Multiphasic Liquid Dosage Forms 2024 PDF

Multi-phase (dispersed) systems Pharmaceutical systems that consist of particulate matter dispersed throughout a continuous phase Suspensions Emulsions Gels Magmas Many of the properties of these dosage forms are related to the presence of a boun...

Multi-phase (dispersed) systems Pharmaceutical systems that consist of particulate matter dispersed throughout a continuous phase Suspensions Emulsions Gels Magmas Many of the properties of these dosage forms are related to the presence of a boundary between two phases (the interface) 1 Dispersed Systems Preparations consisting of solid particulate matter or a dispersed phase distributed throughout a dispersion medium or continuous phase (also “coarse dispersions”) heterogeneous systems must shake well opaque appearance (but see next slide) increased viscosity non-Newtonian flow In non-Newtonian fluids, viscosity can change when force is applied. Can become either more liquid or more solid. Ketchup becomes runnier when shaken and is thus a non-Newtonian fluid. 2 https://edurev.in/studytube/Preparation-of-Colloids-Surface-Chemistry--CBSE--C/00874cf4-0145-4fd7-8a50-e0087e1de197_t 3https://psiberg.com/difference-between-solution-and-suspension/ Advantages of dispersed systems › Similar to advantages of other oral liquid dosage forms – Easy to swallow – Flexible dosing – Easy to administer – Rapid onset of action › Faster than solid dosage forms – Modify the onset of action › Extended or delayed release possible 4 Disadvantages of dispersed systems ▪ Non-homogenous ▪ Tendency to separate (need Shake Well label) ▪ Bulkier than solid dosage forms ▪ Taste may be an issue ▪ Certain drugs are not stable in liquid dosage forms ▪ Dose accuracy ▪ Spills ▪ Incorrect measuring device 5 Additional Excipients Present in Multi-Phase Liquids Emulsifying agents Facilitates the dispersion of two immiscible liquids and stabilizes it Examples: Polysorbate (Tween) 80, Span 80, Acacia (gum that is exuded from the acacia tree) Acacia tree Encapsulating or solubilizing agents To promote and maintain dispersion of finely subdivided droplets of liquid in a vehicle in which it is immiscible Examples: Acacia, Cetomacrogol, Cetyl alcohol, Glyceryl monostearate Sorbitan monooleate 6 Surfactant (Surface active agent) Substances that adsorb onto the interfaces between phases to reduce interfacial tension. May be used as detergents, or emulsifying agents. Examples: Benzalkonium chloride, Polysorbate 80, Sodium lauryl sulfate Levigating Agent Liquid used as an intervening agent to reduce the particle size of a powder by grinding, usually in a mortar Liquid used to ensure complete wetting/even dispersion of a solid ingredient into a liquid or semisolid product Displaces the film of air that exists on the surface of dry powders. Examples: Mineral oil, Glycerin, Propylene glycol Suspending Agent Viscosity-increasing agent used to reduce sedimentation rate of particles in a vehicle in which they are not soluble Examples: Bentonite, Carbomers (Carbopol®), Cellulose derivatives (MC, HEC, 7 HPMC, HPC), Tragacanth, Polyvinyl alcohol Physical Pharmacy and Problems associated with Multi-phase Systems 8 (1) Wetting of solid particles › Most important for suspensions › Some solids float on surface when sprinkled on water (or other liquid) – Talc – Charcoal “Wetting” = Ability of a liquid to displace air and to spread over the entire surface of solid particles Particles need to be “wetted” in order to be immersed in the liquid Liquid must displace air and spread over the surface of the solid 9 Wetting of solid particles How well solids are wetted is described by the contact angle (θ). https://www.face-kyowa.co.jp/english/en_science/en_what_contact_angle.html Depends on the nature of the liquid and the nature of the solid surface (hydrophilic…. hydrophobic) 10 Wetting of solid particles A drop of water is placed on a flat, smooth, horizontal surface The drop behaves in one of the fashions shown below: Surface of solid Surface of solid Complete (absolute) wetting: Contact angle is 0º Readily wetted solids: 0º < contact angle < 90º Poorly wetted solids: 90º < contact angle < 180º Non-wetted: Contact angle is 180º 11 Wetting of solid particles Problems caused by insufficient wetting: 1. Cannot mix powder with liquids to form suspensions 2. Ingredients from tablets and capsules are not wetted by GI fluids causing dissolution problems Incomplete absorption Problems can be increased by too much hydrophobic lubricant in tablets and capsules Wetting agents can be added to increase interfacial contact 12 Practice question › Two liquids (a & b) were determined to take on the following shapes when dropped onto the same solid surface › a. b. › Indicate which of the liquids… › 1. …has the smallest contact angle › 2.. …has the least wettability › 3.. …has the smallest surface tension › 4.. …has the least likelihood of containing a surfactant 1. …has the smallest contact angle – B 2. …has the least wettability – A (larger contact angle → less wettability) 3. …has the smallest surface tension – B (lower surface tension decreases contact angle) 4. …has the least likelihood of containing a surfactant – A (surfactants decrease surface tension, which decreases contact angle, so an absence likely increases contact angle) 13 (2) Particle aggregation / caking Particle aggregation: Small particles are attracted to each other → form larger and heavier particles → fall out of suspension. But resuspendable Caking: Form solid mass at bottom of bottle Agglomerated particles are difficult to resuspend Can be prevented by development (adding) of surface charge 1. Ionization of surface groups: Carboxylic acid groups, Amines 2. Adsorption of electrolytes from the solution onto particle surface 3. Adsorption of charged surfactant molecules from the solution 14 Particle aggregation / caking: Surface charge Importance of Zeta (ζ) potential https://nanocomposix.com/pages/zeta-potential-measurements Or “electrokinetic potential” 15 Zeta (ζ) potential controls the degree of repulsion between adjacent, similarly charged, dispersed particles The higher = The more stable the suspension If Zeta (ζ) potential is below a threshold value: Attractive forces exceed repulsive forces Particles aggregate Suspension becomes unstable https://socratic.org/questions/particles-with-opposite-charges-do-what-to-each-other 16 (3) Interfacial phenomena Surface: Boundary between two phases, Air (gas) where one of them is strictly gas Oil Interface: Boundary between two immiscible phases Water Every surface is an interface too! Surface tension: – Describes the interface between liquids and gas See next slide – Unbalanced molecular cohesive forces exist at or near the surface › Net attractive force is towards the bulk of the liquid – Surface tends to contract and resemble a stretched elastic membrane 17  (4) Surface tension https://www.thoughtco.com/surface-tension-definition-and-experiments-2699204 Each molecule forms a bond with the ones in its vicinity. At the surface the outmost layer of molecules has fewer molecules to “cling to”, therefore “compensates” by establishing stronger bonds with its neighbors, this leading to the formation of the surface tension. https://www.usgs.gov/special-topics/water-science-school/science/surface-tension-and-water 18 (5) Interfacial tension Interfacial tension = Force of attraction between the molecules at the interface of two fluids. At the air/liquid interface, interfacial tension is referred to as surface tension. Interfacial tension = Tension between two immiscible liquids Interfacial tension is the force acting between two different liquids. Higher interfacial tension: Both liquids tend to separate into two phases. Each molecule of one liquid prefers to stay with the other molecules of that same liquid Surface and interfacial tension are reduced as the temperature increases Addition of certain solutes reduces the surface tension (surfactants = surface active agents… more details later) 19 Interfacial tension (γs) correlates to the amount of energy (“E”) required to increase the interfacial (contact) area (“A”) between two immiscible liquids ΔE = γs ΔA To increase the contact area… … we have to add energy in form of heat or vigorously stirring… or… … we decrease the Interfacial tension by We need less energy We need more energy adding a surfactants to produce only to produce these 3-4 droplets 5000 droplets 20 Emulsions A dispersion in which the dispersed phase is composed of small globules of liquid distributed throughout a vehicle in which it is immiscible – Dispersed phase = internal phase, discontinuous phase – Dispersion medium = external phase, continuous phase Emulsions are thermodynamically unstable Thermodynamic instability means a system exists that is not at equilibrium. Require an emulsifying agent to be stable Suitable for topical, oral, and parenteral delivery 21 Emulsions Emulsions consist of: › Small droplets of water dispersed in oil (W/O), or › Small droplets of oil dispersed in water (O/W) Contact area between water and oil is very large More energy for increasing A… Remember: ΔE = γs ΔA therefore energetically unstable Cohesive forces among molecules of the same phase will try to “bring them back together” Water prefers to stay with water Oil prefers to stay with oil 22  Emulsions Image by Venkatasan, 2013 1 Liquid 1 Liquid 2 2 Dispersed phase of Liquid 1 (as droplets) without emulsifier Dispersion medium is Liquid 2 3 Coalescence of dispersed phase without emulsifier Dispersion medium Role of 4 Stable dispersed phase (as droplets) of Liquid 1 with an emulsifier (Blue outer ring) Emulsifier Dispersion medium 23  Emulsion Type https://www.researchgate.net/figure/Concept-of-two-phase-water-in-oil-and-oil-in-water-emulsions_fig2_260376328 Oil-in-water emulsions (O/W) – Oil dispersed in water: Oil is the internal/dispersed/ discontinuous phase Water-in-oil emulsions (W/O) – Water dispersed in oil: Water is the internal/dispersed/discontinuous phase W/O O/W 24 Two definitions needed for next slide “HLB”: Hydrophilic–lipophilic balance: Balance of the size and strength of the hydrophilic and lipophilic moieties of a surfactant molecule (details later) “Bancroft’s Rule”: The phase in which an emulsifier is more soluble constitutes the continuous phase. More water-soluble surfactants tend to give oil-in-water emulsions. More oil-soluble surfactants give water-in-oil emulsions. 25 Factors that affect the emulsion type 1. Emulsifier – Some emulsifiers can form either type of emulsion › Depends on HLB the ingredients – Other emulsifiers form only O/W or only W/O – Bancroft’s Rule: the phase in which the emulsifier is more soluble = external phase 2. Phase-volume ratio Larger volume liquid is almost always the external phase 3. Order of mixing May have some impact on emulsion type 26 Purpose of emulsions and emulsification 1) To prepare relatively stable and homogenous mixtures of two immiscible liquids 2) O/W emulsions are a palatable way of administering distasteful oil 3) Emulsions to be applied to the skin can be prepared as O/W or W/O emulsion. 4) Medications that are irritating to the skin can be administered as an internal phase of a topical emulsion. 5) W/O emulsions allow for uniform mixing of oil-soluble agents Emulsions that are administered orally or by IV route are primarily O/W type, while topically applied emulsions (creams) are W/O or O/W type. 27 Features of a “good” emulsion 1. Emulsion should be stable. 2. The emulsion should be of an even consistency 3. The emulsion should be of a viscosity such that it can be readily removed from its container and used (e.g. lotion should pour/pump, cream should come out of tube or jar easily) 4. Particle size of the droplets should be as small as possible and remain fairly constant. 5. Droplets should aggregate slowly and be easily re-dispersed when the container is shaken. 28 Rheology of emulsions Rheology: Branch of physics that deals with the deformation and flow of matter. Factors that affect rheology – Viscosity of continuous phase – Phase-volume ratio – Emulsifier – Droplet size and size distribution Rheology of emulsions in general is Non-Newtonian Ketchup becomes runnier when shaken and is thus a non-Newtonian fluid. 29 Preparation of emulsions Preparation depends on: – Type of emulsion (we want to prepare) – Emulsifier (which in turn depends on type of emulsion) Three types of emulsifiers (details in following slides): 1) Hydrophilic colloids 2) Finely divided solid particles 3) Surfactants 30 Expected qualities of an emulsifier › Compatible – Should not affect the stability and efficacy of the product › Should not deteriorate in the preparation › Non-toxic › Possess little or no color, odor, taste › Capable of forming desired emulsion, and maintaining it for the shelf life of the preparation 31 1) Hydrophilic colloids Water soluble polymers Tend to form O/W emulsions Form multi-molecular film around the dispersed droplets of oil Do not cause an appreciable lowering in the surface tension Increase the viscosity of the dispersion medium The use of natural hydrophilic colloids in pharmaceuticals has declined in recent years Still commonly used in the food industry 32 Hydrophilic colloids Natural (carbohydrate-based): Acacia, tragacanth, alginates, pectin, agar, carageenan Natural (protein-based): Casein, gelatin Semi-synthetic: Methylcellulose, sodium carboxymethylcellulose Synthetic: Carbopol (derivative of acrylic acid) 33 2) Finely divided solids › Adsorbed at the interface between the two immiscible liquid phases › Form a film of solid particles around the dispersed globules – O/W emulsions formed by powders that are preferentially wetted by water – W/O emulsions formed by powders that are preferentially wetted by oil Examples: Bentonite (O/W and W/O for external use) Magnesium hydroxide (O/W for internal use) Bentonite consists chiefly of crystalline clay minerals, which are hydrous aluminum silicates containing iron and magnesium as well as either sodium or calcium. 34 3) Surfactants Surfactants are adsorbed at oil-water interfaces to form monomolecular films thereby reducing the interfacial tension – Dispersed droplets are surrounded by a coherent monolayer that prevents coalescence of two droplets – Ideally, the film should be flexible – May exert additional effect through the presence of a surface charge Combinations of emulsifiers are used frequently: A predominantly hydrophilic agent in aqueous phase, and a hydrophobic agent in oil phase – form a complex film (closely packed) at the interface 35 Surfactants – Type of emulsion produced depends on the properties of the emulsifying agent – Each emulsifier has a hydrophilic portion and a lipophilic portion › Categorized based on the basis of their HLB (details later) – Surfactants with an HLB of 4-6 produce W/O emulsions and surfactants with an HLB of 8-18 produce O/W emulsions Examples: Tweens and Spans Both are fatty acid esters of sugar alcohol (sorbitan) derivatives Span 80 Tween 20 36 Surfactants Molecules that are adsorbed at interfaces and orient themselves to reduce the interfacial free energy at the interface Require both hydrophobic and hydrophilic portions Decrease interfacial tension by orienting at the interface and separating the immiscible phases from each other Hydrophilic portion stays oriented in aqueous phase Hydrophobic portion stays oriented in non-aqueous phase 37 Surfactants Hydrophobic Hydrophilic https://commons.wikimedia.org/wiki/File:Surfactant.jpg 38 Surfactants › Have polar and non-polar characteristics that allow them to adsorb at interfaces A B C oil conc conc water a “film” develops at the interface and micelle alters the interfacial tension formation polar head A CMC – critical groups on micellular conc. B outside g C non-polar tails in interior conc. 39  https://www.ipcol.com/blog/an-easy-guide-to-understanding-surfactants/ 40 Four main classes of surfactants Four main classes of surfactants 1. Anionic surfactants – Hydrophilic portion contains a negative charge – Electrolytes – Commonly used as detergents, shampoos and body cleansers – Inexpensive – Oral toxicity – can only be used in topical formulations Examples: Soap (sodium salt of a fatty acid) Sodium lauryl sulfate 41 Four main classes of surfactants 2. Cationic surfactants – Cation itself provides the emulsifying properties – Electrolytes – Have disinfectant and preservative properties – Oral toxicity – can only be used in topicals and ophthalmics – Incompatible with anionic surfactants – Often used with non-ionic surfactants to achieve better results Examples: Benzalkonium chlorides 42 Four main classes of surfactants 3. Amphoteric surfactants – Hydrophilic portion possesses both positive and negative charges – Can behave as: › Anionic or Non-ionic or Cationic Species, depending on the pH of the solution – Rarely used as the only surfactant Example: Sodium lauroylsarcosinate 43 Four main classes of surfactants 4. Non-ionic surfactants – Hydrophilic portion possesses no charge – Not electrolytes Examples: Tweens and Spans (see previous slides) Cremophores (Glycerol- PEG-Fatty acid esters) derived from castor oil 44 Naturally occurring surfactants › Derived from plant and animal sources › Two main disadvantages: – Considerable batch-to-batch variability → variable activity – Many are susceptible to bacterial or mold growth › Not widely used in products needing a long shelf-life › Many are still commonly used in compounding Examples: Beeswax Wool fat (lanolin) Wool alcohols Acacia and other plant gums 45 Naturally occurring surfactants › Two main types play important roles in various biological processes: Bile salts Phospholipids 46 Bile salts › Synthesized in the liver and secreted into the gut in response to the presence of fats – Highly surface active – Well-known role in digestion and absorption processes of fats – Allow aqueous fluid containing lipase to come into greater contact with the fat (Bile salts disperse fat) – Poorly water soluble drugs: › Bile salts ↑ dissolution rate → ↑ absorption and bioavailability https://biologydictionary.net/bile-salts/ Tertiary structure 47 Phospholipids Which you are familiar with as building blocks for biological membranes https://en.wikipedia.org/wiki/Phospholipid 48 Phospholipids (as surfactants) › Alveolar lining of lungs: – Natural surfactants: Mixture of phospholipids, neutral lipids, proteins – Deficiency of lung surfactant in newborn leads to a respiratory distress syndrome › Surfactant keeps air sacs from collapsing and allows them to inflate with air more easily › Surfactant (artificial or animal-derived) may be given via an endotracheal tube into the infant’s lungs: Survanta, Surfaxin, Curosurf, Infasurf 49 Phospholipids (as surfactants) › Tear film of the eye: – Surfactants present in the tear film allow it to spread over the cornea › Works to reduce the contact angle and therefore increase wetting of the eye surface – Deficiency of surfactants can cause dry eye syndrome – Artificial tear fluids containing phospholipid surfactants are used to treat dry eye https://www.refreshbrand.com/dryeye/tear-film 50 HLB System › Hydrophilic-Lipophilic Balance – A numerical scale ranging from 0 – 50 – Provides a means of rating a surfactant’s balance between hydrophilicity and lipophilicity – A measure of the degree a surfactant is lipophilic or hydrophilic 0---------------------10---------------------50 lipophilic   → hydrophilic 51 HLB System Two main methods of calculating the HLB value for a surfactant: Griffin’s Method: Based on ratio of the molecular mass of the lipophilic portion versus the molecular mass of the entire molecule Davies’ Method: Takes also into account the different degree of hydrophilicity of hydrophilic groups 52 HLB system Application of surfactants is determined based on their HLB values HLB Value Application 0–3 Antifoaming agents Example 4–6 W/O emulsifying agents 7–9 Wetting agents 8 – 18 O/W emulsifying agents 13 – 15 Detergents 10 – 18 Solubilizing agents W/O: Oil = external, continuous phase Bancroft: Emulsifier is more soluble in continuous phase HLB of surfactant for w/o emulsion should be more lipophilic: 4-6 53 HLB system: Anti-foaming agents › HLB 1-3 Cause foams (gas in aqueous liquid dispersions) to dissipate by reducing the surface tension of gas bubbles causing them to collapse and to coalesce with other gas bubbles. Hydrophobic part orients itself into the gas bubble Foams are sometimes desired, but more often undesirable while manufacturing liquid preparations 54 HLB system: W/O emulsifying agents › HLB 4-6 › Reduce interfacial tension between water and oil › Result in minimizing surface energy through the formation of globules – Without the presence of an emulsifying agent an emulsion is not stable – Example: Span 60 55 HLB system: Wetting agents › HLB 7-9 › When dissolving in water, lower the contact angle between a surface and the liquid and aid in displacing the air phase at the surface and replacing it with water › Example: – Bile salts 56 HLB system: O/W emulsifying agents › HLB 8-18 › Reduce interfacial tension between oil and water › Result in minimizing surface energy through the formation of globules – Without the presence of an emulsifying agent an emulsion is not stable – Example: Tween 80 57 HLB system: Detergents › HLB 13-15 Surfactants that facilitate the mixture of hydrophobic compounds such as oil or grease with water Typically used for cleaning purposes Reduce surface tension and aid in wetting the surface of the material being cleaned and of dirt/grease/oil The dirt/grease/oil will be emulsified Foaming occurs and the dirt/grease/oil is washed away Examples: Sodium lauryl sulfate 58  HLB system: Solubilizing agents › HLB 10-18 › Increase solubility of materials that are insoluble in the formulation › At “critical micelle concentration” (CMC), surfactants start to form micelles › In aqueous solution, the lipophilic portions of surfactants point inward to form a lipophilic core of the micelle – Poorly soluble drug stays inside lipophilic core – Micelle dissolves in water SuperManu https://commons.wikimedia.org/wiki/File:Micelle_scheme-en.svg 59  HLB system: Commonly used surfactants Surfactant HLB value Surfactant HLB value Span 85 1.8 Triethanolamine 12.0 Span 65 2.1 Tween 80 15.0 Span 80 4.3 Tween 40 15.6 Span 60 4.7 Brij 35 16.9 Span 40 6.7 Sodium oleate 18.0 Span 20 8.6 Sodium lauryl sulfate (SLS) 40.0 Spans: sorbitan esters Tweens: polyoxyethylene sorbitan fatty acid esters Often used in combination (typically 2% of total formulation) 60 HLB system: Oil and oil-like substances In addition to calculating HLB values for the emulsifying agents, values are also assigned to oils and oil-like substances. These values depend on whether the oil is used in an o/w or w/o emulsion (see mineral oil in next slide). To prepare a stable emulsion, the surfactant (emulsifying agent) should have an HLB value very similar to the one for the oil phase, depending on the chosen type of emulsion (w/o or o/w) (see next slide) When using a blend of surfactants, their HLB values are additive when their amount in this mixture is taken into account. Fraction x of surfactant A + fraction (1-x) surfactant B: HLBmixture = x HLBA + (1-x) HLBB 61 Required HLB values for common emulsions Ingredient Required HLB for each type of emulsion W/O O/W Stearic acid 6 15 Cetyl alcohol -- 15 Stearyl alcohol -- 14 Anhydrous lanolin 8 10 Cottonseed oil 5 10 Mineral oil 5 12 Petrolatum 5 12 White wax (Beeswax) 4 12 Application example: To prepare a W/O emulsion with mineral oil, we need a surfactant with HLB =5 To prepare O/W emulsion with mineral oil, we need a surfactant with HLB =12 62 Practice problem › Rx Cetyl alcohol 15.0 g White wax 1.0 g Anhydrous lanolin 2.0 g Emulsifier qs Glycerin 5.0 g Distilled water ad 100.0 g a. What kind of emulsion is this O/W or W/O? b. Calculate the HLB of the oil phase c. Using Tween 80 and Span 80 as emulsifiers, calculate the amount of each emulsifier needed so that the total content in the final product is 2% w/v 63 Practice problem › Procedure: – Calculate the HLB of the oil phase – Weighted average of the required HLB of each oil-phase ingredient HLB › Rx Cetyl alcohol 15.0 g x 15 = 225 White wax 1.0 g x 12 = 12 Anhydrous lanolin 2.0 g x 10 = 20 18 257 257 / 18 = 14.3 HLB=14.3 64 Practice problem (Method 1) › Required HLB of the emulsifying agents should be = 14.3 – 2% w/v emulsifier in 100 g total formulation = 2 g total emulsifier Let T and S represent the proportions of Tween and Span 14.3 = HLB of Tween (T) + HLB of Span (S) 14.3 = 15(T) + 4.3(S) and T + S = 1 14.3 = 15 (1-S) + 4.3(S) 14.3 = 15 – 15S + 4.3S -0.7 = -10.7S S = 6.5% of the Span 80 needed T = 93.5% of the Tween 80 needed 0.13 g Span 80 1.87 g Tween 80 65  Practice problem (Method 2) Alligation Method (see Dr. Joshi’s calculation lectures) › Required HLB = 14.3 – 2% w/v emulsifier in 100.0 g total formulation = 2 g total emulsifier – HLB of Tween 80 = 15 – HLB of Span 80 = 4.3 HLB Parts Grams 2𝑔 15 10 parts (14.3-4.3) 10 𝑝𝑎𝑟𝑡𝑠 𝑥 = 𝟏. 𝟖𝟕 𝒈 𝑻𝒘𝒆𝒆𝒏 𝟖𝟎 10.7 𝑝𝑎𝑟𝑡𝑠 14.3 2𝑔 4.3 0.7 parts (15-14.3) 0.7 𝑝𝑎𝑟𝑡𝑠 𝑥 = 𝟎. 𝟏𝟑 𝒈 𝑺𝒑𝒂𝒏 𝟖𝟎 10.7 𝑝𝑎𝑟𝑡𝑠 Total 10.7 parts (10+0.7) 2 g (given) 66 Your Turn › Mineral Oil 40% › Span 60 / Tween 40 qs 5% combo most common › Cherry Syrup qs › M.ft. 60 mL oral emulsion › prepare an O/W emulsion › O/W emulsion rHLB - 10.5 – HLB of Tween 40 = 15.6 – HLB of Span 60 = 4.7 67  5 𝑔 𝑒𝑚𝑢𝑙𝑠𝑖𝑓𝑖𝑒𝑟 › 𝑥 60 𝑚𝐿 𝑜𝑓 𝑅𝑥 = 3 𝑔 𝑒𝑚𝑢𝑙𝑠𝑖𝑓𝑖𝑒𝑟 100 𝑚𝐿 𝑜𝑓 𝑅𝑥 HLB Parts Grams 3𝑔 15.6 5.8 parts (10.5-4.7) 5.8 𝑝𝑎𝑟𝑡𝑠 𝑥 = 𝟏. 𝟔 𝒈 𝑻𝒘𝒆𝒆𝒏 𝟒𝟎 10.9 𝑝𝑎𝑟𝑡𝑠 10.5 3𝑔 4.7 5.1 parts (15.6-10.5) 5.1 𝑝𝑎𝑟𝑡𝑠 𝑥 = 𝟏. 𝟒 𝒈 𝑺𝒑𝒂𝒏 𝟔𝟎 10.9 𝑝𝑎𝑟𝑡𝑠 Total 10.9 parts (5.8+5.4) 3 g (given) 68 Preparation of emulsions › Equipment (pictures see next slide): – Small scale: › Mortar and pestle › Beaker › Blender or mixer › Hand homogenizer › Prescription bottle – Large scale: › Mixing tanks equipped with a high speed impeller › Further processing in a colloid mill or a large homogenizer 69 70 Emulsification using acacia (and similar agents) “Acacia gum: Natural emulsifier obtained from the trunk and branches of Acacia trees. Two species of gums, A. senegal and A. seyal, are authorized by FAO (1999) and commonly used (Arabic Gums, E414 EC) to stabilize oil in water emulsions” Food Chem X. 2020 Jun 30; 6: 100090. Emulsifying properties of Acacia senegal gum: Impact of high molar mass protein-rich AGPs Chutima Aphibanthammakit, Reine Barbar, Michaël Nigen, Christian Sanchez, and Pascale Chalier⁎ Two major methods: 1. Continental or dry gum method 2. English or wet gum method 71 72 Emulsification using acacia (and similar agents) › For both methods, the primary emulsion or nucleus is prepared by using: – The entire quantity of the fixed oil called for in the prescription, and – ½ that volume of water, and – ¼ that volume of acacia (emulsifier) › The ratio is 4 parts fixed oil : 2 parts water : 1 part emulsifier – Fixed oil: non-volatile When volatile oils are used, the ratio is: 2 parts volatile oil 2 parts water 1 part acacia 73 Emulsification using acacia (and similar agents) › Continental or Dry Gum Method – The acacia is first dispersed thoroughly in the oil – Part of the water is added all at once with rapid trituration – The trituration is continued at high speed using a spiral motion of the pestle until a snapping sound is heard – This indicates that a thick primary emulsion has formed – The remainder of the aqueous phase is then added slowly with trituration 74 Emulsification using acacia (and similar agents) › English or Wet Gum Method – Same proportions, but different order of mixing › A mucilage is formed by dispersing the acacia thoroughly in 2 parts of water › Oil is added slowly with rapid trituration › Trituration continues at high speed and the remainder of the water is then added slowly with trituation Slower Less reliable than the dry gum method Useful if the emulsifier is only available as a solution or must be dissolved before using 75 Emulsification using surfactants Selecting emulsifiers –HLB values are algebraically additive –Blends of emulsifiers are possible –Tweens and Spans are most common –Remember example calculation from an earlier slides! 76 Emulsification using surfactants 1) Bottle or Forbes method › Ingredients are shaken together in a closed prescription bottle › Suitable for volatile oils › Suitable for oils with low viscosities Viscous oils cannot be thoroughly agitated in the bottle when mixed with the emulsifying agent 77 Emulsification using surfactants 2) Beaker Method Primary energy source for emulsification is thermal (heat) rather than mechanical (stirring/triturating) Oil and water phases are heated separately High enough temperature to melt solid components Low enough temperature to not scorch oil-phase ingredients or boil water Not suitable for thermolabile drugs When phases are similar in temperature, add smaller-volume phase to larger-volume phase and mix 78 In situ soap emulsions Prepared by beaker or bottle methods 1. Calcium soaps (“hard” soaps) › W/O emulsions › Equal amounts of olive oil (oleic acid) + lime water (calcium hydroxide solution) – Emulsifying agent is the calcium oleate formed on mixing – May need to add a little excess of olive oil in order to ensure a homogenous emulsion Addition of acid can destroy the emulsion: Shifts the equilibrium from the salt form of the soap (the surface active form) to the un- dissociated acid form, which is oil soluble Calamine: Combination of zinc oxide and Example: 0.5% ferric oxide. Against mild itching of skin Calamine Liniment Liniment: Liquid or lotion, especially one made with oil, for rubbing on the body to relieve pain. 79 In situ soap emulsions Prepared by beaker or bottle methods 2. Soft soaps › Usually O/W emulsions › Water soluble and water dispersible › Salts of fatty acids with a univalent positive ion (K+, Na+, NH4+) – Stearic, palmitic, lauric and oleic acids › Give emulsions with a basic pH › Unsuitable for internal use – Taste soapy, have laxative effect › Example: – Cold cream (w/o emulsion) Better example: Shaving and foundation creams (O/W) 80 Addition of drugs to emulsions › Best to incorporate the drug during emulsion formation › Add oleaginous materials to oil phase › Add aqueous materials to water phase › If adding thermolabile drug to emulsion formed using beaker method, must wait until emulsion is formed and has cooled 81  Emulsion Type (i.e. O/W or W/O): Additional points to consider O/W emulsions › May be diluted with water › Addition of a water-soluble dye results in uniform diffusion › Conducts electricity W/O emulsions Cannot be easily diluted with water Addition of a water-soluble dye does not result in uniform diffusion Will not conduct electricity 82 Physical stability of emulsions › Optimum phase volume ratio – An emulsion is most stable when the phase volume ratio is 50:50 › The properties of the interfacial film have the greatest influence on the stability of the emulsion – Tough, elastic, and forms readily during emulsification › Emulsions are also stabilized by electrostatic repulsion between the droplets 83 Emulsion instability 1. Creaming Separation of an emulsion into two regions, one which is richer in the internal phase than the other E.g. Fat globules rising to the top of the product Less likely if densities of two phases are very similar Less likely if external phase is very viscous Storing in refrigerator increases viscosity, slows creaming Reversible process: Can be re-dispersed if coalescence is absent (next slide) However, may not be aesthetically acceptable 84 Emulsion instability 2. Coalescence / Cracking / Breaking Irreversible Film of the emulsifying agent surrounding the droplets of the oil is broken 85  Later… 86 https://www.researchgate.net/figure/Schematic-representation-of-the-types-of-instability-in-emulsions-derived-from-Mulley_fig22_35945482 Emulsion instability 3. Phase inversion Conversion to opposite emulsion type Can be triggered by exposure to temperature extremes Don’t freeze Don’t leave in hot car 87 Preservation of emulsions › Partitioning of preservative between the oil and water phases › Bacteria grow in the water phase › Fungistatic preservatives recommended for o/w emulsions › Frequently used preservatives: – Methyl and propyl paraben – Alcohol 12-15% (do not use if emulsifier is a hydrocolloid) 88  Selected commercially available products: (oral) Only a few remain commercially available in the US › Fish oil emulsions are available as supplements –Often flavored –Example: BioGenesis Omega Emulsion Lemon 89 Selected commercially available products: (oral) › Microlipid® – Unflavored safflower oil emulsion – Medical food used in situations where people need increased calorie content at a low volume › Supplies essential fatty acids › Mix into food or supplements › Can administer via feeding tubes 90  Selected commercially available products: (oral) Liquigen® Unflavored emulsion containing medium chain triglycerides from palm and/or coconut oil Used as a dietary supplement in different situations than Microlipid Does NOT supply essential fatty acids For patients who cannot efficiently digest and absorb long chain fatty acids from foods Generally incorporated into foods (fruit juices) May be used in baking or cooking 91  Selected commercially available products: (ophthalmic) › Restasis® (cyclosporine) – Prescription emulsion eye drop – NOT a natural tears product – Helps increase the eyes’ natural ability to produce tears 92  Selected commercially available products: (injectable) › Intravenous fat emulsions (IVFE) – O/W emulsions used for nutrition support, or as vehicles for delivery of lipid-soluble drugs › Source of calories, and in some cases, fatty acids – Commonly included in total parenteral nutrition (TPN) formulations with amino acids and dextrose 93  Selected commercially available products: (injectable) › Dipravan® (propofol › Cleviprex® (clevidipine injectable emulsion) butyrate) – Sedative-hypnotic used in – Calcium channel blocker anesthesia and ICU sedation administered as IV emulsion in cases where oral blood pressure therapy is not feasible 94 Microemulsions › Consist of large or “swollen” micelles containing the internal phase › Appear as clear (optically) transparent systems › Droplets in internal phase: 10 – 200 nm diameter Uses: More rapid and efficient absorption of drugs administered as microemulsions Topical drug delivery Cancer chemotherapy Transplant medication Cosmetic industry 95 Commercially Available Microemulsions › PropoClear® (propofol) › Neoral® (cyclosporine) microemulsion – Forms a microemulsion – IV product for veterinary use immediately upon contact only with an aqueous environment – Appears transparent to the – Available as oral solution and naked eye (note: Diprivan® soft gelatin capsules does not) 96 Suspensions Definition: Multi-phase systems that contain finely divided solid particles distributed somewhat uniformly throughout a vehicle Can be given many routes: Oral (e.g. ondansetron hydrochloride oral suspension) Topical (e.g. sodium sulfacetamide topical suspension) Otic (e.g. ciprofloxacin and hydrocortisone otic suspension) Ophthalmic (e.g. flurometholone ophthalmic suspension) Rectal (e.g. Rowasa® mesalamine rectal suspension enema) Via IM or SC injection (e.g. insulin, leuprolide microspheres) Must never be given by IV! 97 Suspensions Reasons for preparing suspensions: › Chemical stability – For drugs that are unstable in solution – E.g. oxytetracycline calcium oral suspension › Taste masking – Historical example: chloramphenicol palmitate oral suspension › Insolubility 98 Suspensions Features of a good suspension 1. Should pour readily and evenly 2. Particle size of the dispersed phase should be: – As small as possible (typically 1-5 microns) – Fairly uniform 3. Particles should settle slowly and be easily redispersed into a uniform mixture when the container is shaken 4. Settled particles should not form a cake on standing. 99 Suspensions Flocculation › Flocculation is the formation of light fluffy aggregates of particles, which are held together by weak Van der Waals forces. › Flocs tend to sediment rapidly, producing a distinct boundary between the sediment and the supernatant fluid. Easily reversible by shaking. Deflocculation A deflocculated suspension is one in which the repulsive force between the particles keep the particles dispersed 100 Suspensions Flocculated Suspension Deflocculated Suspension Particles form loose aggregates. Particles exist in suspension as separate entities. Rate of sedimentation is high, since the Rate of sedimentation is slow, since the particles particles settle as flocs. settle separately. A sediment is formed rapidly. A sediment is formed slowly. The sediment is loosely packed. The sediment is closely packed. The suspension is somewhat unsightly, due The suspension has a pleasing appearance, as to rapid sedimentation and the presence of the suspended material remains suspended for a an obvious, clear supernatant region. relatively long time. The supernatant also remains cloudy, even when settling is apparent. 101 102 Suspensions Sedimentation Volume “F” Sedimentation volume (F) is the ratio of the equilibrium (“final”) volume (“ultimate volume”) of the sediment (Vu) to the initial total volume of the suspension (Vo), before settling. 𝑽𝒖 𝐅= 𝑽𝒐 When both volumina are equal, then there is no sediment and F=1 Sedimentation volume (F) generally ranges from 0 to 1 F may exceed 1 if flocs are sufficiently bulky that the aggregate volume exceeds the initial volume An ideal suspension has F = 1; there is no sedimentation or caking; the suspension is aesthetically pleasing. 103 Suspensions Sedimentation Volume F = 0.5 F = 1.0 Image created by Venkatasan, 2013 F=0.5 F=1.0 104 Suspensions Degree of Flocculation If we consider a suspension that is completely deflocculated, the ultimate volume of the sediment will be extremely small: V∞ Degree of Flocculation defined as: β = F / F∞ 105 106 Velocity of sedimentation Expressed by Stokes’ Law: 𝒅𝒙 𝒅𝟐 𝝆𝒔 − 𝝆𝟎 𝒈 𝒗= = Variables in red 𝒅𝒕 𝟏𝟖𝜼 › Where: – dx/dt = rate of particle movement (cm/sec) – v is the terminal velocity – d is the diameter of the particle (cm) (directly proportional) – ρs is the density of the dispersed phase (g/mL) – ρo is the density of the dispersion medium (g/mL) ) (difference is directly proportional) – g is the acceleration due to gravity (980.7 cm/sec2) – η is the viscosity of the dispersion medium (poise or g/cm-sec) (inversely proportional) 107 Velocity of sedimentation Density says how much mass occupies a certain volume while viscosity is how well a liquid sticks together. In fluid dynamics, viscosity is the parameter to measure the thickness or thinness of any given fluid. Density is the measure of spaces between two particles in a given fluid. Viscosity and density are the characteristics of a fluid, but there is no direct relation between viscosity and density 108 Conclusions from Stokes’ Law about the velocity of sedimentation Larger particles fall more quickly (↑d) Denser dispersed phase falls more quickly (at a given vehicle density) (↑ρs) Rate of sedimentation is inversely proportional to viscosity Controlled settling can be achieved by: Particle size reduction Note: if particles are too fine they may form a cake Increasing the viscosity of the dispersion medium by the use of suspending agents Preventing particle aggregation 109  What sedimentation pattern to choose? Points to consider Would be Deflocculated with no or minimal sedimentation ideal, but: Will require greater viscosity and density adjustments May be too viscous difficult to pour Accurate dosing issues Flocculated systems with controlled slow sedimentation “Compromise” Fewer viscosity and density adjustments Allows easy redispersion Education of patients on importance of shaking Separated product might be unsightly 110 Practice Problem › Determine the sedimentation / creaming rate of a powder having a density of 1.3 g/mL and an average particle size of 2.5 μm if it were suspended in water (density - 1 g/ml; viscosity - 1 cps) 111 112 113 Formulation of suspensions Step 1 Check that the particles of the drug will be adequately dispersed in and wetted by the dispersion medium May require the addition of a wetting (or levigating) agent to produce a uniform dispersion See slides# 204 & 205 for overlapping definitions Wetting can be promoted by the use of surfactants Glycerin, propylene glycol, and other hygroscopic materials also act as good levigating agents for aqueous dispersion media 114 Formulation of suspensions Step 2 – Decide on the suspension vehicle (continuous phase) – Several approaches can be taken while preparing suspensions See › Use of structured vehicle Following › Controlled flocculation slides › Flocculation in structured vehicles 115 Formulation of suspensions “Structured Vehicle” (thickening, suspending agent) – Impart, increase viscosity – Slow down sedimentation of the dispersed particles – Concentration depends on the consistency desired – Check that these do not interfere with the availability of the active ingredient 116 Controlled Flocculation › Flocculating agents – Promote loose aggregation of suspended particles – Promote a degree of interaction between the suspended particles that will keep their surfaces apart – Maximizes the sedimentation volume (to get close to initial volume) – Avoids formation of a dense cake of particles in the bottom of the container Flocculates w/o flocculating agent With flocculating (dispersing) agent 117 Controlled Flocculation › Examples: – Electrolytes › Most widely used flocculating agents › Act by reducing the electrical forces of repulsion between the particles to allow the particles to form loose flocs (loosely arranged structures) – Polymers and clays › Part of the chain is adsorbed onto the surface of the particle and the remaining part projects out into the dispersion medium – Surfactants 118 Flocculation in Structured Vehicles › Combination of previous two methods › Must check for incompatibilities between the flocculating agent and the polymer used for the structured vehicle 119 Components of Oral Suspension Dosage Forms 1. Active ingredient 2. Wetting agent – Glycerin – Propylene glycol – Alcohol – Surfactant 3. Dispersion medium 4. Suspending agent 5. Sweetener / flavor 6. Flocculating agent 7. Preservative 120 How to prepare a suspension 1. Particle size reduction › Empty contents of capsule or crush tablet in a mortar › Add any powdered ingredients directly to mortar 2. Wet the particles › Add wetting agent slowly › Triturate with powder to form a paste 3. Add the selected vehicle(s) slowly to the desired final volume › QS to volume in graduated cylinder or calibrated bottle › Do NOT trust the ounce and milliliter markings on a liquid prescription bottle 121  Approaches to the formulation of suspensions: Summary and overview Particles Addition of wetting agent and dispersion medium Uniform dispersion of deflocculated particles Incorporation of Addition of Addition of structured vehicle flocculating agent flocculating agent Flocculated suspension Deflocculated Flocculated suspension suspension as final product Incorporation of in structured vehicle structured vehicle as final product Flocculated suspension in structured vehicle as final product 122 Practice Question › Which of the following typically increases the difficulty of redistributing a suspension after sedimentation? – LO 20 › a. Polymorphism b. Caking c. Flocculation d. b & c e. All of the above 123 Polymorphism in suspensions Slide#37 Affect physical stability of suspensions. Only one form is “stable”, so all “unstable” or meta-stable forms may be converted to the “stable” form over time through recrystallization Meta-stable forms often have different properties such as a higher solubility, dissolution rate, and / or bioavailability. The conversion from meta-stable to stable forms will change these properties Such changes must also be taken into account when determining the appropriate shelf-life for a product 124 Packaging and storing suspensions › Store compounded products in light resistant, airtight containers › Store in the refrigerator unless stability data suggests otherwise › Package in containers having adequate air space above the liquid to permit adequate shaking › Mouth of container should be large enough to permit easy pouring Shake the suspension before use One of the following labels is required: Shake Well Before Using Shake Well and Keep in the Refrigerator Refrigerate, Shake Well, Discard After ___________ 125 Suspensions: Marketed products Many marketed oral and topical products are suspensions 126 Images by Nagel, 9/10/15 Suspensions: Marketed products Dry powders for oral suspension Majority are antibiotics Contain all the necessary ingredients Ready for reconstitution Pharmacist loosens the powder, then adds the label- designated amount of purified water, in portions, and shakes until all the dry powder has been suspended 127 Suspensions: Delayed Release Suspensions › Nexium® (esomeprazole) Contains enteric coated granules (0.2-0.5 mm diameter) of drug along with inactive granules › Inactive granules contain dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose Product comes in single use packets that are reconstituted with water to form a suspension Given by oral, nasogastric or gastric administration 128 Suspensions: Extended Release Suspensions Quillivant XR® (methylphenidate HCl) – Powder that, after reconstitution with water, forms an extended release oral suspension for once daily administration – Contains ~20% immediate release and 80% extended release methylphenidate Tussionex Pennkinetic Extended Release Suspension® (Hydrocodone polistirex and chlorpheniramine polistirex)\ Zmax® (azithromycin) extended release suspension Delayed Release: Drug release from dosage form DELAYED after administration Extended Release: Release over an EXTENDED period of time 129 Gels Semisolid systems consisting of dispersions made up of either small inorganic particles or large organic molecules enclosing and interpenetrated by a liquid Two types of gels: Single-phase Two-phase Both types are considered colloidal dispersions (particle sizes in the range of 1 nm – 0.5 μm) 130 Gels Semi-rigid systems: Movement of the dispersing medium is restricted by an interlacing 3D network of particles or solvated macromolecules of the dispersed phase High degree of physical or chemical cross-linking may be involved Some but not all gels are suitable for oral use 131 Gels: clear versus turbid Some gels are clear like water Example: carbomer gels Turbid gels have ingredients that are not completely molecularly dispersed (soluble or insoluble), or they may form aggregates that disperse light Example: bentonite magma 132 Gels: Physical Properties Syneresis (“weeping of gels”) The expulsion of a liquid from a gel. Interparticular attraction squeezes out the dispersion medium and the gel shrinks Considered an instability in gels Example: Yogurt Imbibition The displacement of one fluid by another immiscible fluid, such as the absorption of water by hydrophilic colloids Does not increase volume appreciably Swelling During gel formation, elastic forces increase as swelling proceeds in macromolecules 133 Single phase gels (Mucilages) Contain soluble organic macromolecules (linear or branched polymers) Continuous phase may be: Aqueous Hydroalcoholic Nonaqueous In molecular dispersions (clear gels), no apparent boundaries exist between the dispersed macromolecules and the liquid 134 Single phase gels (Examples) 1. Natural gums › Tragacanth 2. Semi synthetic cellulose › Methylcellulose 3. Synthetic macromolecules › Carbomer gels http://www.chemical-rawmaterials.com/test/chemical- 135 rawmaterials.com/photo/pl10971129-remark.jpg Two-phase gels The gel mass consists of a network of small, discrete particles – Colloidal dispersions – Particles are water-insoluble, but hydrate strongly Two-phase systems are thixotropic: They are semisolid on standing but liquefy when shaken (see Ketchup) Magmas and milks are subsets of two-phase gels Example: Aluminum hydroxide gel (AlternaGEL®) 136  Single phase vs two phase gels Single phase gel: gels in which macromolecules are distributed so that no apparent boundaries exist between them, it also called organic gels. Two phase gel: gels consist of floccules of small, distinct particles, and frequently called a magma gels or inorganic gels. 137 Two-phase gels: Magmas and milks Two-phase systems in which suspended particles are larger – Sometimes classified as gels, sometimes as suspensions (gels for the purposes of this course) Thick and viscous No need to add a separate suspending agent Require a “shake well” label 138 Magmas › Suspensions of inorganic acids such as clays in water › Tendency for strong hydration and aggregation of the solid › Leads to a gel-like consistency › Exhibit thixotropic rheological behavior Example: Bentonite magma NF: Used as thickener in calamine lotion (Calamine lotion: OTC topical medication that can help relieve itching caused by minor skin irritations) 139 Milks › Suspensions in aqueous vehicles intended for oral and topical administration FOR MAKE-UPS 140