Systematic DOE Approach for Dry Granulation Study at Early Clinical Stage of Novel Drugs: An Industrial Case.

In order to introduce a cost-effective strategy method for commercial scale dry granulation at the early clinical stage of drug product development, we developed dry granulation process using formulation without API, fitted and optimized the process parameters adopted Design of Experiment (DOE). Then, the process parameters were confirmed using one formulation containing active pharmaceutical ingredient (API). The results showed that the roller pressure had significant effect on particle ratio (retained up to #60 mesh screen), bulk density and tapped density. The roller gap had significant influence on particle ratio and specific energy. The particle ratio was significantly affected by the mill speed (second level). The tabletability of the powder decreased after dry granulation. The effect of magnesium stearate on the tabletability was significant. In the process validation study, the properties of the prepared granules met the requirements for each response studied in the DOE. The prepared tablets showed higher tensile strength, good content uniformity of filled capsules, and the dissolution profiles of which were consistent with that of clinical products. This drug product process development and research strategies could be used as a preliminary experiment for the dry granulation process in the early clinical stage.

Determining the Impact of Roller Compaction Processing Conditions on Granulate and API Properties: Impact of Formulation API Load.

Previous work demonstrated that roller compaction of a 40%w/w theophylline-loaded formulation resulted in granulate consisting of un-compacted fractions which were shown to constitute between 34 and 48%v/v of the granulate dependent on processing conditions. The active pharmaceutical ingredient (API) primary particle size within the un-compacted fraction was also shown to have undergone notable size reduction. The aim of the current work was to test the hypothesis that the observations may be more indicative of the relative compactability of the API due to the formulation being above the percolation threshold. This was done by assessing the impact of varied API loads in the formulation on the non-granulated fraction of the final granulate and the extent of attrition of API particles within the non-granulated fraction. The influence of processing conditions for all formulations was also investigated. The results verify that the observations, both of this study and the previous work, are not a consequence of exceeding the percolation threshold. The volume of un-compacted material within the granulate samples was observed to range between 34.7 and 65.5% depending on the API load and roll pressure, whilst the API attrition was equivalent across all conditions.

Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product.

The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical model to guide both formulation and process development of a roller-compacted drug product. True density, compression profiling, and frictional properties of the pre-blend powders are used as inputs for the predictive roller compaction model, while flow properties, particle size distribution, and assay uniformity of roller compaction granules are used to select formulation composition and ribbon solid fraction. Using less than 10 g of a model drug compound for material profiling, roller compacted blend in capsule formulations with appropriate excipient ratios were developed at both 1.4% and 14.4% drug loadings. Subsequently, scale-up batches were successfully manufactured based on the roller compaction process parameters obtained from predictive modeling. The measured solid fractions of roller compaction ribbon samples from the scale-up batches were in good agreement with the target solid fraction of the modeling. This approach demonstrated considerable advantages through savings in both materials and number of batches in the development of a roller-compacted drug product, which is of particular value at early development stages when drug substance is often limited and timelines are aggressive.

[Prediction of formability of flavonoid extract granules by dry granulation based on design space and RBFNN].

In this paper, a flavonoid extract powder properties-process parameters-granule forming rate prediction model was constructed based on design space and radial basis function neural network(RBFNN) to predict the formability of flavonoid extract gra-nules. Box-Behnken experimental design was employed to explore the mathematical relationships between critical process parameters and quality attributes. The design space of critical process parameters was developed, and the accuracy of the design space was verified by Monte Carlo method(MC). Design Expert 10 was used for Box-Behnken design and mixture design. Scutellariae Radix mixed powder was prepared and its powder properties were measured. The mixed powder was then subjected to dry granulation and the granule forming rate was determined. The correlations between powder properties were analyzed by variance influence factor(VIF), and principal component analysis(PCA) was performed for the factors with strong collinearity. In this way, a prediction model of powder properties-process parameters-granule forming rate was established based on RBFNN, the accuracy of which was evaluated with examples. The results showed that the model had a good predictive effect on the granule forming rate, with the average relative error of 1.04%. The predicted value and the measured value had a high degree of fitting, which indicated that model presented a good prediction ability. The prediction model established in this study can provide reference for the establishment of quality control methods for Chinese medicinal preparations with similar physical properties.

Manufacturability and Properties of Granules and Tablets Using the Eco-Friendly Granulation Method Green Fluidized Bed Granulation Compared to Direct Compression.

This study aimed to compare the manufacturability and granule and tablet properties of green fluidized bed granulation (GFBG) and of direct compression (DC). Acetaminophen was used as a low compactability model drug. The process time of GFBG to produce final mixtures was comparable to that of DC, and thus GFBG could be considered a simple process. DC could not produce 30% drug load tablets owing to poor granule flowability, whereas no problems were observed in the GFBG tableting process up to 80% of drug load. Tablets prepared with GFBG showed higher tensile strength than those prepared using DC. Compactability evaluation results show that the yield pressure of the granules prepared with GFBG was significantly lower than that of DC, suggesting that the granules prepared with GFBG were easily plastically deformed. Moreover, tablets prepared with GFBG showed fast disintegration, which was faster than that of DC. We conclude that GFBG produces granules with higher drug content and desired physicochemical properties at low cost.

Evaluation of Microwave-Assisted Extraction Method for Preparation and Assessment of Thai Herbal Medicine Oral Tablets With Enriched Phytochemical Compounds.

In developing countries, populations have employed herbal medicines for primary health care because they are believed to be more appropriate to the human body and have less side effects than chemically synthesized drugs. The present study aimed to develop and evaluate herbal tablets incorporated with a Thai traditional medicinal extract, U-pa-ri-waat (URW), using microwave-assisted extraction (MAE). The extraction efficiency for URW using MAE and traditional solvent extraction was compared based on the percent yield after spray drying. URW tablets were prepared using the dry granulation method. The optimized products were assessed using standard characterization methods based on the United States and British Pharmacopeias. DPPH and ABTS radical scavenging assays were performed to analyze the antioxidant capacity of the microwave-assisted extracts. The results revealed that the flowability of the dry granule with added maltodextrin was improved compared to a granule without additives, as indicated by an angle of repose of 33.69 ± 2.0°, a compressibility index of 15.38 ± 0.66, and a Hausner's ratio of 1.18 ± 0.06. The resulting formulation produced flat tablets with uniform weight variation, hardness, thickness, friability, and optimum disintegration time. The URW extracts showed antioxidant activity and MAE with maltodextrin carrier displayed the strongest DPPH and ABTS radical activities with IC50 values of 1.60 ± 0.02 µg/mL and 4.02 ± 0.24 µg/mL, respectively. The URW tablet formulation passed the quality control tests. Storage of the formulation tablets for 90 days under accelerated conditions had minimal effects on tablet characteristics.

[Exploratory study on preparation of high drug loading granules with traditional Chinese medicine raw powder as carriers].

With Sangtang Yin granule as model drug,and based on the strategy of " unification of medicines and excipients",the feasibility of preparing high drug loading granules with traditional Chinese medicine( TCM) raw powder as carrier was explored. The powder yield,particle size and particle size distribution,fillibility,flowability,hygroscopicity,reconstituability and other key physical properties relating to preparations of 8 herbs( Dioscoreae Rhizoma,Euryales Semen,Atractylodis Macrocephalae Rhizoma,Coicis semen,Poria,Puerariae Lobatae Radix,Puerariae Thomsonii Radix and Coicis Semen by stir-frying with bran) were studied after being smashed,and the feasibility of taking them as excipients of TCM granules was evaluated by co-spray drying,dry granulation and other preparation techniques. According to the results of the physical properties of raw powders,raw powders of Dioscoreae Rhizoma,Euryales Semen and Puerariae Thomsonii Radix had a high powder yield,uniform particle size distribution,good fillibility,poor hygroscopicity and good reconstitutability,with the feature of assisting granule forming. Compared with the prescription of spray dry powder Sangtang Yin without any excipient,the co-sprayed powder had a high yield,good fillibility and compressibility. The yield of dry granules prepared by co-spraying dry powder was increased by more than 10%,and the particles had a uniform color,good fluidity and dissolubility with the drug-loading rate up to 100%. Based on the physical characteristics of TCM raw powder combined with the analysis of the preparation process,Dioscoreae Rhizoma and Puerariae Thomsonii Radix raw powder were selected as the carriers of granule preparations,and Sangtang Yin granule without any excipient was successfully prepared. The findings provide a feasible idea for the preparation of TCM granules with a high drug loading capacity.

[Research on Bayesian fault diagnosis model of traditional Chinese medicine dry granulation based on failure model and effect analysis (FMEA)].

This paper aims to construct a Bayesian(BN) fault diagnosis model of traditional Chinese medicine dry granulation based on the failure model and effect analysis(FMEA), effectively control risk factors and ensure the quality of granules.Firstly, the risk ana-lysis of dry granulation process was carried out with FMEA, and the selected medium and high risk factors were taken as node variables to establish corresponding BN network with causality.According to the mathematical reasoning method of probability theory, the model was accurately inferred and verified by Netica, and the granule nonconformance was used as the evidence for reversed reasoning to determine the most likely cause of the failure that affected the granule quality.The BN fault diagnosis model of traditional Chinese medicine dry gra-nulation was established based on the medium and high risk factors of process, prescription and equipment screened out by FMEA, such as roller pressure, raw material viscosity, clearance between rollers in the paper.The fault diagnosis of traditional Chinese medicine dry granulation process was then carried out according to the model, and the posterior probability of each node under the premise of nonconforming granule quality was obtained.This method could provide strong support for operators to quickly eliminate faults and make decisions, so as to improve the efficiency and accuracy for fault diagnosis and prediction, with innovation in its application.

Optimization of the process variables of roller compaction, on the basis of granules characteristics (flow, mechanical strength, and disintegration behavior): an application of SeDeM-ODT expert system.

The objective of the study was application of SeDeM-ODT expert system for optimization of process variables for roller compaction and for the preparation of granules with better flow, compressibility, and disintegration behavior. In the present study, granules were prepared at pre-determined (on the basis of factorial design) process variables and characterized using SeDeM-ODT expert system. Compatibility of ribavirin with excipients (microcrystalline cellulose, tablettose-80, cross carmellose sodium, and magnesium stearate) was evaluated by binary mixture approach, using FTIR. According to the SeDeM-ODT expert system, granules were characterized for various parameters related to flow, compressibility and disintegration behavior and Index of Good Compressibility and Buccodispersibility (IGCB) was calculated. The process variables resulting in highest IGCB value were considered as optimum. Ribavirin was found compatible with all the excipients used in the study and characteristics peaks were present in FTIR spectra after subjecting to stress conditions (75% relative humidity at 45 ± 5 °C) for 30 days. Both Ribavirin powder and Ribavirin containing powder blend had poor flow and compressibility while disintegration behavior was good due to higher water solubility. Screw speed of 35 rpm and roller speed at 12 rpm resulted in granules with acceptable characteristics. The IGCB value (5.63) of the granules was highest of all, indicating its better characteristics. SeDeM-ODT expert system presents a more practical picture of the granules and also predicts the mechanical strength and disintegration behavior of the tablets prepared from the granules. By proper optimization of screw and roller speed, efficiency of the process can be improved.

Parameter estimation for roller compaction process using an instrumented vector TF mini roller compactor.

Using instrumented roll technology, statistical models relating process parameters such as hydraulic pressure, roll speed and screw speed of Vector TF mini roller compactor to ribbon normal stress and density were developed for placebo blends. Normal stress was found to be directly proportional to hydraulic pressure, roll speed and inversely to screw to roll speed ratio. A power-law relationship between ribbon density and normal stress was observed for placebo blends. Models developed for placebo were found to predict ribbon densities of active blends with good accuracy. Standard optimization of roller compaction process parameters involves the investment of a large amount of time and active ingredient. These models can, therefore, be utilized to predict starting instrument settings required to generate a ribbon of desired solid fraction during early-stage development where material availability & time is limited.

[Discussion on research thought of dry granulation of traditional Chinese medicine: research progress at home and abroad based on dry granulation technology].

Dry granulation technology is a great innovation in granulation technology,which saves many intermediate links and reduces many intermediate costs. It is closely related to the characteristics of materials,dry granulation equipment and process. Dry granulation technology is a systematic engineering science covering many technical fields. The process of dry granulation involves complex mathematical model mechanisms of temperature field,pressure field and velocity field,closely related to the characteristics of materials and drying equipment. However,due to the late start of research on dry granulation technology of traditional Chinese medicine,basic research is still weak. The research on dry granulation technology has achieved great results in the fields of food,chemical industry,agriculture and forestry,showing great reference significance. The advantage of dry granulation of traditional Chinese medicine is that it can be directly granulated by adding an appropriate amount of auxiliary materials in the extract powder of traditional Chinese medicine,without the need of wetting,mixing,drying and other processes. The process is simple and can effectively guarantee the quality of traditional Chinese medicine. The granules obtained by the dry granulation technique are important intermediates for preparing the solid preparations of traditional Chinese medicines,which would directly affect the subsequent molding process and the quality of the preparation products. Therefore,based on the characteristics of dry granulation method in traditional Chinese medicine and by referring to the advanced research results of dry granulation technology in other fields,we would discuss the research ideas of dry granulation in traditional Chinese medicine in terms of the mechanism of dry granulation equipment,technology,on-line detection technology and mathematical model of dry granulation process,hoping to provide reference for the research of dry granulation method in traditional Chinese medicine.

Modification of α-lactose monohydrate as a direct compression excipient using roller compaction.

Roller compaction was used to prepare a direct-compressed lactose excipient using crystalline α-lactose monohydrate. The effect of various roller compaction process parameters (compaction pressure, compaction repetition, and speed ratio) on the characteristics of compacted α-lactose monohydrate was investigated. Results were compared with data obtained using industrial spray-dried lactose and lactose samples with different degrees of crystallinity. XRPD analysis revealed that roller compaction reduced the crystallinity of α-lactose monohydrate, and the resulting material is similar to spray-dried lactose in behavior as a direct compression excipient. Roller compaction introduced desirable characteristics to the raw α-lactose monohydrate by inducing changes in crystallinity and particle morphology. Scanning electron microscopy results indicated that the compaction process converted some of the original torpedo-shaped crystals of α-lactose monohydrate into a more cylindrical shape with rounded edges. Compaction pressure and repetition of compaction have a significant effect on the modification of the crystallinity of the processed, raw α-lactose monohydrate.

Tricalcium citrate - a new brittle tableting excipient for direct compression and dry granulation with enormous hardness yield.

OBJECTIVES: Tricalcium citrate (TCC) was characterized as a tableting excipient for direct compression (DC) and dry granulation (DG). SIGNIFICANCE: Brittle materials usually lead to tablets of inferior mechanical strength compared to plastic deforming materials. A brittle material exhibiting a high tabletability with the ability to retain that behavior during recompression would represent a valuable alternative to the commonly used microcrystalline cellulose. METHODS: Tablets of TCC and other common fillers were directly compressed for the purpose of compression analysis including Heckel analysis, speed dependency, and lubricant sensitivity. DG by roller compaction of TCC was first simulated via briquetting and experiments were subsequently repeated on a roller compactor. RESULTS: TCC appears as an excellent flowing powder of large agglomerates consisting of lower micron to submicron platelets. Despite the brittle deformation mechanism identified in the Heckel analysis, TCC demonstrated a very high mechanical strength up to 11 MPa in conjunction with an astonishingly low solid fraction of 0.85 at a compression pressure of 400 MPa. This was seen along with hardly any speed and lubricant sensitivity. Nevertheless, disintegration time was very short. TCC tablets suffered only a little from the re-compression: a slight loss in tensile strength of 1-2 MPa was observed for granules produced via roller compaction. CONCLUSIONS: TCC was found to be suitable for DC as a predominantly brittle deforming filler, nevertheless demonstrating an enormous hardness yield while being independent of lubrication and tableting speed. TCC furthermore retained enough bonding capacity after DG to maintain this pronounced tabletability.

Implementation of quality by design approach in manufacturing process optimization of dry granulated, immediate release, coated tablets - a case study.

The aim of this study was to optimize the process of tablets compression and identification of film-coating critical process parameters (CPPs) affecting critical quality attributes (CQAs) using quality by design (QbD) approach. Design of experiment (DOE) and regression methods were employed to investigate hardness, disintegration time, and thickness of uncoated tablets depending on slugging and tableting compression force (CPPs). Plackett-Burman experimental design was applied to identify critical coating process parameters among selected ones that is: drying and preheating time, atomization air pressure, spray rate, air volume, inlet air temperature, and drum pressure that may influence the hardness and disintegration time of coated tablets. As a result of the research, design space was established to facilitate an in-depth understanding of existing relationship between CPPs and CQAs of intermediate product (uncoated tablets). Screening revealed that spray rate and inlet air temperature are two most important factors that affect the hardness of coated tablets. Simultaneously, none of the tested coating factors have influence on disintegration time. The observation was confirmed by conducting film coating of pilot size batches.

The performance of HPMC matrix tablets using various agglomeration manufacturing processes.

CONTEXT: The flow and compaction properties of a compaction mixture or powder and the drug-release profile of final tablets are important critical quality attributes (CQAs) that have an impact on the overall performance of hydrophilic matrix tablets. The selection of granulation method can importantly affect these CQAs. OBJECTIVE: This study investigates various agglomeration methods of sustained-release formulation using HPMC K4M as a release polymer with various wet- and dry-granulation techniques. MATERIALS AND METHODS: Flow properties were determined using flow time, angle of response, and the Carr index. Compaction properties were evaluated using "out of die" Heckel model. Release of carvedilol was tested as 12-h drug-dissolution profile. RESULTS AND CONCLUSION: Compression mixtures made using the wet-granulation method exhibit better flow and compression properties than compression mixtures made using the dry-granulation method. The direct compression method proved to be the least appropriate manufacturing method because the compression mixture has very poor flow and the lowest compressibility/compactibility index. The choice of granulation technique significantly influences the swelling behavior and drug-dissolution profile of the final matrix tablets, also resulting in dissimilar release profiles. The choice of granulation method has the greatest influence on the drug-release profile. The direct compression method provides tablets with the fastest drug-release profile, followed by the dry-granulation and wet-granulation methods. The particle size of granules and porosity of tablets play an important role, contributing to differences in drug-release profiles.

Comparative binder efficiency modeling of dry granulation binders using roller compaction.

Roller compaction parameters' impact on granules and tableting properties of coprocessed Avicel® DG [ADG], a physical mixture of the two components at the same composition present in ADG [PADCP], and microcrystalline cellulose and Kollidon® VA-64 Fine physical mixture [KVA64] was quantified by analysis of variance (ANOVA) and multivariate methods. Roller force, roller gap, and roller speed levels were selected for evaluation. A 33 full-factorial experimental design with three center points for roller force, roller gap, and roller speed was used. The response parameters studied were granule-to-fines (GF) ratio, compressibility index (CI), tablet thickness (TT), tablet friability (TF), tablet breaking force (TBF) and disintegration time (DT). A model acetaminophen tablet formulation was roller granulated and tableted at 10 kg scale. Principal component analysis of ADG and PADCP formulations were separated from KVA64 formulations, indicating different granule and tableting properties were binder dependent. This difference in binder performance was also confirmed by ANOVA. The ANOVA also showed that there were no statistical performance differences between coprocessed ADG and its comparable physical blend with the exception of TT. Principal component regression (PCR) analyses of ADG and PADCP revealed that these excipients exhibited a statistically significant negative effect on granules-to-fine (GF) ratio, TT, TBF, and DT. KVA64 demonstrated a positive effect on these parameters. The KVA64 physical mixture demonstrated an overall better performance and binding capability. This study strongly suggests that there is no performance advantage of coprocessed Avicel® DG when compared to a physical mixture of the two components at the same composition.

Effects of hexagonal boron nitride on dry compression mixture of Avicel DG and Starch 1500.

The objective of this study was to investigate the lubrication properties of hexagonal boron nitride (HBN) on a (1:1) binary mixture of Avicel DG and Starch 1500 after using the dry granulation-slugging method and compare it with conventional lubricants, such as magnesium stearate (MGST), glyceryl behenate (COMP) and stearic acid (STAC). MGST is one of the most commonly used lubricants in the pharmaceutical industry. However, it has several adverse effects on tablet properties. In our current study, we employed various methods to eradicate the work hardening phenomenon in dry granulation, and used HBN as a new lubricant to overcome the adverse effects of other lubricants on tablet properties. HBN was found to be as effective as MGST and did not show any significant adverse effects on the crushing strength or work hardening. From the scanning electron microscope (SEM) images, it was concluded that HBN distributed better than MGST. As well as showing better distribution, HBN's effect on disintegration was the least pronounced. Semi-quantitative weight percent distribution of B and N elements in the tablets was obtained using EDS (energy dispersive spectroscopy). Based on atomic force microscope (AFM) surface roughness images, formulations prepared with 1% HBN showed better plastic character than those prepared with MGST.

Tablet formulation of an active pharmaceutical ingredient with a sticking and filming problem: direct compression and dry granulation evaluations.

OBJECTIVE: To develop a tablet formulation for an active pharmaceutical ingredient for which sticking and filming problems occurred during tablet punching. METHODS: Direct compression and dry granulation tableting techniques were evaluated using factorial experimental design. The effects of chrome-coated punch tips, filler types and active percent in the tablet formulation by direct compression were evaluated. Similarly, for dry granulation using the roller compaction technique, three formulation factors - roller compaction pressure, intragranular filler percent and filler type - were studied. Tablets prepared by both techniques were characterized in regard to their compressibility index, tablet hardness, disintegration time, friability index and stickiness-filming index (an arbitrary index). Ten formulations were prepared by each technique. Using multiple response optimizations and estimated response surface plots, the data were analyzed to identify optimum levels for the formulation factors. RESULTS: Compressibility index values for all the formulations prepared by direct compression exceeded 25%, unlike the blends prepared by dry granulation. Both tablet hardness and disintegration time for direct compression formulations were significantly lower than for dry granulation formulations. The friability index values were significantly higher for direct compression formulations than for dry granulation formulations. All the direct compression formulations, unlike the dry granulation formulations, had a high stickiness-filming index. CONCLUSION: Statistical analysis helped in identifying the optimum levels of formulation factors, as well as the method for eliminating sticking and filming. Unlike the direct compression technique, dry granulation yielded tablets for which sticking and filming were completely eliminated.

Rational Function-Based Approach for Integrating Tableting Reduced-Order Models with Upstream Unit Operations: Dry Granulation Case Study.

We present a systematic and automatic approach for integrating tableting reduced-order models with upstream unit operations. The approach not only identifies the upstream critical material attributes and process parameters that describe the coupling to the first order and, possibly, the second order, but it also selects the mathematical form of such coupling and estimates its parameters. Specifically, we propose that the coupling can be generally described by normalized bivariate rational functions. We demonstrate this approach for dry granulation, a unit operation commonly used to enhance the flowability of pharmaceutical powders by increasing granule size distribution, which, inevitably, negatively impacts tabletability by reducing the particle porosity and imparting plastic work. Granules of different densities and size distributions are made with a 10% w/w acetaminophen and 90% w/w microcrystalline cellulose formulation, and tablets with a wide range of relative densities are fabricated. This approach is based on product and process understanding, and, in turn, it is not only essential to enabling the end-to-end integration, control, and optimization of dry granulation and tableting processes, but it also offers insight into the granule properties that have a dominant effect on each of the four stages of powder compaction, namely die filling, compaction, unloading, and ejection.

Exploration of moisture activated dry granulation for the development of gastroretentive tablets aided by SeDeM diagram.

Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM. In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition.