentially disrupting the binding between LM granules after compression, resulting in decreased tablet tensile strength. As shown Fig. 10b and c, the tablet tensile strength of MCC and CS granules was positively influenced by MC and CP, suggesting that the water layer at the particle surface may be regarded as particles; this

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would allow for reduction of the distance between particles and increased intermolecular attractions. Moreover, the water layer may facilitate increased solid bridging between particles. Therefore, as the moisture contents in MCC and CS granules increased, the tablet tensile strength increased. In addition, increased compression force may increase the tablet tensile strength of MCC and CS granules. MCC granules, considered as a plastic-type deformation excipient, can provide a large surface area to facilitate generation of strong bonds between particles. This may greatly increase the tablet tensile strength of MCC granules. Additionally, the tablet tensile strength of CS granules, an elastic-type deformation excipient, was only slightly affected by the CP. The elastic-type excipient shows a higher volume reduction after compression, regardless of the CP. The volume reduction may increase the distance between granules or break the bonds between granules after compression, which might support the low tablet tensile strength of CS granules. 4. Conclusions The effects of moisture content and compression pressure on the physical properties of tablets; i.e., ejection force, tablet porosity, and tablet tensile strength, were evaluated with three deforming excipients: brittle-, plastic-, and elastic-type granules. A factorial design was used to determine the factors that contribute to responses and to construct appropriate empirical models. Surface response analysis indicated that all control factors were significantly related to the physical properties of the tablet. The surface of LM granules dissolved in water had a viscosity that may increase the bonds between granules. In addition, compaction by brittle fracture was accompanied by an increase in the surface area of the compact. Increased MC in granules resulted in the formation of a multilayer water film on the surface of MCC and CS granules. This increased the distance between granules, which in turn affected the bonding force. Moreover, elastic- and plastic-type granules exhibited reduced volumes after compression and increased surface areas for the applied yield strength. Therefore, the factors evaluated in this study significantly influenced the physical properties of tablets. Achieving high quality by careful consideration of the effects of the compression process will ultimately require comprehensive information of the excipient properties. This study will facilitate production of highquality tablets based on the design of the compression process. Acknowledgements This research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean Government, MSIP (NRF-2014M3A9A9073811) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF2015R1A1A1A05000942). References [1] M. Cavinato, M. Bresciani, M. Machin, G. Bellazzi, P. Canu, A. Santomaso, The development of a novel formulation map for the optimization of high shear wet granulation, Chem. Eng. J. 164 (2010) 350–358. [2] E.M. Hansuld, L. Briens, A review of monitoring methods for pharmaceutical wet granulation, Int. J. Pharm. 472 (2014) 192–201. [3] R. Ho, S.E. Dilworth, D.R. Williams, J.Y.Y. Heng, Role of surface chemistry and energetics in high shear wet granulation, Ind. Eng. Chem. Res. 50 (2011) 9642–9649. [4] B.J. Ennis, Theory of granulation: an engineering perspective, in: D.M. Parikh (Ed.), Handbook of Pharmaceutical Granulation Technology, second ed.Taylor & Francis, NY, 2005 (Chapter 2). [5] C.S. Omar, R.M. Dhenge, J.D. Osborne, T.O. Althaus, S. Palzer, M.J. Hounslow, A.D. Salman, Roller compaction: effect of morphology and amorphous content of lactose powder on product quality, Int. J. Pharm. 496 (2015) 63–74.

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