Pharmaceutical Formulation PDF

XYZ is an oleaginous base Ture/False? Oleaginous bases are also termed hydrocarbon bases They -have an emollient effect on the skin -Protect against the escape of moisture -are effective as occlusive dressings -Can remain on the skin for long periods without drying out and -Are difficult to wash off...

XYZ is an oleaginous base Ture/False? Oleaginous bases are also termed hydrocarbon bases They -have an emollient effect on the skin -Protect against the escape of moisture -are effective as occlusive dressings -Can remain on the skin for long periods without drying out and -Are difficult to wash off because of water immiscibility Examples: Petrolatum, white petrolatum, white ointment and yellow ointment (Major difference between ointment/cream or cream/gel or ointment/gel) HLB value ranges for o/w or w/o and for all other kinds of dispersion systems Hydrophilic- lipophilic balance -materials that are highly polar or hydrophilic have been assigned higher numbers than materials that are less polar and more lipophilic Span vs Tween Major difference between Topical and Transdermal For transdermal drug delivery, it is considered ideal for the drug to migrate through the skin to the underlying blood supply without buildup in the dermal layers. This is in direct contrast to the types of topical dosage forms, in which skin is the target organ for drug residence. What kind of drugs are suitable candidates for Topical (Hints: MWt, logP, daily dose etc) Clear idea about 4 different ointment bases (Properties, examples) (a) Oleaginous bases( are difficult to wash off because of water immiscibility ex: petrolatum) (b) Absorption bases( water in oil emulsion; hard to wash off because of the oleaginous external Exp: Hydrophilic petrolatum) (c) Water-removable bases( Oil in water emulsion commonly known as creams Exp: hydrophilic ointment) (d) Water-soluble bases( do not contain oleaginous components water washable; Exp: PEG) Unguator and its uses Ointment mill, an electronic mortar and pestle Used to mix ointment Clear concept of levigation, spatulation and geometric dilution Spatulation- using a spatula to work with ointment Geometric dilution - use so that all portions of the powder and bases are combined Levitating- mixing the solid material in a vehicle in which it is insoluble to make a smooth dispersion Types of creams: vanishing cream Vanishing cream is oil in water emulsion after applying the water evaporates leaving a thin residue of the oleaginous compound behind Gels: define and examples of gelling agents Semisolid systems consisting of the dispersion of small or large molecules in a liquid vehicle rendered jellylike by the addition of a gelling agent Example of gelling agents: carbomer Know about Magma/ Milk of magnesia Two-phase system - gel mass consisting of floccules of small distinct particles. Gels may thicken on standing forming a thixotropy and must be shaken before use to liquefy the gel and enable poring Know your skin/ Skin anatomy (stratum corneum , living epidermis and dermis) The stratum corneum is composed of approximately 40% protein (mainly keratin) and 40% water, with the balance being lipid, principally as triglycerides, free fatty acids, cholesterol, and phospholipids Percutaneous absorption: Factors Percutaneous absorption of a drug generally results from direct penetration of the drug through the stratum corneum, a 10 to 15 mm thick layer of flat partially desiccated nonliving tissue Among the factors playing a part in percutaneous absorption are the physical and chemical properties of the drug including its molecular weight, solubility, partitioning coefficient and dissociation constant(pKa), the nature of the carrier vehicle, and the condition of the skin 1. Drug concentration is an important factor generally the amount of drug percutaneousl absorbed per unit of surface area per time interval increases with an increase in the concentration of the drug in the TDDS 2. The larger the area of application(the larger the TDDS), the more drug is absorbed 3. The drug should have a greater physicochemical attraction to the skin than to the vehicle so that the drug will leave the vehicle in favor of the skin Generally, drugs penetrate the skin better in their unionized form Nonpolar drugs tend to cross the cell barrier through the lipid-rich regions(transcellular route), whereas the polar drugs favor transport between cells For example, the erythromycin base demonstrates better percutaneous absorption than does erythromycin ethyl succinate Drugs with molecular weights of 100 to 800 and adequate lipid and aqueous solubility can permeate skin The Ideal molecular weight of a drug for transdermal drug delivery is believed to be 400 or less Hydration of the skin generally favors percutaneous absorption. The TDDs acts as an occlusive moisture barrier through which sweat cannot pass, increasing skin hydration Percutaneous absorption appears to be greater when the TDDs are applied to a site with a thin horny layer than with a thick one. Names of skin enhancers: chemical and physical Chemical enhancers by definition, chemical skin penetration enhancers increase skin permeability by reversibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance Among the alterations are increased hydration of the stratum corneum, a change in the structure of the lipids and lipoproteins in the intercellular channels through solvent action or denaturation, or both Some drugs have an inherent capacity to permeate the skin without chemical enhancers. However, when this is not the case, chemical permeation enhancers render an otherwise impenetrable substance useful in transdermal drug delivery More than 275 chemical compounds have been cited in the literature as skin penetration enhancers; they include acetone, azone, dimethylacetamide, dimethyl sulfoxide, ethanol, oleic acid, polyethylene glycol, propylene glycol, sodium lauryl sulfate Physical enhancer Iontophoresis and sonophoresis In addition to chemical means, some physical methods are being used to enhance transdermal drug delivery and penetration, namely, iontophoresis and sonophoresis Iontophoresis is delivery of a charged chemical compound across the skin membrane using an electrical field A number of drugs have been the subject of iontophoretic studies; they include lidocaine; dexamethasone; amino acids, peptides, and insulin, verapamil; and propranolol Sonophoresis, or high-frequency ultrasound, is also being studied as a means to enhance transdermal drug delivery Among the agents examined are hydrocortisone, lidocaine, and salicylic acid in such formations as gels, creams, and lotions. It is through that high-frequency ultrasound can influence the integrity of the stratum corneum and thus affect its penetrability Advantages and disadvantages of TDDS TDDs( also called transdermal patches ) are designed to support the passage of drug substances from the surface of the skin through its various layers and into the systemic circulation Technically, TDDss may be categorized into two types Monolithic and membrane controlled systems 1. Monolithic systems incorporate a drug matrix layer between the backing and the frontal layers 2. The drug matrix layer is composed of a polymeric material in which the drug is dispersed 3. The polymer matrix controls the rate at which the drug is released for percutaneous absorption Disperse systems: Types, Define, Examples Disperse system- A system in which materials/substances( the dispersed phase) is distributed throughout a second substance( the continuous phase or vehicle) Dispersed systems consist of two phases: Dispersed phase/internal phase Dispersion medium(continuous phase/ vehicle/ external phase) Dispersion consists of at least one internal phase that is dispersed in a dispersion medium Each phase can exist in a solid, liquid, or gaseous state( ex: suspension, emulsion, and inhaler/aerosol) Very commonly used suspending agents (amoxicillin for oral suspension) Emulsion vs Suspension: know the basic difference Suspensions: Dispersed system: insoluble solid particles are dispersed in a liquid medium Example: Dispersed phase: insoluble solid particles External Phase: liquid medium Emulsion Dispersed system: mixture of immiscible liquids Example Dispersed phase: oil External Phase: water Oral vs For Oral Suspension Suspensions A pharmaceutical suspension is a coarse dispersion in which insoluble solid particles are dispersed in a liquid medium Suspensions are preparations containing finely divided drug particles( the suspensoid) distributed somewhat uniformly throughout a vehicle in which the drug exhitbis a minium degree of solubility Examples- oral antibiotic suspensions, which normally contain 125 to 500 mg of solid drug in each 5 ml Pharmaceutical suspensions can be found in 1. Ready to use form, that is already distributed through a liquid vehicle with or without stabilizers and other additives. Prepared suspensions not requiring reconstitution at the time of dispensing are simply designated as “oral suspension” 2. Dry powders intended for suspension in liquid vehicles Drugs that are unstable in the presence of an aqueous vehicle are most frequently supplied as dry powder mixtures for reconstitution at the time of dispensing. This type of preparation is designated in the USP by a title of the form for oral suspension Particle size range in Susp, colloids, and Molecular dispersions as shown by the Stokes equation, the reduction in the particle size of a suspensoid is beneficial to the stability of the suspension because the rate of sedimentation of the solid particles is reduced as the particles are decreased in size. The reduction in particle size produces slow, more uniform rates of settling. However, one should avoid reducing the particle size too much because fine particles have a tendency to form a compact cake upon settling to the bottom of the container To avoid formation of a cake, it is necessary to prevent agglomeration of the particles into larger crystals One such method is formation of a less rigid or loose aggregation of the particles by weak particle-to-particle bonds. Such an aggregation of particles is termed a floc or a floccule Reasons for making suspension a dosage form Certain drugs are chemically unstable in solution but stable when suspended The drug in suspension exhibits a higher rate of bioavailability than other dosage forms. The ranking of bioavailability is as follows: Solution - suspension- capsules- compressed tablet- coated tablet Concept of Taste Masking in Suspension To mask the bitter or unpleasant taste of drug. Test making easier to achieve in suspension because the contact drug with the test buds is much less in suspension than in solution For many patients, The liquid form is preferred over the solid form of the same drug because of the ease of swallowing and the flexibility in the administration of a range of doses This is particularly advantageous for infants, children, and the elderly The disadvantage of a disagreeable taste of certain drugs in solution form is overcome when the drug is administered as undissolved particles of an oral suspension. In fact, chemical forms of certain poor-tasting drugs have been specifically developed for their insolubility in a desired vehicle for the sole purpose of preparing a palatable liquid dosage form. For example, erythromycin estolate is a less water-soluble ester form of erythromycin and is used to prepare a palatable liquid dosage form of erythromycin as Erythromycin Estolate Oral Suspension, USP. Use of insoluble forms of drugs in suspensions greatly helps in taste-masking For the most part, oral suspensions are aqueous preparations with the vehicle flavored and sweetened to suit the anticipated taste preferences of the intended patient. Stability problems in suspension: cake formation, deflocculation Deflocculated suspension In the deflocculated systems particles Behave independently Deflocculated particles settle slowly over time and form a sediment( a hard cake) that is difficult to re-suspend Flocculated suspension The particles are arranged in loose aggregates or follicles Flocculated particles are weakly boned Settle rapidly Do not form a cake and are easily re-suspended The primary concern with respect to liquid dosage forms are homogeneity and freedom from excessive microbial contamination and growth Instability may be indicated by cloudiness, non-suspendable caking, or organoleptic changes A caked solid phase that cannot be resuspended by a reasonable amount of shaking is a primary indication of instability in a suspension The presence of relatively large particles may mean that excessive crystal growth has occurred Microbial growth may be accompanied by discoloration, turbidity, or gas formation Stoke’s equation: Factors affecting sedimentation As shown by the stokes equation, the reduction in the particle size of a suspensoid is beneficial to the stability of the suspension because the rate of sedimentation of the solid particles is reduced as the particles are decreased in size Purpose of different formulation ingredients: Wetting agents, Chelators, Preservatives, and All others Substances that reduce this resistance encourage a liquid to break up into smaller drops or particles. These tension-lowering substances are surface-active (surfactant) or wetting agents. Examples of suspending agents: Natural and synth Suspending agents are substances that are used to keep finely divided insoluble materials suspended in a liquid media by preventing their agglomeration(coming together) and by imparting viscosity to the dispersion media so that the particles settle more slowly Natural: gun acacia, alginic acid, gentonite, gelatin Syntheic: carbomer(eg carbopol) Why need emulsifiers? Droplet diameters vary enormously in pharmaceutical emulsion but typically cover the range 0.1 um to 25 um The visual appearance of an emulsion reflects the influence of droplet size on light scattering and ranges from transparent or translucent for emulsions composed of small nanosized droplets( smaller than 200nm) to milky white and opaque for emulsions containing larger droplets Because emulsions are thermodynamically unstable, they will revert to separate oil and water continuous phases unless they are kinetically stabilized by the addition of emulsifying agents Examples of emulsion: Parenteral and Topical Sterile intravenous lipid o/w emulsions are used clinically as a source of calories and essential fatty acids for debilitated pateints Such emulsions( intralipid) are also used as intravenous drug carriers for drugs of limited water solubility Marketed produst are available for drugs such as dizepam(diamuls), propfol(Diprovan) and VitaminK Know about surfactants, HLB values, and ranges of HLB for intended applications Emulsification, Interfacial tension, and Coalescence Emulsification enables the pharmacist to prepare relatively stable and homogeneous mixtures of two immiscible liquids When the liquid is in contact with a second liquid in which it is insoluble and immiscible, the force causing each liquid to resist breaking up into smaller particles is called interfacial tension. If two or more drops of the same liquid come into contact with one another, this tendency of joining together is called coalescence, Creaming, Cracking, Ostwald ripening, SEDDS Creaming Aggregation and Coalescence: Aggregates of globules of the internal phase have a greater tendency than do individual particles to rise to the top of the emulsion or fall to the bottom. Such a preparation of the globules is termed the creaming of the emulsion, The term is taken from the dairy industry and is analogous to creaming or rising to the top of cream in milk that is allowed to stand. The creamed portion of an emulsion may be redistributed Cracking More destructive to an emulsion than creaming is coalescence of the globules of the internal phase and separation of that phase into a layer. Separation of the internal phase from the emulsion is called breaking, and the emulsion is described as being cracked or broken. Oswald Ripening When oil and water phases are partially miscible, droplet growth with eventual phase separation may occur by Ostwald ripening rather than coalescence. Ostwald ripening is an irreversible process which involves the growth of large droplets at the expense of smaller ones; Ostwald ripening does not require any contact between droplets and is an important mechanism of instability in sub-micrometre pharmaceutical emulsions. Self Emulsifying Drug Delivery Oral drug delivery using emulsions can be unpredictable because emulsions may become unstable in the low-pH environment of the stomach. Emulsion concentrates, described as self-emulsifying drug delivery systems, are available commercially to minimize instability. Self-emulsifying drug delivery systems (SEDDS) are composed of the drug, oil(s), surfactants and sometimes cosolvents. They are not themselves emulsions, but form an emulsion on mild agitation in the aqueous environment of the stomach pH/buffer conditions in vaginal dosage forms Many vaginal inserts and other types of vaginal dosage forms are buffered to an acid pH usually about 4.5, consistent with the normal vagina. This acidity discourages pathogenic organisms and provides a favorable environment for eventual recolonization by the acid-producing bacilli normally found in the vagina. Types of suppository bases and examples of most common suppository bases BCS class of drugs, USP solubility definition, surfactants, cosolvents, types of water, etc. Water is the most commonly used solvent in pharmaceutical solutions. According to the FDA there are 8 types of water for pharmaceutical use: 1. Non-potable water 2. Potable water 3. USP purified water 4. USP water for injection 5. USP sterile water for injection 6. USP sterile water for inhalation 7. USP bacteriostatic water for injection 8. USP sterile water for irrigation Cosolvents – to increase the solubility of drugs. Examples include glycerol, ethanol, DMSO, etc. Cosolvents increase the solubility of poorly soluble drugs by decreasing the overall polarity of the solvent (water)