Effects of binder rheology on melt agglomeration in a high shear mixer

Lactose monohydrate was melt agglomerated in an 8-l high shear mixer using Gelucire 50/13, Stearate 6000 WL 1644, or polyethylene glycol (PEG) 3000 as meltable binder. The impeller speed was varied at two levels, and massing time was varied at six levels. In order to obtain a similar agglomerate growth, a larger binder volume had to be used with Gelucire 50/13 than with Stearate 6000 WL 1644 and PEG 3000. The lower viscosity of Gelucire 50/13 gave rise to agglomerates of a wider size distribution and a higher porosity as well as more adhesion of mass to the bowl. A lower binder viscosity resulted in more spherical agglomerates at the low impeller speed.     

Effects of physical properties of powder particles on binder liquid requirement and agglomerate growth mechanisms in a high shear mixer.

A study was performed in order to elucidate the effects of the physical properties of small powder particles on binder liquid requirement and agglomerate growth mechanisms. Three grades of calcium carbonate having different particle size distribution, surface area, and particle shape but approximately the same median particle size (4-5 microm), were melt agglomerated with polyethylene glycol (PEG) 3000 or 20,000 in an 8-l high shear mixer at three impeller speeds. The binder liquid requirement was found to be very dependent on the packing properties of the powder, a denser packing resulting in a lower binder liquid requirement. The densification of the agglomerates in the high shear mixer could be approximately predicted by compressing a powder sample in a compaction simulator. With the PEG having the highest viscosity (PEG 20,000), the agglomerate formation and growth occurred primarily by the immersion mechanism, whereas PEG 3000 gave rise to agglomerate growth by coalescence. Powder particles with a rounded shape and a narrow size distribution resulted in breakage of agglomerates with PEG 3000, whereas no breakage was seen with PEG 20,000. Powder particles having an irregular shape and surface structure could be agglomerated with PEG 20,000, whereas agglomerate growth became uncontrollable with PEG 3000. When PEG 20,000 was added as a powder instead of flakes, the resultant agglomerates became rounder and the size distribution narrower.     

Melt pelletization in a high shear mixer. V. Effects of apparatus variables

Effects of two different sets of impeller blades on melt pelletization of lactose with polyethylene glycol (PEG) 3000 were investigated in an 8 litre high shear mixer. Results obtained in the 8 litre mixer were compared with previous results from a 50 litre high shear mixer of the same type. In the 8 litre mixer curved impeller blades were found to give rise to a high power input and smooth pellets of a spherical shape, whereas plane impeller blades caused a lower power input and irregular agglomerates. Agglomerate growth was found to be different in mixers of different scale. This difference was primarily ascribed to differences in movement of the mass, power input and product temperature.     

Effects of interactions between powder particle size and binder viscosity on agglomerate growth mechanisms in a high shear mixer.

A study was performed in order to elucidate the effects of the interactions between powder particle size and binder viscosity on the mechanisms involved in agglomerate formation and growth. Calcium carbonates having mean particle sizes in the range of 5-214 microm and polyethylene glycols having viscosities in the range of approximately 50-100000 mPas were melt agglomerated in a high shear mixer. Agglomerate growth by nucleation and coalescence was found to dominate when agglomerating small powder particles and binders with a low viscosity. Increasing the binder viscosity increased the formation of agglomerates by immersion of powder particles in the surface of the binder droplets. With a larger powder particle size, an increasing binder viscosity was necessary in order to obtain an agglomerate strength being sufficient to avoid breakage. Due to a low agglomerate strength, a satisfying agglomeration of very large particles (214 microm) could not be obtained, even with very viscous binders. The study demonstrated that the optimum agglomerate growth occurred when the agglomerates were of an intermediate strength causing an intermediate deformability of the agglomerates. In order to produce spherical agglomerates (pellets), a low viscosity binder has to be chosen when agglomerating a powder with a small particle size, and a high viscosity binder must be applied in agglomeration of powders with large particles.     

Centrifugal air-assisted melt agglomeration for fast-release "granulet" design

Conventional melt pelletization and granulation processes produce round and dense, and irregularly shaped but porous agglomerates respectively. This study aimed to design centrifugal air-assisted melt agglomeration technology for manufacture of spherical and yet porous "granulets" for ease of downstream manufacturing and enhancing drug release. A bladeless agglomerator, which utilized shear-free air stream to mass the powder mixture of lactose filler, polyethylene glycol binder and poorly water-soluble tolbutamide drug into "granulets", was developed. The inclination angle and number of vane, air-impermeable surface area of air guide, processing temperature, binder content and molecular weight were investigated with reference to "granulet" size, shape, texture and drug release properties. Unlike fluid-bed melt agglomeration with vertical processing air flow, the air stream in the present technology moved centrifugally to roll the processing mass into spherical but porous "granulets" with a drug release propensity higher than physical powder mixture, unprocessed drug and dense pellets prepared using high shear mixer. The fast-release attribute of "granulets" was ascribed to porous matrix formed with a high level of polyethylene glycol as solubilizer. The agglomeration and drug release outcomes of centrifugal air-assisted technology are unmet by the existing high shear and fluid-bed melt agglomeration techniques.     

Effects of droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed.

This study was performed in order to evaluate the effects of binder droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed granulator. Lactose monohydrate was agglomerated with melted polyethylene glycol (PEG) 3000 or Gelucire 50/13 (esters of polyethylene glycol and glycerol), which was atomised at different nozzle air flow rates giving rise to median droplet sizes of 40, 60, and 80 microm. Different product temperatures were investigated, below the melting range, in the middle of the melting range, and above the melting range for each binder. The agglomerates were found to be formed by initial nucleation of lactose particles immersed in the melted binder droplets. Agglomerate growth occurred by coalescence between nuclei followed by coalescence between agglomerates. Complex effects of binder droplet size and type of binder were seen at low product temperatures. Low product temperatures resulted in smaller agglomerate sizes, because the agglomerate growth was counteracted by very high binder viscosity or solidification of the binder. At higher product temperatures, neither the binder droplet size nor the type of binder had a clear effect on the final agglomerate size.     

Investigation of melt agglomeration process with a hydrophobic binder in combination with sucrose stearate

The melt agglomeration process of lactose powder with hydrogenated cottonseed oil (HCO) as the hydrophobic meltable binder was investigated by studying the physicochemical properties of molten HCO modified by sucrose stearates S170, S770 and S1570. The size, size distribution, micromeritic and adhesion properties of agglomerates as well as surface tension, contact angle, viscosity and specific volume of molten HCO, with and without sucrose stearates, were examined. The viscosity, specific volume and surface tension of molten HCO were found to be modified to varying extents by sucrose stearates which are available in different HLB values and melt properties. The growth of melt agglomerates was promoted predominantly by an increase in viscosity, an increase in specific volume or a decrease in surface tension of the molten binding liquid. The agglomerate growth propensity was higher with an increase in inter-particulate binding strength, agglomerate surface wetness and extent of agglomerate consolidation which enhanced the liquid migration from agglomerate core to periphery leading to an increased surface plasticity for coalescence. The inclusion of high concentrations of completely meltable sucrose stearate S170 greatly induced the growth of agglomerates through increased specific volume and viscosity of the molten binding liquid. On the other hand, the inclusion of incompletely meltable sucrose stearates S770 and S1570 promoted the agglomeration mainly via the reduction in surface tension of the molten binding liquid with declining agglomerate growth propensity at high sucrose stearate concentrations. In addition to being an agglomeration modifier, sucrose stearate demonstrated anti-adherent property in melt agglomeration process. The properties of molten HCO and melt agglomerates were dependent on the type and concentration of sucrose stearate added.     

The effect of droplet size and powder particle size on the mechanisms of nucleation and growth in fluid bed melt agglomeration

This study was performed in order to evaluate the effects of binder droplet size and powder particle size on agglomerate formation and growth in fluid bed spray agglomeration using a meltable binder. Three different lactose grades, 100, 125 or 350 mesh, were agglomerated using polyethylene glycol (PEG) 3000 at two different concentrations, 11.5 or 22% (volume/mass), and three spray droplet sizes, 30, 60 or 90 microm were applied. The ratio of droplet size/particle size was found to determine whether the mechanism of nucleation was distribution or immersion. Distribution was promoted by a low ratio, whereas immersion was promoted by a high ratio. Distribution as nucleation mechanism led to a more open agglomerate structure and immersion to a denser structure. When the nucleation phase was terminated, coalescence between rewetted nuclei or agglomerates was the growth mechanism with both preceding mechanisms of nucleation. A larger particle size of the lactose led to larger agglomerates. The difference in the effect on growth between the 30 and 60 microm droplets was generally low. The 90 microm droplets at 22% binder concentration offered a potential for uncontrollable growth giving rise to markedly larger agglomerates and a lower reproducibility than 30 and 60 microm droplets.     

Agglomerate formation and growth mechanisms during melt agglomeration in a rotary processor

The purpose of this study was to investigate the effect of the binder particle size and the binder addition method on the mechanisms of agglomerate formation and growth during melt agglomeration in a laboratory scale rotary processor. Lactose monohydrate was agglomerated with molten polyethylene glycol (PEG) 3000 by adding the PEG either as solid particles from the size fraction 0-250, 250-500, or 500-750 microm or as droplets with a median size of 25, 48, or 69 microm. It was found that the PEG particle size, the PEG droplet size, and the massing time significantly influenced the agglomerate size and size distribution. Agglomerate formation and growth were found to occur primarily by distribution and coalescence for the PEG size fraction 0-250 microm and mainly by the immersion mechanism for the PEG size fractions 250-500 and 500-750 microm. When the PEG was sprayed upon the lactose, the mechanism of agglomerate formation was supposed to be a mixture of immersion and distribution, and the agglomerate growth was found to occur by coalescence regardless of the PEG mean droplet size. Compared to high shear mixers and conventional fluid bed granulators, the mechanisms of agglomerate formation and growth in the rotary processor resembled mostly those seen in the fluid bed granulator.     

Melt pelletization with polyethylene glycol in a rotary processor

The purpose of this study was to investigate the effect of the airflow, the binder concentration, the massing time, the friction plate rotation speed, and the surface structure of the friction plate on melt pelletization in a laboratory scale rotary processor. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 as meltable binder. The study was performed as a full factorial design. An increase in agglomerate size was found when the binder concentration, the massing time, or the friction plate rotation speed was increased. The agglomerate size was also increased when increasing the shearing forces by using a friction plate with a different surface structure. The size distribution of the agglomerates was significantly narrowed when the binder concentration or the shearing forces caused by the friction plate were increased. An increase in the adhesion of material to the friction plate was found when the shearing forces of the friction plate were increased either by the rotation speed or by the surface structure. Generally, the rotary processor was found to be a suitable alternative to melt pelletization in a high shear mixer.     

An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyetilenglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.     

The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer

The aim of this study was to prepare by melt agglomeration agglomerates containing solid dispersions of diazepam as poorly water-soluble model drug in order to evaluate the possibility of improving the dissolution rate. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 or Gelucire 50/13 (mixture of glycerides and PEG esters of fatty acids) as meltable binders in a high shear mixer. The binders were added either as a mixture of melted binder and diazepam by a pump-on procedure or by a melt-in procedure of solid binder particles. Different drug concentrations, maximum manufacturing temperatures, and cooling rates were investigated. It was found to be possible to increase the dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was obtained with a lower drug concentration. Admixing the binders by the melt-in procedure resulted in similar dissolution rates as the pump-on procedure. The different maximum manufacturing temperatures and cooling rates were found to have complex effects on the dissolution rate for formulations containing PEG 3000, whereas only minor effects of the cooling procedure were found with Gelucire 50/13. Gelucire 50/13 resulted in faster dissolution rates compared to PEG 3000.     

Effect of a melt agglomeration process on agglomerates containing solid dispersions

The purpose was to produce solid dispersions of a poorly water-soluble drug, Lu-X, by melt agglomeration in a laboratory scale rotary processor. The effect of binder type and method of manufacturing on the dissolution profile of Lu-X was investigated. Lactose monohydrate and Lu-X were melt agglomerated with Rylo MG12, Gelucire 50/13, PEG 3000, or poloxamer 188. Either a mixture of binder, drug, and excipient was heated to a temperature above the melting point of the binder (melt-in procedure) or a dispersion of drug in molten binder was sprayed on the heated excipient (spray-on procedure). The agglomerates were characterized by DSC, XRPD, SEM, and EDX-SEM. The study showed that the agglomerates containing solid dispersions had improved dissolution rates compared to physical mixtures and pure drug. The melt-in procedure gave a higher dissolution rate than the spray-on procedure with PEG 3000, poloxamer 188, and Gelucire 50/13, whereas the opposite was found with Rylo MG12. This was explained by differences in mechanisms of agglomerate formation and growth, which were dominated by immersion with PEG 3000, poloxamer 188, and Gelucire 50/13, and by distribution and coalescence with Rylo MG12. The spray-on procedure resulted in a higher content of Lu-X in the core of the agglomerates when immersion was the dominating mechanism, and in a higher content in the agglomerate surface when distribution was dominating. The melt-in procedure resulted generally in a homogeneous distribution of Lu-X in the agglomerates. The compounds in the agglomerates were found primarily to be crystalline, and the dissolution profiles were unchanged after 12 weeks storage at 25 degrees C at 50% RH.     

A Study on Microwave-Induced Melt Granulation in a Single Pot High Shear Processor

Microwave-induced high shear melt granulation was compared with conventional melt granulation performed in the same processor. Admixtures of lactose 200M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350. Different heating mechanisms in the two processes necessitated the use of different parameters for process monitoring and control. Mixer power consumption was suitable for monitoring agglomerate growth under microwave-induced heating. Product temperature was a better indicator of agglomeration propensity in conventional melt granulation. These were attributed to the disparities in heat acquisition rates and heating uniformities of the powders as well as variation in baseline mixer power consumption between the two processes.     

A study on microwave-induced melt granulation in a single pot high shear processor

Microwave-induced high shear melt granulation was compared with conventional melt granulation performed in the same processor. Admixtures of lactose 200M and anhydrous dicalcium phosphate were granulated with polyethylene glycol 3350. Different heating mechanisms in the two processes necessitated the use of different parameters for process monitoring and control. Mixer power consumption was suitable for monitoring agglomerate growth under microwave-induced heating. Product temperature was a better indicator of agglomeration propensity in conventional melt granulation. These were attributed to the disparities in heat acquisition rates and heating uniformities of the powders as well as variation in baseline mixer power consumption between the two processes.     

Influence of binder properties, method of addition, powder type and operating conditions on fluid-bed melt granulation and resulting tablet properties.

The aim of the study was to investigate melt granulation in a laboratory scale fluid-bed granulator with respect to granule growth, granule properties and resulting tablet properties. The parameters investigated were method of addition of PEG (spray-on or addition as flakes), binder concentration, PEG type (3000, 4000 and 6000, sprayed-on), size (PEG 4000, added as three different sized flakes), powder type (two different sized lactose types and corn starch) and operating conditions (volume air flow and heating temperature). Addition of binder as flakes led to layering as a growth mechanism when the size of the flakes was high. Coalescence occurred when the size was low. Coalescence also occurred when spraying was the method of addition. Due to the greater viscosity of the PEG 6000 melt it produced bigger granules than 3000 or 4000. The influence of volume air flow was moderate and the influence of heating temperature in the range of 70-90 degrees C was very low with both methods of addition. The disintegration time of tablets from granules where PEG was added as flakes was shorter than from granules where PEG was sprayed-on. The latter method of binder addition led to tablets which did not disintegrate but eroded. This was apparently caused by formation of a binder matrix, which could not be destroyed by the disintegrant.     

Melt pelletisation of a hygroscopic drug in a high shear mixer. Part 2. Mutual compensation of influence variables.

The process of melt pelletisation in a Diosna P10 high shear mixer was examined for sodium valproate and glycerol monostearate. The effects of binder concentration, impeller speed and massing time on mean granule size, size distribution and liquid saturation were investigated. Spherical pellets of almost similar size and size distribution were obtained after 20 min of massing time, with a binder content from 3.1 to 14.1% w/w by adjusting the impeller speed. Granule growth was observed at low levels of binder concentration and liquid saturation (<80%) which is untypical for melt granulation. The liquid saturation seemed to have no major influence on the final pellet size. Additional, mutually compensating effects on granule growth were found to be impeller speed and massing time for a fixed binder concentration. Low levels of both, binder concentration and impeller speed, allowed for good control of the process. The amount of water adsorbed by the hygroscopic drug was found to accelerate granule growth.     

Impact of a non-meltable additive on melt agglomeration with a hydrophobic meltable binder in high-shear mixer

The present study aims to investigate the behavior of melt agglomeration with a low-viscosity hydrophobic meltable binder by using a non-meltable additive. The size, crushing strength, and pore size distribution of resultant agglomerates, the rheological, surface tension, and wetting properties of the molten binder, as well as, the flow characteristics of preagglomeration powder blend were determined. The use of additive showed contradictory agglomerate growth-promoting and -retarding effects on the molten binder surface tension and the interparticulate frictional forces. Critical concentration effects of additive corresponded to threshold transition of agglomeration-promoting to -retarding behavior were discussed.     

Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

The present study aims to investigate the behavior of melt agglomeration with a low-viscosity hydrophobic meltable binder by using a non-meltable additive. The size, crushing strength, and pore size distribution of resultant agglomerates, the rheological, surface tension, and wetting properties of the molten binder, as well as, the flow characteristics of preagglomeration powder blend were determined. The use of additive showed contradictory agglomerate growth-promoting and -retarding effects on the molten binder surface tension and the interparticulate frictional forces. Critical concentration effects of additive corresponded to threshold transition of agglomeration-promoting to -retarding behavior were discussed.     

Melt pelletisation of a hygroscopic drug in a high shear mixer. Part 1. Influence of process variables.

The applicability of a high shear mixer for melt pelletisation of binary mixtures of sodium valproate and glycerol monostearate was investigated. The effects of binder concentration, impeller speed, jacket temperature and massing time on mean pellet size and size distribution were examined in a 2(4)-factorial design. Binder concentration and impeller speed were found to be the most important variables influencing the mean granule size and size distribution. An increase in each of those accelerated the granule growth. Due to the solubility of the drug in the molten binder very low amounts of binder were necessary for the formation of pellets. The modified high shear mixer was found to be suitable for batch sizes of 1-4 kg; granule growth was delayed with increasing load. A common pellet growth pattern, which can be divided into three phases, was derived and confirmed from all trials. The process was monitored by means of a torque measuring system. The torque-time curve can be used to detect the beginning of the destruction phase.