Semisolid Dosage Forms

Semisolid Dosage Forms :

• Definitions, • Types, • Mechanisms Of Drug Penetration,• Factors influencing Penetration, • Semisolid Bases And Their Selection, • General Formulation Of Semisolids & Clear Gels• Manufacturing Procedure, • Evaluation And • Packaging.

Semisolid dosage forms usually are intended for localized drug delivery. In the past few years, however, these forms also have been explored for the systemic delivery of various drugs.

Semisolids constitute a significant proportion of pharmaceutical dosage forms.

They also have major applications in cosmetics.

They can be applied topically to the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining.

Introduction

Definitions• Semisolid dosage forms are dermatological

preparations intended to apply externally on the skin to produce local or systemic effect.

• Semisolid dosage forms are dermatological products of semisolid consistency which are applied to skin or mucous membrane for therapeutic or protective action or cosmetic function.

• Pharmaceutical semisolid preparations may be defined as topical products intended for application on the skin or accessible mucous membranes to provide localized and sometimes systemic effects at the site of application or for cosmetic functions.

• Ex: Ointments , creams , pastes , gels etc

IDEAL PROPERTIES OF SEMISOLIDS

PHYSICAL PROPERTIES Smooth texture Elegant in appearance Non dehydrating Non gritty Non greasy and non staining Non hygroscopic

PHYSIOLOGICAL PROPERTIES Non irritating Do not alter membrane / skin functioning Miscible with skin secretion Have low sensitization index

APPLICATION PROPERTIES Easily applicable with efficient drug release. High aqueous wash ability.

THE SKIN : Structure of skin

SKIN: Summery • Largest multilayer organ.• In adults weighs about 8 lbs.• Covers a surface area exceeding 20,000cm2 .

• Function: Serves as an barrier for physical and chemical attack.Plays a role in regulation of blood pressure.

• Layers of Skin: 3 tissue layers.• Epidermis.• Dermis.• The subcutaneous fat layer.

Functions of the skin• Protection: an anatomical barrier from pathogens and damage

between the internal and external environment in bodily defence; Langerhans cells in the skin are part of the adaptive immune system.

• Sensation: contains a variety of nerve endings that react to heat and cold, touch, pressure, vibration, and tissue injury.

• Heat regulation: the skin contains a blood supply far greater than its requirements which allows precise control of energy loss by radiation, convection and conduction. Dilated blood vessels increase perfusion and heatloss, while constricted vessels greatly reduce cutaneous blood flow and conserve heat.

• Control of evaporation: the skin provides a relatively dry and semi-impermeable barrier to fluid loss . Loss of this function contributes to the massive fluid loss in burns.

Functions of the skin….• Aesthetics and communication: others see our skin and can assess our mood,

physical state and attractiveness.

• Storage and synthesis: acts as a storage centre for lipids and water, as well as a means of synthesis of vitamin D by action of UV on certain parts of the skin.

• Excretion: sweat contains urea, however its concentration is 1/130th that of urine, hence excretion by sweating is at most a secondary function to temperature regulation.

• Absorption: the cells comprising the outermost 0.25–0.40 mm of the skin are "almost exclusively supplied by external oxygen", although the "contribution to total respiration is negligible".

• In addition, medicine can be administered through the skin, by ointments or by means of adhesive patch, such as the nicotine patch or iontophoresis. The skin is an important site of transport in many other organisms.

• Water resistance: The skin acts as a water resistant barrier so essential nutrients aren't washed out of the body

Epidermis is divided into the following 5 sublayers or strata:

o Stratum corneumo Stratum lucidumo Stratum granulosumo Stratum spinosumo Stratum germinativum

(also called "stratum basale").

The layers of epidermis

STRATUM GERMINATIVUM: THE BASAL OR GERMINAL LAYER

• Right Above the Dermis.• Basal cells are nucleated, columner and about 6 μm wide, connected

by cytoplasmic intercellular bridges.• It is often described as one cell thick, though it may in fact be two to

three cells thick in glabrous (hairless) skin.• Metabolically active Layers of epidermis.• The stratum basale is primarily made up of basal keratinocyte cells,

which can be considered the stem cells of the epidermis. • They divide to form the keratinocytes of the stratum spinosum, which

migrate superficially.• The cells flatten and shrink as they slowly die from lack of oxygen and

nutrition.• Other types of cells found within the stratum basale are

melanocytes (pigment-producing cells), Langerhans cells (immune cells), and Merkel cells (touch receptors).

STRATUM SPINOSUM (Prickly Cell Layer)• Cells of this later are produced by morphological and

histochemical alteration of the cells of basal layer as they move upward.

• Cells are interconnected by fine prickles. • Each prickle encloses an extension of cytoplasm.• Opposing tips of the prickles of the adjucent cells adhere to form

intercellular bridges or desmosomes.• This link maintains the integrity of epidermis.• The cells flatten and their nuclei shrinks.

THE STRATUM GRANULOSUM (OR GRANULAR LAYER)• It is a thin layer of cells in the epidermis.• Keratinocytes migrating from the underlying stratum spinosum

become known as granular cells in this layer. • These cells contain keratohyalin granules, which are filled with

histidine- and cystine-rich proteins that appear to bind the keratin filaments together.

• Therefore, the main function of keratohylain granules is to bind intermediate keratin filaments together.

• At the transition between this layer and the stratum corneum, cells secrete lamellar bodies (containing lipids and proteins) into the extracellular space.

• This results in the formation of the hydrophobic lipid envelope responsible for the skin's barrier properties.

• Concomitantly, cells lose their nuclei and organelles causing the granular cells to become non-viable corneocytes in the stratum corneum.

STRATUM LUCIDUM• The stratum lucidum (Latin for "clear layer") is a thin, clear layer of dead

skin cells in the epidermis named for its translucent appearance under a microscope.

• It is readily visible by light microscopy only in areas of thick skin, which are found on the palms of the hands and the soles of the feet.

• Located between the stratum granulosum and stratum corneum layers, it is composed of three to five layers of dead, flattened keratinocytes.

• The keratinocytes of the stratum lucidum do not feature distinct boundaries and are filled with eleidin, an intermediate form of keratin.

• The thickness of the lucidum is controlled by the rate of mitosis (division) of the epidermal cells.

• In addition, melanocytes determine the darkness of the stratum lucidum. • The cells of the stratum lucidum are flattened and non-nuclear.• They are surrounded by an oily substance that is the result of the

exocytosis of lamellar bodies accumulated while the keratinocytes are moving through the stratum spinosum and stratum granulosum.

STRATUM CORNEUM• The stratum corneum (Latin for 'horny layer') is the outermost

layer of the epidermis, consisting of dead cells (corneocytes).• The purpose of the stratum corneum is to form a barrier to

protect underlying tissue from infection, dehydration, chemicals and mechanical stress.

• Desquamation, the process of cell shedding from the surface of the stratum corneum, balances proliferating keratinocytes that form in the stratum basale.

• These cells migrate through the epidermis towards the surface in a journey that takes approximately fourteen days.

• In the human forearm, about 1300 cells per cm2 per hour are shed.

• New cells appear on the surface of SC in every 28-30 days.

STRATUM CORNEUM….

• Consists of compacted, flattened, dead, keratinized cells in stratified layers with a density of 1.55.

• Rate limiting barrier for inward and outward movement of chemical substances.

• Generally 10 μm thick when dry, 40-50 μm thick when fully hydrated, several hundred μm thick in palms of the hands and the soles of the feet.

• Dry state composition: 75-85% protein, 15-20% lipid and 15% water.

• Occlusive dressings or creams applied over the skin prevents natural evaporation of water making SC highly hydrated and some substances become more soluble in it.

Dermoepidermal Junction• Situated Below basal cell layer.• The junction serves 3 functions:1. Dermal-epidermal adherence2. Mechanical Support for epidermis.3. Control of passage of cells and some large molecules across the junction.• Barrier function of the junction 1. For small molecules2. For Large molecules3. For Cells No evidence that the junction significantly inhibits the passage

of water, electrolytes and other low molecular weight materials.

DERMIS or CORIUM• Situated beneath epidermis. • 1/8” thick.• Constitutes the main mass of the skin.• Consists of about 80% of protein in a matrix of

mucopolysaccharide ground substance.• Contains and support numerous:• Blood vessels.• Lymphatics.• Nerves.• Epidermal appendages like hair follicles, sebaceous glands and

sweat glands.• Sweat glands are of two types eccrine and apocrine. • Hair follicles covers 1/1000 of total surface roughly.

The subcutaneous fat layer• The subcutaneous tissue also called the hypodermis, subcutis,

or superficial fascia, is beneath dermis which is beneath epidermis. It is used mainly for fat storage.

• The types of cells found in the hypodermis are fibroblasts, adipose cells, and macrophages.

• It acts as padding and as an energy reserve, as well as providing some minor thermoregulation via insulation.

• Quite elastic layer contains arteries and veins in superficial regions but rest of the portion contains limited number of capilaries and no vital organs.

SUBCUTANEOUS TISSUE CONSISTS OF:• Fibrous bands anchoring the skin to the deep fascia• Collagen and elastin fibers attaching it to the dermis• Fat, except in the eyelids, clitoris, penis, much of pinna, and scrotum• Blood vessels on route to the dermis• Lymphatic vessels on route from dermis• The glandular part of some sweat glands; mammary gland lie entirely

within the subcutaneous tissue (which are modified apocrine sweat glands)

• Cutaneous nerves and free endings• Hair follicle roots• Ruffini and Pacinian corpuscles (mechanoreceptor)• Mast cells• Bursae, in the space overlying joints in order to facilitate smooth

passage of overlying skin• Fine, flat sheets of muscle, in certain locations, including the scalp,

face, hand, nipple, and scrotum, called the panniculus carnosus

What is penetration ?

Skin penetration is differs from skin permeation.

skin penetration is the former describes the passage of an ingredients into the skin ( to target skin layer).

Skin permeation is the passage of an ingredient through the skin to the circulatory system.

Skin Appendages• Skin appendages (of adnexa) are skin-associated structures that

serve a particular function including sensation, contractility, lubrication and heat loss.

• Hair Follicles.• Sebaceous glands like pilosebaceous glands.• Sweat Glands (Eccrine and apocrine)

Drug Penetration Through Skin• Dermatologic Drug therapy: To produce a desired therapeutic

action at specific sites on the epidermal tissue.

• While certain tropical drugs act primarily on the surface of the skin.

• Like: emollients, antimicrobials and deodorants.

• The target area of most dermatological disorders lies in the viable epidermis and the upper dermis.

• This requires diffusive penetration of the skin or percutaneous absorption.

PERCUTANEOUS ABSORPTION.

• Skin (percutaneous, dermal) absorption is a term that describes the transport of chemicals from the outer surface of the skin both into the skin and into the systemic circulation.

• Skin absorption is a route by which substances can enter the body through the skin.

• Along with inhalation, ingestion and injection, dermal absorption is a route of exposure for toxic substances and route of administration for medication.

Routes of Penetration• When a drug system is applied tropically, the drug

diffuses out of its vehicle onto the surface tissues of the skin.

• From there, there are 3 portals of entry:

1. Through the follicular region.2. Through the sweat ducts.3. Through the unbroken stratum corneum

between these appendages.

Percutaneous absorption• TRANSCELLULAR

PENETRATION (across the cells)

• INTERCELLULAR PENETRATION (between the cells)

• TRANSAPPENDAGEAL PENETRATION (via hair follicles, sweat and sebaceous glands, and pilosebaceous apparatus) offers 0.1-1% of total skin area.

Routes of Penetration

• Epidermal appendages: hair follicles, sebaceous glands and sweat glands are scattered sparsely through out the skin.

• Their cross-sectional area 0.1-1% of the skin area.

• Sweat glands are of two types eccrine and apocrine. • Little evidence regarding eccrine glands role in cutaneous

permeability.

• Hair follicles covers 1/1000 of total surface roughly.• Thus epidermis represents an area 100-1000 times more

than other routes of entry.

Routes of Penetration

• Between transepidermal and transappendageal the former is the principle portal of entry for the drugs absorbed through both the pathways as pilosebaceous units offer relatively smaller absorbing surface.

• For substances absorbed primarily by transepidermal route , penetration is rapid but lesser than GIT absorption and always followed by some degree of pilosebaceous penetration.

Interaction between a given compound and

the skin is physicochemical in

nature and depends on the condition of the skin

Thus under the appropriate conditions, each of the contending routes of

permeability may change and may be the

overwhelmingly dominant one.

Mechanism of Penetration• After the application of a substance to the surface of the skin.

• Transient diffusion is shown to be potentially far greater through the appendages than through the matrix of stratum corneum.

• When Steady state diffusion is reached.

• Then diffusion through the matrix of the stratum corneum is dominant.

• Transient diffusion occurs primarily via follicles and ducts and steady state diffusion primarily via intact stratum corneum.

Again flux through the appendegial pathway or the shunts is difficult to

measure experimentally , except possibly through hair.

Mechanism of Penetration

• Diffusion through the stratum corneum is a passive process with little evidence for the presence of specialized active transport mechanisms.

• This passive diffusion depends upon the substance being absorbed, dispersion medium and ambient conditions.

• Percutaneous absorption depends :• Epidermal diffusion -> Dermal clearance -> effective blood

flow, interstitial fluid movement, lymphatics and certain other factors related to dermal constituents.

Mechanism of Penetration: Properties of absorbed substance

• Hydrophilic drugs and ions undergo absorption through the polar pathways of the skin.

• The polar or porous pathways includes the deformities in the lipid bilayers and appendegial pathways or shunt pathway.

• The dry skin is positively charged at physiological pH, thus negatively charged molecules may diffuse more rapidly across the skin than negatively charged molecules followed by non-ionic molecules.

• For most lipophilic molecules (MW <500 Da) , the predominant pathway is via the lipid domains.

• The drug needs to partition through the lipid region of the intercellular space or the transcellular lipids to diffuse across the SC.

The intrafollicular pathway and thesebaceous glands pathway

*(Mainly for lipid and surprisingly it is for a charge and large polar molecule) .

sebaceous gland on the total skin surface represent not more than 0.1% , but some time it will be the target such as acne

*Delivery System Handbook for Personal Care and Cosmetic Products. By Meyer

Follicle distribution

The polar pathway

This route is believed to be hydrophilic in natural , it is composed of aqueous region surrounded by polar lipids that create the walls of microchannels.

The polar pathway

The localization of the

hydrophilic pores is unclear,

but they think that :

1- it is intercellular .

2- it is intracellular keratin .

The polar pathway

We need 3-10 corneocytes to create a columns that form a cluster.

Corneocytes edges inside each cluster were found to intercalate extensively , but neighboring cluster were separated by gaps of a few micrometers.

The polar pathwaySo know we will say that we have

2 different hydrophilic pathway : 1- inter-cluster rout (within low

penetration resistant)2- inter-coreocyte pathway (higher

penetration resistance), it is twisted between coreocyte ,may be act as an actual channel in the skin.

Factors in Skin Penetration

Absorption of substances through the skin depends on a number of factors:

Physicochemical properties of the drug, pH, vehicles.• Concentration• Duration of contact• Solubility of medication• Water/Lipid Partition coefficient of the drug.• Molecule size. Physical condition of the skin: age, area, intact/broken• Part of the body exposed including the amount of hair on the skin. Small molecules penetrate rapidly than large molecules. In general the rate of absorption of chemicals through skin follows the

following scheme from fastest to slowest: Scrotal > Forehead > Armpit≥ Scalp > Back = Abdomen > Palm = under surface of the foot

OTHER FACTORS AFFECTING PERCUTANEOUS ABSORPTION

• Thickness of skin

• Surface area applied

• Friction and heat

• Occlusion (SC 5-10% water to 50% water)

- Cover skin surface easily, mix readily with sebum

-Promotes hydration of skin

• Hair follicles.

• State of the diseased skin(pathologic changes)

• Age of the patient• Type of vehicle • Method of application,

temperature.• A defined duration of use

that maximizes efficacy and minimizes adverse side effects.

Study Methods for Skin Penetration

• In vitro Technique: Diffusion cell. The passage of drug molecules through the animal or human skin into the fluid bath below.

• Alcohol-water /receptor phase or Sink (Chloroform and isopropyl myristate) model depending upon the solubility of the drug in the vehicle and its partition coefficient into the skin imitating sink.

• In Vivo Technique: Dyes, fluorescence, radioactive labelling, substance producing specific chemical reaction, urine analysis but with disadvantages of their own.

Semisolid dosage forms meant for external application Semisolid dosage forms subcategorized are as-

Ointments Creams Jellies / Gels Suppositories Poultices Plasters Pastes Glycero-gelatins Rigid foams

The suppositories are also included in this category but it is a unit dosage forms.

Semisolid dosage forms : Types

OintmentsOintments are homogenous, translucent, viscous, semi solid preparation intended for external application to skin or mucous membranes.

Ointment may be medicated or not.

composed of fluid hydrocarbons meshed in a matrix of higher melting solid hydrocarbons.

Applied to mucous membrane or skin

Ointment Medicated ointments: It may be defined as a medicament or

medicaments dissolved, suspended or emulsified in ointment base.

Use of Medicated ointments: Application of active ingredients to the skin

• Ointment Bases provides Occlusive action.

unmedicated ointment: The ointments are mainly used for their protective or emollient properties

Uses of unmedicated ointment: Emollient, protectants or lubricants.

There is no single ointment base which possesses all the qualities of ideal ointment base, so it become necessary to use more than one ointment base in the preparation of ointment.

Qualities of ideal ointment base

It should be inert, odourless & colourless & smooth. It should be physically & chemically stable. It should be compatible with the skin & with incorporated medicaments. It should be of such consistency that it spread & soften when applied to

skin with stress. It should not retard healing of wound. It should produce irritation or sensitization of the skin.

CREAMSA semisolid dosage form containing one or more drug substances dissolved or dispersed in either a water-in-oil emulsion or an oil-in-water or in an other type of water-washable base.

Viscous semi solid emulsion with opaque appearance asContrasted with translucent ointments

Consistency depends on whether the cream is W/O or O/W

W/O Creams O/W Creams

Contain lipophyllic emulsifying agent

Contains hydrophilic emulsifying agent

Used as emollient or as cleansing agent

O/W creams are elegant drug delivery system

creams

These are viscous semisolid emulsions which are meant for external use.

Cream is divided in to two types namely as

I) Aqueous creams

II) Oily creams In case of aqueous creams the emulsions are o/w type &

it is relatively non greasy. The emulsifying waxes are anionic, cationic & non –ionic used. Generally polysorbate, triethanolamine soap are used as emulsifying agent.

In case of oily creams w/o type & it is relatively greasy. The emulsifying agent such as wool fat, wool alcohols, beeswax & calcium soap is used.

The cream should be store in collapsible tube & supplied in well closed container to prevent evaporation & contamination.

Pastes are semisolid preparations intended for external application to skin.

The pastes are generally very thick & stiff.

They do not melt at ordinary temperature & thus forms a protective coating over the area where they are applied.

pastes

Pastes are differ from ointment as they contain a high proportion of finely powdered medicaments.

Pastes are basically ointments into which a high percentage of insoluble solids have been added.

Contains high percentage of insoluble solid(usually 50% or more)

Pastes are usually prepared by incorporating solids directly into a congealed system by levigation with a portion of base to form paste like mass.

pastes

Pastes

They have good adhesion on skin and less greasy.

They function as a protective barrier on the skin for treating deeper rash or protecting the face or lips from the sun.

They are mainly used as a antiseptic, protective, soothing dressings.

Pastes should be stored & supplied in containers made of materials which do not allow absorption or diffusion of content.

Gels

i. Gels are semisolid systems in which a liquid phase is constrained within a 3D polymeric matrix (consisting of natural or synthetic gums) in which a high degree of physical/chemical cross-linking has been introduced.

ii. Gels are aqueous colloidal system of hydrated forms of insoluble medicaments.

jellies

Jellies are transparent or translucent, non greasy, semi solid preparations mainly used for external application to skin.

These are also used for lubricating catheters, surgical gloves & rectal thermometer.

The substance like gelatin, starch, tragacanth, sodium alginate & cellulose derivatives are used for the formulation of jellies.

Jellies are of three types namely as Medicated jellies Lubricating jellies Miscellaneous jellies carrier for spermicidal agents to be used intra vaginally with diaphargm.

Gels and Jellies

.

Jellies contain more water than gels.

Poultices

1. These are also known as cataplasams.

2. They are soft viscous wet masses of solid substances applied to skin in order to reduce inflammation and in some cases to act as a counter irritant.

3. Poultices must retain heat for a considerable time.

4. After heating the preparation is spread on dressing and applied to the affected area .

5. E.g: Kaolin poultice (B.P.C)

Plasters

These are solid or semi solid masses adhere to the skin when spread up on cotton felt line or muslin as a backing material.

made by incorporating medicaments in the resinous or waxy bases which are melted or spread on suitable baking material..

They are generally used to,

Afford protection and medicinal support.

Furnish on occlusive and macerating action.

Bring medication in to close contact with the surface of skin.

Medicated Plaster for Muscle and Joint Pain

Suppositories It is solid or stiffened semi solid dosage form intended to insertion on body orifices other than mouth where they melt , soften and dissolveand exert local or systemic effect.

Rectal suppositoriesPessariesUrethral bougies Nasal bougies Ear cones

Types

Glycerogelatins Glycero-gelatins: Glycerogelatins are plastic masses containing

gelatin (15%) , glycerin (40%) , water (35%) and an added medicinal substance (10%) such as zinc oxide.

Soften the gelatin in water bath for 10 minutes, then heat it on steam bath until gelatin is dissolved.

Mix the medicinal substance with glycerin and mix with gelatin.

Cool by stirring and congeal.

Before application it is melted and then cooled just above body temperature and applied on the affected area with a fine brush.

Covered with bandage and allowed to remain in place for weeks.

Example: zinc gelatin boot or pressure bandage.

Rigid Foams

Rigid foams: These are systems in which air or some other gas is emulsified in liquid phase to the point of stiffening.

Raw Materials in Semisolid Preparations

• The following are the necessary raw materials to prepare a semisolid dosage form.

• Hydrocarbons• Hydrocarbon waxes• Oleaginous Substances• Fatty acids and alcohols• Emulsifiers• Polyols/ Humectants• Insoluble Powders

Hydrocarbons• Hydrocarbons used in semisolid dosage form preparation are:

• Petrolatum: mixture of semisolid hydrocarbons containing aliphatic, cyclic, saturated, unsaturated, branched and unbranched substances in varying proportion.

• Available in form of short or long fiber.

• Mineral oil obtained from petrolatum: lower viscosity of oils than petrolatum results in less tackiness and greasiness and thus preferred in semisolid dosage form preparation.

Hydrocarbon waxes• Used to increase the viscosity of mineral oil in order to

prevent its separation from an ointment.• Natural waxes include: Paraffin wax, ozokerite, ceresin a

mixture of paraffin and ozokerite wax.• Ceresin has the property to retain oil within a matrix like

structure without the sweating or oozing of oils.

• Synthetic waxes have been developed from vegetable oils and naturally occurring waxes.

• They have long hydrocarbon chans C18-C36 long..• Used together with natural waxes.• Ex: Synchrowaxes with gelling characteristics.

Oleaginous Substances

• Mono-, di- and Tri- glycerides of mixtures of unsaturated and saturated fatty acids.

• Ex: Peanut oil, almond oil, sesame oil and olive oil.• Trace metal contaminants in the oils may catalyze oxidation

reaction.• Prevented by addition of antioxidants like BHA, BHT etc.• Anti-oxidants may cause drug imcompatibiliy or dermal

sensitivity.• The exact chemical composition of a particular vegetable oil

varies due to its natural origin, soil, rainfall, storage, climate etc.

Fatty acids and alcohols

• Mixture of related fatty acids.• Like Stearic and palmitic acids and other fatty acids.• A slide change in the ratio of the saturated fatty acids changes

the structure and size of fatty acid crystals thus solubility.• Thus stearic acid of rigidly controlled purity is used in many

topical preparations.• Steraic acid is used as an emusifier in o/w emulsions.• Stearate soaps of KOH or triethanolamine of 8-20% is also an

emulsifier and the rest increases the consistency.• Creams formed with sodium stearate are much firmer.• Stearyl alcohols, cetyl alcohols are used as auxillary

emulsifiers.

Emulsifiers

• Mixed emulsifier systems are preferred.• The combination of a surfactant and an oil soluble auxiliary

emulsifier.• O/W: Triethanolamine stearate soap with cetyl alcohol• W/O: Beeswax and water soluble surface active agent.• The clay, Mg-Al-Silicate has been used as a thickener,

suspending agent and o/w emulsion stabilizers.• Cationic or nonionic emulsifiers for drugs requiring acid pH .• Nonionic emulsifiers are used in both w/o and o/w semisolid

preparations.

Polyols or Humectants

• Protects moisture on the semisolid preparation.• Gives better texture and viscosity of the preparation.• Prevent cream from drying out.• Prevent the formation of crust when the cream is packed in a

jar.• Improves consistency and rub-out qualities when the cream

is applied on the skin.• Increasing amount of humectants content tends to increase

tackiness/stickiness.• Example: Sorbitol 70%>Glycerine>Propylene Glycol and

polyethylene glycol.

Insoluble Powders• Should be uniformly dispersed to ensure homogeneity.• No grittiness.• Decrease in size provides more surface area of the drug for

contact with the dermal site.• Sub-micron size powders show aggregation problem due

electrically charged surface condition after milling.• Choice of proper crystalline form is important for use in

semisolids.• The maintenance of the selected polymorphic form in the

semi solids.• The components of vehicle and the method of preparation of

the semisolid dosage form affect the stability of the polymorphic form

SKIN PENETRATION ENHANCERS• Materials that are experimentally studied to increase percutaneous absortion are

know as penetration enhancers or accelerants.

• Ex: DMSO, DMA, DMF.

• They are hygroscopic , thus swells and increases the hydration of the Stratum Corneum and permeability.

• Surfactants increase the permeability of water through skin by altering the physical state of water in the skin and increases the permeation of charged hydrophilic substances.

• Ex: Laurate ion (anionic, highest penetration),

• Penetration: Anionic>Cationic>Nonionic surfactants.

• Salts of fatty acids: carbon length of 10 or less and pH lower than 11.

Vehicles: Mechanism

• Vehicles alters the activity of water in the stratum corneum and influences the stratum corneum/vehicle partition coefficient.

• Grease and oils, occlusive, greatest hydration through sweat accumulation at the skin-vehicle interface.

• Humectants and powders decreases the hydration of SC thus decreases penetration.

• Paraffin prevents trans-epidermal water loss by diffusion.

Vehicles: Ideal Properties• Low affinity for the penetrant.• Least solubility for the drug.• High vehicle to receptor phase (Stratum Corneum) partition

coefficient.• High activity coefficient. • Solutes held firmly by vehicle (high affinity of the vehicle),

have low activity coefficient and exhibits slow rate of drug release.

• Solute held loosely by the vehicle (less affinity of the vehicle for the drug substance), have high activity coefficient and thus faster drug release.

Semisolid Bases: Selection Criteria• Vehicles/Bases should posses the following selection

criteria.• Desired release rate of the drug substance from the ointment

base.• Desirability of tropical or percutaneous drug absorption.• Desirability of occlusion of moisture from the skin.• Stability and solubility of the drug in the base.• Effect if any of the drug on the consistency or other features

of the ointment base.• Desire for a base that is easily removed by washing with

water.• Characteristics of the surface to which it is applied.

Concept

• Definition: semisolid preparations intended for

external application are termed ointments.

• Ingredient: drug substance +bases+ adjuvants

Ointment Bases• The earliest ointment bases consisted of fats and the mixture

with other substances.

• But modern bases are mostly non-greasy, water miscible and water washable.

Ointment Bases• Ideal ointment base It should be 1. inert, odourless and smooth.2. Chemically and physically stable.3. compatible with skin and incorporated medicament .4. Easy to compound and remain stable on storage.5. Release the medicament efficiently at the site of application.5. low sensitization and irritation index.7. Should not retard healing of the wound.

Quality requirement

the product is required smooth and uniform with certain

stickiness to skin

the drug in bases even distributed

stability of the ointment

Skin infection preparations are designed to be sterile

Semisolid: Types of ointment Bases • The following are the types of ointment bases as per USP:

Classification of Ointment base• Hydrocarbon/Oleaginous bases.• Absorption Bases.• Emulsion bases.• Water Soluble bases.

Hydrocarbon/Oleaginous bases.

• Salient characteristics:

• They are: 1. Anhydrous 2. hydrophobic (do not absorb water easily) 3. insoluble in water. 4. not removable by water.• They consisted of vegetable and animal fats as well as

petroleum hydrocarbons.

(1) hydrocarbon bases

Hydrocarbon bases (oleaginous bases) are water-free, and aqueous preparations

may be incorporated into them only in small amounts and then with difficulty.

Hydrocarbon bases are retained on the skin for prolonged periods, do not permit

the escape of moisture from the skin to the atmosphere, and are difficult to wash

off.

As such they act as occlusive dressings. They do not "dry out" or change

noticeably upon aging.

Oleaginous/hydrocarbon bases

These bases consist of water soluble hydrocarbons, vegetable oils, animal fats & wax.

The constituents of hydrocarbon bases are soft paraffin, hard paraffin & liquid paraffin.

The vegetable oils are mainly used in ointment to lower the melting point or to soften the bases.

These bases serve to keep the medicaments in prolonged contact with the skin & also act as occlusive dressings. They have a low capacity to absorb water & are used chiefly for their emollient effect.

These bases losing their importance now a days for the many reason.

hydrocarbon bases : materials

• A list of commonly used materials are:

1. Hydrocarbons: Petrolatum (White and yellow), Liquid paraffin, Paraffin wax, Microcrystalline wax, ceresin, Plastibase.

Hydrocarbons• Petrolatum: purified mixture of semisolid hydrocarbons from petroleum. Types: 2. yellow and white soft paraffin (Bleached yellow paraffin). Melting Point: 38-560C • Hard paraffin: purified mixture of solid hydrocarbons obtained from petroleum. colourless, white, translucent, odourless, tasteless wax like substance. used to harden or soften ointment base.

• Liquid paraffin: mixture of liquid hydrocarbons obtained by distillation from petroleum. Colourless, odourless, tasteless and tranceparent oily liquid. Soluble in ether and chloroform but insoluble I water and alcohol. Liquid paraffin is used along with hard and soft paraffin to get a desired

consistency of the ointment.

• Petrolatum

a mixture of semisolid hydrocarbons obtained from petroleum

an unctuous mass, varying in color from yellow to white

It may be used alone or in combination with other agents as an ointment base

Commercial product is Vaseline

• Paraffin

A purified mixture of solid hydrocarbons obtained from petroleum.

A colorless or white, more or less translucent mass that may be used to harden or stiffen

oleaginous semisolid ointment bases.

• Liquid paraffin• a colorless, odorless

oily liquid consisting of a mixture of hydrocarbons obtained from petroleum

• has the same character with paraffin

• be used in combination with paraffin to adjust viscosity

•Hydrophilic Petrolatum is composed of cholesterol, stearyl alcohol, white wax, and white petrolatum

has the ability to absorb water, with the formation of a water-in-oil emulsion.

Aquaphor is a highly refined variation of Hydrophilic Petrolatum and because it can

absorb up to 3 times its weight in water, it has proven useful to incorporate

extemporaneously a water-soluble drug into an oleaginous base.

Mineral Oil

• a mixture of liquid hydrocarbons.

• It is useful as a levigating

substance to wet and to

incorporate solid substances into

the preparation of ointments that

consist of oleaginous bases as

their vehicle.

hydrocarbon bases: materials

2. Vegetable oils and Animal Fats: Coconut, peanut, sesame, almond oil, Bees wax, Lanolin, Spermaceti

Wax (Sperm Whale).

may contain no more than 0.25% of water.

insoluble in water, but mixes without

separation with about twice its weight of

water

The incorporation of water results in the

formation of a water-in-oil emulsion.

Anhydrous Lanolin (refined wool fat)

a semisolid, fatlike substance

obtained from the wool of

sheep.

a water-in-oil emulsion that

contains between 25 and 30%

water.

Additional water may be

incorporated into lanolin by

mixing.

Lanolin (hydrous Wool Fat )

• Beeswax and spermaceti

They are weak sufactants (W/O) and used as stabilization agents in O/W emulsive ointment.

hydrocarbon bases: materials

3. Hydrogenated and Sulphonated oils: Hydrogenated castor, cotton seed, soybean, corn oil. Hydrogenated sulphonated castor oil.

hydrocarbon bases bases: materials

• Alcohols, Acids and esters: cetyl alcohol, Stearyl alcohol, Oleyl alcohol, Lauryl alcohol, Myristyl Alcohol.

Palmatic Acid, Stearic acid, Oleic acid, Lauric acid, Myristic acid.

Glyceryltristearate, Ethyl oleate, Isopropyl myristicate, Ethylene glycol, dilaurate/dioleate/distearate

• Silicones: polysiloxanes. Ex: Dimethy polysiloxanes.

Disadvantages of oleaginous bases

They are greasy. They are sticky & are difficult to remove both from skin & clothing. They retain body heat which may produce an uncomfortable feeling of

warmth. They do not help in the absorption of medicaments.

(2) Absorption bases

These bases are generally anhydrous substance which have the property of

absorbing considerable quantities of water but still retaining their ointment

like consistency.

Absorption bases may be of two types:

(1) Non emulsified bases/Anhydrous Bases: those that permit the incorporation

of aqueous solutions, resulting in the formation of water-in-oil emulsions ,

e.g. Hydrophilic Petrolatum and Anhydrous lanolin i.e., Wool fat, wool

alcohol, beeswax & cholesterol.

(2) Water in oil emulsion : those that are already water-in-oil emulsions

(emulsion bases) that permit the incorporation of small, additional

quantities of aqueous solutions , e.g. Hydrous lanolin i.e. hydrous wool fat

and Cold Cream.

These bases are useful as emollients although they do

not provide the degree of occlusion afforded by the

oleaginous bases.

Absorption bases are not easily removed from the skin

with water washing.

They are also useful pharmaceutically to incorporate

aqueous solutions of drugs, e g., sodium sulfacetamide,

into oleaginous bases.

Absorption Bases: Raw Materials• Having hydrophilic or water absorbing properties.• Generally anhydrous on w/o emulsion• Has the capability to absorb water more than their weight.• Ultimately forms w/o emulsion.

• Wool fat. (can absorb 50% of its weight of water)• Hydrous wool fat. (contains 30% water, emollient)• Wool alcohol. (contains 30% cholesterol, other alcohols,

emulsifying agent producing w/o emulsion, improves texture, stability and emollient property of o/w emulsion)

• Bees wax. (Yellow or white bees wax, used as a stiffening agent in ointments and pastes)

Advantages of Absorption bases:• Compatible with large number of medicaments.• Can absorb a large quantity of water or aqueous substance.• Relatively heat stable.• May be used in their emulsified form or anhydrous form.• Quite greasy but can be easily removed from skin compared

to hydrocarbon bases.

(3)Water-Removable Bases

The water removable bases are o/w emulsions and are referred to as Vanishing Creams.

oil-in-water emulsions that are capable of being washed from skin or clothing with water.

For this reason, they are frequently referred to as "water-washable" ointment bases

may be diluted with water or with aqueous solutions.

have the ability to absorb serous discharges in dermatologic conditions.

Certain medicinal agents may be better absorbed by the skin when present in a base of this type than in other types of bases.

Water Removal Bases Absorption Bases

They are Oil-in water emulsions.

They are Water-in-Oil Emulsions.

Example: Vanishing Cream Example: Cold Cream

(4) Water-Soluble Bases

• contain only water-soluble components.

• are water washable

• Because they soften greatly with the addition of water,

aqueous solutions are not effectively incorporated into

these bases. Rather, they are better used for the

incorporation of nonaqueous or solid substances.

•Polyethylene Glycol Ointment

Polyethylene glycols are polymers of ethylene oxide

and water

The chain length may be varied to achieve polymers

having desired viscosity and physical (liquid, semisolid,

or solid) form.

The general formula for this base calls for the

combining of polyethylene glycol 3350(a solid) and

polyethylene glycol 400 (a liquid) to prepare base.

Water Soluble bases• Prepared from mixture of low and high molecular weight

polyethylene glycol which range in their consistency from liquid to solid.

• Non-volatile and inert.• Possess the ability to form an emollient surface.• Neither hydrolyze nor deteriorate nor support mold growth.

• Medicaments: Benzoic acid, salicylic acid etc.

Water soluble bases

These are commonly known as greaseless ointment bases. Selection of appropriate carbowaxes is depend on their molecular weight.

Adjuvants

• Antioxidants

• Antimicrobial preservatives

•Antioxidants

preparations Antioxidants

aqueous Sodium sulfite(Na2SO3)

sodium bisulfite(NaHSO3), hypophosphorous acid(H3PO2)

ascobic acid( vitamin C)

oleaginous Alpha tocopherol(vitamin E)Butylhydroxyanisole(BHA)ascorbyl palmitate

•Antimicrobial preservatives

frequently require the addition of chemical

antimicrobial preservatives to the formulation to

inhibit the growth of contaminating microorganisms

These preservatives include: para-hydroxybenzoates

(parabens), phenols, benzoic acid, sorbic acid,

quaternary ammonium salts and other compounds.

Preparation of Ointments Both on a large and a small scale, ointments are

prepared by three general methods:

(1) incorporation method

(2) fusion method

(3) emulsification method

The method for a particular preparation depends

primarily upon the nature of the ingredients

(1) incorporation the components of the ointment are mixed together by

various means until a uniform preparation has been

attained.

On a small scale, the pharmacist may mix the

components of an ointment in a mortar with a pestle, or

a spatula and an ointment slab (a large glass or

porcelain plate) may be used to rub the ingredients

together.

(2) fusion

By the fusion method, all or some of the components of an

ointment are combined by being melted together and cooled

with constant stirring until congealed.

Those components not melted are generally added to the

congealing mixture as it is being cooled and stirred.

Naturally, heat-labile substances and any volatile components

are added last when the temperature of the mixture is low

enough not to cause decomposition of volatilization of the

components.

• In the preparation of ointments having an emulsion type of

formula, the general method of manufacture involves a

melting process as well as an emulsification process.

(3) emulsification

the water-immiscible components such as the oil and

waxes are melted together in a steam bath to about 70 to

75°C

Meantime, an aqueous solution of all of the heat-stable,

water-soluble components is being prepared in the

amount of purified water specified in the formula and

heated to the same temperature as the oleaginous

components.

Then the aqueous solution is slowly added, with

constant stirring (usually with a mechanical stirrer), to

the melted oleaginous mixture, the temperature is

maintained for 5 to 10 minutes to prevent

crystallization of waxes

the mixture is slowly cooled with the stirring

continued until the mixture is congealed.

Notice:

• If the aqueous solution were not the same

temperature as the oleaginous melt, there would

be solidification of some of the waxes upon the

addition of the colder aqueous solution to the

melted mixture.

Emulsification ointments

Ⅱophthalmic ointments

• Concept

semisolid preparations intended for

application to the eye are specially prepared

and are termed ophthalmic ointments.

•Preparation of ophthalmic ointments

The methods of preparation just like

ointments,but under the aseptic condition

for prevent eye infection.

•The bases must be non-irritating to the eye and must permit the diffusion of the medicinal

substance throughout the secretions bathing the eye.

Ointment bases utilized for ophthalmics have a melting or softening point close to body

temperature.

In most instances, mixtures of petrolatum and liquid petrolatum (mineral oil) are utilized

as the ointment base.

Sometimes a water-miscible agent as lanolin is added. This permits water and water-

insoluble drugs to be retained within the delivery system.

•The advantage and disadvantage of Ophthalmic Ointment:

The primary advantage of an ophthalmic ointment

over an ophthalmic solution is the increased ocular

contact time of the drug.

One disadvantage to ophthalmic ointment use is the

blurred vision which occurs as the ointment base melts

and is spread across the lens.

Selection of the Appropriate Base

The selection of the base to use in the formulation of an

ointment depends upon the careful assessment of a

number of factors, including :

(a) the desired release rate of the particular drug

substance from the ointment base

(b) the desirability for enhancement by the base of the

percutaneous absorption of the drug

(c) the advisability of occlusion of moisture from the skin

by the base

(d) the short-term and long-term stability of the drug in

the ointment base

(e) the influence, if any, of the drug on the consistency or

other features of the ointment base.

(f) patient factors also play an important role in a base's

selection

Selection of The Ointment Base

• Dermatological Factor1. Absorption and Penetration2. Effect on Skin Function3. Miscibility with Skin secretion and Serum 4. Compatibility with Skin Secretion5. Freedom from irritant effect.6. Emollient properties.7. Ease of application and removal.• Pharmaceutical Factor1. Stability2. Solvent Properties.3. Emulsifying Properties.4. Consistency.

Evaluation Of Topical Dosage Form

Evaluation of ointmentsPenetration

Rate of release of medicaments

Absorption of medicaments into blood stream

Irritant effect

Creams: bases

These bases are semisolid or have cream like consistency. Both o/w or w/o emulsions are used as a base. The o/w emulsion base is more popular now days because

ease of application will easily achieved. The w/o type of emulsion bases are greasy & sticky. The emulsifying ointment is prepared from emulsifying wax,

white soft paraffin & liquid paraffin.

Creams: Formulation

• Cold Cream• Bees Wax………. 25 gm• Borax ……. 1.25 gm• Mineral Oil ……. 25.0 gm• Water …………….. 48.75 gm• Perfume ………… QS• Preservative …… QS• Vanishing Cream• Stearic Acid ………. 17.0 gm• Lanolin ………….. 1.0• Triethanolamine ….. 2.0 gm• Borax …………… 4.0 gm• Glycerine ……… 5.0 gm• Water ……….. 70.5 gm• Perfume ………………. QS• Preservatives ……. qs

Emulsion bases: Creams • Either o/w or w/o emulsions.

• W/O emulsion like cold creams are used as emollients.• The aqueous phase hydrates the skin while the oily phase forms

and occlusive covering and prevents water loss by evaporation.• Serves as bases for medications like ZnO, sulphur etc.• Greasy and sticky.

• O/W emulsions like vanishing cream are used as vehicles for medicinal agents.

• Water being external phase they are easy to remove with water and non-sticky and non-greasy are more acceptable than W/O emulsions.

•Emulsifying agents: Creams sodium lauryl sulfate :O/W emulsion

stearyl alcohol and cetyl alcohol representing the oleaginous phase of the W/O emulsion to improve the stabilization and viscosity.

sodium stearate and calcium stearate: Monovalent soaps form O/W emulsions while polyvalent soaps form W/O emulsions.

Sometimes either an amine (such as triethanolamine) or ammonium hydroxide is used to neutralize stearic acid to form the O/W emulsifier triethanolamine-stearate/ammonium-stearate.

Bancroft’s Rule: the phase where the emulsifier is most soluble will become the external phase.

Glyceryl monostearate: weak W/O emulsifying agents and used as stabilization agents and emollient in the O/W emulsion.

• Spans: W/O emulsifying agents

• Tweens: O /W emulsifying agents

• Peregal O and emulsive OP: O/W

• Stearic acid, beewax and paraffin are the main

oleaginous bases.

• propylene glycol and water representing the aqueous

phase

• Methylparaben and propylparaben are used to preserve

the ointment against microbial growth

Evaluation Of Topical Dosage Form

Evaluation of cream

Rheology

Sensitivity

Biological testing

Pastes: Formulation

• Bases Used For Pastes • Hydrocarbon Bases• Water miscible Bases• Water Soluble Bases

Pastes ointmentContains large amount of finely

powdered SolidsContains dissolved/

suspended/emulsified medicamentsVery thick and stiff Soft semisolid preparation

Less greasy More greasy

Forms a protective coating on the skin Used both as protective or emollient

Applied with a spatula or on lint Simply applied on skin

Less soft/macerating More macerating in action

Contains a large amount of porous powders which allows the

perspiration to escape

Used for the protection of lesions

Pastes: Bases

1. Hydrocarbon Bases• Formulated by using liquid and soft Paraffin• Example: Zinc Oxide Paste ZnO….. 25 gm (Finely Sifted) Starch.. 25 gm (Finely Sifted) White Soft Paraffin .. 50 gmMethod:

• Melt the white soft paraffin on a water bath. • Separately pass the zinc oxide and starch through sieve no. 20.• Mix the required amount of powder in a mortar.• Add small amount of melted base with continuous trituration until

smooth paste is obtained. • Add the remaining base, triturate until cold and a uniform paste is

obtained.

Pastes: Bases2. Water Miscible Base• Emulsifying ointment or glycerin is also used as a water

miscible base for the preparation of a paste.

• Example: Resorcinol …….. 2.5 gm Precipitated Sulphur .. 2.5 gm Zinc oxide finely sifted… 20 gm Emulsifying ointment ….. 25 gm

Method• Triturate the fine powders with a small amount of emulsifying

base until smooth and gradually incorporate the remaining base.

Pastes: Bases

3. Water Soluble Bases

• Suitable combination of high and low molecular weight polyethylene glycols are mixed to obtain desired consistency.

• Example : PEG 400…. 60 gm PEG 4000.. 40 gm

• Softens or melts when applied on the skin.• Bases are water soluble. • Water soluble dental paste containing neomycin sulphate with

macrogol base (PEG Base)

Pastes: Preparation and Storage• Method of Preparation: Prepared by 1. Trituration. 2. Fusion.

• Trituration is used when the base is semisolid or liquid.• Fusion method is used when the base is solid or semisolid.

• Storage: 1. The pastes should be stored in a well closed container and in

a cool place to prevent loss of moisture.2. Container should be made up of materials which do not

allow absorption or diffusion

Evaluation Of Topical Dosage FormEvaluation of paste

Particle size

Consistency

pH of the product

Foaming character

Limit test for arsenic and lead

Volatile matters and moisture

Effect of special ingredients

Gels/Jellies: Gelling Agents• Gelling agents are generally organic hydrocolloids.• Gelling agents are:

1. Natural Gums (Tragacanth, pectin, alginates)2. Gelatin.3. Cellulose Derivatives (MC, HPC, HPMC, EC)4. Carbomers/Carbopols (934, 940, 974, 980)• Preparation: • The gelling agent is added in the aqueous solution of drugs.• The mass is triturated in a mortar until a uniform product is obtained.• Glass mortar and pestle is used in case of dark colored drugs.• Whole gum should be preferred over powdered gum for a clear gel

and uniform consistency.

Clear Gels: Formulation and Manufacturing

• Clear Transparent semisolids containing the solubilized active substances.

• Formed by the aid of an gelling agent.• Example: Carbopol 934, 940, 974. Methyl cellulose• Gelling agents like carbopol swells when dispersed in water and

generally in the presence of an alkaline substance like triethanolamine.

• Formulation: Methyl cellulose …. 2 gm carbopol 934.………. 500 mg propylene glycol…. 5 gm Triethanolamine…. 2 gm water ….. Qs upto 100 gm• Method• Disperse Methyl cellulose and carbopol 934 (Triturated with

propylene glycol) in water. Add triethanolamine in carbopol.• Allow the gelling agents to swell and the mix to obtain gel.

Evaluation Of Topical Dosage FormEvaluation of gel

Drug content

Homogeneity of drug content

Measurement of pH

Viscosity

Spreadability

Extrudability

Gels: Preservation and Storage

• Preservation:

• As the Gels contain large amount of water so it is prone to bacterial and fungal growth.

• Antimicrobial agents used to preserve the gels are: Methyl p-hydroxybenzoate (0.1-0.2%) Propyl p-hydroxybenzoate (0.05%) Benzalkonium Chloride (0.02%) Phenyl Mercuric Nitrate (0.001%)• Storage of Jellies: Well filled and well closed containers to minimize

evaporation of water, stored n a cool place to prevent drying out, sterile gels like catheter lubricants are packed in collapsible tubes.

INDUSTRIAL PROCESSING

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.

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.

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.

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.

The incoming liquid should enter the mixing kettle below the surface of the other liquid.

Completely enclosed kettles are available for the manufacturing of semisolids which tend to aerate excessively.

The sealed vessels can also operate under vacuume.

Full feeding hopper is needed otherwise auger will drive air into the semisolid.

Homogenization frequently increases the consistency of a semisolid emulsion because it increases the number of emulsified particles.

consistency is affected by1. Number of passes through the homogenizer.2. Pressures used for homogenization.

Rheological changes:

PREPARATION OF OIL AND

AQUEOUS PHASES

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.

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.

The components of the aqueous phase are dissolved in the purified water and filtered.

A soluble drug may be added to this aqueous phase.

The phases are usually mixed at a temperature of 70 to 720C,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 0C.

MIXING OF PHASES

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.

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.

Low Energy Emulsification

• Limited utilization of thermal and mechanical energy.

• The use of minimum amount of emulsion phase in the emulsification stage can result in considerable reduction in energy requirements and processing time without compromising the quality of the product.

• The balance of the aqueous phase is added during cooling period thus saving the cost of heating the aqueous phase.

Internal Phase/Dispersed Phase

External Phase Part (1)

Concentrated Emulsion

External Phase Part (2)

Finished Emulsion

Low Energy Emulsification….• Procedure : In Oil-in-Water emulsion the oil phase (oil,

waxes, fats, preservatives and perhaps an emulsifier) and a small portion of the water phase is heated together and mixed.

• Atleast 70% of the water phase can be at the cool dilution stage thus saving energy.

Low Energy Emulsification.. Factors

• The quality, stability, rheology and particle size distribution of the internal phase of the finished product prepared by low energy mixing will depend upon:

1. Temperature required to form conc. Emulsion.2. The ratio of internal and external phase forming the conc.

Emulsion.3. The phase inversion temperature.4. Type and intensity of mixing.5. The rate of addition of the external phase

Equipments used for mixing of phases:

1. Agitator mixers :Sigma mixer and planetary mixer.

2. Shear mixers: Triple roller mill and Colloidal mill.

The mechanism of mixing is shearing. The sigma shaped blades creates high shear.

Advantages: It creates a minimum dead space during mixing..

Disadvantages: It works at a fixed speed.

Sigma blade mixer:

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:

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:

Perfume should be added at 43 to 450c 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.

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.

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.

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.

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.

EVALUATION OF OINTMENTS/SEMISOLIDS

• Content uniformity of drug

• Penetration

• Rate of release of medicament

• Absorption of medicament in blood stream

• Irritant effect:

Packaging & storage Minimum Fill Water content Metal particles Leakage test Sterility test Microbial screening In Vitro and In Vivo

studies

OTHER EVALUATION PARAMETERS FOR SEMI SOLIDS

• Content uniformity of drug

A known weight of ointment is taken and assayed for amount of the drug.

• Penetration A weighed quantity 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.

In Vitro Skin Penetration

• Flow through cell• Franz diffusion cell

They mainly have two compartments 1) Donor 2) Receptor

Method:

mouse skin or human cadaver skin. Placed in between the two compartments. The passage of semisolid preparation through the epidermal surface to

receptor compartment is measured by, Detector ( Flow through type ) Sampling ( Franz diffusion cell )

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 or alternately in a small cup cut in the agar surface.

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.

• Another method for finding out release rate is to smear internal surface of test tubes with thin layers of ointment, fill the tubes with saline/serum and after a gap of time estimating the amount of drug present in the serum/saline.

ABSORPTION OF MEDICAMENT INTO BLOOD STREAM

• The diadermatic ointment should be evaluated for the rate of absorption of drug into the blood stream. This test can be run in-vivo only.

• Definite amount of ointments should be rubbed through 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 are 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.

DRAIZE TEST• Draize skin irritation test:

A known amount of test substance is introduced under a one square inch gauge patch,

The patch is applied to skin of 12 albino rabbits, (6 with intact skin) and (6 with abraded skin),

The patch is secured in place with adhesive tape and the entire trunk of the animal is wrapped with an impervious material for a 24 hour period,

After 24 hours the patches are removed and resulting reaction is evaluated for erythema and edema formation.

The reaction is again scored at the end of 72 hours and the two readings are averaged.

CONCLUSION FROM DRAIZE TEST

CATEGORY DRAIZE

CODE SKIN REACTION

Mild MLD Well defined erythema and slight edema ( edges of area well defined

by definite raising)

Moderate MOD Moderate to severe erythema and moderate edema (area raised

approximately 1 mm)

Severe SEV Severe erythema (beet redness to slight eschar formation (injuries in depth ) and severe edema ( raised more than the 1 mm and extending

beyond area of exposure.

DRAIZE EYE IRRITATION TEST

• A known amount of test material is placed in one eye of each of 6 albino rabbits the other eye remains untreated, serving as a control.

• The eyes are not washed after instillation and are examined at 24,48 and 72 hours for ocular reaction.

• The test is considered positive if ulceration, opacity of the cornea , inflammation of the iris, swelling of the conjunctiva occurs.

• A substance is an eye irritant if, 4 of six rabbits score positive it is considered a non irritant if none or only one of the 6 animals

exhibit irritation.

CONSISTENCY TEST• PENETROMETRY:

PROCEDURE:Preparation of test sample: 3 methods (A,B,C)

A: Carefully and completely fill three containers without forming air bubbles. Level if necessary to obtain a flat surface.

B: Apply a suitable shear to the samples for 5 min carefully and completely fill three containers without forming air bubbles. Level if necessary to obtain a flat surface.

C: melt 3 samples carefully and completely fill three containers without forming air bubbles. Level if necessary to obtain a flat surface.

CAUTION: Store the samples at 25 ± 0.5oC foe 24 hours unless otherwise prescribed.

Determination Of Penetration : Place the test sample on the basis of the

penetrometer. Verify that its surface is perpendicular to the vertical axis of the penetrating object. Bring the temperature of the penetrating object to 25 ± 0.5oC and then adjust its position such that its tip just touches the surface of the sample . Release the penetrating object and hold it free for 5 sec. clam the penetrating object and measure the depth of penetration. Repeat the

test with 2 remaining containers.

RESULT: The penetration is expressed in

terms of mm as the arithmetic mean of the three measurements. If any of the individual results differ from the mean by more than 3%,repeat the

test and express the results of the 6 measurements as the mean

EVALUATION OF CREAMS

As these products are used widely and for various parts of the body, stringent evaluation and quality control is essential. Appearance spread ability, wash ability.

Rheology

Rheology is very important as these creams are marketed in tubes or containers. The rheology or viscosity should remain constant. As these products are normally non-Newtonian in nature, the viscosity 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 or other deformable container, maintaining product shape in a jar or after extrusion rubbing the product onto and into the skin and pumping the product from mixing and storage to filling equipment.

• 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 should be tested before hand. This test is normally done by patch test on and can be either open or occlusive. The test sample is applied along with a standard market product at different places and effect is compared after a period of time.

Quality Control Tests For Creams & Ointments

Universal Tests

Description

Identification

Assay

Impurities

Specific Tests

PH

Apparent Viscosity

uniformity Of Dosage Unit

Water Content

Microbial Limit

Preservative Effect

Particle Size

Special Tests

Phase Separation

Uniformity in Container

In vitro Release Studies

1.Universal Tests:

Description:

This includes visual examination to identify changes in color, separation,

crystallization etc., in the final appearance of the product.

The description should specify the content or label claim of the product.

2.Identification:Quantitative identification of active ingredients in the finished dosage form.Methods:

•IR

•Raman spectroscopy

•Chromatography

3.ASSAY:

The quantity of drug present in unit weight or volume of ointment or

cream is determined by:

•Spectrophotometric method

•Titrimetric method

•Chromatographic method

•Microbial assays

4.MICROBIAL ASSAYS

Microbial assays are recommended for preparations containing antibiotics such as:

•Amphotericin-B•Bacitracin•Chlortetracycline HCl•Gentamycin sulphate

Method:•Cylindrical plate or plate assays•Turbidimetric or tube assays

5.IMPURITIES:

The impurities arising from degradation of drug substance and during

the manufacturing process of drug product should be assessed and

controlled

II.SPECIFIC TESTS:

1.PH

•Creams and ointments contain very limited quantities of water or

aqueous phase,

•Hence this test is not always warranted.

•Formulation dependent.

•Not included in compendia drug product monograph.

2.APPARENT VISCOSITY:

•Formulation and/or process dependent.

•Not included in compendia drug product monograph.

3.UNIFORMITY OF DOSAGE UNIT:

This test is applicable for dosage forms packaged in single unit containers.

4.Water Content:

Determined by Titrimetric methods.

Reagent: KF reagent

Preparations Max., allowable Limit of water

Ointments 0.5 to 1.0%

Bacitracin, Nystatin,

Chlortetracycline HCl ointment

NMT 0.5%

Amphotericin-B, Gentamycin

sulphate, Neomycin sulphate,

Erythromycin sulphate, Tetracycline

HCl

Upto 1%

5.ANTIMICROBIAL PRESERVATIVE EFFECT:

Method: Pour plate technique

Solns of different samples

Mixed with Tryptone Azolectin(TAT) broth separately

Add all cultures into each mixture

Incubate & count no. of organisms on 7,14, 21, 28 days of incubation

On 14thday No.of vegetative cells NMT 0.1%

of intial conc

On 28th day No, of organisms should be below

or equal to intial conc

6.PARTICLE SIZE DETERMINATION:

•Dilute preparation with equal volume of glycerol/ liquid paraffin as per

monograph.

•Mount on glass slide.

•Observe through microscope.

•Calculate the no. of particles having max., diameter within stated limit.

III.SPECIFIC TESTS FOR SEMISOLID DOSAGE FORMS:

1.PHASE SEPARATION TEST:

•Visual tests.

•Done by measuring the volume of separated phases.

2.UNIFORMITY IN CONTAINERS:

Type Assay Limit

Multiple dose products containing

>5gm

90-110% of product label

Multiple dose products containing

<5gm

90-110% of product label

Procedure:

•Expose the product in tube.

•Visually inspect product.

•Remove a sample of product from top, middle and bottom portions

of the tube.

•Perform assay separately

Products Packaged In Containers Other Than Tubes:

•Select a syringe such that it reaches bottom of the container.

•Remove plunger & cut of bottom of syringe barrel.

•Sample from one side of container is slowly withdrawn by slowly

inserting syringe barrel into container until it reaches bottom.

•Twist syringe barrel containing sample core and remove barrel.

•Insert the syringe plunger and carefully extrude the equal portions

representing Top, middle, bottom of container.

•Perform assay separately for each portions

INVITRO DRUG RELEASE STUDIES:

These studies are conducted in order to ascertain the release of drug from

the formulation matrix.

Apparatus: Franz diffusion cell

CONCLUSION:

From this it can be concluded that, though a no. of quality control

tests have been assigned for sold & semisolid dosage forms in IP, BP,

USP yet there occurs some difference between them.

Hence in order to overcome that, the different tests & limits

specified in different pharmacopoeias have to be streamlined and

harmonized in such a way that, tests meets specified limit as per

harmonized one and later meets regulatory requirements of that

particular country.