Pharmaceutical Powders Lecture Notes PDF

PHARMACEUTICAL POWDERS Pharmaceutical powders are solid dosage forms of medicament in which one or more drugs are dispensed in finely divided state with or without excipients. They are available in crystalline or amorphous form. Powders are one of the solid dosage forms apart from granules, tablet...

PHARMACEUTICAL POWDERS Pharmaceutical powders are solid dosage forms of medicament in which one or more drugs are dispensed in finely divided state with or without excipients. They are available in crystalline or amorphous form. Powders are one of the solid dosage forms apart from granules, tablets and capsules. 1  Powders are generally considered to be composed of solid particles of the same or different compositions having equivalent diameters less than 1000 um. The major pharmaceutical use of powders is to produce granules, tablets and capsules. The flow of powders and granules is much more difficult than that of liquids. The flow is often variable and unpredictable. These difficulties are caused by the adhesive and cohesive characteristics of the powder. These are surface properties and thus their magnitude is greatly influenced by particle size, roughness, surface free energy, shape etc. 2  Powder flow is a key requirement for pharmaceutical manufacturing process. Tablets are often manufactured on a rotary multi-station tablet press by filling the tablet die with powders or granules based on volume. Thus, the flow of powder from the hopper into the dies often determines weight, hardness, and content uniformity of tablets. In case capsule manufacturing, similar volume filling of powders or granules is widely used. 3  ADVANTAGES OF POWDERS It is used both internally and externally. It is more stable than liquid dosage form. It is convenient for the physician to prescribe a specific amount of powder Onset of action is faster compared to tablets and capsules because it is easily dissolved in body fluids Easy to carry Easy to administer to the patient orally by dissolving in suitable liquids. 4  Faster dissolution rate Increased bioavailability Increase surface area Increase dissolution Can be taken orally by some patients who are unable to swallow other solid dosage forms such as capsules and tablets. 5  DISADVANTAGES Drugs that have bitter and unpleasant taste cannot be administered in powder form. Drugs that cause nausea cannot be administered. Deliquescent and hygroscopic drugs cannot be dispensed in powder form. They are packed in double wrapping. Drugs which get affected by atmospheric condition are not suitable as powders. Quantity less than 100 mg cannot be weighed conveniently Inaccuracy of dose in case of bulk powder Inconvenient to carry 6 PHARMACEUTICAL APPLICATIONS OF POWDERS They serve as raw materials for the manufacture of other solid dosage forms. They are used in the manufacture of granules and tablets. They are used in the formulation of capsules to mask the bitter taste of drugs or for drugs that are not compressible into tablets. They are used in the treatment of local infection. They are used in the treatment of asthma and other respiratory diseases. 7 Powders are used as counter-irritant e.g. camphor starch dusting powder. Rhubarb powder is used in dyspepsia. Chlorhexidine dusting powder is used as antimicrobial agent. Dover’s powder( ipecacuanha and opium) is used as anti-emetic and anti-pyretic. Magnesium trisilicate powder is used as antacid and anti-flatulent. Powders are also used as antiseptics. 8  Ibuprofen powder is used to treat juvenile arthritis. Rumford is used as aluminium free baking powder. Powders are also used in cosmetics as face powders. Prickly heat powders are used to relief skin burn. Baby powders are used to protect skin and nappy rashes. 9  GRANULES Granules are powder agglomerated to produce large free flowing particles. Granules are particles ranging in size from about 4 to 10 mesh. They are irregularly shaped but may be prepared to be spherical. Granulation are also used as intermediates in the preparation of capsule and tablets, since they flow more smoothly and predictably than small powder particles. 10 Why do we prepare granules when we have powders? To enhance the flow of powder To avoid powder segregation. Granules have higher porosity than powders. To improve the compressibility of powders into tablets. Materials that are hygroscopic, may adhere and form a cake if stored as a powder. 11 DIFFERNCES BETWEEN POWDERS AND GRANULES 12  CLASSIFICATION Granules are classified into following categories: 1) Effervescent granules 2) Coated granules 3) Gastro-resistant granules 4) Modified release granules 13 14  METHOD OF PREPARATION OF GRANULES Granules are generally prepared by three methods. (1)Wet granulation method (2)Dry granulation method (3) Melt granulation method 15  PHARMACEUTICAL USES OF GRANULES Effervescent granules are used as an antacid. Methylcellulose granules are used as a laxative. Granules are used in the formulation of tablets They are used in the manufacture of capsules Granules are used for instant preparation of solutions and suspensions. Lactinex granules are use in uncomplicated diarrhoea. Granules are also used as animal foods. 16  MICROMERITICS It is the science and technology of small particles. The unit of particle size used is the micrometer (µm), micron (µ) and equal to 10-6m. As particle size decreases, the surface area of the particles increases Knowledge and control of the size and the size range of particles are of significant importance in pharmacy because the size and surface area of a particle are related to the physical, chemical and pharmacologic properties of a drug. The particle size of a drug can affect its release from dosage forms that are administered orally, parenterally, rectally and topically. 17 RELATIONSHIP BETWEEN ANGLE OF REPOSE, CARR’S INDEX, HAUSNER RATIO AND POWDER FLOWABILITY 18  In the area of tablet and capsule manufacture, control of the particle size is essential in achieving the necessary flow properties and proper mixing of granules and powders. Particle Size and Size Distribution In a collection of particles of more than one size, two properties are important, namely: 1. The shape and surface are of the individual particles. 2. The particle size and size distributions (the size range and number or weight of particles). 19  APPLICATIONS OF MICROMERITICS 1. Release and dissolution. 2. Absorption and drug action. 3. Physical stability. 4. Dose uniformity 20 METHODS FOR DETERMINING PARTICLE SIZE Many methods are available for determining particle size such as Optical microscopy, Sieving, Sedimentation and Particle volume measurement. 21  FLOW PROPERTIES OF POWDERS Powders may be free-flowing or cohesive (Sticky). Many common manufacturing problems are attributed to powder flow. 1. Powder transfer through large equipment such as hopper. 2. Uneven powder flow results in excess entrapped air within powders causing capping or lamination during tableting. 3. Uneven powder flow increase particle’s friction with die wall causing lubrication problems and increase dust contamination risks during powder transfer. 22  4. Powder storage, which for example result in caking tendencies within a vial or bag after shipping or storage time. 5. Separation of small quantity of the powder from the bulk-specifically just before the production of individual doses such as during tableting, encapsulation and vial filling which affect the weight uniformity of the dose (under or over dosage). 23 FACTORS AFFECTING THE FLOW PROPERTIES OF POWDERS 1. Alteration of Particle’s size and distribution 2. Alteration of Particle shape and texture 3. Alteration of Surface Forces 4. Formulation additives 24  TABLETS These are small compressed masses containing a medicament(s), officially circular in shape. They may be flat or bi-convex. In most instances they contain additional substances necessary for their manufacture, disintegration or appearance. The EP defines tablets as solid preparations each containing a single dose of one or more active substances. A tablet consists of one or more drugs (active pharmaceutical ingredients) as well a series of other substances (excipients) used in the formulation of a complete preparation. The oral route is the most common way of administering drugs and among the oral dosage forms, tablets of various kinds are the most common type of solid dosage form in contemporary use. 25  Tablets may differ greatly in size and weight depending on the amount of drug substance present and the intended method of administration. They are divided into two general classes, whether they are made by compression or molding. Compressed Tablets (CT) They are formed by compression and contain no special coating. They are made from powdered, crystalline or granular materials, alone or in combination with binders, disintegrants, controlled-release polymers, lubricants, diluents and, in many cases, colourants. 26  Sugar-Coated Tablets (SCT) - These are compressed tablets containing a sugar coating. Such coatings may be coloured and are beneficial in covering up drug substances possessing bitter tastes or odours, and in protecting materials sensitive to oxidation. Film-Coated Tablets (FCT) - These are compressed tablets which are covered with a thin layer or film of a water-soluble material. A number of polymeric substances with film-forming properties may be used. Film coating imparts the same general characteristics as sugar coating with the added advantage of a greatly reduced time period required for the coating operation. 27  Enteric-Coated Tablets (ECT) - These are compressed tablets coated with substances that resist solution in gastric fluid but disintegrate in the intestine. It can be used for tablets containing drug substances which are inactivated or destroyed in the stomach, for those which irritate the mucosa or as a means of delayed release of the medication. Multiple Compressed Tablets (MCT) - These are compressed tablets made by more than one compression cycle. They are also known as layered tablets and are prepared by compressing additional tablet granulation on a previously compressed granulation. The operation may be repeated to produce multilayered tablets of two or three layers. Special tablet presses are required to make layered tablets. 28  Press-Coated Tablets are prepared by feeding previously compressed tablets into a special tableting machine and compressing another granulation layer around the preformed tablets. They have all the advantages of compressed tablets, i.e, monogramming, speed of disintegration, etc., while retaining the attributes of sugar-coated tablets in masking the taste of the drug substance in the core tablets. 29  Press-coated tablets also can be used to separate incompatible drug substances. In addition, they can provide a means to give an enteric coating to the core tablets. Both types of multiple- compressed tablets have been used widely in the design of prolonged-action dosage forms. Controlled-Release Tablets - Compressed tablets can be formulated to release the drug slowly over a prolonged period of time. Hence, referred to as prolonged-release or Sustained- Release dosage forms as well. These tablets are categorized into three types: 30  (1) those which respond to some physiological condition to release the drug, such as enteric coatings; (2) those that release the drug in a relatively steady, controlled manner and (3) those that combine combinations of mechanisms to release “pulses” of drug, such as repeat-action tablets Tablets for Solution: Compressed tablets to be used for preparing solutions or imparting given characteristics to solutions must be labeled to indicate that they are not to be swallowed. Examples of these tablet: Potassium permanganate tablets for Solution. 31  Effervescent Tablets: In addition to the drug substance, these contain sodium bicarbonate and an organic acid such as tartaric or citric. In the presence of water, these additives react liberating carbon dioxide which acts as a disintegrant and produces effervescence. Effervescent tablets are normally soluble. Pessaries or Inserts: Vaginal pessaries such as metronidazole and clotrimazole pessaries, are prepared by compression. They are normally inserted into the vagina where they dissolve and are used to treat vagina trichomoniasis infections caused by trichomonal vaginalis. An applicator is normally added to aid the administration of the drug into the vagina. Buccal and Sublingual Tablets: These are small, flat, oval tablets. They are normally placed in the buccal pouch where they dissolve and are absorbed into the blood stream to exert their pharmacological actions. 32  Some newer approaches use tablets that melt at body temperatures. The matrix of the tablet is solidified while the drug is in solution. After melting, the drug is automatically in solution and available for absorption, thus eliminating dissolution as a rate-limiting step in the absorption of poorly soluble compounds. Sublingual tablets: They normally contain nitroglycerin, isoproterenol hydrochloride, are placed under the tongue. Sublingual tablets to be placed under the tongue where they dissolve or disintegrate quickly and absorbed directly without passing through the GIT e.g. Glyceryl trinitrate used in the management of Angina Pectoris. 33  Molded Tablets (Tablet Triturates (TT)): Tablet triturates usually are made from moist material using a triturate mold which gives them the shape of cut sections of a cylinder. Such tablets must be completely and rapidly soluble. The problem arising from compression of these tablets is the failure to find a lubricant that is completely water soluble. Dispensing Tablets (DT): These tablets provide a convenient quantity of potent drug that can be incorporated readily into powders and liquids, thus circumventing the necessity to weigh small quantities. These tablets are supplied primarily as a convenience for extemporaneous compounding and should never be dispensed as a dosage form. 34  Tablets that disintegrate readily when swallowed; e.g. Aspirin Tablets ‘Lozenge’ tablets: These do not disintegrate readily and are intended for slow solution in the mouth, usually to produce a local action on the throat. Tablets to be dissolved in water for administration, either: Orally By external application, or By parenteral injection. Chewable Tablets e.g. Magnesium trisilicate tablet in which mastication ensures thorough breaking up of the mass and diffusion of the antacid, which acts mainly by adsorption. 35  ADVANTAGES OF TABLETS The oral route represents a convenient and safe way of drug administration. Compared to liquid dosage forms, tablets (and other solid dosage forms) have general advantages in terms of chemical, physical and microbiological stability of the dosage form. The preparation procedure enables accurate dosing of the drug. Tablets are convenient to handle and can be prepared in a versatile way with respect to their use and the delivery of the drug. Tablets can be relatively cheaply mass produced, with robust and quality-controlled production procedures giving an elegant preparation of consistent quality. 36  DISADVANTAGES OF TABLETS Poor bioavailability of drugs due to unfavorable drug properties, e.g. poor solubility, poor absorption properties and instability in the GIT. In addition, Some drugs may cause local irritant effects or otherwise cause harm to the GI mucosa. Bitter taste 37  QUALITIES OF TABLETS The attributes that a tablet must possess can be summarized as follows: The tablet should include the correct dose of the drug. The appearance of the tablet should be elegant, and its weight, size and appearance should be consistent. The drug should be released from the tablet in a controlled and reproducible way. The tablet should be biocompatible i.e. not include excipients, contaminants and microorganisms that could harm to patients. 38  The tablet should of sufficient mechanical strength to withstand fracture and abrasion during handling at all stages of its lifetime. The tablet should be chemically, physically, and microbiologically stable during the lifetime of the product. The tablet should be formulated into a product acceptable to the patient. The tablet should be packed in a safe manner. 39  TABLETS EXCIPIENTS In addition to the active or therapeutic ingredients, tablets contain a number of inert materials (excipients). They are classified according to the part they play in the finished tablet. 1. Those which help to impart satisfactory processing and compression characteristics to the formulation (diluents, binders, glidants and lubricants). 2. Those that to give additional desirable physical characteristics to the finished tablet (disintegrants, colours, and in the case of chewable tablets, flavours and sweetening agents, and in the case of controlled- release tablets, polymers or waxes or other solubility-retarding materials. 40  Diluent or filler is an inert substance that is added to increase the bulk in order to make the tablet a practical size for compression. Diluents used for this purpose include lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Diluents used as excipients for direct compression formulas have been subjected to prior processing to give them flowability and compressibility. 41  Selection of the diluent This is based on the experience of the manufacturer as well as on diluent cost and compatibility with other tablet ingredients. In the formulation of new therapeutic agents, the compatibility of the diluents with the drug must be considered, e.g. calcium salts used as diluents for the broad-spectrum antibiotic tetracycline have been shown to interfere with the absorption of the drug from the gastrointestinal tract. When drug substances have low water solubility, it is recommended that water-soluble diluents be used to avoid possible bioavailability problems. 42  Highly adsorbent substances, e.g, bentonite and kaolin, are to be avoided in making tablets of drugs used clinically in small dosage, such as the cardiac glycosides, alkaloids and the synthetic estrogens. These drug substances may be adsorbed after administration. The combination of amine bases or salts with lactose in the presence of an alkaline lubricant, results in tablets which discolour on aging. 43  Microcrystalline cellulose (Avicel) usually is used as an excipient in direct-compression formula. However, its presence in 5-15% concentrations in wet granulations has been shown to be beneficial in the granulation and drying processes in minimizing core-hardening of the tablets and in reducing tablet mottling. Many ingredients are used for several different purposes, even within the same formulation; e.g., corn starch can be used in paste form as binder, in dry form as disintegrant. 44  BINDERS Binders are agents used to impart cohesive qualities to the powdered material to ensure the tablet remains intact after compression, as well as improving the free- flowing qualities by the formulation of granules of desired hardness and size. Commonly used binders include: starch, gelatin and sugars as sucrose, glucose, dextrose, and lactose. Natural and synthetic gums which have been used include acacia, sodium alginate, carboxy- methylcellulose, methylcellulose, polyvinyl pyrrolidone, Veegum. Other agents which may be considered binders under certain circumstances are polyethylene glycol, ethylcellulose, waxes, water and alcohol. 45  The quantity of binder used has considerable influence on the characteristics of the compressed tablets. The use of too much binder or too strong a binder will make a hard tablet which will not disintegrate easily and which will cause excessive wear of punches and dies. Usually materials which have no cohesive qualities of their own will require a stronger binder than those with these qualities. Binders are used both as a solution and in a dry form depending on other ingredients and method of preparation. The same amount of binder in solution will be more effective than if it were in a dry form and moistened with the solvent. 46  So it is preferable to incorporate the binding agent in solution. If the drug substance is adversely affected by an aqueous binder, a non aqueous binder should be used or binder can be added dry. The direct-compression method for preparing tablets requires a material that not only is free-flowing but also sufficiently cohesive to act as a binder. Lubricants prevent adhesion of the tablet materials to the surface of the dies and punches. Reduce inter particle friction. Facilitate the ejection of the tablets from the die cavity. 47  May improve the rate of flow of the granules. Commonly used lubricants include: talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and (PEG). Most lubricants, with the exception of talc, are used in concentrations less than 1%. When used alone, talc may require concentrations as high as 5%. Lubricants are in most cases are hydrophobic materials. Poor selection or excessive amounts can result in “waterproofing” the tablets, resulting in poor tablet disintegration and or delayed dissolution of the drug substance. 48  Anti-adherants: reduce sticking and adhesion of the granules or powder to the faces of the punches or to the die walls. Glidants promote the flow of the granules or powder materials by reducing friction among particles Disintegrant is a substance, or a mixture of substances, added to a tablet to facilitate its breakup or disintegration after administration. Materials serving as disintegrants have been classified chemically as starches, clays, celluloses, gums and cross-linked polymers. 49  The oldest and still the most popular disintegrants are corn and potato starch which have been well-dried and powdered. Starch has a great affinity for water and swells when moistened, thus facilitating the rupture of the tablet matrix. Its disintegrating action in tablets is also due to capillary action rather than swelling. 50  Starch 5%, is suggested, but if more rapid disintegration is desired, this amount may be increased to 10 or 15%. Usually disintegration time would decrease as the percentage of starch increased. A group of materials known as super disintegrants are commonly used these days. Examples include: Croscarmellose, crospovidone and sodium starch glycolate. They are normally effective low concentrations (2 to 4%). Sodium starch glycolate swells 7-12 fold in less than 30 seconds while Croscarmellose swells 4-8 fold in less than 10 seconds. 51  The disintegrating agent usually is mixed with the active ingredients and diluents prior to granulation. In some cases it may be advantageous to divide the starch (disintegrant) into two portions: One part is added to the powdered formula prior to granulation (intragranular incorporation), and the remainder is mixed with the lubricant and added prior to compression (extragranular incorporation). 52  This method is known as intra-extra granular incorporation, in this case, the disintegrant serves two purposes; the portion added to the granules extragranularly rapidly breaks down the tablet to granules, and the disintegrant added intragranularly disintegrates the granules into smaller particles. Other factors other than the presence of disintegrants that can affect the disintegration time of compressed tablets include: 1- The binder 2- Tablet hardness 3- Lubricant. 4- Evolution of carbon dioxide as in the case of effervescent tablets. 53 Colours and dyes serve to Mask off-color drugs. Provide product identification. Produce a more elegant product. Food, drug, and cosmetic dyes are applied as solutions; lakes (dyes that have been absorbed on a hydrous oxide) are usually employed as dry powders. 54  FLAVOURANTS Flavouring agents are usually limited to chewable tablets or tablets intended to dissolve in the mouth. (a) Generally, water-soluble flavours have poor stability; hence, flavour oils or dry powders usually are used. (b) Flavour oils may be added to granules in solvents, dispersed on clays and other adsorbents, or emulsified in aqueous granulating agents. 55  Artificial sweeteners, like flavours, are usually used only with chewable tablets or tablets dissolve in the mouth. (a) Some sweetness may come from the diluent (e.g., mannitol, lactose); sweetners such as saccharin and aspartame can also be added. (b) Saccharin has an unpleasant after taste. (c) Aspartame is not stable in the presence of moisture. ADBSORBENTS Adsorbents(e.g., magnesium oxide, magnesium carbonate, bentonite, silicon dioxide) are substances capable of holding quantities of fluid in an apparently dry state. 56  PROBLEMS ENCOUNTERED DURING TABLETING Capping is the partial or complete separation of the top or bottom crowns of a tablet from the main body of the tablet. Lamination is separation of a tablet into two or more distinct layers. Both of these problems usually result from entrapment of air during processing. Picking is removal of a tablet’s surface material by a punch. Sticking is adhesion of tablet material to a die wall. These two problems result from excessive moisture or substances with low melting temperatures in the formulation. 57  c. Mottling is an unequal colour distribution on a tablet, with light or dark areas standing on otherwise uniform surface. This results from use of a drug with a colour different from that of the tablet excipients or from a drug with coloured degradation products. 58  TABLET EVALUATION Non-official Tests: 1) General appearance i) Organoleptic property ii) Size and Shape iii) Tablet thickness iv) Diameter 59  2) Official tests: i) Weight Variation ii) Content uniformity iii) Dissolution iv) Disintegration v) Hardness vi) Friability 60  TABLET HARDNESS Tablets require a certain amount of strength or hardness to withstand mechanical shocks or vibration due to handling, transportation, packaging and shipping. Tablet hardness is the force required to break a tablet along its diameter by applying compression load. Hardness is sometimes referred to as the tablet crushing strength Hardness is very important in both tablet disintegration and dissolution. 61  HARDNESS TEST The tablet is placed between two anvils, force is applied to the anvils, and the crushing strength that causes the tablet to break diametrically is recorded (in kg). The BP states that the conventional tablet hardness should be between 4 – 8 kg. Tablet hardness tester include:- Monsanto tester Pfizer tester Strong-cobb tester Erweka tester Scleuniger tester 62 The hardness of a tablet depends on the compression force, concentration and type of binding agent If the tablet is too hard, it may fail to disintegrate within the specified period of time. If it is too soft, it may not be able to withstand the necessary multiple shocks or vibration occurring during handling, shipping, transportation and dispensing. 63  FRIABILITY Friability is defined as the percentage of weight loss of powder from the surface of the tablets due to mechanical action and the test is performed to measure the weight loss during transportation, shipping packaging and storage. It is a supplement test for uncoated/compressed tablets other than physical measurement e.g. Hardness (tablet breaking force). Compressed tablets that lose less than 0.5%- 1% of their weight are generally considered acceptable. BP specifies that the friability of tablets should be 110% Content uniformity Test The amount of active ingredients should be within the range of 85% to 115% of the label amount for 9 of 10 capsules, with none outside the range of 70% to 125% of label amount Disintegration test Dissolution test 135  MIXING Mixing is the most widely used operation in which two or more substances are combined together. It is an operation in which two or more components (in a separate or roughly mixed condition) are treated so that each particle lies as nearly as possible in contact with a particle of each of the other ingredients. It is a process that tends to result in a randomization of dissimilar particles within a system.  Perfect or ideal mixing is that in which each particle of one material lies as nearly adjacent as possible to a particle of the other material or when the quantity of materials in all part of a system is the same (e.g. ABABAB). Random mixing: A mix where the probability of selecting a particular type of particle is the same at all positions in the mix, and is equal to the proportion of such particles in the total mix or proportion is different in all parts a system e.g. AB AA BA AB.  SEGREGATION (DE-MIXING): Segregation is the opposite effect to mixing, i.e. components tend to separate out. Segregation occurs because powder mixtures encountered practically are not composed of mono- sized spherical particles, but contain particles that differ in size, shape and density. These variations mean that particles will tend to behave differently when forced to move and hence, tend to separate. TYPES OF SEGREGATION Percolation segregation: Smaller particles tend to fall through the voids between larger ones and so move to the bottom of the mass. It may occur in static powder beds, but occurs to a greater extent as the bed 'dilates' on being disturbed.  Trajectory segregation: Larger particles will tend to have greater kinetic energy imparted to them (owing to their larger mass) and therefore move greater distances than smaller particles before they come to rest. This may result in the separation of particles of different size. Elutriation segregation/dusting out: When a material is discharged from a container, very small particles ('dust') in a mix may tend to be 'blown' upwards by turbulent air currents as the mass tumbles, and remain suspended in the air. When the mixer is stopped or material discharge is complete, these particles will sediment and subsequently form a layer on top of the coarser particles.  OBJECTIVES OF MIXING The main objectives of mixing include: 1. Simple physical mixing of materials to form a uniform mixture e.g. mixing a solid with a solvent to produce a solution 2. To promote a chemical reaction to get uniform products. 3. Dispersion of solid in liquid to form suspension or paste. 4. Dispersion of two immiscible liquids to form an emulsion.  REASONS FOR MIXING It is a unit operation for tablet, capsule because many ingredients are used hence mixing is required. Potent materials (e.g. 0.2µg) such as digoxin and folic acid are difficult to formulate alone hence they have to be mixed with bulking agents and other excipients before formulation.  TYPES OF MIXTURES There are three types of mixtures Positive mixture: Occurs when two or more miscible liquids are mixed together or a soluble solid is dissolved in water (e.g. salt and water). These mixtures do not present any problem in mixing as they mix easily and spontaneously (i.e. requiring no energy input for mixing). The mixture formed is irreversible (separation requires the application of energy e.g. when two or more gases or miscible liquids are mixed together by means of diffusion process (water and milk)  Negative mixtures: occur when two immiscible liquids are mixed together (e.g. oil and water; emulsion) or insoluble solids are mixed with water (magnesium trisilicate and water; suspension). To prepare such types of mixtures, a higher degree of mixing of materials is required and energy is also required to achieve a better degree of mixedness. The mixture formed is a reversible mixture. Negative mixtures require a higher degree of mixing along with the expenditure of energy for mixing to occur. Separation of negative mixture occurs without energy e.g. suspensions of solids in liquids and emulsions of two immiscible liquids. Neutral mixtures: These mixtures are static in behaviour (i.e. they have no tendency to mix spontaneously or segregate when mixed). Both mixing and segregation occurs with expenditure of energy. E.g. physical mixing (pastes, ointments and mixed powders) TYPES OF MIXING Liquid mixing or fluid mixing Powder mixing or solid mixing Semi-solid mixing  LIQUID MIXING A) FLUID/LIQUID MIXING The mixing process may be easy for some fluid and difficult for others. The following three parameters gives necessary knowledge about basic requirement of fluid for mixing. Flow characteristics Mixing mechanisms Mixing equipment FLOW CHARACTERISTICS: The fluid may flow freely or flow with resistance. Fluids show different flow characteristics which may be classified as Newtonian fluid and non – Newtonian fluid.  NEWTONIAN FLUIDS are fluids that flow like water and for them the shear stress (force applied) is directly proportional to the shear rate. Newtonian fluids are those whose viscosity does not change by shear stress. NON-NEWTONIAN FLUIDS These are fluids whose viscosity changes with increase or decrease in shear stress. Non-Newtonian fluids are of three types. 1) PLASTIC/BINGHAM FLOW: A certain shearing stress must be exerted before the flow begins. This stress is termed is Yield value (Flow will not occur by applying stress below this value).  The system behaves like a solid when small stresses (lower than yield value) are applied i.e. the system exhibits elastic deformations that are reversible when these small stresses are removed. PSEUDO-PLASTIC FLOW: A type of flow where no yield value exist and the flow begins immediately on the application of a shearing stress. Viscosity decreases as the shear rate is increased until a constant value is reached DILATANT FLOW: It is opposite to that of pseudo-plastic flow in that the viscosity increases with increase in shear rate. As such material increase in volume during shearing, they are referred to as dilatants and exhibit shear thickening.  MECHANISM OF FLUID MIXING Four types of mechanism are involved in mixing of fluids and they include: Bulk transport mixing Turbulent mixing Laminar mixing Molecular diffusion  FACTORS AFFECTING THE MIXING OF POWDERS There are various physical properties which affect the perfect mixing of powders 1. Particle size: It is easy to mix two powders having approximate the same particle sizes. The variation of particle size can lead to separation also, because the small particles move downward through the spaces between the bigger particles. 2. Particle shape: The ideal particle is spherical in shape for the purpose of uniform mixing. The irregular shapes can become interlocked and there are less chances of separation of particles once these are mixed together. 3. Particle attraction: Some particles exert attractive forces due to electrostatic charges on them. This can lead to separation. 4. Material density: It is difficult to mix two powders having different density. This is due to the fact that dense material always moves downward and settles down at the bottom. Therefore, for uniform mixing of powders, proper attention should be given to their density. 5. Proportions of materials: The best results can be achieved if two powders are mixed in equal proportions by weight or by volume. In case there is a large difference in the proportion of two powders to be mixed, the mixing of powders is always done in the ascending order of their weights.  HOMOGENIZATION Homogenization is the process of preparing fine emulsion from a coarse emulsion by converting the large globules to small globules. Homogenization is done in an apparatus called 'Homogenizer'. The homogenizers are based on the principle that the large globules in a coarse emulsion are broken into smaller globules by passing them under pressure through a narrow orifice. The commonly used homogenizers are: Hand homogenizer Silverson mixer homogenizer Colloidal mill  DRYING Drying is a mass transfer process resulting in the removal of moisture (water) or another solvent, by evaporation from a solid, semi-solid or liquid to end in a solid state. To achieve this, there must be a source of heat. Drying is most commonly used in manufacturing as a unit process in the preparation of granules, which can be dispensed in bulk or converted into tablets or capsules. 152  PURPOSES OF DRYING In pharmaceutical technology, drying is carried out for the following reasons: To avoid or eliminate moisture which may lead to corrosion and decrease the stability of the drug. To improve or keep good properties of a material, e.g. flowability, compressibility. To reduce the cost of transportation of large volume materials (liquids). To make the material easy or more suitable for handling. Drying is the final step in evaporation, filtration and crystallization. 153  LYOPHILIZATION This is also known as freeze drying, gelsicsation or drying by sublimation. The product to be dried is first frozen and then subjected to drying under high vacuum through sublimation. The method is applied only biological products for example, antibiotics (other than penicillin), blood products, vaccines (such as BCG, yellow fever, small pox), enzyme preparation such as hyaluronidase and microbiological cultures. 154 155 The triple point is the temperature and pressure at which a substance can exist in equilibrium in the liquid, solid, and gaseous states. The triple point of pure water is at 0.01°C (273.16K, 32.01°F) and 4.58 mm (611.2Pa) of mercury and is used to calibrate thermometers. It is that temperature and pressure at which the sublimation curve, fusion curve and the vaporization curve meet. In thermodynamics, the triple point of a substance is the temperature and pressure at which the three phases of that substance coexist in thermodynamic equilibrium. The water in pharmaceutical products intended for freeze drying contains dissolved solids, resulting in different temperature- pressure relationship for each solute. 156 In such cases, the point at which solid water is sublimed is known as eutectic point Freeze drying condition Temperature = -10 to -40°C Pressure = 2000 to 100 microns Composition of freeze dryer Chamber for vacuum drying Vacuum source (Vacuum pump, steam ejectors) Heat source Vapour removal system (Condensors, Dessicants, pumps) 157 FREEZE DRYER 158 FREEZE DRYER 159 Advantages: Minimum damage and loss of activity in delicate heat- liable materials Speed and completeness of rehydration Possibility of accurate, clean dosing into final product containers Porous, friable structure Drying takes place at very low temperatures, so that enzyme action is inhibited and decomposition particularly hydrolysis is minimized. 160  The solution is frozen so that the final dry product is a network of solid occupying the same volume as the original solution. Thus, there is no case-hardening and the product is light and porous. The porous form of the product gives ready solubility There is no concentration of the solution prior to drying. Hence, salts do not concentrate and denature proteins as occurs with other drying methods. Under high vacuum, there is no contact with air and oxidation is minimized. 161 Disadvantages: High capital cost of equipment (about three times more than other methods) High energy costs (2-3 times more than other methods) Long process time (typically 24 hour drying cycle) The porosity, ready solubility and complete dryness yield a very hygroscopic product. Unless dried in the final container and sealed in situ, packaging requires special attention. It is very expensive, hence it is limited to certain types of valuable products that cannot be dried by any other means. 162 Uses Lyophilization should be used when the product meets one or more of the following criteria: unstable; heat liable; minimum particulates required; accurate dosing needed; Quick and complete rehydration needed; High value. 163  Hormones Blood serum Plasma Antibiotics Bacterial culture 164  THANK YOU FOR LISTENING BEST WISHES IN YOUR FINAL EXAMS 165