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.     

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.     

Acetazolamide: future perspective in topical glaucoma therapeutics

A 2(4-1) fractional factorial design was used to evaluate the effect of various process variables in fluid bed granulation, on the physico-chemical properties of granule and tablet containing a high dose, poorly water soluble, low density, and micronized drug. The process variables studied were inlet air temperature, inlet air flow, spray rate of the binder solution, and atomization air pressure. Tablets with identical composition, weight, size and hardness were also manufactured in a high shear granulator and their physical properties were determined and compared with those produced by the fluidized bed granulation method. Except for the granule size distribution, other physical properties of granulations and tablets produced in a fluid bed granulator are independent of the selected process variables within the study range. Both atomization air pressure and spray rate of the binder solution had strong impact on granule size distribution. Irrespective of the process conditions used in the fluid bed granulation, granules from this process were more porous, less dense and more compressible than the granules from the high shear granulation process. Comparable tablet dissolution rates to those prepared by the optimized high shear granulation method can be achieved by selecting the appropriate process conditions in fluid bed granulation. These results suggest that wet granulation tablets of a high dose, poorly water soluble, low density, micronized drug can be manufactured using a fluidized bed granulation method, with comparable tablet dissolution rates to those produced with an optimized high shear granulation method.     

Drug-fatty acid salt with wax-like properties employed as binder in melt granulation

The tacky and deformable properties of a wax-like drug-fatty acid salt, propranolol oleate (POA), make particle size reduction and separation challenging. The aim of this study was to investigate the use of POA as binder in a melt granulation procedure to improve processing properties. POA is a suitable candidate for binder phase in melt granulation with a melting temperature of 50-56 degrees C. Small batches (ca 30 g) were manufactured using a high shear mixer with lactose monohydrate as the substrate phase. Optimum uniformity of drug content and minimum friability were found at 10% w/w POA binder concentration. POA melt granules exhibited a >10-fold increase in the rate of in vitro dissolution at pH 7.4 with 0.2% w/v sodium lauryl sulphate compared with raw POA. The increased drug surface area in granular form was thought to be responsible for the change in dissolution behaviour. This study has demonstrated that melt granulation using POA as binder is a viable process which leads to beneficial changes in dissolution behaviour for the lipophilic drug-fatty acid salt.     

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.     

Validation of fluid bed granulation utilizing artificial neural network

Three innovative components (an annular gap spray system, a booster bottom and an outlet filter) have been developed by Innojet Technologies to improve fluid bed technology and to reduce the common interference factors (clogging of nozzles and outlet filters, spray loss, spray drying and fluidized bed heterogeneity). In a fluid bed granulator, three conventional components have been replaced with these innovative components. Validation of the modified fluid bed granulator has been conducted using a generalized regression neural network (GRNN). Under different operating conditions (by variation of inlet air temperature, liquid-binder spray rate, atomizing air pressure, air velocity, amount and concentration of binder solution and batch size), sucrose was granulated and the properties of size, size distribution, flow rate, repose angle and bulk and tapped volumes of granules were measured. To confirm the method's validity, the trained network has been used to predict new granulation parameters as well as granule properties. These forecasts were then compared with the corresponding experimental results. Good correlation has been obtained between the predicted and the experimental data. From these findings, we conclude that the GRNN may serve as a reliable method to validate the modified fluid bed apparatus.     

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.     

Study growth kinetics in fluidized bed granulation with at-line FBRM

In this study, a novel at-line focused beam reflectance measurement (FBRM) technique was developed to investigate granule growth in a fluidized bed granulation (FBG). The chord length distribution (CLD) measured by the FBRM was used to represent granule particle size distribution (PSD). Through a systematic study, it was proved that the trends of the chord length measured by the at-line FBRM technique were identical to those measured by a laser diffraction instrument and sieve analysis in spite of different measurement mechanisms. The portable at-line FBRM technique was successfully applied to a granule growth kinetics study for a fluidized bed granulation performed in a Glatt GPCG-1 granulator. Granule size evolution was clearly exhibited by the at-line FBRM. Spray rate was found to be the most significant factor on the granule growth compared with the other two factors: binder solution concentration and intra- to extra-granular microcrystalline cellulose (MCC) ratio for the formulation studied in this work. The CLD evolution measured by the FBRM confirmed that the granule agglomeration was mainly dominated by the binder on the granule surface. The at-line FBRM enables us to select appropriate process parameters and effectively control the fluid bed granulation process.     

Effects of powder particle size and binder viscosity on intergranular and intragranular particle size heterogeneity during high shear granulation.

A study was performed in order to elucidate the effects of powder particle size and binder viscosity on intergranular and intragranular particle size heterogeneities. Granules were produced by melt granulation in a high shear mixer from each of four calcium carbonates having mean particle sizes in the range of 5.5-63.1 microm. Each of three polyethylene glycols (PEGs) having viscosities in the range of approximately 40-14,000 mPas were applied as meltable binders. The size distribution of the calcium carbonate particles in three granule size fractions (125-250, 355-500, and 800-1000 microm) was measured after disintegration of the granules. Intragranular particle size heterogeneities were evaluated qualitatively by means of scanning electron microscopy. A preferential growth of the smaller particles was found to give rise to a higher content of small particles in large granules when calcium carbonates with mean particle sizes of 11.7, 34.5, and 63.1 microm were granulated with a binder of low viscosity. The use of a binder of medium or high viscosity leads to a marked reduction of these heterogeneities. A preferential growth of larger particles was seen when calcium carbonates with mean particle sizes of 5.5 and 11.7 microm were granulated with a highly viscous binder. The use of a binder with low or medium viscosity resulted in an increased homogeneity. Intragranular particle size heterogeneities were primarily seen when 5.5 and 11.7 microm calcium carbonate particles were granulated with a highly viscous binder.     

Correlation between loose density and compactibility of granules prepared by various granulation methods

The objectives of this study were to prepare the lactose granules by various granulation methods using polyethylene glycol 6000 (PEG 6000) as a binder and to evaluate the effects of granulation methods on the compressibility and compactibility of granules in tabletting. Lactose was granulated by seven granulation methods -- four wet granulations including wet massing granulation, wet high-speed mixer granulation, wet fluidized bed granulation and wet tumbling fluidized bed granulation; and three melt granulations including melt high-speed mixer granulation, melt fluidized bed granulation and melt tumbling fluidized bed granulation. The loose density, angle of repose, granule size distribution, mean diameter of granules, and the tensile strength and porosity of tablets were evaluated. The compactibilities of granules were varied by the granulation methods. However, the difference in compactibility of granules could not be explained due to the difference in compressibility, since there was no difference in Heckel plots due to granulation methods. Among their granule properties, the loose density of granules seemed to have a correlation with the tablet strength regardless of the granulation methods.     

Determination of fluidized bed granulation end point using near-infrared spectroscopy and phenomenological analysis

Simultaneous real-time monitoring of particle size and moisture content by near-infrared spectroscopy through a window into the bed of a fluidized bed granulator is used to determine the granulation end point. The moisture content and particle size determined by the near-infrared monitor correlates well with off-line moisture content and particle size measurements. The measured particle size is modeled using a population balance approach, and the moisture content is shown to follow accepted models during drying. Given a known formulation, with predefined parameters for peak moisture content, final moisture content, and final granule size, the near-infrared monitoring system can be used to control a fluidized bed granulation by determining when binder addition should be stopped and when drying of the granules is complete.     

Process optimization for continuous extrusion wet granulation

Three granulating binders in high drug-load acetaminophen blends were evaluated using high shear granulation and extrusion granulation. A polymethacrylate binder enhanced tablet tensile strength with rapid disintegration in simulated gastric fluid, whereas polyvinylpyrrolidone and hydroxypropyl cellulose binders produced less desirable tablets. Using the polymethacrylate binder, the extrusion granulation process was studied regarding the effects of granulating liquid, injection rate and screw speed on granule properties. A full factorial experimental design was conducted to allow the statistical analysis of interactions between extrusion process parameters. Response variables considered in the study included extruder power consumption (screw loading), granule bulk/tapped density, particle size distribution, tablet hardness, friability, disintegration time and dissolution.     

Microscale granulation in a fluid bed powder processor using electrostatic atomisation

The aim of this study was to use the electrostatic atomisation in miniaturised fluid bed granulation process and define the effect of process parameters. The process parameters included in the study were granulation liquid flow rate, atomisation voltage and binder concentration in the granulation liquid. Altogether 22 batches were granulated in Multichamber Microscale Fluid bed powder Processor (MMFP). Granule size distributions were measured with both sieves and image analyses. With these process conditions, the atomisation liquid flow rate had a strong positive correlation with the granule size. Increasing the atomisation voltage increased the granule size, which is contradictory with the expectations. The effect of the binder concentration remained unclear. Although it is challenging to model the fluid bed granulation process in micro-scale, multivariate methods such as principal component analysis (PCA) are helpful in studying the most important phenomena.     

A PAT Approach to Enhance Process Understanding of Fluid Bed Granulation Using In-line Particle Size Characterization and Multivariate Analysis

The purpose of this study was to achieve improved process understanding of fluid bed granulation using in-line particle size analyzer in conjunction with multivariate methods. The combined use of process analyzers and multivariate tools provides a useful means to drug development within the framework of quality by design utilizing process analytical technology. The evaluation of in-line monitoring manufacturability quality attributes, particle size, and particle size distribution, was conducted using the Parsum probe which is based on spatial filtering technique. Several granulation batches were manufactured and monitored using a commercial-scale fluid bed granulator. Reference measurements by offline Malvern MasterSizer showed good agreement with those by Parsum at end-of-spray phase. Multivariate/batch statistical process control methods were used to evaluate batch process performance, batch-to-batch variation and develop potential control strategy. The results indicated that the Parsum analyzer is a viable tool for in-line particle size characterization and improved process understanding in combination with multivariate tools.     

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.     

Preparation and characterisation of ibuprofen-poloxamer 188 granules obtained by melt granulation.

The aim of this study was to prepare, by melt granulation, granules containing ibuprofen as a poorly water soluble model drug in order to improve its dissolution rate and its availability; lactose as a diluent and poloxamer 188 (Lutrol F68), as a new meltable hydrophilic binder, were used. The granules were prepared in a laboratory-scale high-shear mixer, using a jacket temperature of 50 degrees C and an impeller speed of 500 rpm. The particle size analysis shows that the main fraction was between 200 and 500 microm, while the determination of drug content indicated that ibuprofen was quite uniformly distributed in all the fractions. Scanning Electron Microscopy (SEM), image and fractal analysis revealed that the granules did not have a perfect spherical shape and a rugged surface (D(s)=2.6475). The in vitro dissolution tests showed an increase in the dissolution rate of granules compared to pure drug and physical mixture. The characterisation of the samples, performed by Differential Scanning Calorimetry (DSC) and X-ray powder diffraction (XRD), suggests that the improvement of dissolution rate could be correlated to the formation of a eutectic mixture between the drug and the binder. Stability studies indicated that the granule properties do not change, at least after 1 year of storage at 25 degrees C. In conclusion, the results of this work suggest that the melt granulation technique is an easy and fast method to improve the dissolution rate of ibuprofen, using poloxamer 188 as a new hydrophilic meltable binder.     

Transfer from High‐Shear Batch to Continuous Twin Screw Wet Granulation: A Case Study in Understanding the Relationship Between Process Parameters and Product Quality Attributes

A twin screw to high‐shear batch granulation technology switch was evaluated for a pharmaceutical development project. Differences in granule (particle size distribution and porosity) and tablet (dissolution) quality attributes were analysed for both continuous and batch technologies. Liquid to solid (L/S) ratio, screw configuration and screw speed parameters on the twin screw granulator were varied, with output granule and tablet properties characterised. L/S and screw configuration were found to influence the granule particle size distribution, porosity and tablet dissolution. At 0.15 L/S, the particle size distribution showed a significant proportion of ungranulated material in the output granule. As the L/S is increased, the level of ungranulated material decreased. An increase in L/S and the number of kneader elements caused a decrease in granule porosity and tablet dissolution. Twin screw and batch granulation technologies generated different granule properties (size and shape) at a constant L/S. A lower L/S in twin screw granulation was needed to achieve similar tablet attributes. It is concluded that differences in liquid addition and therefore initial granule nucleation caused differences in granule properties, which impacted tablet attributes and manufacturability. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3075–3082, 2014     

Effect of the melt granulation technique on the dissolution characteristics of griseofulvin

This work describes a melt granulation technique to improve the dissolution characteristics of a poorly water-soluble drug, griseofulvin. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 degrees C and an impeller speed of approximately 20,000 rpm. The effect of drug loading (2.5/5%), binder (PEG 3350/Gelucire 44/14), filler (starch/lactose), and HPMC on the dissolution of griseofulvin was investigated using a half two level-four factor factorial design. The granules were characterized using powder XRD, DSC and SEM techniques. A significant enhancement in the in vitro dissolution profiles of the granules was observed compared to the pure drug and drug excipient physical mixtures. The factorial design results indicated that higher drug loading and the presence of HPMC reduced the extent of dissolution of the drug, whereas, the presence of starch enhanced the dissolution rate. XRD data confirmed crystalline drug in formulation matrices. DSC results indicated monotectic mixtures of griseofulvin with PEG in the granulated formulations. In conclusion, the results of this work suggest that melt granulation is a useful technique to enhance the dissolution rate of poorly water-soluble drugs, such as, griseofulvin.     

Granule size distribution of tablets

The purpose of this study was to determine the variation in the granule size distribution in a die of an eccentric tableting machine. Theophylline anhydrate and α‐lactose monohydrate were granulated with an aqueous solution of polyvinylpyrrolidone, using an instrumented fluid bed granulator. The granules were tabletted, using an instrumented eccentric tableting machine. Punch forces were recorded and tablets were collected in order during the tableting process. Powder samples, which had the same mass as the tablets, were also collected from the die for particle size determination. The particle size distribution was measured, using a spatial filtering technique. In addition, the segregation of microcrystalline cellulose pellets during tableting was analyzed. The particle size distribution changed dramatically during the tableting process, due to a segregation phenomenon. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2061–2069, 2010     

Instrumentation of a gravity feed extruder and the influence of the composition of binary and ternary mixtures on the extrusion forces.

A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.