Scholarly article on topic 'Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry'

Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry Academic research paper on "Chemical engineering"

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Saudi Pharmaceutical Journal
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{"Wet granulation" / "Torque rheometry" / Binder / Excipient / Pellets}

Abstract of research paper on Chemical engineering, author of scientific article — Walid F. Sakr, Mohamed A. Ibrahim, Fars K. Alanazi, Adel A. Sakr

Abstract With over 50years of research in granulation technology, however more research is required to elucidate this widely applicable technology. Wetting phenomena could influence redistribution of individual ingredients within a granule according their solubility and also could affect the drying processes. Binder selection for a particular system is quite often empirical and dependent on the skills and experience of the formulator. Hand squeeze test was and still the main way for determination of wet granulation end point, but it is subjected to individual variation. It depends mainly on operator experience, so it is not possible to be validated. Literature reveals a variety of advanced monitoring techniques following up different wet massing stages. Torque measurement has been proved to be the most reliable control method as its tight relation to mass resistance. Many reports showed successful applications of mixing torque rheometer (MTR) for monitoring the wet massing procedure and scale up in addition to some preformulation applications. MTR as a new approach allows formulators to select a liquid addition range where the granule growth behavior is more predictable.

Academic research paper on topic "Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry"

Saudi Pharmaceutical Journal (2012) 20, 9-19

King Saud University Saudi Pharmaceutical Journal


Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry

Walid F. Sakr, Mohamed A. Ibrahim, Fars K. Alanazi *, Adel A. Sakr

Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia Kayyali Chair for Pharmaceutical Industry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia Center of Excellence in Biotechnology Research, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia

Received 8 March 2011; accepted 30 April 2011 Available online 7 May 2011


Wet granulation; Torque rheometry; Binder; Excipient; Pellets

Abstract With over 50 years of research in granulation technology, however more research is required to elucidate this widely applicable technology. Wetting phenomena could influence redistribution of individual ingredients within a granule according their solubility and also could affect the drying processes. Binder selection for a particular system is quite often empirical and dependent on the skills and experience of the formulator. Hand squeeze test was and still the main way for determination of wet granulation end point, but it is subjected to individual variation. It depends mainly on operator experience, so it is not possible to be validated. Literature reveals a variety of advanced monitoring techniques following up different wet massing stages. Torque measurement has been proved to be the most reliable control method as its tight relation to mass resistance. Many reports showed successful applications of mixing torque rheometer (MTR) for monitoring the wet massing procedure and scale up in addition to some preformulation applications. MTR as a new approach allows formulators to select a liquid addition range where the granule growth behavior is more predictable.

© 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

* Corresponding author. Tel.: +966 503265669; fax: +966 146 762 95.

E-mail address: (F.K. Alanazi).

1319-0164 © 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

Peer review under responsibility of King Saud University. doi:10.1016/j.jsps.2011.04.007


1. Granulation........................................................................................................................................................10

2. Wet granulation..................................................................................................................................................10

3. Different stages of wet granulation........................................................................................................................10

4. Granules voidage and porosity..............................................................................................................................10

5. Binder solutions as granulating agents....................................................................................................................11

5.1. Spreading efficiency...................................................................11

5.2. Viscosity and surface tension............................................................11

5.3. Solvent nature......................................................................11

6. Solid excipient characteristics................................................................................................................................11

6.1. Particle size........................................................................11

6.2. Solubility of solid excipient.............................................................12

7. Mixing torque rheometer (MTR)..........................................................................................................................12

7.1. MTR as pre-formulation tool...........................................................13

7.2. Effect of instrument properties...........................................................14

7.3. Effect of blade orientation..............................................................14

7.4. Effect of mixing time ..................................................................................................................................14

8. Prediction of pellets'quality in extrusion-spheronization........................................................................................15

9. Effect of excipient source variation........................................................................................................................15

10. Quantifying binder characteristics..........................................................................................................................16

11. MTR as scale-up tool in wet granulation................................................................................................................16

12. Conclusion..........................................................................................................................................................17

References ..........................................................................................................................................................17

1. Granulation

Owing to their wide variation in physicochemical and mechanical properties, pharmaceutical powders frequently exhibit poor flowability and compactability (Krycer et al., 1983). Granulation is a unit operation in which fine powders are transformed into granules to improve appearance, flow properties and mixing uniformity, reduce dustiness and, in general, produce engineered particles with enhanced attributes (Gabriel, 2005; Shangraw and Demarest, 1993). In the granulation process the original particles can still be distinguished and may recover when disintegration takes place (Ennis and Lit-ster, 1997).

Granulation is applicable in a wide variety of industries including mineral processing, agricultural products, detergents, pharmaceuticals, foodstuffs and chemicals. In the chemical industry alone it has been estimated that over 60% of products are manufactured as particulates (Ennis et al., 2004).

With over 50 years of research in granulation technology, however more research is required to elucidate this widely applicable technology. Some of the earliest pioneering work was performed by Newit and Conway-Jones (1958), Capes and Danckwerts (1965) and Capes (1980) using sand in drum granulators. Since then, a breakthrough has been started for studying materials ranging from minerals to pharmaceuticals, granulated in equipment ranging from fluidized beds to high shear mixers.

2. Wet granulation

Wet granulation is a way for size enlargement which involves any process whereby small particles are agglomerated into larger, relatively permanent structures with the aid of liquid binder. The wet granulation process must generally achieve the

desired granule properties intended for specific purposes (Lit-ster and Ennis, 2004). Granule voidage controls strength, and controls capsule and tablet dissolution behavior, as well as compaction behavior and tablet hardness (Iveson et al., 1996). If the wet granulation product is pellets, so sphericity is an important issue for adequate coating purposes.

3. Different stages of wet granulation

Generally four mechanisms are included in granulation mechanisms, as primarily shown by Ennis and Litster (1997) and later developed further by Litster and Ennis (2004). These mechanisms are wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage. Granulation can retain a memory about the nuclei size distribution impacting final granule size distribution. Therefore, initial wetting is a critical step towards uniform nuclei formation and enhanced product quality. It has been shown that wide nuclei distributions can lead to a wide granule size distribution. Wetting phenomena could also influence redistribution of individual ingredients within a granule according their solubility and also could affect the drying processes (Ennis and Litster, 1997).

4. Granules voidage and porosity

Granule voidage is an expression indicating free spaces between granules while porosity indicating the voidage inside the granule itself (Ennis et al., 2004). Increased granule voidage and/or porosity impart increased dissolution rate and shorter disintegration time of the final product.

According to saturation state of interparticle voidage with liquid binder, different states of wet massing might exist. The primary pores filling have been defined as pendular state

(single bridges). Upon further saturation results in an interpar-ticle force, indicated as funicular (partially complete filling with single bridges) followed by capillary state (nearly complete filling with multiple bridges) at which saturation is about 80-100%. Loss of wet mass torque is achieved when over wetting arise and is known as drop phase.

Granule growth starts when there is coalescence of existing granules as well as the layering of fine powder onto previously formed nuclei or granules. As granules grow by coalescence, they are simultaneously compacted by consolidation mechanisms, which in turn reduce internal granule voidage and/or porosity (Kapur and Fuerstenau, 1966).

One of the most important parameters affecting granule characteristics and size distribution is binder viscosity. Variation of binder viscosity could be achieved by either formulation changes (e.g., the type or concentration of binder) or by changes in operating temperature.

5. Binder solutions as granulating agents

Binders are polymers which act as the glue connecting particles together which may be natural polymers, synthetic polymers, or sugars. Binder selection for a particular system is quite often empirical and dependent on the skills and experience of the formulator. Type and concentration of binder system are the main variables controlling the desired product quality such as granule friability, tablet friability, hardness, disintegration time, and the drug dissolution rate (Sakr et al., 2011).

5.1. Spreading efficiency

Spreading efficiency of binder solution between solid particles is the main controlling factor in wetting and granulation. Some publications showed that dense non-friable granules are produced when the spreading coefficient of binder over substrate is positive while negative spreading coefficient leads to the formation of porous granules (Rowe, 1990).

It has been shown that polyvinylpyrrolidone (PVP) is more efficient than hydroxypropyl methylcellulose (HPMC) due to the lower work of cohesion and adhesion of the latter. It could be also attributed to the better adhesion of PVP especially to hydrophilic surfaces (Planinsek et al., 2000; Rowe, 1990).

5.2. Viscosity and surface tension

Solid particles collision occurs mainly during mixing or compaction while they are subjected to the shearing force due to agitation (Fig. 1). The results of collision may be sticking of

particles together or getting apart (Hoornaert et al., 1998). Collision energy that keeps the colliding particles together include surface tension as well as viscous and interparticle friction forces (Iveson et al., 1996; Iveson and Lister, 1998b). It was found that increasing binder solution viscosity could lead to increased granule size and decreased amount of binder required to initiate granule growth in both high-shear (Hoornaert et al., 1998) and fluid-bed (Ennis and Litster, 1997) granulation processes. At higher concentrations of the binder solution or when viscosity is very high, other variables could be inversely affected such as binder spreading and distribution arise. It has been shown that surface tension of the binder solution has a role in torque value of the wet mass monitored using MTR (Parker et al., 1991). Reducing binder solution surface tension was also reported to decrease the liquid requirement to reach the maximum torque (Pepin et al., 2001). This may be due to decrease in the capillary suction pressure and friction resistance leading to improved wettability and spreading efficiency (Iveson and Litster, 1998a).

5.3. Solvent nature

The granulating solvent is one of the most important variables which could significantly change granule properties. This change may be due to inherited excipient properties such as solubility and wettability, as well as the mechanism of granule consolidation. Recent federal specifications concerning the pharmaceutical industry permit only water, alcoholic or hydro-alcoholic solvent systems. Alcoholic PVP solution Lactose granulations was shown to produce lactose granules with higher porosity and friability compared to those prepared using water as a granulating solvent (Wikberg and Alderborn, 1993). Increasing the ethanol content in hydroalcoholic solvent systems of granulating solutions has been shown to increase tablet strength (Wikberg and Alderborn, 1993). This may be due to increased fragmentation tendency of granules increased with ethanol content (Alderborn, 1988). Selection of solvent system is of prime importance because it could affect the formulation wettability and binder distribution. For example, PVP distribution in low-shear mixers was improved when water was replaced with a hydroalcoholic solution (Shah et al., 1996).

6. Solid excipient characteristics

6.1. Particle size

Drug or excipient particle size can affect granule strength, porosity, and consolidation rate granulation. Formation of

Figure 1 Schematic diagram of solid-binder arrangements and the shearing effect of the mixing blades, modified from (Parker et al., 1990a).

stronger granules was achieved when smaller particles with higher surface areas were used that may be due to availability of more contact points between colliding particles (Van-den and Vromans, 2002). It should be also noted that the solvent and binder requirements increase as the primary particle size decreases due to increased surface area (Schaefer et al., 1990). It has been shown that at the same binder and solvent level, excipient with larger particle sizes consolidates more easily and produce less porous granules as compared to finer particles (Iveson et al., 1996; Iveson and Litster, 1998a; Iveson and Litster, 1998b). Using drug of smaller particle sizes than filler has lead to the larger granule size fractions which exhibited the highest drug content and when the drug particles were larger, the highest drug concentration was found in the smallest granule size fraction (Vromans et al., 1999).

6.2. Solubility of solid excipient

Figure 2 Hand squeeze test for wet granulation end point determination.

Solubility of the solid fraction of formulation in the granulating solvent can significantly affect the granules' characteristics. Changing the formulation composition of water-soluble excipient can potentially alter the granules' properties. Solubility of the solid excipient in the granulating solvent was found to decrease the solvent requirement and produced granules of uniform particle size distribution with reduced friability (Dias and Pinto, 2002). It has been found that lactose-based granules were formed at a lower degree of water saturation when compared to other insoluble excipient such as dicalcium phosphate and calcium hydrogen phosphate (Kristensen et al., 1984, Kristensen and Schaefer, 1987; Schaefer et al., 1986). This may be due to the increased plasticity of the moist lactose agglomerates owing to its partial water solubility which in turn enhance particle coalescence and growth granulation processes. It has been shown that lactose is less sensitive to moisture content and sheering stress than calcium hydrogen phosphate upon granulation (Holm et al., 1983).

Using PVP solution as granulating agent, it has been found that addition of microcrystalline cellulose (MCC) as insoluble excipient to a lactose-based formulation led to increase in solvent requirement and produced larger granules (Rohera and Zahir, 1993). Smaller granules with a wider particle size distribution were produced when the starch content in lactose: starch-based formulation was increased (Holm et al., 2001). This may be due to the water absorption capacity of starch and the formation of weaker granules that are not able to grow in size to the same extent as when starch was absent (Holm, 1987).

Degree of drug solubility in the binder solution could affect its distribution in different granule size fractions. It was found that drugs with high solubility in the binder solution exhibited migration during drying process leading to higher drug concentration at the outer granular surfaces. High drug concentrations in fines relative to larger granules will appear with subsequent processing due to abrasion and crusts' detachments (Van-den and Vromans, 2002).

7. Mixing torque rheometer (MTR)

Hand squeeze test (Fig. 2) was and still the main way for determination of granulation end point in wet massing but it is subjected to individual variation depending mainly on operator

^^ Maximum Torque ^

^^ Optimum binder ratio

0.5 1.0

Binder Ratio (ml/g)

Figure 3 MTR curve showing the relation between binder ratio (ml/g) and the mean line torque (Nm) with correlation to different wetting phases (a) pendular phase (b) funicular phase, (c) capillary phase and (d) droplet phase.

experience so it is not possible to be validated (Soh et al., 2006). Granulation end point is tightly related to product quality.

The agglomerate growth in wet granulation processes depend mainly on rheology of the wet powder mass, as an adequate consistency is necessary for a controllable coalescence and growth of smaller agglomerates into larger agglomerates. Literature reveals a variety of advanced monitoring techniques following up wet massing stages. Some of them are electrical methods such as ammeters which depend on power consumption and electrical conductivity (Bier et al., 1979; Holm et al., 1985), machine measures the change in torque values (Lindberg et al., 1982), or depending on mass properties such as temperature changes (Holm et al., 1985), moisture content (Fry et al., 1984) and probes inserted into the wet mass (Kay and Record, 1978; Staniforth et al., 1986).

Torque measurement has been proved (Kristensen and Schaefer, 1987), to be the most reliable control method due to its correlation with the different stages of wet massing. Measurement of torque inside mixing bowl is the most accurate torque technique, rather than measuring the torque on the

Pendular Funicular Capillary Droplet

Figure 4 Phases of solid-binder interactions according the degree of binder spreading as modified from (Iveson et al., 2001).

shafts of the blades, because the bowl is generally stationary, and eliminates the frictional effects due to the force driving the blades.

The rheological changes during the wet massing of micro-crystalline cellulose (MCC) were successfully monitored using the MTR (Rowe and Sadeghnejad, 1987). Their results showed high correlation between the observed rheological behavior, binder physical characteristics, such as viscosity and surface tension, and proposed binder-substrate interactions.

Two different parameters are measured using the mixer torque rheometer (Fig. 3). These are the mean line torque increase from the baseline (mean torque) and the volume of binder solution in relation to the solid mass (binder ratio). The mean line torque describes the mass resistance to mixing (York and Rowe, 1994). Four phases of liquid-solid interactions are characterized during wet massing (Fig. 4). Changes in torque profiles obtained from MTR have been related to the different phases of liquid saturation of the wet mass (Rowe and Sadeghnejad, 1987; Hancock, 1991). When moisture content increases, the torque will rise as the liquid saturation goes through the pendular and the funicular phase. A maximum torque will be reached when complete liquid saturation is attained to be known as the capillary phase (Hancock et al., 1994). Any further increase in the amount of liquid content results in the formation of a slurry causing a fall in torque and known as droplet phase.

Evaluation of binder physical properties to predict the influence of the binder on the granulation process and final granule properties were developed to elucidate the detailed molecular interactions. This evaluation is of prime importance to achieve accurate control of the wet granulation process. MTR as a preformulation tool has been successfully used to follow up the changes in rheological behavior which occur when change from one binder solutions to another comparing results to water (Hancock et al., 1992). Different polymers' behaviors were noticed with marked changes in torque values along over the wet massing steps.

Binder-substrate interactions under influence of binder physical properties have been used successfully to explain the observed rheological behavior. Comparing the predicted and observed data was a way to investigate solid-liquid interactions and governing the rheological behavior during wet massing aiming to predict final product performance (Parker et al., 1990b).

Using MTR has been as a tool for predicting agglomeration properties of wet masses in other mixers. The amount of liquid binder added at the maximum torque was found to be comparable with that found for the optimum production of pellets by spheronization (Rowe and Sadeghnejad, 1987; Souto et al., 1998). Other investigators showed that pharmaceutical gran-

ules were indicated to be formed at binder immediately prior to the torque maximum (Hancock, 1991).

Some publications showed the use of MTR to examine the effect of mixing time on the wet mass rheology (Parker et al., 1990a). Batch variations in a pharmaceutical production were successfully examined by the MTR depending on the rheolog-ical properties of wet samples drawn from mixer granulators at different time intervals (Janin et al., 1990). Hot melt agglomeration experiments have been performed in a high shear mixer with polyethylene glycols with successful monitoring with MTR (Schaefer and Mathiesen, 1996a,b).

7.1. MTR as pre-formulation tool

Literature reveals many reports about the successful applications of MTR for monitoring the wet massing procedure (water content optimization). The water content in the formulation has to be tightly controlled for adequate pellet size uniformity (Holm, 1996; Vertommen et al., 1998). It is therefore advantageous to establish an end-point controller which enables the formulation to reach optimal water content and in turn produce spherical pellets of a desired size with a narrow range of distribution.

In some cases, water is used entirely as the binder liquid or in most cases as binder solvent. Over estimating the optimum binder ratio will lead to higher water content in the formulation, which resulted in larger agglomerates (Kristensen et al., 2000, Heng et al., 1996; Wan et al., 1994). In addition, the size distribution of pellets produced in a rotary processor seems to depend on the type of equipment. It might be either increased (Fielden et al., 1992) or decreased (Heng et al., 1996) when more binder liquid was added.

Agglomerate growth by coalescence depends on the plasticity and deformability of the wet mass, in other words, the rhe-ological properties of the mass. Because the torque of a rotating blades or impellers depends on the rheological properties of the mass and its resistance, there is generally supposed to be a correlation between change in torque (DTq) and agglomerate growth. The use of DTq for endpoint control is assumed, therefore, to be also suitable for different formulations and for other types of fluidized bed rotor granulators, as well as mixer granulators (Kristensen et al., 2000).

MTR was used to test the torque profile of a model formulation as a function of water addition levels to understand whether the granule growth behavior is consistent with the liquid saturation states (Wang et al., 2005). Six water levels representing a range of liquid saturation states on the torque profile were selected to produce granules in the MTR. Torque values of the wet granules were measured by the MTR at four different mixing times. Little or no granule growth and densi-

I J l<

Figure 5 Mixing chamber inside mixer torque rheometer showing the rotating blades direction modified from (Luukkonen et al., 1999).

fication were found at a water level corresponding to the pendular liquid saturation state on the torque profile. Granule hyper-growth and significant granule densification were found at water levels corresponding to the capillary and droplet states. In the regime between funicular and capillary state, granule growth was more moderate and could be influenced by adjusting the water addition level. It was concluded that liquid addition level has significant impact on the wet and dry granule properties. Boundaries of liquid addition levels that represent low and hyper granule growth regions can be defined by utilizing the MTR. Assessment of granule growth correlated with the purported liquid saturation states indicated by the MTR. This approach allows formulators to select a liquid addition range where the granule growth behavior is more predictable.

7.2. Effect of instrument properties

Hancock (1991) used two laboratory-scale instrumented mixer torque rheometers to monitor the rheological behavior of a model wet mass. The two instruments differed in the arrangement and gearing of their mixing blades and the results obtained from each were not identical. In both rheometers liquid distribution was identified as being responsible for the initial variation in the rheology of the wet mass and the mechanism of that distribution process depended upon the level of liquid saturation. The rate of liquid distribution was different in each of the two rheometers and this has been attributed to the different mixing intensities of the two instruments. Equilibrium data showed similar trends, thus indicating a means by which different mixing processes could be compared. A cumulative energy of mixing term was derived to describe the energy input during the mixing process. Also, Parker et al. (1990a,b, 1991) used a laboratory scale MTR (Fig. 5) to examine the interactions of microcrystalline cellulose with aqueous solutions of two polymeric binders (PVP and HPMC). The rheo-logical behavior indicated differences, at equivalent viscosity, between the two polymers, which were explained by theories relating binder surface tension to granule properties. The measured surface tension values were then used to calculate the surface free energies, interfacial works of cohesion and adhesion and spreading coefficients for the interaction between the materials used in this study. These data indicated a different degree of interaction between the two polymers and the cellulose substrate, which was probed further using a series of experiments to examine polymer adsorption phenomena.

Figure 6 Mixing blades inside MTR showing different geometry for optimum miximg.

These combined data were used to propose a pattern of behavior based on consideration of 'intra-granular viscosity' which helped to explain the observed rheological behavior.

The rheological properties of a range of model and typical pharmaceutical wet massed systems were monitored using MTR (Hancock et al., 1992). The mixing torque was monitored as a function of the mixing time from the point of liquid addition until the equilibrium rheological state had been attained. In each system the mechanisms and kinetics of mixing varied according to the saturation of the wet mass and the identity of the substrate and binder components. Although the torque variation was different for each wet massed system an equilibrium rheological state was eventually attained in each case. Measurement of this equilibrium torque response should allow the comparison of different wet masses irrespective of their processing history.

7.3. Effect of blade orientation

A commercial mixer torque rheometer has been used to investigate the effect of blade orientation on the two contra-rotating shafts (Rowe, 1996a,b). The mixing blades inside MTR mixer have a special geometric shape for efficient mixing (Fig. 6). Experiments have been performed on a model wet mass consisting of microcrystalline cellulose and water. Blade orientation has significant effects on the measured torque responses with respect to water contents well as on the yield stresses and kinematic viscosities calculated by applying the Casson model to mean torque values obtained on testing specific pre-mixed wet masses. It is essential that blade orientation be kept constant if different wet masses are to be directly compared as in batch monitoring or scale-up.

7.4. Effect of mixing time

Formulators have recognized for many years that mixing time is a critical factor in the granulation process. This has become particularly important with the new generation of high shear mixers that are now available where the variation of a few seconds in mixing time can make the difference between a useable granule and an unusable overworked wet mass. The MTR could be used to estimate the optimum mixing time for wet

massing as well as to examine the effect of mixing time on the rheology of wet masses. The rheological behavior of the wet masses of silicified MCC (Prosolv) and plain MCC was studied as a function of mixing time using MTR (Luukkonen et al., 1999). The study indicated a difference in the mixing time inside the MTR that should be taken into consideration while wet massing especially on large scale.

8. Prediction of pellets' quality in extrusion-spheronization

Although Rowe and Sadeghnejad (1987) studied the rheologi-cal profiles of microcrystalline/water mixes and showed differences between the MCC grades, it was not extended to illustrate the impact of this variation to other pharmaceutical processes such as tableting and pelletization. In fact, limited work has been carried out to evaluate the usefulness of torque measurements in predicting the performance of a wide range of commercially available MCC grades in the process of making spherical pellets.

A strong correlation was observed between the torque parameters of MCC grades and the properties of their pellets (flow, friability, bulk and tapped densities) formed with 30 and 35% (w/w) water (Soh et al., 2006). Since this relationship was valid over broad water content range, rheological assessment for pre-formulation purposes need not be performed at optimized water contents. These results demonstrated the usefulness of torque rheometry as an effective means of comparing and evaluating MCC grades especially when substitution of equivalent grades is encountered. In so doing, the tedious and expensive pre-production (pre-formulation and optimization) work can be considerably reduced.

In recent study (Mahrous et al., 2010), different hydrophilic polymers were mixed with avicel PH-101 to prepare sustained release matrix pellets loaded with indomethacin. In order to establish the massing binder ratio needed to reach an equilibrium torque response, wet massing experiments were performed on avicel. The results revealed that increasing the weight ratio of polyethylene glycol (PEG) was accompanied by a significant reduction of the peak torque magnitude. In the other study by Kristensen et al. (2000), it was found a linear correlation between the torque value and pellet size for the formulations containing 80% (w/w) MCC. They observed that increasing torque values led to higher water content and larger pellet size for both formulations. Furthermore, the size distribution of pellets produced was found to decrease when more binder liquid was added as recorded with Heng et al. (1996).

As mentioned previously, microcrystalline cellulose (MCC) is undoubtedly the most widely used excipient in pellet production by extrusion-spheronization. Its capacity to retain very large quantities of water internally means that wet masses made with MCCs have rheological properties that are very suitable for extrusion-spheronization. However, drug release from MCC extrusion-spheronization pellets is for some drugs very slow, particularly for drugs with low water solubility (Pinto et al., 1992). This has been attributed to the low porosity of MCC extrusion-spheronization pellets due to contraction during drying (Kleinebudde, 1994).

It has been shown that mixtures of MCC with sorbitol (up to 50%) or mannitol (up to 80%) are suitable for hydrochlo-rothiazide pelletization and accelerated drug release (Goyanes et al., 2010).

MTR was used to investigate the rheological behavior of wet granulations with different concentrations of drug, binder, and water (Hariharan and Mehdizadeh, 2002). An experimental design was employed to systematically study the effects of the three formulation variables on the torque profiles of the wet masses over time.

9. Effect of excipient source variation

The rheological behavior of wet powder masses is known to be influenced by physico-chemical and mechanical properties of the substrate being wet massed and excipient variability; therefore, rheological characterization of the wet masses has become increasingly necessary for excipient evaluation.

Recently MTR has gained popularity in characterizing the behavior of powder materials used for wet granulation and other specialized applications, such as pelletization by extru-sion-spheronization. Several studies investigating the effect of excipient source variation (Rowe and Sadeghnejad, 1987; Parker et al., 1992). Chatlapalli and Rohera (2002) investigated the rheological behavior of wet masses containing HPMC obtained from two sources using a mixer torque rhe-ometer. In another study, they (Chatlapalli and Rohera, 1998) studied the rheological behavior of wet powder masses containing two commonly used cellulose ethers, hydroxypro-pyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC), using a mixer torque rheometer.

A powder rheometer has been used to study the properties of wet powder masses and the results have been compared to the mixer torque rheometer (MTR) (Luukkonen et al., 2001). Two different microcrystalline cellulose (MCC) grades (Avicel and Emcocel) and silicified microcrystalline cellulose (SMCC; Prosolv) were used as model powders. In water addition measurements, the torque behaved in a similar way to MTR measurements and the maximum value of zero torque limit (ZTL) was achieved at the capillary state of wet mass. The wet granules exhibited different behavior in the powder rheometer and the MTR experiments, which indicates that these rheometers involve different shear forces or they measure different properties of the wet granules. Emcocel wet masses achieved the capillary state at lower liquid amount than Avicel and Prosolv masses, which indicates that Emcocel is not able to hold as much water in the internal structure as Avicel and Prosolv.

The rheological properties of silicified microcrystalline cellulose (Prosolv 50) were compared with those of standard grades of microcrystalline cellulose (Emcocel 50 and Avicel PH 101) (Luukkonen et al., 1999). Cellulose samples were analyzed using nitrogen adsorption together with particle size, flowability, density and swelling volume studies. The rheolog-ical behavior of the wet powder masses was studied as a function of mixing time using a mixer torque rheometer (MTR). Silicified microcrystalline cellulose exhibited improved flow characteristics and increased specific surface area compared to standard microcrystalline cellulose grades. Although the silicification process affected the swelling properties and mixing kinetics of MCC, the source of MCC had a stronger influence than silicification on the liquid requirement at peak torque.

Lactose was melt agglomerated in a mixer torque rheometer with different polyethylene glycol (PEG) grades as meltable binder (Johansen et al., 1999). A longer massing time caused

an increase in mean torque until a maximum value after which the torque decreased. A smaller particle size of the PEG gave rise to a faster initial rise in mean torque. The higher viscosity of the PEG 20000 resulted in a higher mean torque, whereas no clear difference in mean torque was obtained with the other PEGs.

The rheological properties of binary mixtures of two batches of lactose of median particle size 41.5 and 62.3 im, respectively, with microcrystalline cellulose (MCC) massed with water were studied using mixer torque rheometry (Rowe, 1995). Increasing the lactose concentration resulted in a decrease in the measured torque at saturation and a decrease in the amount of water required to achieve saturation mixtures containing the larger size lactose particles which gave higher values than equivalent mixtures containing smaller size lactose particles.

10. Quantifying binder characteristics

Binders are adhesives that are added to solid dosage formulations. The primary role of binders is to provide the cohesive-ness essential for the bonding of the solid particles under compaction to form a tablet. In a wet-granulation and pellet-ization processes, binders promote size enlargement to produce granules and thus improve flowability of the blend during the manufacturing process (Alderborn, 1988). The cohesive properties of binders may reduce friability. Although the purpose of using binders is not to influence its disintegration and dissolution rate, these properties may be modified due to the altered wettability of the formulation.

The MTR can be used to examine the role of various material parameters such as: binder concentration, viscosity and work of adhesion. MTR curves were used to study the influence of binder characteristics during wet granulation inside the high shear mixer (Chitu et al., 2011). Binders used were ultra-pure water and solutions of varying concentrations of PVP and HPMC. The study conducted by Chitu has proved also that the optimum liquid requirement for granulation varied with binder type and decreased with increasing viscosity.

11. MTR as scale-up tool in wet granulation

Scale-up is generally defined as the process of increasing the batch size. Scale-up of a process can also be viewed as a procedure for applying the same process to different output volumes (Faure et al., 1999, 2001). There is a subtle difference between these two definitions: batch size enlargement does not always translate into a size increase of the processing volume. In moving from research and development (R&D) to production scale, it is sometimes essential to have an intermediate batch scale. This is achieved at the so-called pilot scale, which is defined as the manufacturing of drug product by a procedure fully representative of and simulating that used for full manufacturing scale (Landin et al., 1996a,b). This scale also makes possible the production of enough product for clinical testing and samples for marketing. However, inserting an intermediate step between R&D and production scales does not in itself guarantee a smooth transition. A well-defined process may generate a perfect product in both the laboratory and the pilot plant and then fail quality assurance tests in production.

Chatlapalli and Rohera (2002) has shown that MTR is a predictive tool for granulation behavior and end product properties. Two MTR methods namely ''total water addition'' and ''variable addition'' were developed to study the effect of differing granulating fluid (water) amounts and granulation mixing times. Pilot scale high-shear wet granulation batches were made and the impeller torque measurements were obtained from the granulator during the granulation process. The wet granulations were then processed and compressed into tablets. The milled active pharmaceutical ingredient (API) formulation resulted in higher mean torque, higher rate and extent of increase of torque compared to the micronized API formulation. The torque values obtained from the pilot scale granulator had a similar trend-milled API granulation which resulted in higher torque. The milled API granulation had larger particle size, higher bulk, tapped and apparent granule density, and poor flow. As expected, tablets made with milled API granulation had higher compactability and lower friability. It was shown that MTR correctly predicted the effect of particle size of granulation and resulting tablet properties which confirm suitability of MTR as a predictive tool for granulation behavior and tablet manufacturing scale-up.

Two different types of microcrystalline cellulose, differing only in bulk density, were used as model excipient (Yuichi, 2006). The extrusion and spheronization behavior of two samples of microcrystalline cellulose have been studied by means of mixer torque rheometry and force/displacement curve during ram extrusion. The interaction between water and the surface of high- or low-density microcrystalline celluloses in the mixer torque rheometer is dramatically different both in the position of peak torque and in the magnitude. When the low-density microcrystalline cellulose was used, spherical pellets could be obtained easily over a wide moisture range. However, in contrast to the low-density material, wet massed high-density microcrystalline cellulose samples were successfully extruded only over a narrow moisture range due to its higher viscosity. A steady-state flow condition was difficult to observed in the force/displacement curves of wet massed high-density microcrystalline cellulose samples, resulting in the 'dumbbell' shaped pellets at almost all moisture contents.

MTR was employed to evaluate the granulating solvents used (water, isopropanol, and 1:1 v/v mixture of both) based on the wet mass consistency. This study was carried out to investigate the effect of high shear mixer (HSM) granulation process parameters and scale-up on wet mass consistency and granulation characteristics of P-cyclodextrin (PCD) and ibuprofen (Ghorab and Adeyeye, 2007). The MTR study showed that water significantly enhanced the beta-cyclodextrin (PCD) binding tendency and the strength of liquid bridges formed between the particles, whereas the isopropanol/water mixture yielded more suitable agglomerates. Mini-high shear mixer granulation with the isopropanol/water mixture (1:1 v/ v) showed a reduction in the extent of torque value rise by increasing the impeller speed as a result of more breakdowns of agglomerates than coalescence. In contrast, increasing the impeller speed of HSM resulted in higher torque readings, larger granule size, and consequently, slower dissolution. This was due to a remarkable rise in temperature during granulation that reduced the isopropanol/water ratio in the granulating solvent as a result of evaporation and consequently increased the PCD binding strength. In general, the HSM granulation retarded ibuprofen dissolution compared with

the physical mixture because of densification and agglomeration. However, a successful HSM granulation scale-up was not achieved due to the difference in the solvent mixture's effect from 1 scale to the other.

The use of torque measurements to control production of pellets in a rotary processor has been investigated previously (Kristensen et al., 2000), and it was found that torque-increase measurements were suitable to control the production of pellets because the water content of the mass is reflected in the torque. Random variations in the moisture content of the materials can thus be compensated for by stopping the liquid addition at a certain level of torque. Because the torque has been found to be influenced by the rotation speed of the friction plate and by the batch size, there is no general correlation between torque increase, water content, and pellet size for a certain formulation. If these process variables are kept constant, there seems to be a close correlation between the torque increase and the pellet size.

12. Conclusion

Mixing torque rheometry has strongly replaced hand squeeze test for end point determination of wet granulation. MTR is a valuable tool for preformulation evaluation and scale up of wet granulation products. Evaluation of binder and solid excipient in addition to the source variations are now possible using MTR. Different phases of solid-liquid interaction monitored using MTR facilitated an advanced control of wet massing.


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