SEMI SOLIDS

VENU MADHAV

Introduction
Semisolid pharmaceutical systems comprise a body of products, which when applied to the skin or accessible mucous membranes tend to alleviate or treat a pathological condition or offer protection against a harmful environment. Property to cling to the skin or mucous membrane for a protracted period of time. Adhesion is due to their plastic rheologic behavior which allows semisolid to retain their shape and cling as film until acted upon by an outside force. 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. Can be applied topically to the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining.

DEFINITION Semisolid dosage forms are dermatological products of semisolid consistency and applied to skin for therapeutic or protective action or cosmetic function. IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS 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 washability

Storage properties Stable under various real world storage conditions as per ICH guidelines. Storage of semisolids should be at temperatures not exceeding 25C unless otherwise authorized. They should not be allowed to freeze and must be stored in a well-closed container or, if the preparation contains water or other volatile ingredients, store in an air-tight container. The containers are preferably collapsible metal tubes from which the preparation may be readily extruded. If the preparation is sterile, store in a sterile, airtight, tamper-proof container.

Types of Climatic Zones

Climatic zones I

Definition

Storage/test conditions 21C + 2C 45% RH + 5% RH

Temp. climate

II

Mediterranean & subtropical climate Hot dry climate

25C + 2 C 60% RH + 5% RH 30C + 2C 35% RH + 5% RH

III

IV

Hot, humid climate

30C + 2C 75% RH + 5% RH

Types of Semisolid Dosage Forms

OINTMENTS Soft hydrocarbon based semisolid preparation, composed of fluid hydrocarbon meshed in a matrix of higher melting solid hydrocarbon petrolatum being a tasteless, odorless, unctuous material with a melting range. Principle ingredients forming the system hydrocarbon and silicon oil are generally poor solvent for most drugs, seemingly setting a low limit on the drug delivery capabilities of the system. CREAMS Viscous semisolid emulsion system with opaque appearance as contrasted with translucent ointments. Consistency and rheological character depends on whether the cream is w/o or o/w.

Properly designed O/W creams are elegant drug delivery systems, pleasing in both appearance and feel post application, non greasy and are rinsable. Good for most topical purpose and are considered particularly for application to oozing wounds. PASTES Pastes are basically ointments into which a high percentage of insoluble solid has been added. The extraordinary amount of particulate matter stiffens the system through direct interactions of the dispersed particulates and by adsorbing the liquid hydrocarbon fraction the vehicle on the particle surface. Pastes are usually prepared by incorporating solids directly into a congealed system by levigation with a portion of the base to form a paste like mass.

Pastes are less penetrating and less macerating and less heating than ointment. Good protective barrier when placed on the skin for, in addition to forming an unbroken film, the solid they contain can absorb and thereby neutralize certain noxious chemicals before they ever reach the skin, an effective sun block accordingly. Skiers apply paste around the nose and lips to gain a dual protection. Pastes are less greasy because of the absorption of the fluid hydrocarbon fraction to the particulates. GELS (JELLIES) Gels are semisolid system in which a liquid phase is constrained within a 3-D polymeric matrix (consisting of natural or synthetic gum) having a high degree of physical or chemical cross-linking.

Gels are aqueous colloidal suspensions of the hydrated forms of insoluble medicament. Jellies are transparent or translucent non-greasy semisolid gels. Used for medication, lubrication. POULTICES Soft, viscous, pasty preparation for external use. Applied to skin while they are hot. Poultice must retain heat for a considerable time because they are intended to supply warmth to inflamed parts of body. e.g. Kaolin poultice (B.P.C.) PLASTERS RIGID FOAMS Foams are system in which air or some other gas is emulsified in liquid phase to the point of stiffening. e.g. shaving creams, aerosolized shaving creams

FACTORS AFFECTING SKIN PENETRATION The principle physicochemical factor in skin penetration is the hydration state of stratum corneum, which affects the rate of passage of all substances that penetrate the skin. The temperature of skin and the concentration of the drug play significant roles, but they are secondary to that of hydration. The solubility of a drug determines the concentration presented to the absorption site, the water or lipid partition coefficient influences the rate of transport. An inverse relationship appears to exist between the absorption rate and the molecular weight. Small molecules penetrate more rapidly than large molecules, but within a narrow range of molecular size, there is little correlation between the size and the penetration rate.

Formulation of Semisolid Dosage Forms

1. BASES 2. HYDROCARBON WAXES 3. OLEOGENOUS SUBSTANCES 4. FATTY ACIDS & ALCOHOLS 5. EMULCIFIERS 6. POLYOLS 7. INSOLUBLE POWDERS 8. FRAGRANCES 9. ANTIOXIDANTS 10. PRESERVATIVES 11. CHELATING AGENTS 12. HUMECTANTS

1. BASES An ointment base should be compatible with skin, stable, smooth and pliable, non-irritating, non-sensitizing, inert, capable of absorbing water or other liquid preparations, and of releasing the incorporated medicament, readily. A base for ophthalmic ointments must be non-irritating to the eye, should permit the diffusion of the drug and should retain the activity of the medicament for a reasonable period often under proper storage conditions. It should also be sterilizable conveniently. A) Oleaginous or Hydrocarbon bases

Combination of more than one oleaginous material such as waterinsoluble hydrophobic oils and fats. Combinations of these materials can produce a wide range of melting points and viscosities. e.g. Petrolatum and White ointment (Petrolatum with 5% beeswax)

Commonly used petrolatum consistency, bland, neutral, spread easily difficult to wash, occlusive covering

B) Absorption (Emulsifiable) Bases Formed by addition of substances miscible with hydrocarbons & posses polar group sulfate, sulfonate, carboxyl, hydroxyl, ether Emulsifiable bases because they initially contain no water but are capable of taking it up to yield W/O and O/W emulsions. Absorption bases are W/O type emulsions and have capacity to absorb considerable quantities of water or aqueous solution without marked changes in consistency. e.g. Lanolin, Lanolin isolates, Cholesterol, Lanosterol, Acetylated alcohols or partial esters of polyhydric alcohols (sorbitan mono stearate or mono laurate)added to make hydrocarbon bases hydrophilic.

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Do not absorb moisture , but agitation absorb. 2 types 1. Anhydrous type Lanolin & hydrophilic Petrolatum 2. Emulsion Non ionic emulsifiers Glyseryl mono stearare, Cholesterol, Cetyl alcohol. C). Emulsion or Water removable Bases W/O emulsions are not water-washable as the oil is in the external phase and O/W emulsions are used in dermatological preparations and cosmetic creams. Some of the popular creams include cold creams, vanishing creams. Skin creams, emollient creams, foundation creams, hand creams etc. e.g. Stearic acid, Stearyl alcohol, Cetyl alcohol, GMS

D) Water Soluble Bases Both anhydrous and hydrous dermatological non-emulsion bases which are water soluble and contain no oil phase. e.g. Polyethylene glycols or one or more of the other hydrocolloids. Polyethylene glycols (Carbowaxes) are water soluble, non-volatile, unctuous compounds. Different grade of cabowaxes are available which are designated by a number approximating their average molecular weights e.g.- 200, 300, 400, 600, 1000, 1540, 4000 and 6000. At RT, carbowaxes 200 to 400 are clear liquids whereas carbowaxes 1000 to 60000 are white, waxy solids. A variety of water washable ointment bases with consistencies ranging from semi-solid to solid can be obtained by blending different polyethylene glycols. Polyethylene Glycol Ointment USP is a blend of Carbowaxes 4000 and 400.

Appropriate Selection of Ointment Base

Desired release rate of the drug substance from the ointment base. Rate and extent of topical or percutaneous drug absorption. Desirability of occlusion of moisture from skin. Stability of the drug in the ointment base. Effect of drug on the consistency of base. Easy removal of base on washing. Characteristic of the surface to which it is applied.

2. HYDROCARBON WAXES Frequently employed in mfr of cream & ointments to increase viscosity of mineral oil in order to prevent its separation from ointment. E.g.: Ozokerite M.P. 65-750c consist mixture of hydrocarbons. Paraffin wax M.P. 35-750c obtained from petrolatum. Ceresin mixture of ozokerite & paraffin wax. Synthetic waxes: by Developed from veg oils & naturally occurring oils

process of hydration and catalytic splitting.

Complex mixtures of long chain saturated aliphatic chemical entities. Exhibit thermoplastic and crystalline properties.

3. OLEOGENOUS SUBSTANCES E.g: Veg oils Peanut oil, Almond oil, Sesame oil, Olive oil.

4. FATTY ACIDS & ALCOHOLS FATTY ACIDS: Stearic acid, Palmitic acid . Various ratios are used . Stearic acid used in water removable creams & give matt appearance to skin . Stearate soap used enough KOH or Triehanolamine added

ALCOHOLS: Stearyl alcohol & Cetyl alcohol as emulcifiers or emollients Stearyl alcohol produce firm cream, Cetyl produce softer

5. EMULCIFIERS E.g.: Water soluble soaps Increase viscosity & stability of o/w type emulsion. Combination of surfactant & oil soluble emulsifier called mixed emulsifier. (Triehanolamine stearate soap with cetyl alcohol). Soap type emulsion is unstable in presence of acidic substances. - Cationic or non-ionic emulcifiers are preferable for drugs requiring acid pH (Quaternary ammonium compounds cetyl trimethyl ammonium chloride help to stabilize these compounds along with cetyl alcohol). - Non ionic emulsifiers are used for both o/w & w/o (Promulgens mixture of fatty acids & their ethoxylates) Recently chemically bonded lactic acid with fatty acids. mild & non irritating to skin and eye, produce emollient effect

6.POLYOLS Prevent drying of skin, improve consistency and rubout qualities of cream E.g.: Glycerin, Propylene glycol, Sorbitol(70%). Sorbitol more hygroscopic than glycerine used at low conc. PEG & PG occasionally used in combination with glycerine less moisture absorption.

7.INSOLUBLE POWDERS 8. FRAGRANCES - Lavender oil, Rose oil, Lemon oil, Almond oil 9. ANTIOXIDANTS - BHA, BHT, Propyl gallate.

10. PRESERVATIVES - Parabens, Chlorocresol, Benzoic acid,

11. CHELATING AGENTS

12. HUMECTANTS - PEG, Glycerol or Sorbitol

USE OF PERMEATION ENHANCERS IN FORMULATION OF SEMISOLID DOSAGE FORMS Skin can act as a barrier and prevent deep penetration of drug molecules. With the introduction of various penetration enhancers, however, systemic drug delivery through the transdermal route has gained major footing.

Permeation enhancer Menthol, carvacrol, linalool Limonene Geraniol, nerolidol Oleic acid Lecithin Propylene-glycoldipelargonate Cyclodextrins

Drugs used Propranolol hydrochloride Indomethacin, ketoprofen Diclofenac sodium Piroxicam Hydrocortisone acetate, heparin Heparin Hydrocortisone

Methods of preparation
TRITURATION When base contain soft fats and oils or medicament is insoluble and/or liquid. FUSION When soft fats or waxes are to be incorporated with hard fats or waxes then of this to be melted to get homogenous mixture with stirring. BY CHEMICAL REACTIONS In chemical method a new product is formed by chemical reaction, which involves both fusion and mechanical mixing. Best example of such method is Iodine ointment. OINTMENT MILLS It is used for large scale production where triple roller mill is utilized which is faster then others.

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PACKING AND LABELING

` Large-mouth jar (glass or plastic) ` Metal (Aluminium) or plastic tubes ` Well closed containers to protect against contamination ` Cool place to protect against product separation by heat ` When requires light resistance or opaque container for light sensitive drugs ` In addition to the usual labeling, the USP directs that for certain ointments and creams include the type of base used either water soluble or water insoluble

Quality control of Semisolid Preparations

OTHERS

SPREADABILITY PRESENCE OR ABSENCE OF GRITTY PARTICLES WASHABILITY IRRITANCY STABILITY