Prospective Validation of High-Shear Wet Granulation Process by Wet Granule Sieving Method. I. Selection and Characterization of Sieving Parameters for Wet Granules

To characterize the progression of high-shear wet granulation for various drugs and formulations based on the particle size distribution of wet granules during granulation, a general sieving method for wet granules was investigated. Wet granulation was conducted in a 25-liter high-shear mixer using four model drugs with different solubilities and particle sizes (ethenzamide, unmilled and milled acetaminophen, and antipyrine). Because of its small size and efficient sifting mechanism, a sonic sifter was used to determine the wet granulation particle size distribution. From the good correlation of particle size distribution between wet granules and dry-sized granules, an intensity of 80% of full-scale amplitude and a sieving time of 3 min were selected as wet granule sieving parameters. 7% general sieving method showed good measurement precision as long as the determination was completed within 20 min after sampling, Further, the method was independent of sampling position within the mixer chamber.     

Use of Mixer-Torque Measurements as an Aid to Optimizing Wet Granulation Process

Instrumentation designed for monitoring the wet granulation process is described. A Hobart mixer was instrumented with a slip ring torque sensor using a voltage of 5 volts D.C. to excite a strain gauge bridge. An amplifier was used to magnify the low signal levels produced by the strain gauge bridge and the gain was set at 179.6 so that 2 volts equals 200 inch ounce. The output was recorded using a Bascom-Turner recorder. The relative dynamic torque, was measured in millivolts as a function of granulating fluid added and time to optimize the granulation process using the planetary mixer. The instrumentation described in this paper has considerable potential for optimization and validation studies for wet granulation procedures.     

Evaluation of maltodextrin as binding agent

Different types of maltodextrin were evaluated as binding agents in wet granulation process. Maltodextrins were added during wet granulation process in the dry form or as a solution. The granulation was performed in a planetary and a high shear mixer. Lactose monohydrate and dicalcium phosphate dihydrate were used as bulk materials. This study showed no difference in binding capacity between the different types of maltodextrin. Maltodextrins did not show any advantage as binding agent in comparison to native starch.     

Use of in-line near-infrared spectroscopy in combination with chemometrics for improved understanding of pharmaceutical processes

High shear granulation is a complex unit operation with several interacting process parameters. No generally accepted real-time in-line tools are available to gain insight into this process, and in practice, a highly experienced process formulator and operator are needed to develop a wet granulated solid dosage form. In this study, the use of in-line near-infrared (NIR) spectroscopy as a process analytical tool for high shear granulation was investigated. In combination with principal component-based methods, process analysis of three separate phases of high shear wet granulation (mixing, spraying, and wet massing) was facilitated. Critical information, both chemical and physical, was collected during processing. Chemical information included the homogeneity of the formulation and the amount of water in wet mass. In addition, physical information related to the particle size of granules was extracted. Principal component loadings were fully interpreted to validate the conclusions drawn from scores and predictions. Thus NIR spectroscopy could be used to determine the end points of the three subphases of high shear wet granulation and, as such, provide a fast in-line quality control tool.     

Use of Mixer-Torque Measurements as an Aid to Optimizing Wet Granulation Process

Abstract

Instrumentation designed for monitoring the wet granulation process is described. A Hobart mixer was instrumented with a slip ring torque sensor using a voltage of 5 volts D.C. to excite a strain gauge bridge. An amplifier was used to magnify the low signal levels produced by the strain gauge bridge and the gain was set at 179.6 so that 2 volts equals 200 inch ounce. The output was recorded using a Bascom-Turner recorder. The relative dynamic torque, was measured in millivolts as a function of granulating fluid added and time to optimize the granulation process using the planetary mixer. The instrumentation described in this paper has considerable potential for optimization and validation studies for wet granulation procedures.     

Prospective Validation of High-Shear Wet Granulation Process by Wet Granule Sieving Method. II. Utility of Wet Granule Sieving Method

The general utility of a method for determination of high-shear wet granulation end point by monitoring the wet granule particle size distribution was evaluated. Wet granulation was conducted in a 25-liter high-shear mixer using four model drugs with different solubilities and particle sizes (ethenzamide, unmilled and milled acetaminophen, and antipyrine). For each drug formulation, its wet granule particle size fraction and target range for granulation end point determination were selected based on the tablet characteristics that are known to be influenced by the wet granulation process. Granules manufactured under different conditions (i.e., different main and chopper blade speeds and binder supplying rate) but manufactured to the same granulation end point determined by the selected fraction and range showed very similar granule characteristics and subsequently very similar tabler characteristics. From the fact that there was a good correlation between the wet and dry-sized granule particle size distributions even if the drying method was changed from fluid-bed drying to vacuum drying, the general application of the end point determining method was verified. Further, the method was shown to be sensitive to the critical granulation parameters for granulation progression and to be very capable of determining the granulation extent. Thus, it was suggested that the method is applicable to various drugs and formulations for determination of wet granulation end point.     

Evaluation of maltodextrin as binding agent

Abstract

Different types of maltodextrin were evaluated as binding agents in wet granulation process. Maltodextrins were added during wet granulation process in the dry form or as a solution. The granulation was performed in a planetary and a high shear mixer. Lactose monohydrate and dicalcium phosphate dihydrate were used as bulk materials. This study showed no difference in binding capacity between the different types of maltodextrin. Maltodextrins did not show any advantage as binding agent in comparison to native starch.     

Disintegration and Dissolution Parameters of Compressed Tablets Prepared by Direct Compression-Wet Granulation Process and Compression of Wet Granulation of Both Sections

Hardness, disintegration and dissolution of compressed tablets were assessed by compressing tablets from granulations prepared by dry and wet granulation process of two sections and by composite wet granulation process. Modified USP XVIII apparatus for disintegration, rotating basket apparatus USP XVIII and constant circulation apparatus were employed for measuring dissolution. The constant circulation apparatus was used in the studies as only it proved to be sensitive to reflect the differences in the dissolution rates and was a close analog of physiological situation. Four types of tablets containing acetylsalicylic acid, codeine phosphate and propoxyphene hydrochloride were prepared. Tablets prepared by partial dry and wet granulation process did not show significant differences in the rates of dissolution as compared to those prepared by complete wet granulation process.     

Disintegration and Dissolution Parameters of Compressed Tablets Prepared by Direct Compression-Wet Granulation Process and Compression of Wet Granulation of Both Sections

Abstract

Hardness, disintegration and dissolution of compressed tablets were assessed by compressing tablets from granulations prepared by dry and wet granulation process of two sections and by composite wet granulation process. Modified USP XVIII apparatus for disintegration, rotating basket apparatus USP XVIII and constant circulation apparatus were employed for measuring dissolution. The constant circulation apparatus was used in the studies as only it proved to be sensitive to reflect the differences in the dissolution rates and was a close analog of physiological situation. Four types of tablets containing acetylsalicylic acid, codeine phosphate and propoxyphene hydrochloride were prepared. Tablets prepared by partial dry and wet granulation process did not show significant differences in the rates of dissolution as compared to those prepared by complete wet granulation process.     

Comparison of Moisture-Activated Dry Granulation Profess with Conventional Granulation Methods for Sematilide Hydrochloride Tablets

During the development of a tablet formulation of a cohesive, fluffy investigational drug, a novel moisture-activated dry granulation (MADG) process was studied in comparison with two conventional granulation methods, i.e., wet granulation and dry granulation with a roller compactor, as well as with a direct compression formulation method. The MADG method produced granules with excellent flowability which were equivalent in a number of ways to those produced by either conventional wet granulation or dry granulation methods and which were much better than the powder blend from the direct compression formulation. The tablets prepared using the MADG method had better content uniformity than those made using material from wet and dry granulation processes. Other tablet properties, such as weight variation, friability and dissolution, were similar among the tablets produced by the four processes     

An Evaluation of Process Variables in wet Granulation

Abstract

In wet granulation, determining the process variables which play an essential role in granule quality is crucial for optimizing the manufacturing process. An L16(2⁵) fractional factorial experimental design using the table of orthogonal arrays was employed in order to estimate the relative intensity of the influences of five process variables on granule quality in wet granulation using a high-speed mixer granulator. Total volume and formulation of binder solution, blade rotation speed, granulation time, and amount of powder supplied into the granulator were selected as decisive process variables in the formation of granules. Granule yield, geometrical mean granule size and uniformity of granule size were evaluated as representative properties of granule quality. Experimental results were analyzed according to the analysis of variance (ANOVA).

The results of significance test and contribution ratio in ANOVA indicated that, within the experimental region, only binder solution had a critical effect on the three physical properties of the obtained granules. The effects of other variables were found to be minimal. Further, the contribution of sampling error to total variance was quite small.     

Carboxymethylstarches in Wet Granulation

Abstract

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Evaluation of the influence of granulation processing parameters on the granule properties and dissolution characteristics of a modified release drug

Understanding the relationship between high shear wet granulation processing parameters and the characteristics of intermediate and final products is crucial in the ability to apply quality by design (QbD) and process analytical technologies (PAT) to secondary pharmaceutical processes. This research examined a high shear wet granulation process and subsequent manufacturing of a tablet containing a biopharmaceutics classification system (BCS) class II drug, gliclazide (low solubility, high permeability). Previous studies have concentrated on either granulation or tabletting but not both together; this work brings together the analysis as a single large multivariate process. The design of experiment (DoE) was performed according to an L9 Taguchi method with three replications, in total; thirty-six runs were performed. A full statistical analysis relating both granule and tablet properties to selected process parameters were carried out. The research illustrates that mapping a highly multivariate process is possible. Statistically significant critical process parameters were identified for granule hardness, granule density and granule particle size. These granule properties were also identified as contributing to the dissolution release characteristics. Dissolution modeling and prediction was achieved within the DoE structure. Process noise was identified and measured across the entire production and specifically with respect to the milling process.     

Carboxymethylstarches in Wet Granulation

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Integrated Population Balance Model Development and Validation of a Granulation Process

This study is concerned with the development of an integrated three-dimensional population balance model (PBM) that describes the combined effect of key granulation mechanisms that occur during the course of a granulation process. Results demonstrate the importance of simulating the different mechanisms within a population balance model framework to elucidate realistic granulation dynamics. The incorporation of liquid addition in the model also aids in demarcating the dynamics in different regimes such as premixing, granulation (during liquid addition) and wet massing (after liquid addition). For the first time, the effect of primary particle size distributions and mode of binder addition on key granule properties was studied using an integrated PBM. Experimental data confirms the validity of the overall model as compared to traditional models in the literature that do not integrate the different granulation mechanisms.     

Twin screw granulation – review of current progress

Twin screw granulation (TSG) is a new process of interest to the pharmaceutical community that can continuously wet granulate powders, doing so at lower liquid concentrations and with better product consistency than found by a high shear batch mixer. A considerable body of research has evolved over the short time since this process was introduced but generally with little comparison of results. A certain degree of confidence has been developed through these studies related to how process variables and many attributes of machinery configuration will affect granulation but some major challenges still lay ahead related to scalability, variations in the processing regimes related to degree of channel fill and the impact of wetting and granulation of complex powder formulations. This review examines the current literature for wet granulation processes studied in twin screw extrusion machinery, summarizing the influences of operational and system parameters affecting granule properties as well as strives to provide some practical observations to newly interested users of the technique.     

Effects of manufacturing process variables on in vitro dissolution characteristics of extended-release tablets formulated with hydroxypropyl methylcellulose

The purpose of this study was to investigate the effect of three process variables: distribution of hydroxypropyl methylcellulose (HPMC) within the tablet matrix, amount of water for granulation, and tablet hardness on drug release from the hydrophilic matrix tablets. Tablets were made both by direct compression as well as wet granulation method. Three formulations were made by wet granulation, all three having the exact same composition but differing in intragranular:intergranular HPMC distribution in the matrix. Further, each formulation was made using two different amounts of water for granulation. All tablets were then compressed at two hardness levels. Dissolution studies were performed on all tablets using USP dissolution apparatus I (basket). The dissolution parameters obtained were statistically analyzed using a multilevel factorial-design approach to study the influence of the various process variables on drug release from the tablets. Results indicated that a change in the manufacturing process could yield significantly dissimilar dissolution profiles for the same formulation, especially at low-hardness level. Overgranulation could lead to tablets showing hardness-dependent drug-release characteristics. Studies showed that intergranular addition of a partial amount of HPMC (i.e., HPMC addition outside of granules) provided a significant advantage in making the formulation more robust over intragranular addition (i.e., that in which the entire amount of HPMC was added to the granules). Dissolution profiles obtained for these tablets were relatively less dependent on tablet hardness irrespective of the amount of water added during granulation.     

Alternative Granulation Technique: Melt Granulation

Abstract

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Alternative Granulation Technique: Melt Granulation

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.