Quality Attributes Of Tablets Research Articles

Magnesium Stearate Fatty Acid Composition, Lubrication Performance and Tablet Properties

Magnesium stearate (MgSt) is a common tablet lubricant. As variations in MgSt properties are known to influence tablet attributes, the impact of MgSt fatty acid composition, particularly the significance of the stearate and palmitate contents, and its effects on tablet properties warrant further investigation. This study investigated the effect of MgSt with different stearate and palmitate contents but comparable physical properties (e.g. particle size, crystallinity, specific surface area and morphology) on lubrication performance and resulting tablet quality attributes, including mechanical strength, disintegratability and drug release. The influence of MgSt concentration and blending duration on the resulting tablet properties was also examined. Tablets produced using the lower stearate content MgSt had slightly higher tensile strength. The effect of MgSt stearate content was more apparent in the disintegration time and drug release, whereby MgSt of lower stearate content resulted in tablets with longer disintegration time and slower drug release. The lower stearate content also resulted in a lower lubrication performance, leading to a lesser reduction in tablet ejection force. As expected, a longer blending time of the tablet formulation blend with MgSt yielded tablets with reduced tensile strength, shorter disintegration time and slower drug release. Tablets with higher MgSt concentration showed a greater reduction in tensile strength, longer disintegration time and faster drug release. The study findings reinforced observations by other researchers and provided a better understanding of the fatty acid composition effects of MgSt on lubrication performance and the resulting tablet properties.Graphical

Hybrid modeling of T-shaped partial least squares regression and transfer learning for formulation and manufacturing process development of new drug products

T-shaped partial least squares regression (T-PLSR) is a valuable machine learning technique for the formulation and manufacturing process development of new drug products. An accurate T-PLSR model requires experimental data with multiple formulations and process conditions. However, it is usually challenging to collect comprehensive experimental data using large-scale manufacturing equipment because of the cost, time, and large consumption of raw materials. This study proposes a hybrid modeling of T-PLSR and transfer learning (TL) to enhance the prediction performance of a T-PLSR model for large-scale manufacturing data by exploiting a large amount of small-scale manufacturing data for model building. The proposed method of T-PLSR+TL was applied to a practical case study focusing on scaling up the tableting process from an experienced compaction simulator to a less-experienced rotary tablet press. The T-PLSR+TL models achieved significantly better prediction performance for tablet quality attributes of new drug products than T-PLSR models without using large-scale manufacturing data with new drug products. The results demonstrated that T-PLSR+TL is more capable of addressing new drug products than T-PLSR by using small-scale manufacturing data to cover a scarcity of large-scale manufacturing data. Furthermore, T-PLSR+TL holds the potential to streamline formulation and manufacturing process development activities for new drug products using an extensive database.

Quantitative analysis of the effects of multi-component formulation parameters on granule and tablet properties via a combined population balance and statistical predictive model

In pharmaceutical drug product manufacturing, the use of multi-component mixtures in the formulation is a common practice. However, the introduction of each material alters the powder blend properties and affects the granule growth mechanisms in a wet granulation process. In this study, we quantified the effects of varying formulation parameters on granule growth rate, expressed by the liquid amount required for granulation to reach completion, and on granule and tablet quality attributes. Process models, including population balance and statistical models, were developed to represent the granulation, milling, and tableting process, and predict relevant granule and tablet properties. Overall, prediction of granule properties had an accuracy of above 80% and the prediction of different tablet properties ranged from an R2 of 0.68 to 0.9. These models are computationally efficient and can be simulated serially to predict the performance of different multi-component formulations by using the pre-blend properties as model inputs.

Evaluation of the effect of granule size of raw tableting materials on critical quality attributes of tablets during the continuous tablet manufacturing process using near-infrared spectroscopy

Objective The effects of granule size of raw materials on tablet hardness (TH) and weight (TW) in the continuous tablet manufacturing process (CTMP) were investigated using near-infrared spectroscopy (NIRS). Methods Granule materials of different sizes were prepared by extrusion granulation from a standard granule formula powder containing lactose/starch and 4.5% acetaminophen. Large-, small-, and medium-sized granules were sequentially filled in a hopper, and tablets were produced continuously using a single-shot tableting machine. After arranging approximately 500 tablets in order, the tablets were subjected to NIRS. A total of 450 NIRS datasets were divided into three groups of 150 each (calibration, validation 1, and validation 2 datasets). Results The best fitted calibration models for predicting TH and TW were obtained, with sufficient accuracy, based on NIRS using the partial least squares regression, and comprised both physical and chemical information. The regression and loading vectors of the calibration models suggested that the models used to predict TH and TW involve physical information based on geometrical factors of the tablet and chemical information related to binder-related intermolecular interactions. Conclusions The changes in the predicted value profiles of TH and TW using NIRS reflected the changes in the measured values depending on the raw granule size during CTMP.

Process Validation of Paracetamol tablet as per ICH guidelines

Process validation is an integral part of pharmaceutical manufacturing, ensuring that tablets are consistently produced with quality and efficacy in line with regulatory requirements. The International Council for Harmonization ICH) provides guidelines for the systematic validation of manufacturing processes. This research article presents a comprehensive study on process validation for Paracetamol tablets following the ICH guidelines. The article focuses on various aspects of the validation process, including process design, qualification, and continued process verification, with specific emphasis on Paracetamol tablet manufacturing. Experimental studies were conducted to characterize the critical process parameters and assess their impact on the tablet's quality attributes. The article also discusses the use of statistical analysis techniques for data evaluation and demonstrates the establishment of a robust validation protocol for Paracetamol tablet manufacturing. Through the application of the ICH guidelines, this research contributes to ensuring the consistency and reliability of Paracetamol tablets, enhancing patient safety and meeting regulatory expectations.
 Keywords: Process validation, ICH guidelines, Critical process parameters, Critical Process Attribution, Statistical analysis, and validation protocol;

Influence of compression kinetics during tableting of fluidized bed-granulated microorganisms on microbiological and physical-mechanical tablet properties

As tablets are convenient to administer to patients, ensure safe dosing and allow cost-effective production on a large scale, they are the favored dosage form for numerous active pharmaceutical ingredients but also for the administration of viable probiotic microorganisms. Granules with viable yeast cells (Saccharomyces cerevisiae) formed by fluidized bed granulation with dicalcium phosphate (DCP), lactose (LAC) or microcrystalline cellulose (MCC) as carrier materials were tableted using a compaction simulator. Besides the compression stress, the compression speed was systematically studied by varying consolidation time and dwell time. The microbial survival as well as physical properties of the tablets, e.g., porosity and tensile strength, were determined. Higher compression stresses result in lower porosities. While on the one hand this has a detrimental effect on microbial survival (due to increased pressure and shear stress during particle rearrangement / densification), on the other hand it results in higher tensile strengths. At the same compression stress, a prolonged dwell time resulted in lower porosity and thus in lower survival rates but higher tensile strength. Against that, consolidation time showed no significant influence on the considered tablet quality attributes. Since changes of the tensile strength related survival rate were negligible (due to opposite but balancing dependence on porosity), high production speeds could be used for tableting of these granules without additional loss of viability, as long as tablets with the same tensile strength are produced.

Evaluation of the influence of material properties and process parameters on granule porosity in twin-screw wet granulation

In recent years, continuous twin-screw wet granulation (TSWG) is gaining increasing interest from the pharmaceutical industry. Despite the many publications on TSWG, only a limited number of studies focused on granule porosity, which was found to be an important granule property affecting the final tablet quality attributes, e.g. dissolution. In current study, the granule porosity along the length of the twin-screw granulator (TSG) barrel was evaluated. An experimental set-up was used allowing the collection of granules at the different TSG compartments. The effect of active pharmaceutical ingredient (API) properties on granule porosity was evaluated by using six formulations with a fixed composition but containing APIs with different physical–chemical properties. Furthermore, the importance of TSWG process parameters liquid-to-solid (L/S) ratio, mass feed rate and screw speed for the granule porosity was evaluated. Several water-related properties as well as particle size, density and flow properties of the API were found to have an important effect on granule porosity. While the L/S ratio was confirmed to be the dictating TSWG process parameter, granulator screw speed was also found to be an important process variable affecting granule porosity. This study obtained crucial information on the effect of material properties and process parameters on granule porosity (and granule formation) which can be used to accelerate TSWG process and formulation development.

Influence of punch diameter change on the quality attributes of tablets

Influence of punch diameter change on the quality attributes of tablets

Impact of qualitative formulation variables on critical quality attributes of tablets with fast disintegration

Impact of qualitative formulation variables on critical quality attributes of tablets with fast disintegration

Simultaneous modeling prediction of three key quality attributes of tablets by powder physical properties

Tensile strength (TS), solid fraction (SF), and tablet weight variability (TWV) are all key quality factors to be considered during the tablet manufacturing process. For predicting them, a novel powder texture measurement methodology was proposed to study the texture attributes of 32 types of powders, and 10 types of unknown powders were used to validate the model. Principal component analysis (PCA) was used to classify the powders. Standard least-squares models were constructed to predict the TS and SF of tablets using texture properties as independent variables, with model R2 values of 0.9188 and 0.8672, respectively. Moreover, due to the advantages of decision trees in classification performance and computation time, multi-node decision trees were constructed, and the approximate range of the TS and SF can be quickly predicted by using only 2-4 key texture attributes. Partial least squares-discriminant method (PLS-DA) algorithm was used to determine whether TWV was qualified by using texture and other physical attributes of powders. In conclusion, the constructed models predicted TS, SF, and TWV well and provide an effective reference for facilitating the development of tablet formulation for direct compression (DC).

Does Direct Transfer from A High Shear Granulator To a Fluidized Bed Dryer Improve Finished Tablet Quality Attributes?

Does Direct Transfer from A High Shear Granulator To a Fluidized Bed Dryer Improve Finished Tablet Quality Attributes?

Tracking raw material flow through a continuous direct compression line. Part II of II: Predicting dynamic changes in quality attributes of tablets due to disturbances in raw material properties using an independent residence time distribution model

Continuous manufacturing of pharmaceuticals promises many advantages regarding economics and quality. However, tracing deviating material in such processes is much more challenging than in batch processes due to axial back-mixing. The literature has proven the traceability of disturbances in the active pharmaceutical ingredient (API) by residence time distribution (RTD) models. Nevertheless, pharmaceutical quality attributes (QAs) and disturbances are not limited to the API content. The present study investigates different disturbances affecting the particle size in a direct compression by recording various QAs. The application of a tracer-based model demonstrates the generalizability of RTD models regarding tracing the propagation of nonconforming material. The model applied may predict the appearance of deviating material in the tablets accurately up to 60 s. However, nonlinear and dynamic effects complicate predicting values of the QAs. Due to dynamic effects, tablet masses deviate up to 2.5 percentage points from values measured in steady-state, at an acceptable total deviation of 7.5 %. Consequently, if other QAs are critical, the transfer of control concepts developed for the API content will be challenging due to such effects different from API-based disturbances. Additionally, higher tolerances for errors will be required considering those deviations.

Powder die filling under gravity and suction fill mechanisms

In pharmaceutical tablet manufacturing, the powder formulation is filled into a die and compacted into a tablet using rigid punches. Die fill is important because it limits the productivity of tablet presses and determines key quality attributes of tablets including weight and content uniformity.Die fill occurs due to gravity and suction fill mechanisms. A model linear shoe-die filling system has been instrumented with pressure measurement devices for detailed characterisation of air pressure evolution as the powder mass is delivered in the die. Systematic experiments were carried out using a range of microcrystalline cellulose powders to explore the role of powder properties (such as particle size and bulk density) and operating parameters (such as shoe and die geometry, shoe and suction punch kinematics and powder filling level) on powder delivery. Existing models were found inadequate to describe the mass flow rate of powders under a diversity of gravity and suction filling conditions. The pressure measurements enabled the development of a new die fill model using the Buckingham Π theorem. The model includes separate terms for the contribution of the mass of powder delivered under gravity and suction fill mechanisms. The experimental procedures required to extract the parameters of the model are described. The model is applicable to the handling and dosing of fine and cohesive powders where small differences in air pressure have a significant impact on the powder flow process. The practical application of the model for predicting die filling behaviour in a high-speed rotary tablet press is demonstrated by assuming operating conditions of a typical rotary tablet press. This approach can be adapted to assist formulation design and process development for operations involving handling and dosing of fine and cohesive powders.

Quantitative X-Ray Microcomputed Tomography Assessment of Internal Tablet Defects

Physical tablet defects are related to internal structural defects that are not easily assessed by the traditional methods, such as dusting, laminating, or fracturing during appearance, friability, or hardness testing. Also, these methods do not allow objective and quantitative investigation of the role of formulation and process variables, which is essential for quality-by-design drug product development. In this study, an X-ray microcomputed tomography (XμCT) method to analyze internal tablet defects is developed using tablets from a quality-by-design design-of-experiment study. The design of experiment investigated the effect of roller compaction roll force, filler composition, and the amount of magnesium stearate on tablet quality attributes. Average contiguous void volume by optical image processing and fracture size distribution and direction by artificial intelligence–based image processing quantified the internal tablet fracture severity. XμCT increased formulation and process knowledge in support of scale-up manufacturing. We demonstrated how XμCT can be incorporated as a part of a holistic approach to quantitatively identify and mechanistically assess the risks of internal tablet defects. Furthermore, expanding the use of XμCT with an artificial intelligence–based quantitative analysis can deepen our tableting knowledge from an empirical understanding to a mechanistic understanding of compaction phenomenon.

A novel approach to support formulation design on twin screw wet granulation technology: Understanding the impact of overarching excipient properties on drug product quality attributes

The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models’ validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes.

Provoking an end-to-end continuous direct compression line with raw materials prone to segregation

Continuous manufacturing of solid oral dosage forms is promising for increasing the efficiency and quality of pharmaceutical production and products. In this study a whole train continuous direct compression (CDC) line has been provoked using challenging formulations typically prone to segregation in batch powder processing. Industrial compositions including components with variable size, bulk density and cohesive nature were selected. An experimental design, including variables such as API/mannitol particle size, API amount, powder feed rate and mixer speed, enabled the output quality of the provoked process to be assessed. Contrary to previous studies, a broader range of finished tablet quality attributes were probed, including content, uniformity of content, tensile strength as well as release performance. Overall, the continuous direct compression line was found to be a capable and efficient manufacturing process for the challenging compositions studied and surprisingly tolerable to handle the materials susceptible to segregation in typical batch settings. As expected, and given the ‘fixed’ apparatus configuration used in this study, the particulate material properties were found to have the most significant impact on the finished tablet quality attributes. The results emphasize the importance for taking a holistic approach when developing the operational windows and the strategy for control, e.g. by integrating the appropriate material properties, the actual apparatus design, and the relevant formulation design. The CDC line's ability to handle cohesive materials also seem to be one of the key advantages, thus confirming the recent promising results from other continuous direct compression studies.

Micro-Structural Analysis of Tablet Surface Layers by Intelligent Laser Speckle Classification (ILSC) Technique: an Application in the Study of both Surface Defects and Subsurface Granule Structures

As a consequence of the latest developments in laser technologies it is now possible to develop a low-cost and accurate tablet inspection system by the unification of optical and artificial intelligence methods. The functionality of the proposed system is based on a sequence of texture analysis of laser speckle images (using laser sources of 650 and 808 nm, VIS/IR) followed by the optimization of texture parameters using Bayesian Networks (BN). In the first part of this work, a Bayesian inference method was used to detect microscale tablet defects that are generated “progressively” during production whereas in the second part a Bayesian classifier method was used to discriminate between tablets made from different granule sizes. In part two, it was shown that (i) the comparatively higher energy (5 mW) IR laser light generates different speckle effects than the lower energy visible (Red 3 mW) by interacting with deeper subsurface of the tablets and (ii) by using multi-classifier systems (MCS) to fuse the Bayesian classifiers from both types of speckle images it was possible to achieve a higher discrimination power (88% classification accuracy) for distinguishing between tablets made from different granule sizes than one can achieve from a single image type. It is suggested that this unified method has the potential to provide for a comprehensive analysis of both tablet quality attributes, on the one hand, and failure modes, on the other, that might be used in the development of a low-cost tablet inspection system.

Influence of granulation process parameters on food tablet properties formulated using natural powders (Opuntia ficus and Chlorella spp.)

In this research two natural health supplements, cactus flour (Opuntia ficus) and microalgae biomass (Chlorella spp.) have been examined as novel ingredients to formulate health supplement tablets. The physical and mechanical properties of the pure powders were quantified, and their ability to be tableted directly without additional processing was investigated. High-shear wet granulation (HSWG) was explored to improve the flowability and compression characteristics of the powders. Using an L9 Taguchi experimental design, the effect of critical process parameters of HSWG was examined on quality attributes of tablets. Tablets were successfully formulated without the addition of excipients following wet granulation. Consistent and acceptable quality tablets were produced based on the optimal processing conditions determined by L9 Taguchi design. The tablet tensile strength achieved was 0.91±0.05MPa with a disintegration time <30min and a friability value of 0.05±0.02%. The tablets obtained in the present study are comparable with commercial available natural supplement tablets in terms of disintegration time, friability and tensile strength. The research provided a basis for the potential use of Cactus (Opuntia spp.) and microalgae (Chlorella sp.) powders as novel ingredients for the development of dietary supplements tablets, and to be used as excipients for the production of pharmaceutical tablets.

Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

ABSTRACTPurposeThe aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.MethodsSamples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch.ResultsThe disintegration time (R2 = 0.86) and API dissolved after 15 min (R2 = 0.96) linearly correlates with the effective refractive index, neff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of neff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, αeff, we observed a better correlation with dissolution after 20 min (R2 = 0.96) and a weaker correlation with disintegration (R2 = 0.83) compared to neff.ConclusionThe measurements of neff and αeff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets.

Statistical modeling methods to analyze the impacts of multiunit process variability on critical quality attributes of Chinese herbal medicine tablets.

The quality of Chinese herbal medicine tablets suffers from batch-to-batch variability due to a lack of manufacturing process understanding. In this paper, the Panax notoginseng saponins (PNS) immediate release tablet was taken as the research subject. By defining the dissolution of five active pharmaceutical ingredients and the tablet tensile strength as critical quality attributes (CQAs), influences of both the manipulated process parameters introduced by an orthogonal experiment design and the intermediate granules’ properties on the CQAs were fully investigated by different chemometric methods, such as the partial least squares, the orthogonal projection to latent structures, and the multiblock partial least squares (MBPLS). By analyzing the loadings plots and variable importance in the projection indexes, the granule particle sizes and the minimal punch tip separation distance in tableting were identified as critical process parameters. Additionally, the MBPLS model suggested that the lubrication time in the final blending was also important in predicting tablet quality attributes. From the calculated block importance in the projection indexes, the tableting unit was confirmed to be the critical process unit of the manufacturing line. The results demonstrated that the combinatorial use of different multivariate modeling methods could help in understanding the complex process relationships as a whole. The output of this study can then be used to define a control strategy to improve the quality of the PNS immediate release tablet.