Comparative impact of different binder addition methods, binders and diluents on resulting granule and tablet attributes via high shear wet granulation

    Comparative impact of different binder addition methods, binders and diluents on resulting granule and tablet attributes via high shear wet granulation Dinesh M. Morkhade PII: DOI: Reference:

S0032-5910(17)30576-4 doi:10.1016/j.powtec.2017.07.038 PTEC 12680

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Powder Technology

Received date: Revised date: Accepted date:

21 March 2017 13 June 2017 12 July 2017

Please cite this article as: Dinesh M. Morkhade, Comparative impact of different binder addition methods, binders and diluents on resulting granule and tablet attributes via high shear wet granulation, Powder Technology (2017), doi:10.1016/j.powtec.2017.07.038

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Comparative impact of different binder addition methods, binders and diluents on resulting granule and tablet attributes

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via high shear wet granulation

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Dinesh M Morkhade

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Piramal Healthcare Ltd., Whalton Road, Northumberland, NE613YA, United Kingdom.

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ABSTRACT

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This study investigated comparative impact of different binder addition methods (pouring, dripping, spraying), binders and diluents on resulting granule and tablet attributes via high shear wet granulation. Lactose monohydrate and mannitol as diluents, and hydroxypropyl methylcellulose (HPMC E5) and polyvinylpyrrolidone (PVP K30) as binders were used. Granules were characterized for morphology, bulk-density, tapped-density, flow, size, segregation-potential and friability. To determine granule friability, procedure described in European Pharmacopoeia was slightly modified to reduce manual-variations and obtain appreciable discrimination between the formulations. Binder-diluent affinity was assessed by measuring contact angles of diluent-dispersion droplets on binder films over a period of time. All blends were pressed at the same compression force and resulting tablets were characterized for pharmacotechnical properties. Results revealed that the binder addition methods altered granule-shape, which predominantly governed the granule flow. The binder addition by spraying increased fines, blend segregation-potential, granule friability, tablet tensile-strength and tablet disintegration-time; binder addition by pouring showed an opposite impact. Mannitol granules exhibited lower bulk density, superior flow, lower segregationpotential and higher friability than their lactose counterparts. Amongst binders, PVP produced more friable granules compared to HPMC. The high polydispersity-index of polymer-binder induced non-homogeneity facilitating the blend segregation-potential. Due to higher affinity, HPMC was suitable binder for mannitol, and PVP for lactose to promote granule growth. The binder-diluent affinity dominated viscosity and surface tension of binder solution to improve granule size. Increase in granule size decreased granule-friability, which subsequently decreased tablet hardness, tensile-strength and disintegration-time. Mannitol produced harder tablets, and lactose tablets disintegrated faster by all binders and binder addition methods.

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Keywords: Dripping, Spraying, Mannitol, Lactose, binder polydispersityindex, Granule friability

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1. Introduction

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A well designed and executed formulation development program successfully delivers molecule to market. There are two principal domains; a new chemical entity (NCE) and a

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generic formulation. In NCE formulations, scientists can use the number of pharmaceutical excipients and thus it is important to know how the different excipients behave and affect various formulation attributes. On the other hand, in generics the applicable patents and

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regulatory requirements usually limit the choice of excipients and their amounts in formulation [1], and therefore a good understanding of engineering aspects such as equipment principles and process parameters is essential for the generic product

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development. Nevertheless, in both the domains (NCE and generic), knowledge from drug properties, excipient properties, equipment aspects and process parameters is prerequisite for

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successful formulation development. In this study, we thus aimed to explore two aspects

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namely the components (different diluents and binders) and the process (different binder addition methods) for their impact on various granule and tablet attributes via high shear wet

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granulation. Lactose monohydrate and mannitol in diluents, and HPMC and PVP in binders are the most commonly used pharmaceutical excipients and therefore the present study used them to prepare granules by high shear wet granulation. Granulation is a well-known technique, which has been widely used in the field of

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pharmaceutical science to improve the flow property of blends, densify the blends and prevent segregation of low dose actives in tableting to achieve content uniformity. The aqueous granulations, in addition, provide moisture to blends to improve their compressibility [2] and thus prevent API degradation in few instances [3]. Amongst several granulation techniques, the wet and dry granulation are the most commonly used techniques in research as well as manufacturing domains. Wet granulation can be performed by high shear, low shear or top-spray process using aqueous or organic solvent as a binder medium. Since water is safe and cost effective, it remains a preferred solvent for the purpose of wet granulation. In aqueous granulation, a binder solution (purified water or binder dissolved in water) is usually poured on the rotating or fluidized blends in the granulator. The resulting granules and their tablet properties can be influenced by a number of excipients and process attributes, and 3

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therefore scientists have thoroughly explored the granulation and tableting domains over the past many years. A number of studies have been published investigating the impact of drug properties

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[4,5], diluent grades and particle size [6,7], wettability of blend [8], excipients surface free

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energy [8,9], molecular weight of binder [10], physical state of binder [11], amounts of

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binder [12], granulation methods [13], types of equipment [14], batch size [15,16], impeller design [17], tip speed [18-20] and kneading time [21] on the various granules and tablet attributes. In the above studies, however, those specifically dealt with high shear wet

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granulation, binder solutions were added mostly by the manual pouring technique. In contrast, recently an attempt was made by Oka et al. [22] to incorporate the binder solution using pre-calibrated peristaltic pump in a drip fashion through a tube in the granulator. They

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found that small particles (API or excipients) have tendency to percolate to the bottom of the beds during mixing in high shear granulator, and the binder addition by dripping can produce

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either subpotent or superpotent granules. Studies have also shown that the state of binder i.e. dry (added in dry blends) or wet (added as a solution) greatly influences the resulting granule

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and tablet attributes via high shear wet granulation [23-24]. The above details in particular propose that along with other crucial factors, the way (form) binder access and deals with the

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powder beds in high shear wet granulation markedly affects the granule and tablet

Despite the fact that binder addition methods can have an appreciable impact on

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granule geometry, density, drug content, particle size, porosity, flow, segregation and friability, which subsequently affect the final tablet properties, there is no study in literature describing the impact of different binder addition methods specifically pouring, dripping and spraying in presence of commonly used diluents and binders on resulting granule and tablet attributes via high shear wet granulation. Present study was thus undertaken with an objective to assess the comparative impact of different binder addition methods, diluents and binders on various granules and tablet attributes via high shear wet granulation. The study outcomes will help understanding the interplay of material and process impact on granules and tablet properties to facilitate development of immediate release tablet formulations containing different APIs. 2. Materials and methods 4

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2.1 Materials Microcrystalline cellulose (MCC) (Avicel PH 101, FMC Biopolymer, Ireland),

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lactose monohydrate (Pharmatose 200M, DMV-Fronterra Excipients, Germany), mannitol

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(Pearlitol 50C, Roquette, France), HPMC (Methocel E5 premium LV, Dow Chemical

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Company, Midland), PVP (Kollidon 30, BASF, Germany), croscarmellose sodium (AcDiSol, FMC Biopolymer, Ireland), colloidal silicon dioxide (Aerosil 200 pharma, Evonik Industries, Germany), talc (Imerys talc, Italy), magnesium stearate (Peter Greven, Germany)

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were used from the commercial source. 2.2 Granulation

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The batch size was 3000 tablets (1.35 kg) for each formulation. All excipients (as per Table 1 and 2) except colloidal silicon dioxide, talc and magnesium stearate were sifted

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through ASTM 30 mesh and placed in high shear granulator (5 L bowl equipped with a threeblade impeller and four-blade horizontal chopper). Binder to make 4.0% w/v solution in

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purified water was spared and remaining was included in initial dry mix. Dry mixing was performed at impeller tip speed of 4.6 m/sec for 5 min. Separately, weighed amount of either

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HPMC or PVP was dissolved in purified water (to make 4.0% w/v solution) and stirred for 45 min to ensure polymer hydration. This was used as binder solution to granulate the dry mix in high shear granulator. Amount of binder solution utilized was 60% w/w of dry mix weight,

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which was selected based on initial screening trials. Binder solution was added either by pouring, dripping or spraying method as described below; In pouring method, binder solution was poured manually from stainless still vessel in granulator to complete binder addition in 3 min by continuously monitoring a stopwatch. In dripping method, binder was allowed to drip through stainless still shaft having three arms (each with multiple openings as shown in Fig. 1A). Solution was conveyed to dripper/sprinkler and eventually to granulator using conveying tube and peristaltic pump (set at 20 rpm). In spraying method, spray gun with 1.0 mm nozzle provided with atomization and fan air system was fixed at a solution pouring port of granulator (illustration in Fig. 1B). Binder solution was conveyed to the granulator by peristaltic pump (set at 56 rpm). Spray pressure and fan air pressure were maintained at 0.3 bars till the completion of binder addition. 5

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In all the cases, total binder solution was delivered in 3 min. Post binder addition, wet mass was kneaded at impeller tip speed of 6.4 m/sec and chopper speed of 1440 rpm for 45 sec. Wet mass was dried in fluid bed dryer at a product temperature of 40 ± 2°C till loss on

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drying (LOD) achieved was 0.3±0.1% more than the LOD (practically determined) of initial

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dry mix of that respective batch. Dried granules were milled using quadro comil equipped

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with 1016 µ grated screen and square blade (74 mm diameter) rotating at 2500 rpm without spacers.

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2.3 Granule characterization

Milling may subdue discrimination between formulations in few instances. Therefore,

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unmilled as well as milled granules were characterized for bulk density, tapped density, Carr’s index (CI), Hausner ratio (HR) and granule: fine portions. Milled granules were additionally characterized for morphology, flow properties, particle size and granule

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2.3.1. Morphology

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friability.

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Morphology of native excipients (diluents) and milled granules was examined by scanning electron microscopy (Electron optical services, DAH15P102, England). Granule samples were coated with gold/palladium mixture to make specimens and examined using

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Genie 3000 software.

2.3.2. Bulk and tapped density Bulk and tapped density were determined as per method described in USP (USP32– NF27) [25] using Bulk and tap density tester (JV 2000, Copley, England). 2.3.3. Granule flow property Flow properties were studied by CI and HR values as per the conventional equations. In addition, the flow was also evaluated using ring shear tester (Dietmar Schulze ring shear tester, RST-XS, Germany). Granules were filled gently in sample cell and the excess material was removed from surface, which was then smoothened using a scraper without applying any stress to the sample. The cell was placed on a mounting stand and the lid was placed on it. Loading and tie rods were attached to the lid. During the measurements of normal load, pre6

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shear was adjusted at 5000 Pa. It is the load under which the sample is consolidated and kept in a steady state. Shearing was then proceeded at lower normal loads of 1000, 2000, 3000 and 4000 Pa consequently. The ratio of the consolidation stress to unconfined yield strength is

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termed as flow function index (ffc); higher ffc values indicate better flow. Results were

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analyzed using RST Control 95 software. 2.3.4. Segregation potential

For segregation potential, pretest was carried out to find appropriate air flow requisite

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to fluidize sample adequately. About 50 g sample was then placed in fluidization segregation tester (FFT1026, Jenike and Johanson, M.A, USA), which was operated at air supply of 25

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psi and ramp to high, ramp to low, ramp to zero and hold high for 30 sec. Hold low span was 120 sec. The apparatus divides fluidized sample in three sections, which can be collected separately in top, middle and bottom cells of the instrument. Content of each cell was

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weighed carefully and sieved over ASTM 60 mesh in a sieve shaker (V81, Glen Creston Ltd.,

passed as fines.

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2.3.5. Granule size

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England) at 2 mm vibrations for 2 min. The retained portion was considered as granules and

For particle size determination, in house method was developed on particle size

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analyzer (System-Partikel-Technik, RODOS T4.1, Sympatec, GmbH). About 1 g blend sample was placed on the conveyor belt of apparatus and particle size was determined at primary pressure of 2.1 bar and vacuum depression of 70 ± 5 mbar using R6 0.5/9.0, 1750 µm lens. The particle size of diluents was determined at primary pressure of 3 bars and vacuum depression of 70 ± 5 mbar using R4 0.5/1.8, 350 µm lens. 2.3.6. Granule friability A 10 g sample was sieved on ASTM 100 mesh in a sieve shaker (V81, Glen Creston Ltd., England) at 2 mm vibrations for 2 min. Sieve shaker was used to standardize sieving step and thus to mitigate variations those otherwise would occur due to manual sieving and handling. Retained portion was retrieved carefully and charged to glass container (105 mL), which was then secured in granule friabilator (EGF-1, Electrolab, India). Sample was 7

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oscillated at 200 strokes per min for 2 min and sieved again through ASTM 100 mesh by sieve shaker before weighing. The method was slightly modified from European Pharmacopoeia recommendation to mitigate variations in sieving and parameters used were

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based on our experience to discriminate adequately between the various granule-formulations

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with this instrument. 2.4. Contact angle

To understand the binder-diluent affinity, 30% w/v solution of binder (methocel E5

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premium LV and kollidon 30) was prepared in purified water and allow to hydrate for 45 min. Rectangular glass slides (typically used for microscopy) were dipped 5 times manually

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in the binder solution and dried overnight at 42 ± 2°C in oven. Post drying and cooling to room temperature, slides were placed on a horizontal platform and a drop (100 l) of either lactose monohydrate: Avicel PH 101 (1:1) or mannitol: Avicel PH 101 (1:1) dispersion

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(made as 50% w/w in purified water) was carefully placed over smooth surface of binder film

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from a distance of about 5 mm. The contact angle of dispersion droplet was measured manually using a protractor and a magnifying glass at 1 min interval up to 5 min.

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2.5. Preparation of tablets

Extragranular materials (except magnesium stearate) were sieved through ASTM 30

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mesh and mixed with milled granules in a bin blender rotating at 21 rpm for 10 min. Magnesium stearate (ASTM 60 mesh passed) was added and mixed at 21 rpm for 3 min. Final blends were compressed on a 10 station single rotary compression machine (Korsch XL 100, Germany, Euro B tooling) to form 10.32 mm round standard biconvex tablets with a target weight of 450 mg. The compression force was kept constant to 16 KN for all formulations. The compression force was selected based on initial screening trials to achieve tablet hardness in a conventional range of 10-20 KP. 2.6. Evaluation of tablets All testing was performed in triplicate. For each, 40 tablets were randomly sampled. 10 tablets were evaluated for thickness (micrometer, Mitutoyo, Japan) and hardness (Erweka, 8

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TBH 125-D/TD, Germany). Weight variation was performed on 20 tablets using calibrated Mettler Toledo balance. For friability, 15 tablets were weighed and placed in friabilator (FRV 2000, Copley Scientific Ltd., UK) and friability was determined at 25 rpm for 4 min (100)

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and 12 min (300 revolutions). Disintegration test was performed on 6 tablets without the use

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of disc by disintegration tester (DTG 2000, Copley Scientific Ltd., UK) having a purified

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water maintained at 37 ± 1°C.

The statistical analysis (one way ANOVA and unpaired t-test) was performed using GraphPad Prism software (GraphPad Software Inc., CA, version 3.02, April 2000)

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3. Results and Discussion

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Lactose monohydrate is termed as lactose in following sections; 3.1. Granule morphology

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It was observed that the binder addition by spraying technique improved sphericity of

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granules, whereas the binder addition by pouring produced irregular granules (Fig. 2). This can be explained as; in a wet granulation, the initial mixing of liquid with solid is an

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important parameter in nucleation. Nucleation is the first stage of granule formation and it describes the formation of nuclei as a result of capturing of powder particles by the binder droplets. Litster et al. [26] showed that spraying a binder solution on moving powder bed can

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result in nuclei, which size is determined by the size of the sprayed droplets. They further clarified that at a low spray pressure, the system operates in the drop controlled regime, where one drop forms one nucleus. This suggests that the binder addition by spraying (at a low spray pressure) can produce several discrete nuclei in the top layers of powder bed that can be converted into granules mostly by the layering mechanism. There are two general granule growth mechanisms; layering and coalescence. Coalescence is collision of two particles to form a bigger particle. In order for this to happen particles must collide with a great energy. In a high shear granulator, greater energy exists in the lower-half of powder bed due to high impeller work at the bottom of the bowl. On the other hand, layering is when the fine particles stick to the surface of larger particle/nucleus, and it happens when the impact forces are low. Since the upper-half of powder bed in the granulator moves relatively slowly, one can expect layering as a principle granule growth mechanism in the top layers of powder 9

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bed particularly when the binder is added by the spraying technique. The granules formed by layering mechanism are more regular and spherical than the granules formed by coalescence and attrition. Also, Emady et al. [27] studied the single drops impacting static powder beds to

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explain different granule shapes. They identified three granule growth mechanisms;

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tunneling, spreading, and crater formation. Tunneling occurred for loose, cohesive powder

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beds, and it always produced round granules, spreading produced flat disks, and the crater mechanism produced granules of varying shapes. It is known, for instance, that the powder beds needing granulation usually contain the loose cohesive powders, and we noticed that

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during mixing and granulation in the high shear granulator, top layers of powder bed revolve very slowly. This along with the fact that we obtained round granules when the binder was added by spraying technique, suggests a possibility that the granule formation (when binder

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was added by spraying), in addition to layering, followed the tunneling mechanism (as described by Emady et al. [27]) resulting in round granules. On the other hand, since binder

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addition by pouring delivers more amount of binder solution to the lower half of powder bed, which also has a greater energy due to the high impeller work, coalescence and attrition can

the irregular granules.

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be expected as the primary granule growth mechanism by binder pouring technique to yield

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Regarding the impact of binders, PVP produced spherical granules compared to HPMC (Fig. 2). Johansen and Schaefer [28] studied the impact of interaction between powder particle size and binder viscosity on agglomerate formation via melt granulation.

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They found that the low viscosity binder with small particle-size powders, and the high viscosity binder with large particle-size powders forms spherical agglomerates. In the present study, the powders had smaller particle size (all excipients with D50 < 75 µm) and PVP is a low viscosity binder (than HPMC) [29]. Therefore, it seems that the finding from Johansen and Schaefer [28], though was based on melt granulation, was also applicable to the high shear wet granulation wherein the binders were added in the form of solution. SEM revealed that the exterior of the lactose based granule contained both lactose and MCC particles, whereas the exterior of mannitol based granules principally contained mannitol crystals (Fig. 3). This is discussed in detail in section 3.9.3. 3.2. Bulk density

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3.2.1. Impact of binder addition method on granule bulk density The binder addition by dripping technique produced granules with the highest bulk

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density, whereas the binder addition by spraying technique produced granules with the least

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bulk density (Table 3). The trend was similar in unmilled and milled granules and did not

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change with the change in diluent and binder type. So, it can be stated that the granule bulk density increased in order when the binder was added by spraying < pouring < dripping technique. It was observed that the binder addition by pouring produced bigger granules (Table 4), while the binder addition by spraying yielded spherical granules (Fig. 2). Both the

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increase in particle size and sphericity of granules reduced granule bulk density conceivably by increasing the voids in blends. We further noticed that the binder addition by pouring

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technique produced several granules with structures that facilitate the voids in blend; representative particles are shown in Fig. 4.

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3.2.2. Impact of binders on granule bulk density

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In lactose formulations, HPMC produced granules with the higher bulk density compared to PVP, whereas in mannitol formulations, the impact of binder was inverse.

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Generally the bulk density depends on the volume of the bulk; lower the volume higher is the bulk density when the mass is same. It can be seen from Table 3 and 4 that HPMC/lactose granules had more fines and smaller particle size than the PVP/lactose, and PVP/mannitol

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granules had more fines and smaller particle size than the HPMC/mannitol granules. Fines have propensity to percolate and fill the granular voids and thus the blends containing more fines can be expected to exhibit higher bulk density than the blends having less fines. Similarly, the blends containing smaller granules retain less voids in their bulk and thus exhibit higher bulk density than the blends containing bigger granules. 3.2.3. Impact of diluents on granule bulk density The diluent showed significant impact (p < 0.0001) on the granule bulk density; lactose formed granules of higher bulk density compared to mannitol by all binders and binder addition methods (Table 3). This was because of the higher bulk density of native

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lactose (Pharmatose 200M) compared to mannitol (Pearlitol 50C), which also suggests that lactose retains less voids compared to mannitol in its bulk.

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3.3. Tapped density

Tapped density indicates the ability of material to undergo reduction in volume with

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applied taps. Together with bulk density, it contributes to flow prediction by CI and HR. It is conceivable that along with other factors, geometry can markedly influence the granule tapped density; irregular and smaller granules would have higher tapped density than the

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spherical and bigger granules due to less voidage and greater inter-particle locking ability in the former.

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The granule taped density followed the same trend as of bulk density for the impact of all variables of this study. However, it is noteworthy that the impact of binders on granule bulk and taped density was more prominent in lactose than mannitol formulations suggesting

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that lactose was more sensitive than mannitol for binder change affecting the granule bulk

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and taped density. This was also supported by the contact angle observations wherein the difference in affinity of different binders was greater in the case of lactose compared to

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mannitol (Fig. 5A and B).

3.4 Carr’s index and Hausner ratio.

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3.4.1. Impact of binder addition method on CI and HR In most of the trials, the binder addition by spraying technique improved sphericity of granules (Fig. 2), and thus lowered the granule CI values (indicating better flow) The general experience with bulk solid is that the flowability increases with increasing particle size. However, formulations F11 and F12 despite of their smallest particle size (Table 4) showed the lowest CI and the highest ffc values (superior flow) (Table 3) indicating that the granule shape prevailed over other attributes such as granule size and density to improve the granule flow. Notably, the granulations (milled granules) of this study had particle size (D50) in the range of 93-255 µm and bulk density in the range of 0.52 to 0.68 g/ml. 3.4.2. Impact of binders on CI and HR 12

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Amongst the binders, PVP produced granules with the lower CI and HR values compared to the HPMC. (Table 3). As can be seen from Fig. 2, PVP based granules were relatively spherical and thus achieved the better flow. This was in agreement with Patel et al.

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though their study employed only lactose granulations.

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[30], who observed that the granule flow was improved with PVP as a binder than HPMC;

3.4.3. Impact of diluents on CI and HR

In most of the cases, mannitol granules showed lower CI than their lactose

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counterparts (based on milled granules). CI value decreases with the decrease in difference between bulk and taped density. To understand why mannitol granules had less difference

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between the bulk and taped density (thus lower CI), we compared granule particle size by Sympatec (Table 4). There was no definite correlation between the granule particle size and the difference in their bulk and taped density as the mannitol/HPMC granules were bigger,

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whereas mannitol/PVP granules were smaller than their lactose counterparts, and yet the

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mannitol granules had the lower CI values (superior flow). Next, we compared the morphology and observed that the shape was comparable between the lactose and mannitol

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granulations (Fig. 2). However, the granule: fine portions (Table 3) revealed that mannitol formulations contained less fines than their lactose counterparts. In the blends having more fines, more and more fines can percolate the granular voids with applied taps lowing the tap volume and thus increasing the granule taped density (though to a limiting value). Therefore,

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it appears that the presence of less fines in mannitol formulations has reduced the difference between bulk and taped density lowering the granule CI values. The HR values were in accordance with the CI values (Table 3). Most of the lactose granulations had HR values > 1.25 indicating “passable” flow and most of the mannitol formulations had HR values < 1.25 suggesting the “fair” flow of the granules. 3.5. Ring shear testing Ring shear testing is a more effective way (compared to CI and HR) to predict the granule flow property. Milled granules were subjected to the ring shear testing and the data is summarized in Table 3. The granules prepared by binder spraying technique showed higher

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ffc values compared to the other binder addition methods (Table 3). This was because the binder addition by spraying imparted sphericity to granules improving their flow (Fig. 2). The mannitol granules exhibited better flow (higher ffc values) than their lactose

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counterparts (Table 3), which was in agreement with the CI and HR observations. Notably,

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there was about 2 fold increase in ffc values when PVP was a binder (by dripping and

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spraying technique) compared to HPMC for mannitol granulations. The ffc value of 4-10 indicates “easy flowing”, whereas ffc greater than 10 indicates “free flowing” characteristic of the blend. The ffc values close to or greater than 10 were achieved only in the formulations

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wherein PVP was a binder or the binders were added by the spraying technique, which suggests that PVP and binder addition by spraying improved the sphericity of granules

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improving their flow property. 3.6. Contact angle (binder-diluent affinity)

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While dealing with heterogeneous systems, it is important to know how the different

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phases will behave when brought in contact with each other. It is well known, for instance, that some liquids, when placed in contact with other liquids or solids surface, will remain

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retracted in the form of drop, while other liquids may exhibit a tendency to spread and cover the surface. The phase affinity can be assessed by measuring the contact angle between the phases; lower contact angles indicate higher affinity and lower surface free energy in the phases.

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The contact angles of different diluent-dispersion droplets on binder films over a period of time are plotted in Fig. 5A and B. Results revealed that HPMC has higher affinity towards mannitol, and PVP towards lactose. Looking at the functional groups in these excipients, it appears that the excipients having similar functional groups showed higher affinity towards each other; PVP and lactose have carbonyl groups, while HPMC and mannitol have hydroxyl groups in their structure. Furthermore, HPMC in binders, and lactose in diluents showed greater difference in affinity towards different diluents and binders, respectively. Since the high binder-diluent affinity facilitates binder ingress, distribution, particle-consolidation and granule growth, the impact of binder-diluent affinity can also be learned through the impact of granule particle size and granule: fine portions on other granule and tablet attributes as described in the following sections. 14

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3.7. Granule: Fine portions

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3.7.1. Impact of binder addition method on granule: fine portions

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The binder addition by spraying increased fines, and the binder addition by pouring reduced fines in the final blends (Table 4). The impact, however, was not statistically

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significant (p > 0.05). The binder addition by spraying and pouring respectively deliver the smaller and bigger droplets/stream to the powder-bed under granulation. This suggests that the amount of fines was inversely proportional to the droplet/stream size of liquid binder

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falling on the powder bed in the granulator.

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3.7.2. Impact of binders on granule: fine portions

Amongst the binders, PVP as a binder for lactose, and HPMC for mannitol reduced the fines in final blends. This was due to the higher affinity of PVP for lactose, and HPMC

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for mannitol (Fig. 5A and B). Since fines can alter granule flow, density, segregation and

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compressibility, this was an important finding that can help formulator choosing an appropriate binder based on the diluent to be used in high shear wet granulation. Results of

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this study recommend PVP for lactose, and HPMC for mannitol particularly to reduce the fines in batch via high shear wet granulation.

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3.7.3. Impact of diluents on granule: fine portions Amongst all variables, diluent had significant impact (p < 0.0075) on the granule: fine portions. In most of the cases, lactose formulations contained more fines (%) than their mannitol counterparts (Table 3). This can be ascribed to the smaller particle size of lactose (Table 5) and brittleness of lactose over mannitol. The brittleness of lactose over mannitol is reported in literature; Chang et al. [31] found that lactose-based granules were finer than their mannitol counterparts because of the brittleness of lactose compared to mannitol. Though the granules were produced by roller compaction technique in above study, it confirms the brittleness of lactose over mannitol contributing to the fines in granulation. 3.8. Granule particle size

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3.8.1. Impact of binder addition method on granule size The binder addition by pouring and spraying increased and decreased the granule

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particle size, respectively (Table 4). This suggests that the granule growth was directly

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proportional to the droplet size of binder solution accessing the powder bed in granulation.

3.8.2. Impact of binders and diluents on granule size

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The impact of diluents, binders or binder addition methods, as an individual variable, on granule particle size was not statistically significant (p > 0.05). This was due to the fact that the binder and diluent in combination, based on their affinity for each other,

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predominantly influenced the granule particle size. PVP as a binder for lactose, and HPMC for mannitol increased the granule particle size (Table 4), which was due to the higher

D

affinity of PVP for lactose, and HPMC for mannitol. Besides the higher affinity for mannitol, HPMC yields a solution of higher viscosity and lower surface tension (48 mN/m) than PVP

TE

(68 mN/m) [29], which also facilitates binder ingress, particle consolidation and granule growth in high shear wet granulation. Therefore, the impact of HPMC to increase granule

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particle size was in agreement with the general hypothesis of wet granulation that the granule growth is directly proportional to the viscosity and inversely to the surface tension of binder solution. However, the fact that PVP over HPMC produced bigger granules in all lactose

AC

formulations (Table 4), which was due to the higher affinity of PVP for lactose, clearly indicates that the binder-diluent affinity prevailed over surface tension and viscosity of binder solution to promote the granule growth. Notably, the PVP/lactose granules had bigger particle size compared to both PVP/mannitol and HPMC/lactose granules (Table 4). As stated earlier, lactose retains less voids compared to mannitol in its bulk, and PVP yields a solution of lower viscosity than HPMC [29]. Therefore, we can say, for the blends with less voidage (higher bulk density), low viscosity binders like PVP are more suitable to achieve the higher granule growth. Scientists have also studied the impact of microcrystalline cellulose crystallinity and found that decrease in crystallinity increases the abrasion of material by impeller, which eventually increases the granule particle size [32]. It has also been reported that PVP is suitable for low polarity substrate and HPMC for high polarity substrate to facilitate the 16

ACCEPTED MANUSCRIPT

granule growth [33]. In the present study, PVP was suitable for lactose, and HPMC for mannitol to promote the granule growth, and therefore it seems that lactose is less polar than mannitol. The above details, however, in particular propose that along with the binder-diluent

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ingredients might influence the granule growth kinetics.

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affinity, other factors like the voidage in blend, crystallinity of ingredients and the polarity of

3.9. Granule friability

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3.9.1. Impact of binder addition method on granule friability

The binder addition by pouring decreased granule friability, whereas the binder

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addition by spraying increased granule friability (Table 4). This was because the binder addition by the pouring and spraying produced the bigger and smaller granules, respectively. The bigger granules can be expected to possess more binder-rich domains [34] that impart

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strength rendering the bigger granules less friable than the smaller granules/particles.

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3.9.2. Impact of binders on granule friability

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The binders showed significant (p < 0.05) impact on the granule friability; PVP produced more friable granules compared to the HPMC (Table 4). It is mentioned earlier in this article that granule friability was inversely proportional to the granule particle size,

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however, PVP/lactose granules were bigger than HPMC/lactose granules (Table 4) and yet showed the higher friability. This clearly indicates that granule particle size did not solely influence the granule friability. In a wet granulation, wherein the binders are added in the form of solution, binders have propensity to form a coating/film (partly if not fully) on the powder particles and the resulting granules during granulation and drying. Whilst HPMC can form a tough film, PVP forms a weak and brittle film [35]. The tough HPMC films/coats in the granule-domains make granules more resistant to fragmentation. In addition, since PVP yields solution of lower viscosity and has a weak-film forming propensity, it can be expected that the binder-diluent particles would be held loosely together in the PVP based granules compared to HPMC. Such granules can undergo more fragmentation when subjected to the friability test showing the higher friability.

17

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3.9.3. Impact of diluents on granule friability The mannitol granules were much more friable than their lactose counterparts (Table

T

4). This was contrary to the known fact that lactose is brittle than mannitol [31]. This further

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indicates that the excipients and their granule-form (prepared via high shear wet granulation)

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can behave distinctly in terms of friability, which may be due to the dynamics of high shear wet granulation. During mixing in high shear granulator, ingredients of different particle size have tendency to segregate. Therefore, the nuclei and the exterior of the granule may contain different proportion of excipients. Morin and Briens [13] prepared granules with 1:1 ratio of

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lactose monohydrate and MCC (Avicel PH 101), and noticed that large lactose particles were forced towards the side and bottom of the bowl during mixing in high shear granulator and

MA

thus the nuclei contained only MCC, and lactose existed mostly in the exterior of the granules. However, the above study did not specify the grade and detail particle size of lactose that was used. In the present study, SEM revealed that lactose based granules

D

contained comparable portions of lactose and MCC in the exterior of the granule, whereas the

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exterior of mannitol based granule principally contained mannitol particles/crystals (Fig. 3). The blends in present study used either lactose (Pharmatose 200M): MCC (Avicel PH 101) or

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mannitol (Pearlitol 50C): MCC (Avicel PH 101) in 1:1 ratio. The particle size of lactose, MCC and mannitol was determined by Sympatec and the data is summarized in Table 5. Results show that the lactose and MCC had comparable particle size, whereas the particle

AC

size of mannitol was relatively bigger. So, as described by Morin and Briens [13], it appears that mannitol, because of its larger particle size, segregated in MCC: mannitol blends, whereas MCC: lactose blends did not segregate (due to the comparable particle size of these excipients) during mixing and granulation, and thus the granules from these two distinct blends showed different excipient-arrangements in the exterior of the granules. Since lactose based granule contained comparable portions of MCC and lactose, and MCC is less brittle than mannitol, it showed less friability compared to the mannitol based granules wherein MCC formed nuclei, and mannitol the exterior of granules. In addition, it appears from Fig. 2 and 3 that mannitol granules had more intragranular pores and crystalline regions compared to their lactose counterparts. Intragranular pores reduce granule strength, while crystalline domains encourage granule fragmentation/breakage under stress (oscillations in friability test) leading to the higher granule friability. 18

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According to Handbook of Pharmaceutical Excipients [36], solubility of lactose is slightly higher than mannitol in water. It has also been reported that the increase in excipient solubility in granulation solvent decreases the solvent requirement and leads to the formation

T

of less friable granules [37,38]. However, the solubility difference between lactose and

IP

mannitol in water is very less and thus we anticipate a little contribution from it to the granule

SC R

friability. 3.10. Segregation potential

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Most of the recent APIs have low solubility and thus are synthesized in the smaller particle size. APIs of smaller particle size, post dry mixing in high shear granulator, percolate

MA

to the bottom of the bed rendering top layers of the bed subpotent. Binder solution initially access the top layers of powder bed producing subpotent granules and superpotent fines [22]. In contrast, Vromans et al. [39] reported that micronized steroid when granulated with

D

unmicronized lactose produce superpotent granules and subpotent fines. From these findings,

TE

however, it is apparent that the coarse and fine fraction of granules may contains substantially different amounts of API. Therefore, the factors affecting granule: fine segregation potential

tableting.

CE P

should be evaluated and controlled beforehand to mitigate the content uniformity risk in

If the bulk of solid containing a mixture of coarse and fine fraction is fluidized, a layer of fines remain at the top and coarse particles sink downward. In pharmaceutical

AC

manufacturing, this can happen when the particles-stream fed into the dies during tabletting drags a significant stream of air with it. The blend segregation tendency in such situation can be assessed by the fluidization segregation testers. These instruments fluidize the blend, hold it in a fluidized state for a given period of time and divide it in three parts allowing the collection of samples in top, middle and bottom cell of the apparatus. Fines have propensity to accumulate in the top cell and thus more fines (compared to granules) in top cell indicate the higher segregation potential of the blend. 3.10.1. Impact of binder addition methods on blend segregation potential In lactose formulations, binder addition technique did not substantially affect the blend segregation potential (Table 6). On the other hand, in mannitol formulations, binder 19

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addition by spraying technique facilitated the blend segregation potential. This can be attributed to the presence of higher amount of fines in the formulations prepared by the binder spraying technique (Table 3). The mannitol/PVP granulations wherein the binder was

T

added by spraying technique showed the highest segregation potential, which might be due to

SC R

IP

the presence of the highest amount of fines in this batch amongst all mannitol formulations. 3.10.2. Impact of binders on granule segregation potential

Both in lactose and mannitol formulations, PVP based blends showed greater

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difference in granule: fine portions between the top and bottom cell of the apparatus (Table 6), which indicates the non-homogeneity in these blends. Both HPMC and PVP are the

MA

polymeric materials. HPMC is partly O-methylated and O-(2-hydroxypropylated) cellulose polymer and PVP is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidinone groups. Each polymer has a specific polydispersity index (PI). PI is a ratio of weight average

D

molecular weight to the number average molecular weight of polymer, which indicates the

TE

distribution of individual molecular masses in the batch of polymer. PI values close to unity show that molecules have the same or comparable molecular weights (MWs), while higher PI

CE P

values indicate the presence of fractions with different MWs distributed around the average MW. The PI of PVP (K30) is 5.5, while for HPMC (methocel E5 LV) it is about 1. This indicates a wide and narrow range of molecular weight distribution in PVP and HPMC, respectively. The wide range of Mw distribution in PVP can be expected to induce non-

AC

homogeneity in granulation causing the variations in granule: fine portions, which subsequently can facilitate the blend segregation potential. 3.10.3. Impact of diluents on granule segregation potential In lactose formulations, the amount of fines in top cell was 84-90%, while it was only 47-78% in mannitol formulations (Table 6). This clearly indicates that the mannitol blends had much lower segregation potential than their lactose counterparts. There could be two reasons; first the presence of higher amount of fines in lactose compared to mannitol formulations (Table 3), and secondly the presence of more crystalline domains in mannitol compared to lactose granules (Fig. 3); a network of such crystalline granules in blend could

20

ACCEPTED MANUSCRIPT

impede the escape of fluidized fines to the top cell reducing the percentage of fines in top cell of the apparatus.

IP

T

3.11. Physicochemical properties of tablets

All the blends were compressed at the same compression force of 16 KN and resulting

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tablets were characterized for pharmacotechnical properties. 3.11.1. Tablet hardness and tensile strength

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The diluents, binders and binder addition methods influenced tablet hardness via granule friability. The increase in granule friability increased the final tablet hardness. In this

MA

study, mannitol over lactose, PVP over HPMC, and spraying over other binder addition methods produced tablets with the higher hardness (Table 7). Among the variables of this study, only diluents showed significant (p < 0.0005) impact on the tablet hardness and tensile

D

strength. With respect to the binders, Joneja et al. [40] reported that the cellulose based

TE

binders can produce tablets with the highest toughness, whereas the tablets containing other binders like PVP fail by capping and random cracking in the middle. However, we observed

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that the tablets containing PVP had higher hardness and tensile strengths compared to their HPMC counterparts, which was due to the higher friability of PVP based granules (Table 4). Furthermore, since HPMC forms a tough film and PVP a weak and brittle film, HPMC based

AC

granules can be more resistant to fragmentation and inter-particle bonding in tableting to reduce the final tablet toughness. Regarding the diluents, mannitol based tablets had higher hardness and tensile strengths compared to their lactose counterparts, which was in agreement with Rasenack and Muller [41], who reported that the tabletting factor (T-factor) of mannitol is superior to lactose. Also, Juppo et al. [42] have studied the effect of amount of granulation liquid, compression speed and compression force on compressibility and compactibility of lactose, glucose and mannitol granules and found that mannitol forms the hardest tablets and lactose and glucose the weakest. The tablet tensile strength was calculated as per the literature [43]. The impact of diluents, binders and binder addition methods on tablet tensile strength was based on the granule friability, and the trend was same as discussed above for the tablet hardness. Based on our observations from various other tablet formulations and their shipment studies, we can 21

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say that the tablet tensile strength of > 1.9 indicates satisfactory strength for handling and transportation. In this study, all the values were > 1.9 suggesting an excellent tablet tensile

T

strengths from all the formulations.

IP

3.11.2. Tablet thickness

SC R

According to Food and Drug Administration (FDA, USA), dimensions of solid oral generics are critical and should be targeted comparable to the reference product for better patient compliance [44]. Understanding the impact of excipients and process parameters on

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tablet thickness is therefore important to design an appropriate generic formulation. In this study, tablets containing lactose exhibited lower thickness than their mannitol counterparts

MA

(Table 7), which was due to the higher bulk density of lactose compared to mannitol. Amongst the binders, tablet thickness was lower when HPMC was a binder for lactose, and PVP for mannitol granulations. This was attributed to the higher bulk density, more fines and

D

smaller particle size of these granulations. In the lactose based tablets, thickness was lowest

TE

when the binders were added by the pouring technique, whereas in mannitol tablets, thickness was lowest when the binders were added by the dripping technique. This again was attributed

CE P

to the granule bulk density; binders pouring and dripping increased the granule bulk density in lactose and mannitol granulations, respectively. Amongst the binder addition methods, the binder addition by spraying decreased granule bulk density (Table 3), and thus increased the final tablet thickness. Overall, the impact of diluents on tablet thickness was significant (p <

AC

0.0001), whereas the binders and binder addition methods did not significantly (p > 0.05) alter the final tablet thickness; the change in binder and binder addition method yielded tablets within mean ± 0.3 mm range, which is a well-accepted range in routine tablet manufacturing in the pharmaceutical industries. 3.11.3. Tablet friability In lactose formulations, the binders and binder addition methods did not substantially affect the tablet friability. Whereas in mannitol formulations, PVP as a binder produced less friable tablets compared to the HPMC (Table 7). This was due to the higher friability of PVP based granules compared to HPMC; the tablet friability was inversely proportional to the granule friability. In lactose formulations, granule friability of > 15% produced tablets with 22

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appreciable tensile strength and lower friability, whereas in mannitol formulations, the granule friability of even > 10% produced tablets with high tensile strength and negligible friability. The lactose based tablets were much more friable compared to their mannitol

T

counterparts; the data was confirmed at two different revolutions (100 and 300) in friabilator.

IP

Again, the impact of diluents on tablet friability was significant (p < 0.0001), whereas the

SC R

binders and binder addition methods did not significantly (p > 0.05) affect the tablet friability. 3.11.4. Tablet disintegration

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There are number of factors that can influence tablet disintegration, some of these are the drug properties, excipient properties, type of disintegrant and the tablet hardness. In this

MA

study, lactose and mannitol as diluents, and HPMC and PVP as binders were comparatively evaluated. Since lactose and mannitol have comparable solubility, and the disintegrant and other auxiliary excipients were constant in all formulations, the tablet disintegration time in

D

present study was principally governed by the tablet hardness and tensile strength, which

TE

were directly proportional to the granule friability. The impact of diluents, binders and binder addition methods on granule friability is described in detail earlier in this report. Overall,

CE P

tablet disintegration time increased with the increase in tablet hardness and tensile strength. The diluents followed by binders showed substantial impact, whereas the binder addition methods could not substantially influence the tablet disintegration time. In this study, mannitol over lactose, PVP over HPMC and spraying over other binder addition methods

AC

increased tablet disintegration time (Table 7). 4. Conclusion

This study investigated a comparative impact of different binder addition methods, diluents and binders on various granules and tablet attributes via high shear wet granulation. Binder addition methods altered granule shape, which predominantly governed the granule flow. Binder addition by spraying increased fines, blend segregation potential, granule friability, tablet tensile strength and tablet disintegration time; binder addition by pouring showed an opposite impact. Diluents dominated binders and binder addition methods to influence granule density, segregation potential and friability. Mannitol based granules exhibited lower bulk and taped density, higher friability, superior flow and lower segregation potential 23

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compared to their lactose counterparts. The high polydispersity index of polymer-binder induced non-homogeneity facilitating the blend segregation-potential. The PVP based granules were more friable compared to the HPMC based granules. Contact angle study

T

revealed higher affinity of PVP for lactose, and HPMC for mannitol. The binder-diluent

IP

affinity prevailed over surface tension and viscosity of binder solution to promote granule

SC R

growth. Increase in granule size decreased granule friability, tablet hardness, tensile strength and disintegration time. Mannitol produced harder tablets, and lactose tablets disintegrated faster by all binders and binder addition methods.

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Funding

commercial, or not-for-profit sectors.

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Acknowledgments

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This research did not receive any specific grant from funding agencies in the public,

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TE

The author wish to thank Colin Carr for providing language help for this article.

24

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References [1]

G. Boehm, L. Yao, L. Han, Q. Zheng, Development of the generic drug industry in

T

the US after the Hatch-Waxman Act of 1984, Acta Pharmaceutica Sinica B. 3 (2013)

A. Nokhodchi, An overview of the effect of moisture on compaction and compression, Pharm. Tech. (2005) 46-66.

[3]

S. Spireas, US patent US6979462 B1. Stabilization of solid dosage formulations. (2005).

Z. Belohlav, L. Brenkova, J. Hanika, P. Durdil, P. Rapek, V. Tomasek, Effect of drug

NU

[4]

SC R

[2]

IP

297-311.

active substance particles on wet granulation process, Chem. Eng. Res. Design. 85

[5]

MA

(2007) 974-980.

M. Cavinato, E. Andreato, M. Bresciani, I. Pignatone, G. Bellazzi, E. Franceschinis, N. Realdon, P. Canu, A.C. Santomaso, Combining formulation and process aspects

[6]

TE

(2011) 229-241.

D

for optimizing the high-shear wet granulation of common drugs, Int. J. Pharm. 416

M.B. Mackaplow, L.A. Rosen, J.N. Michaels, Effect of primary particle size on

CE P

granule growth and endpoint determination in high-shear wet granulation, Powder Technol. 108 (2000) 32-45. [7]

I. Sherif, F. Badawy, M.A. Hussain, Effect of starting material particle size on its

AC

agglomeration behavior in high shear wet granulation, AAPS PharmSciTech. 5 (2004) 16-22. [8]

D. Zhang, J.H. Flory, S. Panmai, U. Batra, M.J. Kaufman, Wettability of pharmaceutical solids: its measurement and influence on wet granulation, Colloids Surf. A: Physicochem. Eng. Asp. 206 (2002) 547-554.

[9]

R. Ho, S.J. Hinder, J.F. Watts, S.E. Dilworth, D.R. Williams, J.Y.Y. Heng, Determination of surface heterogeneity of D-mannitol by sessile drop contact angle and finite concentration inverse gas chromatography, Int. J. Pharm. 387 (2010) 79-86.

[10]

M.D. Parker, P. York, R.C. Rowe, Binder-substrate interactions in wet granulation. 2: the effect of binder molecular weight, Int. J. Pharm. 72 (1991) 243-249.

[11]

J. Li, L. Tao, D. Buckley, J. Tao, J. Gao, M. Huber, The effect of the physical state of binders on high-shear wet granulation and granule properties: A mechanistic approach 25

ACCEPTED MANUSCRIPT

to understand the high-shear wet granulation process. Part IV. The impact of rheological state and tip-speeds, J. Pharm. Sci. 102 (2013) 4384-4394. [12]

A.M. Bouwman, M.J. Henstra, D. Westerman, J.T. Chung, Z. Zhang, A. Ingram,

T

J.P.K. Seville, H.W. Frijlink, The effect of the amount of binder liquid on the

IP

granulation mechanisms and structure of microcrystalline cellulose granules prepared

[13]

SC R

by high shear granulation, Int. J. Pharm. 290 (2005) 129-136.

G. Morin, L. Briens, A comparison of granules produced by high-shear and fluidizedbed granulation methods. AAPS PharmSciTech. 15 (2014) 1039–1048. T.M. Chitu, D. Oulahna, M. Hemati, M., Wet granulation in laboratory scale high

NU

[14]

shear mixers: effect of binder properties, Powder Technol. 206 (2011), 25-33. [15]

N. Rahmanian, M. Ghadiri, Y. Ding, Effect of scale of operation on granule strength

[16]

MA

in high shear granulators, Chem. Eng. Sci. 63 (2008) 915-923. C. Mangwandi, M.J. Adams, M.J. Hounslow, A.D. Salman, Effect of batch size on

D

mechanical properties of granules in high shear granulation, Powder Technol. 206 (2011) 44-52.

M. Borner, M. Michaelis, E. Siegmann, C. Radeke, U. Schmidt, Impact of impeller

TE

[17]

design on high-shear wet granulation, Powder Technol. 295 (2016) 261-271. I. Sherif, F. Badawy, M.M. Menning, M.A. Gorko, D.L. Gilbert, Effect of process

CE P

[18]

parameters on compressibility of granulation manufactured in a high-shear mixer, Int. J. Pharm. 198 (2000) 51–61. M. Benali, V. Gerbaud, M. Hemati, Effect of operating conditions and physico–

AC

[19]

chemical properties on the wet granulation kinetics in high shear mixer, Powder Technol. 190 (2009) 160-169. [20]

C. Mangwandi, M.J. Adams, M.J. Hounslow, A.D. Salman, Effect of impeller speed on mechanical and dissolution properties of high-shear granules, Chem. Eng. J. 164 (2010) 305-315.

[21]

L. Shi, Y. Feng, C.C. Sun, Massing in high shear wet granulation can simultaneously improve powder flow and deteriorate powder compaction: a double-edged sword, Eur. J. Pharm. Sci. 43 (2011) 50-56.

[22]

S. Oka, H. Emady, O. Kaspar, V. Tokarova, F. Muzzio, F. Stepanek, R. Ramachandran, The effects of improper mixing and preferential wetting of active and 26

ACCEPTED MANUSCRIPT

excipient ingredients on content uniformity in high shear wet granulation, Powder Technol. 278 (2015) 266-277. [23]

G.D. D'alonzo, R.E. O'connor, J.B. Schwartz, Effect of binder concentration and

T

method of addition on granule growth in a high intensity mixer, Drug Dev. Ind.

J. Zao, L. Tao, J. Li, A.S. Narang, Granule consolidation kinetics and the indication

SC R

[24]

IP

Pharm. 16 (2008) 1931-1944.

on granulation mechanism during high shear wet granulation: effect of binder type, molecular weight, and method of addition, AAPS Annual Meeting (2013), At San

NU

Antonio, TX. [25]

United States Pharmacopoeia, USP32-NF27, p 226.

[26]

J.D. Litster, K.P. Hapgood, J.N. Michaels, A. Sims, M. Roberts, S.K. Kameneni, T.

Technol. 114 (2001) 32-39.

H.N. Emady, D. Kayrak-Talay, W.C. Schwerin, J.D. Litster, Granule formation

D

[27]

MA

Hsu, Liquid distribution in wet granulation: dimensionless spray flux, Powder

mechanisms and morphology from single drop impact on powder beds, Powder

[28]

TE

Technol. 212 (2011) 69-79.

A. Johansen, T. Schaefer, Effects of interactions between powder particle size and

CE P

binder viscosity on agglomerate growth mechanisms in a high shear mixer, Eur. J. Pharm. Sci. 12 (2001) 297-309. [29]

S. Cantor, L.L. Augsburger, S.W. Hoag, A. Gerhardt, Pharmaceutical granulation

AC

processes, mechanism and the use of binders, in: L.L. Augsburger, S.W. Hoag, S.W. (Eds.), Pharmaceutical dosage forms: tablets, volume 1: Unit operations and mechanical properties, Informa Healthcare, New York, 2008, pp. 261-301. [30]

P. Patel, D. Telange, N. Sharma, Comparison of different granulation techniques for lactose, Int. J. Pharm. Sci. Drug Res. 3 (2011) 222-225.

[31]

C.K. Chang, F.A. Alvarez–Nunez, J.V. Rinella Jr., L.E. Magnusson, K. Sueda, Roller compaction, granulation and capsule product dissolution of drug formulations containing a lactose or mannitol filler, starch, and talc, AAPS PharmSciTech. 9 (2008) 597-604.

[32]

T. Suzuki, K. Watanabe, S. Kikkawa, H. Nakagami, Effect of crystallinity of microcrystalline cellulose on granulation in high-shear mixer, Chem. Pharm. Bull. 42 (1994) 2315-2319. 27

ACCEPTED MANUSCRIPT

[33]

R.C. Rowe, Binder-substrate interactions in granulation: a theoretical approach based on surface free energy and polarity, Int. J. Pharm. 52 (1989) 149-154.

[34]

J.D. Osborne, R.P.J. Sochon, J.J. Cartwright, D.G. Doughty, M.J. Hounslow, A.D.

J.N.C. Healey, M.H. Rubinstein, V. Walters, The mechanical properties of some

SC R

[35]

IP

bed granulation, Chem. Eng. Res. Des. 89 (2011) 553-559.

T

Salman, Binder addition methods and binder distribution in high shear and fluidised

binders used in tableting, J. Pharm. Pharmacol. 26 (1974) 41-46. [36]

R.C. Rowe, P.J. Sheskey, M.E. Quinn, Handbook of pharmaceutical excipients, sixth

[37]

NU

ed. Pharmaceutical Press. (2009)

J.I. Wells, C.V. Walker, The influence of granulating fluids upon granule and tablet properties: the role of secondary binding, Int. J. Pharm. 15 (1983) 97-111. V.H. Dias, J.F. Pinto, Identification of the most relevant factors that affect and reflect

MA

[38]

the quality of granules by application of canonical analysis, J. Pharm. Sci. 91 (2002)

[39]

D

273-281.

H. Vromans, H.G. Poels-Janssen, H. Egermann, Effects of high-shear granulation on

[40]

TE

granulate homogeneity, Pharm. Dev. Technol. 4 (1999) 297-303. S.K. Joneja, W.W. Harcum, G.W. Skinner, P.E. Barnum, J.H. Guo, Investigating the

CE P

fundamental effects of binders on pharmaceutical tablet performance, Drug Dev. Ind. Pharm. 25 (1999) 1129-1135. [41]

N. Rasenack, B.W. Muller, Crystal habit and tableting behavior, Int. J. Pharm. 244

[42]

AC

(2002) 45-57.

A.M. Juppo, L. Kervinen, J. Yliruusi, E. Kristoffersson, Compression of lactose, glucose and mannitol granules, J. Pharm. Pharmacol. 47 (1995) 543-549.

[43]

A. Aodah, R.S. Bafail, M. Rawas-Qalaji, Formulation and evaluation of fastdisintegrating sublingual tablets of atropine sulfate: the effect of tablet dimensions and drug load on tablet characteristics, AAPS PharmSciTech. (2016) 1-10.

[44]

FDA (Food and Drug Administration), 2015. Size, shape, and other physical attributes of generic tablets and capsules.

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Table 1

mg/ tablet

Microcrystalline cellulose (Avicel PH 101)

198.0

OR mannitol (Pearlitol 50C)

198.0

Prem. E5 LV) OR Polyvinyl pyrrolidone

22.0

(Kollidon 30)

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Hydroxypropyl methylcellulose (Methocel

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Lactose monohydrate (Pharmatose 200M)

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Ingredients

Croscarmellose sodium (Ac-Di-Sol)

19.0 4.5

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Colloidal silicon dioxide

T

A base composition for granules and tablets

Talc

4.0 4.5

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Magnesium stearate

450.0

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Total

29

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Table 2 Formulation batch numbers F2

F3

F4

F5

F6

F7

F8

Lactose













-

Mannitol

-

-

-

-

-

-



HPMC E5







-

-

-

PVP K30

-

-

-







F10 F11 F12

-

-

-

-

















-

-

-

-

-

-







SC R

-

NU

Binder addition technique

F9

T

F1

IP

Batch number

-



-

-



-

-



-

-



-

-



-

-



-

-



-

-





-

-



-

Dripping

-



-

-

Spraying

-

-



-

MA

Pouring

“” indicates used, and “-” indicates not used. A 40% w/w Avicel PH 101 and 1% w/w each

AC

CE P

TE

D

of talc, aerosil 200 pharma and magnesium stearate were constant in all the blends

30

ACCEPTED MANUSCRIPT

Table 3

F5 F6 F7 F8 F9 F10 F11 F12

(g/mL)

Unmilled

0.644

0.843

Milled

0.660

0.858

Unmilled

0.66

0.856

Milled

0.679

0.863

Unmilled

0.608

Milled

0.642

Unmilled

0.631

Milled

Dripping Spraying Pouring Dripping Spraying Pouring

Dripping Spraying Pouring

Dripping Spraying

ratio

ffc

value

Granule: Fine portions (% w/w)

23.61

1.31

-

60:40

23.08

1.30

7.2

54:46

22.90

1.30

-

62:38

21.32

1.27

7.9

44:56

0.778

21.85

1.28

-

67:33

0.796

19.35

1.24

9.1

41:59

0.806

21.71

1.28

-

64:36

0.649

0.817

20.56

1.26

7.6

57:43

Unmilled

0.652

0.808

19.31

1.24

-

67:33

Milled

18.83

1.23

9.2

50:50

NU

Pouring

index

IP

(g/mL)

MA

F4

method

Carr’s Hausner

D

F3

density

0.823

Unmilled

0.606

0.749

19.09

1.24

-

72:28

Milled

0.624

0.765

18.43

1.23

11.8

44:56

Unmilled

0.540

0.641

15.76

1.19

-

76:24

Milled

0.546

0.679

19.59

1.24

8.0

72:28

Unmilled

0.562

0.702

19.94

1.25

-

71:29

Milled

0.566

0.699

19.03

1.23

8.4

64:36

Unmilled

0.519

0.617

15.88

1.19

-

70:30

Milled

0.524

0.642

18.38

1.23

9.9

63:37

Unmilled

0.541

0.637

15.07

1.18

-

74:26

Milled

0.549

0.683

19.62

1.24

8.8

69:31

Unmilled

0.559

0.694

19.45

1.24

-

72:28

Milled

0.578

0.709

18.48

1.23

13.5

58:42

Unmilled

0.531

0.634

16.25

1.19

-

84:16

Milled

0.529

0.644

17.86

1.22

17.3

49:51

0.668

TE

F2

Granules density

CE P

F1

Tapped

addition

AC

Batch

Bulk

SC R

Binder

T

Physicochemical properties of granules

31

ACCEPTED MANUSCRIPT

Table 4 The particle size and friability of the final milled granules Binder

Granules size (µm) D50

D90

SC R

D10

IP

addition

T

Batch

Granule friability (% w/w)

Pouring

57.85 ± 0.83

131.66 ± 2.34 369.53 ± 1.74

1.49

F2

Dripping

41.70 ± 0.08

116.45 ± 0.62 314.03 ± 3.22

7.25

F3

Spraying

33.96 ± 0.09

98.17 ± 0.21

267.61 ± 0.31

8.75

F4

Pouring

73.63 ± 0.08

231.05 ± 0.33

516.80 ±2.07

4.81

F5

Dripping

59.77 ± 0.13

207.13 ± 3.09

484.37 ±0.56

15.02

F6

Spraying

46.13 ± 0.24

129.25 ± 0.11

417.98 ±3.33

17.46

F7

Pouring

82.01 ± 0.05

255.02 ± 2.42 552.40 ± 9.31

8.05

F8

Dripping

52.16 ± 0.21

221.13 ± 0.36 527.55 ± 2.86

10.85

F9

Spraying

31.03 ± 0.06

168.22 ± 0.89 453.59 ± 0.13

13.19

F10

Pouring

43.21 ± 1.24

122.28 ± 0.11 347.27 ± 0.24

14.79

F11

Dripping

36.82 ± 0.91

109.13 ± 0.07 301.93 ± 1.55

23.47

F12

Spraying

33.01 ± 0.04

93.42 ± 0.05

25.45

214.56 ± 0.09

AC

CE P

TE

D

MA

NU

F1

32

ACCEPTED MANUSCRIPT

Table 5

Particle size (µm) D50

3.8 ± 0.03

48.27 ± 0.08

3.2 ± 0.08

41.26 ± 0.31

101.43 ± 0.22

(Avicel PH 101) Lactose monohydrate

105.61 ± 0.16

75.31 ± 0.07

147.38 ± 0.30

AC

CE P

TE

D

MA

16.8 ± 0.05

NU

(Pharmatose 200M) Mannitol (Pearlitol 50C)

D90

SC R

Microcrystalline cellulose

D10

IP

Excipient

T

Particle size of excipients as determined by Sympatec

33

ACCEPTED MANUSCRIPT

Table 6

F3

F4

(% w/w)

Top

11

89

Middle

51

49

Bottom

76

24

Top

14

86

Middle

39

Bottom

81

Top

14

Middle

54

46

Bottom

83

17

10

90

46

54

93

07

16

84

59

41

98

02

13

87

Middle

72

28

Bottom

94

05

Top

53

47

Middle

59

41

Bottom

72

28

Top

45

55

Middle

65

35

Bottom

69

31

Top

42

58

Middle

69

31

Top Middle

Top Middle Bottom

F7

F8

F9

Top

AC

F6

CE P

Bottom F5

T

(% w/w)

IP

segregation tester

SC R

Fines

NU

F2

Granules

61 19 86

MA

F1

Location of cell in

D

Batch

TE

Granules and fines in top, middle and bottom cell of fluidization segregation tester

34

49

61

Middle

68

32

Bottom

76

24

Top

43

67

Middle

62

38

Bottom

76

24

Top

22

78

Middle

50

50

Bottom

79

SC R

IP

T

Top

D

MA

21

TE

F12

25

CE P

F11

75

AC

F10

Bottom

NU

ACCEPTED MANUSCRIPT

35

ACCEPTED MANUSCRIPT

Table 7

Hardness Thickness

addition

(kp)

(mm)

F1

Pouring

12.5

4.41

2.20

F2

Dripping 13.0

4.37

2.33

F3

Spraying 15.3

4.53

2.58

F4

Pouring

16.8

4.45

2.92

F5

Dripping 17.3

4.51

F6

Spraying 18.3

4.58

F7

Pouring

25.6

4.81

F8

Dripping 23.3

4.78

F9

Spraying 28.4

F10

Pouring

F11

Dripping 32.8

F12

Spraying 34.9

*

6

0.10

0.34

6

0.12

0.41

8

0.09

0.29

9

0.07

0.27

2.94

11

0.04

0.24

3.03

11

0.05

0.25

3.97

16

Nil

0.07

3.60

14

0.03

0.09

4.96

4.15

16

Nil

0.05

4.76

4.41

16

Nil

0.03

4.73

5.16

21

Nil

Nil

4.86

5.26

22

Nil

Nil

time (min)

D

MA

NU

(MPa)

SC R

(%)

TE

28.3

strength

(%)

CE P

Batch

Disintegration Friability* Friability**

IP

Tensile

Binder

T

Tablet properties

Friability post 100 revolutions, ** friability post 300 revolutions.

AC

Hardness values were within ± 1.5 kp, and thickness values were within ± 0.2 mm range for all formulations, so only the mean of 3 determination is presented in the table above.

36

SC R

IP

T

ACCEPTED MANUSCRIPT

AC

CE P

TE

D

MA

NU

Fig. 1

37

Fig. 2

AC

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

38

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

AC

CE P

TE

D

Fig. 3

39

AC

Fig. 4

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

40

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

AC

CE P

TE

D

MA

Fig. 5

41

ACCEPTED MANUSCRIPT

Figure Captions

T

Fig. 1. Granulation set up showing (A) dripping and (B) spraying mechanisms.

IP

Fig. 2. SEM of granules prepared using various diluents, binders and binder addition

SC R

methods.

Fig. 3. SEM showing (A) microcrystalline cellulose (Avicel PH 101), (B) lactose monohydrate (Pharmatose 200M), (C) mannitol (Pearlitol 50C), (D) lactose-based

NU

granule and (E) mannitol-based granule.

Fig. 4. SEM showing various granule structures that can facilitate voids in blends

MA

Fig. 5. Contact angles of lactose: microcrystalline cellulose and mannitol: microcrystalline

AC

CE P

TE

D

cellulose dispersion droplets on (A) PVP films and (B) HPMC films.

42

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

AC

CE P

TE

D

MA

Graphical abstract

43

ACCEPTED MANUSCRIPT

T

IP

SC R NU MA D TE CE P AC

    

Highlights Binder addition methods alter granule shape that predominantly governs granule flow. Binder-diluent affinity dominates other factors to influence the granule growth. PVP as a binder produce more round and friable granules compared to the HPMC. High polydispersity index of polymer-binder facilitates blend segregation potential. Mannitol tablets achieve higher hardness, while lactose tablets dintegrate faster.

44