Particle Size, Moisture, and Fluidization Variations Described by Indirect In-line Physical Measurements of Fluid Bed Granulation

The aim of this study was to evaluate an instrumentation system for a bench scale fluid bed granulator to determine the parameters expressing the changing conditions during the spraying phase of a fluid bed process. The study focused mainly on four in-line measurements (dependent variables): fluidization parameter (calculated by inlet air flow rate and rotor speed), pressure difference over the upper filters, pressure difference over the granules (lower filter), and temperature of the fluidizing mass. In-line particle size measured by the spatial filtering technique was an essential predictor variable. Other physical process measurements of the automated granulation system, 25 direct and 12 derived parameters, were also utilized for multivariate modeling. The correlation and partial least squares analyses revealed significant relationships between various process parameters highlighting the particle size, moisture, and fluidization effect. Fluidization parameter and pressure difference over upper filters were found to correlate with in-line particle size and therefore could be used as estimates of particle size during granulation. The pressure difference over the granules and the temperature of the fluidizing mass expressed the moisture conditions of wet granulation. The instrumentation system evaluated here is an invaluable aid to gaining more control for fluid bed processing to obtain repeatable granules for further processing.     

Investigation of a 2-step agglomeration process performed in a rotary processor using polyethylene glycol solutions as the primary binder liquid

The purpose of this research was to investigate the use of polyethylene glycol (PEG) solutions as the primary binder liquid in a 2-step agglomeration process performed in a rotary processor and characterize the resulting granules and their tableting characteristics. This was done by granulation of binary mixtures of microcrystalline cellulose (MCC) and either lactose, calcium phosphate, acetaminophen, or theophylline, in a 1∶3 ratio, using a 50% (wt/wt) aqueous solution of PEG and water as the binder liquid. Formulations containing lactose were agglomerated using 5 different amounts of the PEG binder solution, giving rise to a PEG content in the range of 6% to 43% (wt/wt). The process outcome was characterized according to adhesion, yield, and water requirement, and the prepared granules were characterized according to size, size distribution, and flow properties as well as tableting properties. The agglomeration of all mixtures resulted in high yields of free-flowing agglomerates and gave rise to good reproducibility of the investigated agglomerate characteristics. The process allowed for the incorporation of 42.5% (wt/wt) PEG, which is higher than the percentage of PEG reported for other equipment. Tables of sufficient strength could be prepared with all investigated excipients using 20% wt/wt PEG; higher PEG contents gave rise to adhesion and prolonged disintegration. In conclusion, agglomeration in a torque-controlled rotary processor using solutions of PEG as the primary binder liquid was found to be a robust process, suitable for the incorporation of high contents of PEG and/or drug compounds.     

Effect of Different Excipients on the Physical Characteristics of Granules and Tablets with Carbamazepine Prepared with Polyethylene Glycol 6000 by Fluidized Hot-Melt Granulation (FHMG)

The objective of this study was to investigate the properties of granules and tablets with carbamazepine which were prepared employing a fluidized hot-melt granulation (FHMG) technique. The FHMG process was carried out at 65°C. Macrogol 6000 (PEG 6000) was used as a binder at the content 10% (w/w) of the granulated mass. Granules containing up to 70% (w/w) of the drug and 20–90% (w/w) of a filler (lactose, mannitol, calcium hydrogen phosphate (Di-Cafos), pregelatinized starch, and microcrystalline cellulose (MCC)) were produced. When the drug content was 30% (w/w), the yield of the process was satisfying (>95%) and flowability of the granules was better than placebo granules or drug-loaded granules prepared by wet granulation. Type of a filler had strong impact on physical properties of granules, and size distribution of the particles was the most homogenous when lactose or Di-Cafos were used. The FHMG technique enabled preparation of granules with better compressability compared with the wet-granulated product or with non-granulated powders. Tablets with shorter disintegration time than 10 min were obtained with 2.0% crospovidone added as a disintegrant. In comparison to tablets prepared from the wet-granulated mass, employment of the FHMG method resulted in tablets with faster dissolution of carbamazepine (more than 80% of the drug released within 15 min). This was achieved with mannitol or lactose/MCC, as fillers.     

Advanced Granulation Technology (AGTTM). An alternate format for serum-free, chemically-defined and protein-free cell culture media

To overcome limitations of conventional milling technology, we investigated the application of fluid bed granulation for the production of dry-form nutrient media. Serum-free, protein-free and chemically-defined specialty media were produced in granulated format and compared with identical formulations manufactured by conventional methods. HPLC analysis of multiple lots of granulated materials demonstrated that biochemical constituents were precisely and homogeneously distributed throughout the granules and that nutrient levels were comparable to conventional formats. Comparison of medium performance in cell proliferation and biological production assays demonstrated equivalence with reference media. The fluid bed granulation process meets pharmaceutical quality requirements and may be applied to a broad range of nutrient formulations required for bioproduction applications. This revised version was published online in July 2006 with corrections to the Cover Date.     

Evaluation of the Physicochemical Properties and Compaction Behavior of Melt Granules Produced in Microwave-Induced and Conventional Melt Granulation in a Single Pot High Shear Processor

Recently, microwave-induced melt granulation was shown to be a promising alternative to conventional melt granulation with improved process monitoring capabilities. This study aimed to compare the physicochemical and compaction properties of granules produced from microwave-induced and conventional melt granulation. Powder admixtures comprising equivalent proportions by weight of lactose 200 M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350 under the influence of microwave-induced and conventional heating in a 10-L single pot high shear processor. The properties of the granules and compacts produced from the two processes were compared. Relative to conventional melt granulation, the rates at which the irradiated powders heated up in microwave-induced melt granulation were lower. Agglomerate growth proceeded at a slower rate, and this necessitated longer massing durations for growth induction. These factors prompted greater evaporative moisture losses from the melt granules. Additionally, nonuniform heating of the powders under the influence of microwaves led to increased inter-batch variations in the binder contents of resultant melt granules and a reliance of content homogeneity on massing duration. Agglomerate growth proceeded more rapidly under the influence of conventional heating due to the enhanced heating capabilities of the powders. Melt granules produced using the conventional method possessed higher moisture contents and improved content homogeneity. The compaction behavior of melt granules were affected by their mean sizes, porosities, flow properties, binder, and moisture contents. The last two factors were responsible for the disparities in compaction behavior of melt granules produced from microwave-induced and conventional melt granulation.     

Tablet formulation containing meloxicam and β-cyclodextrin: Mechanical characterization and bioavailability evaluation

The purpose of this research was to evaluate β-cyclodextrin (β-CD) as a vehicle, either singly or in blends with lactose (spray-dried or monohydrate), for preparing a meloxicam tablet. Aqueous solubility of meloxicam in presence of β-CD was investigated. The tablets were prepared by direct compression and wet granulation techniques. The powder blends and the granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, disintegration time, and in vitro dissolution studies. The effect of β-CD on the bioavailability of meloxicam was also investigated in human volunteers using a balanced 2-way crossover study. Phase-solubility studies indicated an A_L-type diagram with inclusion complex of 1∶1 molar ratio. The powder blends and granules of all formulations showed satisfactory flow properties, compressibility, and drug content. All tablet formations prepared by direct compression or wet granulation showed acceptable mechanical properties. The dissolution rate of meloxicam was significantly enhanced by inclusion of β-CD in the formulations up to 30%. The mean pharmacokinetic parameters (C_max, K_e, and area under the curve [AUC]_0−∞) were significantly increased in presence of β-CD. These results suggest that β-CD would facilitate the preparation of meloxicam tablets with acceptable mechanical properties using the direct compression technique as there is no important difference between tablets prepared by direct compression and those prepared by wet granulation. Also, β-CD is particularly useful for improving the oral bioavailablity of meloxicam.     

Direct pelletization in a rotary processor controlled by torque measurements. III. Investigation of microcrystalline cellulose and lactose grade

The aim of the present study was to investigate the use of different grades of microcrystalline cellulose (MCC) and lactose in a direct pelletization process in a rotary processor. For this purpose, a mixed 2- and 3-level factorial study was performed to determine the influence of the particle size of microcrystalline cellulose (MCC), (≈60 and 105 μm) and lactose (≈30, 40, and 55 μm), as well as MCC type (Avicel and Emcocel) on the pelletization process and the physical properties of the prepared pellets. A 1∶4 mixture of MCC and lactose was applied, and granulation liquid was added until a 0.45 Nm increase in the torque of the friction plate was reached. All combinations of the 3 factors resulted in spherical pellets of a high physical strength. The particle size of MCC was found to have no marked effect on the amount of water required for agglomerate growth or on the size of the resulting pellets. An increasing particle size of lactose gave rise to more spherical pellets of a more narrow size distribution as well as higher yields. The MCC type was found to affect both the release of the model drug from the prepared pellets and the size distribution. Generally, the determined influence of the investigated factors was small, and direct pelletization in a rotary processor was found to be a robust process, insensitive to variations in the particle size and type of MCC and the particle size of lactose. Published: October 24, 2005     

Colorful Drying

Drying is one of the standard unit operations in the pharmaceutical industry and it is important to become aware of the circumstances that dominate during the process. The purpose of this study was to test microcapsulated thermochromic pigments as heat indicators in a fluid bed drying process. The indicator powders were manually granulated with α-lactose monohydrate resulting in three particle-size groups. Also, pellets were coated with the indicator powders. The granules and pellets were fluidized in fluid bed dryer to observe the progress of the heat flow in the material and to study the heat indicator properties of the indicator materials. A tristimulus colorimeter was used to measure CIELAB color values. Color indicator for heat detection can be utilized to test if the heat-sensitive API would go through physical changes during the pharmaceutical drying process. Both the prepared granules and pellets can be used as heat indicator in fluid bed drying process. The colored heat indicators give an opportunity to learn new aspects of the process at real time and could be exploded, for example, for scaling-up studies.     

Tablet formulation studies on nimesulide and meloxicam-cyclodextrin binary systems

The objective of this work was to develop tablet formulations of nimesulide-β-cyclodextrin (NI-β-CD) and meloxicam-γ-cyclodextrin (ME-γ-CD) binary systems. In the case of nimesulide, 3 types of binary systems—physical mixtures, kneaded systems, and coevaporated systems—were studied. In the case of meloxicam, 2 types of binary systems—physical mixtures and kneaded systems—were investigated. Both drug-CD binary systems were prepared at 1∶1 and 1∶2 molar ratio (1∶1M and 1∶2M) and used in formulation studies. The tablet formulations containing drug-CD binary systems prepared by the wet granulation and direct compression methods showed superior dissolution properties when compared with the formulations of the corresponding pure drug formulations. Overall, the dissolution properties of tablet formulations prepared by the direct compression method were superior to those of tablets prepared by the wet granulation method. Selected tablet formulations showed good stability with regard to drug content, disintegration time, hardness, and in vitro dissolution properties over 6 months at 40°C±2°C and 75% relative humidity. Published: May 11, 2007     

Once-daily sustained-release matrix tablets of nicorandil: Formulation and in vitro evaluation

The objective of the present study was to develop once-daily sustained-release matrix tablets of nicorandil, a novel potassium channel opener used in cardiovascular diseases. The tablets were prepared by the wet granulation method. Ethanolic solutions of ethylcellulose (EC), Eudragit RL-100, Eudragit RS-100, and polyvinylpyrrolidone were used as granulating agents along with hydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, and sodium alginate. The granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, and in vitro release studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and complied with in-house specifications for tested parameters. According to the theoretical release profile calculation, a oncedaily sustained-release formulation should release 5.92 mg of nicorandil in 1 hour, like conventional tablets, and 3.21 mg per hour up to 24 hours. The results of dissolution studies indicated that formulation F-I (drug-to-HPMC, 1∶4; ethanol as granulating agent) could extend the drug release up to 24 hours. In the further formulation development process, F-IX (drug-to-HPMC, 1∶4; EC 4% wt/vol as granulating agent), the most successful formulation of the study, exhibited satisfactory drug release in the initial hours, and the total release pattern was very close to the theoretical release profile. All the formulations (except F-IX) exhibited diffusion-dominated drug release. The mechanism of drug release from F-IX was diffusion coupled with erosion.     

A Comparison of Granules Produced by High-Shear and Fluidized-Bed Granulation Methods

Placebo granules were manufactured by both wet high-shear and fluidized-bed techniques. The granules were compared based on size, shape, surface morphology, and a variety of different flowability measurements. This comparison showed that granule formation and growth were different, with induction growth for high-shear granulation and steady growth for fluidized-bed granulation. Final granules from high-shear granulation were more spherical and dense compared with the irregular granules from fluidized-bed granulation. The high-shear granules demonstrated better overall flow properties.     

Roll Compaction and Tableting of High Loaded Metformin Formulations Using Efficient Binders

Metformin has a poor tabletability and flowability. Therefore, metformin is typically wet granulated with a binder before tableting. To save production costs, it would be desirable to implement a roll compaction/dry granulation (RCDG) process for metformin instead of using wet granulation. In order to implement RCDG, the efficiency of dry binders is crucial to ensure a high drug load and suitable properties of dry granules and tablets. This study evaluates dry granules manufactured by RCDG and subsequently tableting of high metformin content formulations (≥?87.5%). Based on previous results, fine particle grades of hydroxypropylcellulose and copovidone in different fractions were compared as dry binders. The formulations are suitable for RCDG and tableting. Furthermore, results can be connected to in-die and out-of-die compressibility analysis. The addition of 7% of dry binder is a good compromise to generate sufficient mechanical properties on the one hand, but also to save resources and ensure a high metformin content on the other hand. Hydroxypropylcellulose was more efficient in terms of granule size, tensile strength and friability. Three percent croscarmellose was added to reach the specifications of the US Pharmacopeia regarding dissolution. The final formulation has a metformin content of 87.5%. A loss in tabletability does not occur for granules compressed at different specific compaction forces, which displays a robust tensile strength of tablets independent of the granulation process.     

Effect of shape of sodium salicylate particles on physical property and in vitro aerosol performance of granules prepared by pressure swing granulation method

The purpose of this research was to investigate the effect of the shape of sodium salicylate (SS) particles on the physical properties as well as the in vitro aerosol performance of the granules granulated by the pressure swing granulation method. SS was pulverized with a jet mill (JM) to prepare the distorted particles, and SS aqueous solution was spray dried (SD) to prepare the nearly spherical particles. The particle size distribution, crushing strength, and pore size distribution of the granules were measured. The adhesive force of the primary particles in the granules was calculated according to Rumpf's equation. The in vitro aerosol performance of the granules was evaluated using a cascade impactor. Both JM and SD particles can be spherically granulated by the pressure swing granulation method without the use of a binder. The size of SD granules was smaller than that of JM granules. Although the crushing strength of the JM and SD granules is almost the same, the internal structures of JM granules and SD granules were found to differ, and the SD particles appear to have been condensed uniformly, resulting in a nearly spherical shape. In the inhalation investigation, the percentage of SS particles of appropriate size delivered to the region for treatment was noticeably higher for SD granules than for JM granules. This finding might be because the adhesive force of the SD primary particles was smaller than that of the JM primary particles in the granules and because the SD granules could be easily separated by air current to obtain the primary particles.     

Process analysis of fluidized bed granulation

This study assesses the fluidized bed granulation process for the optimization of a model formulation using in-line near-infrared (NIR) spectroscopy for moisture determination. The granulation process was analyzed using an automated granulator and optimization of the verapamil hydrochloride formulation was performed using a mixture design. The NIR setup with a fixed wavelength detector was applied for moisture measurement. Information from other process measurements, temperature difference between process inlet air and granules (T_diff), and water content of process air (AH), was also analyzed. The application of in-line NIR provided information related to the amount of water throughout the whole granulation process. This information combined with trend charts of T_diff and AH enabled the analysis of the different process phases. By this means, we can obtain in-line documentation from all the steps of the processing. The choice of the excipient affected the nature of the solid-water interactions; this resulted in varying process times. NIR moisture measurement combined with temperature and humidity measurements provides a tool for the control of water during fluid bed granulation.     

Next generation fluidized bed granulator automation

A system for fluidized bed granulator automation with in-line multichannel near infrared (NIR) moisture measurement and a unique air flow rate measurement design was assembled, and the information gained was investigated. The multivariate process data collected was analyzed using principal component analysis (PCA). The test materials (theophylline and microcrystalline cellulose) were granulated and the calibration behavior of the multichannel NIR set-up was evaluated against full Fourier Transform (FT) NIR spectra. Accurate and reliable process air flow rate measurement proved critical in controlling the granulation process. The process data describing the state of the process was projected in two dimensions, and the information from various trend charts was outlined simultaneously. The absorbence of test material at correction wavelengths (NIR region) and the nature of material-water interactions affected the detected in-line NIR water signal. This resulted in different calibration models for the test materials. Development of process analytical methods together with new data visualization algorithms creates new tools for in-process control of the fluidized bed granulation.     

Preparation and Characterization of a Novel Co-processed Excipient of Chitin and Crystalline Mannitol

A co-processed excipient was prepared from commercially available crystalline mannitol and α-chitin using direct compression as well as spray, wet, and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size, on the properties of the prepared co-processed excipient has been investigated. α-Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol–chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol–chitin (2:8, w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength, and friability of tablets, produced from Cop-MC using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, high-strength, and low-strength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient.     

Specific aerobic granules can be developed in a completely mixed tank reactor by bioaugmentation using micro-mycelial pellets of Phanerochaete chrysosporium

Aerobic granules were firstly developed in a completely mixed tank reactor (CMTR) by seeding micro-mycelial pellets (MMPs) of Phanerochaete chrysosporium. During phenol wastewater treatment, sludge granulation rate reached 67 % after 15-day operation. The granules in CMTR are different from aerobic granules described in literature in morphology, and a majority of them are rod-shaped or rodlike sludge besides spherical granules. The polymorphic granules, having no essential difference with aerobic granules previously reported, achieve advantages over conventional activated sludge in settling ability, biomass concentration, density, integrity coefficient and removal ability to phenol wastewater. The optimized parameters for sludge granulation in CMTR including temperature, inoculum quantity, rotary speed and superficial air upflow velocity are 30 °C, 5–7 g/l, 150 rpm, and 0.5 cm/s, respectively. Analysis on sludge granulation mechanism indicates that MMPs not only result in the formation of aerobic granules containing MMPs as nuclei, but also induce the formation of biogranules which do not have MMP at their cores. The work challenges the general belief that the homogenous circular flow pattern of microbial aggregates is necessary for aerobic sludge granulation.     

Difference in the Lubrication Efficiency of Bovine and Vegetable-Derived Magnesium Stearate During Tabletting

The purpose of this work was to evaluate and compare the functionality of bovine fatty acids-derived (MgSt-B) and vegetable fatty acids-derived (MgSt-V) magnesium stearate powders when used for the lubrication of granules prepared by high-shear (HSG) and fluid bed (FBG) wet granulation methods. The work included evaluation of tablet compression and ejection forces during tabletting and dissolution testing of the compressed tablets. Granules prepared by both granulation methods required significantly lower ejection force (p < 0.01) when lubricated with the MgSt-V powder as compared to those lubricated with the MgSt-B powder. Granules prepared by the HSG method and lubricated with the MgSt-V powder also required significantly lower compression force (p < 0.01) to produce tablets of similar weight and hardness as compared to those lubricated with the MgSt-B powder. The dissolution profiles were not affected by these differences and were the same for tablets prepared by same granulation method and lubricated with either magnesium stearate powder. The results indicate significant differences (p < 0.01) between lubrication efficiency of the MgSt-B and the MgSt-V powders and emphasize the importance of functionality testing of the MgSt powders to understand the impact of these differences. The opinions expressed in this work are only of authors, and do not necessarily reflect the policy and statements of the FDA.     

Investigation on Side-Spray Fluidized Bed Granulation with Swirling Airflow

Top-spray fluidized bed granulation with axial fluidization airflow from the bottom of the granulator is well-established in the pharmaceutical industry. The application of swirling airflow for fluidized bed granulation was more recently introduced. This study examined the effects of various process parameters on the granules produced by side-spray fluidized bed with swirling airflow using the central composite and Box–Behnken design of experiment. Influence of the amount of binder solution, spray rate, and distance between spray nozzle and powder bed were initially studied to establish operationally viable values for these parameters. This was followed by an in-depth investigation on the effects of inlet airflow rate, atomizing air pressure and distance between spray nozzle and powder bed on granule properties. It was found that the amount of binder solution had a positive correlation with granule size and percentage of lumps but a negative correlation with size distribution and Hausner ratio of the granules. Binder solution spray rate was also found to affect the granules size. High drug content uniformity was observed in all the batches of granules produced. Both inlet airflow rate and atomizing air pressure were found to correlate negatively with granule size and percentage of lumps but correlate positively with the size distribution of the granule produced. Percentage of fines was found to be significantly affected by inlet airflow rate. Distance between spray nozzle and powder bed generally affected the percentage of lumps.     

Effect of Lime Pretreatment on Granulation of Switchgrass

Densification of switchgrass into consistent and high-density solid feedstock will reduce the cost of transport, handling, and storage to produce fuels and chemicals. Development a novel, low-cost densification technology is critical for reducing the delivered cost of feedstock while improving the bulk flow properties of densified products. In this paper, a novel wet granulation technology was proposed to investigate the effect of lime pretreatment on the production of switchgrass granules. Granulation is a process of agglomerating fine powders by wetting powder surfaces with liquid binders and mild application of shear/vibrating forces. Switchgrass was size reduced into fine powders using a knife mill and pretreated with three lime loading rates (0.05, 0.1, 0.2 g/g of biomass) at 121 °C for 30 min and at room temperature (25 °C) for 72 h. The structural modification of pretreated samples was analyzed by scanning electron microscopy and autofluorescence microscopy. Pretreated samples were granulated using a pan granulator with pre-formulated starch binder. Granules made from 20 % (0.2 g/g of biomass) lime loading rate had significantly higher single granule density and angle of repose with lower binder requirement than that of untreated granules. Lime treatment did not significantly increase the bulk density and hardness of granules. Lime-treated granules had significantly higher ash content and lower gross calorific value than that of untreated granules. In overall, lime treatment was not attractive to produce granules for thermochemical conversion platform, but lime-treated granules could be used to produce liquid biofuels and platform chemicals in biochemical conversion platform.