This document defines granules and describes reasons for preparing them, including avoiding powder segregation and improving flow and compressibility. It discusses uses of granules as pharmaceutical dosage forms or intermediates. Methods of granulation include wet and dry processes. Wet granulation involves mixing powder with a liquid to form granules, then drying and sieving them. Selection of the granulating liquid depends on properties of the powder and desired granule characteristics. Dry granulation uses compaction and milling to form irregular granules with slower dissolution. Wet granulation is preferred to produce porous granules that dissolve more readily.
This document defines granules and describes reasons for preparing them, including avoiding powder segregation and improving flow and compressibility. It discusses uses of granules as pharmaceutical dosage forms or intermediates. Methods of granulation include wet and dry processes. Wet granulation involves mixing powder with a liquid to form granules, then drying and sieving them. Selection of the granulating liquid depends on properties of the powder and desired granule characteristics. Dry granulation uses compaction and milling to form irregular granules with slower dissolution. Wet granulation is preferred to produce porous granules that dissolve more readily.
This document defines granules and describes reasons for preparing them, including avoiding powder segregation and improving flow and compressibility. It discusses uses of granules as pharmaceutical dosage forms or intermediates. Methods of granulation include wet and dry processes. Wet granulation involves mixing powder with a liquid to form granules, then drying and sieving them. Selection of the granulating liquid depends on properties of the powder and desired granule characteristics. Dry granulation uses compaction and milling to form irregular granules with slower dissolution. Wet granulation is preferred to produce porous granules that dissolve more readily.
Aggregates of fine particles of powder in a mass approximately spherical
in shape Reasons to prepare granules To avoid powder segregation If the powder is composed of particles with different dimensions and densities, separation between these particles will occur To improve powder flow Higher flowability results in better filling of dies or containers during volumetric dose filling Improve the compressibility of powders Granules have higher porosity than powders allowing for better compaction Reasons to prepare granules Reduction of toxic dusts: Granulation of toxic powdered materials will reduce the hazard of generation of toxic dust, which may arise during their handling Prevention of agglomeration and adhesion problems Materials that are slightly hygroscopic may adhere and form a cake if stored as a powder Modification of drug release Uses of granules Granules can be used pharmaceutically as: Individual proper pharmaceutical dosage form Semi-finished product for the preparation of tablets or other dosage forms (granules have excellent compressibility) Uses of granules As a proper pharmaceutical dosage form Example: granules used to prepare solutions or suspensions This type can be packaged as: (examples) Bulk granules (multi-dosage containers) Divided granules (single-dosage containers) Granulation methods Small-scale: In the lab example Industrial preparation of granules: Wet granulation Dry granulation Crystallization Rarely used Depends the presence of water of crystallization in the active material Dry granulation Powders that were mixed homogeneously are compacted into large tablets or sheets then milled and sieved High compression forces are obtained using: Special tableting machines Roller compaction These methods will be discussed in details in your future industrial pharmacy course Dry granulation Tableting machines (special) In this method, powders that were mixed homogeneously are compressed to obtain large tablets These machines are provided with large dies of diameter 2-3 cm (this will allow better filling as fine powders have low flowability) The die content is compressed using 2 punches forming large tablets of 2-3 cm in length The tablets are then milled and sieved Dry granulation Roller compaction: The powder mixture flows between two rollers to form a compressed sheets The sheets are then milled and sieved Dry granulation Sieving: The sieving process gives three fractions of granules: Very coarse: can be subjected to repeated milling Very fine: can be granulated again A fraction with optimal dimensions for subsequent manufacturing steps Dry granulation Dry granulation methods produce granules with: Irregular shapes Slow dissolution rates due to the high compression force used to compact the powders Poor dissolution: The resulting granules are poorly permeable to water due to low porosity (water cannot permeate them easily in order for disintegration and dissolution to occur) Can have substantial effect in the reduction of in vivo dissolution and bioavailability Dry granulation Dry granulation issues (contd): If the granules are highly porous, water can penetrate easily into the pores and disintegrate the granules Higher porosity and high specific surface area increase the dissolution rate and higher bioavailability Dry granulation is only used for powders which cannot be granulated with wet granulation Wet granulation The most commonly used method to prepare granules The main disadvantage of this method is the number of steps present in this process compared with the other methods Wet granulation Steps: Wetting of the powder with a liquid or solution to form a paste (wet massing) Formation of granules starting from the paste Drying Sieving and separation Wet granulation Wetting of the powder with a liquid or solution to form a paste Characteristics of the granulating liquid: Should have all required characteristics of pharmaceutical excipient (purity, safety, etc) Should be a mild solvent for the powder in question (if the powder is soluble in the solvent, a solution or suspension will be obtained instead of a wet mass) Wet granulation Characteristics of the granulating liquid (contd): If the solvent cannot dissolve the powder, sufficient cohesion between the particles forming the granules will not be obtained Dissolved particles can re-crystallize again forming solid bridges between the undissolved particles after drying Granule formation When two particles become in contact with each other, they interact with each others: Forces of electrostatic nature (week in nature) Forces of adhesive natures (most important) If these forces are sufficiently strong, the particles remain attached to each others forming granules The liquid used in the wet granulation must be mild solvent for the powder Granule formation Granule formation Steps in granule formation: At low moisture levels, the particles are held together by lens-shaped rings of liquid (pendular state) These cause adhesion because of the surface tension forces of the liquid/air interface and the hydrostatic suction pressure in the liquid bridge When all the air has been displaced from the space between the particles the capillary state is reached, and the particles are held by capillary suction at the liquid/air interface, which is now only at the granule surface Granule formation Steps in granule formation: The funicular state represents an intermediate stage between the pendular and capillary states Moist granule tensile strength increases about three times between the pendular and the capillary state Granule formation Steps in granule formation: It may appear that the state of the powder bed is dependent upon the total moisture content of the wetted powders, but the capillary state may also be reached by decreasing the separation of the particles In the massing process during wet granulation, continued kneading/mixing of material originally in the pendular state will condense the wet mass, decreasing the pore volume occupied by air and eventually producing the funicular or capillary state without further liquid addition Granule formation Steps in granule formation: The suspension state: Important in the process of granulation by spray drying of a suspension In this state, the strength of the droplet is dependent upon the surface tension of the liquid used Wet granulation: solvents The most used solvents in wet granulation: Water Ethanol Isopropanol Others Wet granulation: solvents Considerations: Few solvents are suitable for pharmaceutical granulation We cannot totally eliminate the solvent If traces of the solvent remain in the formula at the end of the manufacturing, these traces must be nontoxic Wet granulation: solvents Water: If we want to use water for granulation, the powder must be: Partially soluble in the water Compatible with water Wet granulation: solvents If water cannot be used for some reason, another liquid is used such as: Aqueous solutions (e.g., syrup) Co-solvents Aqueous polymeric solutions Wet granulation: solvents Simple syrup Syrup has lower dissolving capacity than the pure water The majority of water molecules are involved in the hydrating and dissolving sugar molecules instead of powder molecules Wet granulation: solvents Co-solvent system: If the powder is water insoluble A mixture between water and another water-soluble solvent with high dissolving capacity toward the powder Wet granulation: solvents Aqueous solutions of polymers Upon the evaporation of water, these polymers can increase the adhesion between the particles of the powder Wet granulation: solvents Polymeric solutions that can be used in wet granulation include: Gelatin solution, 5 -10% Such viscous solutions increase the adhesion of the particles of the powders When water evaporates, gelatin solidifies between the two particles of powder and maintains them glued together Starch paste, 5 -10% Pre-gelatinized starch, which has the characteristic to swell in a cold water
Semi-synthetic polymers like MC and CMC
Synthetic polymers like PVP (polyvinly pyrrolidone) Wet granulation: solvents Some of these polymeric materials can be used in organic solvent (e.g., ethanol) as a granulation fluid Useful in case of thermo-sensitive compounds Reduce the cost of production Granules obtained using this method (polymeric solutions) are called agglutinated granules Granulation The second step is the granulation or the formation of granules starting from the paste (wet mass) To achieve this, several granulators are available (see industrial pharmacy): Rotatory granulator Oscillating granulator High speed mixer-granulator Fluidized bed granulator Freund granulator Roller compaction granulator Granulation The quality of the granules depends on the: Granulating solvent Type of granulator Nature of the powder Granulation endpoint On a lab scale, the granulation endpoint is identified when the resulting wet mass does not slip between the fingers of the hand (i.e., it should remain aggregated but easily crumbled) Very broad reference point Modern granulating equipment can provide qualitative and quantitative evaluation of the process Granulation endpoint One way is to measure the energy consumption of the granulating machine. The powder is placed in the granulator The granulating liquid is gradually added The contents are mixed using electrical motor This motor measures the absorbed power as a function of time and as a function of the quantity of added liquid A plot of the absorbed power vs. the percentage of the added liquid is constructed Granulation endpoint Granulation endpoint How is the appropriate volume of granulating liquid required for granulation is estimated? By measuring the absorbed power (in real time) during the addition of the granulating liquid The increase in the required power is related to the increase of the viscosity of the wet mass, due to the formation of the liquid bridges (adhesive and viscous types) Generally, most modern granulation equipment are able to generate the power consumption plot Granulation endpoint Interpretation of the plot: Initially, the addition of the granulating liquid does not produce a significant change in the absorbed power At point II, increasing quantity of the granulating liquid increases the absorbed power Granulation endpoint Interpretation of the plot: At this point (II), the following type of interactions are formed: Electrostatic interactions (less important) Liquid bridging between particles (important) These forces bind the powder particles together to form the granules The granulating equipment requires higher power to maintain constant the number of rounds/minute Granulation endpoint Interpretation of the plot: With continued addition of the liquid, the absorbed power become constant on a certain value (between points (III) and (IV) on the plot) At this point, optimal adhesion between the particles is achieved The shape of the resulting plot depends on the type of the granulating equipment Granulation endpoint Interpretation of the plot: After point (IV), a sharp drop in the absorbed power is observed This occurs because the wet mass become a suspension with increasing amount of liquid The plot provides information on the appropriate quantity of the liquid required for granulation Granulation endpoint The plot can also subdivide the granulators in: Slow granulator (low-shear, e.g., fluidized-bed granulator and dryer) Speed granulators (high-shear, e.g., plates and rotate granulators) See industrial pharmacy Drying of granules The last step in granulation is the evaporation of the granulation liquid Water is more difficult to dry compared to organic solvents: If the powder is thermosensitive, heating for long period can affect the stability of the drug The energy consumption is higher than the organic solvents Slower Drying Three forms of water in the granulated mass: Water of crystallization: very difficult to remove without causing the decomposition of the product or changing its crystalline form Adsorbed water: water that is absorbed by the powder from moist air, depends on the nature of the drug and the relative humidity of the air Imbibed water: water which impregnates the granules, this water is easily removed by simple evaporation Drying Depending on the dryer, imbibed water and a part of adsorbed water can be removed Total removal of adsorbed water is not recommended: May create electrostatic charges leading to electrostatic interaction between granules, and with the walls of the equipment, these charged granules are difficult to handle Drying Total removal of adsorbed water (contd): If a hydrophilic polymer solution is used n the granulation, the hydrophilic polymer may assume a glassy consistency These glassy characteristics cause the fragmentation of granules during subsequent manufacturing steps A defined quantity of moisture is useful to improve the manipulation of the granules Dryers The dryers include (see industrial pharmacy): Static oven Rotary dryer Fluidized-bed dryer Vacuum oven Microwave dryer Spray dryer Rotary atomizer IR dryer Sieving and classification The last step in granulation: Coarse granules Fine granules Granules with the optimal size Sieving and classification Granule size: Large granules require large measuring tools, small granules can be measured using small measuring tools Granules should have uniform size, and a size range compatible with the diameter of the die Sieving and classification Granule size The granules should be finer as the die becomes smaller There are well-defined correlations between the size of the granules and the diameter of the die to obtain uniform filling of the die to produce tablets that remain within the limits of the weight uniformity tests Sieving and classification Example: A die with diameter of 3/16 of inch, requires granules which pass through a sieve with mesh no. 20 A die with diameters of 7/16 inch, requires granules that pass through a sieve of mesh no. 12 Quality control of granules Weight uniformity test Dissolution profile Friability test Granules should be: Packaged in order to be used as final pharmaceutical dosage form Added to other substances to prepare other dosage forms such as tablets The transformation of the granules back into powder should be avoided during granule manipulation processes QC
Friability Tester Miscellaneous Some special function granules: Sustained release granules Enteric coated granules Effervescent granules