Granulation Aggregation

Wet granulation Solvent granulation (crust granules) Binder granulation (sticked granules) Granulation liquid Water Water + alcohol mixture Macromolecular colloidal solution i.e.: starch, gelatine, polividon, cellulose ethers (MC, HEC, HPMC, etc.)

Wet granulation Drug(s) + excipient(s) Grinding Blending Agglomeration Granule/Pellet Aggregation Drying Press through sieves (particle size adjustment) Dispersion

Wet granulation

Melt granulation

Melt granulation Advantages Neither solvent nor water used in this process. Good alternative for water sensitive drugs. Fewer processing steps needed since wetting & drying phases eliminated, thus less time consuming There are no requirements on compressibility of active ingredients, entire procedure simple, continuous and efficient. Uniform dispersion of fine particle occurs. Good stability at varying ph and moisture levels. Safe application in humans due to their non-swellable and water insoluble nature. Clinically advantaged dosage forms, such as drug abuse and dose dumping deterrent technology. Sustained, modified and targeted release capabilities. Better content uniformity was obtained from HME process among granules of different size ranges. Reduced number of unit operations. Production of a wide range of performance dosage forms

Melt granulation Disadvantages Thermal process (drug/polymer stability). Requires high energy input. The melt technique is such that the process cannot be applied to heat-sensitive materials owing to the elevated temperatures involved. Lower-melting-point binder risks situations where melting or softening of the binder occurs during handling and storage of the agglomerates Higher-melting-point binders require high melting temperatures and can contribute to instability problems especially for heat-labile materials. Flow properties of the polymer are essential to processing. Limited number of available polymer

Melt granulation Hydrophylic binders Binder Typical melting range ( C) Gelucire 50/13 44-50 Poloxamer 188 50.9 PEG 2000 42-53 PEG 3000 48-63 PEG 6000 49-63 PEG 8000 54-63 PEG 10000 57-64 PEG 20000 53-66

Binder Melt granulation Hydrophobic binders Typical melting range ( C) Beeswax 56-60 Carnauba wax 75-83 Cetyl palmitate 47-50 Glycerin monostearate 47-63 Paraffin wax 47-65 Stearic acid 46-69 Glyceryl behenate 67-75 Glyceryl palmitostearate 48-57 Glyceryl stearate 54-63 Hydrogenated castor oil 62-86 Microcrystalline wax 58-72 Stearyl alcohol 56-60

Melt granulation Plasticizers Type Examples Citrate esters Fatty acid esters Sebacate esters Phatalate esters Glycol derivatives Others Triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate Butyl stearate, glycerol monostearate, stearyl alcohol Dibutyl sebacate Dietyl phtalate, dibutyl phtalate, dioctyl phosphate Polyethylene glycol, propylene glycol Triacetin, mineral oil, castor oil

Melt extrusion

Dry granulation

Tasks & Preparations 1. Granule preparation o Pro-C-epT (high shear granulator) o Z-shaped kneader 2. Moisture content determination (analysis of drying process of granules) 3. Grinding, sieve analysis (ball grinder & vibrating sieve) 4. Mixing (rotating cube mixer)

Wet granulation Tasks & Preparations Granulatum piracetami (a., b., c.): Piracetam 42.0 g PVP 3.0 g Microcrystalline cellulose 50.0 g a. Aqua purificata 15.0 g b. Aqua purificata 20.0 g c. Aqua purificata 25.0 g Preparation parameters: Impeller (rpm): 1000 RPM Chopper (rpm): 1100 RPM Liquid addition: 10ml/min Pre-mixing: 3 min Pro-C-epT High shear granulator

Wet granulation Tasks & Preparations Pellet preparation (a., b.): Avicel PH 102 65.00 g Ethylcellulose 4.00 g Lactose 48.00 g Preparation parameters: Pre-mixing: 3 min Impeller (rpm): 1000 RPM Chopper (rpm): 1100 RPM Liquid addition: 10ml/min Pro-C-epT High shear granulator Total liquid (Aqua purificata): a. 52 ml b. 70 ml

Wet granulation Tasks & Preparations Granule preparation I. Solani amylum 238.0 g Lactose 710.0 g II. Aqua purificata Solani amylum 170.0 g 30.0 g Z-shaped kneader Make a suspension with a cold water from the starch. Heat the liquid with water-bath while the starch becomes gelatinous (10-15 min). Cool down the granulating liquid to 40 C and refill the evaporated water. Homogenise the sieved powders, and knead it with small details of granulating liquid in Z-shaped kneader. Break the wet stuff through the granulating sieve IV (1.2 mm). Use oscillating granulator.