Drug Development and Industrial Pharmacy, 2012; 38(4): 439446 2012 Informa Healthcare USA, Inc.

. ISSN 0363-9045 print/ISSN 1520-5762 online DOI: 10.3109/03639045.2011.609561

RESEARCH ARTICLE

To determine the end point of wet granulation by measuring powder energies and thermal properties
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Rutesh H. Dave1, Stephen H. Wu2, and Labdhi D. Contractor1

1

Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Division of Pharmaceutical Sciences, Long Island University, Brooklyn, NY, USA and 2Covidien Research & Development Center, Webster Groves, MO, USA
Abstract Wet granulation has been widely used in pharmaceutical industry as a tablet manufacturing process. However, endpoint determination of wet granulation process has always remained a challenge. Many traditional methods are available for end-point determination, yet accuracy and reproducibility still remain a challenge. Microcrystalline cellulose, widely used as an excipient in pharmaceutical industry, was granulated using water. Wet mass was passed through sieve # 12 and dried till constant percentage loss on drying was obtained and dried granules were obtained. Wet and dried granules collected were subjected to basic flow energy, specific energy, bulk density, pressure drop, differential scanning calorimetry and effusivity measurements. Analysis of data revealed various stages of granule growth from initial seed formation by adding 200400 g of water, granule growth was observed by adding 600800 g of water and over wetting was observed at 1155 g of water. In this work, we have justified our work to properly identify and utilize this technique for practical purpose to correctly identify the end-point determination of microcrystalline cellulose and explain various principles underlying energies associated with powder and thermal measurements. Keywords: Wet granulation, microcrystalline cellulose, end point, effusivity, powder rheology, granules, differential scanning calorimetry, granulation, permeability, dry granulation

Introduction
Pharmaceutical industry runs under a number of regulations, which are imposed, by Food and Drug Administration and other regulatory authorities. So, it is very important to achieve and maintain quality required in the pharmaceutical field. Therefore manufacturing of consistent quality product requires an effective manufacturing and optimization of process. Tablets and capsules are most common and convenient solid oral dosage form. Wet granulation is commonly used technique in tablets and capsules. Wet granulation is a process of collecting particles together by creating bonds between them. When homogenous mix of components cannot be obtained by simply mixing the ingredients, it should be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Though direct compression is cheaper method, it is not applicable to all formulations. End-point determination of wet granulation process has been a challenge for decades1,2.

It is very important to determine the quantity of water or binder solution required, as many of the tablet properties such as hardness, friability, disintegration time3, dissolution time4, compressibility and unit dose accuracy5 are affected by the granule properties68. End point in wet granulation is defined as a point at which formulator gets target particle size mean or distribution and at this point, granules follow the principle of Equifinality9. At this point, granules approach a state of dynamic equilibrium, while continuous addition would result in the collapse of liquid bridges and formation of wet mass. Microcrystalline cellulose (MCC) is widely used as an excipient in pharmaceuticals owing to its different characteristics based on different grades. Charges based on grades in terms of pre-formulation and formulation characteristics have noted previously10,11. Microcrystalline cellulose is a partially depolymerized cellulose containing many hydroxyl groups which form hydrogen bonds with neighboring chain12. Due to its

Address for Correspondence: Dr. Rutesh H. Dave, Ph.D., Division of Pharmaceutical Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, 11201, NY, USA. Tel: 718-488-1660. E-mail: rutesh.dave@liu.edu (Received 24 March 2011; revised 23 July 2011; accepted 25 July 2011)

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structure, MCC can absorb large amount of water and it enables to produce wet mass with different amounts of water. There are many methods reported in literature to characterize wet granulation end point using power consumption13, torque rheometer7, acoustic emission14, reaction torque7, application of artificial neural network15, near infra red spectroscopy16,17, focus beam reflectance measurements17, surface responses18 etc. These methods have their own limitations including reproducibility. Application of torque and force measurement for powder flowability has been reported in literature1921. These measurements provide important insight into the formation of granules. Effusivity measurements have been reported in literature as a process analytical technology (PAT) tool for determination of blend uniformity, for monitoring roller compaction process etc22,23. Thermal effusivity and power consumption have also been used as a PAT tool to determine the formation of wet granules24 and to optimize, monitor and control the fluid bed drying process25. The purpose of this study is to analyse energies associated in pharmaceutical powders with thermal properties and to establish an end-point determination using microcrystalline cellulose.

Characterization of granules using powder rheometer

Rheological characterizations were performed on the wet granules, dried granules and control (MCC 101) using Freeman technology rheometer (FT-4) (Worcestershire, UK). The instrument was initially calibrated for force, torque and height measurements. Before performing test, conditioning was applied to the powder bed employing a slicing action to gently lift the powder and then deposit it behind the blade, providing loosening of powder and aerated powder bed ready for testing. Conditioning was performed in both upward and downward directions. During the test mode, two kinds of forces were acting on the blade, rotational force or torque and another axial force which helped to measure basic flow energy (BFE) and specific energy. Dynamic and bulk properties were measured.

BFE measurement
A cylindrical vessel with a dimension of 50 160 mL was filled with respective materials and set on platform of the rheometer. To measure BFE, particular flow pattern was generated by downward anti-clock wise motion of 48-mm diameter twisted-blade at 100 mm/s tip speed and 5 helix angle, which resulted into relatively high stress flow mode in the powder and energy was calculated by work done during this downward traverse. The force-distance profile of the powder bed between 10 and 100 mm of the distance blade traveled was integrated for BFE calculation.
Energy consumed: dE = (T/(R tan ) + F ) dH

Materials and methods

Materials
Microcrystalline Cellulose (MCC) (Avicel 101, lot # P108820025, FMC Corp, Philadelphia, PA) was used as received. Deionized water (Barnstead NanopureThermoscientific system, Waltham, MA) was collected below 13 mcm.

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Wet granulation and dried granules preparation

Wet granules were prepared using a Cuisinart mixer (East Windsor, NJ). Granulation was performed on batch size of 700 g of MCC 101. Adding 200 g (22.22% w/w), 400 g (36.63% w/w), 600 g (46.15% w/w), 700 g (50% w/w), 800 g (53.33% w/w) and 1155 g (62.26% w/w) of water, five separate experiments were performed and wet granules were prepared. Addition of water was accomplished in 30 s and blade speed of 4070 rpm was employed. Speed of 70 rpm was applied for 1155 g water addition due to formation of over-wet mass. After subsequent addition of water, wet mass obtained was subjected to rheometer for additional testing. Remaining wet mass was passed through sieve # 12 and dried at 60C until 35% moisture is retained and dried granules were collected for further analysis. Percentage of moisture was determined using loss on drying (Ohaus, MB 200, Pinebrook, NJ) measurements. After drying, each batch was further subjected to powder characterization. All experiments were performed in triplicates to measure reproducibility and standard deviations obtained were <10%.

Where, R = Blade radius dH = Increment or decrement of vertical displacement = Helical path angle F = Axial force on the blade in Newtons (N) T = Torque acting on blade (Nm)

Specific energy (SE) measurement

SE was also measured during BFE measurements; however, the flow pattern was generated by upward clock-wise motion of 48-mm diameter twisted-blade at 100 mm/s tip speed and 5 helix angle, which resulted into gentle lifting and low stress flow of the powder. SE was calculated by work done during this upward traverse.

Bulk density (BD) measurement

BD was also measured during BFE and SE measurements. As the vessel volume was fixed (85 mL), mass of the samples was measured by inbuilt weighing balance while loading the samples.

Pressure drop (PD) measurement

For PD testing, a cylindrical vessel, which was covered with an aeration base at the bottom, having a dimension of 50 85 mL was used. During this test mode, vented piston provided 15 kPa of stress on the system. Air was
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End-point determination 441 supplied at 10 mm/s constant velocity. PD across the powder bed was measured for applied normal stress and is represented by following equation. k = q m L/P where, = Permeability (cm2) = Air viscosity (Pas) (1.74 105 Pas) q = Air flow rate (cm/s) L = Length of powder bed (cm) P = Pressure drop across the powder bed (mbar) (2)

Sieve analysis test

The particle size distribution of dried granules was characterized by sieve analysis (Octagon 200, Endecotts, UK). A fixed amount, 100 g of each dried granules was passed through a set of a sieves consisting United Standards sieves # 12, 14, 18, 20, 30 and 60 and ran for 5 min. Opening sizes of these sieves are 1.70, 1.40, 1, 0.850, 0.600 and 0.250 mm, respectively. Sets of sieves are fitted with a collecting pan at bottom. Sieved were weighed before and after the experiments and particle size distribution calculated accordingly.

Differential scanning calorimetry (DSC)

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DSC analysis was performed using Q100 (TA Instruments, New Castle, DE) instruments with nitrogen (50 mL/min) as purge gas. The experiments were performed in hermetically sealed aluminum pans and the weight of each sample was 12 3 mg. Heating rate was 10C/min from 40200C. DSC was calibrated using Indium before start of experiments.

Results and discussion

Characterization of energies associated in wet and dried granules (BFE and SE)
BFE results for wet and dried granules are shown in Figure 1, wherein for wet granules, initially BFE values remains almost similar till 400 g of water is added and initiates seed formation for further granule growth, after which it starts to increase linearly until 700 g addition of water. Highest BFE is observed at 800 g of water, suggesting granule growth, after which BFE starts to decrease26. This is due to the fact that in BFE testing, blade of the rheometer pushes downwards in anti-clock motion through the material and with subsequent addition of water nuclei starts to form and connection of nuclei takes place resulting in bonding between particles giving rise to BFE27. Further addition of water will result in closely packed granules with little air entrapment forming high inter particle bonds28. These resulting granules will require more energy from the blade to pass through, resulting in even higher BFE values. Better the formation of granules, particles will tend to attain more spherical shape (optimum granulation stage), which tends create more closely packed mass and this phenomena is observed by addition of 600800 g of water (Figures 1 and 2). Further addition of water (e.g. 1155 g of water) will form irregular shaped granules resulting in over-granulation/overwetting and creating more void space between granules

Effusivity measurements
Effusivity measurements were conducted using the thermal conductivity (TC) Probe (Mathis Instruments, Canada). Samples were placed in direct contact with probe and were as flat as possible to ensure maximum contact with the probe. The instrument detects interfacial heat flow from materials based on its heat capacity, density and thermal conductivity. Effusivity is also a function of thermal conductivity, density and heat capacity of a material, which is calculated using Equation (3). Effusivity = krCp Where, = Thermal conductivity (W/mK) = Density (kg/m3) Cp = Heat capacity (J/kgK) Apart from the above-mentioned samples in preparation of wet and dried granules, two additional experiments were performed to see the impact of water on wet granulation and were performed using 700 g of MCC 101 and adding 1691.6 2 g (70.76% w/w, 70 rpm) and 2376.5 g (77.25% w/w, 70 rpm) of water. After each experiment, approximately 23 g of total sample weight were collected from different locations and subjected to effusivity measurements. This data were not subjected to rheological measurements due to formation of over-wet mass, which hinders the movement of blades. After addition of water, wet masses were dried as mentioned above and further effusivity measurements were performed using dried granules. As was the case before, dried granules obtained by addition of 1155g or higher amounts of water, resulted in formation of heavy lumps which could not be used for effusivity measurements. Feasibility experiments were initially performed using 3 g of MCC 101 and adding equivalent %w/w of water only for effusivity measurements.
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Figure 1. Comparison of basic flow energy for wet and dried granules vs. addition of water.

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R.H. Dave et al. after addition of 1155 g of water resulted into large mass of cohesive powder, which resulted in over-load to continue further measurements. BFE values are much less compared to the wet mass due to above-mentioned phenomena except when 200 g of water is added. This is due to the fact that 200 g addition of water is not sufficient to initiate granule formation and so after drying, the energy required to move the blade will be similar for wet and dried granules.

(Figure 3). These void spaces will act as a cushion to blade movement resulting in decrease of BFE values. Further, for dried granules we can see that initially from 200400 g of dried powder the formation of granules have not taken place due to more fines in the powder blends (Figure 4). For dried granules obtained after addition of 600800 g of water, increase in BFE values were observed, this is due to do formation of more granular particles and decrease in fines in powder. Dried granules obtained

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Figure 2. (A) Blade movement in non-cohesive particle; (B) Blade movement in cohesive particle.

Figure 3. Images of wet granules containing 200, 400, 600, 700, 800 and 1155 g of water.
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End-point determination 443 SE takes into consideration the energies and forces involved in formation of cohesive and adhesive attraction between particles. SE is measured during upward movement of blades in clock-wise direction and provides understanding between confined and nonconfined materials in which gravity also plays an important role. In Figure 5, for wet granules, we can see that as the addition of water increases, the material becomes cohesive and try to resist the movement of blade while the blade is moving in upward direction. A slight discrepancy is observed after addition of 600 g of water, after which further addition resulted in formation of wet mass giving rise to increase in SE. This is due to m1g < fcoh12 + fcoh13 (Figure 6) where fcoh denotes cohesion forces between like particles and mg is a gravitational force acting on a particle in which if the mass of the particle and gravity is less than the combined forces acting on a particle, it will tend to stick with other materials; however in opposite case, the particle is free to fall, as the forces acting on the particles are less than the combined mass and gravitational forces resulting in free flowing of material. In case of dried granules (Figure 5), we can see that due to formation of initial granules, less amount of material is on the blade resulting in similar values of SE from 600 g to 800 g points. However, in the beginning the SE decreases slightly due to uneven formation of granules resulting in weight variation to further produce decrease in SE. lower volumes. After initial granules formation, granules achieve more definite shape resulting in less voids and increase in BD.

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Figure 5. Comparison of specific energy of wet and dried granules vs. addition of water.

Bulk density studies

As shown Figure 7, increase in BD for MCC with addition of water has been previously noted29. During wet granulation, initial phase (200400 g) liquid bridges starts to build up resulting in higher volume and decrease in BD30. However, as the amount of water starts to increase and granules begin to form this will result in much wetter mass and void space being depleted resulting in higher BD (4001155 g). In case of dried granules during initial phase (200400 g), the BD is higher as compared to wet granules due to more fines in powder resulting in

Figure 6. Forces between particles. fcoh, cohesion forces between like particles; mg, gravitational force acting on a particle.

Figure 4. Sieve analysis of dried granules.

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Figure 7. Bulk density of wet and dried granules at various amount of water.

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PD studies
As shown in Figure 8, for wet granules, the PD linearly declines after 200 g addition of water suggesting formation of granules. This suggests that formation of granules have started and with subsequent addition of water, they attain more granular form allowing the air to pass without resistance resulting in decreased PD. After 800 g addition of water, there is sudden increase in PD as over-wetting occurs. This erratic behavior at 1155 g of wet granules is due to the fact that material is highly over-wetted and as the air is trying to pass in-between the over-wetted mass, the pressure generated is highly variable. Another explanation is air, which is passing through bottom-up will have to change direction/or pass through more hindrance depending on the formation of lumps as the piston generates the pressure from top, which results in variation in location and amount of mass. In case of dried granules, PD decreases with the formation of better granules and offering least resistance at 700 g (0.04 mbar) and 800 g (0.05 mbar), suggesting that better granules are formed at this stage and least resistance is offered to the air passing through the powder bed.

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Figure 8. Pressure drop of wet and dried granules at various amount of water.

DSC
MCC 101 shows a typical polymer relaxation, which shifts towards right due to addition of water. As the amount of water increases, DSC showed an increasing trend in enthalpy30 and relaxation phenomenon decreases leading to formation of broader peak as shown in Figure 9. As mentioned previously, once MCC absorbs water to a certain point, it will start resisting intake of water and water will be present on the surface. This is clearly seen that at 1155 g of water, we see surface phenomena with as light bend in peak around 125C representing water on the surface.

Figure 9. DSC measurements of wet granules with addition of different amount of water.

Effusivity measurements
This measurement is critical in determining the end-point region for wet granulation. As effusivity is proportional to thermal conductivity, density and heat capacity, small increment in water content will generate change in effusivity values. Water has highest effusivity (~1600 Ws1/2/ m2K). Particle size also affects the density. Heat capacity also changes depending on water absorbed. A schematic representation is shown in Figure 10 (Chart type). As seen in Figure 11, as the amount of water increases, effusivity starts to increase in initial stage (0400 g), further addition of water (400800 g, optimum granule growth stage 700800) results in better granule growth after which any further addition (11551691.62 g) creates marked increase in effusivity which resulted in over-wetting of granules, after which it turns into slurry form (2376.5 g water). Critical step here is to identify the formation of proper granules by supporting data from rheometer; we see that, addition of 700 and 800 g of water results in ideal granule formation. Further increase in water (1155 g) content results in increased effusivity values. Once MCC 101 has absorbed enough water, further addition of water

(1691.92 and 2376.5 g) will result in water being on the surface of particle resulting in higher and constant effusivity, this value also corresponds to water effusivity, suggesting presence of water on surface of powder, analogous to the granulation optimization, utilizing torque measurement technique31. Another important consideration is similarity between feasibility studies and lab scale experiments. Due to equipments ability to be used as online PAT tool, it can be used to detect end point for granulation. In case of dried granules as seen in Figure 12, effusivity also decreases almost in linear fashion in initial stage (0400 g); this sudden decrease becomes smaller as granules have attained proper shape (600800 g). Effusivity at 700 and 800 g addition of water remains same, suggesting formation of ideal particles.

Conclusion
End-point determination for wet granulation always remains a challenge. There are many traditional methods are available for end-point determination, but they have their own limitation of reproducibility and accuracy.
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End-point determination 445

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Figure 10. Schematic diagram explaining the effect of effusivity on granule formation.

In this study, we have attempted to develop a simple and practical approach to determine end point for wet granulation using MCC 101, characterized and differentiated between formations of various stages of granules. Incorporating effusivity measurements together with fundamental energies involved in powder can be a powerful, yet simple technique to measure the end point of wet granulation. Authors understand that further work is needed in terms of using different materials and binders.

Declarations of interest
The authors report no conflicts of interest.

References
Figure 11. Effusivity measurements of wet granules performed at feasibility scale and lab scale.
1. Miwa A, Yajima T, Itai S. (2000). Prediction of suitable amount of water addition for wet granulation. Int J Pharm, 195:8192. 2. Chirkot T. (2002). Scale-up and endpoint issues of pharmaceutical wet granulation in a V-type low shear granulator. Drug Dev Ind Pharm, 28:871888. 3. Zhao N, Augsburger LL. (2006). The influence of granulation on super disintegrant performance. Pharm Dev Technol, 11:4753. 4. Unvala H, Schwartz J, Schnaare R. (1988). The effect of the wet granulation process on drug dissolution. Drug Dev Ind Pharm, 14:13271349. 5. Mehrotra A, Chaudhuri B, Faqih A, Tomassone M, Muzzio F. (2009). A modeling approach for understanding effects of powder flow properties on tablet weight variability. Powder Technol, 188:295300. 6. Leuenberger H, Puchkov M, Krausbauer E, Betz G. (2009). Manufacturing pharmaceutical granules: Is the granulation end point a myth? Powder Technol, 189:141148. 7. Achanta AS. (1997). End point determination and its relevance to physicochemical characteristics of solid dosage forms. Drug Dev Ind Pharm, 23:539546. 8. Shiakura O, Yamada M, Hashimoto M, Ishimaru S, Takayama K, Nagai T. (1992). Effect of amount and composition of granulating solution on physical characteristics of tablets. Drug Dev Ind Pharm, 18:10991110.

Figure 12. Effusivity measurement of dried granules.

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21. Giry K, Viana M, Genty M, Wthrich P, Chulia D. (2010). Surface responses and desirability functions to determine optimal granulation domains. Drug Dev Ind Pharm, 36:10161026. 22. Lonard G, Bertrand F, Chaouki J, Gosselin PM. (2008). An experimental investigation of effusivity as an indicator of powder blend uniformity. Powder Technol, 181:149159. 23. Ghorab MK, Chatlapalli R, Hasan S, Nagi A. (2007). Application of thermal effusivity as a process analytical technology tool for monitoring and control of the roller compaction process. AAPS PharmSciTech, 8:23. 24. Okoye P, Fariss G, Keintz R. (2006). Thermal effusivity and power consumption as PAT tools for monitoring granulation end point. Pharmaceut Tech [online]. Available at http://pharmtech. findpharma.com/pharmtech/Process+analytical+technology+( PAT)/Thermal-Effusivity-and-Power-Consumption-as-PAT-To/ ArticleStandard/Article/detail/333033. Accessed on 20 May 2010. 25. Roy Y, Closs S, Mathis N, Nieves E. (2004). Thermal effusivity as a process analytical technology to optimize, monitor and control fluid-bed drying. Pharm Technol, 28:2128. 26. Arnaud P, Brossard D, Chaumeil JC. (1998). Effect of the granulation process on nitrofurantoin granule characteristics. Drug Dev Ind Pharm, 24:5766. 27. Bouwman AM, Henstra MJ, Westerman D, Chung JT, Zhang Z, Ingram A et al. (2005). The effect of the amount of binder liquid on the granulation mechanisms and structure of microcrystalline cellulose granules prepared by high shear granulation. Int J Pharm, 290:129136. 28. Schwartz J. (1998). Granulation. Drug Dev Ind Pharm, 14:20712090. 29. Luukkonen P, Maloney T, Rantanen J, Paulapuro H, Yliruusi J. (2001). Microcrystalline cellulose-water interactiona novel approach using thermoporosimetry. Pharm Res, 18:15621569. 30. Buckton G, Yonemochi E, Yoon WL, Moffat AC. (1999). Water sorption and near IR spectroscopy to study the differences between microcrystalline cellulose and silicified microcrystalline cellulose before and after wet granulation. Int J Pharm, 181:4147. 31. Cavinato M, Massimo B, Marianna M, Bellazzi G, Canu A, Santomaso A. (2010). Formulation design for optimal high shear wet granulation using on-line torque measurements. Int J Pharm, 387:4855.

Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by Apotex Inc on 03/13/12 For personal use only.

9. Levin M. (1992). Wet granulation: End-point determination and scale-up. In: Swarbrick J, Ed. Encyclopedia of pharmaceutical technology. New York (USA): Marcel dekker Inc, 40784098. 10. Javadzadeh Y, Shariati H, Movahhed-Danesh E, Nokhodchi A. (2009). Effect of some commercial grades of microcrystalline cellulose on flowability, compressibility, and dissolution profile of piroxicam liquisolid compacts. Drug Dev Ind Pharm, 35:243251. 11. Aljaberi A, Chatterji A, Shah NH, Sandhu HK. (2009). Functional performance of silicified microcrystalline cellulose versus microcrystalline cellulose: A case study. Drug Dev Ind Pharm, 35:10661071. 12. Mihranyan A, Llagostera AP, Karmhag R, Strmme M, Ek R. (2004). Moisture sorption by cellulose powders of varying crystallinity. Int J Pharm, 269:433442. 13. Pepin X, Blanchon S, Couarraze G. (2001). Power consumption profiles in high-shear wet granulation. I: Liquid distribution in relation to powder and binder properties. J Pharm Sci, 90:322331. 14. Gamble JF, Dennis AB, Tobyn M. (2009). Monitoring and end-point prediction of a small scale wet granulation process using acoustic emission. Pharm Dev Technol, 14:299304. 15. Kachrimanis K, Karamyan V, Malamataris S. (2003). Artificial neural networks (ANNs) and modeling of powder flow. Int J Pharm, 250:1323. 16. Otsuka M, Mouri Y, Matsuda Y. (2003). Chemometric evaluation of pharmaceutical properties of antipyrine granules by near-infrared spectroscopy. AAPS PharmSciTech, 4:E47. 17. Frake P, Grierson SM, Hempenstall JM, Rudd DR. (1997). Process control and end point determination of a fluid bed granulation by application of near infra red spectroscopy. Int J Pharm, 151:7580. 18. Navaneethan CV, Missaghi S, Fassihi R. (2005). Application of powder rheometer to determine powder flow properties and lubrication efficiency of pharmaceutical particulate systems. AAPS PharmSciTech, 6:E398E404. 19. Freeman RE. (2004). Predicting flowability and characterizing powders. Pharm Technol Eur, 16:4143. 20. Staniforth JN, Baichwal AR, Hart JP, Heng WS. (1988). Effect of addition of water on the rheological and mechanical properties of microcrystalline cellulose. Int J Pharm, 41:231236.

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