SEMI SOLID DOSAGE FORM

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Slide 1:

SEMISOLID DOSAGE FORM SHUBHRAJIT MANTRY Asst.Prof Kottam Institute of Pharmacy. A.P

Slide 2:

SYLLABUS Semi solid dosage form Definition Types Mechanism of drug penetration Factors influencing Penetration Semi solid bases and their selection General formulation of Semi solids Clear gels manufacturing Procedure, Evaluation and Packaging

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B) Dispersed system: Suspension- Suspension formation Formulation and evaluation Emulsion- Formulation, Study of mechanical equipment for emulsification, Chemical Parameters Stability testing and assessment of shelf life.

Slide 4:

DEFINITION: Semisolid dosage forms are dermatological preparations intended to apply externally on the skin to produce local or systemic effect.

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1- PHYSICAL PROPERTIES: a)Smooth texture b) Elegant in appearance c) Non dehydrating d) Non gritty e) Non greasy and non staining f) Non hygroscopic 2-PHYSIOLOGICAL PROPERTIES: a) Non irritating b) Do not alter membrane / skin functioning c) Miscible with skin secretion d) Have low sensitization effect 3-APPLICATION PROPERTIES: a) Easily applicable with efficient drug release b) High aqueous washability IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS

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Semi solid dosage form Ointments Creams Pastes Gel Poultices Plasters Types

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OINTMENTS Ointments are semisolid preparations meant for external application to the skin or mucous membrane. They usually contain a medicament or medicaments dissolves, suspended or emulsified in the base. CREAMS Creams are viscous emulsions of semisolid consistency intended for application to the skin or mucous membrane O /W type W/O type

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PASTES Pastes are the preparations contain a large amount of finely powdered solids such as starch and zinc oxide. These are generally very thick and stiff. JELLIES These are thin transparent or translucent, non greasy preparations. They are similar to mucilages because they are prepared by using gums but they differ from mucilages in having jelly like consistency.

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GELS These are jelly-like semisolid dispersions of drug meant to be applied on the skin. SUPPOSITORIES These are meant for insertion in to the body cavities other than mouth. They may be inserted in to rectum,vagina or urethra.

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POULTICES These are also known as cataplasams. They are soft viscous wet masses of solid substances. PLASTERS These are semi solid masses applied to the skin to enable prolonged contact of drug with the skin. Or Substances intended for external application, made of such materials and consistency as to adhere to the skin and thereby attach as dressing.

Slide 11:

The skin is the largest organ of the body. Human skin is, on average, 0.5 mm thick (ranging from 0.05 mm in eye lid to 2 mm). Structure of the skin: its barrier properties

Slide 12:

Classification of skin based on the epidermis alone especially the surface layer (stratum corneum): thick: palms of hand, soles of feet thin: rest of the body Although the skin is one of the major sites for noninvasive delivery of therapeutic agents into the body, this task can be relatively challenging owing to the impermeability of the skin.

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Skin Structure The skin consists of three major layers: Epidermis Dermis Subcutaneous tissues

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Layers of epidermis

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Layers of epidermis

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Mechanism of drug penetration

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Drugs Sebum Transepidermal Transappendageal Transfollicular Intercellular Diffusion Intracellular (Transcellular Diffusion) Eccrine Glands Hair Follicles Sebaceous Glands Dermis Systemic Circulation M E C H A N I S M OF DRUG P E N E T R A T I O N Subcutaneous tissue

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S T R U T U R E OF S K I N

PERCUTANEOUS ABSORPTION:

PERCUTANEOUS ABSORPTION It involves passive diffusion of substance through skin. Transepidermal penetration: Intra cellular penetration. Inter cellular penetration. Transappendegeal Penetration.

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Factors influencing Penetration

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Physiological and Pathological Condition of Skin Physico-Chemical Properties Of Active Substances Effect of Vehicles Effect of Additives Factors influencing Penetration :

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Reservoir effect of the Horney layer Skin condition Skin Hydration Skin Age Blood Flow Skin Temperature Cutaneous Biotransformation Regional Skin Site Species Variation Lipid Film A) Physiological and Pathological Condition of Skin:

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B) Physico-Chemical Properties Of Active Substances : Molecular Characteristic of drug Drug Concentration Solubility and Partition coefficient Molecular modification polymorphism

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C) Effect of Vehicles : Viscosity pH volatility

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D) Effect of Additives : Surfactants Humectants Penetration enhancers

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Semi solid bases and their selection

Slide 28:

There are four (4) classes or types of bases which are differentiated on the basis of their physical composition. These are: Oleaginous bases. Absorption bases. Emulsifying base. (Water in oil emulsion bases & Oil in water emulsion bases ) 4. Water soluble bases. Semi solid bases

Slide 29:

These bases are fats, fixed oils, hydrocarbon or silicones. They are anhydrous, non-washable does not absorb water. They should not be applied to infected skin. they are used as protectants, emollients , vehicles for hydrolysable drugs. Example: White Petrolatum, White Ointment Oleaginous bases.

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Oleaginous base + w/o surfactant. These bases are generally anhydrous substances which have the property of absorbing (emulsifying) considerable quantities of water but still retaining their ointment-like consistency. The absorption bases are of two types:- i) Non-emulsified bases ii) Water in oil emulsion Absorption bases The non-emulsified bases absorb water and aqueous solution producing w/o emulsion Example: Wool fat, wool alcohol, beeswax and cholesterol. The water in oil emulsion are capable of absorbing more water and have the properties of non-emulsified bases. Example: Hydrous wool fat (lanolin)

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Water in oil emulsion bases These are anhydrous, hydrophilic, absorbs water and non water removable, with low thermal conductivity and occlusive. They have the same properties as the absorption basees . They are used as emollients, cleansing creams, vehicles for solid, liquid, or non- hydrolyzable drugs . Examples: Cold Cream type, Hydrous Lanolin, Rose Water Ointment, Hydrocream ™, Eucerin ®, Nivea ® . Emulsifying base

Slide 32:

Oil in water emulsion bases. These bases are anhydrous, water soluble, absorb water and water washable. They are either Carbowaxes Polyethylene Glycols (PEGs) or hydrated gums (Bentonite, gelatin, cellulose derivatives). They are used as drug vehicles. Examples: PEG Ointment, Polybase™

Slide 33:

Water soluble bases Water soluble does not contain oily and are called greaseless base and are completely soluble in water. Example: A) polyethylene glycol (PEGs), polyoxyl 40 stearate and plysorbates. B) Macrogols They are mixture of water and polycondensation products of ethylene oxide. They are of three types : i) Solid Macrogols ii) Liquid Macrogols iii) Semisolid Macrogols

Slide 34:

The water-soluble bases have the advantages of being: Water soluble and washable Non-greasy, non-staining Non/less occlusive Lipid free Relatively inert Does not support mold growth Little hydrolysis, stable -Disadvantages: May dehydrate skin and hinder percutaneous absorption.

Slide 35:

Requirement for percutaneous or topical absorption. After of the drug on the consistency and other properties of the base. Physicochemical properties like solubility and stability of a drug in the base. Required rate of drug release from the base. Compatibility of the base with the drug and additives. Types of skin lesion at the affected site. Need for preventing the loss of moisture from the skin. Quantity of the liquids to be incorporated in the formulation Selection of Semi solid base

Slide 36:

Selection of the Appropriate Base Based on: 1. Dermatological factors 2. Pharmaceutical factors

Slide 37:

Dermatological factors (a) Absorption and Penetration: ‘Penetration’ means passage of the drug across the skin i.e. cutaneous penetration, and ‘absorption’ means passage of the drug into blood stream. · Medicaments which are both soluble in oil and water are most readily absorbed though the skin. · Whereas animal and vegetable fats and oils normally penetrate the skin. · Animals fats, e.g. lard and wool fat when combined with water, penetrates the skin. · o/w emulsion bases release the medicament more readily than greasy bases or w/o emulsion bases. (b) Effect on the skin · Greasy bases interfere with normal skin functions i.e. heat radiation and sweating. They are irritant to the skin. · o/w emulsion bases and other water miscible bases produce a cooling effect due to the evaporation of water. (c) Miscibility with skin secretion and serum Skin secretions are more readily miscible with emulsion bases than with greasy bases. Due to this the drug is more rapidly and completely released to the skin.

Slide 38:

(d) Compatibility with skin secretions: The bases used should be compatible with skin secretions and should have pH about 5.5 because the average skin pH is around 5.5. Generally neutral ointment bases are preferred. (e) Non-irritant All bases should be highly pure and bases specially for eye ointments should be non-irritant and free from foreign particle. (f) Emollient properties Dryness and brittleness of the skin causes discomfort to the skin therefore, the bases should keep the skin moist. For this purpose water and humectants such as glycerin, propylene glycol are used. Ointments should prevent rapid loss of moisture from the skin. (g) Ease of application and removal The ointment bases should be easily applicable as well as easily removable from the skin by simple washing with water. Stiff and sticky ointment bases require much force to spread on the skin and during rubbing newly formed tissues on the skin may be damaged.

Slide 39:

2. Pharmaceutical factors (a) Stability Fats and oils obtained from animal and plant sources are prone to oxidation unless they are suitably preserved. Due to oxidation odour comes out. This type of reactions are called rancidification . Lard, from animal origin, rancidify rapidly. Soft paraffin, simple ointment and paraffin ointment are inert and stable. Liquid paraffin is also stable but after prolonged storage it gets oxidized. Therefore, an antioxidant like tocopherol ( Vit -E) may be incorporated. Other antioxidants those may be used are butylated hydroxy toluene (BHT) or butylated hydroxy hydroxy anisole (BHA). (b) Solvent properties Most of the medicaments used in the preparation of ointments are insoluble in the ointment bases therefore, they are finely powdered and are distributed uniformly throughout the base.

Slide 40:

(c) Emulsifying properties Hydrocarbon bases absorbs very small amount of water. Wool fat can take about 50% of water and when mixed with other fats can take up several times its own weight of aqueous solution. Emulsifying ointment, cetrimide emulsifying ointment and cetomacrogol emulsifying ointment are capable of absorbing considerable amount of water, forming w/o creams. (d) Consistency The ointments produced should be of suitable consistency. They should neither be hard nor too soft. They should withstand climatic conditions. Thus in summer they should not become too soft and in winter not too hard to be difficult to remove from the container and spread on the skin. The consistency of an ointment base can be controlled by varying the ratio of hard and liquid paraffin.

Slide 41:

General formulation of Semi solids

Slide 42:

METHODS OF PREPARATION Trituration Method Fusion Method Emulsification Method: a) Preparation of Oil and Aqueous Phases b) Mixing of the Phases c) Cooling the Emulsion d) Homogenization 4) Chemical Reaction Method

Slide 43:

Trituration Method It is the most commonly used for the preparation of semisolid. when base contains soft fats and oils, or medicament is insoluble or liquid, then this method is used with spatula or motar and pestle.

Slide 44:

Fusion Method The ingredients of the base are melted together and properly mixed to obtain a uniform product. On small scale, fusion method is carried out in a porcelain dish, which is placed in a waterbath. Initially the ingredient of high melting point is melted. Then remaining ingredient of the base are added in the decreasing order of their melting points and melted with constant stirring. The above mixture is removed from the water bath and stirred in order to cool it. If the drug is soluble in the base, then its powdered from is added to the molten base. Liquid or semisolid are added at a temperature of 40 o c. Insoluble additives are added in small quantities with proper stirring, when the thickening of the base starts. Localized cooling of the molten base and vigorous stirring should be avoided to prevent aeration of the ointment.

Slide 45:

Emulsification Method Preparation of Oil and Aqueous Phases Place the ingredients of the oil phase into the stainless steel steam-jacketed kettle and melt them whilst mixing. Filter the oil phase through several layers of cheese cloth to remove any foreign matter. Heat the emulsion mixing kettle to the temperature of the oil phase. This avoids congealing of higher melting component. Transfer the oil phase into the emulsion mixing kettle. Dissolve the ingredient of the aqueous phase in purified water and filter the solution. A soluble drug which is thermostable may be added to the aqueous phase in this step.

Slide 46:

The phases are usually mixed at a temperature of 70 to 72 0 C,because at this temperature intimate mixing of the liquid phases can occur. The properties of some emulsions depend on the temperature at which the phases are mixed. The initial mixing temperature must be raised above 70 to 72 degrees. Mixing of the Phases

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Three ways of mixing the phases: 1.Simultaneous blending of the phases. 2.Addition of the discontinuous phase to the continuous phase. 3.Additon of the continuous phase to the discontinuous phase.

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Equipments used for mixing of phases: Agitator mixers : Sigma mixer and planetary mixer. Shear mixers: Triple roller mill and Colloidal mill.

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The rate of cooling is generally slow to allow for adequate mixing while the emulsion is still liquid. The temperature of the cooling medium in the equipment should be decreased gradually and at a rate consistent with the mixing of the emulsion and scrapping of the kettle walls to prevent formation of congealed masses of the ointment or cream . Cooling the Emulsion Perfume should be added at 43 to 45 0 c to avoid chilling the emulsion in case of oil in water type emulsion. Perfume should be added at room temperature in water in oil type emulsion. If the drug is not added in the aqueous phase then it should be added in solution form or in the form of crystals.

Slide 50:

The creams or ointments that require further treatment are then transferred to the proper homogenizer, the selection of which is governed by the degree and rate of shear stress required. The choices include a low-shear gear pump, roller mill, a colloidal mill, a valve type homogenizer. Homogenization Roller mill colloidal mill

Slide 51:

In this product is formed by chemical reaction, which involves both fusion and mechanical mixing. Best example of this method is Iodine ointment. Chemical Reaction Method Procedure: Powder iodine in a mortar and pestle and add it to arachis oil taken in a flask. Heat the mixture to 50 0 C with occasional stirring until greenish black colour appears. Add yellow soft paraffin to the above mixture and heat it to 40 0 C with mixing. Cool the Ointment.

Slide 52:

CLEAR GELS

Slide 53:

Gels Gel are transparent semisolid preparation meant for external application to the skin or mucous membrane. Gels are semisolid systems consisting of either suspensions made up of small inorganic particles or large organic molecules in an liquid vehicle rendered jelly like by the addition of a GELLING AGENT. Sometimes called JELLIES

Slide 54:

Important for gel (jelly) semisolid preparations These are organic hydrocolloids or hydrophilic Inorganic substances. They are Tragacanth, Sodium Alginate, Pectin, Starch, Gelatin, Cellulose Derivatives, Carbomer, and Poly Vinyl Alcohol Clays . There are numerous gelling agents varying in gelling ability. Commonly used gelling agents

Slide 55:

Clear gels are microemulsions in which the diameter of the dispersed phase globules is in the range of 10 to 60 nm. These emulsions are thermodynamically stable. Microemulsions are transparent as the globule diameter of the disperse phase is less than the wavelength of light. Microemulsions can be distinguished from other types of gels by the vibrations or ‘ringing’ that occurs when the emulsion is subjected to impact. Clear gels INTRODUCTION

Slide 56:

manufacturing Procedure of Gel Gel can be prepared by mixing a suitable thickening agent with an aqueous vehicle. The drug is dissolved in an aqueous vehicle and the thickening is added by triturating in a mortar. The trituration is carried out until a homogenous preparation is formed. Generally, whole gum is preferred to powdered gum in order to obtain a product of clear uniform consistency.

Slide 57:

Ingredient Quantity for 50gm SCMC (thickening agent) 2.5gm Glycerol (binding agent) 1.5gm Preservative 0.05gm Colour 0.0005gm Purified water (vehicle) To make 50gm Method: Dissolved methyl paraben in water by heating. Add SCMC to glycerin and stir thoroughly. Add this mixture to the aqueous vehicle and stir in a uniform, homogenous preparation is formed. Add the dye colour and stir. Transfer to a suitable container.

Slide 58:

Evaluation of Clear Gel Gel cannot be evaluated based in single property such as viscosity as they exhibit non-Newtonian rheological behaviour. The various evaluation parameters involved the assessment of the properties of the gels are be as follows: Yield Value Spreadability Stability Safety

Slide 59:

Yield Value It is a measure of the force required to extrude the material from the deformable bottle tube. It can be determined by the use of an instrument called the Penetrometer. Penetrometer consist of a metal needle that pierces through the system and the distance of penetration of the needle is measured, from which the yield value may be calculated.

Slide 60:

Spreadability The Spreadability test is performed to determine the extent of Spreadability of gels based on their rheological properties. Stability This test is known as the shipping test and is performed to determine the extent of stability of gels at varying temperature, which the product may experience while exporting to other countries. Safety The safety of the product on use should be determined in order to check the effect of the product by evaluating the physiological properties of the raw materials.

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Dispersed system

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Dispersed system: Suspension- Suspension formation Formulation and evaluation Emulsion- Formulation, Study of mechanical equipment for emulsification, Chemical Parameters Stability testing and assessment of shelf life.

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The term "Disperse System" refers to a system in which one substance (The Dispersed Phase) is distributed, in discrete units, throughout a second substance (the continuous Phase or vehicle). Each phase can exist in solid, liquid, or gaseous state . Dispersed system

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The phase which is dispersed in a medium is known as an internal phase or dispersed phase The medium is known as External phase, continuous phase, or dispersion medium

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e.g. of liquid-liquid systems: In milk -fat is dispersed in water

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SUSPENSION

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Definition A Pharmaceutical suspension is a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly throughout the suspending vehicle with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.

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Examples of Pharmaceutical Suspensions: Antacid oral suspensions Antibacterial oral suspension Dry powders for oral suspension (antibiotic) Analgesic oral suspension Anthelmentic oral suspension Anticonvulsant oral suspension Antifungal oral suspension

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1- Based On General Classes Oral suspension e.g. antacid, antibiotic Externally applied suspension e.g.lotion Parenteral suspension Ophthalmic suspension 2- Based On Proportion Of Solid Particles Dilute suspension (2 to10% w/v solid) Concentrated suspension (50% w/v solid) 3- Based On Electrokinetic Nature Of Solid Particles Flocculated suspension Deflocculated suspension Classification of suspensions:

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1) Precipitation method I) Organic solvent precipitation- II) Precipitation effected by changing pH of medium- protaminezinc insuline III) Double decomposition: preparation of “White Lotion”, that is forming zinc polysulphideby mixing zinc sulfate and sulfuratedpotash solutions Suspension formation

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2) Dispersion method Vehicle must be formulated so that the solid phase is easily wetted and dispersed. The use of surfactant is desirable to ensure uniform wetting of hydrophabicsolids

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Formulation of Suspension Suspension are prepared or formulated by using: Structured Vehicles Wetting agents Flocculating agents Suspending agents Other additives

Slide 73:

Structured vehicles called also thickening or suspending agents. They are aqueous solutions of natural and synthetic gums. These are used to increase the viscosity of the suspension. It is applicable only to deflocculated suspensions. E.g . Methyl cellulose, sodium carboxymethyl cellulose, acacia, gelatin and tragacanth . These are non-toxic, pharmacologically inert, and compatible with a wide range of active and inactive ingredients. Structured vehicle

Slide 74:

These structured vehicles entrapped the particle and reduces the sedimentation of particles. Although, these structured vehicles reduces the sedimentation of particles, not necessarily completely eliminate the particle settling. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage. Structured vehicles are pseudoplastic or plastic in their rheological behaviors.

Slide 75:

Wetting agents: These are the substances which reduce the interfacial tension between the solid particles and liquid medium , thus producing a suspension of required quality. This may achieved by adding a suitable wetting agent which is absorbed at the soli/liquid interface in such a way that the affinity of the particles for the surrounding medium is increased and interparticular forces are decrease. Example: Alcohol in tragacanth mucilage, Glycerin in sodium alginate or Bentonite dispersion, Polysorbate in oral and Parenteral suspension

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Flocculating agents: Electrolytes Surfactants Polymers Flocculating agents are used to obtain and promote controlled flocculation. Example of Flocculating agents:

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( e.g . Nacl, sulfate, citrates, phosphates salts ) Reduce or decrease the zeta potential (energy of potential) between the solid particles. This leads to decrease in repulsion potential and makes the particle come together to from loosely arrange structure (floccules). - The flocculating power increases with the valency of the ions. As for example, calcium ions are more powerful than sodium ions because the valency of calcium is two whereas sodium has valency of one. 1)Electrolytes EX: bismuth subnitrate with KH 2 PO 4

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Caking Diagram

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In 1st caking zone : Addition of KH 2 PO 4 à↓in + ve zeta potential (owing to adsorption of negatively charged phosphate anion) which accompanied by ↑in Vu/Vo In Non caking zone: ↑ KH 2 PO 4 à More reduction in Zeta zone ( ~ zero) while Vu/Vo remain unchanged (approached the plateau) In 2nd caking zone: ↑ KH 2 PO 4 à ↑ zeta potential in negative direction till becomes sufficient to re-induce deflocculated suspension while Vu/Vo ↓ Caking Diagram

Slide 80:

Both ionic and non-ionic surfactants can be used to bring about flocculation of suspended particles. Ionic surfactants: cause neutralization of the charge on each particle. The particles are then attracted towards to each other by van der waals forces and forms loose agglomerates. II) Non-ionic surfactant: they are adsorbed on to more than one particle thus forming a loose flocculated structure. 2.Surfactants

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(e.g. alginate, starch, cellulose derivatives) Polymers possess long chain in their structures. The part of the long chain is adsorbed on the surface of the particles and remaining part projecting out into the dispersed medium. Bridging between these later portions, also leads to the formation of flocs . 3. Polymers

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Suspending agents Other additives Preservatives: Methyl paraben, propyl paraben, benzoic acid, sodium benzoate etc. Organoleptic agents: (Flavouring, Sweetening and colouring agents) are added to oral suspension in order to improve their appearance and palatability. only colouring agents and perfume are added to topical suspension

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Steps involved in formulation of Suspension

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A comparison of properties of flocculated and deflocculated suspension particles Flocculated Deflocculated 1) Particles forms loose aggregates and form a network like structure 1)Particles exist as separate entities 2) Rate of sedimentation is high 2) Rate of sedimentation is slow 3) Sediment is rapidly formed 3) Sediment is slowly formed 4) Sediment is loosely packed and doesn’t form a hard cake 4) Sediment is very closely packed and a hard cake is formed 5) Sediment is easy to redisperse 5) Sediment is difficult to redisperse 6) Suspension is not pleasing in appearance 6) Suspension is pleasing in appearance 7) The floccules stick to the sides of the bottle 7) They don’t stick to the sides of the bottle

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Sedimentation behaviour of flocculated and deflocculated suspensions

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EVALUATION OF SUSPENSION Suspensions can be evaluated by using parameter of sedimentation and official method . Parameter: These are two parameters i.e. A) Sedimentation volume (F) B) Degree of flocculation . 2) Official Method: a) Sedimentation method b) Electrokinetic method c) Rheological method d) Micromeritic method

Slide 87:

Sedimentation volume (F) Sedimentation volume Since redispersibility is one of the major considerations in assessing the acceptability of a suspension, and since the sediment formed should be easily dispersed by moderate shaking to yield a homogeneous system, measurement of the sedimentation volume and its ease of redispersion are the two common evaluative procedures. Definition: The sedimentation volume, F, is defined as the ratio of the final, or ultimate volume of the sediment (Vu), to the original volume of the suspension (Vo), before settling. Thus F = Vu / Vo The sedimentation volume can have values less than 1 to greater than 1. If the volume of sediment in a flocculated system equals the original volume of suspension, then F = 1. Such a product is said to be in ‘flocculation equilibrium’. Procedure: The suspension is taken in a measuring cylinder upto a certain height and left undisturbed. The particles will settle gradually. The value of F is determined from the ratio of the volume of the sediment at that instant of time (Vu) and the original volume of the suspension (Vo). The value of F is plotted against time (t). The plot will, will start at 1.0. at time zero. The curve will either run horizontally or gradually sloping downward to the right as time goes on. One can compare different formulations and choose the best by observing the line, the better formulation obviously producing lines that are more horizontal and/or less steep. If the suspension is highly concentrated then the suspension is diluted with the continuous medium (liquid phase) and then the sedimentation volume is determined.

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Sediment Volume

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ß = F / F  (Vu /V o ) flocculated ß = -------------------- (Vu /V o ) deflocculated Degree of flocculation : (ß), degree of flocculation is the ratio of the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the deflocculated suspension, F  Sedimentation volume of flocculated suspension (F) ß = ----------------------------------------------------- Sedimentation volume of deflocculated suspension (F) Degree of flocculation

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Sedimentation method Electrokinetic method Rheological method Micromeritic method

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EMULSION

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Emulsion may be defined as a biphasic system consisting of two immiscible liquids usually water and oil , one of which is finely subdivided and uniformly dispersed as droplets throughout the other. Since such a system is thermodynamically, a suitable emulsifying agent is required to stabilize the system. To stabilize these droplets, emulsifying agent should be added EMULSIONS

Slide 93:

The phase which makes globules or droplets is known as internal phase or disperse phase and other is external or continuous phase. Oil can be present as internal and external phase and water also as internal or external phase. Emulsion is normally opaque . It can be used orally, topically and parentally. Microemulsion: Droplets size range 0.01 to 0.1 mm Macroemulsion: Droplets size range approximately 5 mm.

Slide 94:

Oil in water (O/W) emulsions and 2. Water in Oil (W/O) emulsions .

Slide 95:

O/W emulsion By dispersion of oil into water the oil drops are the inner, dispersed phase. Water is the outer, continuous phase. Cosmetic / pharma applications --> removable by water oil drop water phase

Slide 96:

W/O Emulsion By dispersion of water into oil the water drops are the inner, dispersed phase. Oil is the outer, continuous phase. Cosmetic / pharma applications --> water resistant Water Oil

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Formulation Formulation of emulsion involves following component: Emulsifying agents Other additives I) Antioxidant II) Preservative III) Flavours

Slide 98:

Antioxidant During storage of emulsions, the fats (obtained from vegetable and animal sources) and emulsifying agents (such as wool fat, wool alcohol) undergo oxidation by atmospheric oxygen. This can be avoided by using antioxidant, such as, tocopherol, gallic acid, propyl gallate and ascorbic acid. Some times oxidation occurs due to enzymes produced by microorganism. Such problems should be prevented by adding a suitable antimicrobial preservative.

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The following are some of the qualities of an ideal anti-oxidants : 1.It should be readily soluble or dispersible in the medium. 2. It should be non toxic. 3.It should be non irritant. 4.It should be colourless , odourless and tasteless.

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Flavours Vanillin is a good flavouring agent for liquid paraffin emulsion. Benzaldehyde is generally used as a flavouring and sweetening agent provides greater palatability to emulsion.

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Preservatives Emulsion which are prepared by using emulsifying agent, such as carbohydrates, proteins, sterol, and non-ionic surfactants may lead to the growth of bacteria, fungi and moulds in the presence of water. The contamination of emulsions by these microorganisms may cause unpleasant odour , taste and discoloration. Due to breakdown of emulsifying agent changes occur in the consistency of an emulsion which may lead to cracking of emulsion.

Slide 102:

The contamination of an emulsion may occur due to any one of the following reasons : 1.The equipment used in the preparation of emulsion are carelessly cleaned. 2.By using contaminated natural emulsifying agent such as gums, starches and clays. 3.The ratio of oil and water is not proper. 4.By using not properly stored deionised and purified water. 5.pH of the preparation.

Slide 103:

The following steps can minimised the above factors and helps to maintain a stable emulsion : 1.Use throughly cleaned equipment. 2.Use ingredients of standard quality. 3.Maintain the prescribed ratio of oil, water and gum while preparing the emulsions. 4.Use freshly boiled and cooled water to destroy microorganism. 5.Use containers and closures of good qulity . The closure should fit well on the containers. 6.Maintain the prescribed of the emulsion.

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Preparation The following methods are commonly used for the preparation of emulsion on a small scale: Dry gum method Wet gum method Bottle method Other methods

Slide 106:

Dry gum method Measure the required quantity of oil in a dry measure and transfer it into a dry mortar. Add calculated quantity of gum acacia into it and triturate rapidly so as to form a uniform mixer. Add required quantity of water and triturate vigorously till a clicking sound is produced and the product becomes white or nearly white due to the total internal reflection of light. This emulsion produced at this stage is known as Primary Emulsion. Add more of water to produce required volume

Slide 108:

2) Wet gum method In this method the proportion of oil: water: gum for preparing the primary emulsion. Calculate the quantity of oil, water and gum required for preparing the primary emulsion. Powder the gum acacia in a mortar. Add water and triturate it with gum so as to form a mucilage. Add the required quantity of oil in small portions with rapid trituration until a clicking sound is produced and the product becomes white or nearly white. At this stage the emulsion is known as primary emulsion . Add more of water in small portions to the primary emulsion with trituration to produced the required volume. Stirr thoroughly so as to form a uniform emulsion. Transfer the emulsion to a bottle, cork, label and dispense.

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3) Bottle method It is used for preparation of emulsions of volatile and other non-viscous oils. The proportion of oil : water : gum is 2:2:1 Measured the required quantity of the oil and transfer into a large bottle. Add the required quantity of powdered gum acacia. Shake the bottle vigorously, until the oil and gum are mixed thoroughly. Add the calculated amount of water all at once. Shake the mixture vigorously to form a primary emulsion. Add more of water in small portion with constant agitation to produce the required volume.

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4) Other methods Various blenders and homogenizer are used for preparing emulsion. Hand homogenizer, silversion mixer homogenizer and colloidal mill are some of the homogenizers which are used for preparation of extemporaneous emulsion.

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MECHANICAL EQUIPMENT FOR EMULSIFICATION Various type of equipment for emulsification such as: Mechanical Stirrer Homogenizers Ultra-sonifiers Colloid Mill

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Mechanical Stirrer An emulsion may be stirred by means of various impellers mounted on shafts, which are placed directly into the system to be emulsified. Simple top entering propeller mixer are adequate for routine development work in the laboratory and the production purposes, if the viscosity of the emulsion is low. If more vigorous agitation is required, or if the preparation has moderate viscosity ,turbine type mixers are employed both in the laboratory and the production. Other mixers, provided with paddle blades, counter rotating blades, or planetary action blades, are available for special requirement.

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. The degree of agitation is controlled by the speed of impeller rotation, but the pattern of liquid flow and the resultant efficiency of mixing are controlled by the type of impeller, its position in the container, the presence of baffles, and the general shape of the container. Despite the variation in flow behavior and the efficient mixing that can be produced, the use of stirrers for the formation of emulsions is often limited when vigorous agitation of viscous systems is required, when extremely fine droplets are needed, or when foaming at high shear rates must be avoided.

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Mechanical Stirrer

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Turbine stirrer Propeller stirrers

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Homogenizers In an homogenizer, the dispersion of two liquids is achieved by forcing their mixers through a small inlet orifice at high pressures. A homogenizer generally consists of a pump that raises the pressure of the dispersion to arrange of 500 to 5000 psi and an orifice through which this fluid impinges upon the homogenizing valve held in place on the valve seat by a strong sprig. As the pressure builds up, the spring is compressed, and some of the dispersion escapes between the valve and valve seat. At the point, the energy that has been stored in the liquid as pressure is released instantaneously and the subjects the product to intense turbulence and hydraulic shear. Homogenizers can also be built with more than one emulsifier stage, and it is possible to recycle the emulsion and pass it through the homogenizer more then one time. Homogenizer of varying design are useful for handling either liquids or pastes, since the rate of throughput is little affected by viscosity .

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It must be remembered, however, that homogenization raises the temperature of the emulsion and subsequent cooling may be required. The use of homogenizer is warranted when ever a reasonably mono disperse emulsion of low particle size (1nm) is required. Another useful piece of equipment, which combines mixing with some homogenizing action, is the rotor-stator homogenizer.

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Homogenizers

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ULTRA-SONIFIERS The use of ultrasonic energy to produce pharmaceutical emulsions has been demonstrated, and many laboratory size models are available. These transuded piezoelectric devices have limited output and are relatively expensive. They are useful for the laboratory preparation of fluid emulsion of moderate viscosity and extremely low particle size. Commercial equipment is based on the principle of the Pohlman liquid whistle. The dispersion is forced through an orifice at modest pressure and is allowed to impinge upon a blade. The pressure required range from approximately 150-350 psi and cause the blade to vibrate rapidly to produce an ultrasonic note. When the system reaches a steady state, cavitational field is generated at the leading edge of the blade, and pressure fluctuations of approximately 60 tons psi can be achieved in commercial equipment.

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Colloid Mill Homogenizers and ultrasonic equipment depend on sudden changes in pressure to effect the dispersion of liquids by contrast, colloid mill operate on the principle of high shear, which is normally generated between the rotor and stator of the mill. Colloid mill are used primarily for the comminution of solids and for the dispersion of suspensions containing poorly wetted solids but are also useful for the preparation of relatively viscous emulsions.

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Colloid mill

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FACTORS AFFECTING THE STABILITY OF AN EMULSION Particle size: Increased particle size of the internal phase causes the decreased stability of an emulsion. Smaller size of the particles of internal phase is always preferable. Particle-particle interaction: Deflocculated particles are always preferable because the less the particle-particle interaction the more the stability of an emulsion. Particle density: The less the particle density the more the stability of an emulsion. Bulk phase/external phase density: the more the bulk phase density the more the stability of an emulsion. Bulk phase viscosity: Generally the more the viscosity of bulk phases the more the stability of emulsion. Stability testing of Emulsion

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Emulsion Stability

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Instability of an emulsion: Various deviations from ideal behavior of an acceptable emulsion is known as its instability. The signs of instability are : Flocculation or coagulation 2. Creaming 3. Coalescence 4. Breaking or cracking Phase inversion Miscellaneous physical and chemical changes.

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Flocculation: Flocculation is the joining together of globules to form large clumps or floccules within the emulsion. In flocculation the interfacial film and the individual droplets remain intact the globules do not coalesce and may be redispersed by shaking.

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Creaming – it is a concentration of the floccules of the internal phase formed upward or downward layer according to the density of internal phase.

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Cause: Creaming is influenced by gravity on the globules. So it depends on the sedimentation or creaming rate. This rate depends i. diameter of the dispersed globules ii. Viscosity of the dispersion medium iii. Density difference between two phases Creaming of emulsion can be explained by stokes law D2 (d1-d2)g 2r2 (d1-d2)g V=------------------------ V=------------------------ 18η 9η Where V= rate of creaming r= particle radius in cm D =particle diameter in cm d1=density of the internal phase d2=density of the external phase g= gravitational constant η= viscosity of the external phase

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From the equation we can say i. Increase diameter of globules increases the velocity and vice versa. ii. Increase viscosity of the dispersion medium decreases the velocity and vice versa. iii. If d1>d2- downward creaming d1<d2- upward creaming d1=d2- No creaming

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Cause: Coalescence depends on the structural properties of the interfacial film. So it occurs when emulsifying agent loses its activity or the amount of emulsifying is insufficient. Remedy: By adding sufficient amount of emulsifying agent and passing the product through the proper emulsifying machinery. ii. During preparation the addition of emulsifying agent should be appropriate because the use of wrong emulsifying agent loses its activity within a short period of time. Coalescence is the process by which emulsified particles merge with each to form large particles. Coalescence

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Breaking - Due to Coalescence and creaming combined, the oil separates completely from the water so that it floats at the top in a single, continuous layer. Breaking

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Cracking When an emulsion cracks during preparation, i.e., the primary emulsion does not become white but acquires an oily translucent appearance. In such a case, it is impossible to dilute the emulsion nucleus with water and the oil separates out. Cracking of emulsion can be due to: 1- addition of an incompatible emulsifying agent e.g. monovalent soap + divalent soap e.g. anionic + cationic emulsifying agent

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2- chemical or microbial decomposition of emulsifying agent. e.g. alkali soaps decomposed by acids e.g. monovalent soaps salted out by electrolytes such as NaCl e.g. nonionic emulsifying agents are incompatible with phenols e.g. alcohol precipitates gums and gelatin 3- exposure to increased or reduced temperature 4- Addition of common solvent e.g. addition of a solvent in which the two phases are soluble (alcohol)

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Phase inversion: In phase inversion o/w type emulsion changes into w/o type and vice versa. It is a physical instability. It may be brought about by: 1- the addition of an electrolyte e.g. addition of CaCl2 into o/w emulsion formed by sodium stearate can be inverted tow/o. 2- by changing the phase volume ratio. 3- by temperature changes. Phase inversion can be minimized by: 1- using the proper emulsifying agent in adequate concentration. 2- keeping the concentration of dispersed phase between 30 to 60 % 3- storing the emulsion in a cool place. Phase inversion:

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Miscellaneous: Care must be taken to protect emulsion against deterioration caused by light, temperature and freezing and thawing

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