PHD211 Semi-solid Dosage Forms: Creams PDF

PHD211 Semi-solid dosage forms Creams By: Dr. Wong Yuet Yen Faculty of Pharmacy UiTM Cawangan Pulau Pinang, Bertam Campus...

PHD211 Semi-solid dosage forms Creams By: Dr. Wong Yuet Yen Faculty of Pharmacy UiTM Cawangan Pulau Pinang, Bertam Campus [email protected] 1  1 Getting to know creams o Definition 3 Creams in practice o Characteristics o Dispensing creams o Types and uses Packaging o Formulation Storage Beyond-use-date Labelling 2 o Cream instabilities o Cream dilution Compounding creams o Terminologies o General principles o Incorporating solids or liquids into cream bases 2  Learning Outcomes To describe the characteristics, uses and formulation of creams. To distinguish between o/w and w/o creams. To apply essential principles in the compounding and dispensing of creams. To describe the common cream instabilities. 1 Getting to know creams o Definition o Characteristics o Types and uses o Formulations 4  Creams Creams are formulated to provide preparations that are essentially miscible with the skin secretion. They are intended to be applied to the skin or certain mucous membranes for protective, therapeutic or prophylactic purposes, especially where an occlusive effect is not necessary. British Pharmacopoeia (BP) 5 Uses of creams To protect skin or mucous membrane from chemical or physical irritants in the environment. To provide hydration of the skin or emollient effect. To provide a vehicle for applying a medication for local or systemic effect. 6  Creams vs. Emulsions  Similar disperse system Consist of 2 immiscible Thermodynamically unstable → liquids, one of which is emulsifying agent is required to distributed through the other maintain even distribution + emulsifying agent Photomicrograph 7   Types of bases are similar Oil-in-water (o/w) Water-in-oil (w/o) Internal (disperse) phase Water as disperse phase Oil as disperse phase Emulsifying agent Water as continuous phase Oil as continuous phase External (continuous) phase 8   Differ in terms of rheological properties Rheology = the study of the flow and deformation properties of matter Cream Emulsion Pourable Pseudoplastic system Less viscous than cream Greater consistency than emulsion 9  In pharmacy practice, dosage form for Emulsion internal use (both oral & parenteral) Lotion fluid emulsions or suspensions often be prepared from diluting the o/w cream with water or an aromatic water such as rose water. for external use this also dilutes preservative →  beyond-use date Cream 10  Key Features of Creams Viscous semisolid emulsions For external use only Medicaments Emulsified preparations can be dissolved which contain water; or suspended in hence, susceptible to either the o/w or microbial growth w/o cream base 11  Creams Advantages Disadvantage Promotes prolonged contact Less hydrophobic, hence at the site of the application higher risk of contamination Non-sticky and easily washable Non-irritating on application to the skin Dry the injured area more quickly than ointment 12  Types of creams Oil-in-water (o/w) cream Water-in-oil (w/o) cream Also known as aqueous cream, Also known as oily cream vanishing cream Produced by synthetic waxes Produced by natural emulsifiers (e.g. macrogol, cetomacrogol) Emulsifying agent (e.g. beeswax, wool fat or wool alcohols) Thin, white and smooth in Creamy, white or translucent and consistency Appearance rather stiff Water washable base→ use Provide good emollient properties, for rapid absorption and Application not readily washable by water → penetration of drugs gives a cooling sensation aqueous cream, cosmetic Cold cream Examples creams 13 TO DISTINGUISH BETWEEN O/W AND W/O CREAM BASE: O/W Types of test W/O Miscible with water Miscibility test Miscible with oil Coloured droplets Microscopic examination Coloured background after staining with an oil- soluble dye Droplets fluoresce Microscopic observation Continuous phase under UV radiation fluoresces Conductor of electricity Conductivity Poor conductor of measurement electricity 14 Cream Formulations Other additives 15  Oily Vehicles Oils used in external preparations come from one of three sources: Mineral oils (paraffins) Vegetable oils Synthetic oils 16 MINERAL OILS (PARAFFINS) o Most widely used. o Complex mixtures of saturated hydrocarbons. o Occlusive. o Chemically inert. o Do not give good skin penetration. 17  MINERAL OILS (PARAFFINS) Paraffins Commonly used Soft Liquid Hard paraffins paraffins paraffins Yellow White soft soft paraffin Used to thin paraffin or thicken products Choice depends on colours of ingredients. 18 VEGETABLE OILS Plant sources: peanut, castor, olive and coconut. Occlusive and give good skin penetration. May go rancid. Extra caution with patients with nut allergies. 19 SYNTHETIC OILS o Example: silicone oils (Dimethicone BP). o Very hydrophobic → use as water repellent and occlusive. o Dimethicone cream BPC → as a barrier cream for prevention of napkin rash or pressure sore. 20  Aqueous Phase In extemporaneous compounding, purified water is commonly used. o Deionisation or distillation or by reverse osmosis of potable H2O. o Used when presence of salts in potable H2O is undesirable. o May gain  content of vegetative organisms if allowed to stand. o freshly boiled and cooled before use. 21 Emulsifying Agents o Facilitate product dispersion by:  Interfacial tension. Maintain droplets separation by forming a barrier at the interfaces. o Effective emulgents are surface active agents. o Surfactants usually  skin penetration of any drug. 22 o 3 types of emulsifying agents are commonly used: Synthetic substances Natural products Finely divided solids o Selection of emulgents is based on the type of cream base required. Examples of Synthetic Natural emulsifier Finely divided emulsifiers emulsifiers solids Emulsifying wax Wool fat, beeswax Bentonite, magnesium hydroxide o/w cream   w/o cream   23  Emulsifiers o/w cream base w/o cream base o Emulsifying waxes are the most used o Wool fat (lanolin) → from sheep emulsifiers in the extemporaneous wool compounding of o/w creams o Wool alcohol → a solid o Emulsifying wax + fatty bases (oily phase) + water  o/w cream o Hydrous wool fat → 7 parts wool fat + 3 parts water (a softer material) Emulsifying wax o Beeswax Cetostearyl Surface active alcohol (CSA) agent (SAA) o Varying amount of CSA → increases consistency of cream 24  EMULSIFYING WAXES Name of Waxes Charge CSA SAA Emulsifying Wax BP Anionic 9 parts Sodium lauryl 1 part sulphate Cetrimide Emulsifying Cationic 9 parts Cetrimide 1 part Wax BPC Cetomacrogol Non-ionic 8 parts Cetomacrogol 2 parts Emulsifying wax BP 1000 CSA = cetostearyl alcohol SAA: surface active agent The ointments formulated with these emulsifying waxes will absorb considerable amount of water to form stable o/w cream bases. 25  Example Cetomacrogol Cream BP Ingredients Master Formula Cetomacrogol Emulsifying Ointment BP 300 g Chlorocresol BP 1g Purified Water, freshly boiled & cooled To 1000 g Cetomacrogol Emulsifying Ointment BP White Soft Paraffin BP 500 g Cetomacrogol Emulsifying Wax BP 300 g Liquid Paraffin BP 200 g 26  Task Cetrimide cream BP Master Formula (BP 1988) 1000 g Cetrimide BP 5g Cetostearyl Alcohol BP 50 g Liquid Paraffin BP 500 g Freshly boiled and cooled purified 445 g water What cream base is this? (o/w or w/o?) and why? 27 Other additives o Preservatives o Antioxidants o Humectants 28 PRESERVATIVES o Creams → a good substrates for growth of micro-organisms → spoilage and pathogenicity. o  preservatives that are both fungicidal and bactericidal are required. o Common preservatives used: Benzoic acid 0.1% ✓ Effective at pH< 5 Parahydroxybenzoic 0.1% ~ 0.2% ✓ Mixtures of methyl, ethyl, propyl acid esters & butyl esters. ✓ Most effective at pH 7~9. Chlorocresol 0.1% ✓ Activity  in the presence of vegetable oil & at  pH. Phenoxyethanol 0.5% ~ 1% ✓ Effective against P. aeruginosa when used with hydroxybenzoate. 29  The preservation system is often a challenging task for pharmaceutical scientist. Efficacy Clinical acceptability Ability to cope with Formulation stability heavy microbial contamination? o Ideally, creams should be prepared using aseptic techniques. o However, not feasible in extemporaneous dispensing. o  Strict hygiene must be practiced. 30 ANTI-OXIDANTS o Therapeutic agent and oils selected for oily phase & emulgents → liable to oxidation. o Especially, if oils are from vegetable or animal origins. o Oxidation can be controlled by adding approved antioxidants: Butylated hydroxyanisole 0.02~0.5% w/w Butylated hydroxytoluene 0.02~0.5% w/w Sodium metabisulphite 0.01~1% w/v Sodium sulphite 0.1% w/v 31 HUMECTANTS o Hydroscopic materials added to  the rate of water loss from creams. o Used at concentration of 5~15%. o Examples: Glycerol (glycerin) Propylene glycol Polyethylene glycol 300 32 PHD211 Semi-solid dosage forms 2 Compounding creams o Terminologies o General principles o Incorporation of solids or liquids into cream bases 33 Terminologies Mixing by fusion Trituration (= mixing) Levigation (= grinding) 34 MIXING BY FUSION S1-Pharmaceutics Making Ointments Melt together the fatty bases over a water bath before incorporating any other ingredients. Usually 60o~70oC is adequate. Starts with material with highest melting point. 35 TRITURATION (MIXING) o Incorporation into the base, of finely divided insoluble powders or liquids. Powders: Powders place on tile and base is incorporating using the “doubling up” technique. Liquids: Place a small amount of base on tile and make a “well” in the centre, mix a small amount of liquid each at a time. 36 LEVIGATION (WET GRINDING) o Incorporate insoluble coarse powders into a base. V2 - Levigation o Shearing force is applied to avoid a gritty product. o Powder rubbed down into a semi-solid base. 37 General Principles of Compounding Creams 1 Hygiene is extremely important! Clean all surfaces, spatulas and other equipments with ethanol. 38  2 Always make an excess Never possible to transfer the entire cream into final container  2~4 g of a cream maybe lost in the compounding process Reference suggested an extra of 10% from the required amount Actual experience in the previous practical labs suggested that at least 5 g extra needed for each cream compounding. Reference: 1. Thompson J. & Davidow L.W. (2009). A Practical Guide to Contemporary Pharmacy Practice, 3rd edition, Lippincott Williams & Wilkins. 39 Hospital Manufacturing Unit In the lab, 40  3 Check solubility Determine which of the ingredients are soluble in or miscible with aqueous phase and which with oily phase. 41  4 Prepare fatty base Melt the fatty base in an evaporating dish over a water bath at the lowest possible temperature. Start with the base with high melting point (Note. To check melting point!). Then, cool the fatty base to 60oC. Overheating can denature emulsifying agent. Use thermometer to check temperature regularly. Add and mix other ingredients that are soluble/miscible with oily phase into the melted fatty base. 60oC 42  5 Prepare aqueous phase Heat up aqueous phase and temperature adjusted 60oC to 60oC. May consider to heat up aqueous phase a few degrees higher than the oily phase before mixing → aqueous phase tends to cool faster than oily phase. Dissolve water-soluble ingredients in the aqueous phase. 43  6 At same temperature ( 60oC), add disperse phase to continuous phase Oily phase W/O cream (fatty base) O/W cream Aqueous phase Pour the oily phase Pour aqueous (or melted fatty phase into oily base) into aqueous phase (or melted Aqueous phase fatty base) Oily phase phase (fatty base) Reference: 1. Marriot et al. (2010). Pharmaceutical Compounding and Dispensing, 2nd edition. Pharmaceutical Press 44 In practical, 60oC O/W 60oC cream 45 7 Stir continuously to mix Stir the resulting emulsion continuously (but not too vigorously) without incorporating air, until the product sets. Do not hasten cooling → poor product. 46  Video example V3 - Pharmaceutics Prepare Dimethicone cream BPC 1973 Making Creams Master Formula (BP 1973) 1000 g Liquid Paraffin BP 400 g Oily phase Dimethicone 350 BP 100 g Miscible with oily phase Cetrimide BP 5g Emulsifying wax Cetostearyl Alcohol BP 50 g Chlorocresol 1g Preservative Freshly boiled and cooled purified water 444 g Aqueous phase *This is an o/w cream base. *Use as a barrier cream, for prevention of napkin rash or pressure sores. 47 8 Incorporation of other ingredients into cream bases Solids Liquids Soluble Non-volatile, miscible Insoluble Volatile or Coarse immiscible Fine 48 INCORPORATION OF SOLIDS INTO A CREAM BASE Types of solids Methods Soluble solids 1. Add solids to the molten cream at the lowest possible temperature. 2. Stir the mixture until cold. Insoluble solids 1. If > 1 power to be added, triturate the powders first using mortar and pestle. 2. Then, incorporate the powders on ointment tile using spatula by applying “doubling up” trituration method. 49  Types of solids Methods Coarse powders Use levigation technique, then: 1. After levigation, the powder/fatty base mixture may then be returned to the evaporating dish with the remaining cream & stir until cold; 2. Alternatively the remaining cream in evaporating dish may be allowed to cool & triturated with the V1-Pharmaceutics Making powder/cream mixture on the tile Ointments using doubling up technique. V2 - Levigation Fine powders On ointment tile, triturate the powder with cream base using doubling up technique. 50 INCORPORATION OF LIQUIDS INTO A CREAM BASE Types of liquids Methods Non-volatile, 1. Mixed with the molten cream. miscible liquids 2. If pre-prepared cream base is used, then incorporate as the methods for volatile/immiscible liquids (see slide 51). 51  Types of liquids Methods Volatile or immiscible Trituration technique. liquids (eg: cold tar) Method (1): 1. A small amount of cream should be placed on the tile and a “well” made in the centre. 2. Fold in small amount of liquid each time to avoid splashing. Method (2): 1. Spread small amount of the cream on the tile & “score” it with a spatula. V1-Pharmaceutics Making 2. Add small quantities of liquid and fold Ointments into the base gently. 52 PHD211 Semi-solid dosage forms 3 Creams in practice o Dispensing creams: packaging, storage, beyond-use- date, labelling o Cream instabilities o Cream dilution 53 PACKAGING OF CREAM o Choose a suitably sized container to match the volume of preparation → reduce headspace is best for decreasing the loss of water and tendency towards rancidity. o Collapsible metal or flexible tube are preferable → reduced risk of contamination. o Wide-mouthed squat jars may be used for creams where risk of contamination is minimal, e.g. oily creams. 54 o Containers must be well closed and prevent from water evaporation. o Mouth of the jar should be covered with a disc of greaseproof paper. o Amber glass jars are preferred as they protect preparation from light. o Plastic jars are available but not preferred → may react with products. (Nonetheless, commonly used in practice nowadays). Smooth the cream surface with spatula 55 STORAGE o Stored at cool, dry place but not allowed to freeze. o Proprietary cream products → refer to manufacturers’ recommendation. 56 BEYOND-USE DATE o Proprietary products → as recommended by manufacturers. o Extemporaneous prepared → 4 weeks. o Diluted creams → freshly prepared and should not be used for more than 2 weeks after issue. o To avoid misunderstanding, use the term “Discard after” followed by a definite date/time. 57 LABELLING FOR EXTERNAL USE ONLY 30 gram Mometasone Cream BP Apply to affected areas 2 times a day Patient’s Name: Sherry Date of Dispensing: 5/11/2024 Discard after 2/12/2024 Store in cool and dry place KEEP OUT OF REACH OF CHILDREN CONTROLLED MEDICINE UiTM Pharmacy 58 Cream Instabilities 1 Cracking or change of viscosity Possible reasons: Addition of incompatible emulsifying agent. Chemical or microbial decomposition of emulsifying agent. Significant change in pH. Change in storage temperature. 59  2 Lumpy or having granular appearance. Possible reasons: Too vigorous mixing which traps air bubbles. Very Smooth Too Slight lumpy cream watery granular Rapid cooling →’cold cream spot’→ higher melting point ingredients precipitate out. 60 Dilution of creams o Dilution of proprietary creams is not encouraged unless insisted by prescribers. o Choice of diluent is crucial as: Dilution may impair preservative system in the cream. May affect bioavailability of any active ingredients.  risk of contamination. 61 o Diluted creams must be freshly prepared without application of heat and with strict hygiene. o Shelf life: < 2 weeks after issue. o Suitable sources to provide information on the dilution of creams: National Pharmacy Association Diluent Directory. Manufacturers’ product data sheet. Reports in the pharmaceutical literature. 62 COMMON TYPES OF DILUENTS Diluent Note Aqueous Cream BP Only stable if < 50% of the resultant cream. Buffered Cream BP May raise pH of the resulting cream. Cetomacrogol Cream BP Difference between (Formula A or B) formula A and B is that they contain different preservatives. 63 CETOMACROGOL CREAM BP Formula A Cetomacrogol Emulsifying Ointment BP 300 g Chlorocresol BP 1g Purified water, freshly boiled & cooled To 1000 g Formula B Cetomacrogol Emulsifying Ointment BP 300 g Benzyl Alcohol BP 15 g Propyl Hydroxybenzoate BP 0.8 g Methyl Hydroxybenzoate BP 1.5 g Purified water, freshly boiled & cooled To 1000 g 64 Cream Dilution: Example Name: XY Age: 18 y-o Date: 1/11/2023 Rx Dermovate® Cream (1:4), apply b.d. Mitte: 50 g How should you start?? Dermovate cream → a proprietary cream contains 0.05% clobetasol propionate, a corticosteroid used for topical application for short term treatment of inflammatory skin disorders. 65 CREAM DILUTION: STEP-BY-STEP 1) Dermovate cream 1: 4? 1 (25%) part of proprietary cream, 3 parts (75%) of diluent. 2) Which diluent to choose? Check your diluent information sources (slide 63). 66 Aqueous cream Stable only if < 50%,  not the right choice. Buffered cream May  pH of product. Cetomacrogol Cream BP Checked resources, no (Formula A) problems with dilution. Cetomacrogol Cream BP (Formula A) is the right choice of diluent. 67 3) Calculate the correct amount of ingredients. Master 100 g 50 g 55 g Dermovate Cream 25% 25 g 12.5 g 13.75 g Cetomacrogol Cream BPC 75% 75 g 37.5 g 41.25 g (Formula A) 4) Methods: 1. Weigh 13.75 g of Dermovate Cream and transfer to the ointment tile. 2. Weigh 41.25 g of Cetomacrogol Cream BPC (Formula A) and transfer to the tile. 3. On an ointment tile, triturate the Dermovate cream with Cetomacrogol Cream BPC (Formula A) with spatula using doubling up technique. 4. Weigh 50 g of the final cream. 5. Pack into a collapsible tube or amber jar, label & dispense. 68 5) Label: FOR EXTERNAL USE ONLY 50 gram Dermovate Cream 25% w/w Apply to affected areas 2 times daily Name: XY Date of Dispensing: 5/11/2024 Discard after 18/11/2024 Store in cool and dry place KEEP OUT OF REACH OF CHILDREN CONTROLLED MEDICINE UiTM Pharmacy 2 weeks only for diluted cream 69 Please attempt cream lab worksheet #1 before lab practical session: Note: we do not have pre-formulated emulsifying ointment BP in the lab, students need to check out the formula and compound in the lab. 70 Recommended reading 71