The Effect of the Physical State of Binders on High-Shear Wet Granulation and Granule Properties: A Mechanistic Approach to Understand the High-Shear Wet Granulation Process. Part IV. The Impact of Rheological State and Tip-speeds

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

The Effect of the Physical State of Binders on High-Shear Wet Granulation and Granule Properties: A Mechanistic Approach to Understand the High-Shear Wet Granulation Process. Part IV. The Impact of Rheological State and Tip-speeds JINJIANG LI,1 LI TAO,1 DAVID BUCKLEY,1 JING TAO,1 JULIA GAO,1 MARIO HUBERT2 1 2

Drug Product Science & Technology, Bristol-Myers Squibb New Brunswick, New Jersey 08901 Analytical & Bioanalytical Development, Bristol-Myers Squibb New Brunswick, New Jersey 08901

Received 8 August 2013; revised 11 September 2013; accepted 25 September 2013 Published online 17 October 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23750 ABSTRACT: The purpose of this study is to provide a mechanistic understanding concerning the effect of tip-speed on a granulation at various binder rheological states; the in situ rheological state of a binder was controlled by exposing a granulation blend to 96% relative humidity. This approach allowed us to investigate the impact of tip-speed on granule consolidation coupled with the in situ binder state, which was not possible using a conventional granulation approach. Experimentally, the rheological state of binders was characterized using a rheometer. Granule size and granule porosity were measured by Qicpic instrument and Mercury Intrusion Porosimetry, respectively. For the granulations containing binders at viscous state (PVP K17 and PVP K29/32), the granule size increased significantly with mixing time and the growth rate increased with tip-speed until 5.8 m/s; when binders were at viscoelastic state, tip-speed had no impact on granulation. Furthermore, the granule porosity was higher for granulation with binders at viscoelastic state (HPC and PVP K90), whereas it was lower for granulation with binders at viscous state. In addition, the impeller tip-speed had minimal impact on the porosity of the final granules. C 2013 Wiley Periodicals, Inc. and Finally, Ennis’ model was used for interpreting results, providing mechanistic insights on granulation.  the American Pharmacists Association J Pharm Sci 102:4384–4394, 2013 Keywords: granulation; viscosity; wetting; water sorption; polymers; surface energy; rheology; glass transition; formulation; kinetics

INTRODUCTION Because high-shear wet granulation with a premixed dry binder followed by addition of water is a common practice in the pharmaceutical industry (binder added in dry), this study aims to provide some mechanistic understanding about this process, specifically the effect of the impeller tip-speed on granulation at a controlled rheological state of a binder.1,2 In comparison with other studies on tip-speed, the current approach provided an opportunity to address specifically the impact of the tipspeed granule growth in coupled with the in situ binder state. As reported in the literature, most of the mechanistic studies in the high-shear wet granulation were carried out with the binder already dissolved in the granulation liquid and focused on the effect of binder properties (solution viscosity) and processing parameters.3,4 Liquid content (the ratio of liquid to solid) in a granulation or the saturation ratio was typically used to study the effect of binder properties and processing conditions on granule growth.4 In addition, the binder viscosity before addition, not the in situ binder rheological state, which is not readily accessible because of the lack of instrumentation, was frequently used. When binder is added in a dry state, the percentage of water added is often used as the measure of liquid to solid ratio. Kayrak–Talay and Litster applied the concept of nucleation regime map, developed for high-shear wet granulation process with binder addition in solution, to granulations Correspondence to: Jinjiang Li (Telephone: +732-227-6584; Fax: +732-2273784; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 102, 4384–4394 (2013)  C 2013 Wiley Periodicals, Inc. and the American Pharmacists Association

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with binders added in dry; they correctly predicted the granule size and size distribution.5 However, the predicted drop penetration time by water was much shorter than the experimental value.5 This unexplained discrepancy could be because of the fact that a different physical process is expected for a granulation process with a binder added in dry. As shown in our previous studies, for a wet granulation process with a binder added in dry, the physical state change of a binder from a glassy state to a rubbery/solution state is the main factor influencing granule growth and the final granule properties.6,7 After transition, as indicated in the Part 3, the rheological properties such as viscosity of the binder in granulation, which depends on both binder molecular weight and water content, strongly impact the flow behavior of the binder during mixing.8 Consequently, the flow behavior of the binder in the granulation or coverage should influence the kinetics of the granule formation as well as the final granule properties.9 In this study, three representative impeller tip speeds were selected, and the speed effect on granule growth at specific rheological states was examined.9 In addition, the current study focused on the kinetic aspect of granule growth, granule consolidation, and granule properties. Specifically, the kinetic impact of impeller tip speed has been investigated with consideration of the rheological state of a binder. In this paper, the physical mixtures of a binder, efavirenz (active pharmaceutical ingredient—API), and lactose monohydrate were preexposed to 96% relative humidity (RH) at room temperature for 4 weeks to equilibrate to a certain rheological state. In parallel, the binder was exposed to the same RH for the same length of time separately, and its rheological state was

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Table 1.

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The Sampling Time Intervals for Four Different Binders at Three Different Tip-speeds

Binder PVP K17 PVP K29/32 PVP K90 HPC

Sampling Intervals (4.2 m/s)

Sampling Intervals (5.8 m/s)

Sampling Intervals (7.0 m/s)

15 s, 30 s, 1 min, 1.5 min, 2 min 15 s, 30 s, 1 min, 1.5 min, 2 min, 2.5 min, 3 min 15 s, 30 s, 1 min, 2 min, 3 min, 5 min 15 s, 30 s, 60 s, 1.5 min, 2 min, 3 min, 5 min

15 s, 30 s, 45 s, 1 min 15 s, 30 s, 1 min, 1.5 min, 2 min 15 s, 30 s, 1 min, 2 min, 3 min, 5 min 30 s, 1 min, 2 min, 3 min, 5 min

15 s, 30 s, 45 s, 1 min 15 s, 30 s, 1 min, 1.5 min, 2 min 15 s, 30 s, 1 min, 2 min, 3 min, 5 min 30 s, 1 min, 2 min, 3 min, 5 min

then characterized. As the binder was intimately mixed with API and lactose monohydrate, it is assumed that wetting and nucleation already occurred during humidity exposure before further mixing in a granulator. Here, we assumed that during the humidity exposure, the binder in the blends achieved the same rheological state as that binder alone because water sorption data presented in Part I demonstrated that the majority of the water was taken by the binders and the sorption kinetic was not impacted by other components. In addition, uniform distribution of water in the blends was ensured by extending the exposure time and turning around the powder during exposure so that the rheological state of the binder was kept the same throughout the blends. This enabled us to focus on the effect of the binder in situ rheological state and tip speed on granule consolidation without the interference from other phenomenabinder distribution, wetting, and nucleation.

EXPERIMENTAL Materials Four polymeric binders (simply referred to as binders in the following text), including polyvinylpyrrolidone (PVP) PVP K17, PVP K29/32, and PVP K90 as well as hydroxypropylcellulose (HPC EXF), were used in this study. PVP K17, PVP K29/32, PVP K90, and HPC were all purchased from Ashland Inc. (Covington, Kentucky). Lactose monohydrate from Foremost Farms, USA (Rothschild, Wisconsin) was used as filler and efavirenz provided by Bristol-Myers Squibb Company (New Brunswick, New Jersey) was used as a model compound. Potassium sulfate (K2 SO4 , 99% ACS reagent), purchased from Sigma–Aldrich Chemicals Inc. (St. Louis, Missouri), was used to control the RH for preparing granulation samples. Ziplock plastic bags (4 mil, 12 × 18 in.) (resealable zipper storage bags) purchased from VWR International (West Chester, Pennsylvania) were used as humidity chambers. Preparation of Granules

Preparation of Dry Blends The procedure for the preparation of dry blends used for this study is the same as that used for previous studies.7,8 The detailed description was described in a previous publication (Part 3 of this series).8

Preparation of Granules To produce granules, the ternary blends of efavirenz, lactose monohydrate, and each binder at the binder concentrations of 7.5% (w/w) were first exposed to 96% RH at room temperature for 4 weeks in sealed Ziplock plastic bags. The humidity levels in these plastic bags were controlled in the same way as described previously.7 To granulate, a Diosna granulator with a 2-L bowl was used for all blends. Three representative impeller DOI 10.1002/jps.23750

speeds: 470 rpm—low (tip-speed: 4.2 m/s), 650 rpm—medium (tip-speed: 5.8 m/s), and 780 rpm—high (tip-speed: 7.0 m/s) were used and chopper-speed was kept at 1200 rpm for all preparations. Granule samples were taken after mixing for different time intervals as shown in Table 1. Selection of time intervals was based on visual observation. At the end of the granulation, all samples were tray dried at 40◦ C followed by delumping through an 18 mesh screen. Granule size distribution, porosity, and friability measurements were then obtained for all samples. Characterization

Measurement of Rheological Properties Powder samples of four binders: PVP K17, PVP K29/32, PVP K90, and HPC were first dispensed into plastic trays followed by exposure to 96% RH at room temperature in plastic Ziplock bags. The humidity level was controlled by a saturated solution of potassium sulfate. All binder samples were exposed to 96% RH for 4 weeks to reach equilibrium. A TA AR2000 rheometer (software version 5.4.7) was used to measure the viscoelastic properties of the binder samples immediately after the humidity exposure. Each measurement consisted of a frequency sweep (frequency 1–10 Hz, strain 0.05%) and a time sweep (3 min duration, frequency 1 Hz, strain 0.05%). Reported results are average values from the time sweep experiment. Both sweeps employed noniterative sampling mode for controlling strain and the minimum torque for the measurement was set to 50 :N m. A 20 mm stainless steel solvent trap plate-plate (Peltier stage) geometry with 1000 :m sample gap was used. No time dependent behavior was observed.

Granule Size Analysis A dynamic microscope with image analysis capability from Sympatec QICPIC instrument equipped with a compressed airdispense system (Rodos) and a 4 mm injector (Lawrenceville, New Jersey) was used to measure the particle size distribution (PSD) of granules. The instrument employs dynamic imaging analysis to derive particle size information. The measurement procedure involved an M6 lens with a measuring range of 5–1705 :m (25 logarithmically spaced channels), a dispersion pressure of 2 bar, an image acquisition rate of 400 images per second, and a measurement time of 40 s. The diameter of an equal projection area of the measured particle was used to represent the particle size. PSD and PSD statistics are volume based. Each sample was measured in triplicate. The average size of D10, D50, and D90 particle sizes was calculated from these results, where D10, D50, and D90 represent the average particle size at 10, 50, and 90 percentiles, respectively. The relative standard deviation of the D50 (median particle size) typically ranged from 2% to 10%. The number of measured particles in each measurement ranged from 100,000 to 1,000,000, whereas a typical number was around 500,000. In addition, Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

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Table 2.

The Rheological Properties of Binders after Exposure to 96% Humidity

Polymer

Complex Viscosity (n’) (Pa s)

Phase Angle (*) (◦ )

Storage Modulus (G’) (Pa)

Loss Modulus (G ) (Pa)

188.00 715.80 3.59 0.22

68.64 39.87 90.59 106.80

430.40 3452.00 −0.23 −0.39

1100.00 2883.00 22.54 1.30

HPC PVP K90 PVP K29/32 PVP K17

sieve analysis was performed on selected samples to confirm the data obtained from the Sympatec QICPIC.

Porosity Measurement The pore volume distribution of granules of various batches was determined by Mercury Intrusion Porosimetry (AutoPore III; Micromeritics, Norcross, Georgia). A sample size of 250 mg was used for the analysis. Incremental and cumulative pore volumes were determined at different pressures ranging from 1 to 60,000 psi. The data were analyzed for pore sizes between 0.1 and 10 :m to exclude the porosity contribution from intergranular free space. This is because mercury intrusion data typically consist of porosity contributions from both intergranular (void space between particles) and intragranular pores and the size of intragranular pores typically falls in this range. In addition, in this study, we are interested in the microstructure change of granules after each granulation.

RESULTS Effect of Binder Rheological State As reported in the literature, the physical properties of binders can greatly affect granulation and granule properties. As mentioned by Mort,10 the rheological state of the binder is a critical factor affecting the granulation. The rheological properties of all four binders, after being exposed to 96% RH for 4 weeks, are listed in Table 2.8 As seen from Table 2, PVP K17 and PVP K29/32 exhibit viscous solution behavior after exposure, although the solution of PVP K29/32 is a little more viscous than that of PVP K17. As for PVP K90 and HPC, both polymers are shown to be viscoelastic after exposure as indicated by their storage modulus and phase angle values. Compared with HPC, PVP K90 is more elastic than HPC as indicated by the measurement for elastic modulus and phase angle. As shown by the results of this paper (Figs. 1 and 2), the less viscous polymeric binder of the two, PVP K17, generated a faster granulation because of its relative ease of flow under shear force. When the viscosity of a binder was increased, the binder did not flow well and became less effective, which then caused the rate of consolidation to slow down. For the granulations with PVP K90 as well as HPC (see Figs. 3 and 4), the average granule size remained unchanged over the course of granulation regardless of the impeller tip-speed. PVP K90 and HPC did not deform or flow even at the highest shear force applied (the highest impeller tip-speed). Therefore, there was no consolidation of particles. This observation is extremely important. It demonstrates that when a binder is dry mixed, it is made effective by the addition of water which is needed to hydrate the polymer to transform it from a glassy state to a viscoelastic state, and then finally to a viscous solution state where it effectively forms granules. The granulation time and end point are all affected by these transitions. Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

The impact of the rheological state on the granule porosity was more pronounced than the impact of impeller tip-speed as shown in Figure 5. Granules prepared with PVP K17 and PVP K29/32 were less porous compared with those prepared with PVP K90 and HPC. The blends containing PVP K17 and PVP K29/32 can flow readily during mixing, because of the fact that both polymers exhibit viscous solution behavior, and therefore, the granules were significantly densified. This phenomenon is typically called dilation behavior for low viscosity binders. On the contrary, the blends containing polymers PVP K90 and HPC exhibited viscoelastic behavior after exposure. Typically, viscoelastic materials require more energy to deform or flow, and therefore, binder particles/molecules in granulations containing either PVP K90 or HPC had less chance to contact the particles of other components, which results in less or no granulation. As these polymers did not deform under low stress, they act as gel-like soft particles between granule particles and thereby the granules generated were highly porous and low in strength. Better granules would be generated by further hydration to transform the binders from viscous-elastic state to the viscous state. Effect of Impeller Tip-Speed on Granulation The effect of impeller tip-speed on granulation was examined as the rate of granule growth. As shown in Figure 1, the average granule size of the PVP K17 granulation is displayed as a function of granulation time for three different impeller tip-speeds: 4.2, 5.8, and 7.0 m/s. The top plot of indicates the size change with time for D10 (Fig. 1a), and the middle and bottom plots show the size change of D50 (Fig. 1b) and D90 (Fig. 1c), respectively. In general, the granule size increased with time for all three tip-speeds. The size fluctuation of D90 (Fig. 1c) may be because of the breakup of some large granules under high-shear forces. Specifically, at a tip-speed of 4.2 m/s, the increase of the average granule size with time (the slope of the curve) was low, indicating a slow granule growth as compared with other impeller tip-speeds (5.8 m/s and 7.0 m/s). In addition, a time lag or slow-growth period was also observed, especially for the growth of D10 (Fig. 1a) and D50 (Fig. 1b), during which granule size remained almost unchanged. As the impeller tip-speed increased from 4.2 to 5.8 m/s or 7.0 m/s, the average granule size increased quickly with time, suggesting that size change per unit of time was higher at higher impeller tip-speeds. This is in agreement with the observation reported in the literature in which an increase in impact energy typically enhanced granule growth.11 In addition, as seen from Figure 1, the rate of granule growth remained similar when the tip-speed of the impeller was increased from 5.8 to 7.0 m/s. This indicates that any increase in impact energy beyond the one generated by the tip-speed of 5.8 m/s will not enhance the consolidation of granules despite the visual observation that the powder bed moved faster when the impeller tip-speed was raised to 7.0 from 5.8 m/s. This observation is practically DOI 10.1002/jps.23750

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D10 (µm)

400

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Figure 1. Granule size increase as a function of time for PVP K17 binder at three different tip-speeds: 4.2 m/s (), 5.8 m/s ( ), and 7.0 m/s ( ).

important because choosing processing parameter is very critical for wet granulation and process scaleup. In Figure 2, the average granule size for the PVP K29/32 granulation is shown as a function of time, where the top plot shows the particle size of D10 (Fig. 2a), and the middle and bottom plots display the particle size of D50 (Fig. 2b) and D90 (Fig. 2c), respectively. Similarly, the results from the granulation of PVP K29/32 showed that the average granule size increased with time for all three impeller tip speeds. Similar to Figure 1, the increase of particle size with time was higher at tip-speeds of 5.8 and 7.0 m/s than at 4.2 m/s. The granule-growth curve remained the same as the tip-speed increased from 5.8 to 7.0 m/s. However, when comparing the granulation of PVP K29/32 with that of PVP K17, their rates of consolidation for all three impeller tip-speeds were lower, indicating that the granule growth for the PVP K29/32 granulation was slower and the lag time or slow growth time appeared to be longer than that of the granulation of PVP K17. This behavior can be interpreted using Ennis’ model with bed microdynamic explanation; the kinetic of particle collision was slowed down by the higher viscosity of the binder in the microenvironment.12 DOI 10.1002/jps.23750

Figures 3 and 4 exhibit the average granule size change as a function of time for the granulations of PVP K90 and HPC. The top plots show the granulation behavior of D10 (Figs. 3a and 4a), and the middle and bottom plots are for D50 (Figs. 3b and 4b) and D90 (Figs. 3c and 4c), respectively. As indicated in Figures 3 and 4, the average granule size for PVP K90 and HPC blends essentially remained unchanged with time. It is also shown in Figures 3 and 4 (Figs. 3b and 3c, and Figs. 4b and 4c) that some large granules initially formed (compared with that of physical mixture before being exposed to 96% RH—see Part II for some data) were actually broken down at higher impeller tip speeds (5.8 and 7.0 m/s), indicating that the granules initially formed were weak and then fragile when subjected to higher shear force. This granule fragmentation is particularly evident for the granules with HPC. In summary, viscous binders (PVP K17 and PVP K29/32) behaved differently under various shear forces compared with viscoelastic binders (PVP K90 and HPC); this can be attributed to the effect of binder rheological state. The large granules observed in Figures 3 and 4 probably formed during the initial exposure due to the adhesion between binder particles and the Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

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Figure 2. Granule size increase as a function of time for PVP K29/32 binder at three different tip-speeds: 4.2 m/s (), 5.8 m/s ( ), and 7.0 m/s ( ).



particles of other components as indicated by the size increase from powder mixture to exposed blends (data not shown here).7 This is because the PVP K90 and HPC binder were very viscous after exposure. However, these granules were not densified during granulation because of the viscoelastic nature of the binders. Porosity plays a key role in the granule performance in terms of compaction and dissolution behavior. In Figure 5, the cumulative pore volume is plotted against the pore size for the granules prepared with PVP K17, PVP K29/32, PVP K90, and HPC at all three impeller tip-speeds: 4.2, 5.8, and 7.0 m/s. The effect of impeller tip-speed on the porosity of the final granules is minimal. This is consistent with observations reported in the literature.13 However, when comparing the granules made with binders of viscoelastic state (Fig. 5a—PVP K90 and HPC) against viscous state (Fig. 5b—PVP K17 and PVP K29/32), a significant difference in porosity was observed in terms of the initial cumulative pore volume and the shape of the curve besides that the cumulative pore volume decreased much quicker for PVP k29/32 in the beginning. This indicates that the rheological state of binders can impact the properties of granules prepared. Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

DISCUSSION Literature Background and the Significance of this Work The fundamental research on granulation goes back to the pioneering work by Newitt, Conway-Jones, and Rumpf who described at a microscopic level the mathematical model of liquid bridging or capillary forces resulted from interfacial tension.14,15 In fact, the liquid content or saturation ratio in a granulation is responsible for controlling the formation of liquid bridges among particles and the resultant interfacial tension is the major force holding particles together. As for granule consolidation, Ouchiyama and Tanaka16 first generated their well-known model on granule consolidation with the following assumptions; granules were only held together by the capillary pressure of the binder solution, and the binder viscosity as well as particle detachment were not significant. The Ouchiyama– Tanaka16 model predicted that the consolidation rate was proportional to the impact energy and inversely proportional to the liquid surface tension. However, with the wide-spread usage of polymeric binders in the pharmaceutical industry, the effect of viscosity of binder solution cannot be ignored as interaction due to viscosity is much greater than capillary force from interfacial DOI 10.1002/jps.23750

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Figure 3. Granule size increase as a function of time for PVP K90 binder at three different tip-speeds: 4.2 m/s (), 5.8 m/s ( ), and 7.0 m/s ( ).

tension (Ca > 10−3 ). Litster and Ennis17 recognized this as a “viscous force” factor, representing the interaction of the chain entanglement of polymers, and they introduced “viscous Stoke number” (Stv ) (the ratio of kinetic energy to viscous dissipation) in their model for granule consolidation. According to Ennis’ model, the balance between the kinetics of colliding particle and viscous dissipation determines the granule growth—the rate of granule consolidation/coalescence.17,18 They predicted that the amount of consolidation per collision would increase according to: x = 1 − exp(−Stv ) (1) h where x and h are the reduction of distance between two particles and the surface thickness of the binder layer, and Stv is the viscous Stoke number which is expressed as: Stv =

8Dru 90

(2)

where D, r, u, and 0are the particle density, radius, velocity, and binder viscosity at the granule surface. The schematic for particle collision is shown in Figure 6.17 Ennis’ model predicts that DOI 10.1002/jps.23750

increasing the binder viscosity decreases the Stoke number– consolidation rate, and any increase in the impact energy increases the consolidation rate up to a certain point.18 Experimentally, the effect of impeller tip-speed on the granule growth (the rate of granule consolidation and coalescence) in high-shear wet granulation has been investigated by many authors.19 Typically, low viscosity binders such as glycerol and PEG 400, added in solution, were often used to investigate the granulation mechanism as reported in the literature.20 One of the challenges to understand granule consolidation for binder addition in solution is to separate the effect of impeller tip-speed on granule consolidation from other phenomena—the binder distribution, wetting, and nucleation. Consequently, it is difficult to identify the specific effect of impeller tip-speed just on granule consolidation. Furthermore, because it is impossible to measure the rheological state of binder in a granulation, the torque values of granulations are typically used to characterize the “rheological state” of the granulation to determine the process end point.21 Although this approach is practically useful, it will not clearly indicate how the rheological state of the binder affects the granule growth, specially, the granule Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

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Figure 4. Granule size increase as a function of time for HPC binder at three different tip-speeds: 4.2 m/s (), 5.8 m/s ( ), and 7.0 m/s ( ).

consolidation/coalescence. Moreover, because the in situ viscosity or rheological state of the binder at the granule surface is unknown, it cannot correlate with Ennis’ model prediction. In this paper, because the blends of API, lactose monohydrate, and a binder were preequilibrated to 96% RH, during which wetting for the binder and granule nucleation already occurred, granule consolidation can be investigated during subsequent operation mixing. As the rheological state of the binder was known after humidity exposure, which represented the binder rheological state at granule surface, it was reasonable to use Ennis’ model for qualitative prediction. With the binder rheological state well controlled, the effect of the impeller tip-speed on granule consolidation can be clearly characterized as discussed below. This is particularly interesting for granulations with a binder added in dry as the binder experiences various rheological states during water addition as reported before.7 Mechanistically, it is important to understand the effect of the binder state on granule consolidation under various tip-speeds as this Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

information is critical for both binder selection and process control. Effect of Binder Rheological State The rheological state of a binder plays a significant role in a granulation process and this was demonstrated by the results presented in Part 3.8 As stated before, the effect of the physical properties of binders on the granulation has been investigated by many authors; typically, the viscosity of a binder solution is measured before addition.19 However, the rheological properties of the binder such as viscosity or viscoelastic properties in the granulation are different from that of the binder solution before the addition. For granulations with the binder added in dry, the rheological state of the binder varies with amount of water added. As the results show in Figures 1 and 2, the increase of viscosity from PVP K17 to PVP K29/32 (see Table 2) after exposure caused a significant decrease in the DOI 10.1002/jps.23750

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Figure 5. (a) Cumulative pore volume versus pore size for granules with binders of PVP K90 and HPC at three different impeller tip-speeds (from bottom to top: HPC at 5.8 m/s, HPC at 7.0 m/s, HPC at 4.2 m/s, PVP K90 at 4.2 m/s, PVP K90 at 5.8 m/s, and PVP K90 at 7.0 m/s). (b) Cumulative pore volume versus pore size for granules with binders of PVP K17 and K29/32 at three different impeller tip-speeds (from bottom to top: PVP K29/32 at 5.8 m/s, PVP K29/32 at 7.0 m/s, PVP K29/32 at 4.2 m/s, PVP K17 at 5.8 m/s, PVP K17 at 4.2 m/s, and PVP K17 at 7 m/s). (c) Cumulative pore volume of granules made with four binders at the tip-speed of 5.8 m/s.

Figure 6. The diagram showing two granules colliding-the basis for the coalescence/rebound criteria where h and ha represent the thickness of surface layer and the thickness of surface roughness (asperities).

rate of granule growth, although the granules made with these two binders have similar final porosity values. At the molecular level, the viscosity or the rheological properties of a binder is closely related to the molecular weight of the binder polymer and its chemical structure. Typically, viscosity value increases with molecular weight for polymers of the same chemical composition. On the basis of the entanglement theory, the polymers DOI 10.1002/jps.23750

of high molecular weight are entangled in solution, which consequently affects the viscoelastic properties of the solution.22 On the basis of its molecular weight, PVP K29/32 is on the verge of forming entanglement.7 With further increase of PVP molecular weight (such as the case of PVP K90), the binder became viscoelastic after exposure (as indicated in Table 2), suggesting the formation of entanglement. Because of the viscoelastic nature of PVP K90, nonflowable under mixing, the granulations containing PVP K90 were insensitive to the impeller tip speed change (as indicated in Fig. 3). In contrast, some large particles were believed to break down at a higher impeller tip speed (7.0 m/s). As seen in Table 2, PVP K90 is fairly elastic after being exposed to 96% RH because of its high storage modulus (3452 Pa). This indicates that PVP K90 particles may remain as “soft particles” in the granulations after exposure, which did not flow upon mixing. This also explains why granules made with PVP K90 have higher porosity as the “soft gel-like binder particle” between the granules created many voids. A similar trend was observed for the granulations with HPC as HPC also exhibited elastic behavior (storage modulus: 430 Pa) after the humidity exposure. The difference between PVP K90 and HPC is that HPC binder is less viscous and less elastic than PVP Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

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K90 after exposure, as shown in Table 2. This is also reflected in their granulation behavior and the final granule porosity. As shown in Figures 4 and 5, the granules made with HPC are generally smaller in size and less porous compared with PVP K90. In summary, granulation behavior varied significantly as the rheological state of the binder changed from viscous to viscoleastic and the porosity of the final granules mainly depends on the rheological state of the binder.

but not the final granule properties. This is consistent with the fact that both the final granule size distribution and granule porosity under different tip-speeds were all comparable for a given blend. In other words, the impeller tip-speeds in a certain range can affect the rate of consolidation, but they will not change the final granule porosity, which is determined by the rheological state of binders in the granulation. This was also demonstrated by other systems in the literature.23 Analysis Based on Ennis’ Model

Effect of Impeller-Speed Impeller tip-speed plays a significant role in granulation process and process scaleup. As reported in the literature, particle velocity in a granulation which affects granule collision is, in general, proportional to the impeller tip-speed assuming that flow pattern change is not altered.21 In this study, there was no flow pattern change observed as the impeller tip-speed increased from 4.2 to 7.0 m/s. Therefore, the following discussion will focus on the effect of the increase of particle kinetic energy, as resulted from the increase of the impeller tip-speed, on the rate of consolidation. Logically, a lower impeller tip-speed generates a lower shear force and produces less impact energy, which probably results in a fewer successful collision. So, it takes longer time for granules to grow with a lower impeller tip-speed. With the impeller tip-speed increased from 4.2 to 5.8 and 7.0 m/s, the collision frequency among particles increased and so did the impact energy. Consequently, the rate of consolidation increased for the granulations of PVP K17 and PVP K29/32 (viscous dissipation dominant). However, it was also observed that the consolidation rate remained unchanged as the impeller tip-speed increased from 5.8 to 7.0 m/s, suggesting that any increasing collision frequency and impact energy beyond that of 5.8 m/s did not result in granule formation. This is rather interesting as further increase of kinetic energy input did not seems to benefit granulation for these systems. It was also noted that for the granulations of PVP K17 and PVP K29/32, the impact of the impeller tip-speed on the granule growth was very similar, with 5.8 m/s being the critical impeller tip-speed. This can be attributed to the collision regime change based on Ennis’ model, which will be discussed in detail in the following section. However, as shown in Figures 1 and 2, at the same impeller tip-speed, the granulation of PVP K29/32 exhibited a slower granule growth. The possible explanation can be that because of its higher viscosity, the PVP K29/32 binder solution flows at a slower rate at the given impeller tip-speeds (4.2 and 5.8 m/s); especially the mobility of PVP K29/32 in the microenvironment of the granulations is lower compared with that of PVP K17. The impact of impeller tip-speeds on the granulations with PVP K90 and HPC are minimal. Although it was observed that the blends of PVP K90 and HPC exhibited granule size increase immediately after exposure in comparison with their powder blends, it is evident that blending did not cause further granule growth. The reason could be that the shear-force generated by the impeller rotation was not strong enough to deform these polymers, and therefore, there was not much intimate contact created between particles because of mixing. As for the impact of the impeller tip-speed on the porosity of granules, it appears that the granules produced using different impeller tip-speeds reached similar porosity values at the end of granulation.11,13 This suggests that for a given binder rheological states, impeller tip-speeds mostly impact the kinetics Li et al., JOURNAL OF PHARMACEUTICAL SCIENCES 102:4384–4394, 2013

According to Rumpf’s theory, surface tension plays a critical role for low viscosity binders such as water and glycerol in a high-shear wet granulation process.14,20 In pharmaceutical applications where polymeric binders are typically used, the viscous force from chain entanglement (viscous force) becomes dominant. Based on Ennis’ model, the viscous force dominates over capillary pressure when Ca is greater than 10−3 (Ca is U0/(), where U is the speed of particles, and 0 and ( are the in situ viscosity and surface tension of the binder liquid. For granulations with polymeric binders, in general, the viscous force is significant as the viscosity of polymeric solutions is typically high. In this case, the model devised by Litster and Ennis17 is more suitable for discussion. As mentioned, the critical term in Ennis’ model is the “viscous Stoke number”, Stv , (see Equation (2); the key relation in this model is the value of Stv relative to that of the critical viscous Stoke number, Stv * . Stv * is defined as:     hb 1 ln St∗ = 1 + er ha

(3)

where er , hb , and ha are the coefficient of restitution, liquid layer thickness, and height of surface asperities. Granules grow when Stv is less than St* , which is called noninertia regime. When Stv is equal to or greater than St* , granules stop growing; these regions are termed inertia or coating regimes. Stv can be decreased by increasing the viscosity of the binder solution or decreasing particle collision. However, the modification of the binder viscosity also changes the value of St* . In this paper, the results indicated that the granulations with PVP K17 and PVP K29/32 might operate in noninertia regime (granule growth) when the tip-speed of impeller is equal to or less than 5.8 m/s. At the tip-speed of 4.2 m/s, the growth rate is slower compared with 5.8 and 7.0 m/s primarily because the collision velocity or frequency of particle collision at the microlevel is probably lower. It was interesting to observe that the growth rate remained the same when the tip-speed increased from 5.8 to 7.0 m/s. In other words, the efficiency of coalescence was unchanged as the collision velocity increased. This may indicate a transition from noninertia regime to inertia/coating regimes as the tip-speed increased from 5.8 to 7.0 m/s, which needs to be further verified. Comparing the granulation of PVP K17 with that of PVP K29/32, it is evident that the granule growth rate of the latter is lower. This is interesting because at the same “collision velocity,” the higher viscosity of PVP K29/32 should give a lower Stv if other factors remain constant, and according to Ennis’ model, consolidation rate should be lower. The results for the granulations of PVP K29/32 at all three tipspeeds supported this prediction. This can be also explained by the fact that the granulations of PVP K17 and PVP K29/32 are both in the granule growth regime, but dynamically the particles in the granulations of PVP K17 interact more frequently DOI 10.1002/jps.23750

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than those in the granulations with PVP K29/32 because of the fact that PVP K17 is less viscous. A similar explanation was given by Ennis et al.12 in their paper, which was referred as “bed hydrodynamics.” In other words, the “true collision velocity” at the microlevel also depends on the in situ binder viscosity. Furthermore, when binders are in viscoelastic states such as HPC and PVP K90, the model by Ennis et al. is not applicable anymore as only viscous dissipation was considered in the model. The granule deformation was considered in the modified version of the model, but it assumed that collided granules came to surface contact.23 Further study needs to be carried out to verify these models. Implications in Practice To manufacture pharmaceutical products through high-shear wet granulation, binder is one of the most important formulation components. Regarding process control, the water content in a granulation is one of the critical parameters to control both processes end-point and product quality.24,25 More specifically, for a particular granulation, the optimum liquid content is related to the binder used. On the basis of the results presented in this paper, the granulation process and the resulting microstructure of granules depend on the rheological state of the polymeric binder used, which is determined by the molecular weight of the binder and its water content. The rate of water addition and the absorption of water by the binder polymer control the transition of the binder rheological state during granulation. Therefore, the granulation process also depends on the rate of water addition and the hydrophilic properties of the binder. As expected, the granulation with a polymeric binder of higher molecular weight, such as PVP K90, takes more time to reach the same end-point in comparison with PVP K17 (low molecular weight). This is because higher molecular weight polymeric binders require more water to change from a glassy state to a viscous/solution state and binders with high viscosity needs more energy and time to deform or flow. If the granulation occurs when the binder is in or close its viscoelastic state, the resulting granules will be more porous. In other words, granulations with binders such as HPC or PVP K90 that transit from glassy state through viscoelastic state to viscous/solution state will occur at a later time point in a granulation process and the end products may have different properties. In terms of the process end-point control, this can be beneficial as the granulation will not have a sharp end-point. Another important process parameter is the impeller tipspeed. As indicated by the results from this study, the impact of the impeller tip-speed on granule growth depends on the rheological state of the binder used. For the granulations containing viscous binders, an increase in the impeller tip-speed can shorten the granulation time. An increase of the impeller tip-speed will not always benefit the granulation process. As shown in the literature, high impeller tip-speed can cause granule breakage and attrition. Therefore, optimization of the impeller tip-speed based on formulation properties is needed for process control.

CONCLUSIONS The results indicate that the impact of the impeller tip-speed (shear force) on the rate of granule growth is coupled with the rheological state of the binder used in a granulation. When the DOI 10.1002/jps.23750

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binder is in its viscous state, it readily deforms, and therefore flows well under mixing. Consequently, the impact of the impeller tip-speed is significant; as shown in this paper for the granulations of PVP K17 and PVP K29/32. When the binder is in its viscoelastic state, the impact of the impeller tip-speed is minimal. This is because the gel-like soft particles of the binder are fairly elastic, and they do not deform and flow under the shearing force caused by impeller mixing. Therefore, further contacting opportunities between the particles of the binder and the particles of other components due to mixing are significantly reduced so that the binder cannot adhere to drug or excipients. The porosity of the final granules depends on the rheological state of the binder rather than the impeller tip-speed. When the binder is in the desired rheological state, whether viscous or viscoelastic, the effect of the impeller tipspeed on granule porosity is minimal; the porosity of the final granules is comparable regardless of the impeller tip-speed used. However, the rheological state can significantly affect the final porosity of granules; the granules with the binder in its viscoelastic state appear to be more porous than those with a binder in its viscous state. In addition, the impact of an impeller tip-speed on granule growth can be explained based on Ennis’ model for granulations with viscous binders. As the tip-speed increases from 4.2 to 5.8 m/s, granule growth increases predominantly because of the fact that impact energy is increased. With further increase of the tip-speed to 7.0 m/s, the granule growth curve remained unchanged. This phenomenon can be explained using Ennis’ argument that the increase of the impeller tip-speed may shift the granulation from the noninertial regime to the inertial regime. Consistent with Ennis’s model, the granule growth slows down when a more viscous binder is used. As we know from polymer science, the rheological state of a polymeric binder is controlled by the molecular weight and the water content as well as the chemical nature of the polymer. In practice, the rheological state of the polymeric binder should be considered in terms of selection of a binder for all formulations.

ACKNOWLEDGMENTS The authors would like to thank the management of the Drug Product Science and Technology department at BMS for support and Dr. Munir Hussain of Scientific Council at BMS for encouragement.

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DOI 10.1002/jps.23750