B.pharm- semisolid dosage form

Semisolid dosage forms: Definitions, classification, mechanisms and factors influencing dermal penetration of drugs. Preparation of ointments, pastes, creams and gels. Excipients used in semi solid dosage forms. Evaluation of semi solid dosages forms

1. SEMISOLID DOSAGE FORMS Presented By: K. Arshad Ahmed Khan M.Pharm , ( Ph.D ) Departmernt of Pharmaceutics RIPER.

2. The skin is very effective as a selective penetration barrier. The epidermis provides the major control element for drug penetration.

3. Mechanism of drug penetration through skin Three potential entry MACRO ROUTES to the viable tissue: Via the sweat ducts Across the continuous stratum corneum Through the hair follicles with their associated sebaceous glands.

4. MICRO ROUTES

5. Low molecular weight molecules penetrate through stratum conium to some extent. Skin appendages are main route for Electrolytes, polar steroids, antibiotics and colloidal particles. Particles of 3-10 µ penetrate through hair follicle and particles less than 3µ penetrate through stratum conium. Hair follicle route may be important for ions and large polar molecules. Topically applied agents such as steroids, hexachlorophane , griseofulvin , sodium fusidate and fusidic acid may form a depot or reservoir by binding within the stratum corneum .

6. Once drug permeates through horny layer it readily enters living tissue and systemic circulation. The average residence time of drug in dermis may be 1 min before it is washed away by blood. NSAIDS reach far down to muscles to form depots.

7. Factors influencing dermal penetration of drugs I. Biological factors: Skin condition Skin age Blood flow Regional skin site Skin metabolism Species difference. II. Physicochemical factors: Skin hydration Temperature and pH Diffusion coefficient Drug concentration Partition coefficient Molecular size and shape.

8. BIOLOGICAL FACTORS: 1. Skin condition The intact, healthy skin is a tough barrier but acids and alkalis injure barrier cells and thereby promote penetration. Mixtures of non-polar and polar solvents, such as chloroform and methanol, remove the lipid fraction and molecules pass more easily. Disease alters skin condition, skin inflamed, with loss of stratum corneum thus permeability increases. If organ thickened, with corns, calluses and warts, drug permeation decrease. 2. Skin age Skin of the young and the elderly is more permeable than adult tissue. Children are more susceptible to the toxic effects of drugs and chemicals, because of their greater surface area per unit body weight; thus potent topical steroids, Causes severe side-effects and death.

9. 3.Blood flow: An increased blood f;low could reduce the amount of time a penetrant remains in the dermis, and also raise the concentration gradient across the skin. In clinically hyperaemic disease damages the skin barrier and increase absorption. 4. Regional skin sites : Variations in permeability depend on the thickness and nature of the stratum corneum and the density of skin appendages. Absorption changes with substance, volunteer and site. Permeabilities depend on thickness of stratum corneum and the overall thickness of the tissue. Plantar and palmar callus may be 400-600 µm thick compared to 10-20 µm for other sites. The hyoscine Transderm system employs in postauricular skin (i.e. behind the ear) because the layers of stratum corneum are thinner Facial skin in general is more permeable than other body sites

10. 5. Skin metabolism: The skin metabolizes steroid hormones, chemical carcinogens and some drugs. This is advantage to prodrugs . Skin can metabolize 5% of topical drugs . 6. Species differences: Mice, rats and rabbits are used to assess percutaneous absorption, but their skins have more hair follicles than human skin and they lack sweat glands. Hairless mouse, monkey and pig skins are most like that of humans. Hairless rat and fuzzy guinea pig may be better models for humans. To obtain skin penetration data it is best to use human skin

11. Physicochemical factors 1. Skin hydration: When water saturates the skin the tissue swells, softens and wrinkles and hydration of the stratum corneum increases permeability. Dusting powders or lotions, provide a large surface area for evaporation and therefore dry the skin 2. Temperature and pH: The penetration rate of material through human skin can change tenfold for a large temperature variation. Occlusive vehicles increase skin temperature and increase permeability. According to pH-partition hypothesis, only unionized molecules pass readily across lipid membranes. Weak acids and bases dissociate to different degrees, depending on the pH and their PKa or Pkb values. Stratum corneum is resistant to alterations in pH, range of 3-9.

12. 3. Diffusion coefficient: The diffusional speed of a molecule depends mainly on the state of matter of the medium. In gases, diffusion coefficients are large than liquids In skin, the diffusivities reach their lowest values within the compacted stratum corneum matrix. The diffusion coefficient of a drug in a topical vehicle depends on the properties of the drug and the diffusion medium and on the interaction between them. 4. Drug concentration: Drug permeation and flux of solute is proportional to the concentration gradient across the barrier. drug permeation follows Fick's law, saturated donor solution gives maximum flux. pH change, complex formation, or the presence of surfactants, micelles or cosolvents modify the effective partition coefficient

13. 5. Partition coefficient(K): The partition coefficient is important in establishing the flux of a drug through the stratum corneum . Drug (K<1) are water soluble, (K>1) are oil soluble. Polar cosolvent mixtures, such as propylene glycol with water, produce saturated drug solutions and maximize the concentration gradient across the stratum corneum . Surfactants disruption of intercellular lipid packing in the stratum corneum , act as penetration Enhancers. Complex formation of drug increases the apparent partition coefficient may promote drug absorption. 6. Molecular size and shape: Absorption is apparently inversely related to molecular weight. Small molecules penetrate faster than large ones. It is more difficult to determine the effect of molecular shape, as it is related to partition coefficient.

14. Definitions: 1. OINTMENT: these are semi solid preparations meant for external application to the skin/ mucous membrane. 2. PASTE: these are semisolid preparations intended for external application to skin. 3. CREAM: these are viscous semisolid emulsions meant for external use. 4. GELS: these are semisolid dispersion systems which may contain suspension of either small /large organic molecules dispersed in a suitable liquid.

15. CLASSIFICATIONS Classification of ointments 1. Based on penetration Epidermic - Meant for action on epidermis Endodermic- Action on deeper layers of cutaneous tissue Diadermic - Meant for deep penetration 2. According to therapeutic uses Antibiotic Antifungal Antiinflammatory Antipruritic Astringent Keratolytic

16. Classification of Pastes: Fatty paste Aqueous gel paste Hydrocolloid paste Classification of Creams: Aqueous creams (O/W creams) anionic emulsifying agent cationic emulsifying agent non-ionic emulsifying agent 2. Oily creams (W/O creams) sterol creams soap creams Classification of Gels: Basing on use Medicated gels Lubricating gels Miscellaneous gels 2. Basing on nature of colloidal system Single phase system (organic gels) Two phase system (inorganic gels) 3. Basing on solvent nature Hydrogels Organogels

17. Excipients in semisolid dosage forms Ointment Paste Cream Gel Ointment base Paste base Penetration enhancer Gelling agent Preservatives Preservatives Oil/oleaginous substances Preservative Anti-oxidant Anti-oxidant Emulgents Hygroscopic substances Chelating agent perfume Co-emulsifiers Chelating agents. Humectant Emulsion stabilizers perfume Mixed emulsifier systems Humectants Stabilizers perfumes

18. Ointments DEF: these are semisolid preparations meant for external application to skin or mucous membrane. OINTMENT BASES: Selected after Toxity & Irritability test. It is one of the most important ingredient used in the formulation of semisolid dosage form Ointments and suppository base do not merely acts as the carrier of the medicaments, but they also control the extent of absorbtion of medicaments incorporated with them USFDA- list of ointment bases and their concentrations used.

19. Ideal properties of a base They should be: Compatible with skin pH and drug Inert ,non irritating and non sensitizing Good solvent and/or emulsifying agent Emollient , protective , non greasy and easily removable Release medicaments easily at the site of administration Pharmaceutical elegant and possess good stability.

20. Classification Of Bases

21. 1. Oleaginous ( hydrocarbon) bases: They consist of a combination of more than one oleaginous material such as water insoluble hydrophobic oils and fats Disadvantages: Greasy, sticky-non washable Retain body heat Do not increase absorption Prevent drainage on oozing area. They are anhydrous, do not absorb water & insoluble in water. Hydrocarbons: Paraffin wax, Soft paraffin, Liquid paraffin Vegetable oils and animal fats : Peanut oil, Coconut oil, Lanolin, Bees wax Hydrogenated & sulfated oils: Hydrogenated castor oil, Hydrogenated & sulfated castor oil. Acids, Alcohols & Esters: Stearic acid, Stearyl alcohol, Isopropyl Myristicate . Silicones: Dimethyl polysiloxanes

22. A) Soft paraffin (Petrolatum): This is purified mixture of semisolid hydrocarbons obtained from petroleum. Types Yellow soft paraffin – M.pt=38 C, used in ophthalmic ointments. White soft paraffin- M.pt=56 C, obtained from bleaching Yellow soft paraffin. B) Hard paraffin: purified mixture of solid hydrocarbons obtained from petroleum. USE - harden/soften ointment base c) Liquid paraffin (white mineral oil/ liquid petroleum): mixture of liquid hydrocarbons obtained from petroleum by distillation. USE - Combine with hard/ soft paraffin to harden/soften ointment base.

23. 2. Absorption ( Emulsifiable ) base: Qualities : Anhydrous Forms w/o emulsion Absorbs 50% water Due to the presence of sterol emulgent Easily removable by water Classification 1. Non-emulsified bases: Absorb water and aqueous solutions to produces w/o emulsions Eg . wool fat, wool alcohol, beeswax, cholesterol. 2. W/0 emulsions: Absorb more water than non-emulsified bases. Eg . Hydrous wool fat (lanolin)

24. 1. Wool fat (Anhydrous lanolin): This is fat from wool of sheep. Can absorb 50% water of its weight. USE: ointment base preparation, ophthalmic ointments. 2. Wool alcohol: Wool fat is alkalized to obtain cholesterol & alcohol. USE: Emulsifying agent in preparation of W/O emulsions. 3. Bees wax: Wax from honey comb of bees. 2 types- yellow & white bees wax USE: stiffening agent in paste & ointments. 4. Hydrous wool fat: Purified fat from wool of sheep. Insoluble in water, soluble in ether, chloroform. Contains 70% wool fat+ 30% water. USE: Emollient.

25. Advantages of Absorption bases Compatible with most of the medicaments Absorb large quantity of water or aqueous substances Relatively heat stable Easily spreadable Less occlusive and good emollients Aqueous substances can be incorporated Disadvantages Undesirable due to greasy nature Chances of microbial contamination.

26. 3. Emulsion bases: Ability to absorb water, serum discharges and forms o/w and w/o emulsions. According to the type of emulsion these bases are classified as either W/O or O/W. W/O- greasy, sticky. Ex: Sulfur & zinc ointments O/W- easily removed from skin. Ex: vanishing cream. Emulsifying ointment: Anionic, cationic or non-ionic Emulsifying wax 30% White soft paraffin 50% Liquid paraffin 20% *When applied on skin leaves behind a layer of fat.

27. Advantages Of Emulsion bases Miscible with exudates from lesions Does not interfere with skin function Good contact with skin because of surfactant content High cosmetic acceptability. Easy removable from the hair. Disadvantages of Emulsion bases W/o emulsion greasy and sticky Its acceptance is less Difficult to remove from body and clothing.

28. 4. Water soluble Bases: ( Grease less Base ) 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) For low viscosity - Glycerin, Glyceryl mono stearate .

29. Carbo waxes ( Macrogols / Polyethylene glycols) General formula CH 2 OH. (CH 2 OCH 2 )n . CH 2 OH These are mixtures of polycondensation products of ethylene oxide and water Average Molecular weight is represented by numbers Macrogols 200, 300, 400 -- viscous liquids Macrogol 1500 -- greasy semi solid Macrogols 1540, 3000,4000, 6000 -- waxy solids Liquids Clear and colourless Faint characterisitic odour Miscible with water, alcohol and other glycols

30. Solids White or cream in colour Hard lumps or flakes Soluble 1 in 3 in water and 1 in 2 in alcohol Solidifying points range from 40 to 60°c Macrogols Properties: Non-toxic and non-irritating pH – 4 to 7.5 Can be sterilised by heat (solids – dry heat, liquids – autoclave) water soluble, non-volatile and inert substances. Different carbowax mixture produces different consistency.

31. Paste base: 1. Hydrocarbon bases:-- soft paraffin , liquid paraffin. 2. Water miscible bases:-- glycerin, emulsifying ointment. 3. Water soluble bases:-- poly ethylene glycols. Chelating agent: Heavy metals cause degradation of gel bases and medicament. Chelating agents form complex with heavy metals and prevent degradation. Ex: EDTA Humectant : To maintain humidity in the preparation and to prevent drying. Ex: glucerin , sorbitan . Hygroscopic substances: These prevent quick loss of water due to evaporation in gels and prevents drying, flake formation. Ex: glycerol, propylene glycol

32. Gelling agents These are organic hydrocolloids/ hydrophilic inorganic substances. Natural gelling agents– gum tragacanth , starch, pectin, gelatin, clays, cellulose derivatives, etc., Synthetic gelling agents– sodium alginate, carbomer , poly vinyl alcohol, etc., CLAYS: 7-20% bentonite is used as dermatological base. 10% aluminium magnesium silicate is used in medicated gels. Gels are not clear and form powdery residue on skin.

33. 1.Tragacanth : Used for preparations of Lubricating, Medicated & Contraceptive Jellies. Concentrations used for Lubricating (2 to 3%) & Dermatological vehicle (5%). Tragacanth is poorly wettable On addition to water lumps are formed which is difficult to disperse Dispersing agent is generally used to get a homogenous product Alcohol, glycerol or volatile liquids are used as dispersing agent

34. Disadvantages : Obtained from natural sources, so vary in viscosity After evaporation, the film left on the skin tends to flake Loss viscosity outside the pH range of 4.5 – 7 Can’t be stored for longer time Prone to microbial growth

35. 2 . Pectin : Good gelling agent suitable for acid products Used in many preparations including edible Jellies Glycerine is used as dispersing agent & humectant Pectin jelly is good medium for bacterial growth, add preservative Storage: Well closed container to prevent loss of moisture by evaporation

36. 3 . Starch : Used in combination with other Jelling agent Provides a water soluble dermatological base Starch + Gelatin + Glycerin jelly product is still used Glycerin (up to 50%) may be added which acts as preservative and humectant Note: Must be freshly prepared Well closed container to prevent loss of moisture by evaporation

37. 4 . Gelatin : Insoluble in cold water (swells and soften) Soluble in hot water 2% gelatin forms jelly on cooling Stiff medicated Jellies can be prepared (15%) Melted before use and after cooling to desired temperature, applied with a brush. Affected area covered with bandage and left in place for several weeks Suitable preservative is required

38. 5 . Cellulose derivatives : Produce neutral jellies of very stable viscosity Afford good resistance against microbial growth High clarity & produce a soft film after drying Sodium CMC Used for preparation of lubricating & sterile jellies Withstand autoclaving temperature without deterioration Example Methyl cellulose - 3% Sodium carboxy methyl cellulose 1.5 - 5% - lubricant gels, 5% - Dermatological gels

39. 6 . Sodium aliginate : 1.5 to 2% Used as Lubricant gel & Dermatological vehicle 5 To 10% Viscosity can be increased by adding soluble calcium salt Salting out is observed with high conc. 2-4% alcohol, glycerine , propylene glycol are used as dispersing agent Advantages over tragacanth Available in several grades of standard viscosity

40. 7. Carbomer : 0.3-1% in lubricating gels & 0.5-5% as dermatological vehicle. These have high gelling efficiency and used in low concentrations. 8. Poly vinyl alcohol (PVA): PVA gels provide protection as they dry quickly to form a strong residual film on skin. These are available in various grades and viscosities.

41. Methods of Preparation of Ointments & Creams Trituration Fusion Chemical reaction Emulsification Methods of Preparation of Pastes Trituration Fusion Method of Preparation of Gels General method

42. Trituration Method Widely used method For extemporaneous preparation of ointments. When the base is soft and medicament is solid insoluble Small amount of liquid to incorporated in the base Advantage Involves mixing as well as size reduction Procedure: Reduce the solid medicament to fine powder Medicament is mixed with small amount of base on ointment slab with a stainless steel spatula until a homogeneous product is formed.

43. 3. Add remaining quantities of base with uniform mixing 4. Incorporate any liquid ingredient if present (mortar and pestle to be used in case of large quantity of liquid) Eg : Prepare and dispense 100 g of sulphur ointment R x Sublimed sulphur , finely sifted - 10 g Simple ointment - 90g Prepare an ointment Direction - Apply the ointment to the affected area as directed.

44. 2. Fusion method: Suitable when ointment base contains number of solid ingredients of different melting points. Procedure: Ointment base are melted in decreasing order of their melting point. Highest melting point should be melted first, low melting point next. This avoids over heating of substances of low melting point Incorporate medicament slowly to the melted mass Stir thoroughly until mass cools down and homogeneous product is formed.

45. 6. Liquid ingredients or aqueous substance should be heated to the same temperature as the melted bases before addition. 7. If not, wax or solids will cool down quickly and get separated Precautions: Strring is done continously - homogeneous mass Vigorous stirring should be avoided to prevent entrapment of air Rapid cooling should be avoided to get a uniform product. To remove the dust or foreign particles strain through muslin cloth

46. Eg : Prepare and dispense 100 g of Citrimide ointment R x Cetrimide - 1 g Cetostearyl alcohol – 10 g White soft paraffin – 10 g Liquid paraffin – 29 g Pure water – 50 g Procedure: Melt ointment bases in decreasing order of M.Pt . Dissolve cetrimide in water and heat the solution Mix cetrimide solution to hot molten mass and stir.

47. 3. Chemical reaction method Preparation of some ointment involves chemical reactions Eg – (a)Iodine ointment (iodine free form) (b)Iodine ointment (iodine combined form with ointment base) (a)Ointments containing free iodine Iodine is slightly soluble in fats and vegetable oils. Readily soluble is potassium iodide solution in water due to formation of polyiodides (KI. I 2 , KI. 2I 2 , KI.3I 2 ) Poly iodides are readily soluble in water, alcohol and glycerin. These solutions may be incorporated with the molten absorption type ointment base.

48. (b) Ointments containing combined iodine Fixed oils and many fats obtained from vegetable and animal sources contain unsaturated constituents Iodine combines with double bonds CH 3 (CH 2 ) 7 CH=CH (CH 2 ) 7 COOH + I 2 (Oleic acid) CH 3 (CH 2 ) 7 CHI.CHI (CH 2 ) 7 COOH (Di- iodo stearic acid) Free iodine is not available, So ointments appear dark, greenish black in colour Leaves no stain when rubbed into the skin, Hence known as non-staining iodine ointment

49. 4. Emulsification method Facts, oils and waxes an melted together to a temperature and 70 c. Aqueous solution of the heat stable, water soluble compounds is also heated to the same temperature. Aqueous Solution is slowly added to the melted bases, with continuous stirring until cool. Emulsifying agent is needed to make a stable emulsion Water soluble soaps are commonly used as emulsifier for semisolid o/w emulsions. Combination of triethanolamine stearate soap and cetyl alcohol is used in o/w emulsion Bees wax and divalent calcium ions used in w/o emulsion.

50. Laboratory Scale: Ointment slab & spatula Motor & pestle Electric motor & pestle

51. Industrial Scale: Ointment mill, Triple roller mill, Hobart type mixer

52. Types of gels Based on its application classified into Medicated, (2) Lubricating, (3) miscellaneous gels 1. Medicated gels: Used on mucous membrane/ skin Actions-Lubrication, antiseptic, Vasoconstrictor, Contraceptive. Mechanism: Evaporation of water Produces a cooling sensation to skin Contents remaining stick as film to the applied area gives protection Ex: Ephedrine sulphate Jelly- Vasoconstrictor Phenyl mercuric Nitrate- Contraceptive (spermicidal)

53. 2.Lubricating gels: Properties: Should be thin, transparent & water soluble. Must be sterile when inserted into sterile regions of the body. Used for lubrication in: Rectal Thermometers Urinary Bladders Fingerstalls Cystoscopes Surgical gloves Catheters

54. 3.Miscellaneous gels: Patch testing Used as vehicle for allergens applied on skin in allergy test Electrocardiography Jellies contain Nacl , pumice powder & glycerin. To reduce electrical resistance between skin and electrode

55. Preparation of Gels: Usually prepared by adding thickening agent ex:Tragacanth,Carboxymethyl cellulose Thickening agent is added to aqueous solution in which drug has to be dissolved Mass is triturated in a mortar until a smooth product is obtained When coloured drug to be incorporated glass mortar is used Whole gum is preferred to powdered gum to get clear preparation of uniform consistency

56. Example: R x Icthammol -20g Tragacanth -5g Alcohol (90%) -10g Glycerine -2g Water - qs 100g Send 100g Icthammol jelly Procedure: Tragacanth + alcohol  motor  mucilage. Icthammol + glycerine + water Drug solution Drug solution + mucilage triturate Add water qs 100g Transfer into container, label & dispense.

57. Evaluations of ointment and creams: Drug content Release rate of medicament from base Penetration rate of medicament Absorption of medicament into blood stream Consistency of the preparation Irritant effect

58. 1. Drug content:-- Minimum fill test Select any 10 filled containers Weigh the required amount of ointment Medicament is extracted in a suitable solvent Drug Content is determined by suitable analytical technique Results should be with in labeled quantity. 2. Release rate of medicament from base:-- Two in vitro techniques are used Agar cup plate method Diffusion method

59. Agar cup Plate method Used to determine the release rate of antibacterial ointment Tested in agar medium seeded with staphylococus aures . Zone of inhibition of bacterial growth is measured around circular cups

60. Diffusion method: Used to find the release rate of any type of medicament from the base A parchment membrane is tied at one end of glass tube Ointment is filled in the tube, properly spread on the membrane Tube is dipped in the distilled water maintained at 37±1 O C Samples are withdrawn after a specified period of time. Samples are immediately replaced with fresh distilled water Analyzed for the drug content Plot a graph between drug concentration and time

61. 3. Penetration rate of medicament: Determined by rubbing weighed amount into defined areas for a fixed time Unabsorbed material is removed completely and weighed Difference in weight provides total base penetrated Rate is then calculated 4. Absorption of medicament into blood stream: Diadermic ointments are tested by in-vivo method. Determined by assaying drug content in either blood, urine, faeces or tissues after rubbing defined amount under standard conditions

62. 5. Consistency of the preparation: Determined by sliding a glass plate over the product by means of a pulley. Product is spread evenly on another glass plate fixed on a wooden block Weights are added to the pan so that sliding of the movable glass plate is obtained Ointment which require more weights to allow the plate to slide-over have high consistency or vice-versa

63. 6. Irritant effect:-- Test is performed on skin and eyes of rabbit or human skin Ointment is injected in to thigh muscles and under abdonimal skin in rats. Results are observed daily for a week Irritant effect of dermatological preparation is shown as lesions on cornea, iris and conjunctiva Evaluation of gels Rheological properties Determination of yield value Spreadability Stability test Safety evaluations.

64. 1. Rheological properties: Gels exhibit non- newtonian rheological behaviour and thixotropy (gel ↔sol). Brook field viscometer is used for determination. 2. Determination of yield value: Penetrometer is used to measure force required to exudate the gel form collapsible tube. 3.Spreadability: This is related to rheological property of gel, tested using slides. 4. Stability test: Gel stability at various temperatures is tested for shipping. 5. Safety evaluations: Safety is determined by evaluating physical properties of raw materials.

65. Evaluation of pastes: Evaluation of heat stability Determination of viscosity Compatibility with container Determination of safety of product Teat for sensitization Determination of particle size Determination of gelation behavior.

66. THANK YOU…….