Academic literature on the topic 'High-shear wet granulation, Process development, Quality-by-Design, Design of Experiment'

In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors. Additionally, we performed Monte Carlo simulations by optimizing the process parameters to deriving and building a robust design space. In the second stage, we identified the IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated with granule size. Our results suggest that the desired drug quality may result through IQAs monitoring during the process and that the integrated QbD approach utilizing MVA can be used to develop a control strategy for producing high-quality drug products.

In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors. Additionally, we performed Monte Carlo simulations by optimizing the process parameters to deriving and building a robust design space. In the second stage, we identified the IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated with granule size. Our results suggest that the desired drug quality may result through IQAs monitoring during the process and that the integrated QbD approach utilizing MVA can be used to develop a control strategy for producing high-quality drug products.

Maximization of drug-loading can significantly reduce the size of dosage form and consequently decrease the cost of manufacture. In this research, two challenges were addressed: poor flow and tableting problems of high-drug loading (>70%) formulation of canagliflozin (CNG), by adopting the moisture-activated dry granulation (MADG) process. In this method, heating and drying steps were omitted so, called green granulation process. A 32 full-factorial design was performed for optimization of key process variables, namely the granulation fluid level (X1) and the wet massing time (X2). Granulation of CNG was carried out in the presence of polyvinylpyrrolidone, and the prepared granules were compressed into tablets. Regression analysis demonstrated the significant (p ≤ 0.05) effect of X1 and X2 on properties of granules and corresponding tablets, with pronounced impact of X1. Additionally, marked improvement of granules’ properties and tableting of CNG were observed. Furthermore, the optimized process conditions that produced good flow properties of granules and acceptable tablets were high level of granulation fluid (3.41% w/w) and short wet massing time (1.0 min). Finally, the MADG process gives the opportunity to ameliorate the poor flow and tableting problems of CNG with lower amounts of excipients, which are important for successful development of uniform dosage unit.

Background: High shear wet granulation (HSWG) is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. However, study of HSWG is complex and challenging due to the relatively poor understanding of HSWG, especially for sticky powder-like herbal extracts. Aim: In this study, we used Salvia miltiorrhiza granules to investigate the HSWG process across different scales using quality by design (QbD) approaches. Methods: A Plackett–Burman experimental design was used to screen nine granulation factors in the HSWG process. Moreover, a quadratic polynomial regression model was established based on a Box–Behnken experimental design to optimize the granulation factors. In addition, the scale-up of HSWG was implemented based on a nucleation regime map approach. Results: According to the Plackett–Burman experimental design, it was found that three granulation factors, including salvia ratio, binder amount, and chopper speed, significantly affected the granule size (D50) of S. miltiorrhiza in HSWG. Furthermore, the results of the Box–Behnken experimental design and validation experiment showed that the model successfully captured the quadratic polynomial relationship between granule size and the two granulation factors of salvia ratio and binder amount. At the same experiment points, granules at all scales had similar size distribution, surface morphology, and flow properties. Conclusions: These results demonstrated that rational design, screening, optimization, and scale-up of HSWG are feasible using QbD approaches. This study provides a better understanding of HSWG process under the paradigm of QbD using S. miltiorrhiza granules.

High shear wet granulation is commonly applied technique for commercial manufacturing of tablets. Granulation process for tablets manufacturing is generally optimized by hit and trial which involves preparation of granules under different processing parameters, compression of granules and evaluation of the resultant tablets; and adjustment is made in granulation process on the basis of characteristics of tablets. Objective of the study was to optimize the process of high shear wet granulation and prediction of characteristics of tablets on the basis of properties of granules. Atenolol granules were prepared by high shear wet granulation method, using aqueous solution of polyvinyl pyrrolidone (PVP k-30) as binder. Concentration of binder solution and granulation time were taken as process variables, both studied at three levels. Different combinations of process variables were determined by Design Expert software. Granules were evaluated for different parameters on the basis of SeDeM-ODT (Sediment Delivery Model-Oro Dispersible Tablets) expert system. Granules from all the trials were compressed using round (10.5 mm) flat faced punches at compression weight of 250 mg/tablet. Tablets were evaluated of different quality control parameters as per USP. Results showed that both the process variables had positive effect on mechanical strength of tablets and negative effect on disintegration and dissolution rate. Granule prepared with highest level of binder concentration (15%) and highest granulation time (60 sec) resulted in tablets with highest crushing strength (11.8 kg), specific crushing strength (0.328 kg/mm2), tensile strength (0.208 kg/mm2), lowest value of friability (0.19%) and highest disintegration time (10.9 min), as predicted from granules characteristics on the basis of SeDeM-ODT expert system. Drug release from Trial-13 (processed under highest level of both process parameters) was also lower than rest of the trials. It is concluded from the study that quality characteristics of tablets can be predicted from granules characteristics using SeDeM-ODT expert system. Furthermore, SeDeM-ODT expert system can also be used for optimization of the process of high shear wet granulation.

A robust manufacturing process and the relationship between intermediate quality attributes (IQAs), critical quality attributes (CQAs), and critical process parameters (CPPs) for high-shear wet granulation was determined in this study. Based on quality by the design (QbD) approach, IQAs, CQAs, and CPPs of a telmisartan tablet prepared by high-shear wet granulation were determined and then analyzed with multivariate analysis (MVA) to evaluate mutual interactions between IQAs, CQAs, and CPPs. The effects of the CPPs on the IQAs and CQAs were quantitatively predicted with empirical models of best fit. The models were used to define operating space, and an evaluation of the risk of uncertainty in model prediction was performed using Monte Carlo simulation. MVA showed that granule size and granule hardness were significantly related to % dissolution. In addition, granule FE (Flow Energy) and Carr’s index had effects on tablet tensile strength. Using the manufacture of a clinical batch and robustness testing, a scale-up from lab to pilot scale was performed using geometric similarity, agitator torque profile, and agitator tip speed. The absolute biases and relative bias percentages of the IQAs and CQAs generated by the lab and pilot scale process exhibited small differences. Therefore, the results suggest that a risk reduction in the manufacturing process can be obtained with integrated process parameters as a result of the QbD approach, and the relationship between IQAs, CQAs, and CPPs can be used to predict CQAs for a control strategy and SUPAC (Scale-Up and Post-Approval Guidance).

Understanding the tabletability change of materials after granulation is critical for the formulation and process design in tablet development. In this paper, a material library consisting of 30 pharmaceutical materials was used to summarize the pattern of change of tabletability during high shear wet granulation and tableting (HSWGT). Each powdered material and the corresponding granules were characterized by 19 physical properties and nine compression behavior classification system (CBCS) parameters. Principal component analysis (PCA) was used to compare the physical properties and compression behaviors of ungranulated powders and granules. A new index, namely the relative change of tabletability (CoTr), was proposed to quantify the tabletability change, and its advantages over the reworking potential were demonstrated. On the basis of CoTr values, the tabletability change classification system (TCCS) was established. It was found that approximately 40% of materials in the material library presented a loss of tabletability (i.e., Type I), 50% of materials had nearly unchanged tabletability (i.e., Type II), and 10% of materials suffered from increased tabletability (i.e., Type III). With the help of tensile strength (TS) vs. compression pressure curves implemented on both powders and granules, a data fusion method and the PLS2 algorithm were further applied to identify the differences in material properties requirements for direct compression (DC) and HSWGT. Results indicated that increasing the plasticity or porosity of the starting materials was beneficial to acquiring high TS of tablets made by HSWGT. In conclusion, the presented TCCS provided a means for the initial risk assessment of materials in tablet formulation design and the data modeling method helped to predict the impact of formulation ingredients on the strength of compacts.

Metal cutting processes are associated with excessive forces, friction and heat generation due to continuous intensive contact between the active cutting tools and the work which degrades the machined surface quality. The hardened tool steel having excellent wear resistance property receives an extensive promotion, investigation and application in the die manufacturing industries. In this research, the machinability of hardened AISI D3 tool steel has been investigated using TiN-coated Al2[Formula: see text](C,N) ceramic tool inserts as per Taguchi’s [Formula: see text] orthogonal design of experiments is in horizontal turning under the dry condition. The experimental dataset was used for the regression model development of primary process outputs as well as mean cutting force using the response surface methodology (RSM) which was found to be significant. The parametric interaction effects on each process output were studied along with with chip morphology in detail. The cutting force as well as material removal rate was found to be significantly influenced by depth of cut, whereas machined surface quality was primarily dependent on tool feed rate. The wider with less prominent saw tooth chips got changed to narrower saw-tooth form with intensive shear bands at higher feed rates. Finally, an attempt has been made to develop an optimal parametric setting using particle swarm optimization technique to achieve minimum surface roughness and maximum material removal rate at less cutting force. The optimal parametric setting was high cutting speed (308[Formula: see text]m/min), high tool feed rate (0.08[Formula: see text]mm/rev) with medium depth of cut (0.6[Formula: see text]mm) to achieve each objective. This evolutionary particle swarm optimization technique was found to be highly accurate (within 8% error) as per validation experiment.

Granulation is one of the most crucial processes for the pharmaceutical industry. It allows to improve the tabletability and the flowing properties of the powdered formulations. Moreover granules production reduces the dust presence in the working environment improving the operator safety. Several granulation techniques exist and are divided in two main groups: dry and wet granulation processes. Among these, high-shear mixer is one of the most employed wet granulation techniques in the pharmaceutical industries. Despite its wide application, the complete control of the process is far to be achieved. This is mainly due to the several variables which affect the resulting product; in fact high-shear wet granulation presents several process parameters which need to be controlled and most of them are formulation dependent. For this reason the process development is particularly difficult with this technique, with the risk for high-shear mixers to become the last choice when a new formulation needs to be granulated. However, the characteristics of granules produced in a high-shear mixer are strongly affected by the rheology of the wet mass which is processed; thus, it could be a useful tool to obtain preliminary indications about the evolution of the high-shear wet granulation process (HSWG). Several works in literature studied the application of the on-line and off-line wet mass rheology for process control, end-point determination and scale-up. Despite those studies, it is still not possible to employ wet mass rheology unambiguously to predict the granulation process. The possibility to predict several aspects of the granulation process, such as: the amount of liquid binder which need to be employed, the granules growth regimes and the parameters which have a important impact on the granules characteristics, would be of dramatic importance for process development and in particular from a Quality-by-Design (QbD) perspective. The aim of the present work is to investigate the possibility of employing a mixer torque rheometer to predict: the amount of liquid for the process, the granules growth mechanisms and the critical process parameters using different formulations. Results obtained in the first phase of the project have shown that an easy and fast prediction of the optimal liquid amount, required to produce granules with acceptable technological properties, could be carried out by a rheological characterization using a mixer torque rheometer. Moreover the application of the second derivative to the torque profile have permitted to develop a reliable method to identify the optimal value of L/S, following confirmed by granulation experiments. In the second phase, evaluation of the wet granules strength (expressed as consistency) has permitted to highlight a relationship between wet granule cohesion and the granules growth regimes. In particular, the value of wet mass consistency showed to be indicative of the growth mechanism followed by the granules during the process. In order to predict, and not only to describe, the granule growth mechanism, the torque evolution of wet masses was registered along time and it was used to evaluate the maximum value of the wet mass cohesion, corresponding to the Torque peak. Torque peak showed to be directly related to the final consistency of the granules produced with the same formulation and thus it could be used for the granules growth regimes prediction. Finally in the last phase of the project was also investigated the possibility to predict the critical process parameters of the HSWG process through rheological measurements. Results highlighted that Torque peak could represent a potential tool for critical process parameters assessments. Moreover it seems able to give important indications about the granule growth kinetic for those formulations which presented a steady growth regime. In particular, torque peak seemed to be a feasible tool for the prediction of the parameters which had the most significant impact on the mean diameter of the granules. In fact, the data acquired with the mixer torque rheometer in terms of Torque peak showed good accordance with the results obtained from granulation experiments. In conclusion, the results achieved with this study demonstrated the possibility of employing the wet mass rheology to predict several aspects of the high-shear wet granulation process and gain the necessary knowledge to improve the process development phase.
La granulazione è uno dei processi più importanti per l'industria farmaceutica. Permette di migliorare le caratteristiche di comprimibilità e scorrevolezza delle polveri da processare. Inoltre la granulazione permette di ridurre la presenza di polveri nell'ambiente di lavoro migliorando la sicurezza degli operatori. Esistono molteplici tecniche di granulazione e sono divise in due gruppi: granulazione a secco ed ad umido. I granulatori High-shear sono tra i più utilizzati tra le tecniche di granulazione ad umido. Tuttavia, nonostante il suo largo utilizzo, la totale comprensione del processo non è ancora stata raggiunta. Ciò è principalmente dovuto alle numerose variabili che influenzano le caratteristiche del prodotto; infatti i granulatori high-shear presentano molteplici parametri di processi che devono essere controllati e molti di questi sono formulazione dipendenti. Per questo motivo lo sviluppo di processo con questo tipo di macchinari e particolarmente complicato e rischia di diventare l'ultima scelta tra le diverse tecniche di granulazione quando una nuova formulazione deve essere prodotta. Tuttavia le caratteristiche dei granuli ottenuti con la granulazione high-shear sono fortemente influenzate dalla reologia della massa umida processata. Per questo motivo lo studio reologico può giocare un ruolo strategico nell'ottenere indicazioni riguardanti l'evoluzione del processo di granulazione high-shear. La misurazione della reologia della massa umida operata sia on-line che off-line è stata studiata in letteratura per controllare il processo e nel passaggio di scala. Tuttavia non è ancora possibile utilizzare in maniera univoca questo tipo di misurazione per prevedere il processo stesso. Prevedere vari aspetti della granulazione, come per esempio: il quantitativo di liquido da utilizzare, i regimi di crescita dei granuli e i parametri che hanno maggior impatto sulle caratteristiche del granulato ottenuto, sarebbe di enorme importanza nell'ambito dello sviluppo di processo e da un punto di vista di Quality-by-Design. Lo scopo di questa tesi è di valutare la possibilità di utilizzare un reometro per masse umide chiamato Mixer Torque Rheometer per prevedere gli aspetti della granulazione precedentemente menzionati. Nella prima fase del progetto, i risultati hanno dimostrato come la reologia della massa umida permetta una rapida ed affidabile predizione del quantitativo di liquido che deve essere impiegato in granulazione. Inoltre l'applicazione della derivata seconda al profilo reologico ottenuto permette di identificare il quantitativo corretto in modo affidabile. Nella seconda fase del progetto è stato possibile osservare come la resistenza dei granuli umidi (identificata come "consistency") sia direttamente correlata ai regimi di crescita dei granuli. Inoltre, studiando l'evoluzione della reologia della massa umida nel tempo si è osservato come il massimo valore di resistenza ottenuto nel tempo mostri una correlazione diretta con la "consistency" dei granuli ottenuti con la stessa formulazione. Ciò permette di utilizzare il massimo valore di resistenza della massa umida ottenuto nel tempo per prevedere il regime di crescita con cui si formeranno i granuli. Infine nell'ultima fase del progetto è stata studiata la possibilità di prevedere i parametri critici di processo per la granulazione in high-shear attraverso lo studio reologico della massa umida. In particolare, i risultati hanno mostrato come il picco massimo di resistenza della massa misurato nel tempo rappresenta un potenziale strumento per identificare i parametri critici di processo. Inoltre questo picco massimo di resistenza della massa umida sembra capace di dare importanti informazioni sulla cinetica di crescita dei granuli. Concludendo, i risultati ottenuti con questa tesi dimostrano la possibilità di utilizzare la reologia della massa umida per predire diversi aspetti della granulazione in high-shear ed ottenere la conoscenza necessaria per facilitare la fase di sviluppo di processo.