Unit Operations Phar 261 2024 PDF

PHAR 261 Introduction to Pharmaceutical Technology I Assist. Prof. Hasan Ali Hussein / 2024 Unit operations UNIT OPERATIONS Operations performed in case active substances and excipients cannot be directly used in drug manufacture and to make them suitable for use in pro...

PHAR 261 Introduction to Pharmaceutical Technology I Assist. Prof. Hasan Ali Hussein / 2024 Unit operations UNIT OPERATIONS Operations performed in case active substances and excipients cannot be directly used in drug manufacture and to make them suitable for use in production  UNIT OPERATIONS Granulation Mixing Sieving Heat transfer – Drying Filtration Distillation Extraction  UNIT OPERATIONS Granulation Granulation, It is mechanical reduction of the size of solid particle sizes, It includes operations such as cutting, crushing, grinding, dispersing, crumbling and comminuting UNIT OPERATIONS Granulation Why grinding? To reduce the sizes of particles in order to increase their specific surface area, improve their contact with the environmental liquid, and thereby to increase their rate of dissolution and absorption and improve their bioavailability, To increase the flow of powders and facilitate tablet pressing, To be able to administer accurate doses of drug by ensuring homogeneity, UNIT OPERATIONS Granulation Why grinding? To facilitate drying due to the smaller particle sizes and bigger surface areas, To facilitate suspendability, To prevent needle occlusion during administration of parenteral suspensions, To ensure access to the targeted site of the inhalation preparations in the bronchopulmonary system UNIT OPERATIONS Granulation Disadvantages of Grinding Active ingredient can turn into an unstable or inactive crystal form during grinding, As the particle size decreases, hygroscopic attribute of substances increases and this affects the stability negatively, As a result of particles being very fine, surface energy increases and caking tendency is witnessed UNIT OPERATIONS Grinding Methods Manual Grinding Particle size reduction is performed with mortar in pharmacies, Trituration; reducing the size of particles through crushing in mortar, The mortar is the mostly used tool for grinding UNIT OPERATIONS Grinding Methods Manual Grinding The glass and porcelain mortars are commonly used in pharmaceutics, Glass mortar is used for grinding colored and oxidant substances such as iodine, methylene blue and potassium, When working with other materials, porcelain mortar may be preferred because it ensures easier and better grinding due to its rough surface, UNIT OPERATIONS Grinding Methods When mixing in the mortar, widening circular motions of pestle are performed to the edge of the mortar and then the same motion is repeated back to the center of the mortar, Mixing in the mortar should be based on the geometric dilution principle. UNIT OPERATIONS Grinding Methods Grinding by the aid of a solvent In adhesive substances that difficult to grind, The substance is grinded by using a little alcohol or different volatile solvents, then the solvent is evaporated and the remaining powder is taken, For example, iodine crystals can be grinded by using some ether UNIT OPERATIONS Grinding Methods Levigation A paste is prepared by using a compound that does not dissolves the substance, and it is grinded by crushing with spatula, This method is used in the preparation of dermatological and ophthalmic ointments and suspensions UNIT OPERATIONS Grinding Methods Another tool used in grinding is spatula, The spatula is used to gather the particles and the material accumulated at the edge of the mortar to the center of the mortar, Made of porcelain, stainless steel, hard rubber and bone; porcelain is used for substances that react upon contact with metal. Spatulas with large head are used to prepare ointments  UNIT OPERATIONS Grinding Methods Grinder types 1.Grinders that make rough grinding: The particles obtained are bigger than 840 µm. Hammered mills, rotating crushers, etc. 2.Grinders that make moderate grinding: The particles obtained are between 74-840 µm. Rotating cutters, hammered and rotating mills, crushing mills, etc. 3.Grinders that make fine grinding: The particles obtained are smaller than 74 µm. Hammered mills, ball mills, cutter mills, dispenser mills, pounder mills, cylinder mills, jet mills, colloidal mills and liquid energy mills, etc. Blade grinders: It is suitable for hard Blade grinder fibrous substances and drugs. It is not suitable for fragile particles. Hammered grinders: There are fixed Hammered or moving blades on a shaft rotating with a high rpm. grinder Cylinder grinders: It is used for Cylinder thinning ointments and giving them a smooth appearance. grinder Block grinders: Grinding takes place Block when the balls made of porcelain or steel compress the material and grinder particles are rubbed against each other. Colloidal grinders: Wet grinding is Colloidal done. It is preferred more for suspensions and emulsions. grinder  UNIT OPERATIONS Grinding Methods Factors Affecting Grinding Material properties; – Material being hard, soft, fibrous or hygroscopic – Moisture content of the materials – Melting degree of the material – Stability of the material – Shape of the particle being grinded  UNIT OPERATIONS Grinding Methods Factors Affecting Grinding Grinder properties – Easily demountable – Strength – Simple mechanism – Easy operation – Capacity  UNIT OPERATIONS Methods for particle size determination The science and technology of small particles is «micromeritics»! In pharmaceutical technology, knowing and controlling the particle size is very important for determination the properties and stability of the preparation.  UNIT OPERATIONS Methods for determination of the particle size : 1. Microscope methods 2. Sieve analysis 3. Sedimentation method 4. Conductivity method – Coulter counter 5. Laser light scattering method 6. Photon correlation spectroscopy 7. Permeability method 8. Adsorption method  UNIT OPERATIONS Mixing Distributing powders or solvents among each other is called «mixing», when homogeneous system is prepared its called «mixture», In the drug preparation, homogenous mixing of the substances is important  UNIT OPERATIONS Mixing Mixing in pharmaceutical technology Mixing of liquids with each other (solutions, emulsion) Mixing of solids in liquids (actual solution, colloidal solution, suspension, wet granulation) Mixing of powders with each other, (tablet, capsule) Mixing semi solids (cream, ointment paste, suppository)  UNIT OPERATIONS Mixing Factors affecting the mixer choice Mixing material's Density Viscosity Miscibility Energy spent Equipment maintenance Cleaning Mixing time  UNIT OPERATIONS Mixing Mixing of Powders This is the fore-step of preparation of solid dosage forms such as tablets or capsules, It is made for providing homogeneous mixture and dosage uniformity  UNIT OPERATIONS Mixing Mixing Mechanisms of Powders 1.Mixing by transport (convection): Mixing through overturn of the pile of powder or transport of powder from one position to other 2.Mixing by sliding: Mixing through mutual sliding of powder masses 3.Mixing by diffusion: Moving of particles from one place to another in the mixture based on random movements  UNIT OPERATIONS Mixing Segregation and Aggregation Mixing the powder homogeneously ensures the same amount of the API in each tablet or capsule, When two powders with different densities mixed, segregation among particles may occur due to different particle weights. In this situation, the particles with smaller density aggregate on the top while heavier ones at the bottom Non-homogeneous powder mix is called ”Segregation”  UNIT OPERATIONS Mixing Segragation Reasons; Powders having: » different particle sizes » different particle shapes » different particle caking » different ratio of substances in the mixture #Segregation prevention methods Geometric dilution Adding small amount of water into the mixture  UNIT OPERATIONS Mixing Aggregation: Is the accumilation of the small particles on the surface of the large particles During mixing, the surface energy of small particles increased, and as a result they tend to combine with each other to reduce this surface energy, and this makes the powder aggregate.  UNIT OPERATIONS Mixing Serial mixing It is made by mixers with different geometric shapes that rotate around their own axises. (a) (b) (c) (d) (a) cube mixer (b) v type mixer (c) cylinder mixer (d) double-cone mixer  UNIT OPERATIONS Mixing Propeller mixers; ın solution and syrup manufacture, propeller mixers can be used for mixing solutes with a liquid. Simple propeller mixer Inclined mixer Lever mixer  UNIT OPERATIONS Mixing Air jets; Muller mixers. Mixing happens by crushing mechanism. Air separator Air exit Valve Manifold Pressurized air Mixers which mix by air flow  UNIT OPERATIONS Mixing Continuous Mixing : It is done by mixers with mixing blades, Usually it is used for mixing powders with liquids, especially for wet granulation process  UNIT OPERATIONS Mixing Planet mixers: The system consists of S or Z shaped blades rotating around a shaft at the center of a horizontal container. While the cylinder rotates around its own axis, the blades too rotate Ribbon mixer Planet mixer Continuous mixers  UNIT OPERATIONS Mixing Properties of an ideal mixer It should be able to move powders in 3 directions, There shouldn't be any dead point in the container, Materials amount should be able to be adjusted in the container There shouldn't be any segregation cone during unloading UNIT OPERATIONS Sieving  UNIT OPERATIONS Sieving Types of Sieving #Manual sieving The substance is placed on a perforated wire with frame and passed through the holes of sieve using a spatula by applying pressure, Sensitive medicines such as salicylic acid, ascorbic acid should be sieved through plastic sieve instead of metal sieve  UNIT OPERATIONS Sieving #Mechanical sieving Vibrant, shaking or air-flow sieves with standard hole diameters are used for this purpose 1- Electromagnetic or vibrant sieves 2- Air flow sieve 3- Air-jet sieve 4- Shaker sieve 5- Wet sieving  UNIT OPERATIONS Drying Purposes of drying dry form is more stable than liquid form, easier to transport, drying prevent microorganism growth during storage.  UNIT OPERATIONS Drying Heat transfer and drying energy for heating process provided by: Electricity (small scale manufacturing) Solid fuels (large scale manufacturing) Liquid fuels (large scale manufacturing) Gas fuels (large scale manufacturing). Dry heating may be direct or indirect. direct heating, heat is passed through the material indirect heating, the material is inside a container and dried by heating  UNIT OPERATIONS Drying Methods in Drying Process: Drying in dry hot air incubator Drying in fluidized bed Drying by vacuum Dielectric (by microwave) drying Drying in tunnel Drying with rotating surface  UNIT OPERATIONS Drying Dryer Types Tray dryers: Substance is spread over tray and hot air is passed over, Tunnel dryers: The trays move inside the dryer tunnel, providing discontinued drying, Drum dryers: Drying in a continuously rotating drum heated with conduction, Fluidized bed dryers: The solid substance inside the cylindrical system is dried by suspension in the air with airflow from below, Spray dryers: Air is sprayed from the same direction with the substance to be dried in a cylindrical or conic chamber. It is used in obtaining microspheres and microcapsules  UNIT OPERATIONS Drying Rotational dryers: The substance is heated inside the moving horizontal cylinder with hot air or peripheral convection, Conveyor dryers: Hot air applied vertically on the substance on the belt and rapid drying is facilitated, Vacuum dryers: Other than the vacuum being present in the environment, it works like tray dryers, Freeze dryers: Substance is present on the shelves or vacuum room where the strips are. Material is frozen very rapidly.  UNIT OPERATIONS Drying Lyophilization/freeze drying: It is a suitable method for drying heat and moisture sensitive substances. Lyophilization is, freeze-drying procedure which removes water from a Product by sublimation. SOLID GAS without becoming ice UNIT OPERATIONS Filtration  UNIT OPERATIONS Filtration It is the mechanical separation of substances in the mixture and optical extraction of transparent liquids, Solid particles separated with filtration is called the «sediment», and the clean product obtained is called the «filtrate» In some references, the solid particles on the surface are called as « filter cake», If the filtration is performed just for the purpose of obtaining filter cake, it is called as «cake Filtration»  UNIT OPERATIONS Filtration Purposes of Filtration  Removing the sediment from medium,  Clarifying the solution,  Obtaining filtrate, Correcting taste and appearance, Eliminating pathogens such as bacteria, virus, protozoa... Etc.  UNIT OPERATIONS Filtration Characteristics of a Good Filtration Medium: It should retain the solid particles that have wide range sizes, Pressure against the filtrate flow should be low, Solid substance should be easily removed, It should be chemically inert It should not swell when come into contact with the filtrate or washing liquid, It should be durable to the temperature, It should be durable to filtration pressure, The particles must not get stuck in pores.  UNIT OPERATIONS Filtration Membrane Filters and Sterile Filtration The membrane filters are used in: Every stage of pharmaceutical manufacturing where filters are necessary, In sterilization of liquids that cannot be sterialized by other methods, In filtering buffer, reactive or sample liquids, within the scope of microbiological and radiochemical studies. UNIT OPERATIONS Filtration Membrane filter (Diameter: 0.45 µm)  UNIT OPERATIONS Filtration Sterile filtration: is the removal of microorganisms using filtration. Membrane filters with 0.22 µm pore diameters are used, Microorganisms are retained on the membrane filter or at a near section, The membrane filters with 0.45 µm pore diameter are used to sterilize antibiotics and steroids in the organic carriers, immediately before aseptic crystallization process.  UNIT OPERATIONS Filtration Filter Integrity Test Filter integrity is particularly important for sterility of the product obtained by sterile filtration. Integrity testing is generally performed by applying bubble point test. The pressure value for a membrane filter is determined by the manufacturer. In the case of deterioration in a filter, pore diameter increases and pressure drop is observed.  UNIT OPERATIONS Filtration Membrane Filter Sterilization Membrane filters can be sterilized by various methods such as autoclave, vapor or ethylene oxide.  UNIT OPERATIONS Filtration Ultrafilter: In some situations, a filter with a pore diameter smaller than 0.1 µm can be necessary, In such a case, in order to reduce the resistant of filter to filtration, the filter thickness can be decreased down to 0.1 µm, Ultrafilters are special membrane filters with pore diameters between 0.001-0.1 µm and manufactured with a support layer that is not effective in filtration but increase the physical resistance of the filter.  UNIT OPERATIONS Filtration Accelarating Filtration Filtration process can be accelerated by; 1.Increasing the filtration surface, 2.Hot filtration, 3.The help of vacuum and pressure, 4.Using adsorbent substance.  UNIT OPERATIONS Filtration Filtration excipients These are solid substances not dissolving or compressed in the solvent and used for easing the filtration of preparations that are hard to filtrate Example: talk, siliceous earth, kieselguhr, clay, coal, magnesium carbonate, bentonite, silica gel, diatomite, pearlite  UNIT OPERATIONS Filtration Filtration flasks: a)Porcelain filtration flasks: Pores are visible and filtration can be performed by placing a filter paper or cotton over it. Filtration can be accelareted by the help of water squinch or vacuum. b)Glass filtration flasks : Made of jena glass with different pore sizes Glass fiber Various filtration flasks used in filtration  UNIT OPERATIONS Filtration Filtration plugs: Berkefeld, Mandler plugs are commonly used filtration systems in practice. Sometimes used with pressure and sometimes with vacuum Berkefeld Plug Solution Porcelain plug  UNIT OPERATIONS Distillation It is the process of physically separating one or more components with different boiling points in a mixture, It is also known as refining.  UNIT OPERATIONS Distillation Distillation: It is the process of heating liquid till it boils,then capturing and collecting the vapor formed, and at last collecting the condensed liquid. The product obtained from distillation is called distillate, and the remaining part is called residual,  UNIT OPERATIONS Distillation Pharmaceutical Application of Distillation Purification of water, Purification of volatile component substances, Purification and identification of natural raw materials  UNIT OPERATIONS Extraction Extraction: is the process of extracting the active substances in drugs with the aid of solvent, It is also called depletion. There are two phases during extraction; solute containing phase Solvent phase  UNIT OPERATIONS Extraction There are 3 methods of extraction: Extraction by mechanical means Extraction by solvents Extraction by distillation  UNIT OPERATIONS Extraction A-Extraction by mechanical means Its applied by compression and scratch a)Compression (Pressure, stress): The application is made by applying pressure, b) Scratching: It is applied by scratching the surface of the plant or by squeezing it. For example:, etheric oils (citrus and bergamot extracts)  UNIT OPERATIONS Extraction B-Extraction by using solvents I- Maceration In this method, diffusion and osmosis forces are active, The drug is waited for a certain duration at a dark place in tightly closed and preferably colored containers.  UNIT OPERATIONS I- Maceration Extraction Advantages Disadvantages It is not laborious, Fast degradation may occur It can be implemented for by the influence of mold substances that easily and bacteria, dissolve in the solvent, The active ingredients may With the solvents such as change by the influence of wine, vinegar and ether plant enzymes, that can evaporate by heat Inadequate and slow and starch, pectin and consumption may occur, mucilage containing drugs, The drug holds the solvent working in cold is possible and thus the active ingredient together  UNIT OPERATIONS Extraction II- Percolation Percolation is the extraction method performed with solvent flowing over the drug, Its principle is the consumption of the active ingredients in the drug of a suitable thickness placed in a percolator by passing a solvent that can dissolve them  UNIT OPERATIONS Extraction C- Extraction by Distillation It is a method used for drugs which has easily evaporating active ingredients. It is separated into two: Wet distillation - Direct distillation -Distillation with water vapor or alcohol vapor (Etheric oils, Aromatic waters, Alcoholates) Dry distillation : Heat is applied on the drug using special distillers. Extraction by Distillation