University of Sulaimani College of Pharmacy Dept. of Pharmaceutics 5 th stage Second Semester

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1 University of Sulaimani College of Pharmacy Dept. of Pharmaceutics 5 th stage Second Semester 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 1

2 Outlines Powder flow Introduction Factor affecting powder flowability Determination methods Improvement of powder flowability Granulation 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 2

3 Introduction The majority of the APIs are administered as solid dosage forms, prepared by processing and formation of powders. A powder is defined as a dry, solid substance, consisting of a large number of finely divided particles (varying 10nm-1000μm), and typically obtained by crushing, grinding, or comminuting. Besides acting as pharmaceutical excipients, such as diluents, disintegrating agents, and lubricants, powders can also present as a pharmaceutical dosage form. Properties of powder Particle characterization (particle size, particle density, specific surface area, porosity, crystallization and amorphous Powder flowability 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 3

4 Introduction cont. Flowability means how easy the powder will flow under a specified conditions. It has a great impact on many pharmaceutical processes, such as blending, transfer, and compression. Why free flowing powder? Dose uniformity 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 4

flowability decreased < 10 μm poor flowability 2.

5 Factor affecting powder flowability 1. Effect of particle size Particles 250 μm good flow With decreased particle size the flowability decreased < 10 μm poor flowability 2. Particle shape Sphere better flow than irregular Irregular shaped particles may experience mechanical interlocking 3. Moisture content 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 5

Determination of methods 1. Angle of repose is the maximum angle that can be obtained between the freestanding surface of a powder heap and the horizontal plane.

6 Determination of methods 1. Angle of repose is the maximum angle that can be obtained between the freestanding surface of a powder heap and the horizontal plane. It is a practical technique for measuring resistance to particle movement. tan angle = hight radius of the base Angle value of 20 to 40 indicated good flowability. And more than 50 bad flowability. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 6

7 Determination of methods cont. 2. Carr s compressibility index I = 100. (1- Bulk density Tapped density ) I = < 15% good flow I = >25% poor flow 3. Hausner ratio H = Tapped dnesity Bulk density H 1.18 good flow H 1.35 poor flow 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 7

Flow activator (glidant) It has a high surface area as colloidal silicon dioxide (Aerosil ) It coats the

8 Improvement of powder flowability 1. Alteration of particle size and size distribution 2. Alteration of particle shape or texture 3. Flow activator (glidant) It has a high surface area as colloidal silicon dioxide (Aerosil ) It coats the larger excipient and active ingredient particles, thus reducing van der Waals attractive forces between them. It can also absorb moisture 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 8

9 Outlines Powder flow Granulation Reasons for granulation Granulation process Granulation mechanism Equipment 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 9

10 Granules Granules are aggregated of powder particles to form larger particles sufficiently robust to withstand handling. Granulation is the process in which dry primary powder particles are processed to adhere to form larger multiparticle entities called granules. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm. After granulation, the granules will either: be packaged they may be mixed with other excipients prior to tablet compaction or capsule filling. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 10

11 Reasons for granulation 1. To prevent segregation of the constituents of the powder mix. Segregation occurs primarily due to differences in the size and/or density of the components of the mix Powder Granulation Granules Segregated powder Mono-sized granules 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 11

12 Reasons for granulation cont. 2. To improve the flow properties Many powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well. 3. To improve the compaction characteristics of the mix 4. Other The granulation of powdered toxic materials will reduce the hazard associated with the generation of toxic dust Materials which are slightly hygroscopic may adhere and form a cake if stored as a powder. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 12

13 Outlines Powder flow Granulation Reasons for granulation Granulation process Granulation mechanism Equipment 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 13

Production of a large tablet (slug 25 mm diameter, 10-15 mm thick) in a

The powder is squeezed between two rollers to produce a sheet or flakes of

14 Granulation process 1. Dry granulation Powder particles are aggregated at high pressure. A. Production of a large tablet (slug 25 mm diameter, mm thick) in a heavy-duty tableting press (a process known as slugging) B. The powder is squeezed between two rollers to produce a sheet or flakes of material (roller compaction). Milling then sieving Used for moisture sensitive drugs. Alexanderwerk Protec 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 14

15 Granulation process cont. 2. Wet granulation Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The granulating fluid contains a solvent that must be volatile, and non-toxic. E.g. water, ethanol and isopropanol either alone or in combination. The granulation liquid may be used alone or, with a binder. The disadvantages of water It may adversely affect drug stability, causing hydrolysis of susceptible products It needs a longer drying time The primary advantage of water is that it is non-flammable 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 15

16 Outlines Powder flow Granulation Reasons for granulation Granulation process Granulation mechanism Equipment 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 16

17 Granulation mechanism To form granules, bonds must be formed between powder particles so that they adhere and these bonds must be sufficiently strong At low moisture levels, termed the pendular state, the particles are held together by lens-shaped rings of liquid When all the air has been displaced from between the particles, the capillary state is reached 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 17

18 Granulation mechanism cont. The funicular state represents an intermediate stage between the pendular and capillary states Solid bridges can be formed by: 1. Partial melting 2. Binders Like PVP, cellulose derivative and pregelatinized starch. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 18

19 Granulation mechanism cont. 3. Crystallization of dissolved substances. The solvent used to mass the powder during wet granulation may partially dissolve one of the powdered ingredients. crystallization e.g. lactose 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 19

20 Granulation mechanism cont. Ball growth If agitation is continued, granule coalescence will continue and produce an unusable, over-massed system, It depends on the amount of liquid added and the properties of the material being granulated. Mechanisms of ball growth Coalescence Breakage Abrasion transfer Layering 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 20

21 Outlines Powder flow Granulation Reasons for granulation Granulation process Granulation mechanism Equipment 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 21

22 Equipment 1. High shear mixer/granulator A stainless steel mixing bowl A three-bladed main impeller which revolves in the horizontal plane A three-bladed auxiliary chopper (or breaker blade) 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 22

23 Equipment cont. The advantage of the high speed granulator The powder blending, wet massing and granulation are all performed in a few minutes in the same piece of equipment. Oscillating granulator The moist mass is to be transferred to a granulator 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 23

24 Equipment cont. 2. Fluidized-bed granulators They have a similar design and operation to fluidized-bed driers The powder particles are fluidized in a stream of air, but in addition granulation fluid is sprayed from a nozzle onto the bed of powder 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 24

Equipment cont. 4. Spheronizers/pelletizers Extrusion/spheronization is a multi-step process used to make uniformly sized spherical particles. Advantages Controlled drug release applications.

25 Equipment cont. 4. Spheronizers/pelletizers Extrusion/spheronization is a multi-step process used to make uniformly sized spherical particles. Advantages Controlled drug release applications. Improve flow properties and reduce the problems of dust High API loading without producing excessively large particles (i.e. minimal excipients are necessary). 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 25

26 Spheronizers The main steps of the process are: 1. Dry mixing of ingredients to achieve a homogeneous powder dispersion 2. Wet massing to produce a sufficiently plastic wet mass The amount of fluid needed to achieve spheres of uniform size and sphericity is likely to be greater than that for a similar tablet granulation. 3. Extrusion to form rod-shaped particles of Wet mass is forced through dies and shaped into small cylindrical particles with uniform diameter spheronization to round off these rods into 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 26

27 Spheronizers cont. Extruders screw-feed extruder gravity-feed extruder 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 27

28 Spheronizers cont. 4. Spheronization: is to round off the rods produced by extrusion into spherical particles. The working part consists of a bowl having fixed side walls, with a rapidly rotating bottom plate or disc 5. Drying. A drying stage is required in order to achieve the desired moisture content. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 28

Spheronizers cont. These pellets can either be filled into hard gelatin capsule shells or compacted with suitable excipients into tablets to form unit dosage forms.

29 Spheronizers cont. These pellets can either be filled into hard gelatin capsule shells or compacted with suitable excipients into tablets to form unit dosage forms. Pellets can be coated to form rapid-, intermediate- and prolonged-release pellets in the same capsule shell. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 29

30 Equipment cont. 5. Rotorgranulator The base plate rotates at high speed and centrifugal force keeps the moist mass at the edges of the rotor. It is possible to continue the process and coat the pellets by subsequently spraying coating solution onto the rotating dried pellets. Or to be used for layering. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 30

31 Equipment cont. 6. Melt granulation It is a process in which a thermosetting material (hot-melt binder) is used to bind the primary powder particles into granules. It is a water-free process. Techniques Hot-melt binder + drug is mixed rise temperature above melting point of the binder (50 90 C) cooled down Hot-melt binder is heated above the melting point sprayed on to the powder 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 31

carnauba wax, hydrogenated castor oil, hydrogenated cottonseed oil, and stearic acid.

32 Equipment cont. Hot-melt binders can be either hydrophilic/ water soluble like PEGs or hydrophobic/ water insoluble like carnauba wax, hydrogenated castor oil, hydrogenated cottonseed oil, and stearic acid. Hot-melt extrusion/spheronization low melting point waxes and heating are used in the extrusion process. Spheronization and cooling are carried out simultaneously. 2/26/2018 Industrial Pharmacy II, Dr. rer. nat. Rebaz Ali 32

ADVANTAGES OF MULTIPARTICULATES (PELLETS):

ADVANTAGES OF MULTIPARTICULATES (PELLETS): INTRODUCTION: Multiparticulate Drug Delivery Systems (MDDS): The concept of multiple unit dosage form was initially introduced in the early 1950 s.these forms play a major role in the design of solid dosage