PM3125: Lectures 18 to 21 Content of Lecture 18: Compression & Compaction in Tablets Formation Prof. R. Shanthini 22 Oct 2012

Active substance synthesis Blending and Granulation Principle of tablet production Active substance synthesis Blending and Granulation Compression Coating The manufacturing process of tablets can be divided into two different sub-processes: -Active substances synthesis (production of pharmaceuticals in multi-level procedures) -Pharmaceutical manufacturing Blending and granulation: Tablets are most commonly compressed using powder mixtures which are previously granulated. The blending itself is done in so-called blenders wherein active substances and additives are blended homogeneously. This mixture is granulated afterwards in e.g. fluidized bed granulators where coupling agents are added. Granulate is produced from these moistly particles. Compression: Homogeneously and accurately dosed granulate is compressed into tablets or pill cores under high pressure by high performance tablet presses. Coating: Tablets are coated in so-called coaters by protective finishes or suspensions. Film-coated tablets are coated by polymer solutions and pills by sugar. Package Package Prof. R. Shanthini 22 Oct 2012

Compressed tablets Advantages and disadvantages of compressed tablets Types of tablets Tablet compression machine Tableting methods Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Advantages Production aspect User aspect (doctor, pharmacist, patient) Large scale production at lowest cost Easiest and cheapest to package and ship High stability User aspect (doctor, pharmacist, patient) Easy to handling Lightest and most compact Greatest dose precision & least content variability Coating can mark unpleasant tastes & improve acceptability Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Disadvantages Some drugs resist compression into dense compacts Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailability Bitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Types of tablets – Production process Compressed tablets Multiple compressed tablets Tablet within a tablets: core and shell Multilayer tablet Sugar coated tablets Protect tablets from moisture Mask odor and flavor Elegance Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Types of tablets – Production process Film coated tablets Thin film coat Soluble or insoluble polymer film Chewable tablets Rapid disintegrate Antacid, flatulance: rapid action Children drug Effervescent tablets Dissolve in the water before drink Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Ingredients used in tablet formulations Drugs Fillers, diluent, bulking agent To make a reasonably sized tablet Binders To bind powders together in the wet granulation process To bind granule together during compression Disintegrants To promote breakup of the tablets To promote rapid release of the drug Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Ingredients used in tablet formulations (contd.) Lubricants To reduce the friction during tablet ejection between the walls of the tablet and the walls of the die cavity Glidants Reducing friction between the particles To improve the flow properties of the granulations Antiadherants To prevent adherence of the granules to the punch faces and dies Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Ingredients used in tablet formulations (contd.) Dissolution (enhancers and retardants) Wetting agents Antioxidants Preservatives Coloring agents Flavoring agents Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Essential properties of tablets Accurate dosage of medicament, uniform in weight, appearance and diameter Have the strength to withstand the rigors of mechanical shocks encountered in its production, packaging, shipping and dispensing Release the medicinal agents in the body in a predictable and reproducible manner Elegant product, acceptable size and shape Chemical and physical stabilities Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Tablet production Powders intended for compression into tablets must possess two essential properties Powder fluidity The material can be transported through the hopper into the die To produce tablets of a consistent weight Powder flow can be improved mechanically by the use of vibrators, incorporate the glidant Powder compressibility The property of forming a stable, intact compact mass when pressure is applied Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Tableting procedure Filling Compression Ejection Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Prof. R. Shanthini 22 Oct 2012

A — Die filling B — Compression C — Decompression D — Lower punch removal and reapplication of load to the upper punch E — Tablet fully ejected 1 refers to the final compaction conditions  Schematic diagram showing the manufacture of single and bilayer tablets utilising uniaxial compaction. Prof. R. Shanthini 22 Oct 2012

1. Milling and mixing of drugs and excipients WET GRANULATION DRY GRANULATION DIRECT COMPRESSION 1. Milling and mixing of drugs and excipients 2. Preparation of binder solution 2. Compression into slugs or roll compaction 2. Compression of tablet 3. Wet massing by addition of binder solution or granulating solvent 3. Milling and screening of slugs and compacted powder   4. Screening of wet mass 4. Mixing with lubricant and disintegrant 5. Drying of the wet granules 5. Compression of tablet 6. Screening of dry granules 7. Blending with lubricant and disintegrant to produce “running powder” 8. Compression of tablet Prof. R. Shanthini 22 Oct 2012

Granulation It is a process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. It is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Prof. R. Shanthini 22 Oct 2012

Granulation (contd.) The most common reasons given to justify granulating are: To impart good flow properties to the material, To increase the apparent density of the powders, To change the particle size distribution, Uniform dispersion of active ingredient. Prof. R. Shanthini 22 Oct 2012

Binders Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling. In some instances the binding agent imparts viscosity to the granulating solution so that transfer of fluid becomes difficult. This problem can be overcome by adding some or all binding agents in the dry powder prior to granulation. Prof. R. Shanthini 22 Oct 2012

Some granulation, when prepared in production sized equipment, take on a dough-like consistency and may have to be subdivided to a more granular and porous mass to facilitate drying. This can be accomplished by passing the wet mass through an oscillating type granulator with a suitably large screen or a hammer mill with either a suitably large screen or no screen at all. Prof. R. Shanthini 22 Oct 2012

Oscillating type granulator Hammer mill Prof. R. Shanthini 22 Oct 2012

Drying The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity. The important factor to consider as part of scale-up of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays. If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules. Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load. Prof. R. Shanthini 22 Oct 2012

Fluidized bed dryers are an attractive alternative to the circulating hot air ovens. The important factor considered as part of scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity. Prof. R. Shanthini 22 Oct 2012

Reduction of Particle size Compression factors that may be affected by the particle size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, and tablet color uniformity. First step in this process is to determine the particle size distribution of granulation using a series of “stacked” sieves of decreasing mesh openings. Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device. Prof. R. Shanthini 22 Oct 2012

Oscillating type granulator Hammer mill Prof. R. Shanthini 22 Oct 2012

Blending Type of blending equipment often differs from that using in laboratory. In any blending operation, both segregation and mixing occur simultaneously are a function of particle size, shape, hardness, and density, and of the dynamics of the mixing action. Particle abrasion is more likely to occur when high-shear mixers with spiral screws or blades are used. When a low dose active ingredient is to be blended it may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface of the blender. Prof. R. Shanthini 22 Oct 2012

Equipments used for mixing Sigma blade mixer. Planetary mixer. Twin shell blender. High shear mixer Planetary mixer Prof. R. Shanthini 22 Oct 2012

Dry Granulation (slugging) A dry powder blend that cannot be directly compressed because of poor flow or compression properties. This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less. Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾ inch in diameter for materials that are more difficult to compress and require more pressure per unit area to yield satisfactory compacts. If an excessive amount of fine powder is generated during the milling operation the material must be screened & fines recycled through the slugging operation. Prof. R. Shanthini 22 Oct 2012

Dry Compaction Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch. Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. One of the best examples of this process is the densification of aluminum hydroxide. Pilot plant personnel should determine whether the final drug blend or the active ingredient could be more efficiently processed in this manner than by conventional processing in order to produce a granulation with the required tabletting or encapsulation properties. Prof. R. Shanthini 22 Oct 2012

Compression The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press. During compression, the tablet press performs the following functions: Filling of empty die cavity with granulation. Precompression of granulation (optional). Compression of granules. Ejection of the tablet from the die cavity and take-off of compressed tablet. Prof. R. Shanthini 22 Oct 2012

Tablet compression machines Hopper for holding and feeding granulation to be compressed Dies that define the size and shape of the tablet Punches for compressing the granulation within the dies Cam tracks for guiding the movement of the punches Feeding mechanisms for moving granulation from the hopper into the dies Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Singe punch machine The compression is applied by the upper punch Stamping press Prof. R. Shanthini 22 Oct 2012 Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

Singe punch rotary machine Prof. R. Shanthini 22 Oct 2012

Singe punch machine Upper and Lower Collar Collar locker