Powders and Granules PDF

Powders and Granules Prof Thiru Govender Discipline of Pharmaceutical Sciences  Powders & Granules Powder: formulation where drug powder is mixed with other powdered excipients to produce a final product. Granules: powder particles that have been aggregated to...

Powders and Granules Prof Thiru Govender Discipline of Pharmaceutical Sciences  Powders & Granules Powder: formulation where drug powder is mixed with other powdered excipients to produce a final product. Granules: powder particles that have been aggregated to form larger entities called granules) Products can be dispensed as: 1) Bulk powders or granules for internal use 2) Divided powders/ granules (single dose) for internal use 3) Dusting powders for external use  Advantages & Disadvantages of Powdered & Granulated products Advantages: ž Solid preparation, therefore has > stability than liquid preparations. Antibiotic powders can have shelf life of 2-3 years. When reconstituted with liquid– they are stable for 1-2 weeks. ž Convenient form to dispense drugs with large doses. ž Have faster dissolution rate than tablets or capsules → since these must first disintegrate before drug dissolves-quicker acting. ž Ease of administration. Disadvantages: ž Inconvenient to carry bulk powder. ž Masking of unpleasant taste may be a problem → effervescence (bubble formation) + flavouring can be used. ž Bulk powders or granules cannot be used to administer potent drugs in low doses. ž Not a suitable method for administering drugs which are inactivated in the stomach. ž Separation or “demixing” of the powders/granules can occur during manufacturing and packaging- due to different densities of components.  Dispensed Preparations 1. Bulk Powders — Mixed ingredients packed into bulk containers. — Constituents are relatively non-toxic eg. Magnesium Trisilicate, De Witts Antacid Powder 2. Divided Powders — Similar to bulk powders but individual doses separately packed e.g. GrandPa 3. Bulk Granules — Difference in particle size→ can lead to separation, therefore granulate powder mix eg. Methylcellulose granules BP 4. Divided Granules — Granulated products → individually wrapped eg. Fybogel 5. Dusting Powders — Contain ingredients are used for therapeutic, prophylactic or lubricant purposes → external used eg. Talc Dusting Powder BP Powders and Granules 6. Inhalers — Powders/granules placed in inhalers for inhalation ○ Spinhaler® ○ Rotahaler®  Granulation ž Process in which powder particles are made to adhere to form larger particles called granules. ž Undertaken in production of tablets and capsules. ž Can be used as a dosage form itself.  Reasons for Granulation 1. To prevent segregation of constituents in powder mix. Segregation occurs→ due to difference in size or density of components — Important to control particle size distribution → A wide size range leads to granule segregation → occurs in hoppers of tablet machines, sachet machines and capsules filling machines. 2. To improve flow properties of the mix — Because of small particle size of powder → there is greater cohesion between powders and therefore they do not flow well. — Poor flow can lead to wide fill weight variation when compressing tablets, packing in containers etc. Granulation to prevent powder segregation 3. To improve compression characteristics of the mix. Powders are difficult to compress → whilst granules can be more easily compressed, producing stronger tablets NB → Points 1-3 are the PRIMARY reasons for granulation! 4. Other Reasons — Granulation of toxic materials will ↓ hazard of dust generation. — Materials which are hygroscopic – can adhere and form a cake if stored as a powder. Granules can absorb moisture but retain their flowability because of their size. — Granules occupy less volume/unit weight – are therefore more convenient for storage and transport.  Methods of Granulation 1) Dry Granulation - powder particles are aggregated using high pressure. - 2 methods → slugging or roller compaction. Appropriate for drugs which do not compress well after wet granulation or those sensitive to H2O. 2) Wet Granulation - involves massing of the powder mix using a solvent. - solvents used are volatile, non-toxic eg. Ethanol, H2O, isopropanol. - solvents can be used alone or in combination - solvents may also be used with a dissolved adhesive (binder) - causes particle adhesion. - H2O → can adversely affect drug stability causing hydrolysis of products and longer drying times are required – this can an affect stability. - Advantage - water is non-flammable - no need for expensive precautions. Organic solvents used when H2O sensitive drugs are manufactured , as an alternative to dry granulation or when rapid drying time is needed.  Particle Bonding Mechanisms - To form a granule → bonds must form between powder particles to adhere. Must be strong to prevent breakdown of granules to powder during handling. - 5 bonding mechanisms: 1. adhesion and cohesion forces in immobile liquid films 2. interfacial forces in mobile liquid films 3. solid bridges 4. attractive forces between solid particles 5. interlocking bonds  1. Adhesion & Cohesion forces in Immobile Films ž The liquid in the powder forms a very thin layer (immobile) between particles → this ↓ interparticulate distance and ↑ contact area between particles → leads to↑ bond strength. ž The absorbed moisture is responsible for the cohesion of slightly damp powders. ž In dry granulation → pressures used will ↑ the contact area between adsorption layers and ↓ the interparticulate distance → leading to↑ granule strength.  2. Interfacial Forces In Mobile Liquid Films ž During wet granulation sufficient amount of liquid (to exceed that needed for immobile films) is added to the powder mix → is distributed as mobile films around and between particles. ž During wet granulation → different states of water distribution: — at low moisture levels → pendular state → particles are held together by the lens-shaped rings of liquid → this causes adhesion because of surface tension and hydrostatic suction pressure in the liquid bridge. — When all the air is displaced from between the particles, the capillary stage is reached and the particles are held by capillary suction at the liquid- air interface which is now only at the granule surface. — Funicular state – is the intermediate stage between pendular and capillary states. — Another state is Droplet state – is important in the process of granulation by spray drying of a suspension. — Strength of a droplet is dependant on the surface tension of liquid used. Water distribution between particles of a granule during formation and drying  3. Solid Bridges ž Can be formed by: i. Partial melting ii. Hardening binders iii. Crystallization of dissolved substances i. Partial Melting — Pressures used in dry granulation; may cause melting of materials of low melting point. — When pressure is relieved, crystallization will take place → can lead to binding of particles. ii. Hardening Binders — Is a common mechanism in wet granulation when an adhesive is included in the granulating solvent. — Liquid forms liquid bridges. When the adhesive hardens or crystallizes on drying → solid bridges form. ○ Adhesives eg. Polyvinylpyrolidone (PVP) ○ carboxymethylcellulose iii. Crystallization of Dissolved Substances — Solvent used during wet granulation may dissolve one of the powdered ingredients. — When the granules are dried crystallization of this material will take place → the dissolved substance acts as a hardening binder. — Any material soluble in granulating liquid functions in this way eg. Sucrose and dry powder granulated with H2O. — Size of crystals in bridge → is influenced by rate of drying of granules → the slower the drying time → the larger the particle size.  4. Attractive Forces Between Solid Particles ž 2 forces: electrostatic forces and Van der Waals forces can exist between particles in pharmaceutical systems in the absence of liquids and solid bridges formed by binding agents. ž Electrostatic Forces: May be important in causing powder cohesion and initial formation of aggregates. Insignificant to final strength of granule. ž Van der Waals Forces is 4 times greater than electrostatic forces and contributes significantly to the strength of granules produced by dry granulation. Mechanism of Granule Formation žThere are 3 broad stages: —Nucleation —Transition —Ball growth ○coalescence, ○breakage, ○abrasion transfer, ○layering 1. Nucleation — Begins at the capillary state →Number of particles will join to form the pendular state. The particle/ bodies act as nuclei for further granule growth. 2. Transition — Nuclei can grow as single particles added to nuclei or 2 or more nuclei combine. — At this stage there are large numbers of granules with wide size distribution. 3. Ball Growth — With further granule growth→ large, spherical granules are produced. If agitation is continued → can lead to unusable, overmassed system. — Ball growth→ can produce granules too large for pharmaceutical purposes. — 4 mechanisms of ball growth ○ Coalescence → 2 or more granules join to form a large granule. ○ Breakage → granules break into fragments which adhere to other granules forming a layer of material over the surviving granule. ○ Abrasion transfer → agitation of granule bed→ causes attrition of materials from granules. Abraded material adheres to other granules→ leads to increase granule size. ○ Layering → 2nd powder mix added to bed of granules→ powder will adhere to granules→ will form layer over granule→ leads to ↑size.  Coalescence Breakage Abrasion transfer Layering Pharmaceutical Granulation Equipment Wet Granulators - shear granulators - high speed mixers/ granulators - fluidized bed granulators - spray driers - spheronizers/ pelletizers Dry Granulators - sluggers - roller compacters Fluidised-bed granulator