Ten years of the manufacturing classification system: a review of literature applications and an extension of the framework to continuous manufacture.

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.

Croscarmellose Sodium as Pelletization Aid in Extrusion-Spheronization.

Only few excipients are known to be suitable as pelletization aids. In this study, the potential use of croscarmellose sodium (CCS) as pelletization aid was investigated. Furthermore, the impact of cations on extrusion-spheronization (ES) of CCS was studied and different grades of CCS were tested. The influence of different cations on the swelling of CCS was investigated by laser diffraction. Mixtures of CCS with lactose monohydrate as filler with or without the inclusion of different cations were produced. The mixtures were investigated by mixer torque rheometry and consequently extruded and spheronized. Resulting pellets were analyzed by dynamic image analysis. In addition, mixtures of different CCS grades with dibasic calcium phosphate anhydrous (DP) and a mixture with praziquantel (PZQ) as filler were investigated. Calcium and magnesium cations caused a decrease of the swelling of CCS and influenced the use of CCS as pelletization aid since they needed to be included for successful ES. Aluminum, however, led to an aggregation of the CCS particles and to failure of extrusion. The inclusion of cations decreased the uptake of water by the mixtures which also reduced the liquid-to-solid-ratio (L/S) for successful ES. This was shown to be dependent on the amount of divalent cations in the mixture. With DP or PZQ as filler, no addition of cations was necessary for a successful production of pellets, however the optimal L/S for ES was dependent on the CCS grade used. In conclusion, CCS can be used as a pelletization aid.

Drying behavior of a horizontal vibrated fluidized bed dryer for continuous manufacturing.

Twin-screw wet granulation offers the possibility to granulate continuously. A drying step after wet granulation is required to realize a full continuous manufacturing line. Aim of this study was to gain insights into the drying behavior of a continuous vibrated fluidized bed dryer intended for pharmaceutical research and development. A Design of Experiment was conducted to examine the influence of process parameters during the drying of granules using drying temperature, air flow, and vibration acceleration as factors. The obtained temperature and humidity profiles during the drying of lactose-MCC and mannitol granules displayed the first and second drying stage which is spatially resolved. With a higher drying temperature or higher air flow, the second drying stage was achieved earlier. An increase in vibration acceleration shortened the residence time and by this, the second drying stage was reached later at a lower granule temperature and thus higher residual moisture of the granules. Formulation-dependent impact of the drying parameters was observed as lactose-MCC led to smaller granules when increasing the temperature or air flow.

Scale-up in twin-screw wet granulation: impact of formulation properties.

The focus of this study was to investigate the sensitivity of different drug formulations to differences in process parameters based on previously developed scale-up strategies. Three different formulations were used for scale-up experiments from a QbCon® 1 with a screw diameter of 16 mm and a throughput of 2 kg/h to a QbCon® 25 line with a screw diameter of 25 mm and a throughput of 25 kg/h. Two of those formulations were similar in their composition of excipients but had a different API added to the blend to investigate the effect of solubility of the API during twin-screw wet granulation, while the third formulation was based on a controlled release formulation with different excipients and a high fraction of HPMC. The L/S-ratio had to be set specifically for each formulation as depending on the binder and the overall composition the blends varied significantly in their response to water addition and their overall granulation behavior. Before milling there were large differences in granule size distributions based on scale (Earth Mover's Distance 140-1100 µm, higher values indicating low similarity) for all formulations. However, no major differences in granule properties (e.g. Earth Mover's Distance for GSDs: 23-88 µm) or tablet tensile strength (> 1.8 MPa at a compaction pressure of 200 MPa for all formulations with a coefficient of variation < 0.1, indicating high robustness for all formulations) were observed after milling, which allowed for a successful scale-up independent of the selected formulations.

Evaluation of In-Die Compression Data for a Deeper Understanding of Altered Excipient Properties upon Temperature Rise.

The thermodynamic analysis of tablet formation includes the thermal and mechanical analysis during compression. The aim of this study was to evaluate alterations of force-displacement data upon temperature rise as an indicator for changed excipient properties. The tablet press was equipped with a thermally controlled die to imitate the heat evolution from tableting on an industrial scale. Six predominantly ductile polymers with a comparably low glass transition temperature were tableted at temperatures ranging from 22-70°C. Lactose served as a brittle reference with a high melting point. The energy analysis included the net and recovery work during compression, from which the plasticity factor was calculated. The respective results were compared to the changes in compressibility obtained via Heckel analysis. Elevated temperatures reduced the necessary work for plastic deformation for the ductile polymers, which was reflected in decreasing values for the net work of compaction and the plasticity factor. The recovery work slightly increased for the maximum tableting temperature. Lactose showed no response to temperature variations. Changes in the net work of compaction showed a linear correlation to the changes in yield pressure, which could be correlated to the glass transition temperature of a material. It is therefore possible to detect material alterations directly from the compression data, if the glass transition temperature of a material is sufficiently low.

Towards a better understanding of the role of stabilizers in QESD crystallizations.

Quasi-emulsion solvent-diffusion crystallization (QESD) is a type of spherical crystallization which can be used as a particle design method to improve the flowability and micromeritic properties of drugs or excipients. Spherical particles are generated by dispersing a solvent phase in an antisolvent so that a transient emulsion is formed. Within the droplets the material can crystallize and agglomerate into spherical, hollow particles. Surfactants, such as surface-active polymers like hypromellose, are often required to stabilize the quasi-emulsion. To gain further understanding for the role of the stabilizer, a new screening-method was developed which compared different surface active polymers in solution at similar dynamic viscosities rather than at a set concentration. The dynamic viscosities of a low-viscosity grade hypromellose solution used in the previous publications describing the QESD crystallization of metformin hydrochloride by the authors was used as a target value. QESD crystallizations of metformin hydrochloride (MF) and celecoxib showed that the type of stabilizer and whether it is dissolved in the solvent or antisolvent has an effect on the agglomerates. For MF, the type of hypromellose used can have a significant influence on the properties of the agglomerates. More polymers could be used to stabilize the transient emulsion of celecoxib than previously found in literature. Furthermore, QESD crystallizations seem to be more robust when the stabilizer is dissolved in the antisolvent, however this can lead to a reduced drug load of the agglomerates.

Alternatives to titanium dioxide in tablet coating.

Titanium dioxide (TiO2) is one of the most commonly used pharmaceutical excipients. It is widely used as a white pigment in tablet and pellet coatings. However, it has recently been under massive criticism as a number of studies suggest a cancerogenic potential. It can therefore no longer be taken for granted that TiO2 will continue to be universally available for drug products. Finding suitable alternatives is hence of special relevance. In this study, a number of different pigments were coated on tablets and their covering potential analyzed. None of the alternative pigments showed comparable effectiveness and efficiency to TiO2, though the CaCO3/CaHPO4-based coating showed the second-best results. Regarding the ability to protect photosensitive active ingredients, ZnO showed a comparable potential as TiO2, while all other pigments failed. Using the alternative pigments as markers for in-line Raman spectroscopy as a process analytical technology was challenging and led to increased prediction errors. Again, the CaCO3/CaHPO4-based coating was the only of the tested alternatives with satisfying results, while all other pigments led to unacceptably high prediction errors.

A comparative study of the influence of alpha-lactose monohydrate particle morphology on granule and tablet properties after roll compaction/dry granulation.

The influence of particle morphology and size of alpha-lactose monohydrate on dry granules and tablets was studied. Four different morphologies were investigated: Two grades of primary crystals, which differed in their particle size and structure (compact crystals vs. agglomerates). The materials were roll compacted at different specific compaction forces and changes in the particle size distribution and the specific surface area were measured. Afterwards, two fractions of granules were pressed to tablets and the tensile strength was compared to that from tablets compressed from the raw materials. The specific surface area was increased induced by roll compaction/dry granulation for all materials. At increased specific compaction forces, the materials showed sufficient size enlargement. The morphology of lactose determined the strength of direct compressed tablets. In contrast, the strength of granule tablets was leveled by the previous compression step during roll compaction/dry granulation. Thus, the tensile strength of tablets compressed directly from the powder mixtures determined whether materials exhibited a loss in tabletability after roll compaction/dry granulation or not. The granule size had only a slight influence on the strength of produced tablets. In some cases, the fraction of smaller granules showed a higher tensile strength compared to the larger fraction.

Influence of granulation temperature on particle size distribution of granules in twin-screw granulation (TSG).

This study investigated an influence of granulation temperature during twin-screw granulation (TSG) on particle size distributions (PSDs). The influence of the granulation temperature on granule size distributions varied, depending on the liquid to solid (L/S) ratio, the kind of binders, the method of binder addition, and the filler material. The PSD of granules was broad and bimodal at a barrel temperature of 30 °C. Granules size distributions became narrow and second height decreased at high barrel temperature. While the L/S ratio had an effect on the sharpness of granule size distributions, this effect was minor compared to the granulation temperature. Granule size distributions were influenced by binder addition methods. When the binder was added as solution, PSD became broad. In formulations using lactose as filler, PSD became broad and bimodal at 90 °C. Much lactose was dissolved in granulation solution at high temperature, because the solubility of lactose rises significantly with the solution temperature leading to higher effective L/S ratio in the granulator. Hence, granulation was proceeded and large granules were formed. From these results, the granulation temperature is one of important parameters to obtain mono-modal PSD in TSG.

Fibrillated Cellulose via High Pressure Homogenization: Analysis and Application for Orodispersible Films.

Powdered cellulose (PC) and microcrystalline cellulose (MCC) are common excipients in pharmaceuticals. Recent investigations imply that particle size is the most critical parameter for the different performance in many processes. High-pressure homogenization (HPH) was used to reduce fiber size of both grades. The effect of the homogenization parameters on suspension viscosity, particle size, and mechanical properties of casted films was investigated. PC suspensions showed higher apparent viscosities and yield stresses under the same process conditions than MCC. SLS reduced shear viscosity and thixotropic behavior of both cellulose grades probably due to increased electrostatic repulsion. Homogenization reduced cellulose particle sizes, but re-agglomeration was too strong to analyze the particle size correctly. MCC films showed a tensile strength of up to 16.0 MPa and PC films up to 4.1 MPa. PC films disintegrated within 30 s whereas MCC films did not. Mixtures of MCC and PC led to more stable films than PC alone, but these films did not disintegrate anymore. Diclofenac sodium was incorporated in therapeutic dose with drug load of 47% into orodispersible PC films. The content uniformity of these films fulfilled requirements of Ph.Eur and the films disintegrated in 12 s. In summary, PC and MCC showed comparable results after HPH and most differences could be explained by the smaller particle size of MCC suspensions. These results confirm the hypothesis that mainly the fiber size during processing is responsible for the existing differences of MCC and PC in pharmaceutical process, e.g., wet-extrusion/spheronization.

Continuous Single-Step Wet Granulation with Integrated in-Barrel-Drying.

PURPOSE: It was investigated if continuous wet granulation and drying could be combined in a twin-screw granulator with the aim to provide (pre-)dried granules in a single-step process, i.e. in-barrel-drying. METHODS: To have a consistent and robust material propulsion mechanism, a twin-screw granulator was divided into two compartments. One compartment was operated at lower temperature to granulate and to pre-heat the material, while another compartment was operated at very high temperature to evaporate the granulation liquid as rapidly as possible. Design of experiments was used to investigate the in-barrel-drying process in detail. The process was further investigated for twin-screw wet granulation with API suspension feed, and compared against traditional fluidised-bed drying. Granule and compact properties were evaluated to study the process impact on the product quality. RESULTS: In-barrel-drying was demonstrated as feasible and yielded completely dried and granulated material at specific settings. The evaporation zone temperature and the processed mass of water were identified as key parameters to balance the evaporation capacity of the process and the material throughput. Granules and compacts showed an acceptable product quality. CONCLUSIONS: In-barrel-drying can be used to condense the wet granulation and drying process steps into one piece of equipment, thereby limiting or even omitting downstream drying process steps.

Impact of roll compaction design, process parameters, and material deformation behaviour on ribbon relative density.

Ribbons from microcrystalline cellulose (MCC), mannitol, and their 50:50% mixture were produced using the roll compactors AlexanderWerk BT120, Hosokawa Alpine Pharmapaktor C250, L.B. Bohle BRC 25, and Gerteis Mini-Pactor in the frame of multilevel full factorial experimental plans. The specific compaction force (SCF)/hydraulic pressure (HP), gap width (GW), roll speed, and fraction of MCC were analyzed as quantitative factors, whereas the roll surface and sealing system were examined as qualitative factors. Ribbon relative density was investigated as response of the models. The SCF/HP is found to be the most significant factor in each model. A significant inverse effect of the GW is obtained in the models of AlexanderWerk BT120, Pharmapaktor C250, and BRC 25 roll compactors, using smooth rolls. The principle of the establishment of a conversion factor (cf) is introduced based on the obtained data sets of AlexanderWerk BT120 and Mini-Pactor. This can facilitate the transfer of a roll compaction process between different types of roll compactors.

Roll Compaction and Tableting of High Loaded Metformin Formulations Using Efficient Binders.

Metformin has a poor tabletability and flowability. Therefore, metformin is typically wet granulated with a binder before tableting. To save production costs, it would be desirable to implement a roll compaction/dry granulation (RCDG) process for metformin instead of using wet granulation. In order to implement RCDG, the efficiency of dry binders is crucial to ensure a high drug load and suitable properties of dry granules and tablets. This study evaluates dry granules manufactured by RCDG and subsequently tableting of high metformin content formulations (≥ 87.5%). Based on previous results, fine particle grades of hydroxypropylcellulose and copovidone in different fractions were compared as dry binders. The formulations are suitable for RCDG and tableting. Furthermore, results can be connected to in-die and out-of-die compressibility analysis. The addition of 7% of dry binder is a good compromise to generate sufficient mechanical properties on the one hand, but also to save resources and ensure a high metformin content on the other hand. Hydroxypropylcellulose was more efficient in terms of granule size, tensile strength and friability. Three percent croscarmellose was added to reach the specifications of the US Pharmacopeia regarding dissolution. The final formulation has a metformin content of 87.5%. A loss in tabletability does not occur for granules compressed at different specific compaction forces, which displays a robust tensile strength of tablets independent of the granulation process.

Influence of drug load on dissolution behavior of tablets containing a poorly water-soluble drug: estimation of the percolation threshold.

Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.

Preparation and physicochemical characterization of matrix pellets containing APIs with different solubility via extrusion process.

In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process.

MCC-mannitol mixtures after roll compaction/dry granulation: percolation thresholds for ribbon microhardness and granule size distribution.

In roll compaction, the specific compaction force, the gap width and the roll speed are the most important settings as they have a high impact in the products obtained. However the mechanical properties of the mixture being compacted are also critical. For this reason, a multilevel full factorial design including these parameters as factors plus three repetitions of the center point was performed for microcrystalline cellulose, mannitol and five binary mixtures (15, 30, 50, 70 and 85% MCC). These two reference excipients were chosen in order to investigate the plastic/brittle behavior of mixtures for the roll compaction process. These materials were roll compacted in a 3-W-Polygran® 250/50/3 (Gerteis) and the ribbons obtained were collected and milled into granules which were characterized regarding granule size distribution. After statistical evaluation, it was found that the most critical factors affecting the D10, D50, D90 and the fines fraction from the granules were the gap width and the specific compaction force, as well as the proportion of MCC together with its quadratic effect and the interaction between force and proportion of MCC. The microhardness of the ribbons from the center point as well as the D10, D50, D90 and the fines fraction from the granules produced at these same conditions were characterized. In all the cases, the proportion of MCC, i.e. the composition of the mixture, showed also an important effect on these properties measured. In this sense, the percolation theory was applied in order to study further the importance of the plastic/brittle ratio by calculating the percolation threshold or the limit over which the behavior of the system changes. This resulted in values of 34% for the HU (expression of microhardness), 27% and 28% for the D10 and fines, respectively (percolation of MCC) and 84% and 85% for the D50 and D90, respectively (percolation of mannitol).

Development of a New Dissolution Test Method for Soft Chewable Dosage Forms.

Soft chewable dosage forms are a new approach to improve the compliance of medication for special patient populations. Based on their texture, they are chewed several times before they get swallowed. A suitable dissolution method based on in vivo chewing data was developed. The method covers parts of dissolution within the oral cavity (simulation of chewing) as well as the dissolution of the swallowed bolus within the gastrointestinal tract. Chewing was simulated by the help of a steel tooth assembled to a texture analyzer and wedge gliding on an inclined plane, imitating the occlusal glide. Chewing cycles of non-brittle, elastically deformable foods were predicted by a multiple linear regression (R adj = 0.985) using hardness, stickiness, fat/water content, and softening behavior as independent variables. Cross-validation of three sets of chewing data led to a root mean square error of prediction of 0.408 or 0.658 chewing cycles, respectively. The new method is able to distinguish between different soft chewable formulations which had been approved as similar by the dissolution method of the European Pharmacopoeia. Furthermore, it provides information about the drug content released within the time of chewing (7-15%).

Combined application of mixture experimental design and artificial neural networks in the solid dispersion development.

This study for the first time demonstrates combined application of mixture experimental design and artificial neural networks (ANNs) in the solid dispersions (SDs) development. Ternary carbamazepine-Soluplus®-poloxamer 188 SDs were prepared by solvent casting method to improve carbamazepine dissolution rate. The influence of the composition of prepared SDs on carbamazepine dissolution rate was evaluated using d-optimal mixture experimental design and multilayer perceptron ANNs. Physicochemical characterization proved the presence of the most stable carbamazepine polymorph III within the SD matrix. Ternary carbamazepine-Soluplus®-poloxamer 188 SDs significantly improved carbamazepine dissolution rate compared to pure drug. Models developed by ANNs and mixture experimental design well described the relationship between proportions of SD components and percentage of carbamazepine released after 10 (Q10) and 20 (Q20) min, wherein ANN model exhibit better predictability on test data set. Proportions of carbamazepine and poloxamer 188 exhibited the highest influence on carbamazepine release rate. The highest carbamazepine release rate was observed for SDs with the lowest proportions of carbamazepine and the highest proportions of poloxamer 188. ANNs and mixture experimental design can be used as powerful data modeling tools in the systematic development of SDs. Taking into account advantages and disadvantages of both techniques, their combined application should be encouraged.

Quantitative Assessment of Mass Flow Boundaries in Continuous Twin-screw Granulation.

In pharmaceutical manufacturing, there is an increasing interest in continuous manufacturing. As an example for fast continuous processes in general of considerable complexity, this study was focussed on improving the understanding of twin-screw wet granulation. The impact of the liquid-to-solid (L/S) mass flow ratio on product quality (granules) as well as on downstream process operations (tableting) was investigated in detail. Initially two methods were used to define L/S ratio boundaries for the granulation regime in twin-screw wet granulation. It was shown that the first method, which is based on measuring the wet granule mass flow variation, can be used to define the upper L/S ratio boundary of the granulation regime. The second method, based on measuring the granule size distribution, can be used to define the lower L/S ratio boundary of the regime. Using these methods, the granulation regime for different formulations could be established. This information was then used to show that the formulation could be optimised such that the process is more robust (i.e. wider L/S ratio boundaries for the granulation regime). Also it could be used to optimise the formulation considering further downstream processing such as drying (using as little water as possible to reduce drying efforts) or tableting (obtain granules with optimised tableting properties). Preferably, the process should be performed close to the lower L/S ratio boundary of the granulation regime. In summary, these tools enabled the quantitative establishment of granulation regime boundaries in a twin-screw wet granulation process and can be used to optimise formulation and to create a robust process. Analogies to other continuous processes in completely different applications can be conceived.

A critical review on tablet disintegration.

CONTEXT: Tablet disintegration is an important factor for drug release and can be modified with excipients called tablet disintegrants. Tablet disintegrants act via different mechanisms and the efficacy of these excipients is influenced by various factors. OBJECTIVE: In this review, the existing literature on tablet disintegration is critically reviewed. Potential disintegration mechanisms, as well as impact factors on the disintegration process will be discussed based on experimental evidence. METHODS: Search terms for Scopus and Web of Science included "tablet disintegration", "mechanism tablet disintegration", "superdisintegrants", "disintegrants", "swelling force", "disintegration force", "disintegration mechanisms", as well as brand names of commonly applied superdisintegrants. References of identified papers were screened as well. RESULTS: Experimental data supports swelling and shape recovery as main mechanisms of action of disintegrants. Other tablet excipients and different manufacturing techniques greatly influence the disintegration process. CONCLUSION: The use of different excipients, experimental setups and manufacturing techniques, as well as the demand for original research led to a distinct patchwork of knowledge. Broader, more systematic approaches are necessary not only to structure the past but also future findings.