Semisolid Dosage Forms

Semisolid Dosage Forms

• Topical dosage forms for therapeutic, protective, or cosmetic functions
• Applied to the skin, nasally, vaginally, or rectally.
• Contain one or more active ingredients.
• Use a suitable base and excipients like emulsifiers, viscosity-increasing agents, antimicrobial agents, antioxidants, or stabilizing agents.
• Semisolids include ointments, creams, pastes, gels/jellies, poultices, and suppositories.

Classification of Semisolids

• Ointments are for external application to the skin or mucous membranes and contain dissolved, suspended, or emulsified medication.
• Creams are viscous emulsions of semisolid consistency for skin or mucous membrane application and can be oil-in-water (o/w) or water-in-oil (w/o) types.
• Pastes contain a large amount of finely powdered solids like starch and zinc oxide, making them thick and stiff.
• Jellies are thin, transparent or translucent, non-greasy, and prepared using gums, differing from mucilages with jelly-like consistency.
• Gels are jelly-like semisolid drug dispersions for skin application.

Classification of Ointments

• Epidermic: meant for action on epidermis.
• Endodermic: action on deeper layers of cutaneous tissue.
• Diadermic: meant for deep penetration.
• Therapeutic uses include antibiotic, antifungal, anti-inflammatory, antipruritic, astringent, and keratolytic applications.

Classification of Pastes

• Fatty pastes.
• Aqueous gel pastes.
• Hydrocolloid pastes.

Classification of Creams

• Aqueous creams (O/W creams) use anionic, cationic, or non-ionic emulsifying agents.
• Oily creams (W/O creams) include sterol creams and soap creams.

Classification of Gels

• Medicated gels, lubricating gels, and miscellaneous gels are based on use.
• Single-phase (organic gels) and two-phase systems (inorganic gels) are based on the nature of the colloidal system.
• Hydrogels and organogels are based on solvent nature.

Excipients in Semisolid Dosage Forms

• Ointments: ointment base, preservatives, anti-oxidants, chelating agents, humectants, and perfume.
• Pastes: paste base, preservatives, anti-oxidants, and perfume.
• Creams: penetration enhancer, oil/oleaginous substances, emulgents, co-emulsifiers, emulsion stabilizers, mixed emulsifier systems, humectants, stabilizers and perfumes.
• Gels: gelling agent, preservative, hygroscopic substances, and chelating agents.

Ointments

• Semisolid preparations are meant for external application to the skin or mucous membranes.
• Ointment bases are selected after toxicity and irritability tests.
• The ointment base is important in semisolid dosage form formulation.
• Ointments and suppository bases control the extent of medicament absorption.
• USFDA lists ointment bases and their concentrations.

Ideal Properties of a Base

• Compatible with skin pH and drug.
• Inert, non-irritating, and non-sensitizing.
• Good solvent or emulsifying agent.
• Emollient, protective, non-greasy, and easily removable.
• Release medicaments easily at the site of administration.
• Pharmaceutically elegant with good stability; optimal skin pH is between 5.2-5.7.

Classification of Bases

• Oleaginous bases.
• Absorption bases.
• Emulsion bases.
• Water-soluble bases.

Oleaginous (Hydrocarbon) Bases

• Combination of water-insoluble hydrophobic oils and fats.
• Disadvantages: greasy, sticky, non-washable, retain body heat, prevent drainage, and do not increase absorption.
• They are anhydrous, do not absorb water & insoluble in water.
• Include hydrocarbons like paraffin wax, soft paraffin, and liquid paraffin.
• Also include vegetable oils, animal fats, hydrogenated & sulfated oils, acids, alcohols, esters, and silicones.

Types of Paraffin

• Soft paraffin (petrolatum) is a purified mixture of semisolid hydrocarbons from petroleum.
  • Yellow soft paraffin has a melting point of 38°C and is used in ophthalmic ointments.
  • White soft paraffin has a melting point of 56°C and is obtained from bleaching yellow soft paraffin.
• Hard paraffin is a purified mixture of solid hydrocarbons from petroleum and can be used to harden or soften ointment bases.
• Liquid paraffin (white mineral oil/liquid petroleum) is a mixture of liquid hydrocarbons from petroleum distillation and can be combined with hard or soft paraffin to adjust the ointment base consistency.

Absorption (Emulsifiable) Bases

• Anhydrous.
• Forms w/o emulsion.
• Absorbs 50% water due to the presence of a sterol emulgent.
• Easily removable by water.
• Non-emulsified bases absorb water and aqueous solutions to produce w/o emulsions using wool fat, wool alcohol, beeswax, and cholesterol.
• W/O emulsions absorb more water with hydrous wool fat (lanolin).

Wool Fat

• Anhydrous lanolin is fat from sheep wool.
• Can absorb 50% of its weight in water.
• It is used in ointment base preparation and ophthalmic ointments.
• Wool alcohol is wool fat that is alkalized to get cholesterol & alcohol, used as an emulsifying agent in W/O emulsions.
• Bees wax is a wax from honeycomb of bees.
  • Yellow and white types can stiffen paste & ointments.
• Hydrous wool fat is purified fat from wool of sheep, insoluble in water but soluble in ether and chloroform, contains 70% wool fat and 30% water, and used as an emollient.

Advantages & Disadvantages of Absorption Bases

• Compatible with most medicaments.
• Absorbs large quantities of water or aqueous substances.
• Relatively heat stable and easily spreadable.
• Less occlusive and good emollients; aqueous substances can be incorporated.
• Undesirable due to a greasy nature and risk of microbial contaminations.

Emulsion Bases

• Absorb water and serum discharges, forming o/w and w/o emulsions.
• W/O is greasy and sticky in sulfur and zinc ointments.
• O/W is easily removed from the skin, like vanishing cream.
• Emulsifying ointment contains 30% anionic, cationic, or non-ionic emulsifying wax, 50% white soft paraffin, and 20% liquid paraffin, leaving a layer of fat on the skin.

Advantages and Disadvantages of Emulsion Bases

• Miscible with exudates from lesions
• Surfactant content ensures good skin contact.
• Does not interfere with skin function.
• High cosmetic acceptability and easy removal from hair.

Disadvantages of Emulsion Bases

• W/o emulsion greasy and sticky
• Its acceptance is less
• Difficult to remove from body and clothing.

Water Soluble Bases (Grease-less Bases)

• Carbo waxes 200, 300...1500 for viscous liquids.
• Carbo waxes 1540, 3000.. 6000 for viscous solids.
• Pectin, Tragacanth & Cellulose derivatives (Form plants).
• Gelatin (Animal).
• Silica Gel, Bentonite (Chemical).
• Glycerin, Glyceryl mono stearate for low viscosity.

Carbo Waxes (Macrogols/ Polyethylene Glycols)

• General formula CH2OH. (CH₂OCH₂)n. CH2OH.
• Mixtures of polycondensation products of ethylene oxide and water.
• Macrogols 200, 300, and 400 are viscous liquids with average molecular weights represented by numbers.
• Macrogol 1500 is a greasy semi solid and Macrogols 1540, 3000, 4000, and 6000 are waxy solids.
• Liquids are clear, colorless with a faint characteristic odor miscible with water, alcohol, and glycols.
• Solids are white or cream in colour, hard lumps or flakes, soluble 1 in 3 in water and 1 in 2 in alcohol, and have solidifying points ranging from 40 to 60°C.
• Considered non-toxic, non-irritating, pH 4-7.5, sterilizable by heat, and water-soluble non-volatile inert substances.

Paste Base Components

• Hydrocarbon bases: soft paraffin, liquid paraffin.
• Water-miscible bases: glycerin, emulsifying ointment.
• Water-soluble bases: poly ethylene glycols.

Chelating Agent

• Heavy metals can degrade gel bases and medicaments, so chelating agents like EDTA are added to form complexes and prevent degradation.

Humectant

• Humectants like glycerin and sorbitan are added to maintain humidity and prevent drying in preparations

Hygroscopic Substances

• Hygroscopic substances like glycerol and propylene glycol prevent quick water loss due to evaporation in gels and stop drying and flake formation.

Gelling Agents

• Organic hydrocolloids or hydrophilic inorganic substances.
• Natural gelling agents include gum tragacanth, starch, pectin, gelatin, clays, cellulose derivatives, etc.
• Synthetic gelling agents include sodium alginate, carbomer, poly vinyl alcohol, etc.
• Clays include using 7-20% bentonite as a dermatological base and 10% aluminum magnesium silicate in medicated gels.

Tragacanth

• Used for lubricating, medicated, and contraceptive jellies.
  • Concentrations used: 2-3% for lubricating, 5% as a dermatological vehicle.
• Dispersing agent used to get a homogenous product.
• Alcohol, glycerol or volatile liquids used as dispersing agent.
• Disadvantages include sources vary in viscosity, film left on the skin tends to flake after evaporation, can't be stored for longer time and prone to microbial growth and lose viscosity outside the pH range of 4.5 – 7.

Pectin

• A good gelling agent that is suited for acid products
• It is used in many preparations including edible jellies.
• Glycerine is used as dispersing agent & humectant.
• Pectin jelly is a good source for bacteria, preservatives should be added

Starch

• Used in combination with other Jelling agent.
• Provides a water soluble dermatological base.
• Glycerin(up to 50%) may be added which acts as preservative and humectant.

Gelatin

• Insoluble in cold water (swells and soften)
• Soluble in hot water
• 2% gelatin forms jelly on cooling
• A suitable preservative is required

Cellulose Derivatives

• Produce neutral jellies of very stable viscosity, afford good resistance against microbial growth and produce a soft film after drying.
  • Sodium CMC is used for preparation of lubricating & sterile jellies and withstand autoclaving temperature without deterioration
• Example methyl cellulose - 3%.

Sodium Aliginate

• 1.5 to 2% Used as Lubricant gel & Dermatological vehicle 5 To 10%
• Advantages over tragacanth and available in several grades of standard viscosity
• Viscosity can be increased by adding soluble calcium salt.
• 2-4% alcohol, glycerine, and propylene glycol are used as dispersing agents.

Carbomer

• Consists of 0.3-1% in lubricating gels & 0.5-5% as dermatological vehicle.
• These have high gelling efficiency and used in low concentrations.

Preparation of Gels

• Gels are usually prepared by adding a thickening agent.
• Thickening agents are added to the aqueous solution where the drug can be dissolved
• Mass is triturated in a mortar until a smooth product is obtained
• When coloured drug is to to be incorporated glass mortar needs to be used
• It is preferred that gum is whole in order to get a uniform consistency

Permeation Enhancers

• Enhance penetration of the drug through the skin.
• Oleic acid works as a permeation enhancer.

Methods of Preparation

• Ointments & Creams: trituration, fusion, chemical reaction, and emulsification.
• Pastes: trituration and fusion.
• Gels: general method.

Trituration Method

• This is a widely used method for extemporaneous preparation of ointments.
• Use when the base is soft and medicament is solid insoluble
• A small amount of liquid can be incorporated in the base
• Mixing and size reduction occur.
• Solid medicament reduced to fine powder and mixed with a small amount of base on an ointment slab using a stainless steel spatula until a homogeneous product is formed.

Sulphur Ointment Example

• To prepare 100g of sulphur ointment using sublimed sulphur (10g) and simple ointment (90g), combine ingredients,add remaining quantities of base with uniform mixing and apply to affected area as directed.

Fusion Method

• Suitable for ointment base contains number of solid ingredients of different melting points.
• The ointment bases are melted in decreasing order of their melting point.
• Start with the ingredients with the highest melting point first.
• Avoid overheating of low-melting-point substances and incorporate medicament slowly into the melted mass.
• Stir continuously until mass is homogenized and cooled down.
• Liquid ingredients or aqueous substance should be heated to the same temperature as the melted bases before addition.
• If not, wax or solids will cool down quickly and get separated

Precautions for Fusion Method

• Vigorous stirring avoided, rapid cooling avoided, and the mass strained through muslin cloth to remove impurities.

Chemical Reaction Method

• Preparation of some ointment involves chemical reactions
  • (a) Iodine ointment(iodine free form)
  • (b) Iodine ointment ( iodine is combined with base)

Emulsification Method

• Melt fats, oils, and waxes together to a temperature about 70°c.
• The aqueous solution of the heat-stable, water-soluble compounds needs to be heated at the same temperature.
• Aqueous Solution is slowly added to the melted bases, with continuous stirring until cool.

Laboratory and Industrial Scale Equipment

• Laboratory: ointment slab & spatula, motor & pestle, and electric motor & pestle.
• Industrial: ointment mill, triple roller mill, and Hobart type mixer.

Types of gels

• Based on its application is (1) Medicated,(2) lubricant and (3) miscellaneous
• Medicated: use on mucous membranes and skin for actions like lubrication, antiseptic, vasoconstriction, and contraception.

Lubrication Gels

• Need to be thin, transparent and soluble in water, also sterile when being used for lubrication in areas such rectal thermometers, urinary bladders, fingerstalls, and etc

Evaluations for Ointments and Creams

• Drug content: use minimum fill test.
• Release rate of medicament from base: use agar cup plate/diffusion method.
• Penetration rate of medicament.
• Absorption of medicament into blood stream.
• Consistency of the preparation.
• Irritant effect, which involves testing on the skin and eyes of rabbits or human skin. For the Drug content evaluations are done using filled containers where medicament is extracted in suitable solvent and analyzed

Diffusion Method

• Used to find the release rate of any type of medicament from the base.
  • Analyzed for the drug where T Tube is dipped in the distilled water maintained at 37±1°C.
• A parchment membrane is tied at one end of glass tube and a plot of the drug concentration and time is created
• Samples are withdrawn after a specified period of time and samples are immediately replaced with fresh distilled water

Determinations for Penetration Rate

• The amount of drug that penetrated the skin over the time given
  • Base penetrates a weight from rubbing a weighed amount into a specific defined area
• Diadermic ointments are tested by in-vivo method to assay for content in in blood or other things

Consistency Determination

• Sliding a lass plate over the product by means of a pulley, a determined weight on pan is added

Evaluation of Gels

• Rheological properties are tested
• A Brook field viscometer is used for determination.
• Yield valve and Spreadability are tested using slides
• A penetrometer is used to measure force required to to exude the gel form
• A gel stability test for various temperatures is tested for shipping
• Safety evaluations are determined by physical properties

Evaluation of Pastes

Evaluation of heat stability, viscosity, and compatibility with the container are tested. In addition to that, safety, sensitization, and the gelation behavior is observed

Human Skin

• Epidermis: The outermost layer of the skin.
  • Dermis: The layer underneath the epidermis, containing hair follicles, sweat glands, and blood vessels
• Subcutaneous tissue: The innermost layer of the skin.
• The skin is very effective as a selective penetration barrier.
• The epidermis provides the major control element for drug penetration.

Mechanism of Drug Penetration through Skin

• Potential MACRO ROUTES to the viable tissue through the sweat ducts and continuous Stratum corner

Factors Influencing Dermal Penetration of Drugs

• Biological factors: skin condition, skin age, blood flow, regional skin site, skin metabolism, and species difference.
• Physicochemical factors: skin hydration and temperature pH, Diffusion coefficient, drug concentration, partition coefficient,

Skin Condition

• The intact, healthy skin is a tough barrier but acids and alkalis injure barrier cells and therefore promote penetration.
• Non-polar and polar solvents, such as chloroform and methanol, remove the lipid fraction and molecules pass more easily.
• If the organ thickened, with corns, calluses and warts, drug permeation decrease.
• Skin of the young and the elderly is more permeable than adult tissue.
• Children are more susceptible to the toxic effects of drugs.

Blood Flow

• An increased blood flow could reduce the amount of time a penetrant remains in the dermis, and also raise the concentration gradient across the skin.

Skin Metabolism

• The skin metabolizes steroid hormones, chemical carcinogens and some drugs.
• Advantage to prodrugs, about 5% of topical drugs can be metabolized in the skin

Diffusion Coefficient

• The diffusional speed of a molecule depends mainly on the state of matter of the medium.

Drug Concentration

• Proportional to the concentration gradient across the barrier, drug permeation follows Fick's law, saturated donor solution gives maximum flux

Partition Coefficient (K)

• Important factor to establish a drug, (K<1) are water soluble, (K>1) are oil soluble