Granulation Liquid Research Articles

In-line indirect concentration measurement of ultralow dose API during twin-screw wet granulation based on NIR and Raman spectroscopy

Twin-screw wet granulation (TWSG) is a promising continuous alternative of pharmaceutical wet granulation. One of its benefits is that the components dissolved in the granulation liquid are distributed homogeneously in the granules. This provides an elegant way to manufacture products with ultralow drug doses. Near-infrared (NIR) and Raman spectroscopy are well-established process analytical technology (PAT) tools that can be used for the in-line monitoring of TSWG. However, their detection limit does not enable the measurement of components in the ultralow (i.e., ppm) range. In this paper, an indirect approach is presented that enables the real-time determination of the concentration of a drug in concentrations between 40 and 100 ppm by using the signal of an excipient, in this case, the polyvinylpyrrolidone (PVP). This component is also dissolved in the granulation liquid; therefore, it is distributed in the same way as the active ingredient. Results of HPLC measurements have proved that the models trained to quantify the concentration of PVP in real-time gave an accurate determination for the active ingredient as well (root mean squared error was 7.07 ppm for Raman and 5.31 ppm for NIR spectroscopy, respectively). These findings imply that it is possible to indirectly predict the concentration of ultralow dose drugs with in-line analytical techniques based on the concentration of an excipient.

Studying the API Distribution of Controlled Release Formulations Produced via Continuous Twin-Screw Wet Granulation: Influence of Matrix Former, Filler and Process Parameters.

Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content uniformity issues during downstream processing. Therefore, the current study investigated the root cause of the non-homogeneous theophylline distribution. The effect of process parameters (L/S-ratio and screw configuration) and formulation parameters (matrix former and filler type) on content uniformity was studied. Next, the influence of the formulation parameters on tableting and dissolution behavior was investigated. Altering the L/S-ratio or using a more aggressive screw configuration did not result in a homogeneous API distribution over the granule sieve fractions. Using microcrystalline cellulose (MCC) as filler improved the API distribution due to its similar behavior as HPMC. As excluding HPMC or including a hydrophobic matrix former (Kollidon SR) yielded granules with a homogeneous API distribution, HPMC was identified as the root cause of the non-homogeneous API distribution. This was linked to its fast hydration and swelling (irrespective of the HPMC grade) upon addition of the granulation liquid.

Analysis of the effect of formulation properties and process parameters on granule formation in twin-screw wet granulation

In the last few years, twin-screw wet granulation (TSWG) has become one of the key continuous pharmaceutical unit operations. Despite the many studies that have been performed, only little is known about the effect of the starting material properties on the stepwise granule formation along the length of the twin-screw granulator (TSG) barrel. Hence, this study obtained a detailed understanding of the effect of formulation properties (i.e., Active Pharmaceutical Ingredient (API) properties, formulation blend particle size distribution and formulation drug load) and process settings on granule formation in TSWG. An experimental set-up was used allowing the collection of granules at the different TSG compartments. Granules were characterized in terms of granule size, shape, binder liquid and API distributions. Liquid-to-solid (L/S) ratio was the only TSG process parameter impacting the granule size and shape evolution. Particle size and flow properties (e.g., flow rate index) had an important effect on the granule size and shape changes whereas water-related properties (e.g., water binding capacity and solubility) became influential at the last TSG compartments. The API solubility and L/S ratio were found to have a major impact on the distribution of binder liquid over the different granule size fractions. In the first TSG compartment (i.e., wetting compartment), the distribution of the API in the granules was influenced by its solubility in the granulation liquid.

The Influence of Wet Granulation Parameters on the Compaction Behavior and Tablet Strength of a Hydralazine Powder Mixture.

The aim of this paper was to describe the influence of high-shear wet granulation process parameters on tablet tensile strength and compaction behavior of a powder mixture and granules containing hydralazine. The hydralazine powder mixture and eight types of granules were compacted into tablets and evaluated using the Heckel, Kawakita and Adams analyses. The granules were created using two types of granulation liquid (distilled water and aqueous solution of polyvinylpyrrolidone), at different impeller speeds (500 and 700 rpm) and with different wet massing times (without wet massing and for 2 min). Granulation resulted in improved compressibility, reduced dustiness and narrower particle-size distribution. A significant influence of wet massing time on parameters from the Kawakita and Adams analysis was found. Wet massing time had an equally significant effect on tablet tensile strength, regardless of the granulation liquid used. Granules formed with the same wet massing time showed the same trends in tabletability graphs. Tablets created using a single-tablet press (batch compaction) and an eccentric tablet press showed opposite values of tensile strength. Tablets from granules with a higher bulk density showed lower strength during batch compaction and, conversely, higher strength during eccentric tableting.

Effect of process parameters in high shear granulation on characteristics of a novel co-processed mesoporous silica material

In this study, insights into the development and optimization of a co-processed excipient based on mesoporous silica are presented. The main advantage of such a material is that it is appropriate for direct tablet compression and has a sufficiently large specific surface area to be suitable for potential subsequent drug loading and formulation of (amorphous) solid dispersions. Our aim was to use a Design of Experiments approach to investigate which process parameters in high shear granulation affect the characteristics of such a co-processed material. The parameters included were the amount of binder (isomalt), the amount of water (granulation liquid), the water addition rate and the speed of the impeller. The responses evaluated and modelled were particle size and its distribution, specific surface area, bulk density, flowability, compressibility and compactibility. The models obtained showed good quality in terms of goodness of fit and predictive power. Active effects were identified for all responses, giving a thorough insight into factors affecting the material characteristics. Optimization experiments resulted in products with the desired characteristics (high specific surface area, large particle size, good flow and compression properties) and confirmed the validity of the generated models.

Attribute transmission and effects of diluents and granulation liquids on granule properties and tablet quality for high shear wet granulation and tableting process

This study aims to examine (i) the effect of diluent types (lactose monohydrate, corn starch, and microcrystalline cellulose) and granulation liquids (20% polyvinylpyrrolidone K30, 65% alcohol, and dispersion containing 40% model drug– Pithecellobium clypearia Benth extracted powder) on granule properties and tablet quality for high shear wet granulation and tableting (HSWG-T) and, more importantly, (ii) the attribute transmission in the process. In general, the impact of diluents on granule properties and tablet quality was more dominant than that of granulation liquids. Attribute transmission patterns were revealed as follows. The granules’ ISO. Roundness and density correlated with raw material (i.e., model drug, diluent, and/or granulation liquid) properties such as density and viscosity. The granules’ compressibility parameter a correlated with the granules’ Span, and parameter y0 correlated with the granules’ flowability and friability. Compactibility parameters ka and kb correlated mainly with granules' flowability and density, and parameter b correlated significantly and positively with tablet tensile strength. The compressibility correlated negatively with tablet solid fraction (SF) and friability, while the compactibility correlated positively with tablet disintegration time. Moreover, the rearrangement and elasticity of granules correlated positively with SF and friability, respectively. Overall, this study provides some guides for achieving high-quality tablets via HSWG-T.

Evaluation of the Formulation Parameter-Dependent Redispersibility of API Nanoparticles from Fluid Bed Granules.

The production of nanosuspensions of poorly soluble active pharmaceutical ingredients (API) is a popular technique to counteract challenges regarding bioavailability of such active substances. A subsequent drying of the nanosuspensions is advantageous to improve the long-term stability and the further processing into solid oral dosage forms. However, associated drying operations are critical, especially with regard to nanoparticle growth, loss in redispersibility and associated compromised bioavailability. This work extends a previous study regarding the applicability of an API (itraconazole) nanosuspension as a granulation liquid in a fluidized bed process with focus on the influence of applied formulation parameters on the structure of obtained nanoparticle-loaded granules and their nanoparticle redispersibility. Generally, a higher dissolution rate of the carrier material (glass beads, lactose, mannitol or sucrose) and a higher content of a matrix former/hydrophilic polymer (PVP/VA or HPMC) in the granulation liquid resulted in the formation of coarser and more porous granules with improved nanoparticle redispersibility. HPMC was found to have advantages as a polymer compared with PVP/VA. In general, a better redispersibility of the nanoparticles from the granules could be associated with better dispersion of the API nanoparticles at the surface of the granules as deduced from the thickness of nanoparticle-loaded layers around the granules. The layer thickness on granules was assessed by means of confocal Raman microscopy. Finally, the dispersion of the nanoparticles in the granule layers was exemplarily described by calculation of theoretical mean nanoparticle distances in the granule layers and was correlated with data obtained from redispersibility studies.

Systematic Study of the Effects of High Shear Granulation Parameters on Process Yield, Granule Size, and Shape by Dynamic Image Analysis.

The aim of the work was to analyze the influence of process parameters of high shear granulation on the process yield and on the morphology of granules on the basis of dynamic image analysis. The amount of added granulation liquid had a significant effect on all monitored granulometric parameters and caused significant changes in the yield of the process. In regard of the shape, the most spherical granules with the smoothest surface were formed at a liquid to solid ratio of ≈1. The smallest granules were formed at an impeller speed of 700 rpm, but the granules formed at 500 rpm showed both the most desirable shape and the highest process yield. Variation in the shape factors relied not only on the process parameters, but also on the area equivalent diameter of the individual granules in the batch. A linear relationship was found between the amount of granulation liquid and the compressibility of the granules. Using response surface methodology, models for predicting the size of granules and process yield related to the amount of added liquid and the impeller speed were generated, on the basis of which the size of granules and yield can be determined with great accuracy.

Complete Cocrystal Formation during Resonant Acoustic Wet Granulation: Effect of Granulation Liquids.

The manufacturing of solid pharmaceutical dosage forms composed of cocrystals requires numerous processes during which there is risk of dissociation into parent molecules. Resonant acoustic wet granulation (RAG) was devised in an effort to complete theophylline–citric acid (THPCIT) cocrystal formation during the granulation process, thereby reducing the number of operations. In addition, the influence of granulation liquid was investigated. A mixture of anhydrous THP (drug), anhydrous CIT (coformer), and hydroxypropyl cellulose (granulating agent) was processed by RAG with water or ethanol as a granulation liquid. The purposes were to (i) form granules using RAG as a breakthrough method; (ii) accomplish the cocrystallization during the integrated unit operation; and (iii) characterize the final solid product (i.e., tablet). The RAG procedure achieved complete cocrystal formation (>99%) and adequately sized granules (d50: >250 μm). The granulation using water (GW) facilitated formation of cocrystal hydrate which were then transformed into anhydrous cocrystal after drying, while the granulation using ethanol (GE) resulted in the formation of anhydrous cocrystal before and after drying. The dissolution of the highly dense GW tablet, which was compressed from granules including fine powder due to the dehydration, was slower than that of the GE tablet.

A Study on The Formulation of Plant Matrix Tablets From Coarse Botanical Materials Using Cinnamon Bark and Areca Nut as The Model Botanical Materials

Background: There is much interest in formulating botanical materials into tablets due to the compactness and ease of administration. However, tableting of coarse milled botanical materials poses a challenge due to poor tableting properties. Objective: To evaluate the feasibility of wet granulation to produce tablets from coarse milled botanical materials and to assess the effect of formulation on properties of the tablets. Materials and Methods: Cinnamon bark and areca nut were milled to obtain 1–2 mm particle size, which was subsequently used in wet granulation using maltodextrin solution as a granulating liquid. Two diluents were tried; microcrystalline cellulose (MCC) or mannitol at a different ratio to the botanical materials. Tablets were then produced from the granules and evaluated for tensile strength and surface roughness. Results: Tablets formulated with MCC had higher tensile strength than tablets formulated with mannitol. Additionally, granules prepared using mannitol were more friable than those with MCC. The effect of diluent to botanical material ratio was more prominently observed on tablet surface roughness. Tablets containing a higher ratio of botanical material had a rougher surface, which could have implications on the mouth-feel of the tablets. Conclusion: Wet granulation could be a viable pre-processing method to produce tablets from coarse milled botanical materials.

The Dynamics of P Granule Liquid Droplets Are Regulated by the Caenorhabditis elegans Germline RNA Helicase GLH-1 via Its ATP Hydrolysis Cycle.

P granules are phase-separated liquid droplets that play important roles in the maintenance of germ cell fate in Caenorhabditis elegans Both the localization and formation of P granules are highly dynamic, but mechanisms that regulate such processes remain poorly understood. Here, we show evidence that the VASA-like germline RNA helicase GLH-1 couples distinct steps of its ATPase hydrolysis cycle to control the formation and disassembly of P granules. In addition, we found that the phenylalanine-glycine-glycine repeats in GLH-1 promote its localization at the perinucleus. Proteomic analyses of the GLH-1 complex with a GLH-1 mutation that interferes with P granule disassembly revealed transient interactions of GLH-1 with several Argonautes and RNA-binding proteins. Finally, we found that defects in recruiting the P granule component PRG-1 to perinuclear foci in the adult germline correlate with the fertility defects observed in various GLH-1 mutants. Together, our results highlight the versatile roles of an RNA helicase in controlling the formation of liquid droplets in space and time.

Meloxicam Carrier Systems Having Enhanced Release and Aqueous Wettability Prepared Using Micro-suspensions in Different Liquid Media.

One of the conventional methods of alleviating the problem of poor drug solubility is the particle size reduction. The efficiency of this approach depends on successful formulation suppressing the drug agglomeration. The aim of this study was to circumvent the dissolution problems of model hydrophobic meloxicam drug (MLX) by using liquid media of different wetting capacity to comminute and formulate a rapidly dissolving carrier system without the use of surfactants. Micro-suspensions of MLX were prepared by ball milling, using water or n-Heptane as a liquid medium. The suspensions were used as granulation liquids to formulate granulate from microcrystalline cellulose and lactose mixture. The release kinetics from prepared granulates were studied using the USP-4 dissolution apparatus. Micro-suspensions prepared via wet milling in non-water liquid media exhibited a massive improvement of release rate compared with source meloxicam and they outperformed their water-milled counterparts. The release rates from those formulations, despite not comprising any surfactant, were comparable to those obtained by different authors using surfactant stabilized nanosuspension formulations. Thus, they can present an interesting formulation alternative for hydrophobic drugs that are dissolution limited.

Continuous Manufacturing of Homogeneous Ultralow-Dose Granules by Twin-Screw Wet Granulation

Homogeneous ultralow-dose (30 mg) tablets were prepared from perfectly free-flowing granules manufactured by continuous Twin-Screw Wet Granulation. The gravimetrically fed mixture of lactose and potato starch of low particle size was successfully agglomerated and the size enlargement technology proved to be very robust. Since the incorporated drug was dissolved in ethanol-based granulation liquid, the resulting homogeneity largely depended on the dosing of the applied liquid administering units.A peristaltic pump generated higher deviation of the drug content in tablets (Relative Standard Deviation (RSD): 7.7 %) compared to a syringe pump (RSD: 2.3 %) or a piston pump (RSD: 4.6 %). This is due to the pulsation of the liquid flow generated by the peristaltic pump according to the real-time measured mass of the fed liquid. A good correlation was found between the RSD of the liquid mass flow (calculated from the recorded masses) and the RSD of the drug content. Based on the results, the goodness of Content Uniformity, as the most relevant critical quality attribute of low-dose products, was determined by the characteristics of the applied dosing units. The feeding characteristic of the different pumps could be easily measured by the introduced balance-based method and therefore, the applicability of the pumps could be evaluated.

The crucial effect of water and co-solvent on Liqui-Pellet pharmaceutical performance

Liqui-Pellet is considered to be the next generation oral dosage form. It is highly commercially feasible unlike its predecessor, liquisolid formulation. Liqui-Pellet uses Liqui-Mass system, allowing the formulation to overcome some of the critical drawbacks in liquisolid technology, which persisted more than two decades. These drawbacks include poor flowability, poor compressibility and inability for high dose without product being too heavy and bulky for swallowing. The investigation is an extension of the previous work on the Liqui-Pellet. In order to make this novel oral delivery system a commercial product, it is prudent to further understand the parameters affecting its drug release rate. Two major parameters affecting the dissolution rate that is investigated are water and liquid vehicle (Tween 80) contents. It is found out that reducing water content (from 8.62 ml to 4.76 ml which is 1.9 ml/0.95 ml per 20 g of API and excipients) and increasing Tween 80 concentration (from 28% w/w to 32 or 36% w/w) in naproxen Liqui-Pellet results to an increase in drug release rate; however, there is a limit of how much water and Tween 80 can be employed. Outside of this range limit, the formulation would fail to produce Liqui-Pellet due to agglomeration. The range limit of granulation liquid and liquid vehicle content are dependent on one another. In the successful formulation where Liqui-Pellets are formed, the excellent-good flow properties, resistant to friability and narrow size distribution makes it ideal for commercial production. SEM of the Liqui-Pellet shows a smooth surface which is ideal for coating. The solid state analysis via XRPD and DSC indicated reduced crystallinity of the drug which is expected.

Liquisolid pellets: Mixture experimental design assessment of critical quality attributes influencing the manufacturing performance via extrusion-spheronization

A Quality by Design approach was taken to assess the influence of several formulation parameters on critical quality attributes of liquisolid pellets (LPs) obtained by extrusion-spheronization. Two mixture experimental designs were used, one for each of the non-volatile solvents (NVS) studied: Kolliphor® EL or PEG 400. The studied parameters were the concentrations of NVS (A-Kolliphor® EL, 0–40% w/w; or PEG 400, 0–31.1% w/w), coating material (B-crospovidone, 0–50.3% w/w) and carrier (C-microcrystalline cellulose, MCC, 27–100% w/w). The critical quality attributes assessed were amount of granulation liquid required for extrusion/spheronization, residual moisture, particle size, particle size distribution, bulk density, tapped density, true density, Carr's Index, Hausner Ratio, aspect ratio, angle of repose and friability. All hierarchical terms and interactions were evaluated to determine the statistical relevance of each term. Mathematical models were determined by linear regression, taking into account statistically relevant terms. Lack of Fit, R2, adjusted R2 and adequate precision were assessed to determine the fitness of each mathematical model. It was possible to identify and understand parameters affecting critical quality attributes of LPs, as well as the magnitude of these effects. The mathematical models developed were robust and can be used to predict optimal LPs excipient compositions within the experimental domains assessed. This study provides an overall understanding of the impact of excipients on quality attributes of blank LPs, a critical knowledge to the implementation of this novel application of liquisolid systems.

Dynamic Image Analysis to Determine Granule Size and Shape, for Selected High Shear Granulation Process Parameters

Abstract The aim of this study was to investigate the usage of Dynamic Image Analysis for determination of size, shape and distribution of granules of microcrystalline cellulose, created by high shear granulation. A series of experiments was carried out to analyse the effect of process parameters on a created granule morphology. The amount of the granulation liquid and speed of the impeller have a significant effect on the median size granule value, the sphericity, the granule distribution width, but also on the granulation process yield.

Formation of Indomethacin-Saccharin Cocrystals during Wet Granulation: Role of Polymeric Excipients.

Formulation of a cocrystal into a solid pharmaceutical dosage form entails numerous processing steps during which there is risk of dissociation. In an effort to reduce the number of unit operations, we have attempted the in situ formation of an indomethacin-saccharin (INDSAC) cocrystal during high-shear wet granulation (HSWG). HSWG of IND (poorly water-soluble drug) and SAC (coformer), with polymers (granulating agents), was carried out using ethanol as the granulation liquid and yielded INDSAC cocrystal granules. Therefore, cocrystal formation and granulation were simultaneously accomplished. Our objectives were to (i) evaluate the influence of polymers on cocrystal formation kinetics during wet granulation and (ii) mechanistically understand the role of polymers in facilitating the cocrystal formation. Polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO) were chosen to investigate the influence of soluble polymers. The cocrystal formation kinetics was influenced by the polymer (PVP < HPC < PEO) and its concentration. The interaction of the polymer with cocrystal components inhibited the cocrystal formation. Complete cocrystal formation was observed in the presence of PEO, a polymer which does not interact with IND and SAC.

Mechanistic modelling of fluid bed granulation, Part II: Eased process development via degree of wetness.

The performance of a fluid bed granulator was investigated through experimental and numerical study to develop a stand-alone fluid bed granulation model. The single-compartment model proposed in part I (for agglomeration modeling) was extended to account for i) evaporation of freely-flowing droplets, and ii) particle drying. This model enables us to predict the granule liquid content and temperature besides the granule size. Accurately, the equations of heat and mass conservation were solved in parallel to the population balance calculation of the agglomeration. In the same manner as for the agglomeration model, the model parameters associated with the drying model were estimated and correlated to the relevant quantities. The analysis of the experimental results revealed the significant contribution of the system "degree of wetness" to the bed performance, i.e., granule size and loss on drying (LoD). As the agglomeration model parameters were partially correlated to LoD in Part I, the presented model was revisited by inclusion of the degree of wetness. The reliability of the developed model in predicting the temporal evolution of granule size, liquid content, and temperature was proven through comparing the bed performance between simulation and experiment. Subsequently, to lowering the costs associated with experimental run, an approach was proposed based on the degree of wetness, aimed at reducing the number of experiments required for the design of experiment (DoE). The results of our simulation using reduced experiments demonstrated that the degree of wetness can be a promising indicator for the performance of the fluid bed granulator as well as for more efficient design of experiment.

Elucidating molecular properties of kappa-carrageenan as critical material attributes contributing to drug dissolution from pellets with a multivariate approach

Multivariate data analysis (MVDA) and artificial neural networks (ANN) are supporting statistical methodologies required for successful development and manufacturing of drug products. To address this purpose, a complex dataset from 49 industrially produced capsules filled with pellets was first analyzed through the development of a multiple linear regression model focused on determining raw material attributes or process parameters with a significant impact on drug dissolution. Based on the model, the following molecular and micrometrics properties of κ-carrageenan have been identified as critical material attributes with the highest contribution to drug dissolution: molecular weight and polydispersity index, viscosity, content of potassium ions, wettability, particle size, and density. The process parameters identified to control the drug dissolution behavior of pellets were amount of granulation liquid, torque of dry blend, spheronization parameters, and yields after screening. To further scrutinize the dataset, an ANN model was subsequently built, incorporating 29 batches addressing drug particle size and process parameters such as torque during granulation and spheronization time as critical factors. Finally, this study demonstrates the ability of MVDA and ANN to allow prediction of the key performance drivers influencing the drug dissolution of industrially developed capsules filled with pellets and it highlights their complementary relationship.

Stage-wise characterization of the high shear granulation process by impeller torque changing rate

Fine cornstarch powders are wet granulated in a lab-scale high shear granulator. The torque required for maintaining the impeller passing through the bed with a constant rotating speed is monitored during the continuous binder addition granulation process. A new method is proposed to identify 6 stages during the granulation process based on the fraction of the positive impeller torque changing rate in a characteristic period of time. The morphologies and the behavior of the bed are found intrinsically different in the identified 6 stages. The influence of the impeller blade inclined angle on the impeller torque in each stage is initially reported. The impeller with planner 45° blades requires higher torques in Stages I and II due to the overall powder bed mass loading. The impeller with steeper 60° blades requires higher torques in Stages III and IV due to the higher collision frequencies between the blade and granules. The suitable granulation liquid binder to solid powder mass ratio can be readily identified in Stages II and III, and its range is found to increase with the increasing of the impeller rotational speed and is independent to the blade inclined angle.