SEMISOLID DOSAGE FORMS

 

(a) Ointments:-Type of ointments, classification and selection of dermatological vehicles. Preparation and stability of ointments by the following processes: (i) Trituration, (ii) Fusion, (iii) Chemical reaction, (iv) emulsification.

(b) Pastes: Differences between ointments and pastes. Bases of pastes. Preparation of pastes and their preservation.

(c) Jellies: An introduction to the different types of jellies and their preparation.

(d) An elementary study of poultice.

(e) Suppositories and pessaries: Their relative merits and demerits, types of suppositories, suppository bases, classification, properties, preparation and packing of suppositories. Use of suppositories for drug absorption.

 

Ointments are soft semisolid preparations meant for external application to the skin or mucous membrane.

They usually contains medicament which is either dissolved or suspended in the base.

They have emollient and protective action.

Creams are semisolid emulsions and are generally of softer consistency and lighter than ointments.

They are less greasy and are easy to apply.

Pastes are semisolid preparations for external application that differ from similar products in containing a high proportion of finely powdered medicaments.

They are stiffer and are usually employed for their protective action and for their ability to absorb serous discharges from skin lesions.

Thus when protective, rather than therapeutic action is desired, the formulation pharmacists will favour a paste, but when therapeutic action is required, he will prefer ointments and creams.

Jellies are transparent or translucent, non-greasy, semisolid preparation mainly used externally.

The gelling agent may be gelatin, starch, tragacanth, sodium alginate or cellulose derivative (e.g. carboxy methyl cellulose).

OINTMENT

Definition: Ointments are semisolid preparations for application to the skin or mucosae. The ointment bases are almost always anhydrous and generally contains one or more medicaments in suspension or solution.

Characteristics of an ideal ointment:

1.      It should be chemically and physically stable.

2.      It should be smooth and free from grittiness.

3.      It should melt or soften at body temperature and be easily applied.

4.      The base should be non-irritant and should have no therapeutic action.

5.      The medicament should be finely divided and uniformly distributed throughout the base.

Classification of ointments

According to their therapeutic properties based on penetration of skin.

According to their therapeutic uses.

Ointments classified according to their therapeutic properties based on penetration are as follows:

(a) Epidermic, (b) Endodermic, (c) Diadermic

(a) Epidermic ointments

These ointments are intended to produce their action on the surface of the skin and produce local effect.

They are not absorbed.

They acts as protectives, antiseptics and parasiticides.

(b) Endodermic ointments

These ointments are intended to release the medicaments that penetrate into the skin. They are partially absorbed and acts as emollients, stimulants and local irritants.

(c) Diadermic ointments

These ointments are intended to release the medicaments that pass through the skin and produce systemic effects.

According to therapeutic uses the ointments are classified as follows:

(i) Acne treatment          :resorcinol, sulfur.

(ii) Antibiotics               :Used to kill microorganisms.

                                    e.g. bacitracin, chlortetracycline, neomycin.

(iii) Antieczematous       :Used to stop oozing and exudation from vesicles on the skin.

                                    e.g. hydrocortisone, coal tar, ichthamol, salicylic acid.

(iv) Antifungal              :Used to inhibit or kill the fungi.

                                    e.g. benzoic acid, salicylic aid, nystatin, clotrimazole, etc.

(v) Anti-inflammatory    :Used to relieve inflammatory, allergic and pruritic conditions of the                              skin

                                    e.g. betamethasone valerate, hydrocortisone, triamcinolone acetonide

(vi) Antipruritic             :Used to relieve itching.

                                    e.g. benzocaine, coal tar.

(vii) Antiseptic              :Used to stop sepsis.

                                    e.g. ammoniated mercury, zinc oxide.

(vii) Astringent              :Reduces the secretion of glands or discharge from skin surface.

                                    e.g. calamine, zinc oxide, aluminium acetate and subacetate, acetic                               acid and tannic acid.

(ix) Counter irritant        These are applied locally to irritate the intact skin, thus reducing or relieving another irritation or deep seated pain. e.g. capsicum oleoresin, iodine (Iodex), methyl salicylate.

(x) Dandruff treatment    :e.g. salicylic acid and cetrimide (cetyl trimethyl ammonium bromide)

(xi) Emollient                 :Used to soften the skin (for example in the dry season).

                                      e.g. soft paraffin

(xii) Keratolytic              Used to remove or soften the horny layer of the skin.

                                      e.g. resorcinol, salicylic acid and sulfur.

(xi) Keratoplastic            :Tends to increase the thickness of horny layer e.g. coal tar.

(xii) Parasiticide             :These ointments destroy or inhibit living infestations such as lice and ticks.

                                      e.g. benzyl benzoate, gamma-benzene hexachloride (GBH), sulfur etc.

(xiii) Protective               :Protects the skin from moisture, air, sun rays or other substances such as soaps or chemicals.

                                      e.g. silicones, titanium dioxide, calamine, zinc oxide, petrolatum.

OINTMENT BASES

The ointment base is that substance or part of an ointment preparation which serves as carrier or vehicle for the medicament.

An ideal ointment base should be inert, stable, smooth, compatible with the skin, non-irritating and should release the incorporated medicaments readily.

Classification of ointment bases:

1.      Oleaginous bases

2.      Absorption bases

3.      Water-miscible bases

4.      Water soluble bases

OLEAGINOUS BASES

These bases consists of oils and fats. The most important are the

Hydrocarbons i.e. petrolatum, paraffins and mineral oils.

The animal fat includes lard.

The combination of these materials can produce a product of desired melting point and viscosity.

(a) Petrolatum (Soft paraffin)

This is a purified mixture of semi-solid hydrocarbons obtained from petroleum or heavy lubricating oil.

Yellow soft paraffin (Petrolatum; Petroleum jelly)

This a purified mixture of semisolid hydrocarbons obtained from petroleum. It may contain suitable stabilizers like, antioxidants e.g. a-tocopherol (Vitamin E), butylated hydroxy toluene (BHT) etc.

Melting range : 38 to 56⁰C.

White soft paraffin (White petroleum jelly, White petrolatum)

This a purified mixture of semisolid hydrocarbons obtained from petroleum, and wholly or partially decolorized by percolating the yellow soft paraffin through freshly burned bone black or adsorptive clays.

Melting range : 38 to 56⁰C.

Use: The white form is used when the medicament is colourless, white or a pastel shade. This base is used in

Dithranol ointment B.P.

Ammoniated Mercury and Coal tar ointment B.P.C.

Zinc ointment B.P.C.

(b) Hard paraffin (Paraffin)

This is a mixture of solid hydrocarbons obtained from petroleum.

It is colourless or white, odorless, translucent, wax-like substance. It solidifies between 50 and 57⁰C and is used to stiffen ointment bases.

(c) Liquid paraffin (Liquid petrolatum,; White mineral oil)

It is a mixture of liquid , hydrocarbons obtained from petroleum. It is transparent, colourless, odourless, viscous liquid.

On long storage it may oxidize to produce peroxides and therefore, it may contain tocopherol or BHT as antioxidants.

It is used along with hard paraffin and soft paraffin to get a desired consistency of the ointment. Tubes for eye, rectal and nasal ointments have nozzles with narrow orifices through which it is difficult to expel very viscous ointments without the risk of bursting the tube. To facilitate the extrusion upto 25% of the base may be replaced by liquid paraffins.

Advantages of hydrocarbons bases:

(i)     They are not absorbed by the skin. They remain on the surface as an occlusive layer that restricts the loss of moisture hence, keeps the skin soft.

(ii)   They are sticky hence ensures prolonged contact between skin and medicament.

(iii) They are almost inert. They consist largely of saturated hydrocarbons, therefore, very few incompatibilities and little tendency of rancidity are there.

(iv)  They can withstand heat sterilization, hence, sterile ophthalmic ointments can be prepared with it.

(v)   They are readily available and cheap.

Disadvantages of hydrocarbon bases;

(i)     It may lead to water logging followed by maceration of the skin if applied for a prolonged period.

(ii)   It retains body heat, which may produce an uncomfortable feeling of warmth.

(iii) They are immiscible with water; as a result rubbing onto the surface and removal after treatment both are difficult.

(iv)  they are sticky, hence makes application unpleasant and leads to contamination of clothes.

(v)   Water absorption capacity is very low, hence, these bases are poor in absorbing exudate from moist lesions.

ABSORPTION BASE

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 (some times called emulsifiable ointment bases) are generally anhydrous substances which have the property of absorbing (emulsifying) considerable quantity of water yet retaining its ointment-like consistency.

            Preparations of this type do not contain water as a component of their basic formula but if water is incorporated a W/O emulsion results.

Wool Fat (anhydrous lanolin)

It is the purified anhydrous fat like substance obtained from the wool of sheep.

·        It is practically insoluble in water but can absorb water upto 50% of its own weight. Therefore it is used in ointments the proportion of water or aqueous liquids to be incorporated in hydrocarbon base is too large.

·        Due to its sticky nature it is not used alone but is used along with other bases in the preparation of a number of ointments.

e.g. Simple ointment B.P. contains 5% and the B.P. eye ointment base contains 10% woolfat.

Hydrous Wool Fat (Lanolin)

·        It is a mixture of 70 % w/w wool fat and 30 % w/w purified water. It is a w/o emulsion. Aqueous liquids can be emulsified with it.

·        It is used alone as an emollient.

·        Example:- Hydrous Wool Fat Ointment B.P.C., Calamine Coal Tar Ointment.

Wool Alcohol

It is the emulsifying fraction of  wool fat. Wool alcohol is obtained from wool fat by treating it with alkali and separating the fraction containing cholesterol and other alcohols. It contains not less than 30% of cholesterol.

Use:-  

·        It is used as an emulsifying agent for the preparation of w/o emulsions and is used to absorb water in ointment bases.

·        It is also used to improve the texture, stability and emollient properties of o/w emulsions.

Examples :- Wool alcohol ointment B.P. contains 6% wool alcohol and hard, liquid and soft paraffin.

Beeswax

It is purified wax, obtained from honey comb of bees.

It contains small amount of cholesterol. It is of two types: (a) yellow beeswax and (b) white beeswax.

Use:-

Beeswax is used as a stiffening agent in ointment preparations.

Examples:-Paraffin ointment B.P.C. contains beeswax.

Cholesterol

It is widely distributed in animal organisms. Wool fat is also used as a source of cholesterol.

Use:- It is used to increase the water absorbing power of an ointment base.

Example:- Hydrophilic petroleum U.S.P. contains:

            Cholesterol                   3%

            Stearyl alcohol              3%

            White beeswax             8%

            White soft paraffin        86%

Advantages of absorption bases:

(i)      They are less occlusive nevertheless, are good emollient.

(ii)   They assist oil soluble medicaments to penetrate the skin.

(iii) They are easier to spread.

(iv)  They are compatible with majority of the medicaments.

(v)   They are relatively heat stable.

(vi)  The base may be used in their anhydrous form or in emulsified form.

(vii)They can absorb a large quantity of water or aqueous substances.

Disadvantages: Inspite of their hydrophilic nature, absorption bases are difficult to wash.

WATER MISCIBLE BASES

They are miscible with an excess of water. Ointments made from water-miscible bases are easily removed after use.

There are three official anhydrous water-miscible ointment bases:-

Example:-        

Emulsifying ointment B.P.                                           - contains anionic emulsifier.

Cetrimide emulsifying ointment B.P.                            - contains cationic emulsifier

Cetomacrogol emulsifying ointment B.P.                      - contains non-ionic emulsifier

Uses: they are used to prepare o/w creams and are easily removable ointment bases

e.g. Compound Benzoic Acid Ointment  (Whitfield’s Ointment) - used as antifungal ointment.

Advantages of water miscible bases:

(i)     Readily miscible with the exudates from lesions.

(ii)   Reduced interference with normal skin function.

(iii) Good contact with the skin, because of their surfactant content.

(iv)  High cosmetic acceptability, hence there is less likelihood of the patients discontinuing treatment.

(v)   Easy removal from the hair.

WATER SOLUBLE BASES

Water soluble bases contain only the water soluble ingredients and not the fats or other greasy substances, hence, they are known as grease-less bases.

Water soluble bases consists of water  soluble ingredients such as polyethylene glycol polymers (PEG) which are popularly known as “carbowaxes” and commercially known as “macrogols”.

They are a range of compounds with the general formula:

                                                CH₂OH . (CH₂OCH₂) _n CH₂OH

The PEGs are mixtures of polycondensation products of ethylene and water and they are described by numbers representing their average molecular weights. Like the paraffin hydrocarbons they vary in consistency from viscous liquids to waxy solids.

Example:-

            Macrogols 200, 300, 400                                   - viscous liquids

            Macrogols 1500                                                - greasy semi-solids

            Macrogols 1540, 3000, 4000, 6000                     - waxy solids.

Different PEGs are mixed to get an ointment of desired consistency.

Advantages of PEGs as ointment base:

(a)    They are water soluble; hence, very easily can be removed from the skin and readily miscible with tissue exudates.

(b)   Helps in good absorption by the skin.

(c)    Good solvent properties. Some water-soluble dermatological drugs, such as salicylic acid, sulfonamides, sulfur etc. are soluble in this bases.

(d)   Non-greasy.

(e)    They do not hydrolyze, rancidify or support microbial growth.

(f)    Compatibility with many dermatological medicaments.

Disadvantages:

(a)    Limited uptake of water. Macrogols dissolve when the proportion of water reaches about 5%.

(b)   Reduction in activity of certain antibacterial agents, e.g. phenols, hydroxybenzoates and quaternary compounds.

(c)    Solvent action on polyethylene and bakelite containers and closures.

Certain other substances which are used as water soluble ointment bases include tragacanth, gelatin, pectin, silica gel, sodium alginate, cellulose derivatives, etc.

FACTORS GOVERNING SELECTION OF AN IDEAL OINTMENT BASE

1. Dermatological factors

2. Pharmaceutical factors

1. 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.

(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.

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.

(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.

PREPARATION OF OINTMENTS

A well-made ointment is -

(a) Uniform throughout i.e. it contains no lumps of separated high melting point ingredients of the base, there is no tendency for liquid constituents to separate and insoluble powders are evenly dispersed.

(b) Free from grittiness, i.e. insoluble powders are finely subdivided and large lumps of particles are absent. Methods of preparation must satisfy this criteria.

Two mixing techniques are frequently used in making ointments:

1. Fusion, in which ingredients are melted together and stirred to ensure homogeneity.

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

1. Ointments prepared by Fusion method:

When an ointment base contain a number of solid ingredients such as white beeswax, cetyl alcohol, stearyl alcohol, stearic acid, hard paraffin, etc. as components of the base, it is required to melted them. The melting can be done in two methods:

Method-I

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

Advantages:

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

Method-II

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

Advantages:

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 ingredients.

Cautions:

(i)     Melting time is shortened by grating waxy components (i.e. beeswax, wool alcohols, hard-paraffin, higher fatty alcohols and emulsifying waxes) by stirring during melting and by lowering the dish as far as possible into the water bath so that the maximum surface area is heated.

(ii)   The surface of some ingredients discolors due to oxidation e.g. wool fats and wool alcohols and this discolored layers should be removed before use.

(iii) 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 spatula 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.

(iv)  Vigorous-stirring, after the ointment has begun to thicken, causes excessive aeration and should be avoided.

(v)   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 through muslin supported by a warm strainer. In both instances the clarified liquid is collected in another hot basin.

(vi)  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.

Example:

(i) Simple ointment B.P. contains

                                                Wool fat                       50g

                                                Hard paraffin                50g

                                                Cetostearyl alcohol       50g

                                                White soft paraffin        850g

Type of preparation:                  Absorption ointment base

Procedure:

Hard paraffin and cetostearyl alcohol on water-bath. Wool fat and white soft paraffin are mixed and stirred until all the ingredients are melted.

If required decanted or strained and stirred until cold and packed in suitable container.

(ii) Paraffin ointment base

Type of preparation : Hydrocarbon ointment base

(iii) Wool alcohols ointment B.P.

Type of preparation: Absorption base

(iv) Emulsifying ointment B.P.

Type of preparation: Water-miscible ointment base.

(v) Macrogol ointment B.P.C

Type of preparation: Water soluble ointment base

Formula:          Macrogol 4000

                        Liquid Macrogol 300

Method: Macrogol 4000 is melted and previously warmed liquid macrogol 300 is added. Stirred until cool.

2. OINTMENT PREPARED BY TRITURATION

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

(i)     Solids are finely powdered are passed through a sieve (# 250, # 180, #125).

(ii)   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 this additional quantities of the base are incorporated and triturated until the medicament is mixed with the base.

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

Example:

(i) Whitfield ointment (Compound benzoic acid ointment B.P.C.)

Formula:          Benzoic acid, in fine powder     6gm

                        Salicylic acid, in fine powder     3gm

                        Emulsifying ointment               91gm

Method: Benzoic acid and salicylic acid are sieved through No. 180 sieves. They are mixed on the tile with small amount of base and levigated until smooth and dilute gradually.

(ii) Salicylic acid sulphur ointment B.P.C.

3. 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, both of the 1959 B.P.C.

(a) Ointment containing free iodine

Iodine is only slightly soluble in most fats and oils but readily soluble.

Iodine is readily soluble in concentrated solution of potassium iodide due to the formation of molecular complexes KI.I₂, KI.2I₂, KI.3I₂ etc.

These solutions may be incorporated in absorption-type ointment bases.

e.g. Strong Iodine Ointment B.Vet.C (British Veterinary Pharmacopoeia) is used to treat ringworm in cattle. It contains free iodine. At one time this type of ointments were used as counter-irritants in the treatment of human rheumatic diseases but they were not popular because:

(i)     They stain the skin a deep red color.

(ii)   Due to improper storage the water dries up and the iodine crystals irritate the skin, hence glycerol was some times to dissolve the iodine-potassium iodide complex instead of water.

Example: Strong Iodine Ointment B. Vet.C.

                        Iodine

                        Woolfat

                        Yellow soft paraffin

                        Potassium iodide

                        Water

Procedure:

(i)     KI is dissolved in water. I₂ is dissolved in it.

(ii)   Woolfat and yellow soft paraffin are melted together over water bath. Melted mass is cooled to about 40⁰C.

(iii) I₂ solution is added to the melted mass in small quantities at a time with continuos stirring until a uniform mass is obtained.

(iv)  It is cooled to room temperature and packed.

Use: - Ringworm in cattle.

(b) Ointment containing combined iodine

Fixed oils and many vegetable and animal fats absorb iodine which combines with the double bonds of the unsaturated constituents, e.g.

CH₃.(CH₂) ₂.CH = CH.(CH₂) ₇.COOH + I₂ ® CH₃.(CH₂) ₂.CHI CHI.(CH₂) ₇.COOH

                                    Oleic acid                                             di-iodostearic acid

Example: Non-staining Iodine Ointment B.P.C. 1968                 Iodine

                                                                                                Arachis Oil

                                                                                                Yellow Soft Paraffin

Method:

(a)    Iodine is finely powdered in a glass mortar and required amount is added to the oil in a glass-stoppered conical flask and stirred well.

(b)   The oil is heated at 50⁰C in a water-bath and stirred continually. Heating is continued until the brown color is changed to greenish-black; this may take several hours.

(c)    From 0.1g of the preparation the amount of iodine is determined by B.P.C. method and the amount of soft paraffin base is calculated to give the product the required strength.

(d)   Soft paraffin is warmed to 40⁰C. The iodized oil is added and mixed well. No more heat is applied because this causes deposition of a resinous substance.

(e)    The preparation is packed in a warm, wide-mouthed, amber color, glass bottle. It is allowed to cool without further stirring.

4. PREPARATION OF OINTMENTS BY EMULSIFICATION

An emulsion system contain an oil phase, an aqueous phase and an emulsifying agent.

For o/w emulsion systems the following emulsifying agents are used:

            (i) water soluble soap

            (ii) cetyl alcohol

            (iii)glyceryl monostearate

            (iv) combination of emulsifiers: triethanolamine stearate + cetyl alcohol

            (v) non-ionic emulsifiers: glyceryl monostearate, glyceryl monooelate, propylene glycol stearate

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

            (i) polyvalent ions e.g  magnesium, calcium and aluminium are used.

            (ii) combination of emulsifiers: beeswax + divalent calcium ion

The viscosity of this type of creams prevent coalescence of the emulsified phases and helps in stabilizing the emulsion.

Example:

Cold cream:

Procedure:

(i)     Water immiscible components e.g. oils, fats, waxes are melted together over water bath (70⁰C).

(ii)   Aqueous solution of all heat stable, water soluble components are heated (70⁰C).

(iii) Aqueous solution is slowly added to the melted bases with continuous stirring until the product cools down and a semi-solid mass is obtained.

N.B. The aqueous phase is heated otherwise high melting point fats and waxes will immediately solidify on addition of cold aqueous solution.

STABILITY OF OINTMENTS

The ointments should remain stable from the time of preparation to the time when the whole of it is consumed by the user.

(i)     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.

(ii)   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.

(iii) Some ingredients like wool fat and wool alcohols are susceptible to oxidation. Therefore, a suitable antioxidant may be incorporated to protect the active ingredients from oxidation.

(iv)  Incompatible drugs, emulsifying agents and preservatives must be avoided. The drugs which are likely to hydrolyze must be dispensed in an anhydrous base.

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

(vi)  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.

PASTE

Syllabus:

               Differences between ointments and pastes.

               Bases of pastes

               Preparation of paste and their preservation.

Differences between pastes and ointments;

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

(ii)   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.

(iii) 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.

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

(v)   Most of the pastes are unsuitable for treating scalp conditions because they are difficult to remove from the hair.

BASES OF PASTES:

1. Hydrocarbon base:

Soft paraffin and liquid paraffin are commonly used bases for the preparation of paste.

Name of the preparation	Active ingredients	Base	Use
1.      Compound Zinc Paste B.P. 2.      Compound Zinc & Salicylic acid Paste B.P. (Lassar’s Paste) 3.      Coal tar paste 4.      Dithranol paste compound 5.      Aluminium paste B.P.C.       (Baltimore Paste)	Zinc oxide Zinc oxide & Salicylic acid Coal tar Dithranol Aluminium oxide	Soft paraffin Soft paraffin Soft paraffin Soft paraffin Liquid paraffin	Eczema, psoriasis. Eczema, psoriasis. Eczema Ring worm or psoriasis Protectant

2. Water miscible base:

Name of the preparation	Base	Use
1.      Resorcinol & sulfur Paste B.P.C. 2.      Zinc & Coal tar Paste 3.      Magnesium sulfate paste B.P.C. (Morison’s paste) 4.      Titanium dioxide paste B.P.C.	Emulsifying ointment Emulsifying wax Magnesium sulfate -45% Phenol in glycerol Suspension of TiO2, ZnO, light kaolin and red Fe2O3 in glycerol + water.	Dandruff, and are easily removable from the hair. Eczema Used to treat boils, because of their powerful osmotic effect of the salt and the glycerol. Absorbs exudates from weeping skin conditions.

3. Water soluble bases

Water soluble bases are prepared from mixtures of high and low molecular weight polyethylene glycols (or macrogols).

Name of the preparation	Base	Use
1.      Water soluble dental pastes 2.      Triamcinolone Dental paste B.P.C.	Neomycin sulfate Triamcinolone acetonide in an adhesive paste (NaCMC, pectin, + gelatin)	Sterilizing infected root canal Anti-inflammatory

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.

Preparation 1.

Name:              Compound Zinc Paste

Formula           Zinc oxide, finely sifted            25 g

                        Starch, finely sifted                   25 g

                        White soft paraffin                    50 g

Type of preparation: Paste with semi-solid base prepared by fusion and trituration.

Procedure;

(a)    Zinc oxide and starch powder are passed through No. 180 sieve.

(b)   Soft paraffin is melted on a water bath.

(c)    The required amount of powder is taken in a warm mortar, triturated with little melted base until smooth. Gradually rest of the base is added and mixed until cold.

Preparation 2.

Name:              Zinc and Coal tar Paste B.P.C.

Formula:          Zinc oxide, finely sifted

                        Coal tar

                        Emulsifying wax

                        Starch

                        Yellow soft paraffin.

Type of preparation: Paste with semi-solid base prepared by fusion.

Procedure:

Method-I

(a)    Emulsifying wax is melted in a tared dish (70⁰C).

(b)   The coal tar is weighed in the dish. Stirred to mix.

Soft paraffin is melted in a separate dish (70⁰C) and about half is added to the tar-wax mixture; stirred well. Remainder is added; stirred again until homogeneous.

Allowed to cool at about (30⁰C) and zinc oxide (previously passed through 180 mesh) and starch, in small amount with constant stirring. Stirred until cold.

Method-II

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.

JELLIES

Definition:

Jellies are transparent or translucent, non-greasy, semisolid preparation generally applied externally.

They are used for medication, lubrication and some miscellaneous applications.

Types of jellies:

Medicated jellies

(i)     Water soluble drugs like local anaesthetics, spermicides and antiseptics are suitable for incorporation in the jellies.

(ii)   They are easy to apply and evaporation of the water content produces a pleasant cooling effect. The medicinal film usually adheres well and gives protection but is easily removed by washing when the treatment is complete.

e.g.       ephedrine sulfate jelly - used to arrest bleeding from nose.

            pramoxine HCl , a local anaesthetic - relieves discomfort of pruritis and haemorrhoids.

            phenylmercuric nitrate - as spermicidal contraceptive.

Lubricant jelly

Catheters, items of eletrodiagnostic equipment, such as cystoscopes, and rubber gloves or finger stalls used for rectal and other examinations require lubrication before use.

The lubricants must be sterile for articles inserted into sterile regions of the body, such as urinary bladder.

For painful investigations a local anaesthetic may be included as in Lignocaine Gel B.P.C.

Miscellaneous uses

The following are more specialized jellies -

(a) Patch testing

Here the jelly is the vehicle for allergens applied to the skin to detect sensitivity. Several allergens may be applied on one person. The viscosity of the jelly and it leaves on drying help to keep the particles separate.

(b) Electrocardiography

to reduce electrical resistance between the patients skin and electrodes of the cardiograph, an electrode jelly may be applied. This contains NaCl to provide good conductivity and often pumice powder which, when applied onto the skin, removes part of the horny layer of the epidermis, the main layer of electrical resistance.

FORMULATION

Pharmaceutical jellies are usually prepared by adding a thickening agent such as tragacanth or carboxy methylcellulose (CMC) to an aqueous solution in which drug has been dissolved.

The mass is triturated in a mortar until a uniform product is obtained.

For the preparation of jellies whole gum is preferred  rather than powdered gum because the former gives a clear preparation of uniform consistency.

The following gelling agents are used for the preparation of jellies.

(i) Tragacanth

the main hydrophilic component of tragacanth that gels in water has been named bassorin - hence, tragacanth jellies are sometimes called bassorin paste.

The amount of gum required for a preparation varies with its use:

(a)    For lubricating jelly 2 to 3%.

(b)   Fro dermatological vehicles about 5%.

(c)    For incorporation of ichthamol, resorcinol, salicylic acid and other medicaments, about 5% is generally used. All formulations contain alcohol and/or glycerol and/or a volatile oil to disperse the gum and prevent lumpiness when water is added.

(d)   They vary in viscosity, due to the natural origin of the gum and variations in milling and storage.

(e)    The film left on the skin tends to flake.

(f)    Viscosity is rapidly lost outside the pH range of 4.5 to 7.0; for example if benzoic acid is used as the preservative.

(g)   They are susceptible to microbial growth.

Example:

Formula           Ichthamol                                 1.0 g

                        Tragacanth                               2.5 g

                        Alcohol 90%                             5.0 g

                        Glycerin                                   1.0 g

                        Purified water q.s.                     50.0g

Procedure:

(i)     Alcohol is taken in a 100 ml, wide mouthed jar; and then tragacanth is added to it. (The reverse order may lead to lump formation). Mixed well.

(ii)   Water is added as quickly as possible and mixed.

(iii) Separately ichthamol, glycerin and 10 ml water is mixed. Final weight is adjusted by adding more of water.

2. Sodium alginate

Uses:-   As lubricant - 1.5 to 2 % is used.

            As dermatological vehicle - 5 to 10 % is used.

A trace of Ca - salt (CaCl₂) may be added to increase the viscosity and most formulations contain glycerol as a dispersing agent.

Advantage: Sodium alginate has an advantage over tragacanth that is available in several grade or standardized viscosity.

3. Pectin

·        Pectin is a very good gelling agent and is used in the preparation of many types of jellies including edible jellies.

·        Glycerin is used as a dispersing agent and humectant in dermatological jellies.

·        Jellies must be packed in well-closed containers because they lose water rapidly by evaporation and this lose water rapidly by evaporation and this is increased by the susceptibility of pectin gels to syneresis (i.e. exudation of the aqueous phase as a result of contraction of the gel).

4. Starch

Starch in combination with gelatin and glycerin is commonly used for preparations of jellies.

Glycerin in 50% may act as preservative.

Medicaments are incorporated in the cold jelly by trituration.

5. Gelatin

Insoluble in cold water but swell and softens in it. It is soluble  in hot water.

Hot solution contain 2% gelatin forms a jelly on cooling.

Very stiff  (15%) jellies are melted before used  and after cooling to desired temperature are applied with a brush to the affected area. The area is covered with bandage and the dressing may be left in place for several weeks.

Zinc-gelatin jelly (Unna’s paste) is such an example.

Formula:          Zinc oxide                    15g

                        Gelatin                         15g

                        Glycerin                       35g

                        Water                           35g

Procedure:

(i)     Gelatin soaked in water until softened.

(ii)   Glycerin is added and heated over bath until the glycerin is dissolved.

(iii) Adjust the weight to 85 g if necessary by adding more amount of water.

(iv)  ZnO is passed through sieve (#120). Required amount is added in small amounts to the molten base with gentle stirring. Stirring is continued until a viscous product is obtained.

(v)   The product so obtained is poured in a tray to a depth of about 1 cm with continuous trituration throughout the operation. When the  mass is set, carefully the mass is cut into pieces of about 1.5cm²  with a blade or sharp knife.

6. Cellulose derivative

Methyl cellulose and sodium carboxy methyl cellulose

1.      produce neutral jellies of stable viscosity.

2.      Have good resistance against microbial  growth.

3.      Clear due to freedom from insoluble impurities.

4.      Produce strong film after drying on the skin.

Use: Sodium carboxy methyl cellulose can be used to prepare lubricating jellies and sterile jellies.

                                    e.g.  lignocine gel - because it can withstand autoclaving temperature.

N.B. Other cellulose derivatives are

                                                            Hydroxy propyl methyl cellulose (Hypermellose)

                                                            Carbomer

                                                            Polyvinyl alcohols.

7. Clays

Gels containing 7 to 20 % of bentonite can be used as dermatological bases.

Disadvantages:

1.      They are opalescent and lack attractiveness.

2.      Their pH is about 9.0 i.e. not suitable for application on the skin.

3.      Residue on the skin is powdery and rather silky.

Preservation of jellies:

Although some bases like clays and cellulose derivative(s) resist microbial contamination but since all the jellies contain large amount of water, therefore must be suitably preserved.

e.g. Methyl paraben 0.1 to 0.2 % is commonly used.

Loss of water can quickly lead to skin formation on jellies and to prevent the hygroscopic substances, e.g. glycerol, propylene glycol or sorbitol solution may be added.

Bases and medicaments sensitive to heavy metals are sometimes protected by a chelating agent e.g. ethylene diamine tetra acetic acid (EDTA)

POULTICE

Definition: Poultice are paste-like preparations used externally to reduce inflammation because they retain heat well. After heating, the preparation is spread thickly on a dressing and applied, as hot as the patient can bear it, to the affected area.

Uses;

(i)     Glycerol, because of its hygroscopic nature, is believed to draw infected materials from the tissues when the poultice is used for boils and similar infections.

(ii)         Methyl salicylate (an antirheumatic drug),

            thymol (a powerful bactericide),

            boric acid (a weak antimicrobial agent),

            and peppermint oil (which contributes to the smell) are used for different purposes.

Method of applying the poultice:

(i)     Fro use, the poultice is heated, with occasional  stirring, until it can only be  tolerated on the back of the hand.

(ii)   Then it is spread thickly on lint or other dressing  and applied to the affected area which is sometimes first covered with muslin to facilitate removal after use.

(iii) A thick layer of cotton wool is applied to retain the heat and a covering of oiled silk may be added to protect clothing.

Example:

The only example given in the pharmacopoeia is Kaolin Poultice B.P.C.

Formula:                      Heavy kaolin, finely sifted and dried at 100⁰C                52.7 g

                                    Boric acid, finely sifted                                                 4.5 g

                                    Methyl salicylate                                                          0.2 ml

                                    Thymol                                                                                    50 mg

                                    Peppermint oil                                                              0.05 ml

                                    Glycerin                                                                       42.5 g

Procedure:

(a)    Kaolin is spread in a suitable quantity of kaolin in a thin layer, e.g.  on a tray of aluminium foil, and dried at 100⁰C until the weight is constant. Allowed to cool down and then passed through No. 180 sieve.

(b)   Boric acid and kaolin are mixed in a mortar. Gradually the mixed powder is triturated with glycerol to form a smooth paste.

(c)    The paste is transferred to a heat-resistant glass-jar, protected either wit a paper or aluminium foil and heated at 120⁰C for 1 hour in a hot-air oven, with occasional stirring. The antimicrobial effects of the heat and glycerol destroy the sporing pathogens that may be in the kaolin. (Above 1200C glycerin may degrade).

(d)   After cooling a mixture of thymol, methyl salicylate and peppermint oil are mixed. (Eutectic mixture).

(e)    Kaolin poultice is stored in well closed containers to prevent loss of volatile ingredients and absorption of moisture from the atmosphere by glycerin.

SUPPOSITORIES AND PESSARIES

Syllabus:

Their relative merits and demerits

Types of suppositories, Suppository bases, classification, properties, preparation and packaging of suppositories.

Use of suppositories for drug absorption.

Definition:

·        Suppositories are specially shaped solid dosage form of medicament for insertion into body cavities other than mouth.

·        They may be inserted into rectum, vagina or the urethra.

·        This products are so formulated that after insertion, they will either melt or dissolve in the cavity fluids to release the medicament.

Advantages of rectal suppositories:

(i)     Mechanical action: The rectal suppositories are extensively used as a mechanical aid to bowel evacuation which produce its action by either irritating the mucous membrane of the rectum (e.g. glycerol and bisacodyl) or by lubricating action or by mechanical lubrication.

(ii)   Local action: The rectal suppositories may be used for soothing, antiseptic, local anaesthetic action or for astringent effect. Therefore, they may contain

      soothing                  e.g. zinc oxide

      local anaesthetic-    e.g. cinchocaine, benzocaine

      astringents              e.g. bismuth subgallate, hamamelis extract and tannic acid

      antiinflammatory    e.g. hydrocortisone and its acetate.

(iii) To provide systemic action: Suppositories are convenient mode of administration of drugs which irritate the gastrointestinal tract, cause vomiting, are destroyed by the hepatic circulation, or are destroyed in the stomach by pH changes, enzymes etc.

Partial bypass: The lower portion of the rectum affords a large absorption surface area from which the soluble substances can absorb and reach the systemic circulation.

e.g.       aminophylline               used in asthmatic and chronic bronchitis.

            morphine                      a powerful analgesic

            ergotamine tartarate      used to treat migraine

            indomethacin and phenyl butazone         analgesic and anti-inflammatory actions.

Systemic treatment by the rectal route is of particular value for

(a)    treating patients who are unconscious, mentally disturbed or unable to tolerate oral medication because of vomiting or pathological conditions of the alimentary tract.

(b)   administering drugs, such as aminophylline, that cause gastric irritation, and

(c)    treating infants.

PESSARIES

Pessaries are solid medicated preparations for introducing into the vagina, where they melt or dissolve and exert a local action.

They are used mainly for vaginitis (inflammation of the vagina) and leucorrhoea (unpleasant vaginal discharge). Vaginitis may be caused by a variety of micro-organisms or key old age. The medicaments in official pessaries are:

acetarsol           an antiprotozoal agent

di-iodohydroxyquinoline for yeast and protoplast infections.

lactic acid         often useful in leucorrhoea

nystatin             for yeast infections

crystal violet     for various microbial infections.

TYPES OF SUPPOSITORIES:

1. Rectal suppositories

These are meant for introduction into the rectum for their systemic effect. They are tapered at one or both ends and usually weigh about 2 gm. The rectal suppositories meant for children are smaller in size and weight is 1 gm.

2. Vaginal suppositories:

They are meant for introduction into vagina.

They are larger than rectal suppositories and vary in weight from 3 to 6 gm or more.

They may be conical, rod-shaped or wedge shaped.

They a re exclusively used for their local action on vagina.

3. Urethral Suppositories (or Urethral bougies)

They are meant for introduction into the urethra.

Their weight varies from 2 to 4 gm and length from 2 to 5 inch. Urethral suppositories are very rarely used.

4. Nasal suppositories (Nasal bougies)

They are meant for introduction into nasal cavity.

They are similar in shape to urethral bougies.

Their weight is about 1 gm and length 9-10 cm.

They are always prepared with glycero-gelatin base.

5. Ear cones (aurinaria)

They are meant for information into the ear.

Generally theobroma oil is used as a base.

They are prepared in an urethral bougies mould and cut according to the required size.

Properties of an Ideal Suppositories Base

1.      It should melt at body temperature or dissolve or disperse in body fluids.

2.      It should release any medicament readily.

3.      It should keep its shape when being handled.

4.      It should be non-toxic and non-irritant to the mucous membrane.

5.      It should be stable on storage.

6.      It should be compatible with any added medicament.

7.      It should be stable if heated above its melting point.

8.      It should be easily moulded and should not adhere to the mould.

9.      It should be easily mouldable by pouring or cold compression.

[Since it is not possible to get all the above mentioned qualities in a single base, so a combination of bases is used to get a product of required qualities. A number of patent “improved” suppository bases are available. Most of these are mixtures of fats, waxes and/or esters in specific proportions according to the desired qualities of the product to be obtained. Glycerogelatin and polyethylene glycols are being widely used as suppository bases, though theobroma oil is extensively used in extemporaneous preparations but it is losing its importance because it is unstable to heat and has undesirable physical properties.]

Types of Suppository Bases

Suppository bases fall into two classes -

1. Fatty bases - these melt at body temperature.

2. Water-soluble or water miscible bases - these dissolve or disperse in rectal secretions.

3. Emulsifying bases

FATTY BASES

Theobroma oil (Cocoa butter)

It is a yellowish-white solid with a chocolate-like odour. It is a mixture of glyceryl esters of stearic, palmitic, oleic and other fatty acids. Its valuable characteristics include -

Advantages:

(a)    A melting point range of 30 to 36 ⁰C; hence it is solid at normal room temperatures but melts in the body.

(b)   Ready liquefaction on warming and rapid setting on cooling.

(c)    Miscibility with many ingredients.

(d)   Blandness i.e. does not produce irritation.

Disadvantages:

(a) Polymorphism

When melted and cooled it solidifies in different crystalline forms, depending on the temperature of melting, rate of cooling and size of the mass. If melted at not more than 36⁰C and slowly cooled it forms stable beta crystals with normal melting point, but if over-heated it may produce, on cooling, unstable gamma crystals, which melt at about 15⁰C, or a-crystals, melting at about 20⁰C. These unstable forms eventually return to the stable condition but this may take several days and meanwhile, the suppositories may not set at room temperature or, if set by cooling, may remelt in the warmth of the patient’s home.

This lowering of the solidification point can also lead to sedimentation of suspended solids and delay in issuing the product to the patient. Consequently, great care must be taken to avoid over-heating the base when making theobroma oil suppositories.

(b) Adherence to mould

Because theobroma oil doesn’t contract enough on cooling to loosen the suppositories in the mould, sticking may occur, particularly if the mould is worn. This is prevented by lubricating the mould before use.

(c) Softening point too low for hot climates

To raise the softening point, whit beeswax may be added to theobroma oil suppositories intended for use in tropical and subtropical countries.

(d) Melting point reduced by soluble ingredients

Substances, such as chloral hydrate, that dissolve in theobroma oil, may lower its melting point to such an extent that the suppositories are too soft for use. To restore the melting point, a controlled amount of white beeswax may be added.

(e) Slow deterioration during storage

This is due to oxidation of the unsaturated glycerides.

(f) Poor water absorbing capacity

This fault can be improved by the addition of emulsifying agents.

(g) Leakage from the body

Sometimes melted base escapes from the rectum or vagina. This is most troublesome with pessaries because of their larger size, and therefore, these are rarely made with theobroma oil.

(h) Relatively high cost

Synthetic fats

As a substitute of theobroma oil  a number of hydrogenated oils, e.g. hydrogenated edible oil, arachis oil, coconut oil, palm kernel oil, stearic and a mixture of oleic and stearic acids are recommended.

N.B. Synthetic suppositories bases are by hydrogenation and subsequent heat treatment of vegetable oils such as palm oil and arachis oil. The oils are generally esters of unsaturated fatty acids. Hydrogenation saturates the unsaturated fatty acids and heat treatment splits some of the triglycerides into fatty acids and partial esters (mono- and di-glycerides).

Advantages of these synthetic fats over theobroma oil:

1.      Their solidifying points are unaffected by overheating.

2.      They have good resistance to oxidation because their unsaturated fatty acids have been reduced.

3.      Their emulsifying and water absorbing capacities are good. [They usually contain a proportion of partial glycerides some of which, e.g. glyceryl monostearate, are w/o emulsifying agents and, therefore, their emulsifying and water absorbing capacity are good.

4.      No mould lubricant is required because they contract significantly on cooling.

5.      They produce colorless, odourless and elegant suppositories.

Disadvantages:

1.      They should not be cooled in refrigerator because they become brittle if cooled quickly. Certain additives e.g. 0.05 % polysorbate80, help to correct this fault.

2.      They are more fluid than theobroma oil when melted and at this stage sedimentation rate is greater. Thickeners such as magnesium stearate , bentonite and colloidal silicon dioxide, may be added to reduce this.

WATER SOLUBLE AND WATER MISCIBLE BASES

Glycero-Gelatin base

·        This is a mixture of glycerol and water made into a stiff jelly by adding gelatin.

·        It is used for the preparation of jellies, suppositories and pessaries. The stiffness of the mass depends upon the proportion of gelatin used which is adjusted according to its use.

·        The base being hydrophilic in nature, slowly dissolves in the aqueous secretions and provide a slow continuous release of medicament. Glycerogelatin base is well suited for suppositories containing belladonna extract, boric acid, chloral hydrate, bromides, iodides, iodoform, opium, etc.

·        Depending upon the compatibility of the drugs used a suitable type of gelatin is selected for the purpose. Two types of gelatins are used as suppository base

(i)         Type-A or Pharmagel-A which is made by acid hydrolysis (has isoelectric point between 7 to 9 and on the acid side of the range behaves as a cationic agent, being most effective at pH 7 to 8. ) is             used for acidic drugs.

(ii)        Type-B or Pharmagel-B which is prepared by alkaline hydrolysis (having an isoelectric point                between 4.7 to 5 and on the alkaline side of the range behaves as an anionic agent, being most effective at pH 7             to 8 ) is used for alkaline drugs

Disadvantages:

Glycerogelain base suppositories are less commonly used than the fatty base suppositories because:

(i)     Glycerol has laxative action.

(ii)   They are more difficult to prepare and handle.

(iii) Their solution time depends on the content and quality of the gelatin and the age of the base.

(iv)  They are hygroscope, hence must be carefully stored.

(v)   Gelatin is incompatible with drugs those precipitate with the protein e.g. tannic acid, ferric chloride, gallic acid, etc.

Soap-Glycerin Suppositories

·        In this case gelatin and curd soap or sodium stearate which makes the glycerin sufficiently hard for suppositories and a large quantity of glycerin upto 95% of the mass can be incorporated.

·        Further the soap helps in the evacuation of glycerin.

·        The soap glycerin suppositories have the disadvantage that they are very hygroscopic, therefore they must be protected from atmosphere and wrapped in waxed paper or tin foil.

Polyethylene glycol bases / Macrogol bases (Carbowaxes)

Depending on their molecular weight they are available in different physical forms.

Examples of Macrogol bases:

	I	II	III	IV
Macrogol 400 Macrogol 1000 Macrogol 1540 Macrogol 4000 Macrogol 6000 Water	- - - 33 47 20	- - 33 - 47 20	20 - 33 - 47 -	- 75 - 25 - -

By choosing a suitable combination a suppository base with the desired characteristics can be prepared.

Advantages:

1.      The mixtures generally have a melting point above 42⁰C, hence, does not require cool storage and they are satisfactory for use in hot climate.

2.      Because of the high melting point they do not melt in the body cavity, rather they gradually dissolve and disperse, releasing the drug slowly.

3.      They do not stick to the wall of the mould since they contract significantly on cooling.

EMULSIFYING BASES

These are synthetic bases and a number of proprietary bases of very good quality are available, few of which are described below:

Witepsol

They consist of triglycerides of saturated vegetable acids (chain length C12 to C18) with varying proportions of partial esters.

Massa Esterium

This is another range of bases, consisting of a mixture of di-, tri- and mono- glycerides of saturated fatty acids with chain lengths of C11 to C17.

Massuppol

It consists of glyceryl esters mainly of lauric acid, to which a small amount of glyceryl monostearate has been added to improve its water absorbing  capacity.

Advantages of these bases over cocoa butter:

1.      Over heating does not alter the physical characteristics.

2.      They do not stick to the mould. They do not require previous lubrication of the mould

3.      They solidify rapidly.

4.      They are less liable to get rancid.

5.      They can  absorb fairly large amount of aqueous liquids.

PREPARATION OF SUPPOSITORIES

Suppositories are prepared by two processes: moulding (hot process or fusion process) and cold compression.

Mould

Various types and sizes of suppository moulds are available. In the dispensary suppository moulds with six or twelve cavities with desired shape and size may be used. For large scale production moulds up to 500 cavities may be used.

Moulds are made up of stainless steel, nickel-copper alloy, brass, aluminium or plastic.

For cleaning, lubrication and removal of suppositories the mould can be opened longitudinally by removing the screw in the centre of the plates.

The nominal capacities of the common moulds are 1g, 2g, 4g and 8g.

Calibration of the mould

The nominal capacity of a mould is not always correct. It will vary for different bases. Each mould should be calibrated before use by preparing a set of suppositories or pessaries using the base alone, weighing the products and taking the mean weight as the true capacity. This is repeated for each base and the value is recorded for future use.

Displacement value

The volume of a suppository from a particular mould is uniform but its weight will vary because the densities of medicaments  usually differ from the density of the base with which the mould was calibrated.

To prepare products accurately, allowance must be made for the change in density of the mass due to added medicaments. For this purpose the displacement value of a medicament is taken into consideration.

Definition: The number of parts of medicament (drug) that displaces one part by weight of the base is known as the displacement value of that drug.

The following table lists the displacement values, with reference to theobroma oil, for substances prescribed in suppositories and pessaries.

Table

Aminophylline Bismuth subgallate Castor oil Chloral hydrate Cinchocaine Hydrochloride Cocaine hydrochloride Hydrocortisone

1.5 3.0 1.0 1.5 1.5 1.5 1.5

Hydrocortisone acetate Ichthammol Morphine Hydrochloride Phenobarbitone Resorcinol Tannic acid Zinc oxide

1.5 1.0 1.5 1.0 1.0 1.0 5.0

Example:-

To prepare ten suppositories each containing 300 mg bismuth subgallate.

Mould size is 1 g.

Displacement value of bismuth subgallate is 3.

300 mg bismuth subgallate = 0.3 g bismuth subgallate

Displacement value of bismuth subgallate means 3 g bismuth subgallate displaces 1 g theobroma oil.

Therefore, 0.3 g bismuthsubgallate will displace

(1 ¸ 3) ´ 0.3 = 0.1 g      suppository base (i.e. theobroma oil)

So the working formula for each suppository will be

                                                Bismuth subgallate                   0.3g

                                                Theobroma oil                          0.9g

                                                Total                                        1.2g

Determination of Displacement value of a Medicament

The displacement value of a given medicament can be determined as follows:

·        Six suppositories are prepared with theobroma oil only (or other base) and their total weight =a mg

·        Six suppositories are prepared containing 40% of the medicament and their total weight = b mg.

·        Amount of theobroma oil    = c mg              = 60% of b  mg                         = 0.6 ´ b mg

·        Amount of medicament      = d mg             = 40% of b mg              = 0.4 ´ b mg

·        The weight of theobroma oil displaced by d  mg of medicament = (a - c) mg

·        Displacement value of the medicament = d / (a - c)  mg

For example:

Weight of six unmedicated suppositories   = 6g

Weight of six suppositories containing 40% of zinc oxide    = 8.8 g

                                                                 60
Theobroma oil in this                      =  ---    ´  8.8   =  5.28 mg
                                                                100

                                                                 40
Zinc oxide in this                             =  ---    ´  8.8   =  3.52 mg
                                                                100

Theobroma oil displaced by 3.52 g of zinc oxide                    = 6 - 5.28  =  0.72 g

Therefore, the displacement value of zinc oxide             =   3.52 / 0.72   =  5 (approximately)

Lubrication of Moulds

·        If the cavities of the mould are imperfect, i.e. poorly polished or scratched, it may be difficult to remove the cocoa butter suppositories without damaging their surfaces unless a lubricant is used. In this case an aqueous lubricant is used.

·        Glecero-gelatin base is sticky in nature hence they are lubricated with an oily lubricant e.g. liquid paraffin or arachis oil.

·        It is unnecessary to lubricate the mould when synthetic fat or macrogol bases are used. The products have better surface if the mould is dry.

For theobroma oil the following lubricating preparation is found to be useful:

                        Soft Soap                      10 g

                        Glycerol                       10 ml

                        Alcohol (90 %)             50 ml

The lubricant should be applied on a pad of gauze or muslin, or with a small fairly stiff brush.

To avoid excess lubrication the moulds are closed and kept inverted on a clean tile to drain out excess lubricant.

DOWN LOAD----ORIGINAL----SEMISOLID DOSAGE FORMS

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