A combined experimental and modeling approach to study the effects of high-shear wet granulation process parameters on granule characteristics

The purpose of the current work is to study the effects of high-shear wet granulation process parameters on granule characteristics using both experimental and modeling techniques. A full factorial design of experiments was conducted on three process parameters: water amount, impeller speed and wet massing time. Statistical analysis showed that the water amount has the largest impact on the granule characteristics, and that the effect of other process variables was more pronounced at higher water amount. At high water amounts, an increase in impeller speed and/or wet massing time showed a decrease in granule porosity and compactability. A strong correlation between granule porosity and compactability was observed. A three-dimensional population balance model which considers agglomeration and consolidation was employed to model the granulation process. The model was calibrated using the particle size distribution from an experimental batch to ensure a good match between the simulated and experimental particle size distribution. The particle size distribution of three other batches were predicted, each of which was manufactured under different process parameters (water amount, impeller speed and wet massing time). The model was able to capture and predict successfully the shifts in granule particle size distribution with changes in these process parameters.     

Study of effect of excipient source variation on rheological behavior of diltiazem HCl-HPMC wet masses using a mixer torque rheometer

In the wet massing of powders and powder blends, the rheological behavior of the wet powder masses not only plays a critical role in the unit process but also influences the attributes of the product. The physical properties of the powder excipients, such as particle size and size distribution, shape, surface area, bulk and tapped density and surface morphology, are a major source of variability in the rheological behavior of wet powder masses and the quality attributes of the final product. The objective of the present investigations was to study the rheological behavior of wet masses containing hydroxypropyl methylcellulose (HPMC) obtained from two sources (Methocel from Dow and Pharmacoat from Shin-Etsu) using a mixer torque rheometer. In order to simulate a real formulation, diltiazem HCl (DTZ) (40% loading) was used as part of the substrate powder mass. Hydroxypropyl cellulose (HPC) was used as the binder. Since HPMC is water-soluble, isopropyl alcohol (IPA) was used as the wet massing liquid. The rheological behavior of the wet powder masses was studied as a function of mixing time and amount of wet massing liquid (IPA). The rheological profiles obtained for DTZ-Methocel and DTZ-Pharmacoat exhibited same magnitude for mean torque, however, for DTZ-Pharmacoat the peak was more extended than that for DTZ-Methocel. The extended peak for DTZ-Pharmacoat indicated that the wet mass will stay suitable during the process for larger quantities of the wet massing liquid before turning into paste and becoming unsuitable for the process as compared with the DTZ-Methocel system. The mixing kinetics of the two powder systems appeared to be quite different. These differences in the rheological behavior of the wet masses may be attributed to the difference in the particulate and surface properties of the two HPMCs. Some of the properties of the two HPMCs, such as particle size and size distribution, surface area, surface morphology and DSC thermograms, explain the difference observed in their rheological behavior. The difference in the rheological profiles of the two DTZ-HPMC systems indicated superiority of Pharmacoat over Methocel considering their wet massing behavior.     

Binder-substrate interactions in wet granulation. 3: The effect of excipient source variation

The effect of excipient source variation on the interactions during wet granulation between microcrystalline cellulose and aqueous solutions of two molecular weight grades of two polymer binders has been studied using an instrumented mexer torque rheometer. The wet massing data confirmed previous observations that dissimilar polymers interact differently with cellulose substrates during the wet massing process. In addition, for a second cellulose material, variations were also observed in the pattern of interaction between the binders and the excipient. An examination of particulate and surface energetic properties revealed differences in the cellulose materials which were then related to the observed rheological behaviour.     

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.     

A priori performance prediction in pharmaceutical wet granulation: testing the applicability of the nucleation regime map to a formulation with a broad size distribution and dry binder addition

In this study, Hapgood's nucleation regime map (Hapgood et al., 2003) was tested for a formulation that consists of an active pharmaceutical ingredient (API) of broad size distribution and a fine dry binder. Gabapentin was used as the API and hydroxypropyl cellulose (HPC) as the dry binder with deionized water as the liquid binder. The formulation was granulated in a 6 l Diosna high shear granulator. The effect of liquid addition method (spray, dripping), liquid addition rate (29-245 g/min), total liquid content (2, 4 and 10%), and impeller speed (250 and 500 rpm) on the granule size distribution and lump formation were investigated. Standard methods were successfully used to characterize the process parameters (spray drop size, spray geometry and powder surface velocity) for calculating the dimensionless spray flux. However, the addition of dry binder had a very strong effect on drop penetration time that could not be predicted from simple capillary flow considerations. This is most likely due to preferential liquid penetration into the fine pores related to the dry binder particles and subsequent partial softening and dissolution of the binder. For systems containing a dry binder or other amorphous powders, it is recommended that drop penetration time be measured directly for the blended formulation and then scaled to the drop size during spraying.Using these approaches to characterize the key dimensionless groups (dimensionless spray flux and drop penetration time), Hapgood's nucleation regime map was successfully used to predict a priori the effect of process conditions on the quality of the granule size distribution as measured by lump formation and the span of the size distribution, both before and after wet massing for range of conditions studied. Wider granule size distributions and higher amount of lumps were obtained moving from intermediate to mechanical dispersion regime. Addition of the liquid in the dripping mode gave the broadest size distribution with ungranulated fines and highest percentage of lumps compared to spraying mode. Addition of the liquid by spraying in the intermediate regime gave the narrowest size distribution with the lowest amount of lumps. The effects of impeller speed and wet massing time on granule size distribution were complex. At 2% liquid content, increasing the impeller speed and adding wet massing time caused some breakage of lumps and the production of fines. At higher liquid contents, the effects were less clear, likely due to a balance between increased breakage and increased granule consolidation and growth. Nevertheless, this work has demonstrated that for complex formulations with dry binder addition, the final granule size distribution still depends strongly on the homogeneity of the initial liquid distribution which is well predicted by the nucleation regime map analysis.     

Analysis of wet granulation process with Plackett-Burman design--case study

According to Process Analytical Technology perspective, drug product quality should be ensured by manufacturing process design. Initial step of the process analysis is investigation of critical process parameters (CPPs). It is generally accepted to type the CPPs based on project team knowledge and experience [5]. This paper describes the use of Design of Experiments tool for selection of the CPPs. Seven factors of wet granulation process were investigated for criticality. Low and high levels of each factor represented maximal and minimal settings of wide operational ranges. Granulates were produced in line with Plackett-Burman experimental matrix, blended with extra-granular excipients and compressed into tablets. Semi-products and final products were tested. Out of specification result of any critical quality attribute was treated as critical failure. The high-shear granulation factors, i.e. quantity of binding solution, rotational speed of impeller and wet massing time were considered of critical importance. Operational ranges of the parameters were optimized. The process performance was confirmed in qualification trials.     

Physical characterization of HPMC and HEC and investigation of their use as pelletization aids

Pelletization of drugs with suitable excipients by extrusion/spheronization is one of the popular approaches in the development of solid dosage forms, especially for extended-release formulations. However, the choice of pelletization aids is limited to the use of microcrystalline cellulose (MCC), which is generally wet massed using water. In the formulation of water-sensitive drugs, however, pelletization excipients which may be wet massed using an organic liquid are desired. In the present study therefore, two cellulose ethers, hydroxypropyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC), were characterized for their physical properties, such as moisture content, bulk and tapped densities, median particle size and size distribution, surface area and surface morphology, in an attempt to evaluate the feasibility of their use as pelletization aids. Since HPMC and HEC are water-soluble, but insoluble in isopropyl alcohol, the latter was used as the wet massing liquid for pelletization. Microcrystalline cellulose, because of its established uniqueness as a pellet former, was used as the reference material and was also wet massed using isopropyl alcohol for consistency and comparison. Placebo pellets of the three cellulosic excipients, HPMC, HEC and MCC, were prepared by extrusion/spheronization. The placebo pellets were evaluated for their size and size distribution, hardness, friability, bulk and tapped densities and sphericity. Of the three cellulosic excipients, HPMC and MCC produced pellets with the most desirable attributes. In water as the dissolution medium, the HPMC pellets absorbed water and formed a single viscous gel matrix that slowly dissolved. HEC pellets were swollen but intact and slowly eroded, whereas MCC pellets stayed intact without dissolution or erosion. These findings indicate that HPMC will find application in pellet formulations of water-sensitive drugs, as well as in those formulations where water may not be used as wet massing liquid and an organic liquid must be used. It will also be a good choice as a pelletization excipient when complete water-solubility of all the formulation excipients is desired. It may be anticipated that modification of drug release from pelletized formulations may also be achieved by using cellulose ethers of varying viscosity grades and hydration rates.     

The distribution of components in the different size fractions of granules prepared from binary mixtures.

Boric acid, sulphanilamide and citric acid have been mixed separately with lactose and then granulated by massing and screening. The granules have been fractionated by sieving and each fraction has been analysed for lactose content. The effect of premixing time, massing time, binder volume and ratio of components on the distribution of lactose between size fractions of granules prepared from lactose: boric acid mixtures has been investigated. Uneven distribution of lactose has been found for all blends examined. There is a premixing time and massing time that gives the optimum distribution of lactose for any given blend and binder volume. Increased binder volume in some cases improves granule uniformity. The proportion of lactose in the blend has a major effect on the distribution of this component in the granules, as does the particle size of the lactose. Granules prepared from blends of lactose with sulphanilamide and with citric acid were also examined for lactose distribution.     

The distribution of components in the different size fractions of granules prepared from binary mixtures

Boric acid, sulphanilamide and citric acid have been mixed separately with lactose and then granulated by massing and screening. The granules have been fractionated by sieving and each fraction has been analysed for lactose content. The effect of premixing time, massing time, binder volume and ratio of components on the distribution of lactose between size fractions of granules prepared from lactose: boric acid mixtures has been investigated. Uneven distribution of lactose has been found for all blends examined. There is a premixing time and massing time that gives the optimum distribution of lactose for any given blend and binder volume. Increased binder volume in some cases improves granule uniformity. The proportion of lactose in the blend has a major effect on the distribution of this component in the granules, as does the particle size of the lactose. Granules prepared from blends of lactose with sulphanilamide and with citric acid were also examined for lactose distribution.     

A PAT Approach to Improve Process Understanding of High Shear Wet Granulation Through In-Line Particle Measurement Using FBRM C35

This article summarizes the investigation of in-line particle characterization during high shear wet granulation (HSWG) using focused beam reflectance measurement (FBRM) for enhanced process understanding, which is part of an effort to develop this drug product within the framework of quality by design (QbD) and process analytical technology (PAT). Traditionally, the effectiveness of in-line monitoring of HSWG processes is hindered by wet and sticky material fouling the probe resulting in inconsistent and erroneous data collection. For this study, a FBRM C35 probe was used which incorporates a scraping mechanism to maintain a clean probe window ensuring consistent measurements throughout each batch. The evaluations were conducted on nine scale-up DOE development batches and eight clinical sub-lots. In the DOE campaign, the purpose of FBRM was used to study the impact of varying water amount and wet massing time on granule dimension and count during granulation, while batch-to-batch variation or batch reproducibility was evaluated under the same process conditions for the clinical batches. In addition, a preliminary investigation of the most optimal probe position was conducted. The results indicate that FBRM is capable of monitoring the rate and degree of change to granule dimension/count during HSWG, and could be a potential technique for granulation endpoint determination.     

Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry

With over 50 years of research in granulation technology, however more research is required to elucidate this widely applicable technology. Wetting phenomena could influence redistribution of individual ingredients within a granule according their solubility and also could affect the drying processes. Binder selection for a particular system is quite often empirical and dependent on the skills and experience of the formulator. Hand squeeze test was and still the main way for determination of wet granulation end point, but it is subjected to individual variation. It depends mainly on operator experience, so it is not possible to be validated. Literature reveals a variety of advanced monitoring techniques following up different wet massing stages. Torque measurement has been proved to be the most reliable control method as its tight relation to mass resistance. Many reports showed successful applications of mixing torque rheometer (MTR) for monitoring the wet massing procedure and scale up in addition to some preformulation applications. MTR as a new approach allows formulators to select a liquid addition range where the granule growth behavior is more predictable.     

Rheological characterization of diltiazem HCl/cellulose wet masses using a mixer torque rheometer

The objective of the present investigations was to study the rheological behavior of wet powder masses containing two commonly used cellulose ethers, hydroxypropyl methylcellulose (HPMC) and hydroxyethyl cellulose (HEC), using a mixer torque rheometer. In order to simulate a real formulation, diltiazem HCl (DTZ) (40% loading) was used as part of the substrate powder mass. Hydroxypropyl cellulose (HPC) was used as the binder. Since both the cellulose ethers used for the study are water soluble, isopropyl alcohol (IPA) was used as the wet massing liquid. For comparison purposes, microcrystalline cellulose (MCC) was used as a reference material. In addition, pelletization studies of these powder formulations were carried out to establish a critical window of the wet massing liquid needed for successful extrusion/spheronization. The rheological behavior of the wet powder masses was studied as a function of mixing time and amount of wet massing liquid (IPA). The rheological profiles of wet masses of DTZ–MCC and DTZ–HEC systems were similar and indicated poor liquid spreading, poor substrate wetting and weak substrate/binder interaction, and exhibited a narrow window of tolerance for the wet massing liquid. In contrast, the rheological profiles of DTZ–HPMC system indicated that this powder system has relatively better liquid spreading, better substrate wetting and higher degree of substrate/binder interaction, and higher liquid retention capability. During pelletization, in contrast to the other two powder systems, the DTZ–HPMC system could be extruded/spheronized using a relatively wider range of IPA level in Nica® extruder/spheronizer without becoming over-wet, which concurs with the observations made from the mixer torque rheometer studies. The study concludes that with DTZ being the common component in the three powder systems, the critical liquid requirement of the three powder systems is a function of the individual cellulosic component of the system. Of the three cellulosic excipients, HPMC exhibited a relatively higher affinity for IPA and the ability to be extruded/spheronized successfully with a wider range of the liquid.     

Combining formulation and process aspects for optimizing the high-shear wet granulation of common drugs

The purpose of this research was to determine the effects of some important drug properties (such as particle size distribution, hygroscopicity and solubility) and process variables on the granule growth behaviour and final drug distribution in high shear wet granulation. Results have been analyzed in the light of widely accepted theories and some recently developed approaches.A mixture composed of drug, some excipients and a dry binder was processed using a lab-scale high-shear mixer. Three common active pharmaceutical ingredients (paracetamol, caffeine and acetylsalicylic acid) were used within the initial formulation. Drug load was 50% (on weight basis).Influences of drug particle properties (e.g. particle size and shape, hygroscopicity) on the granule growth behaviour were evaluated. Particle size distribution (PSD) and granule morphology were monitored during the entire process through sieve analysis and scanning electron microscope (SEM) image analysis. Resistance of the wet mass to mixing was furthermore measured using the impeller torque monitoring technique. The observed differences in the granule growth behaviour as well as the discrepancies between the actual and the ideal drug content in the final granules have been interpreted in terms of dimensionless quantity (spray flux number, bed penetration time) and related to torque measurements. Analysis highlighted the role of liquid distribution on the process. It was demonstrated that where the liquid penetration time was higher (e.g. paracetamol-based formulations), the liquid distribution was poorer leading to retarded granule growth and selective agglomeration. On the other hand where penetration time was lower (e.g. acetylsalicylic acid-based formulations), the growth was much faster but uniformity content problem arose because of the onset of crushing and layering phenomena.     

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.     

The effect of starch type,concentration and distribution on the penetration and disruption of tablets by water

The effect of starch type, and its concentration and distribution, on the pore structure of tablets of aspirin and magnesium carbonate has been measured using air permeability and liquid penetration techniques. The addition of starch had no significant effect on the pore structure of the dry tablet but caused disruption and alteration of this structure when penetrated by water. When each starch was incorporated into the granules in wet massing the rate of disruption decreased in the order potato, maranta, wheat, corn, waxy corn and rice; but a more complicated pattern was produced when the starch was added to the granules as a pre-dried powder. Maximum breakup efficiency of magnesium carbonate tablets was produced when 10 % potato starch was incorporated internally and the tablet compacted to a porosity of 28 %.     

Role of excipients in hydrate formation kinetics of theophylline in wet masses studied by near-infrared spectroscopy.

Hydrate formation is a phase transition, which can occur during wet granulation. This kind of processing-induced transformation (PIT) can influence the quality of a finished product. The aim of the study was to investigate the effect of excipients on the kinetics of hydrate formation in wet masses. Anhydrous theophylline was chosen as the hydrate-forming model drug compound and two excipients, silicified microcrystalline cellulose (SMCC) and alpha-lactose monohydrate, with different water absorbing properties, were used in formulation. An early stage of wet massing was studied with anhydrous theophylline and its 1:1 (w/w) mixtures with alpha-lactose monohydrate and SMCC with 0.1g/g of purified water. The changes in the state of water were monitored using near-infrared spectroscopy, and the conversion of the crystal structure was verified using X-ray powder diffraction (XRPD). SMCC decreased the hydrate formation rate by absorbing water, but did not inhibit it. The results suggest that alpha-lactose monohydrate slightly increased the hydrate formation rate in comparison with a mass comprising only anhydrous theophylline.     

Batch and continuous processing in the production of pharmaceutical granules

A quasicontinuous granulation and drying process to avoid scale-up problems is introduced in this work. Consistent and reproducible granule quality is a key factor in robust dosage form design and fits ideally the prerequisites of a drug quality system for the twenty-first century and the Food and Drug Administration's Process Analytical Technology (PAT) initiative. In scale-up, factors that simulate or reproduce the laboratory scale must be considered. This system provides a new possibility for industrial manufacturing and galenical development of pharmaceutical solids. The quasicontinuous method described in the present work, and the laboratory and production batches and the granulating equipment used to produce them, are the same. Once a robust process has been defined in the laboratory, it is merely repeated as many times as necessary to achieve the desired final batch size. The quasicontinuous process gives new possibilities to simplify manufacturing procedures and to validate them faster. The quality of the resulting granules and tablets compared with classical methods is equal until better. In many cases, existing products have been transferred to the multicell process without formulation changes. The quasicontinuous production concept for high-shear granulation and fluid-bed drying offers many advantages over the classical methods used to produce pharmaceutical granules. The wet massing process may be monitored by the power consumption of the mixer motor for each subunit, as in classical high-shear granulation processes. The air volume, temperature, and humidity of each of the drying cells may be controlled individually to avoid overheating of temperature-sensitive materials. All processing variables must be precisely controlled by a computer, and the data must be collected for documentation. As such, product quality and reproducibility for each subunit is assured.     

Modelling of initial distribution of drugs following intravenous bolus injection

Based on a recirculatory pharmacokinetic model, a physiologically realistic definition of the initial distribution volume has been developed to characterize the overall distribution process occurring shortly after rapid bolus injection of a drug. This apparent volume of distribution, which refers to the peak right atrial blood concentration, depends on the cardiac output and basic pharmacokinetic parameters usually derived from the whole blood concentration vs time curve. The initial distribution process appears to be affected by changes in the variance of the distribution of residence times of the drug in the body. The influence of the site and time of early blood sampling on the estimated initial distribution volume is discussed. This relatively simple a priori model should prove useful in predicting to a first approximation the principal characteristics of the initial distribution process.     

Investigation of Solution and Vapor Phase Mediated Phase Transformation in Thiamine Hydrochloride

Thiamine hydrochloride (THCl) can exist as an anhydrate (AH), a hemihydrate (HH) and as a nonstoichiometric hydrate (NSH) where the water content can range between 0 and ~1 mole of water per mole of THCl. We have investigated the NSH → HH phase transformation, in the presence of microcrystalline cellulose (MCC), following (i) wet massing, (ii) fluid- bed granulation, and (iii) exposure to water vapor (40°C/75% RH). Based on Raman spectroscopy (40°C), wet massing of NSH alone caused near complete transformation to HH in < 100 min. In the presence of MCC, the transformation rate was decelerated. During fluid-bed granulation, ~20% of NSH was transformed to HH and the deceleratory effect of MCC was much less pronounced. Exposure to water vapor, of both NSH-MCC powder blends and granules (prepared by fluid-bed) resulted in complete HH formation within 6 days. Presence of MCC in the powder blend did not affect HH formation kinetics, but facilitated phase transformation in the granules. NSH → HH conversion appeared to follow two-dimensional nucleation and growth model in powder blends, whereas the granules showed either three-dimensional diffusion controlled or a first-order kinetics. In a wet mass, polyvinyl pyrrolidone, a widely used binder, was much more effective than MCC in inhibiting HH formation during wet massing. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3941–3952, 2010     

Processing-induced phase transitions of theophylline--implications on the dissolution of theophylline tablets

Aqueous wet massing of stable anhydrous theophylline (A) with polyvinylpyrrolidone (PVP) resulted in its complete transformation to theophylline monohydrate (M). Drying at 45 degrees C, resulted in the formation of metastable anhydrous theophylline (A*) which then transformed to A. PVP, a known crystallization inhibitor, was effective in inhibiting the A* --> A transition. The higher molecular weight polymer, PVP K90, was more effective in inhibiting the A* --> A transition as compared to PVP K17. The disappearance of M, and the formation of A* and A was simultaneously monitored by XRD. An increase in the drying temperature from 45 to 55 degrees C accelerated the A* --> A transition. In granules prepared by the high-shear process, approximately 50% of theophylline existed as A and the rest as A*. In contrast, the fluid-bed granulation process yielded granules containing only A. Thus, the physical form of theophylline in tablets was influenced by the molecular weight of the binding agent, the granulation method, and the drying temperature. Using A as the starting material, tablets were manufactured by high-shear aqueous wet granulation process and the A* content was quantified. These tablets were stored under various relative humidity (RH) conditions at 25 degrees C for 2 weeks. Storage at RH >or= 33% caused complete A* --> A conversion accompanied by a pronounced decrease in the initial dissolution rate indicating that phase transitions during processing and storage can have a significant influence on product performance.