Granules

1. Granules Presented By: Dr. Abdel NaserZaid

2. Granules are aggregations of fine particles of powders in a mass of about spherical shape.

3. Why we prepare granules when we have powders? • To avoid powder segregation, if the powder is composed of particles with different dimensions & different densities, a separation between these particles will occur. • To enhance the flow of powder, Higher flowability gives better filling of the dies or containers, during a volumetric dosage.

4. Granules have higher porosity than powders, To improve the compressibility of powders. The granulation of toxic materials will reduce the hazard of generation of toxic dust, which may arise during the handling of the powders. Materials, which are slightly hygroscope, may adhere & form a cake if stored as a powder.

5. Technologically, granules are used according to two visions: • As a true & proper pharmaceutical dosage form form, These granules are used to prepare an instant solution or suspension. Granules, can be packaged as: • Bulk granules (Multi-dosage containers), • Divided granules (Mono-dosage containers ).

6. Semi-finished products for the preparation of tablets or other dosage forms. Usually, granules have an excellent compressibility,

7. Methods of Granulation • Some of the available methods in the industrial field for the preparation of granules: • Wet Granulation. • Dry granulation methods. • Granulation by Crystallization. • Granulation by Crystallization. • This method exploits the presence of crystallization water in the active material; this method is rarely used.

8. Dry Granulation. Pharmaceutical powders that were mixed homogeneously together are compressed to obtain large tablets. The high compression forces are obtained by using one of the following procedures: • Tabling machines (see industrial pharmacy). These machines are provided with dies of 2-3 cm diameters (the fine powders have low flowability) So, large dies are easily filled in this case, the dies travel between two punches, which press the powder forming large tablets, with 2-3 cm of diameters.

9. Roller compaction (see industrial pharmacy). The powder mixture flow between two rollers to form a compressed sheet. These large tablets or sheets are milled. The milled sheets are sieved.

10. The sieving process gives three fractions of granules : • Very coarse granules, which return back to the milling process. • Very fine fraction, which return back to the compaction. • Fraction with optimal dimensions for following manufacturing steps.

11. This system produces granules with: • irregular shape, • low rate of dissolution due to the high compression force used to aggregate the powders. These granules are poorly water-permeable due to the low porosity. So, water can’t permeate them easily in order to disintegrate & dissolve them. This will extremely reduce the velocity of dissolution & so the bioavailability of the active material.

12. Vice versa if the granules have high porosity the molecules of water can penetrate easily into the pores, & disintegrate the granules. High Porosity means high specific surface area, leading to an increasing in the dissolution velocity of the granules, & thus their bioavailability. Thus, we can say that the dry granulation method is used only for those powders, which cannot be granulated with the wet granulation method.

13. Wet Granulation • This is the most used method to prepare granules. • The main disadvantage of this method is the higher number of steps present in this process when compared with the other two methods.

14. Steps of Wet Granulation: • The 1st step is the wetting of the powder with a liquid or solution to form a paste. Characteristics of the granulating liquid: • It should have all required characteristics of pharmaceutical excipient, & • It should dissolve the powder only within a certain limit (mild solvent): If the powder is soluble in the solvent, a solution or suspension will be obtained instead of the paste.

15. From another side, if the solvent cannot absolutely dissolve the powder, we cannot obtain the liquid forces, which stick together the powder particles. The fraction of powder, which dissolves in the solvent, & then re-crystallizes, after the drying, will form bridges between the particles of the powder.

16. When two particles become in contact between each other by certain forces, they institute: • forces of electrostatic nature (week forces) & • forces of viscous or/and adhesive natures (which are the most important) so the particles remain attached to each others. • Thus the used liquid in the wet granulation must be mild solvent for the powder.

18. There is a few number of solvents available for pharmaceutical granulation. • This is because we can’t totally eliminate the solvent, so if traces of the solvent remain in the formula at the end of the manufacturing, these traces must be non toxic for the patient.

19. The most used solvents in wet granulation : • Water. • Ethanol. • Isopropanol. • If we want to use water for granulation, the powder must be: • fairly or discreetly soluble in the water, & • compatible with it. • If the powder is very soluble in water, we can use another liquid or the following arrangements: • Water Solutions.

20. Simple Syrup This syrup has less dissolving capacity than the pure water, because the majority of water molecules are involved in the hydration & dissolving of the sugar molecules instead of the powder molecules. But if the powder is water insoluble, A co-solvent is recommended. This is a mixture between water & another water-soluble pharmaceutical solvent with high dissolving capacity toward the powder. We can also use a water solution of polymers, The evaporation of water can determine the adhesion between the particles of the powder.

21. Polymers solutions that can be used in the wet granulation: • Gelatin solution at 5-10%. Such viscose solutions determine the adhesion of the particles of the powders, When water evaporates the gelatin solidifies between the two particles of powder and maintain them stuck together. • Starch past 5 -10%. Pre-gelatinized starch, which has the characteristic to swell in a cold water. • Semi-synthetic polymers like CMC, MC. • Synthetic polymers like P.V.P.

22. Some of these compounds can be used in organic solvent like ethanol, • This is useful in case of thermo-sensitive compounds, & • To reduce the cost of production. The granules obtained in this way are called agglutinated granules.

23. The 2nd step is the granulation or the formation of granules starting from the paste. To achieve this, many granulators are available (see industrial pharmacy): • Rotative granulator, • Oscillating granulator, • High speed mixer granulator, • Fluidized bed granulator, • Freund granulator, • Roller compaction granulator.

24. The quality of the granules depends on the: • Granulation solvent, • Type of granulator, • Powder nature. • The paste that we have to obtain mustn’t drains between the fingers of the hand, which means that must remain aggregated & easily crumbled. • This is a very coarse reference, but nowadays there is the possibility to have a qualitative evaluation.

25. we can measure the energy that we must provide to the system in which we carry out the wetting process. How? Put the powder for granulation in the granulator, Add gradually the granulating liquid, Then mix by the use of electrical motor This motor measures the absorbed power in function of the time & so in function of the putted liquid.

26. How can we calculate the exact volume of granulating liquid for powder kneading? • We can evaluate the liquid quantity for the kneading process by measuring continuously the absorbed power during the addition of the granulating liquid. • The increase in the required power is connected with the increase of the viscosity of the dough mass, due to the formation of the liquid bonds (adhesive & viscous types). • Generally, all instruments are able to form a curve, as in the following figure:

28. Perform the curve by putting the absorbed power in Y- axis, & the volume of the granulating liquid in X- axis. • Interpretation of the obtained curve: • Initially, the addition of the granulating liquid doesn’t produce a significant change in the absorbed power, • At point 2 we fined that any added quantity of the granulating liquid, increases proportionally the absorbed power.

29. At this point we have initial formation of: Electrostatic bonds (less important), Liquid bonds (more important). These bonds start to bind together the powder particles & to form the granules. Therefore the equipment meet higher resistance to maintain constant the number of rounds/minute.

30. Then continuing in the liquid addition, we note that the absorbed power will be stabilized on a certain value (interval between 3-4), this means that the system was reached an equilibrium state. • At points 3-4, we have an excellent adhesion between the various particles of powder & • The granule shape depends on the type of the used granulator.

31. The addition of further liquid, will give phase 5 where we note a sharp drop in the absorbed power, because the granulate will be transformed in a suspension. In this manner we have an idea about the percentage quantity of the granulating liquid, which we have to add, by evaluating the curve.

32. This curve can subdivide the granulators in: • Slow granulator (fluidized bed granulator and dryer). • Speed granulators (e.g. plates and rotate granulators…etc, see industrial pharmacy). • The 3rd step is the Drying Process. Water is more difficult to be eliminated than the organic solvents, therefore the water gives some problems: • When the powder is thermosensitive the heating for long period of time can alter the stability of the powder, • The consumption of energy is higher than the organic solvents.

33. We have three kinds of water in the granulate mass: Water of Crystallization, It is very difficult to be eliminated without causing the decomposition of the product or variation of its crystalline form. Adsorped water, The amount of water, which was absorbed by a drug present in a moist air, this amount depends on the nature of the drug & the relative humidity of the air. Imbibition of water, The amount of water, which impregnates the granules, this water is easy to be eliminated by simple evaporation.

34. According to the used dryer, we can eliminate the total amount of imbibition’s water & a portion of the adsorpted water. • The elimination of the total amount of the adsorbed water is not advisable. • For example the elimination of the total amount of the adsorbed water, may create electrostatic charges, • This lead to the attraction or repulsion of the granules between themselves & the walls of the equipment, • This type of granules are very difficult to be managed.

35. If we use a hydrophilic polymer solution, as a granulating liquid, & we proceed for long time in the drying process, the hydrophilic polymer will assume a glassy consistency. These glassy characteristics cause the fragmentation of the granules during the following manufacturing processes. Thus, a certain quantity of moisture is useful to improve the manipulation of the granules.

36. The dryers are (see industrial pharmacy): Static Oven, Rotary Drier, Fluidized Bed Drier, Vacuum Oven, Microwave Drier, Spray Drier, Rotary Atomizer, I.R Drier.

37. The 4th step is the Classification of the granules. The last step is the classification according to particles dimension: • Coarse granules, which must be milled, • Fine granules, which must be re-granulated. • Optimum granules with optimum dimensions, which are ready for use.

38. We have two problems correlated to the size of granules: • Concerning the filling of big volume (i.e. sachets or bottles). If we have big granules we can use big measuring tool, while if the granules have small size, we can use small measuring tool. The most critical problem is : • when we must to fill the die of the tableting machine in order to prepare the tablet. In this case: it is not only important to have granules with equal dimensions, but it is also important that the size of these granules are within a certain range, which is in function with the diameter of the die.

39. The essential concept when producing tablets, is that the granules which we want to fill the die with, must be more fine as the die becomes smaller. • In fact there are well-defined relations between the size of the granules & the diameters of the die, in order to have a filling uniformity of the die, & so to obtain tablets, which remain within the limits of the weight uniformity.

40. For example: If we have a die with diameter of 3/16 of inch, we should prepare granules, which pass through a sieve with mesh 20 (20 mesh /1 linear inch). If we have a die with diameters of 7/16 inch, we have to have granules with dimensions that pass through a sieve of mesh 12.

41. Quality Controls • Weight uniformity test. • Dissolution profile. • Friability test. The granules must be: packaged in order to be used as final pharmaceutical dosage form, or added to other substances for example to prepare the tablets, So, we must avoid the transformation of the granules into powder during the manipulation processes.

42. Friability tester

43. Some Particular Granules: • Sustained release granules. • Enteric coated granules. • Effervescent granules.