Pharmaceutics -3 Lecture 2 PDF

Pharmaceutics -3 LECTU RE 2 1 DR/ OMNIA SARHAN  Granules DR/ OMNIA SARHAN 2  Granules Divination: It is the process in which primary powder particles are made to adhere to form larger, multi- particle called granules. Pharmac...

Pharmaceutics -3 LECTU RE 2 1 DR/ OMNIA SARHAN  Granules DR/ OMNIA SARHAN 2  Granules Divination: It is the process in which primary powder particles are made to adhere to form larger, multi- particle called granules. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on their subsequent use Advantages of granular dosage form 1- More chemically stable than liquid ones. 2- Suitable to dispense active ingredients in large dose. 3- Faster dissolution rate than tablets or capsules. Disadvantages of granular dosage form 1- Less convenient to carry than a small container of tablets or capsules. 2-The masking of unpleasant tastes may be a problem with this type of preparation. A method of attempting this is by formulating the powder into a pleasantly tasting or taste-masked effervescent powder, whereas tablets and capsules are a more common alternative for low-dose products. 3- Bulk powders or granules are not suitable for administering potent drugs with a low dose. 4. Not suitable for the administration of drugs which are inactivated in, or cause damage to the stomach. DR/ OMNIA SARHAN 3  Causes of Granulation 1- To prevent segregation of the constituents of the powder mix. Segregation or demixing is due to differences in the size or density of the components of the mix, the smaller and/or denser particles concentrating at the base of a container with the larger and/or less dense ones above them. 2- To improve the f low properties of the mix. Many powders, because of their small size, irregular shape or surface characteristics are cohesive and not f low well. Poor f low will often result in a wide weight variation within the f inal product owing to variable f ill of tablet dies. Granules produced from such a cohesive system will be large and more isodiametric, both factors contributing to improved f low properties. 3-To improve the compaction characteristics of the mix. Some powders are dif ficult to compact even if a readily compactable adhesive is included in the mix, but granules of the same formulation are often more easily compacted and produce stronger tablets. This is associated with the distribution of the adhesive within the granule and is a function of the method employed to produce the granule. 4- The granulation of toxic materials will reduce the hazard associated with the generation of toxic dust that may arise when handling powders. 5- Materials, which are slightly hygroscopic, may adhere and form a cake if stored as a powder. Granulation may reduce this hazard. 6- Granules, being denser than parent powder mix, occupy less volume per unit weight, they are thereforeDR/more convenient for storage or shipment. OMNIA SARHAN 4  Methods of Granulation a- Dry granulation Dry granulation converts primary powder particles into granules using the application of pressure without the intermediate use of a liquid. -Avoids heat-temperature combinations that might cause degradation of the product. - For drugs that do not compress well after wet granulation. For drugs which are sensitive to moisture. Sluggers 'slugging' The dry powders can be compressed using a conventional tablet machine. The compact made in the process (typically 25 mm diameter by about 10-15 mm thick) being termed a 'slug'. Roller compactors The powder mix being squeezed between two rollers to form a compressed sheet. The sheet normally is weak and brittle and breaks immediately into flakes. These flakes need gentler treatment to break them into granules. DR/ OMNIA SARHAN 5  Methods of Granulation b-Wet granulation Wet granulation involves the massing of a mix of dry powder particles with a granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry. Water is commonly used for economical and ecological reasons, but; Its disadvantages are; - It may adversely affect drug stability, -Causing hydrolysis of susceptible products, -It needs a longer drying time than do organic solvents, -Not suitable for water-sensitive drugs and organic solvents are used. DR/ OMNIA SARHAN 6  Methods of Granulation b-Wet granulation Its advantage are; It is non-f lammable, which means that expensive safety precautions such as the use of flame proof equipment need not be taken. Tray drying suffers from three major disadvantages: 1- The drying time is long. 2- Dissolved material can migrate to the upper surface of the bed of granules, as the solvent is only removed from the upper surface of the bed on the tray. 3- Granules may aggregate owing to bridge formation at the points of contact of the granules. DR/ OMNIA SARHAN 7  Mechanisms of Granulation A- Particle-bonding mechanisms To form granules, bonds must be formed between powder particles so that they adhere and these bonds must be suf ficiently strong to prevent breakdown of the granule to powder in subsequent handling operations. There are four primary bonding mechanisms between particles will be occur in pharmaceutical granulation which are: I- Adhesion and cohesion forces in immobile films If sufficient liquid is present, a cohesion & adhesion forces are formed; - Form a very thin, immobile layer, Inter-particulate distance In-contact area between the particles bond strength between the particles as the van der Waals forces of attraction are proportional to the particle diameter and inversely proportional to the square of the distance of separation. DR/ OMNIA SARHAN 8  Mechanisms of Granulation I- Adhesion and cohesion forces in immobile films This situation will arise also; - Hygroscopic powder. - After drying of granules prepared by wet granulation. *In dry granulation, however, the pressures used will; - Increase the contact area between the powder particles. -Decrease the interparticulate distance. This will contribute to the final granule strength. DR/ OMNIA SARHAN 9  Mechanisms of Granulation II- Interfacial forces in mobile liquid films During wet granulation; liquid (suf ficient liquid ) is usually added to exceed that necessary for an immobile layer and to produce a mobile film. There are four states of water distribution between particles; 1- Pendular state; the particles are hold together by lens-shaped rings of liquid, which cause adhesion due to: * Surface tension forces at the liquid/air interface *Hydrostatic suction pressure in the liquid bridge 2- Capillary state; When all the air has been displaced from between the particles and the particles are held by *Capillary suction at the liquid/air interface, which is now only at the granule surface. 3- Funicular state; represents an intermediate stage between the pendular and capillary states. Moist DR/ OMNIA SARHAN 10  Mechanisms of Granulation II- Interfacial forces in mobile liquid films 4- The droplets, this will be 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. DR/ OMNIA SARHAN 11  Mechanisms of Granulation III- Solid bridge These can be formed by; a- Partial melting Although not considered to be a predominant mechanism in pharmaceutical materials, it is possible that the pressures used in dry granulation methods may cause melting of low melting-point materials where the particles touch and high pressures are developed. When the pressure is relieved, crystallization will take place and bind the particles together. b- Hardening binders This is the common mechanism in pharmaceutical wet granulation when an adhesive is included in the granulating solvent. The liquid will form liquid bridges, as discussed above, and the adhesive will harden or crystallize on drying to form solid bridges to bind the particles. Adhesives such as polyvinylpyrrolidone, cellulose derivatives (such as carboxymethylcellulose) and pregelatinized starch function in this way. DR/ OMNIA SARHAN 12  Mechanisms of Granulation III- Solid bridge c- Crystallization of dissolved substances The solvent used to mass the powder during wet granulation may partially dissolve one of the powdered ingredients. When the granules are dried, crystallization of this material will take place and the dissolved substance then acts as a hardening binder. Any material soluble in the granulating liquid e.g. lactose incorporated into dry powders granulated with water. will function in this manner, The size of the crystals produced in the bridge will be inf luenced by the rate of drying of the granules: the slower the drying time, the larger the particle size. It is therefore important that the drug does not dissolve in the granulating liquid and recrystallize, because it may adversely affect the dissolution rate of the drug if crystals larger than that of the starting material are produced. DR/ OMNIA SARHAN 13  Mechanisms of Granulation IV- Attractive forces between solid particles In the absence of liquids and solid bridges formed by binding agents. There are two types of attractive force that can operate between particles in pharmaceutical systems: - Electrostatic forces may be important in causing powder cohesion and the initial formation of agglomerates, e.g, during mixing. In general they do not contribute signif icantly to the f inal strength of the granule. Van der Walls forces, however, are about four orders of magnitude greater than electrostatic forces and contribute signif icantly to the strength of granules produced by dry granulation. The magnitude of these forces will increase as the distance between adjacent surfaces decreases, and in dry granulation this is achieved by using pressure to force the particles together. DR/ OMNIA SARHAN 14  Mechanisms of Granulation B- Mechanisms of granule formation using the granulating machine: * In the dry methods, particle cohesion takes place because of applied pressure. A compact or sheet is produced which is larger than the granule size required, and therefore the required size can be attained by milling and sieving (sizing). *In wet granulation methods, liquid added to dry powders has to be distributed through the powder by the mechanical agitation created in the granulator. The particles adhere to each other because of liquid f ilms, and further agitation and / or liquid addition causes more particles to adhere according to the following steps: a- Nucleation Granulation starts with particle-particle contact and adhesion due to liquid bridges. A number of particles will join to form the pendular state. Further agitation densif ie s the pendular bodies to form the capillary state, and these bodies act as nuclei for further granule growth. DR/ OMNIA SARHAN 15  Mechanisms of Granulation B- Mechanisms of granule formation using the granulating machine: b- Transition Nuclei can grow in two possible ways: - Single particles can be added to the nuclei by pendular bridges -Two or more nuclei may combine, which reshaped by the agitation of the bed. This stage is characterized by the presence of a large number of small granules with a fairly wide size distribution. Providing that this distribution is not excessively large, this is a suitable end-point for granules used in capsule and tablet manufacture, as relatively small granules will produce a uniform tablet die or capsule f il l. Larger granules may give rise to problems in small-diameter dies owing to bridging across the die and uneven fill. DR/ OMNIA SARHAN 16  Mechanisms of Granulation B- Mechanisms of granule formation using the granulating machine: c- Ball growth Further granule growth produces large, spherical granules and the mean particle size of the granulating system will increase with time. If agitation is continued, granule coalescence will continue and produce an unusable, over massed system, although this is dependent upon the amount of liquid added and the properties of the material being granulated. Although ball growth produces granules that may be too large for pharmaceutical purposes, some degree of ball growth will occur in planetary mixers and it is an essential feature of some spheronizing equipment. The four possible mechanisms of ball growth are; Coalescence: Two or more granules join to form a larger granule. Breakage: Granules break into fragments which adhere to other granules, forming a layer of material over the surviving granule. DR/ OMNIA SARHAN 17  Mechanisms of Granulation B- Mechanisms of granule formation using the granulating machine: c- Ball growth Abrasion transfer: Agitation of the granule bed leads to the attrition of material from granules. This abraded material adheres to other granules, increasing their size. Layering: When a second batch of powder mix is added to a bed of granules, the powder will adhere to the granules forming a layer over the surface and increasing the granule size. This mechanism is only relevant to the production of layered granules using spheronizing equipment. DR/ OMNIA SARHAN 18 DR/ OMNIA SARHAN 19