Influence of Granulating Method on Physical and Mechanical Properties,Compression Behavior,and Compactibility of Lactose and Microcrystalline Cellulose Granules

The physical and mechanical properties of lactose (LC) and microcrystalline cellulose (MCC) granules prepared by various granulating methods were determined, and their effects on the compression and strength of the tablets were examined. From the force-displacement curve obtained in a crushing test on a single granule, all LC granules appeared brittle, and MCC granules were somewhat plastically deformable. Intergranular porosity ε_inter clearly decreased with greater spherical granule shape for both materials. Decrease in intragranular porosity ε_intra enhanced the crushing force of a single granule F_g. Agitating granulation brought about the most compactness and hardness of granules. In granule compression tests, the initial slope of Heckel plots K₁ appeared closely related to ease of filling voids in a granule bed by the slippage or rolling of granules. The reciprocal of the slope in the succeeding step 1/K₂ in compression of MCC granules indicated positive correlation to F_g, while in LC granules, no such obvious relation was evident. 1/K₂ differed only slightly among granulating methods. Tensile strength of tablets T_t obtained by compression of various LC granules was low as a whole and was little influenced by granulating method. For MCC granules, which are plastically deformable, tablet strength greatly depended on granulation. Granules prepared by extruding or dry granulation gave strong tablets. Tablets prepared from granules made by the agitating method showed particularly low T_t. From stereomicroscopic observation, the contact area between granule particles in a tablet appeared smaller; this would explain the decrease in intergranular bond formation.     

Evaluation of Binder Activities on the Physical Properties and Compression Characteristics of Granules Prepared by Two Different Modes

Abstract

The effects of various binders and binder concentrations in production of granules by two different granulation modes were first investigated on the basis of the granule size distribution. Increasing the amount of binder produced larger and less friable granules associated with a decrease in flow rate and an increase in angle of repose. The strength of granules prepared by either the wet conventional or the fluidized bed was a function of its mean particle diameter and of binder-content with the later factor being more predominant. The inclusion of paracetamol into the placebo formula decreased the granule crushing strength. The effect was more pronounced with smaller granules and decreased with increasing granule size.

The rank order of the paracetamol-PVP granules crushing strength was reversed for the tensile strength of their corresponding tablets, viz., the paracetamol-PVP tablets prepared from fluidized granulation exhibited a higher tensile strength than that compressed from wet granules. A new parameter index “ø_b index” which combines tablet characteristics is presented. The index proposed allowed an overall simpler quantitative evaluation of a binder activity. Incorporated into this index are four tablet parameters, viz., tensile strength, percent porosity, median dissolution time, and percent friability. A higher “ø_b, index” infers better physical properties of tablets. Binders used in this study are then classified according to this index: PVP > gelatin > PEG 6000.     

The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.     

The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.     

Process Considerations in Reducing Tablet Friability and Their Effect on in vitro Dissolution

The tablet friability resulting from manufacturing process variations was studied for two differently sized tablets using the same formulation. Granulations containing lower moisture contents required higher compression and ejection forces to manufacture a tablet at a given hardness, although this did not influence friability. Increased tablet hardness (and to a lesser extent decreased tablet thickness) decreased the tablet friability of the larger tablet. An increase in the quantity of granulating fluid increased the granulation particle size and slightly improved compactibility without significantly affecting friability. Tablet dissolution increased as the quantity of granulating fluid was decreased. There was a strong interaction, with respect to dissolution, between moisture content and the amount of granulating fluid. Tablet hardness did not significantly influence dissolution. Doubling the quantity of magnesium stearate in the granulation in one tablet strength decreased the maximum tablet hardness that could be obtained, and for the other tablet strength increased friability. It also resulted in slower tablet dissolution.     

Extrusion granulation and high shear granulation of different grades of lactose and highly dosed drugs: a comparative study

Formulations containing different lactose grades, paracetamol, and cimetidine were granulated by extrusion granulation and high shear granulation. Granules were evaluated for yield, friability, and compressibility. Tablets were prepared from those granules and evaluated for tensile strength, friability, disintegration time, and dissolution. The different lactose grades had an important effect on the extrusion granulation process. Particle size and morphology affected powder feeding and power consumption, but had only a minor influence on the granule and tablet properties obtained by extrusion granulation. In contrast, the lactose grades had a major influence on the granule properties obtained by high shear granulation. Addition of polyvinylpyrrolidone (PVP) was required to process pure paracetamol and cimetidine by high shear granulation, whereas it was feasible to granulate these drugs without PVP by extrusion granulation. Granules prepared by extrusion granulation exhibited a higher yield and a lower friability than those produced by high shear granulation. Paracetamol and cimetidine tablets compressed from granules prepared by extrusion granulation showed a higher tensile strength, lower friability, and lower disintegration time than those prepared from granules produced by high shear granulation. Paracetamol tablets obtained via extrusion granulation exhibited faster dissolution than those obtained via high shear granulation. For all lactose grades studied, extrusion granulation resulted in superior granule and tablet properties in comparison with those obtained by high shear granulation. These results indicate that extrusion granulation is more efficient than high shear granulation.     

The Effect of Lubricants on the Properties of Chloroquine Phosphate Tablets

Abstract

The properties of tablets prepared from different size fractions of chloroquine phosphate granules using different lubricants were evaluated. Lubricants used were magnesium stearate, stearic acid and talc, tablet properties studied include weight variation, crushing strength, friability and disintegration time

The effects obtained were largely dependent on the type and concentration of lubricant. Generally, as granule size increased, tablets were found to show increased weight variation, decreased hardness and increased friability. With tablets containing talc as lubricant, disintegration time was shown to decrease with increase in granule size.

There appears to be an optimum lubricant concentration for the compression of different granule size fractions.     

Tensile strength and bonding in compacts: a comparison of diametral compression and three-point bending for plastically deforming materials

The tensile strength of tablets is frequently used as a measure of the bonding achieved during compaction. Tablets from two plastically deforming materials and one brittle material have been subjected to tensile strength testing using diametral compression and three-point bending. The plastically deforming materials exhibited marked inhomogeneities, with the surfaces of the tablets considerably more compact than the inner material. The results from the two tests were different, with the three-point bending test giving higher results for tensile strength. The rate of change of tensile strength with overall tablet porosity was, however, the same for the two tests. Diametral compression would thus appear to give a reasonable estimate of bonding despite the non-homogenous nature of tablets prepared from plastically deforming materials.     

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.     

Optimization of Tablet Friability,Maximum Attainable Crushing Strength,Weight Variation and In Vitro Dissolution by Establishing In-Process Variable Controls

Abstract

The level of intragranular microcrystalline cellulose, volume of granulating water, granulation moisture content and tablet crushing strength were used as in-process variables for optimizing tablet friability, maximum attainable crushing strength, weight variation and in vitro dissolution. A computer optimized experimental design (COED) allowed optimal characterization of the variables by designing 22 experiments. The results were analyzed by means of a general quadratic response surface model. Response surfaces were generated for tablet friability, maximum attainable crushing strength, weight variation and in vitro dissolution as a function of the in-process variables. The study provided a useful method in setting optimum ranges for the in-process variables in order to optimize the important tablet parameters.     

Polymorphic Changes of Thiamine Hydrochloride During Granulation and Tableting

Thiamine hydrochloride was granulated using an instrumented fluidized bed granulator (Hüttlin HKC 05-TJ). Granules consisting of pure thiamine hydrochloride were produced using an aqueous solution of thiamine hydrochloride as the granulating liquid. The effects of process variables such as inlet air temperature, spray rate, and amount of granulating liquid on granule properties are described. Particle size distributions of granules depended mainly on the amount of granulating liquid sprayed into the powder bed. Granules were tableted on a rotary tablet press at four different compression forces. Crushing strengths and disintegration times of all tablets were found to be very low after manufacture, but increased considerably after 4 months of storage at room temperature. Granular materials showed “caking” under the same storage conditions. These changes could be attributed to alterations of the polymorphic form of thiamine hydrochloride. The water-free form, being present directly after granulation, absorbs humidity very fast and is transformed into the monohydrate, which is stable at room temperature. Loss of water takes place during the drying phase of the granulation process and on storage of the substance at temperatures of 50°C and 80°C. During storage at room temperature while exposed to humidity, a transformation into the hemihydrate was observed. This polymorph is transformed during thermal analysis at about 190°C to a water-free form that is stable at higher temperatures.     

Polymorphic changes of thiamine hydrochloride during granulation and tableting

Thiamine hydrochloride was granulated using an instrumented fluidized bed granulator (Hüttlin HKC 05-TJ). Granules consisting of pure thiamine hydrochloride were produced using an aqueous solution of thiamine hydrochloride as the granulating liquid. The effects of process variables such as inlet air temperature, spray rate, and amount of granulating liquid on granule properties are described. Particle size distributions of granules depended mainly on the amount of granulating liquid sprayed into the powder bed. Granules were tableted on a rotary tablet press at four different compression forces. Crushing strengths and disintegration times of all tablets were found to be very low after manufacture, but increased considerably after 4 months of storage at room temperature. Granular materials showed "caking" under the same storage conditions. These changes could be attributed to alterations of the polymorphic form of thiamine hydrochloride. The water-free form, being present directly after granulation, absorbs humidity very fast and is transformed into the monohydrate, which is stable at room temperature. Loss of water takes place during the drying phase of the granulation process and on storage of the substance at temperatures of 50 degrees C and 80 degrees C. During storage at room temperature while exposed to humidity, a transformation into the hemihydrate was observed. This polymorph is transformed during thermal analysis at about 190 degrees C to a water-free form that is stable at higher temperatures.     

Physical Properties of Granules Containing Polysorbate 80

Abstract

The friability and crushing load of granules containing polysorbate 80 were determined. It was found that while polysorbate 80 decreased granule hardness, as indicated by the load required to crush it, friability values increased to a maximum then decreasing at higher polysorbate 80 concentration. Thus the use of granule friability to measure granule strength may be erroneous unless good correlation between granule friability and direct crushing weight was obtained.

Direct measurement of granule strength tends to vary with granule shape and size giving a rather wide scatter of results. For overcoming this difficulty, tablet triturates could be prepared and the crushing strength determined. The crushing strength of the tablet triturates was found to be similar to that of granules but with a smaller scatter and more easily handled.

Studies of other physical properties of the granules containing polysorbate 80 were also made. Small amounts of the nonionic surfactant (0.002 - 0.2%) generally improved granule fluidity as characterised by the orifice flow velocity and the angle of repose of the granules.     

Effect of fill level in continuous twin-screw granulator: A combined experimental and simulation study

Twin-screw granulators for continuous wet granulation have attracted interest in the pharmaceutical industry. The physical properties of granules and tablets prepared through the twin granulation process depend on several factors, such as screw and barrel geometries, operating conditions, and formulations of raw materials. The fill level has been reported to be one of the most important factors in determining granule properties. However, the mechanism of the fill level effect on granule properties has not yet been fully clarified. In this study, the effects of the fill level in the twin-screw granulator on granule and tablet properties were investigated through a combination of experimental and simulation studies. In the experiment, temporal changes in the fill level were directly measured. It was found that a high fill level increased granule strength, resulting in large tablet hardness. The discrete element method simulations demonstrated that the compressive force on the particles in the granulator strongly depends on the fill level. In addition, by combining the experimental and simulation results, it was quantitatively revealed that a high fill level increased the interparticle adhesion, leading to the high hardness of tablets prepared with the granules.     

Aluminium-Magnesium Hydroxide Tablets: Effect of Processing and Composition of Granulating Solution on the Granule Properties and In Vitro Antacid Performance

Abstract

Wet granulation experiments on aluminium-; magnesium hydroxide; mannitol blends were carried out, in order to produce chewable antacid tablets.

The influence of binder solvent, of type and concentration of polyvinylpyrrolidone as a binder and of granulating and drying equipment on the granule and tablet characteristics was investigated.

Water as a binder solvent offered several advantages over the use of alcohol. The use of high molecular weight polyvinylpyrrolidone reduced the antacid capacity and caused some manufacturing problems.

The granulating equipment (high shear granulator or planetary mixer) and the drying technique (oven or fluidized bed) had no major influence on the granule and tablet characteristics.     

Optimization and evaluation of time-dependent tablets comprising an immediate and sustained release profile using artificial neural network

The aim of this work was to optimize time-dependent tablets using artificial neural network (ANN). The time-dependent tablet consisted of a tablet core, which contained sustained release pellets (70% isosorbide-5-mononitrate [5-ISMN]), immediate release granules (30% 5-ISMN), superdisintegrating agent (sodium carboxymethylstarch, CMS-Na), and other excipients, surrounded by a coating layer composed of a water-insoluble ethylcellulose and a water-soluble channeling agent. The chosen independent variables, i.e., X₁ coating level of tablets, X₂ coating level of pellets, and X₃ CMS-Na level, were optimized with a three-factor, three-level Box-Behnken design. Data were analyzed for modeling and optimizing the release profile using ANN. Response surface plots were used to relate the dependent and the independent variables. The optimized values for the factors X₁-X₃ were 4.1, 14.1, and 29.8%, respectively. Optimized formulations were prepared according to the factor combinations dictated by ANN. In each case, the observed drug release data of the optimized formulations were close to the predicted release pattern. An in vitro model for predicting the effect of food on release behavior of optimized products was used in this study. It was concluded that neural network technique could be particularly suitable in the pharmaceutical technology of time-dependent dosage forms where systems were complex and nonlinear relationships often existed between the independent and the dependent variables.     

Determination of precompression and compression force levels to minimize tablet friability using simplex

Pilot simplex experiments for improving the tablet strength of three aspirin tablet formulations based on precompression and compression forces were presented. As each simplex moved towards the direction of the optimum, the friability was being minimized and the crushing strength was concomittantly being maximized. Because it followed a systematic direction, simplex process would locate a local optimum rapidly. The appropriate levels of precompression and compression forces that produced tablets with the desired strength were attained in five trials. By contrast, random search for this force combination required at least ten trials. Simplex technique is a cost and time effective means for determining the precompression and compression forces that will reduce the friability or increase the hardness of a tablet formulation. Results appeared to also indicate that crushing strength might be a more reliable measure of tablet strength than friability.     

Role of continuous moisture profile monitoring by inline NIR spectroscopy during fluid bed granulation of an Enalapril formulation

Background: Granulation and tableting are closely related process steps in the supply chain of pharmaceutical products. Even today, these steps are still optimized independently by trial and error. On the framework of a process analytical technology approach, these processes were evaluated in an integrated approach. Enalapril maleate is a low-dose drug substance with poor granulating and tableting behavior. In order to verify how granulation influences tableting properties, different granulation experiments were performed. Methods: Granulation experiments with fast spraying rate and fast drying as well as fast spraying rate and slow drying, and also combinations of both were run. The obtained granules were then promptly compressed into tablets in a rotary press and subjected to hardness testing. The progress of spraying and drying was controlled by a continuous near-infrared spectroscopic measuring setup. This study confirms that the tablet characteristics. Result/Conclusion: after compression of the granules in comparison to placebo granules are dependent not only on the residual moisture content of the granules but also on the moisture profiles during the entire fluid bed granulation process.     

Determination of precompression and compression force levels to minimize tablet friability using simplex

Abstract

Pilot simplex experiments for improving the tablet strength of three aspirin tablet formulations based on precompression and compression forces were presented. As each simplex moved towards the direction of the optimum, the friability was being minimized and the crushing strength was concomittantly being maximized. Because it followed a systematic direction, simplex process would locate a local optimum rapidly. The appropriate levels of precompression and compression forces that produced tablets with the desired strength were attained in five trials. By contrast, random search for this force combination required at least ten trials. Simplex technique is a cost and time effective means for determining the precompression and compression forces that will reduce the friability or increase the hardness of a tablet formulation. Results appeared to also indicate that crushing strength might be a more reliable measure of tablet strength than friability.     

High shear wet granulation: Improved understanding of the effects of process variables on granule and tablet properties of a high-dose,high-hydrophobicity API based on quality by design and multivariate analysis approaches

High shear wet granulation (HSWG), as a widely used granulation technology, has been studied extensively. However, for the HSWG of formulations containing hydrophobic components, the influence of process variables on the properties of granules and tablets has not been reported. In the present study, based on a combination of quality by design and multivariate analysis (MVA) approaches, quercetin with high-dose and high-hydrophobicity was used to study the relationship between process variables, granule properties, and tablet properties in HSWG systematically. Control and response variables were determined using risk assessment. The optimal fitting empirical models established by Box-Behnken design showed that the liquid to solid ratio and impeller speed were the most important factors, which affected all product properties except Carr’s index and yield pressure. Instead, the influence of wet massing time was relatively small (only the effects on yield, granule size, granule hardness, and compression ratio were significant). Then, the process design space was obtained by limiting the related critical quality attributes, which was verified effectively. Scanning electron microscope images showed that smooth granules were produced using higher process parameters, whereas rough and porous granules resulted at lower process parameters. Furthermore, the MVA results demonstrated that increasing the granule hardness led to an increase in the compression ratio and a decrease in tensile strength of the tablets. Tablet fragility and disintegration time were mainly affected by granule density and bulk density, respectively, and both were negatively correlated. The established research paradigm is not only conducive to the successful development of quercetin products, but also provides valuable guidance for improving HSWG–based product development with such formulation characteristics.