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

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

Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study.

Daprodustat, an orally bioavailable hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease. Part A of this 2-part, randomized, double-blind, single-dose, cross-over study (NCT04640311) compared pharmacokinetic properties of a single oral dose of daprodustat 4 mg tablets manufactured via twin-screw wet granulation (process 1) to 2 sets of 4 mg tablets manufactured via high-shear wet granulation (process 2), to assess the impact of different dissolution profiles on pharmacokinetics. Part B assessed the bioequivalence of daprodustat tablets manufactured via process 1 with tablets manufactured via process 2 at 5 different dose strengths (1, 2, 4, 6, and 8 mg). In part A, mean plasma concentrations of daprodustat were comparable over a 24-hour period despite differences in manufacturing processes and dissolution profiles. In part B, the 90% confidence intervals of the ratios of the least squared means for area under the concentration-time curve and maximum observed plasma concentration fell within the 0.8-1.25 bioequivalence range for all doses, except for maximum observed plasma concentration at 8 mg. A prespecified sensitivity analysis jointly assessing all doses showed bioequivalence for all doses tested. No new safety concerns for daprodustat were identified.

A new methodology of understanding the mechanism of high shear wet granulation based on experiment and molecular dynamics simulation.

In high shear wet granulation (HSWG), the interaction mechanism between binder and powder with different sugar content is still unclear. Herein, the law and mechanism of the interaction between binder and powder were studied on the molecular level by combining experiment analysis through the Kriging model and molecular dynamics (MD) simulation. For the sticky powder with high sugar content, the ethanol in the binder played a pivotal role in dispersing water into powders, and the amount of water determined the growth of granules. In the saturating stage, the reduction of sugar content facilitates the penetration of ethanol molecules. The concentration of ethanol determines whether the mixture is blended uniformly in the merging stage. The simulation results are consistent with the actual situation and explain the competition mechanism of interaction with binder and powder. Therefore, this research offers an efficient strategy for the in-depth understanding of the HSWG process where the powder is sticky, as well as providing guidelines for the practical application of preparation for Traditional Chinese Medicine (TCM) granules.

Using a Material Library to Understand the Change of Tabletability by High Shear Wet Granulation.

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.

Real-Time Monitoring of Critical Quality Attributes during High-Shear Wet Granulation Process by Near-Infrared Spectroscopy Effect of Water Addition and Stirring Speed on Pharmaceutical Properties of the Granules.

To produce high-quality pharmaceuticals, a real-time monitoring method for the high-shear wet granulation process (HSWG) was developed based on near-infrared spectroscopy (NIRS). Samples consisting of lactose, potato starch, and hydroxypropyl cellulose were prepared using HSWG with varying amounts of purified water (80, 90, and 100 mL) and impeller speed (200, 400, and 600 rpm), which produces granules of different characteristics. Twelve batches of samples were used for the calibration and nine batches were used for validation. After drying, the median particle size (D50), tapped density (TD), and Hauser ratio (HR) were measured. The best calibration models to predict moisture content (MC), D50, TD, and HR were determined based on pretreated NIR spectra using partial least squares regression analysis (PLSR). The temporal changes in the pharmaceutical properties under different amounts of water added and stirring speed were monitored in real time using NIRS/PLSR. Because the most important critical quality attribute (CQA) in the process was MC, granule characteristics such as D50, TD, and HR were analyzed with respect to MC. They might be used as robust and simple monitoring methods based on MC to evaluate the pharmaceutical properties of HSWG granules.

[Material manufacturability classification in high shear wet granulation process of Chinese medicine].

The high shear wet granulation(HSWG) process of Chinese medicine has a complicated mechanism. There are many influencing factors that contribute to this process. In order to summarize the manufacturability of different kinds of materials in HSWG, this paper constructed a material library composed of 11 materials, including 4 Chinese medicine extracts and 7 pharmaceutical excipients. Each material was described by 22 physical parameters. Several binders were employed, and their density, viscosity and surface tension were characterized. Combining empirical constraints and the principle of randomization, 21 designed experiments and 8 verification experiments were arranged. The partial least squares(PLS) algorithm was used to establish a process model in prediction of the median granule size based on properties of raw materials and binders, and process parameters. The surface tension and density of binders, as well as the maximum pore saturation were identified as key variables. In the latent variable space of the HSWG process model, all materials could be divided into three categories, namely the Chinese medicine extracts, the diluents and the disintegrants. The granulation of Chinese medicine extracts required low viscosity and low amount of binder, and the resulted granule sizes were small. The diluent powders occupied a large physical space, and could be made into granules with different granule sizes by adjusting the properties of binders. The disintegrants tended to be made into large granules under the condition of aqueous binder. The combination use of material database and multivariate modeling method is conducive to innovate the knowledge discovery of the wet granulation process of Chinese medicine, and provides a basis for the formulation and process design based on material attributes.

A Novel Use of Nanocrystalline Suspensions to Develop Sub-Microgram Dose Micro-Tablets.

Developing solid oral drug products with good content uniformity (CU) at low doses is challenging; this challenge further aggravates when the tablet size decreases from a conventional tablet to a micro/mini-tablet (1.2-3 mm diameter). To alleviate the CU issues, we present a novel use of nanocrystalline suspension combined with high shear wet granulation for the first time. In this approach, nanomilled drug in the form of nanocrystalline suspension is sprayed onto the powder bed to ensure uniform distribution. The resulting granules had adequate particle size distribution and flow characteristics to enable manufacturing of micro-tablets with good weight uniformity and tensile strength. Nanomilled drug resulted in excellent content uniformity among individual micro-tablets even at a dose strength as low as 0.16 mcg, whereas micronized drug resulted in unacceptable CU even at 5x higher dose strength (0.8 mcg). Besides, the use of nanomilled drug has enhanced the dosing flexibility of micro-tablets and showed superior dissolution performance in comparison with micronized drug with no impact of storage conditions (40 °C/75%RH for six months) on their dissolution performance. The proposed approach is simple and can be easily incorporated into traditional high shear wet granulation process to develop sub-microgram dose solid oral drug products.

An Integrated Approach for High-Shear Wet Granulation (HSWG) Processing of TPGS-Based Formulations: Demonstration of Process Robustness through Experimental Design Conditions.

The goal of this study was to understand the impact of high-shear wet granulation (HSWG) processing conditions on product attributes for a tablet formulation containing the non-ionic surfactant TPGS. The use of TPGS in oral solid drug products has been reported to be challenging due to the low melting temperature of TPGS. In addition, literature on TPGS-based HSWG formulations, especially practical processing and scale-up knowledge, is limited. Presented here is an extension of this TPGS application in a tablet formulation, with a focus on the HSWG processing and scale-up across different granulators. To understand the processing space for this TPGS-based HSWG formulation, two consecutive studies were conducted with different objectives. First, an exploratory study was conducted to understand the impact of extreme processing conditions on product attributes. Subsequently, a factorial design of experiment (DoE) study assessed the separate contributions and interactions from HSWG processing variables. The outcome of both studies led to a successful process scale-up and product transfer from lab to commercial development using different granulators. The TPGS-based formulation was demonstrated to provide robust downstream processing (improved flowability and reduced segregation potential) within a wide HSWG operating space, while having a minimal impact on product performance across different granulators.

Control Strategy for Process Development of High-Shear Wet Granulation and Roller Compaction to Prepare a Combination Drug Using Integrated Quality by Design.

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.

Material manufacturability classification in high shear wet granulation process of Chinese medicine / 中国中药杂志

The high shear wet granulation(HSWG) process of Chinese medicine has a complicated mechanism. There are many influencing factors that contribute to this process. In order to summarize the manufacturability of different kinds of materials in HSWG, this paper constructed a material library composed of 11 materials, including 4 Chinese medicine extracts and 7 pharmaceutical excipients. Each material was described by 22 physical parameters. Several binders were employed, and their density, viscosity and surface tension were characterized. Combining empirical constraints and the principle of randomization, 21 designed experiments and 8 verification experiments were arranged. The partial least squares(PLS) algorithm was used to establish a process model in prediction of the median granule size based on properties of raw materials and binders, and process parameters. The surface tension and density of binders, as well as the maximum pore saturation were identified as key variables. In the latent variable space of the HSWG process model, all materials could be divided into three categories, namely the Chinese medicine extracts, the diluents and the disintegrants. The granulation of Chinese medicine extracts required low viscosity and low amount of binder, and the resulted granule sizes were small. The diluent powders occupied a large physical space, and could be made into granules with different granule sizes by adjusting the properties of binders. The disintegrants tended to be made into large granules under the condition of aqueous binder. The combination use of material database and multivariate modeling method is conducive to innovate the knowledge discovery of the wet granulation process of Chinese medicine, and provides a basis for the formulation and process design based on material attributes.

Development of low dose micro-tablets by high shear wet granulation process.

Low dose micro-tablets with acceptable quality attributes, specifically content uniformity (CU), would not only enhance the dose flexibility in the clinic, but also decrease excipient burden in pediatric population. Considering the CU challenges associated with directly compressed low dose micro-tablets, in this study, high shear wet granulation (HSWG) process was evaluated to manufacture micro-tablets with reduced CU variability. The impact of active pharmaceutical ingredient (API) particle size (D90 - 18-180 µm) and loading (0.67-16.67% w/w) on the critical quality attributes of micro-tablets (1.2 and 1.5 mm) like weight variability, CU, and dissolution were evaluated. Experimental results showed that final blends with flow function coefficient (ffc) ≥ 5.4 or Hausner ratio (HR) ≤ 1.43 facilitated robust compression of micro-tablets. With enhanced weight control, all the batches except the 1.2 mm micro-tablets and 2.0 mm micro-tablets with 0.67% w/w API loading and coarse API particle size (D90 - 180 µm) resulted in CU variability that meets the USP <905> CU acceptance criteria for individual micro-tablets. Apart from the above mentioned 1.2 mm micro-tablets, all the batches meet the USP <905> CU acceptance criteria for composites of 10 or more micro-tablets. Precise delivery of micro-tablets manufactured in the current study would allow dose titration in the increments of 11 mcg. The API particle size and loading impacted the in-vitro dissolution performance of micro-tablets with smaller API particle size and lower loading resulting in faster release profiles. This study provides a framework for developing low dose micro-tablets with acceptable quality attributes using HSWG process for micro-dosing, enhanced dose flexibility, and decreased excipient burden.

Converting a batch based high-shear granulation process to a continuous dry granulation process; a demonstration with ketoprofen tablets.

When one wishes to convert a batch based manufacturing process of an existing tablet product to a continuous process, there are several available strategies which can be adopted. Theoretically, the most straightforward way would be to proceed with the corresponding processing principles, for example to change a wet granulation (WG) batch process into its continuous WG counterpart. However, in some cases, the choice of roller compaction (RC) could be very attractive due to the notably simpler and inherently continuous nature of the RC manufacturing principle. The aim of this study was to examine a process conversion from batch based high-shear wet granulation (HSWG) to continuous RC manufacturing, without any significant formulation changes. An optimization of the formulation is often needed during the process conversion. However, our primary goal was to demonstrate the possibilities to perform this kind of process adaptation with minimal formulation changes. Furthermore, the effect of three different locations of lubrication feeding with two production rate levels was studied. An additional target was to identify possible over-lubrication with these manufacturing configurations, and to clarify which of these three possibilities steps produced a final product that conformed to the same quality requirements as HSWG tablets. Previously, the effects of lubrication only on compacted ribbons (Miguelez-Moran A.M, 2008) and final product with CDC (continuous direct compression) (Taipale-Kovalainen, et al., 2017; 2019) have been investigated. Here, the effect of lubrication on both ribbon and on final product was examined. No signs of over-lubrication were observed, but there was a clear effect of the feeding location of lubricant on the final product. On the basis of these results, it is concluded that in the future, if a good product/process understanding of the alternative manufacturing process with different techniques can be obtained, it will be possible to devise more flexible and effective ways to allow the pharmaceutical industry to switch from batch manufacturing towards CM.

Partial Least Squares Regression-Based Robust Forward Control of the Tableting Process.

In this study, we established a robust feed-forward control model for the tableting process by partial least squares regression using the near-infrared (NIR) spectra and physical attributes of the granules to be compressed. The NIR spectra of granules are rich in information about chemical attributes, such as the compositions of any ingredients and moisture content. Polymorphism and pseudo-polymorphism can also be quantitatively evaluated by NIR spectra. We used the particle size distribution, flowability, and loose and tapped density as the physical attributes of the granules. The tableting process was controlled by the lower punch fill depth and the minimum distance between the upper and lower punches at compression, which were specifically related to the tablet weight and thickness, respectively. The feed-forward control of the process would be expected to provide some advantages for automated and semi-automated continuous pharmaceutical manufacturing. As a result, our model, using a combination of NIR spectra and the physical attributes of granules to control the distance between punches, resulted in respectable agreement between the predicted process parameters and actual settings to produce tablets of the desired thickness.

In situ monitoring of the crystalline state of active pharmaceutical ingredients during high-shear wet granulation using a low-frequency Raman probe.

Optimization of manufacturing processes based on scientific evidence is important in the quality control of active pharmaceutical ingredients (APIs) and drug products, particularly when crystal forms change during production, which could affect subsequent drug performance. In this study, we verified crystalline states using various crystal faces and excipients during high-shear wet granulation based on non-contact low-frequency (LF) Raman probe monitoring. Four model drugs [indomethacin (IND), acetaminophen (APAP), theophylline (TP), and caffeine (CAF) polymorphs and cocrystals] were mixed with microcrystalline cellulose and hydroxypropyl cellulose with the addition of water over time. The LF Raman probe showed comparatively high sensitivity in monitoring 5-20% APAP and IND in a wet mass. Notably, as observed from the characteristic LF Raman peak shifts, form I TP and CAF and their cocrystals were more susceptible to transformation to the monohydrate form than form II. This method was also shown to be applicable in monitoring a commercial formulation of eight excipients and revealed crystalline transformations after 15 min of mixing. Therefore, probe-type LF Raman spectroscopy can be successfully employed to distinguish and monitor the crystalline state of APIs in real time during high-shear wet granulation, in which there is a risk of crystal transformation.

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

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

Improved Understanding of the High Shear Wet Granulation Process under the Paradigm of Quality by Design Using Salvia miltiorrhiza Granules.

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.

Comprehensive Study of Intermediate and Critical Quality Attributes for Process Control of High-Shear Wet Granulation Using Multivariate Analysis and The Quality by Design Approach.

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).

Monitoring of multiple solvent induced form changes during high shear wet granulation and drying processes using online Raman spectroscopy.

Form changes during drug product processing can be a risk to the final product quality in terms of chemical stability and bioavailability. In this study, online Raman spectroscopy was used to monitor the form changes in real time during high shear wet granulation of Compound A, a highly soluble drug present at a high drug load in an extended release formulation. The effect of water content, temperature, wet massing time and drying technique on the degree of drug transformation were examined. A designed set of calibration standards were employed to develop quantitative partial least square regression models to predict the concentration of each drug form during both wet granulation and the drying process. Throughout all our experiments we observed complex changes of the drug form during granulation, manifest as conversions between the initial non-solvated form of Compound A, the hemi-hydrate form and the "apparent" amorphous form (dissolved drug). The online Raman data demonstrate that the non-solvated form converts to an "apparent" amorphous form (dissolved drug) due to drug dissolution with no appearance of the hemi-hydrate form during water addition stage. The extent of conversion of the non-solvated form was governed by the amount of water added and the rate of conversion was accelerated at higher temperatures. Interestingly, in the wet massing zone, the formation of the hemi-hydrate form was observed at a rate equivalent to the rate of depletion of the non-solvated form with no change in the level of the "apparent amorphous" form generated. The level of hemi-hydrate increased with an increase in wet massing time. The drying process had a significant effect on the proportion of each form. During tray drying, changes in drug form continued for hours. In contrast fluid bed drying appeared to lock the final proportions of drug form product attained during granulation, with comparatively small changes observed during drying. In conclusion, it was possible to simultaneously monitor the three forms in real time during wet granulation and drying using online Raman spectroscopy. The results regarding the effect of process parameters on the degree of transformation are critical for designing a robust process that ensures a consistent form in the final drug product.

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations.

The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and in vitro dissolution were also studied. Following post-granulation drying at 60 °C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25 °C/60% RH and 40 °C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.

Enhancing tablet disintegration characteristics of a highly water-soluble high-drug-loading formulation by granulation process.

The objective of this study was to improve the disintegration and dissolution characteristics of a highly water-soluble tablet matrix by altering the manufacturing process. A high disintegration time along with high dependence of the disintegration time on tablet hardness was observed for a high drug loading (70% w/w) API when formulated using a high-shear wet granulation (HSWG) process. Keeping the formulation composition mostly constant, a fluid-bed granulation (FBG) process was explored as an alternate granulation method using a 2(4-1) fractional factorial design with two center points. FBG batches (10 batches) were manufactured using varying disingtegrant amount, spray rate, inlet temperature (T) and atomization air pressure. The resultant final blend particle size was affected significantly by spray rate (p = .0009), inlet T (p = .0062), atomization air pressure (p = .0134) and the interaction effect between inlet T*spray rate (p = .0241). The compactibility of the final blend was affected significantly by disintegrant amount (p < .0001), atomization air pressure (p = .0013) and spray rate (p = .05). It was observed that the fluid-bed batches gave significantly lower disintegration times than the HSWG batches, and mercury intrusion porosimetry data revealed that this was caused by the higher internal pore structure of tablets manufactured using the FBG batches.