Continuous high-shear granulation: Mechanistic understanding of the influence of process parameters on critical quality attributes via elucidating the internal physical and chemical microstructure

Over the past decade, continuous wet granulation has been emerging as a promising technology in drug product development. In this paper, the continuous high-shear mixer granulator, Lӧdige CoriMix® CM5, was investigated using a low-dose formulation with acetaminophen as the model drug. Design of experiments was deployed in conjunction with multivariate data analysis to explore the granulator design space and comprehensively understand the interrelation between process parameters and critical attributes of granules and tablets. Moreover, several complementary imaging techniques were implemented to unveil the underlying mechanisms of physical and chemical microstructure in affecting the tablet performance. The results indicated that L/S ratio and impeller speed outweighed materials feeding rate in modifying the granule and tablet properties. Increasing the degree of liquid saturation and mechanical shear input in the granulation system principally produced granules of larger size, smaller porosity, improved flowability and enhanced sphericity, which after compression generated tablets with slower disintegration process and drug release kinetics due to highly consolidated physical microstructure. Besides, in comparison to batch mixing, continuous mixing integrated with a conical mill enabled better powder de-agglomeration effect, thus accelerating the drug dissolution with increased surface area.     

集成过程分析技术和群体粒数衡算模拟的药物材料造粒过程决策支持系统

通过集成在线近红外光谱仪、实时图像采集与处理系统和群体粒数衡算模型,开发了高剪切湿法造粒过程的决策支持系统(Decision support system,DSS)。利用近红外光谱仪和图像系统实时测量多个过程变量和产品质量指标,包括粉体混合均匀度、颗粒粘合剂含量、粒径分布以及团聚、破裂行为等,能够快速确定过程操作空间。同时,由过程分析平台得到的信息经分析处理后输入工艺过程模型模块,用于估算和校准群体粒数衡算模型中的团聚和破裂速率常数,以此持续提高模型精度。另一方面,模型可以指导实验体系寻找最优操作空间。该决策支持系统成功应用到了以微晶纤维素和甘露醇为原料,3%聚乙烯吡咯烷酮水溶液为粘合剂的高剪切湿法造粒过程中,对两个粘合剂喷淋速率下的造粒过程进行监测。DSS认定粘合剂喷淋过程分为四个阶段:润湿期、成核期、快速生长期和慢速生长期。不同阶段之间的分界点与粘合剂喷淋速率有关。在较高喷淋速率下,颗粒进入成核期和快速生长期所需粘合剂较少,但是对颗粒最终粒径无明显影响。此外,通过近红外光谱测定混合均匀度,确定了粉体的混合终点。该DSS系统将基于过程分析技术的高效实验和过程模拟结合,可以快速确定操作空间以及颗粒的生长行为,实时提供大量数据用于持续提高模型精确度和稳健性,提高造粒过程的优化效率。     

Evaluation of the influence of granulation processing parameters on the granule properties and dissolution characteristics of a modified release drug

Understanding the relationship between high shear wet granulation processing parameters and the characteristics of intermediate and final products is crucial in the ability to apply quality by design (QbD) and process analytical technologies (PAT) to secondary pharmaceutical processes. This research examined a high shear wet granulation process and subsequent manufacturing of a tablet containing a biopharmaceutics classification system (BCS) class II drug, gliclazide (low solubility, high permeability). Previous studies have concentrated on either granulation or tabletting but not both together; this work brings together the analysis as a single large multivariate process. The design of experiment (DoE) was performed according to an L9 Taguchi method with three replications, in total; thirty-six runs were performed. A full statistical analysis relating both granule and tablet properties to selected process parameters were carried out. The research illustrates that mapping a highly multivariate process is possible. Statistically significant critical process parameters were identified for granule hardness, granule density and granule particle size. These granule properties were also identified as contributing to the dissolution release characteristics. Dissolution modeling and prediction was achieved within the DoE structure. Process noise was identified and measured across the entire production and specifically with respect to the milling process.     

Prediction of Drug Content and Hardness of Intact Tablets Using Artificial Neural Network and Near-Infrared Spectroscopy

The purpose of this study was to predict drug content and hardness of intact tablets using artificial neural networks (ANN) and near-infrared spectroscopy (NIRS). Tablets for the drug content study were compressed from mixtures of Avicel® PH-101, 0.5% magnesium stearate, and varying concentrations (0%, 1%, 2%, 5%, 10%, 20%, and 40% w/w) of theophylline. Tablets for the hardness study were compressed from mixtures of Avicel PH-101 and 0.5% magnesium stearate at varying compression forces ranging from 0.4 to 1 ton. An Intact Analyzer™ was used to obtain near infrared spectra from the tablets with varying drug contents, whereas a Rapid Content Analyzer™ (RCA) was used to obtain spectral data from the tablets with varying hardness. Two sets of tablets from each batch (i.e., tablets with varying drug content and hardness) were randomly selected. One set of tablets was used to generate appropriate calibration models, while the other set was used as the unknown (test) set. A total of 10 ANN calibration models (5 each with 10 and 160 inputs at appropriate wavelengths) and five separate 4-factor partial least squares (PLS) calibration models were generated to predict drug contents of the test tablets from the spectral data. For the prediction of tablet hardness, two ANN calibration models (one each with 10 and 160 inputs) and two 4-factor PLS calibration models were generated and used to predict the hardness of test tablets. The PLS calibration models were generated using Vision® software. Prediction of drug contents of test tablets using the ANN calibration models generated with 10 inputs was significantly better than the prediction obtained with the ANN calibration models with 160 inputs. For tablets with low drug concentrations (less than or equal to 2%w/w), prediction of drug content was better with either of the two ANN calibration models than with the PLS calibration models. However, prediction of drug contents of tablets with greater than or equal to 5% w/w drug was better with the PLS calibration models than with the ANN calibration models. Prediction of tablet hardness was better with the ANN calibration models generated with either 10 or 160 inputs than with the PLS calibration models. This work demonstrated that a well-trained ANN model is a powerful alternative technique for analysis of NIRS data. Moreover, the technique could be used in instances when the conventional modeling of data does not work adequately.     

Melt granulation in fluidized bed: a comparative study of spray-on versus in situ procedure

Objective: The aim of this study was to investigate the influence of process parameters, binder content and binder addition method on characteristics of the granules obtained by melt granulation (MG) in fluidized bed.

Methods: Spray-on experiments were performed according to 2³ full factorial design. The effect of binder content, molten binder feed rate, and spray air pressure on granule size and size distribution, granule shape, ?owability and drug release rate was investigated. In the in situ experiments, the influence of binder particle size and binder content was evaluated. Solid-state characterization was performed by means of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy.

Results: Size of the granules obtained by spray-on procedure was significantly influenced by binder content and spray air pressure, while the width of particle size distribution was mainly affected by binder feed rate. Spray air pressure showed the most significant influence on granule shape. It was shown that smooth and spherical particles with good flow properties may be obtained by both procedures, spray-on and in situ MG. The results obtained indicated the influence of agglomeration mechanism on granule sphericity, with higher degree of granule sphericity observed when immersion and layering was the dominant mechanism. Paracetamol release from granulates was very rapid, but after compression of the granules into tablets, drug release was considerably slower. Solid-state analysis confirmed that the physical form of the granulate components remained unaffected after the MG process.

Conclusion: The results presented indicate that MG in fluidized bed could be a good alternative to conventional granulation techniques.     

Application of near-infrared spectroscopy to optimize dissolution profiles of tablets according to the granulation mechanism

We developed a method for the optimization of dissolution properties of solid oral dosage forms manufacturing using high shear wet granulation (HSWG) by using near-infrared spectroscopy (NIRS) with chemometrics in small-scale experiments. The changes in rheology and NIR spectra of the granules were monitored to verify the granulation mechanism and determine the suitable water amount for model formulation during the HSWG. Tablets were manufactured by altering the added water amount to investigate the impact of the granulation mechanism on drug product qualities. Model formulation granules were prepared with 10–20% w/w water in a funicular state, corresponding to the plateau region in score plots obtained by principal component analysis (PCA). The dissolution rate of model formulation tablets manufactured with more than 20% w/w of water was significantly delayed while tablets manufactured with 15% w/w water showed 100% dissolution at 15?min. NIRS and PCA are applicable to the optimization of dissolution properties via the process understanding of HSWG at the early formulation development stage and could facilitate drug development.     

High shear wet granulation: Improved understanding of the effects of process variables on granule and tablet properties of a high-dose,high-hydrophobicity API based on quality by design and multivariate analysis approaches

High shear wet granulation (HSWG), as a widely used granulation technology, has been studied extensively. However, for the HSWG of formulations containing hydrophobic components, the influence of process variables on the properties of granules and tablets has not been reported. In the present study, based on a combination of quality by design and multivariate analysis (MVA) approaches, quercetin with high-dose and high-hydrophobicity was used to study the relationship between process variables, granule properties, and tablet properties in HSWG systematically. Control and response variables were determined using risk assessment. The optimal fitting empirical models established by Box-Behnken design showed that the liquid to solid ratio and impeller speed were the most important factors, which affected all product properties except Carr’s index and yield pressure. Instead, the influence of wet massing time was relatively small (only the effects on yield, granule size, granule hardness, and compression ratio were significant). Then, the process design space was obtained by limiting the related critical quality attributes, which was verified effectively. Scanning electron microscope images showed that smooth granules were produced using higher process parameters, whereas rough and porous granules resulted at lower process parameters. Furthermore, the MVA results demonstrated that increasing the granule hardness led to an increase in the compression ratio and a decrease in tensile strength of the tablets. Tablet fragility and disintegration time were mainly affected by granule density and bulk density, respectively, and both were negatively correlated. The established research paradigm is not only conducive to the successful development of quercetin products, but also provides valuable guidance for improving HSWG–based product development with such formulation characteristics.     

Near-infrared spectroscopic applications in pharmaceutical particle technology

Abstract

Near-infrared spectroscopy (NIRS) is nowadays an established analytical technique in the pharmaceutical industry. The aim of this review is to present the progress of NIRS in providing useful information for pharmaceutical particle technology. NIR methods are now developed to characterize a wide variety of materials (active pharmaceutical ingredients, excipients, co-processed powders, and physical mixtures) and pharmaceutical dosage forms (conventional, modified drug release technologies, and phytomedicines). This review also provides a number of spectra to illustrate the fundamental understanding of NIRS which has been gained. The sampling that must occur prior to the acquisition of near-infrared spectra is also discussed, as well as developments in monitoring mixing, tableting, and coating. This review will be valuable for product formulation and process engineering specialists.     

On the composite characteristics of small binary granules formed in a continuous rotating conical vessel with grinding media

In order to produce small composite granules having binary components of CaCO₃ and SiC powders, experiments were carried out by the simultaneous operation of granulation, grinding, and separation in a single continuous rotating conical vessel with grinding media. To characterize these composite granules, SiC agglomerates contained in a granule were separated by chemical methods, and the size distributions of granules and SiC agglomerates were measured by an image analyzer through a microscope. The structure of a composite granule was characterized by comparing the size of a composite granule with that of SiC agglomerates in the granule. It was found that composite structures of the granules could be classified into six kinds of structural models, and that the composite structure depended on the size of the granules and the volume fraction of the SiC component in the granule.     

In situ determination of growing stages and harvest time of tomato (Lycopersicon esculentum ) fruits using fiber-optic visible-near-infrared (Vis-NIR) spectroscopy

Nondestructive in situ measurement of tomato fruits is essential to determine growing stages and to assist in automatic picking of fruits. This study evaluates the applicability of visible and near-infrared (Vis-NIR) spectroscopy for in situ determination of growing stages and harvest time of three cultivars of tomato fruits. A mobile fiber-type AgroSpec Vis-NIR spectrophotometer (Tec5 Co., Germany) with a spectral range of 350-2200 nm was used to measure tomato spectra in reflection mode. A new growing stage (GS) index defined as the ratio of the current growing age in days to the on-vine duration before harvest in days was proposed. After dividing spectra into a calibration set (70%) and an independent prediction set (30%), spectra in the calibration set were subjected to a partial least squares regression (PLSR) with leave-one-out cross-validation to establish calibration models relating GS to the spectra of tomato fruits. Separate models were developed for each tomato cultivar and compared with a general model that used combined spectra of all three cultivars. The results show that PLSR based on the new GS is successful and robust in predicting the growing stages and harvest time of tomato fruits. Validation of calibration models on the independent prediction set indicates that successful prediction of GS can be achieved using the three models developed separately for each cultivar with a coefficient of determination (R(2)) of 0.91-0.92, root mean square error of prediction (RMSEP) of 0.081-0.097, and residual prediction deviation (RPD) of 3.29-3.70. General calibration using the combined spectra produces good prediction performance, although less accurate than that for the three individual cultivar models. The analysis of regression coefficient plots resulting from PLSR analysis indicates consistent assignment of important wavelengths for individual cultivar spectra and combined spectra. It is concluded that the Vis-NIR PLSR based on GS index can be adopted successfully for in situ determination of growing stages and harvest time of on-vine tomato fruits, which allows for automatic picking of fruits by a horticultural robot.     

An investigation on process of seeded granulation in a continuous drum granulator using DEM

Numerical simulation of wet granulation in a continuous granulator is carried out using Discrete Element Method (DEM) to discover the possibility of formation of seeded granules in a continuous process with the aim of reducing number of experimental trials and means of process control. Simple and scooped drum granulators are utilized to attain homogenous seeded granules in which the effects of drum rotational speed, particles surface energy, and particles size ratio are investigated. To reduce the simulation time a scale-up scheme is designed in which a dimensionless number (Cohesion number) is defined based on the work of cohesion and gravitational potential energy of the particles. Also a mathematical/numerical method along with a MATLAB code is developed by which the percentage of surface coverage of each granule is predicted precisely. The results show that use of continuous granulator for seeded granulation is promising provided that a high level of shear is considered in the granulator design, i.e. using baffles inside drum granulators is essential for producing seeded granules. It is observed that the optimum surface energy for seeded granulation in scooped granulator (used in this study) with rotational speed of 50 rpm is 3 J/m², which is close to the value predicted by the concept of Cohesion number. It is also shown that increasing the seed/fine size ratio enhances the seeded granulation both quantitatively (60% increase in seeds surface coverage) and qualitatively (more homogeneous granules).     

Effect of fill level in continuous twin-screw granulator: A combined experimental and simulation study

Twin-screw granulators for continuous wet granulation have attracted interest in the pharmaceutical industry. The physical properties of granules and tablets prepared through the twin granulation process depend on several factors, such as screw and barrel geometries, operating conditions, and formulations of raw materials. The fill level has been reported to be one of the most important factors in determining granule properties. However, the mechanism of the fill level effect on granule properties has not yet been fully clarified. In this study, the effects of the fill level in the twin-screw granulator on granule and tablet properties were investigated through a combination of experimental and simulation studies. In the experiment, temporal changes in the fill level were directly measured. It was found that a high fill level increased granule strength, resulting in large tablet hardness. The discrete element method simulations demonstrated that the compressive force on the particles in the granulator strongly depends on the fill level. In addition, by combining the experimental and simulation results, it was quantitatively revealed that a high fill level increased the interparticle adhesion, leading to the high hardness of tablets prepared with the granules.     

Effect of the granulation process on nitrofurantoin granule characteristics

We studied four granulation methods on the same quantitative and qualitative formula: wet massing by forced agglomeration (L?dige) and free agglomeration (Glatt); and dry massing by slugging and roller compaction technique. Three different particle sizes of nitrofurantoin (bioinequivalent drug) were used. The nitrofurantoin particle size has a very low influence on the physical characteristics of the granules. The granulating process influenced the binding of the particles. Granules processed using the wet granulating method were harder than those made by dry process. L?dige granules were more bonded than Glatt granules. Granules prepared by dry massing presented broken particles. The surface area and the porosity of Glatt granules were the most important parameters. Dissolution studies must be effected to make a correlation between the physical results and the dissolution rates. It is necessary to effect a new validation and a comparison of the results when a new granulating apparatus is used.     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly     

An Evaluation of Process Variables in wet Granulation

Abstract

In wet granulation, determining the process variables which play an essential role in granule quality is crucial for optimizing the manufacturing process. An L16(2⁵) fractional factorial experimental design using the table of orthogonal arrays was employed in order to estimate the relative intensity of the influences of five process variables on granule quality in wet granulation using a high-speed mixer granulator. Total volume and formulation of binder solution, blade rotation speed, granulation time, and amount of powder supplied into the granulator were selected as decisive process variables in the formation of granules. Granule yield, geometrical mean granule size and uniformity of granule size were evaluated as representative properties of granule quality. Experimental results were analyzed according to the analysis of variance (ANOVA).

The results of significance test and contribution ratio in ANOVA indicated that, within the experimental region, only binder solution had a critical effect on the three physical properties of the obtained granules. The effects of other variables were found to be minimal. Further, the contribution of sampling error to total variance was quite small.     

High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties

Context: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation.

Objective: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer.

Methods: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the ‘out-of-die’ Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4?L, 300?L, and 600?L.

Results and conclusion: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

Abstract

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly     

The use of near-infrared spectroscopy for the quantitation of a drug in hot-melt extruded films

The objective of the study was to demonstrate the utility of near-infrared spectroscopy (NIRS) for quantitative analysis of a model drug in hot-melt extruded film formulations. Polyethylene oxide (PEO) films with clotrimazole (CT) as a model drug were prepared by hot-melt extrusion (HME) incorporating drug concentrations ranging from 0-20% and analyzed using a Fourier transform near-infrared (FT-NIR) spectrophotometer in the reflectance mode. High performance liquid chromatography (HPLC) was the reference method used for this study. The NIR calibration model derived for CT was composed of 21 frequency ranges that were correlated to the values quantified using the HPLC reference method. The NIR method developed resulted in an assayed CT amount in the film matrix to be within 3.5% of the quantity determined by the reference method. These studies clearly demonstrate that NIRS is a powerful method for the quantitation of active drug substances contained in films produced by HME and warrants further investigation.     

Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO

Context: Niacin (vitamin B3) is a micronized active pharmaceutical ingredient (API) with poor flow properties making the production of high-dose sustained-release tablets by direct compression a challenge.

Objective: We evaluated various wet granulation processes as a simple and efficient approach to obtain high-dose (500 and 1000?mg) niacin sustained-release lipid matrix tablets.

Materials and methods: A high melting-point lipid (Compritol® 888 ATO) was used as the sustained-release agent. Tablets were prepared by various wet granulation techniques, with different process parameters and binder concentrations to identify the optimal process conditions.

Results: A binder (PVP) was needed to increase particle bonding and tablet strength. Process parameters, such as spray rate and quantity of liquid, had only a slight impact on the properties of the granules and resultant tablets, in the presence of low binder concentrations. Increasing binder concentration improved granule wetting, resulting in significant granule growth and improved flow properties. Sustained-release over 12?h was observed for all the compacted granules, irrespective of the drug dose. The sustained-release kinetics for 1000?mg niacin matrix tablets with Compritol 888 produced with the identified optimal parameters were similar to those for the market reference product, Niaspan® FCT 1000?mg. The tablets were stable for up to six months when stored at 25 and 40?°C.

Conclusions: Wet granulation with Compritol 888 presents an effective approach to improve material flow and compressibility. High-dose lipid matrix tablets with sustained release profiles can be successfully produced.     

Monitoring of the manufacturing process for ambroxol hydrochloride tablet using NIR-chemometric methods: compression effect on content uniformity model and relevant process parameters testing

This study aimed at using near-infrared (NIR) spectroscopy to monitor compaction pressure for simultaneously determining the tensile strength and content uniformity, as well as moisture and mean particle size of ambroxol hydrochloride tablets. The content uniformity, compression force and tensile strength of the laboratory samples were obtained by pressing a mixture of active principle and excipient components into tablets. To reduce the spectral baseline shift of the laboratory samples, the compaction pressure applied to the mixture was assessed by a variable pressure test. Production samples were added to the test and subjected to principal component analysis. The expanded partial least-squares (PLS) calibration model used to quantify the active content was more accurate than the model constructed from laboratory samples using the production tablets included in the calibration set. The model showed good predictability, with correlation coefficient (R) 0.9977. The validation and reliability of the content model were evaluated to determine trueness and reliability for the measurement of individual production tablets and the laboratory tablets with drug content ranging from 24 to 36?mg. The PLS calibration models for compression force and tensile strength were constructed using the same spectral set assuming both were highly related. These models yielded high R values (0.9955 and 0.9910). The R values of the moisture and mean particle size were 0.9994 and 0.9919, respectively. This study demonstrated that NIR spectroscopy combined with chemometric techniques can be successfully used to quantitatively monitor the tablet manufacturing process in the pharmaceutical industry.