Semi-Solid Dosage Form

Chapter 5

Semi-Solid Dosage Form

Introduction

Definition: Semi-solid dosage forms are dermatology ictal preparations intended to apply externally on the skin to produce local or systemic effect e.g., ointments, creams, gels and pastes. They contain one or more active ingredients dissolved or uniformly dispersed in a suitable base and any suitable excipients such as emulsifiers, viscosity increasing agents, antimicrobial agents, antioxidants, or stabilizing agents. Semisolids can adhere to the application surface for sufficiently long periods before they are washed off. This property helps prolong drug delivery at the application site. Novel semisolids are non-greasy since they are made up of water washable bases. Hence, they cause less irritation to skin and are superior to conventional semisolid dosage form.

Ideal Properties of Semi-solid Dosage Forms

Physical Properties

•  They should have smooth texture.
•  They should be elegant in appearance.
•  They should be non-dehydrating.
•  They should be non-gritty in nature.

Physiological Propertie 

• They should be non -irritating.
• They should not alter skin functioning.
• They should be easily miscible with skin secretion.
• They should have low sensitization effect.

Classification

Ointments: Ointments are semisolid preparations meant for external appIicat”ion 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 and o/w type and w/o type.

Pastes: Pastes are the preparations which contains 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 muc”i Pages in having jelly like consistency

Suppositories: These are meant for insertion into the body cavities other than mouth. Hey may be inserted into rectum, vagina or urethra.

Poultices: These are also known as cataplasms. 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 appIicat”ion, made of such materials and consistency as to adhere to the sk in and thereby attach as dressing.

Factors Influencing Dermal Penetration of drugs:

Physiological and Pathological Condition of Skin

• Reservoir effect of the horny layer: The horny layer is thickest on palms and soles and thinnest on the face; penetration rate increases with decreased thickness of horny layer.

• Skin condition: The permeability of the skin is affected by age, disease, climate and injury. For example, absorption occurs rapidly in children and if the dermis is exposed by a wound or burn.

• Skin hydration: The hydration of keratinized cells is raised by covering the area with a moisture -proof plastic film to prevent evaporation of perspiration. Hydration increases the drug penetration. 

• Skin age: The young skin is more permeable than older. Childrens are more sensitive for skin absorption of toxins. Thus, skin age is one of the factors affecting penetration of drug. 

•   Blood flow: Changes in peripheral circulation can affect transdermal absorption. 

•   Skin temperature: The permeation of drug increase ten folds with temperature variation. The diffusion coefficient decreases as temperature falls. Weak acids and weak bases dissociate depending on the pH and pKa or pKb values. The proportion of unionized drug determines the drug concentration in skin. Thus, temperature and pH are important factors affecting drug penetration.

Effects of Vehicles

The vehicles may enhance the penetration of a drug in one or more of the following ways:

• By ensuring good contact with the surface of the body.
• By increasing the degree of hydration of the stratum corneum.
• By penetrating the epidermis.
•  By directly altering the permeability of the skin.

Effects of Additives

• Surfactants increases the penetration because they are surface active agents which reduces the surface tension e.g., quaternary ammonium compounds, alkali soaps etc
• Humectants increases the solubility of active ingredients. To elevate its skin preparation and to elevate the hydration of the skin e.g., glycerite, polyethylene glycol etc.   
• Penetration enhancers- Penetration can be improved by addition of penetration enhancers like methanol, oleic acid etc.

Classification of Semi-solid Bases and their Selection

There are four 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 and Oil in water emulsion bases) Water soluble bases.

1. Oleaginous Bases

• 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 protestants, emollients, vehicles for hydrolysable drups. Examples. White Petrolatum, White Ointment.

2. Absorption Bases

• The term absorption base is used to denote the water absorbing or emulsifying property of these bases and not to describe their action on the skin.

• 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 bases.

3. Emulsifying Buses

• These are anhydrous, hydrophilic, absorbs water and non-water removable, with low thermal conductivity and occlusive. They have the same properties as the absorption bases. They are used as emollients, cleansing creams, vehicles for solid, liquid, or non-hydrolysable drugs. Examples Cold Cream type, Hydrous Lanolin, Rose Water Ointment, Hydrocream, Nivea.

Oil in water emulsion bases

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

Water Soluble Bases

Water soluble does not contain oily substances and are called greaseless base and are completely soluble in water. Examples:

• Polyethylene glycol (PEGs), polyoxyl 40 stearate and polysorbates. Macrogols: They are mixture of water and polycondensation products of ethylene oxide.

Advantages

• They are water soluble and washable
• They are non-greasy, non-staining, non or less occlusive, lipid free in nature
• They are relatively inert
• They do not allow mould growth

Methods of Preparation

• Trituration method
• Fusion method

• 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.
• Fusion Method: The ingredients of the base are melted together and properly mixed to obtain a uniform product. 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 form is added to the molten base. Liquid or semisolid are added at a temperature of 40°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.

• Emulsification MethodPreparation 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 foreig n 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.The phases are usually mixed at a temperature of 70 to 72°C, because at this temperature into mate mixing of the liquid phases can occur. The properties of some emulsions depend on the temperature at which the phases are mixed. Three ways of mixing the phases: 1. Simultaneous blending of the phases. 2. Addition of the discontinuous phase to the continuous phase. 3. Addition of the continuous phase to the discontinuous phase.

• Chemical reaction: This method is used to prepare several apes of ointments. This method involves both fusion and mechanical mixing. Best example of this method is Iodine ointment. Chemical Reactor\ Method Procedure for iodine ointment: Powder iodine in a mortar and pestle and add it to arachis oil taken in a flask. H eat the mixture to 50°C with occasional stirring until g reenis h black colour appears. Add yellow soft paraffin to the above mixture and heat it to 40°C with mixing. Cool the Ointment.

Preparation of Ointments

An ointment should be:

L/aitorm i.e., it contains no lumps of separated high melting pointing redients of the base, there is no tendency for liquid constituents to separate and insoluble powders are evenly dispersed.Free /rom griftiness, i.e., insoluble powders are finely subdivided, and large lumps of particles are absent. Methods of preparation must satisfy this criterion.

Two mixing techniques are frequently used in making ointments.

• Fusion, i n which ingredients are melted together and stirred to ensure homogeneity.

• Trituration, in which finely-su divided insoluble medicaments are evenly distributed by grinding with a small amount of the base are one of its ingredients followed by dilution with gradually increasing amounts of the base.

Ointments Prepared by Fusion Method

When an ointment base contains a number of solid ingredients such as white bees wax, cetyl alcohol, stearyl alcohol, stearic acid, hard paraffin, etc. as components of the base, it is required to melt them.

Method-I 

•   The components are melted in the decreasing order of their melting point i.e. the higher. substance should be melted first, the substances with next melting point and so on. The medicament is added slowly in the melted ingredients and stdrred thoroughIy until the mass cools down and homogeneous product is formed.

This will avoid over-heating of substances having low melting point.

Method-II 

  All the components are taken in subdivided state and melted together. 

Advantage

The maximum temperature reached is lower than Method -I, and less time was taken possibly due to the  solvent action of the lower melting point substances on the rest of the redients.

• After melting, the ingredients should be stirred until the ointment is cool, taking care not to cause localized cooling, e.g. by using a cold spatul a or stirrer, placing the dish on a cold surface (e.g. a plastic bench top) or transferring to a cold container before the ointment has fully set. If these precautions are ignored, hard lumps may separate.

• Vigorous stirring, after the ointment has begun to thicke n, causes excessive aeration and should be avoided.

• Because of their greasy nature, many constituents of ointment bases pickup dirt during storage, which can be seen after melting. This is removed from the melt by allowing it to sediment and decanting the supernatant, or by passage throu gh muslin supported by a warm stra iner. Tn both in stances the clarified liquid is collected in another hot basin. 

• If the product is granular after cooling, due to separation of high M.P. constituents, it should be remelted, using the minimum of heat, and again stirred and cooled.

Ointment Prepared by Trituration

This method is applicable in the base or a liquid present in small amount.

• The powder is taken on an ointment-slab and triturated with a small amount of the base. A steel spatula with long, broad blade is used. To these additional quantities of the base are incorporated and triturated until the medicament is mixed with the base.

• Finally, liquid ingredients are incorporated. To avoid loss from splashing, a small volume of liquid is poured into a depression in the ointment and thoroughIy incorporated before more is added in the same way. Splashing is more easily controlled in a mortar than on a tile.

• Method: $ublimed suIphur is sieved through no. 180 sieves. Then sublimed suIphur is triturated with small amount of simple ointment. Then the remaining amount of simple ointment is added and the mixture is levigated until smooth and homogenous mass is obtained.

Ointment Preparation by Chemical Reaction

Chemical reactions were involved in the preparation of several famous ointments of the past, e.g. Strong Mercuric Nitrate Ointment of the 1959 B.P.C.
Iodine is only slightly soluble in most fats and oils.Iodine is readily soluble in concentrated solution of potassium iodide due to the formation of molecular complexes KI I , KI 21, KI 312 etc.

• These solutions may be incorporated in absorption-type ointment bases.
• Example, Strong Iodine Ointment (British Veterinary Pharmacopoeia) is used to treat ringworm in cattle. It contains free iodine. At one time this type of ointments was used as counterirritants in the treatment of human rheumatic diseases, but they were not popular. Because they stain the skin a deep red colour. Due to improper storage the water d ries up and the iodine crystals irritate the skin, hence glycerol is sometimes added to dissolve the iodine-potassium iodide complex instead of water.

Preparation of Ointments/Cream by Emulsification

• Water soluble soap
• Cell alcohol
• Glyceryl monostearate
• Combination of emulsifiers. triethanolamine stearate + cetyl a\coho\
• Non-ionic emulsifiers: glyceryl monostearate, glyceryl monooleate, propylene glycol
• stearate

For w/o emulsion creams the following emulsifiers are used:

• Polyvalent ions e.g., magnesium, calcium and aluminium are used
• Combination of emulsifiers: bees wox + divoient calcium ion
• The viscosity of this type of creams prevents coalescence of the emulsified phases and helps in stabilizing the emulsion

Paste

• Pastes are semisolid preparations for external application containing a hiph proportion of finely powdered medicaments. They are stiffer and are usually employed for their protective action and for their ability to absorb serpus discharges from skin lesions. They do not melt at ordinary temperature they form a coating over the affected area. Pastes are used as protective, antiseptic, and soothing dressings.

Differences Between Pastes and Ointments

• Pastes generally contains a large amount (50%) of finely powdered solids. So they are often stiffer than ointments.

• When applied to the skin pastes adhere well, forming a thick coating protects and soothes inflamed and raw surfaces and minimizes the damage done by scratching in itchy conditions such as chronic eczema. It is comparatively easy to confine pastes to the diseased areas whereas ointments, which are usually less viscous, tend to spread on to healthy skin, and this may result in sensitivity reactions if the preparations contain a powerful medicament such as dithranol.

• Because of the powder contents pastes are porous; hence, perspiration can escape. Since, the powders absorbs exudate, pastes with hydrocarbon base are less macerating than ointments with a similar base.

• They are less greasy than ointments but since their efficacy depends on maintaining a thick surface layer they are far from attractive cosmetically. 

• Most of the pastes are unsuitable for treating scalp conditions because they are diffiCult to remove from the hair.

Methods of Preparation

• Like ointment, pastes are prepared by trituration and fusion methods. Trituration method is used when the base is liquid or semisolid.Fusion method is used when the base is semisolid and/or solid in nature.

• Soft paraffin is melted in a separate dish (70°C) and about half is added to the tar-wax mixture; stirred well. Remainder is added; stirred again until homogeneou s.

• Allowed to cool at about (30”C) and zinc oxide (previously passed through 180 mesh) and starch, in small amount with constant stirring. Stirred until cold.

• Wax and paraffin melted together, mixed well and stirred until just setting. Powders are mixed on a slightly warm tile and the tar is incorporated. This method eliminates the risk of over heating.

Gels

• Gels 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 appear jelly like by the addition of a pellinp agent.

• These are organic hydrocolloids or hydrophilic inorganic substances.

• They contain Tragacanth, Sodium Alginate, Pectin, Starch, Gelatin, Cellulose Derivatives, Carbomer, and Poly Vinyl Alcohol Clays. These are numerous gelling agents varying in gelling ability.

• Clear gels are microem ulsions in which the diameter of the dispersed phase globules is in the range of 10 to 60 nm. These emulsions are thermodynamically stable. Microemulsion s 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.

Procedure of Clear Gel

• Gel is 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.

Method: Dissolved methyl paraben in water by heating. Add SCMC to glycerine 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.

Excipients used in Semisa lid Dosage Forms

• API: Any substance or mixture of substances intended to be used in the manufacture of a drug (medic”inal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Active pharmaceutical ingredient is any part of drug which produces any effect.

• Preservatives: To stop microbial growth preservatives are added. Preservatives for ointment includes p-hydroxy benzoates, phenol, benzoic acid, sorbic acid, methyl paraben, propyl paraben, quaternary ammonium compounds, mercury compounds etc. The preservatives should not react with any of the component of the formulation. Plastic containers may absorb the preservative and thereby decreasing the concentration of preservative available for killing the bacteria.

• Humectants: such as, glycerin, propylene glycol and sorbitol may be added to prevent the loss of moisture from the preparation.

• Organoleptic agents: suitable colouring agent — (amaranth, brilliant blue etc.) flavorings agent (vanilla strawberry, raspberry) is added. Ointment must be stored at an optimum temperature otherwise separation of phases may take place in the emulsified products which may be very difficult to remix to get a uniform product.

Evaluation of Semi Solid Dosage Form

• Content uniformity of drug: A known weight of ointment is taken and assayed for amount of the drug.

• Penetration: A weighed quanti of ointment is rubbed over skin for a given period of time and unabsorbed ointment is collected and weighed. The differences in weights represent the amount absorbed.

• Rate of release of medicament: To assess rate of release of medicament, small amount of the ointment can be placed on the surface of nutrient agar contained in a Petri dish. If the medicament is bactericidal the agar plate is previously seeded with a suitable organism like S. aureus. After a suitable period of incubation, the zone of inhibition is measured and correlated with the rate of release.

• Absorption of medicament into blood stream: Ointment should be evaluated for the rate of absorption of drug into the blood stream. This test can be run in-vfvo onIy. Definite amount of ointments should be rubbed throug h the skin. Under standard conditions and medicaments are estimated in the blood plasma or urine.

• Irritant effect: In general, no ointment should possess irritant effect on the skin or mucous membranes the tests for irritancy can be carried out on the skin and eyes of rabbits or the skin of human beings. The irritant effect can also be judged to a certain extent by injecting the ointment into thigh muscles and under the abdominal skin of rats. Reaction is noted at intervals of 24, 48, 72 and 96 hours. Lesions on cornea, iris, conjunctiva are used for judging the irritancy to the eyes. Presence of patches on the skin within 2 weeks indicate irritancy to pressing skin.

• Rheology: The rheology or viscosity should remain constant. As creams are normally non-Newtonian in nature, the Viscosi can be measured using viscometers used for such liquids. Rheologic measurements are utilized to characterize the ease of pouring from a bottle, squeezing from a tube, maintaining product shape in ajar etc.

• Sensitivity: As various types of ingredients are used with occasional use of antiseptics hormones etc. there is a possibility of sensitization or photosensitization of the skin. This test is normally done by patch test. The test sample is applied along with a standard market product at different places and effect is compared after a period of time.

In-situ Gel

ft is a drug delivery system which is in a solution form before the administration in the body, but it converts into a gel form after the administration. There are various routes such as oral, ocular, vaginal, rectal, intravenous, intraperitoneal.

Advantages

• They have ease of administration.

• In-situ gel shows improved local bioavailability.

• They possess reduced dose concentration and reduced dosing frequency.

• It allows improved patient compliance and comfort.

•  It can be administered by unconscious patients.

• Drug gets released in a sustained and controlled manner.

• Natural polymers have inherent properties of biocompatibility, biodegradability, and biologically recognizable moieties that support cellular activities.

• Synthetic polymers usually have well-defined structures that can be modified to yield tailorable degradability and functionality.

• In-situ gels can also be engineered to exhibit bioadhesiveness to facilitate drug targeting, espec ially throug h mucous membranes, for non-invasive drug administration.

• In-situ gels offer an important” stealth” characteristic” in-vivo, owing to their hydrophilicity which increases the in-vivo circulation time of the delivery device by evading the host immune response and decreasing phagocytic activities.

Importance of In-situ Gelding System

• The major importance is the possibilities of administrating accurate and reproducible quantities compared to already formed gel.

• In-situ forming polymeric delivery system such as ease of administration and reduced frequency of administration improved patient compliance and comfort.

• Poor bioavailability and therapeutic response exhibited by Conventional ophthalmiC solution due to rapid precorneal elimination of drug may be overcome by use of gel system that are instilled as drops into eye and undergoes a sol-gel transition from instilled dose.

• Liquid dosage form that can sustain drug release and remain in contact with cornea of eye for extended period of time is ideal.

• Reduced systemic absorption of drug drained through the nasolacrimal duct may result in some undesirable side effects.

Swelling: Tn -situ formation may also occur when material absorbs water from surrounding envy ronment and expand to desired space. One such substance” is mineral (glycerol mono-oleate), which is polar lipid that swells in water to form lyotropic liquid crystalline phase structures. It has some bioadhesive properties and can be degraded in-vivo by enzymatic action.

Diffusion: This method involves the diffusion of solvent from polymer solution into surrounding tissue and results in precipitation or solidification of polymer matrix. N -methyl pyrrolidone (NMP) has been shown to be usefuI solvent for such system. In -situ formation based on chemical reactions mechanism Chemical reactions that results in-situ gelation may involve precipitation of inorganic solids from supersaturated ionic solutions, enzymatic processes, and photo-initiated processes.