FORMULATION AND DEVELOPMENT OF SOLID DOSAGE FORM

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FORMULATION DEVELOPMENT OF SEMISOLID DOSAGE FORMS:

FORMULATION DEVELOPMENT OF SEMISOLID DOSAGE FORMS PRESENTED BY B.SUNIL KUMAR REDDY M.PHARMACY

INDUSTRIAL PROCESSING:

INDUSTRIAL PROCESSING

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Semisolid dosage forms are dermatological preparations intended to apply externally on the skin to produce local or systemic effect. Ex: Ointments, creams, pastes, gels etc Definition:

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IDEAL PROPERTIES OF SEMISOLIDS PHYSICAL PROPERTIES Smooth texture Non dehydrating Non gritty and non greasy Elegant in appearance

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PHYSIOLOGICAL PROPERTIES Non irritating Do not alter membrane or skin functioning Miscible with skin secretion APPLICATION PROPERTIES Easily applicable with efficient drug release. High aqueous wash ability.

Types of semisolid bases:

Types of semisolid bases The ointment base is the substance or part of ointment, which serves as carrier or vehicle for the medicament. Ointment bases are of following types A) Oleaginous bases or Hydrocarbon base Ex. Hard paraffin, Yellow soft paraffin. B) Absorbent base Ex. Hydrous wool fat, lanolin C) Emulsion bases or water miscible bases D) Water soluble bases Ex. PEG, Polysorbate

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FORMULATION: 1)Hydro carbons : Petrolatum and mineral oil are the most widely used substances in semisolids Petrolatum is a complex mixture of semisolid hydrocarbons, containing aliphatic, cyclic, saturated, unsaturated, branched and unbranched substances in varying proportions. Petrolatum is available in the form of a short or long fiber. Mineral oil is obtained from petrolatum, by collection of a particular viscosity-controlled faction.

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It is produced in many viscosity and specific gravity ranges. The lower viscosity oils are preferred for semisolids, since they are less tacky and greasy. 2)Hydrocarbon waxes: These waxes are frequently employed in the manufacture of Creams and ointments to increase the viscosity of mineral oil in order to prevent its separation from an ointment

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Paraffin wax is obtained from petrolatum and available in variety of melting points ranging from 35 to 75°C. Ozokerite is a mined wax with a melting point range of 65 to75°C. Synthetic waxes have been developed from vegetable oils and naturally occurring waxes by a process of hydrogenation and catalytic splitting. Synthetic waxes are chemically closely related to the naturally occurring waxes in that they contain long chain wax fatty acids, but are not considered to be direct replacements for them.

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3)Oleaginous substances: vegetable oils such as peanut oil, almond oil and olive oil are mono, di, and tri glycerides of mixtures of unsaturated and saturated fatty acids. 4)Fatty acids & alcohols: The commercially available fatty acids are stearic acid and palmitic acid. Stearic acid is used in water-removable creams as an emulsifier to develop a certain consistency in the cream and to give a matt effect on the skin.

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5) Emulsifiers: The water-soluble soaps were among the first emulsifiers used for semisolid oil-in-water emulsions. Nearly all semisolid creams and emulsified ointments require more than one emulsifier. The combination of a surface active agent with an oil-soluble auxiliary emulsifier is referred to as a mixed emulsifier system.

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6) Polyols: Glycerine, propylene glycol, sorbitol 70% and the low molecular weight polyethylene glycols are used as humectants in creams. These materials prevent the cream from drying out and prevent the formation of a crust when the cream is packaged in a jar.

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7)Insoluble powders: Insoluble drugs must be uniformly dispersed throughout the vehicle to ensure homogeneity of the product. Milling of a drug to a finely divided state provides more surface area for contact with the dermal site and increases the rate of dissolution of poorly soluble substances.

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PASTES,GELS AND JELLIES : Pastes are dispersions of high concentrations of insoluble powdered substances(20 to 50%) in a fatty or aqueous base. The fatty bases are less greasy as well as stiffer in consistency than ointments because of the large amount of powdered material present. Jellies are water-soluble bases prepared from natural gums such as tragacanth , pectin and alginates.

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Gels are usually clear transparent semisolids containing the solubilized active substances like hydroxypropylcellulose and hydroxy propylmethylcellulose. OPHTHALMIC OINTMENTS:- Semisolid ophthalmic vehicles contain soft petrolatum, an absorption base or a water soluble base.

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All materials used in the ophthalmic ointment should be impalpable to avoid eye discomfort and possible irritation. PRESERVATION FROM MICROBIAL SPOILAGE: Chemical preservatives for semisolids must be carefully evaluated for their stability with regard to the other components of the formulation as well as to the container.

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Plastic containers may absorb the preservative and there by decrease the quantity available for inhibiting or destroying the micro organisms responsible for spoilage. The preservatives are added to semisolids to prevent contamination, deterioration and spoilage by bacteria and fungi, since many of the components in these preparations serve as substrates for these microorganisms.

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The paraben esters of p-hydroxy benzoic acid is popular as preservative because their toxicity is low, odorless & non irritating to the skin. ANTIOXIDANTS:- These are added to semi solids when ever oxidative deterioration is anticipated.

PREPARATION OF SEMI SOLIDS:

PREPARATION OF SEMI SOLIDS Trituration method Fusion method Chemical reaction method Emulsification method Ex. Ointments creams pastes Ex. Ointments creams pastes Ex. Ointments creams Ex. Ointments creams (Ointments, creams, pastes)

PREPARATION METHODS FOR SUPPOSITORIES:

PREPARATION METHODS FOR SUPPOSITORIES Hand molding Heat molding Automatic machine molding Compression molding Ex. Rotary machine linear machine

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Pilot plant or small scale production equipment is essential in developing a manufacturing procedure for a production size batch. The preparation of many batches ranging in size from 2.5 to 25 or more kilograms, for product evaluation and clinical testing provides opportunity to observe, improve and correct the variations. Mixing and stirring operations are critical in the preparation these can be controlled in 0.5- 1.0kg batches of finished product. Industrial processing

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The electrically operated propeller type mixer can be manually adjusted and positioned in the laboratory mixing vessel to achieve maximum turbulence. The angle of entry of the propeller shaft and the depth of the propeller can be easily varied in the laboratory to prevent aeration. A metal spatula can be held or positioned in the beaker during mixing to serve as a baffle to increase turbulence with out entrainment of air.

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Aeration should be avoided, since it may lead to emulsion instability and variation in density with in a batch. Entrainment can occur Homogenizing Milling stage Filling equipment Packaging operation.

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Aeration maybe prevented at the primary emulsion step if one phase is introduced into the other in such a manner that splashing and streaming are avoided. Splashing can overcome by careful adjustment of the mixing conditions and liquid flow pattern. Completely enclosed kettles are available for the manufacturing of semisolids which tend to aerate excessively.

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Rheological changes: Homogenization frequently increases the consistency of a semisolid emulsion because it increases the number of emulsified particles. consistency is affected by Number of passes through the homogenizer. Pressures used for homogenization.

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HOMOGENIZERS : For homogenization colloidal mill is used. Colloidal mill:It consists of two steel discs one is stationary and other is rotating.when the material is passed through these discs they get sheared. Thus,coarse particles are broken down to small particles due to shear. Uses: Used for preparation of suspensions,ointments . Advantage:It can be easily sterilised . Disadvantage:Heat is generated during milling.

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Fusion method: Anhydrous ointments are prepared by fusion method. Active substances is dissolved in the melted fats and waxes and then mixed with base. The melted mass must mixed while cooling because the fatty alcohols, fatty acids, and waxes do not form true solutions, but crystallize from the melt as the temperature falls.

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Manufacture of emulsions: Time, temperature and mechanical work are the three variables in the manufacture of emulsified semisolids. The three factors are interrelated and must be carefully controlled if the same high quality batches are to manufactured. Equipment is available for automatically controlling many aspects of emulsion manufacture, such as the complete control of the temperature in the jacket and regulation of the mixing time and rate of agitation.

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PREPARATION OF OIL AND AQUEOUS PHASES

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The components of the oil mixtures are placed into a stainless steel steam jacketed kettle,melted and mixed. Some of the solid components e.g. stearic acid,cetyl alchol are available in many different forms like cakes,flakes or powder. The flakes are more preferable because of the convenience of handling. Petrolatum is inconvenient to handle unless it is melted and transferred by pumping or pouring from its drum.

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The oil phase is then strained through several layers of cheese cloth to remove any foreign matter. If petrolatum is used as oil phase then it should be passed through filter medium particularly in ophthalmic preparations. The oil phase is transferred by gravity or pump to the emulsion mixing kettle.

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The components of the aqueous phase are dissolved in the purified water and filtered. A soluble drug may be added to this aqueous phase.

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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 0 C. MIXING OF 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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The simultaneous blending of the phases requires the use of a proportioning pump and a continuous mixer. This method is used for continuous or large batch operation. The second method is used for emulsion systems that have a low volume of dispersed phase. The third process is preferred for many emulsion systems.

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Equipments used for mixing of phases: 1. Agitator mixers :Sigma mixer and planetary mixer. 2. Shear mixers: Triple roller mill and Colloidal mill.

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The mechanism of mixing is shearing.The sigma shaped blades creates high shear. Advantages: 1.It creates a minimum dead space during mixing. 2.It is used for wet granulation process. Disadvantages: 1.It works at a fixed speed. Sigma blade mixer:

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It consists of two steel discs.Here one disc rotates and another one is stationary. When the material is passed through these discs they get sheared.Thus coarse particles are break down to small particles due to shear. Advantages: 1.It can be used in the production of sterile products. Disadvantages: 1.It is not used for dry milling. 2.Heat is generated during milling. 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 SEMISOLID EMULSION:

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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.

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STORAGE OF SEMI-SOLIDS Unless rapid in process methods of analysis are developed, it is the usual practice to store the semisolid until the specified quality control tests have been completed before packaging into appropriate. containers: tubes, jars, or single dose packets. A product is considered to be in process until it has been packaged.

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Evaporation of water from a cream must be retarded; this can be effectively accomplished by placing non-reactive plastic sheeting in direct contact with the cream, as well as covering the storage container with a tight-fitting stainless steel lid. The active substance in the cream or ointment may react with the storage container unless a Highly resistant, stainless steel, is used for bulk storage.

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TRANSFER OF MATERIAL FOR PACKAGING The semi-solid may be gravity fed, if it is a two-Level operation or pumped to the filling equipment. It must be able to resist the shear stress developed in the transfer of the product, as well as that due to the mechanical action of the filling equipment. Once a formal manufacturing procedure has been established, there should be no deviation from it. The manufacturing and packaging equipment should be sanitized following thorough cleaning with detergents.

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They should be flushed with chlorinated water, formalin, or other suitable sterilant followed by a bacteria-free water rinse. Water and swab samples should be taken to verify microbial elimination.

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