Liquid dosage form- Monophasic & Biphasic liquids

suspension

1. Liquid dosage form The active ingredients may be dissolved in aqueous media, an organic solvent, or a combination of the two, by suspending the drug (if it is insoluble) in an appropriate medium or by incorporating the active pharmaceutical ingredient into one of the phases of an oil and water emulsion. Such solutions, suspensions, and emulsions are further defined in subsequent paragraphs, but some, with similar properties and applications.

2. Advantage The major advantage of the liquid dosage method is that it is better for patients who have difficulty swallowing solid medicines because it is easier to swallow than solid dosage forms. Liquid dosage forms have faster absorption than solid dosage forms. It is suitable for use patients with infants, geriatric, and mental health problems. Doses may vary from per tablespoon to milliliter, which is difficult in solid dosage forms. Liquid dosage forms are absorbed faster than solid dosage forms because APIs are already dissolved. This may provide greater flexibility in achieving the appropriate dose of the drug. It can be designed for any route of administration. It is the best choice for children and old people. This can be attractive by container and color. Flavors (sweetening agents/sugar) can be added to mask the bitter or unpleasant taste and odor.

3. Disadvantage The major disadvantage of the liquid dosage form is that, is less stable than other doses and has a shorter shelf life which is due to the nature of being in a liquid. The liquid dosage form is more susceptible to bacterial microorganisms than tablets and capsules. Some drugs are poorly soluble hence difficult to formulate. It is bulky so it is difficult to handle , transport and store . It requires special storage conditions because it is less stable. Its manufacturing process is complex, so the production cost is high. It is easily affected by temperature, light, and microorganisms. Each time of dose needs to be measured, so the accuracy of the dose may vary each time. A loss can occur as the container breaks and falls . Difficult to mask the unpleasant taste or odor compared to tablets and capsules.

4. CLASSIFICATION

5. EXCIPIENTS

6. HLB Scale (Hydrophilic - Lipophilic Balance)

7. Monophasic dosage form refers to liquid preparation containing two or more components in one phase system , it is represent by true solution. A true solution is a clear homogenous mixture that is prepared by dissolving solute in a suitable solvent.

8. Pharmaceutical Syrup The syrup is a saturated or concentrated, viscous aqueous solution of sucrose/sugar substitute with or without flavor/medicinal substances in  purified water . Composition   of   Syrup Most syrups contain the following components in addition to the purified water and drugs: (a) Sugar, or other sugar substitutes are used to provide sweetness and viscosity, (Sugar-free alternative- Sorbitol , Saccharine, Aspartame) (b) Antimicrobial preservatives, (c) flavorings & coloring agents, (d) Syrups may also contain solubilizing agents, thickeners, or stabilizers.

9. Advantages of Syrup Retard oxidation because it partly hydrolyzed into dextrose & levulose (reducing sugary ) – So prevent decomposition of many substances – No preservative needed. Exert high osmotic pressure prevents the growth of MOs (Bacteria, Fungi, molds etc) Palatable sweet a vehicle for bitter / Nouseous substances.

10. TYPE OF SYRUP

11. Method of Preparation For Syrup 1. Hot Process: This method is used when active constituents are neither volatile nor heat-labile. Procedure: Weighed sucrose is taken in a beaker. Purified water is added. Heated on a water bath (less than 70°C) till a solution is obtained. The product is filtered. Volume is made upto q.s . Excessive heat may lead to the inversion of sucrose. 2. Percolation: Sucrose is placed in percolator. Water is passed through sucrose slowly. The neck of the percolator is packed with cotton. The rate of percolation regulates the rate of dissolution. After complete dissolution, the final volume is made up to q.s .

12. 3. Agitation Without Heat: Procedure for heat-labile constituents Sucrose and other ingredients are weighed properly. Dissolved in purified water. Kept in a bottle of about twice the volume of syrup followed by continuous agitation. Prepared syrup volume is made up to q.s . 4. Addition of Medicating or Flavouring Liquid to Syrup: This method is used when fluid extracts, tinctures, or other liquids are to be added to syrup. Alcohol is added to dissolve the resinous or oily substances. Alcohol acts as a preservative also.

13. Syrup Vehicle :  Syrups are prepared by using purified water . Adjuncts :  The following adjuncts are generally added to improve the formulation of syrup. Chemical Stabilizer:  Glycerin, sorbitol , propylene glycol is added in small quantity to syrup to prevent the crystallization. Colouring agent:  Many syrups are attractively coloured with coal tar dyes such as amaranth, compound tartrazine and Green S. Flavouring agents: ( i ) Tinctures: Lemon and ginger tincture (ii) Fruit juice: Cherry, Raspberry (iii) Essence: Vanilla, orange Preservatives: Use sterilized and closures container for prevent contamination. Benzoyl acid, sodium bentonite , methy paraben . Storage : store at room temperature Label : Shake well before use

14. Gargles Gargles are aqueous solutions frequently containing antiseptics, antibiotics, and anesthetics used in the mouth and throat. It is dispensed in conc. Forms with directions for dilution with warm water before use. It is highly medicament than mouth wash. Pleasant flavor 5.0-9.5 pH to be safe. Relieved soreness of throat infection Containers: Fluted glass bottles with plastic screw cap; Label : External Use only; Dilute before use Example : phenol gargle , thymol glycerin compound.

15. Mouth wash Mouth wash are Aqueous Solution with a pleasant taste & odor used to make clean & deodorize the buccal cavity. It Contain sweetening, antibacterial flavoring agent, alcohol & coloring agents, glycerin, surfactant, sweeteners. Container : Mouth wash are dispensed in  white   fluted  bottles Direction : Two teaspoonful to be diluted in a glass of water before use. Example Antisceptic : Listerine  or phenolic  mouthwash Analgesic: lidocaine hydrochloride Anticavity : Floride rinse

16. Throat Paint Viscous liquid preparation used for mouth & throat infection. Base- Glycerin (most commonly used)- provide adheres to mucous membrane for a longer period. They may be aqueous or alcoholic solutions. Supplied in  Fluted  bottle to distinguish from preparation used for internal use. Storage : airtight containers in a cool place Example Compound Iodine Paint : used for pharyngitis or tonsillitis. Iodine throat paint is designed to kill germs. It can be used on sore throats and ulcers to ease them Crystal Violet Paint  – used for thrush. Tannic acid Glycerin , has astringent action, relieve from sore throat.

17. Ear drops These are solutions that are instilled into the ear with a dropper. Drops are Prepared in water, glycerine , propylene glycol & dilute alcohol as vehicles. Ear drops are used for Cleaning the , Softening the wax,Treating the infection, antiseptic- anaesthetic . Containers = colored fluted glass bottle with a dropper in the cap or suitable plastic container. Example : chloramphenicol ear drops Phenol ear drops Spirit ear drops Sodium bicarbonate ear drops

18. Nasal drops These are  isotonic solution  that are installed into the nose with a dropper. Nasal drops should: Isotonic with 0.9% NaCl Neutral pH 5.5-7.5 – (phosphate buffer of pH 6.5 as a vehicle) Viscosity similar to nasal secretion by using 0.5% methylcellulose. Preparation must not interfere with the cleansing action of epithelial cilia of the nasal mucosa. Dispensed in–colored fluted bottles filter with a dropper plastic container. CONTAINER: fluted colored glass bottel with plastic screw cap and dropper. LABEL: External Use only , stored in a cool place

19. Liniment and lotion Liniment Also known as  embrocains Liquid or semisolid preparation Meant for application to skin  with friction & Rubbing of the skin May contain alcohol or oily solution or emulsion Liniment should  not be applied to broken skin or broken skin Liniment should be dispersed in  colored fluted  Bottles in order to distinguish it from preparation meant for internal use Label – External Use only; shake well before use & not to be applied to open wound and broken skin. Higher viscosity than lotion Example: Terpintine liniment Lotion Also known as Moisturizer , or emollient a thick, smooth liquid preparation for medicinal or cosmetic purposes. Meant for external application  without friction  with the help of absorbent material like cotton wool or gauze soaked in it. It should be applied to broken skin Used  for local action cooling, soothing, protective, antiseptic Dispensed in  Fluted bottles   in order to distinguish it from preparation meant for internal use Label: External Use only; shake well before use Lower viscosity than liniments Example: Bentonite lotion, Calamine lotion

20. Suspension A Pharmaceutical suspension is a coarse dispersion in which internal phase (API) is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a range of size(0.5 to 5 microns) which is maintained uniformly through out the suspending vehicle with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use. Suspensons are widely used for – Oral route External use Ophthalmic use Lotions and washes Eye drops I.M. injections Parenteral use

21. The reasons for the formulation of a pharmaceutical suspension: when the drug is insoluble in the delivery vehicle. To mask the bitter taste of the drug. To increase drug stability. To achieve controlled/sustained drug release. SOME PHARMACEUTICAL SUSPENSIONS Antacid oral suspensions Antibacterial oral suspension Dry powders for oral suspension (antibiotic) Analgesic oral suspension Anthelmentic oral suspension Anticonvulsant oral suspension Antifungal oral suspension

22. Advantage Pharmaceutical suspensions may be formulated to mask the unpleasant odor / taste of drug. E.g. Chloramphenicol. Suspensions may serve as an alternative means used to administer drugs to children including paediatric and geriatric patients and older patients who have difficulty swallowing solid dosage forms.  Drug in suspension exhibits higher rate of bioavailability than other dosage forms. Bioavailability is in following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet. It may be formulated to provide controlled drug delivery, e.g. as intramuscular injections.

23. Chemical stability of certain drugs e.g., Procaine penicillin G can be improved when formulated as suspensions. Pharmaceutical suspension offers resistance to degradation of drugs due to hydrolysis, oxidation or microbial activity. Duration and onset of action can be controlled e.g., Protamine Zinc-Insulin suspension. When compared to solution dosage forms, relatively higher concentration of drugs can be incorporated into suspension products.

24. Suspension is the only choice if the drug is not soluble in water and non-aqueous solvent is not acceptable, e.g., corticosteroids suspension.

25. Disadvantage Accuracy of dosage is less reliable than with solution unless suspension is packed in unit dosage form. Suspension formulations may be bulky and therefore difficult for a patient to carry. Preparation must be shaken prior to measuring a dose. Pourability and syringeability issues (e.g., injectable suspensions) Crystal formation (Ostwald ripening) and breaking of suspension. Sedimentation of solids occasionally gives poor form of product. It may lead to caking (formation of compact mass), which is difficult to dispense.

26. CLASSIFICATION Classified into 4 main class: Oral suspension : Paracetamol suspension antacids, cefixime , cefpodoxime , sucralfate , Tetracycline HCl Parenteral suspension : Procaine penicillin G, Insulin Zinc Suspension Ophthalmic suspension : Fluorometholone drops, Natamycin , Ciprofloxacin Suspension For external use : Topical formulations(antifungal), calamine lotion

27. Flocculated and non flocculated suspensions When individual particles are in contact with each other and form a network like structure is called as flocculated suspension . When the individual particles exists as separate entity is called as deflocculated suspension .

28. Flocculated Sedimentation rate is fast Particles are loosely packed Inelegant Clear supernant High sediment volume Particle size attractive force Bioavailability is less Rheology plastic and pseudoplastic Redispersibility easy Deflocculated Sedimentation rate is low Particles are very closely packed Good appearance Cloudy supernant Low sediment volume Particle size repulsive force Bioavailability is high Rheology dialent Redispersibility difficult Comparison

29. API Therapeutic active substance Wetting agents The concentration used is less than 0.5 %. Added to disperse solids in the continuous phase. Decrease interfacial tension between solid particles and liquid mediums. E.g. Alcohol in tragacanth mucilage, Glycerin in sodium alginate.  Flocculating agents (Surfactant & Polymer) . To floc the drug particles. They lead to a decrease in repulsion potential and make particles come together to form loosely arranged floccules. Act by reducing the surface tension. E.g. SLS, Tweens , Span, Carbowax Thickened & Suspending agents Impart viscosity of the suspension a. Polysaccharide=> Natural- Acacia, Starch, Talc ; Synthetic- MC, b. HPMC b. Inorganic agents=> Clay, AI(OH) 3 c. Synthetic => Carbomer , Collodial SiO 2 Buffer/ pH adjusting To stabilize the suspension at the desired pH range Formulation of suspensions

30. Osmotic agent To adjust osmotic pressure (Specially Parenteral preparation) Organoleptic additive To impart desire color to improve elegance Coloring agent, sweetening agent, Flavoring agents Preservative To prevent Microorganism growth Benzoic acid,  Methylparaben , Benzoic acid, Sodium benzoate Protective Colloids They are absorbed on insoluble particles and increase the strength of the hydration layer formed around suspended particles through hydrogen bonding and molecular interaction. E.g - Gelatin, natural gum and cellulosic derivatives.  

31. List of Suspending Agents Alginates Methylcellulose Hydroxyethylcellulose Carboxymethylcellulose Sodium Carboxymethylcellulose Microcrystalline cellulose Acacia Tragacanth Xantham gum Bentonite Carbomer Carrageen Powdered cellulose Gelatin

32. Evaluation of Suspensions Sedimentation method Rheological method Electro kinetic method Micromeritic method

33. Sedimentation method It is most important parameter in the evaluation of the stability of suspension. Sedimentation volume was calculated according to the equation: F = Vu/Vo Where, F = sedimentation volume, Vu = ultimate height of sediment Vo = initial height of total suspension

34. Rheological method It provide information about Settling behaviour . The arrangement of the vehicle and the particle structural features. Brookfield viscometer is used to study the viscosity of the suspension Electro kinetic method Measurement of Zeta-potential using Micro electrophoresis apparatus & ZetaPlus It shows the stability of a disperse system

35. Micromeritic method : The stability of suspension depends on the particle size of the dispersed phase. Visual Inspection: With Visual Inspection, the ingredients and the final products are carefully examined for purity and for appearance . Physical appearance of products for patient adherence and compliance is critical so it should be: Good looking Elegance in appearance .

36. Application of Suspension in Pharmaceutics Suspension is usually applicable for drug which is insoluble (or ) poorly soluble; E.g. Prednisolone suspension To prevent degradation of drug or to improve stability of drug; E.g. Oxy tetracycline suspension To mask the taste of bitter of unpleasant drug.E.g . Chloramphenicol palmitate suspension Suspension of drug can be formulated for topical application. e.g. Calamine lotion Suspension can be formulated for parentral application in order to control rate of drug absorption.E.g . penicillin procaine Vaccines as a immunizing agent are often formulated as suspension.E.g . Cholera vaccine X-ray contrast agent are also formulated as suspension. eg : Barium sulphate for examination of alimentary tract

37. EMULSIONS

38. EMULSIONS Emulsion is a thermodynamically unstable two-phase system consisting of at least two immiscible liquids, one of which is dispersed in the form of small droplets throughout the other, and an emulsifying agent. The dispersed liquid is known as the  internal or discontinuous phase the dispersion meadium is known as the  external or continuous phase . Emulsions are used in many routes of administration. Oral administration can be used, but patients generally object to the oily feel of emulsions in the mouth. But some times, emulsions are the formulation of choice to mask the taste of a very bitter drug

39. emulsions are used for topical administration. Topical emulsions are  creams  which have emollient properties. They can be either o/w or w/o and are generally opaque, thick liquids or soft solids. Emulsions are also the  bases used in lotions , as are suspensions. The term "lotion" is not an official term, but is most often used to describe fluid liquids intended for topical use. Lotions have a lubricating effect. They are intended to be used in areas where the skin rubs against itself such as between the fingers, thighs, and under the arms. Emulsions are also used  a ointment bases  and intravenously administered as  part of parenteral nutrition therapy. Examples of emulsions:  Milk (fat in water), Butter (water in oil), Liquid paraffin (paraffin in water), etc.

40. Uses of Emulsion: Pharmaceutical Application:  Due to the high bioavailability and absorption rate, it used in the pharmaceutical industry. Mostly it used for topical preparations like creams, lotions, etc. Cosmetic industry:  There is a huge application of emulsion in the cosmetic industry. Example: creams, lotions, hair conditioners, etc. Food industry:  Food products like milk, peanut butter, ice cream, etc. are some examples of emulsion. So you can easily understand the application of emulsion in this industry. Paint industry:  Examples like emulsion paints and inks. Fire extinguisher:   Thixotropic high internal phase ratio emulsion  is non-flammable. So used as a fire extinguisher.

41. Advantages of Emulsion: 1.Cover up the unpleasant taste. 2.Increase the bioavailability of the dose. 3.Sustained release medication. 4.Very cost-effective Disadvantages of Emulsion: 1.Problem of creaming and sedimentation 2.Phase inversion 3.problem of handling

42. TYPE OF EMULSION

43.   Oil in Water Emulsion (O/W) Oil is the dispersed phase and water is the dispersion medium. They are nongreasy and easily washed from the skin surface. They are used externally to provide a cooling effect, for example, vanishing cream.  Water-soluble drugs are more quickly released from O/W emulsions. They are preferred for oral formulations as the taste of oils can be masked. O/W emulsions give a positive conductivity test since the external phase is water, which is a good conductor of electricity. Water in Oil Emulsion (W/O)  Water is the dispersed phase and oil is the dispersion medium. They are greasy and not easily washed by water. They are used externally to prevent evaporation of moisture from the surface of the skin, for example, cold cream Oil-soluble drugs are more quickly released from W/O emulsions They are preferred for topical preparations such as creams. W/O emulsions do not give a positive conductivity test since the external phase is oil, which is a poor conductor of electricity.

44. Classification of Emulsifying Agent: 1. Natural emulsifying agents : Vegetable sources-  Agar, Tragacanth , Gum acacia, etc. Animal sources-  Wool fat, Gelatin, etc. 2. Semi-synthetic emulsifying agents :  Methylcellulose, Sodium CMC, etc. 3. Synthetic emulsifying agents: Anionic emulsifying agents:  Sodium lauryl sulfate(SLS) Cationic emulsifying agents:   Benzalkonium Chloride Non-ionic emulsifying agents:  Glyceryl ester 4. Inorganic emulsifying agents:   Milk of magnesia Magnesium oxide Bentonite Magnesium trisilicate 5. Alcohols : Lecithins Cholesterol ( cetyl alcohol, stearyl alcohol) Carbowaxes

45. Formulation or Preparation of Emulsion 1. Trituration Method: ( i ) Dry Gum Method (ii) Wet Gum Method 2. Bottle or Forbes Bottle Method 3. Auxiliary Method 4. Nascent Method or In Situ Soup Method 5. Beaker Method

46. Emulsion testing parameters and methods: Identification of type of emulsion: Dilution test:  This test is important to know the solubility of the continuous phase of the emulsion.   For example - In O/W emulsion, a dilution test is done to know it's diluted with water or not. Conductivity Test:  This test is important to know, which is a good conductor of electricity to find out the continuous phase.  For example - In O/W emulsion, water is a continuous phase. Because water is a good conductor of electricity than oil.

47. Dye-Solubility Test:  This test is done by mixing the emulsion with water or an oil-soluble dye, and checked under a microscope to know which is in a continuous phase or dispersed phase. Fluorescence test:  Oils have the property of fluorescence under UV light, while water doesn’t. Therefore, O/W emulsion shows a spotty pattern while W/O emulsion fluoresces.

48. Evaluation of emulsion Determination of particle size and particle count: Determination of changes in the average particle size or the size distribution of droplets is an important parameter used for the evaluation of emulsions. It is performed by optical microscopy, sedimentation by using Andreasen apparatus and Coulter counter apparatus. 2. Determination of viscosity: Determination of viscosity is done to assess the changes that might take place during aging. Emulsions exhibit non- newtonian type of flow characterstics . The viscometers which should be used include cone and plate viscometers

49. 3. Determination of phase separation : This is another parameter used for assessing the stability of the formulation. Phase separation may be observed visually or by measuring the volume of the separated phases. 4. Determination of electrophoretic properties: Determination of electrophoretic properties like zeta potential is useful for assessing flocculation since electrical charges on particles influence the rate of flocculation. O/W emulsion having a fine particle size will exhibit low resistance but if the particle size increase, then it indicates a sign of oil droplet aggregation and instability.

50. Appearance p. H Viscosity Specific gravity Microbial count Leakage test for filled bottle Check the cap sealing Fill volume determination Particulate matter testing Stress test

51. SUSPENSION It is heterogeneous mixture There are two types: Flocculated Non flocculated Dispersed particle settle on standing Particle size < 1000 nm Particles are not visible through the naked eye Dispersed in solid, liquid, gas Emulsifying agent are required It cannot be separate by filtration Freezing should be avoided during as it leads to cracking There are no test to identify the type of suspension EMULSION It is heterogeneous of two immiscible liquids mixture There are two types: o/w w/o Dispersed particle do not settle on standing Globule size > 1000 nm Particles are visible through the naked eye Dispersed in liquid Suspending agent are required It can be separate by filtration Freezing should be avoided during as it leads to aggregation There are several tests to confirm the type of emulsion