DrCuiStudyGuide List of things to know: Surface tension Surface tension is an effect within the surface layer of a liquid that causes the layer to behave as an elastic sheet. • Surface tension = tendency of liquids to reduce their exposed surface to the smallest possible area. Work = g ΔA Work required to increase the surface area A of a liquid by 1 area unit. mN/m = dynes/cm The molecular interactions in the bulk of a liquid is very different from that on the surface of the same liquid. In the bulk, one molecule interaction equally in all directions with other similar molecules. However, when a molecule is located on the surface of the same liquid, the molecule will only be attracted by other similar molecules in the liquid, but not from above the surface. Thus, a liquid has the tendency to reduce its exposed surface to the smallest possible area. It is defined as the work required to increase the surface area A of a liquid by 1 area unit. Its unit is dynes per cm or mNewton per meter. Therefore, the surface tension is unique to each individual liquid. Interfacial tension Surface tension is what happens if a liquid or solid is exposed to area. It is a special case of interfacial
Transcript
DrCuiStudyGuideList of things to know:
Surface tensionSurface tension is an effect within the surface layer of a liquid that causes the layer to behave as an elastic sheet.
• Surface tension = tendency of liquids to reduce their exposed surface to the smallest possible area.
Work = g ΔA
Work required to increase the surface area A of a liquid by 1 area unit.
mN/m = dynes/cm
The molecular interactions in the bulk of a liquid is very different from that on the surface of the same liquid. In the bulk, one molecule interaction equally in all directions with other similar molecules. However, when a molecule is located on the surface of the same liquid, the molecule will only be attracted by other similar molecules in the liquid, but not from above the surface. Thus, a liquid has the tendency to reduce its exposed surface to the smallest possible area. It is defined as the work required to increase the surface area A of a liquid by 1 area unit. Its unit is dynes per cm or mNewton per meter. Therefore, the surface tension is unique to each individual liquid.
Interfacial tension Surface tension is what happens if a liquid or solid is exposed to area. It is a special case of interfacial interaction. Let’s take a look at what will happen if two liquids are put together. If oil and water are putting together. There will be two phases/layers, with the oil on the top of water. The question is that will the density of the liquids change abruptly or gradually in the interface region. Experimental data showed that B is correct. This region is called interfacial region. In the bulk of water and oil, every molecule will have coherent attraction from similar molecules in all directions. However, in the interfacial region, the water molecules will be attracted by water in one half, and by oil in another half. Thus, the molecules in the interface region behave differently from those in the bulk phase of both water and oil.
Surfactants Surfactants reduce the surface tension of water by adsorbing at the air-water
interface. They also reduce the interfacial tension between oil and water by
adsorbing at the liquid-liquid interface. Many surfactants can also assemble in the bulk solution into aggregates that are known as micelles. The concentration at which surfactants begin to form micelles is known as the critical micelle concentration or CMC. When micelles form in water, their tails form a core that is like an oil droplet, and their (ionic) heads form an outer shell that maintains favorable contact with water. When surfactants assemble in oil, the aggregate is referred to as a reverse micelle. In a reverse micelle, the heads are in the core and the tails maintain favorable contact with oil.
In Index Medicus and the National Library of Medicine (NLM, USA Dept. of Health and Human Services), "surfactant" is reserved for the meaning pulmonary surfactant (see "alveoli" link below). For the more general meaning, "surface active agent" is the heading.
Thermodynamics of the surfactant systems are of great importance, theoretical and practical, because surfactant systems represent a systems between ordered and disordered state of matter-surfactant solutions may contain ordered phase (micelles) and disordered phase (free surfactant mollecules and/or ions in the solution).
Any substance that when dissolved in water or an aqueous solution reduces its surface tension or the interfacial tension between it and another liquid. Also called surfactant
Surfactants are usually organic compounds that are amphipathic, meaning they contain both hydrophobic groups (their "tails") and hydrophilic groups (their "heads"). Therefore, they are typically sparingly soluble in both organic solvents and water.
• Surface tension decreases and reaches a constant (critical micelle concentration)
Light scattering is a measurement of the presence of particles.
Surfactants need to form micelles to have detergency activity because any dirts have to be solubilized into the micelles.
o Requirements for a surfactanto Soaps
o Soaps = salts of fatty acids
Soft soap Hard soap Soft soap: positive ion is univalent, such as Na+, K+, and NH4+. Hard soap: positive ion is divalent, such as Ca++, Mg++
o Anionic surfactants: fatty acids, sulfate (SDS or SLS), sulfonate, sodium chlorate, bile salts
o Sodium dodecyl sulfate (SDS or NaDS) (C H 3(CH2)11O S O3Na) (FW 288.38), also known as sodium lauryl sulfate (SLS), is an ionic surfactant that is used in household products such as toothpastes, shampoos, shaving foams and bubble baths for its thickening effect and its ability to create a lather. The molecule has a tail of 12 carbon atoms, attached to a sulfate
group, giving the molecule the amphiphilic properties required of a detergent.
o Sodium laureth sulfate, or sodium lauryl ether sulfate (SLES), is a detergent and surfactant found in many personal care products (soaps, shampoos, toothpaste etc.). It is an inexpensive and very effective foamer
oo All of the soaps (sodium oleate, etc) are fatty acid salts. They are
characterized by a long hydrocarbon chain and a carboxylate group at the end.
oo Docusate sodium [USP] is anionic surfactant used as a stool softener and
is administered orally or rectally; as a tablet disintegrant or as an emulsifier and dispersant in topical preparations. When sold as Colace, it is docusate sodium, or sodium salt of dioctyl sodium sulfosuccinate (DSS).
o Cationic surfactants: CTAB, benzalkonium chlorideo Benzalkonium chloride (alkyl dimethyl benzyl ammonium chloride) is
an organic compound that is used as an antiseptic and spermicide. This product is a nitrogenous cationic surface-acting agent belonging to the quaternary ammonium group. Benzalkonium chloride is a mixture of alkylbenzyl dimethylammonium chlorides of various alkyl chain lengths. The greatest bactericidal activity is associated with the C12-C14 alkyl derivatives.
o It is one of the safest synthetic biocides known, and has a long history of efficacious use. Applications are extremely wide ranging, from disinfectant formulations to microbial corrosion inhibition in the oilfield sector. It is deemed safe for human use, and is widely used in eyewashes, hand and face washes, mouthwashes, spermicidal creams, and in various other cleaners, sanitizers, and disinfectants. The mechanism of bactericidal/microbicidal action is thought to be due to disruption of intermolecular interactions. This can cause dissociation of cellular membrane bilayers, which compromises cellular permeability controls and induces leakage of cellular contents. Other biomolecular complexes within the bacterial cell can also undergo dissociation
o Cetyl trimethyl ammonium bromide (CTAB) , also known as hexadecyltrimethylammonium bromide or 1-hexadecanaminium, N,N,N-trimethyl-, bromide[1] (C16H33)N(CH3)3Br[2]) is one of the components of the antiseptic cetrimide [3] . It is a cationic surfactant[citation needed ]. Its uses include providing a buffer solution for the extraction of DNA.
o As any surfactant, it forms micelles in aqueous solutions. At 303 K (30 °C) it forms micelles with aggregation number 75-120 (depending on method of determination, usually avg. ~95) and degree of ionization α (fractional charge) 0.2 - 0.1 (from low to high concentration).
- Lecithin is extracted from plant (soy) or eggs. There are very biocompatible. It’s a natural component of cell membrane. ( Amphoteric surfactant )
o Neutral Surfactants /Non ionic surfactants Span
Here is list of Spans, their chemical names, HLB values, and other properties. As can be seen, the HLB values of span decrease as the Span XX increase. This is because Span 85 has three oleate chains, and is very lipophilic.
Tween
Tween is polyoxyethylene sorbate ester. The polyoxyethylene groups are more hydrophilic, and the R group is more lipophilic. Due to the many polyoxyethylene groups, Tweens are in general more hydrophilic and have larger HLB.
Poloxmers are polyoxyethylene/polyoxypropylene block copolymers.
Micelles (structure, properties, applications, factors affecting CMC and size of micelles)
o Krafft point--the temperature at which an ionic surfactant becomes equal to its CMC. Below the Kraft point, the surfactant precipitates instead of forming Micelles.
o A micelle is an aggregate of the surfactant molecules dispersed in a liquid colloid. Colloid = a kind of dispersed system with particle size ranging from 1 nm to 0.5 mm. Aggregation number
o Critical micelle concentrationo The concentration of surfactant at which micelles form.o Micelle aggregation numbero The number of surfactants that aggregate to form a micelle.o CMC of the mixture of two surfactantso 1/CMC = f1/CMC1 + f1/CMC2 o (f = mole fraction)o Micelles are not a solid particles. The indi Factors affecting CMC
and micelle size individual molecules in the micelles are in dynamic equilibrium with monomers in the bulk and at the interface.
o Factors affecting CMC and micelle size Structure of hydrophobic group Nature of hydrophilic group Nature of counter ions Addition of electrolytes to ionic surfactants decreases CMC and increase size Effect of temperature Many surfactants can also assemble in the bulk solution into aggregates that are
known as micelles. The concentration at which surfactants begin to form micelles is known as the critical micelle concentration or CMC. When micelles form in water, their tails form a core that is like an oil droplet, and their (ionic) heads form an outer shell that maintains favorable contact with water. When surfactants assemble in oil, the aggregate is referred to as a reverse micelle. In a reverse micelle, the heads are in the core and the tails maintain favorable contact with oil.
We now know that when a surfactant is added in water, it will decrease the surface tension. The question is that will it decrease the surface tension to zero. When surfactants are added into water, they will preferentially absorbed on the surface of the water. In the end, a highly compacted surfactant monolayer will be formed. After reaches this point, the extra surfactants added into the water will try to dissolve into the bulk phase of the water. At a certain concentration, the surface tension of the
Let the weight fraction of A = x; the weight fraction of B will be (1-X).
8X + 12 (1-X) = 9; 8X + 12 -12X = 9; -4X = -3
X = 3/4; 1-X = 1- ¾ = ¼
The ratio of A to B, A/B = 3:1
B = ¼, A = ¾
• HLB of Tween 80 = 15• HLB of Span 80 = 4.3• We need 2 g of Tween 80 and Span 80 blend having a HLB value of 10.6. How
much Tween 80 and Span 80 are needed?• Suppose we need X fraction of Tween 80; the fraction of Span 80 will be 1-X• 15X + 4.3 (1-X) = 10.6; X = (10.6-4.3)/(15-4.3) = 0.59• Fraction of Span 80 = 1- 0.59 = 0.41• Weight of Tween 80 = 2 * 0.59 = 1.18 g• Weight of Span 80 = 2 * 0.41 = 0.82 g
Applications of surfactants Detergents Emulsifiers Paints Adhesives Inks Alveoli
An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases, one of which is dispersed as globules in the other liquid phase, stabilized by the presence of an emulsifying agent.
Butter, margrine, salad dressings.
Why it is thermodynamically unstable: creating small droplets will create large surface area. Since the surface has the tendency to decrease due to surface tension, emulsions are unstable.
A’. Two immisicble liquids, not emulsified; B’. An emulsion of Phase B dispersed in Phase A; C’. The unstable emulsion progressively separates; D’. The (purple) surfactant positions itself on the interfaces between Phase A and Phase B, stabilizing the emulsion
Internal vs. external; dispersed vs. continuous phase.
o External/Internal/Continious phaseo Thermodynamically unstable?o Theory of emulsification
Change from A to B will significantly increase of the surface area of phase.
e.g., if 1 cm3 of mineral oil is dispersed into globules having diameter of 0.01 mm in 1 cm3 of water, how much will be the surface area increased.
The surface area will become 600 m2 (greater than a basketball court); the surface free energy will increase by 8 calories. Therefore, emulsions are thermodynamically unstable, and the droplets have the tendency to coalesce.
Emulsifying agents are needed to decrease the surface tension and to stabilize the droplets.
Emulsifying agents can prevent coalescence or at least reduce its rate to negligible. It will form a film around the dispersed globules. The strength of an emulsifying agent lies in its ability to form a firm film.
o Emulsifying Agents (surfactants, hydrocolloids, particles) Acacia, tragacanth, veegum, pectin, bentonite, etc.
Creaming is the upward movement of dispersed droplets of emulsion relative to the continuous phase (due to the density difference between two phases)
• Stoke’s law: dx/dt = d2 (ri-re)g/18h
dx/dt = rate of setting D = diameter of particles r = density of particles and medium
g = gravitational constant h = viscosity of medium
Reversible. Need to be shaken well prior to use. It does not look good. Also, if not uniformally distributed, required amount of the active ingradient might not be achieved.
• Breaking, coalescence, aggregation• Breaking is the destroying of the film surrounding the particles.• Coalescence is the process by which emulsified particles merge with each to form
large particles.• Aggregation: dispersed particles come together but do not fuse. • The major fact preventing coalescence is the mechanical strength of the interfacial
film.
• Phase inversion
An emulsion is said to invert when it changes from an o/w to w/o or vice versa.
• Addition of electrolyte
Addition of CaCl2 into o/w emulsion formed by sodium stearate can be inverted to w/o.
• Changing the phase:volume ratio
Changing from a soft soap into a hard soap, a hydrophilic surfactant into lipophilic surfactant.
o Methods of emulsion preparation Continental Method (Dry Gum)
The continental method is used to prepare the initial or primary emulsion from oil, water, and a hydrocolloid or "gum" type emulsifier (usually acacia). The primary emulsion, or emulsion nucleus, is formed from 4 parts oil, 2 parts water, and 1 part emulsifier. The 4 parts oil and 1 part emulsifier represent their total amounts for the final emulsion.
In a mortar, the 1 part gum (e.g., acacia) is levigated with the 4 parts oil until the powder is thoroughly wetted; then the 2 parts water are added all at once, and the mixture is vigorously and continually triturated until the primary emulsion formed is creamy white.
Additional water or aqueous solutions may be incorporated after the primary emulsion is formed. Solid substances (e.g., active ingredients, preservatives, color, flavors) are generally dissolved and added as a solution to the primary emulsion. Oil soluble substance, in small amounts, may be incorporated directly into the primary emulsion. Any substance which might reduce the physical stability of the emulsion, such as alcohol (which may precipitate the gum) should be added as near to the end of the process as possible to avoid breaking the
emulsion. When all agents have been incorporated, the emulsion should be transferred to a calibrated vessel, brought to final volume with water, then homogenized or blended to ensure uniform distribution of ingredients.
Example of Prep Method: Cod liver oil 50 mL Acacia 12.5 g Syrup 10 mL Flavor oil 0.4 mL Purified water, qs ad 100 mL Accurately weigh or measure each ingredient Place cod liver oil in dry mortar Add acacia and give it a very quick mix Add 25 mL of water and immediately triturate to form the thick, white,
homogenous primary emulsion Add the flavor and mix Add syrup and mix Add sufficient water to total 100 mL Cod liver oil, as its name suggests, is an oil extracted from cod livers. It is a
nutritional supplement, in the past commonly given to children. Cod liver oil is one of the most effective providers of omega-3 fatty acids and is widely taken to ease the pain and joint stiffness associated with arthritis but has also been clinically proven to have a positive effect on heart, bone and brain health, as well as helping to nourish skin, hair and nails. [citation needed ]
As well as being an excellent source of vitamin A and vitamin D, it is also a good source of omega-3 fatty acids (EPA and DHA). Depending on the quality of the oil, the flavor and aroma range from a mild sardine-like flavor, to an intense and obnoxious odor of rotten fish and rancid oil. High quality cod liver oil is "a pale-yellow, thin, oily liquid, having a peculiar, slightly fishy, but not rancid odor, and a bland, slightly fishy taste." It has recently become popular to flavor cod liver oil with citrus or mint essence to make it more palatable. People who grew up in Asia often have terrible childhood memories of being force-fed Scott's Emulsion (a popular brand of cod liver oil supplement) until the orange-flavoured version was released.
Cod liver oil is made by cooking cod livers with steam and then pressing/decanting the cooked livers to extract the oil. By contrast, fish oils are extracted from the cooked whole body tissues of fatty fish during the manufacture of fish meal. Cod liver oil and fish oil are similar but have a somewhat different composition: fish oil has a much lower content of vitamins A and D compared to liver oils.
This may pose a problem in that one may need to exceed the Recommended Dietary Allowance (RDA) of vitamins A and D in order to obtain therapeutic amounts of EPA and DHA from cod liver oil. These vitamins are fat soluble, so it's possible for dietary excess (well above the RDA) to accumalate and become harmful.
Because the body naturally produces vitamin D when exposed to sunlight, a common way to benefit from both oils while avoiding a vitamin D overdose is to take cod liver oil during late fall through winter, and fish oil during spring through summer. The ideal dosage and timing of consumption depends on your seasonal sun exposure (and therefore natural vitamin D production). The only way to be certain of any possible vitamin D deficiencies or overdosing (from supplements) is to have your levels checked.
On the other hand, the RDA of vitamin D is considered by many to be strongly understated. Most adults don't even meet the RDA. In 2005 researchers at the University of California reported that Vitamin D can dramatically lower the risk of developing different types of cancers, cutting in half the chances of getting breast, ovarian, or colon cancer
Triturate (Tricherat): To rub, crush, grind, or pound into fine particles or a powder; pulverize.
English Method (Wet Gum) In this method, the proportions of oil, water, and emulsifier are the same (4:2:1),
but the order and techniques of mixing are different. The 1 part gum is triturated with 2 parts water to form a mucilage; then the 4 parts oil is added slowly, in portions, while triturating. After all the oil is added, the mixture is triturated for several minutes to form the primary emulsion. Then other ingredients may be added as in the continental method. Generally speaking, the English method is more difficult to perform successfully, especially with more viscous oils, but may result in a more stable emulsion.
Bottle Method (Forbes Bottle) This method may be used to prepare emulsions of volatile oils, or oleaginous
substances of very low viscosities. This method is a variation of the dry gum method. One part powdered acacia (or other gum) is placed in a dry bottle and four parts oil are added. The bottle is capped and thoroughly shaken. To this, the required volume of water is added all at once, and the mixture is shaken thoroughly until the primary emulsion forms. It is important to minimize the initial amount of time the gum and oil are mixed. The gum will tend to imbibe the oil, and will become more waterproof.
Auxiliary Method An emulsion prepared by other methods can also usually be improved by passing
it through a hand homogenizer, which forces the emulsion through a very small orifice, reducing the dispersed droplet size to about 5 microns or less.
Nascent Soap Method (In situ soap) In situ soap method
Calcium soaps: w/o emulsions contain oils such as oleic acid, in combination with lime water (calcium hydroxide solution, USP). Prepared by mixing equal volumes of oil and lime water.
In situ soap method is also called nascent soap methods. Nascent means beginning to exist or to develop. The emulsifier is formed as the emulsions are made.
• Oil phase: olive oil/oleic acid; olive oil may be replaced by other oils, but oleic acid must be added
• Lime water: Ca(OH)2 should be freshly prepared. • Equal volume of oil and lime water• The emulsion formed is w/o or o/w?• Method of preparation:
Bottle method:
Mortar method: when the formulation contains solid insoluble such as zinc oxide and calamine.
o Primary or initial emulsion ???
o Incorporation of drugs in emulsionso Addition of drug during emulsion formationoo Addition of drugs to a preformed emulsiono 1. Addition of oleaginous materials into a w/o emulsiono 2. Addition of oleaginous materials to an o/w emulsiono 3. Addition of water soluble materials to a w/o emulsiono 4. Addition of water soluble materials to an o/w emulsiono Oleaginous materials in o/w emulsion: a, occasionally, a small amount of
oily material is added if sufficient emulsifier was used in the original formation
o B, a small amount of oil-soluble drug can be added if it is dissolved in a very small quantity of oil.
oo Potentional drug solvent interaction should be avoided. o
Rheology/Viscosity/Thixothropy Rheo = flow Viscosity (h, poise) is an expression of the resistance of a fluid to flow (1 p = 0.1
Pa.s) Fluidity (f) = 1/h Newton’s theory
When a shear stress is applied to a solid body, the body deforms until the deformation results in an opposing force to balance that applied; forming an equilibrium. However, when a shear stress is applied to a fluid, such as a wind blowing over the surface of the ocean, the fluid flows, and continues to flow while the stress is applied. When the stress is removed, in general, the flow decays due to internal dissipation of energy. The "thicker" the fluid, the greater its resistance to shear stress and the more rapid the decay of its flow.
In general, in any flow, layers move at different velocities and the fluid's "thickness" arises from the shear stress between the layers that ultimately opposes any applied force.
Laminar shear of fluid between two plates. Friction between the fluid and the moving boundaries causes the fluid to shear. The force required for this action is a measure of the fluid's viscosity.
Laminar shear, the non-linear gradient, is a result of the geometry the fluid is flowing through (a pipe).
Isaac Newton postulated that, for straight, parallel and uniform flow, the shear stress, τ, between layers is proportional to the velocity gradient, ∂u/∂y, in the direction perpendicular to the layers, in other words, the relative motion of the layers.
Here, the constant μ is known as the coefficient of viscosity, viscosity, or dynamic viscosity. Many fluids, such as water and most gases, satisfy Newton's criterion and are known as Newtonian fluids. Non-Newtonian fluids exhibit a more complicated relationship between shear stress and velocity gradient than simple linearity.
The relationship between the shear stress and the velocity gradient can also be obtained by considering two plates closely spaced apart at a distance t. Assuming that the plates are very large, with a large area A, such that edge effects are neglected and that the lower plate is fixed, let a force F be applied to the upper plate. Incidentely, if this force causes the plate to move, the substance is concluded to be a fluid. The velocity of the moving plate and the top of the fluid must have the same velocity U. Now, by experimentation, the applied force is proportional to the area and velocity of the plate and inversely proportional to the distance between the plates. Combining these three relations results in the equation F = mu(AU/t). Where mu is the proportionality factor called the absoulte viscosity (with units Pa-s or slugs/s-ft). The equation can be expressed in terms of shear stress; rho = F/A = mu(U/t). U/t is the rate of angular deformation and can be written as an angular velocity, du/dy. Hence, through this method, the relation between the shear stress and the velocity gradient can be obtained.
In many situations, we are concerned with the ratio of the viscous force to the inertial force, the latter characterised by the fluid density ρ. This ratio is characterised by the kinematic viscosity, defined as follows:
James Clerk Maxwell called viscosity fugitive elasticity because of the analogy that elastic deformation opposes shear stress in solids, while in viscous fluids, shear stress is opposed by rate of deformation.
Viscosity is the principal means by which energy is dissipated in fluid motion, typically as heat.
• F’/A = h dn/dr; h = F/G;
G = dn/dr = velocity gradient/rate of shear
F = F’/A = shear stress
• Rate of shear is directly proportional to shearing stress.
h = A e EvRT (A is a constant, Ev is the activation energy required to initiate flow between molecules
Consider a block of liquid consisting of parallel plates of molecules, similar to a deck of cards. The bottom layer is fixed, the top layer is moved at a constant velocity, each lower layer will move with a velocity directly proportional to ints distance from the bottom layer. The velocity different between two different layers, dv/dr, is called shear rate. A force per unit area, F’/A, required to bring about flow is called shear stress. Newton recognized that the higher the viscosity of a liquid, the greater a certain force per unit area required to produce a certain rate of shear.
flows, the plot of shear rate vs. shear stress is a linear line. Majority of pharmaceutical systems are non-newtonian flow. The relationship between shear stress and shear rate is not linear.
This can be divided
into three categories.
Simple plastic flow or bingham plastic. In plastic flow, the liquid does not flow only when the shear stress is above a certain value, which is called the Yield Value. Once above the yield value, the flow behaves just like a newtonian flow. Below the yield value, the substance acts as an elastic material. Rheologists classify bingham bodies as a solid. Flocculated particle suspensions usually behave like this. A yield stress has to be applied to break the structure formed between two adjacent particles. The frictional forces between moving particles can also contribute to yield value.
Pseudoplastic like natural and synthetic gums (tragacanth, Naalginate, MC, NaCMC). It is typically exhibited by polymers in solution. No yield value exists. The viscosity of the pseudoplastic material cannot be expressed by a single value. Viscosity decreases as the
shear rate increase. Shear-thinning. As shear stress increases, normally disarranged molecules begin to align their long axes in the direction of flow. This orientation reduce the internal resistance and allows great shear rate at each successive shear stress. IN addition, some of the solvent associated with the polymers may be released, resulting in the lowering of the concentration and size of the polymer dispersion.
Certain suspensions with a high % of dispersed solids exhibit an increase in resistance to flow with increased rate of shear. The volume of the system increase when sheared, thus called dilatant flow. Viscosity increase at shear rate increases. Shear thickening flow.
Certain suspensions with a high % of dispersed solids exhibit an increase in resistance to flow with increased rate of shear. The volume of the system increase when sheared, thus called dilatant flow. Viscosity increase at shear rate increases. Shear thickening flow.
Non-newtonian systems
1. Bingham plastic flow
• does not begin to flow until a shear stress corresponding to the yield value is exceeded.
• Flocculated colloid particles
2. Pseudoplastic flow
• Typically exhibited by polymers in solution (tragacanth, sodium alginate, methylcellulose, NaCMC)
• Viscosity decreases with the increase of shear rate/shear thinning• Caused by the re-alignment of polymer and/or the release of solvents associated
with the polymers.
3. Dilatant flow
• Volume increases when sheared• Shear-thickening• Suspension containing a high concentration of small, deflocculated particles
Thixothropy and anti-thixotropy
We have shown that the shear rate progressively increased when plotted against the resulting shear stress. One may wondering what will happen if the rate of shear is reduced once the desired maximum shear stress is reached. Will the down curve overlays the upcurve? This is only true for newtonian flow. For non-newtonian flows, the downcurve is usually displaced relative to the upcurve. For shear-thinning systems, the downcurve is usually displaced to the left of the upcurve. This indicates the breakdown of structure that does not immedidately reform when stress is removed or reduced. This phenomena is called thixotropy. Thixotropy can only be applied to shear-thinning materials. How do you explain it? Asymetric particles, when stand, can form some loose associations to confer some degree of rigidity to the system. When stress is applied, the contact is broken, and a gel-to-sol transition occurs. On removal of the stress, the structure starts to reform, but this process is not instantaneous.
Some times, one may observed a totally different phenomena. That represents an increase in consistency in the downcurve, which is in the right of the upcurve. Magnesia magma at shear rate above 30 1/sec. One cannot indefinitely repeat this cycle.
Thixotropy in formulation
• Procaine benzylpenicillin• Procaine benzylpenicillin, also known as procaine penicillin, is a combination
of benzylpenicillin with the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin – thus it used used where prolonged low concentrations of benzylpenicillin are required.
• This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin. It is widely used in veterinary settings.
Thixotropy is a desirable property for liquid pharmaceutical systems including topical medications such as lotion, cream, ointments. The system should have high consistency in container, and yet pour or spread easily. An ideal system will be stable in container. Becomes fluid when shaken, and stay fluid for long enough for a dose to be dispensed. IT will then regain consistency and be a stable suspension.
Colloids (3-types) a mixture in which one substance is divided into minute particles (called colloidal
particles) and dispersed throughout a second substance. Size: 1 nm to 0.5 mm Visible under electron microscope Not resolved by ordinary microscope Do not pass through semipermeable membrane (k l´oid) (KEY) [Gr.,=gluelike], a mixture in which one substance is divided into
minute particles (called colloidal particles) and dispersed throughout a second substance. The mixture is also called a colloidal system, colloidal solution, or colloidal dispersion. Familiar colloids include fog, smoke, homogenized milk, and ruby-colored glass. 1 Colloids, Solutions, and MixturesThe Scottish chemist
Thomas Graham discovered (1860) that certain substances (e.g., glue, gelatin, or starch) could be separated from certain other substances (e.g., sugar or salt) by dialysis. He gave the name colloid to substances that do not diffuse through a semipermeable membrane (e.g., parchment or cellophane) and the name crystalloid to those which do diffuse and which are therefore in true solution. Colloidal particles are larger than molecules but too small to be observed directly with a microscope; however, their shape and size can be determined by electron microscopy. In a true solution the particles of dissolved substance are of molecular size and are thus smaller than colloidal particles; in a coarse mixture (e.g., a suspension) the particles are much larger than colloidal particles. Although there are no precise boundaries of size between the particles in mixtures, colloids, or solutions, colloidal particles are usually on the order of 10-7 to 10-5 cm in size. 2 Classification of ColloidsOne way of classifying colloids is to group them according to the phase (solid, liquid, or gas) of the dispersed substance and of the medium of dispersion. A gas may be dispersed in a liquid to form a foam (e.g., shaving lather or beaten egg white) or in a solid to form a solid foam (e.g., styrofoam or marshmallow). A liquid may be dispersed in a gas to form an aerosol (e.g., fog or aerosol spray), in another liquid to form an emulsion (e.g., homogenized milk or mayonnaise), or in a solid to form a gel (e.g., jellies or cheese). A solid may be dispersed in a gas to form a solid aerosol (e.g., dust or smoke in air), in a liquid to form a sol (e.g., ink or muddy water), or in a solid to form a solid sol (e.g., certain alloys). 3A further distinction is often made in the case of a dispersed solid. In some cases (e.g., a dispersion of sulfur in water) the colloidal particles have the same internal structure as a bulk of the solid. In other cases (e.g., a dispersion of soap in water) the particles are an aggregate of small molecules and do not correspond to any particular solid structure. In still other cases (e.g., a dispersion of a protein in water) the particles are actually very large single molecules. A different distinction, usually made when the dispersing medium is a liquid, is between lyophilic and lyophobic systems. The particles in a lyophilic system have a great affinity for the solvent, and are readily solvated (combined, chemically or physically, with the solvent) and dispersed, even at high concentrations. In a lyophobic system the particles resist solvation and dispersion in the solvent, and the concentration of particles is usually relatively low. 4 Formation of ColloidsThere are two basic methods of forming a colloid: reduction of larger particles to colloidal size, and condensation of smaller particles (e.g., molecules) into colloidal particles. Some substances (e.g., gelatin or glue) are easily dispersed (in the proper solvent) to form a colloid; this spontaneous dispersion is called peptization. A metal can be dispersed by evaporating it in an electric arc; if the electrodes are immersed in water, colloidal particles of the metal form as the metal vapor cools. A solid (e.g., paint pigment) can be reduced to colloidal particles in a colloid mill, a mechanical device that uses a shearing force to break apart the larger particles. An emulsion is often prepared by homogenization, usually with the addition of an emulsifying agent. The above methods involve breaking down a larger substance into colloidal particles. Condensation of smaller particles to form a colloid usually involves chemical reactions—typically displacement, hydrolysis, or oxidation and
reduction. 5 Properties of ColloidsOne property of colloid systems that distinguishes them from true solutions is that colloidal particles scatter light. If a beam of light, such as that from a flashlight, passes through a colloid, the light is reflected (scattered) by the colloidal particles and the path of the light can therefore be observed. When a beam of light passes through a true solution (e.g., salt in water) there is so little scattering of the light that the path of the light cannot be seen and the small amount of scattered light cannot be detected except by very sensitive instruments. The scattering of light by colloids, known as the Tyndall effect, was first explained by the British physicist John Tyndall. When an ultramicroscope (see microscope) is used to examine a colloid, the colloidal particles appear as tiny points of light in constant motion; this motion, called Brownian movement, helps keep the particles in suspension. Absorption is another characteristic of colloids, since the finely divided colloidal particles have a large surface area exposed. The presence of colloidal particles has little effect on the colligative properties (boiling point, freezing point, etc.) of a solution. 6The particles of a colloid selectively absorb ions and acquire an electric charge. All of the particles of a given colloid take on the same charge (either positive or negative) and thus are repelled by one another. If an electric potential is applied to a colloid, the charged colloidal particles move toward the oppositely charged electrode; this migration is called electrophoresis. If the charge on the particles is neutralized, they may precipitate out of the suspension. A colloid may be precipitated by adding another colloid with oppositely charged particles; the particles are attracted to one another, coagulate, and precipitate out. Addition of soluble ions may precipitate a colloid; the ions in seawater precipitate the colloidal silt dispersed in river water, forming a delta. A method developed by F. G. Cottrell reduces air pollution by removing colloidal particles (e.g., smoke, dust, and fly ash) from exhaust gases with electric precipitators. Particles in a lyophobic system are readily coagulated and precipitated, and the system cannot easily be restored to its colloidal state. A lyophilic colloid does not readily precipitate and can usually be restored by the addition of solvent. 7Thixotropy is a property exhibited by certain gels (semisolid, jellylike colloids). A thixotropic gel appears to be solid and maintains a shape of its own until it is subjected to a shearing (lateral) force or some other disturbance, such as shaking. It then acts as a sol (a semifluid colloid) and flows freely. Thixotropic behavior is reversible, and when allowed to stand undisturbed the sol slowly reverts to a gel. Common thixotropic gels include oil well drilling mud, certain paints and printing inks, and certain clays. Quick clay, which is thixotropic, has caused landslides in parts of Scandinavia and Canada.
• Systems containing colloidal particles that interact to an appreciable extend with the dispersion medium.
• Acacia in water or celluloid in amyl acetate lead o the formation of a sol.• Solvation, hydration, hydrophilic sols (gelatin, acacia, insulin, albumin in water),
lipophilic sols (rubber, polystyrene in non-aqueous solvents)
2. Lyophobic colloids (solvent-hating)
• Colloids are composed of materials that have little attraction, if any, for the dispersion medium.
• No solvent sheath around the particles• Gold, silver, arsenous sulfide, silver oxide in water
3. Association colloids
Ointment Bases (examples, properties) Hydrocarbon Oleaginous bases Emollient effect: hydrates skin due to sweat accumulation Occlusive dressing Difficult to wash-off/remove Small amount of water can be incorporated into it with difficulty and can be
protective to water labile drugs such as tetracycline and bacitracin. Is greasy and can stain clothing.
• Liquid petrolatum• Is a mixture of refined liquid saturated hydrocarbons obtained from petroleum• Levigating agent to incorporate lipiphilic solids• An excipient in topical formulations where its emollient properties are exploited
Absorption bases• Those that permit the incorporation of aqueous solution resulting in he formation
of w/o emulsions
--hydrophilic petrolatum, USP
Cholesterol 30 g, Stearyl alcohol 30 g
White wax 80 g, White petrolatum 860 g
--Aquaphor: A gentle healing ointment to help heal dry, cracked skin
(Petrolatum. Other Ingredients: Mineral Oil, Ceresin, Lanolin Alcohol, Panthenol, Glycerin, Bisabolol)
• Those that are w/o emulsion
Hydrous lanolin: w/o emulsion containing 25% of water
lanolin USP: Anhydrous, contains < 0.25% of water, absorbs twice its weight in water, also called wool wax, wool fat, or wool grease, a greasy yellow substance from wool-bearing animals, acts as a skin ointment, water-proofing wax, and raw material (such as in shoe polish).
• Vanishing cream: o/w emulsion contains la large % of water and humectant. An excess of stearic acid in the formula helps to form a thin film when the water evaporates.
• Dermovan: a hypoallergenic, greaseless emulsion• Unibase: non-greasy emulsion base has pH close to that of skin
Properties……..
• Water-washable, easier to remove• Non/less greasy• Can be diluted with water• Non/less occlusive• Better cosmetic appearance• Better compliance
- Only a small amount of liquid (<5%) can be incorporated
- If 6-25% of liquid is to be incorporated, 50 g of the 400 g of PEG 3350 may be replaced with stearyl alcohol
• Examples
ZOVIRAX®, (acyclovir), GSK, Ointment 5%
BACTROBAN® SmithKline Beecham Mupirocin Topical Antibiotic (Each g of ointment contains: mupirocin 20 mg (2%) in a bland water-soluble ointment base consisting of PEG 400 and PEG 3 350 (PEG ointment, USP).
• Glyceryl monstearate
polyhdric alcohol esters
wildly used in cosmetic and ointment bases
• Cellulose derivatives
Methylcellulose
Cellulose
Hydroxyethyl cellulose
• Carbopol/carbomer
synthetic high MW polymers of acrylic acid cross-linked with either allysucrose or allyl ethers of pentaerythritol
Properties………
• Water soluble and washable• Non-greasy• Non/less occlusive• Lipid free• Synthetic base
Relatively inert
Does not support mold growth
Little hydrolysis, stable
May dehydrate skin and hinder percutaneous absorption.
Levigating Agents • A spatula with a long, broad blade should be used• Insoluble substances should be powdered finely in a mortar and mixed with an
equal amount of base until a smooth mixture is obtained. The rest of the base is added in increment.
• Levigation of powders into small portion of base is facilitated by the use of levigating agents.
• Levigating agents:
Mineral oil for oily bases or bases where oil are the external phase
Glycerin for bases where water is the external phase.
Levigating agent should be equal in volume to the solid material.
• When liquid is added into an ointment, care must be taken to consider the capacity of the ointment in accepting the liquid. When it is necessary to add an aqueous preparation to a hydrophobic base, the solution should be added into minimal amount of the hydrophilic base first. The mixture should be then added into the hydrophobic base.
The particle sizes of sulfur and salicylic acid are reduced separately in a mortar and then blended together. The powder mixture is then levigated with the base using geometric dilution.
Creams/vanishing and coldSemisolid preparations containing one or more medicinal agents dissolved in either an o/w or w/o emulsion or in another type of water-washable base.
Vanishing cream: o/w with high % of water and stearic acid.
Cold cream: (an emulsion for softening and cleansing the skin): w/o, white wax, spermaceti, almond oil, sodium borate.
• Typically of low viscosity, two phase system (w/o or o/w)• Appears “creamy white” due to the scattering of light.• Traditionally, it is the w/o cold cream• Currently and most commonly, it is the o/w emulsion.• w/o emulsion frequently using a borax-beewax combination as the emulsifying
agent and mineral oil or vegetable oil as the oily phase. A protective film remains on the skin following the evaporation of the water. The slow evaporation of water gives the skin a cooling effect.
• To prepare, melt white wax, spermaceti, and almond oil together, adding host aqueous solution of sodium borate, and stir until the mixture is cool.
• Good patient acceptance• Water evaporation concentrates drug on skin surface• Must avoid drug crystallization• Can add co-solvents such as propylene glycol
Borax-beewax Gels/jellies Jellies are water soluble bases prepared from natural gums such as tragcanth,
pectin, alginates, boroglycerin, or from synthetic derivatives of natural substances such as methylcellulose and NaCMC.
Gels: semisolids consisting of dispersions of small or large molecules in an aqueous liquid vehicle rendered jelly-like through the addition of a gelling agent.
Single-phase gel: Carbomers: high Mw water soluble polymers of acrylic acid cross-linked with
allyl ethers of sucrose or pentaerythritol. Two-phase system: magma/milk of magnesia/magnesia magma, a gelatinous
precipate of magnesium hydroxide Skin anatomy (Stratum corneum, stratum corneum, stratum corneum. Did I
mention stratum corneum?)
Five main target regions/sites in dermatology• Surface treatment
Acne Acne vulgaris is a disorder of the pilosebaceous units. A plug of the pilosebaceous duct and follicle opening. Drugs have to get into the hair follicles and pilosabaceous units
Acne is a disorder of the pilosebaceous units, mainly in face, hest, and back. The lesions usually start as open or closed comedones, and evolves into inflammatory papules and pustules that can evolve into nodules and cysts. The definitions of all this terms are rather confusing. Please refer to the above website if you would like to get more information.
Acne is common in young people in the age of 12-24. In fact, over 85% of all people in the age of 12-24 are affected. It does occur in adults too.
Pustule—A dome-shaped, fragile lesion containing pus that typically consists of a mixture of white blood cells, dead skin cells, and bacteria. A pustule that forms over a sebaceous follicle usually has a hair in the center. Acne pustules that heal without progressing to cystic form usually leave no scars. This photo shows pustules, papules and comedones on the face of an acne patient:
Papule—A papule is defined as a small (5 millimeters or less), solid lesion slightly elevated above the surface of the skin. A group of very small papules and microcomedones may be almost invisible but have a "sandpaper" feel to the touch. A papule is caused by localized cellular reaction to the process of acne. This photo shows papules and comedones on the face of an acne patient:
Comedo (plural comedones)—A comedo is a sebaceous follicle plugged with sebum, dead cells from inside the sebaceous follicle, tiny hairs, and sometimes bacteria. When a comedo is open, it is commonly called a blackhead because the surface of the plug in the follicle has a blackish appearance. A closed comedo is commonly called a whitehead; its appearance is that of a skin-colored or slightly inflamed "bump" in the skin. The whitehead differs in color from the blackhead because the opening of the plugged sebaceous follicle to the skin’s surface is closed or very narrow, in contrast to the distended follicular opening of the blackhead
Etiology
• Increased sebum production
Androgens regulate sebum production. Testosterone converted to DHT, which induces sebaceous glands to increase in size and activity, resulting in increased amount of sebum.
• Abnormal clumping of epithelial horny cells in the pilosebaceous unit
Horny cells usually sloughed off from epithelial lining of the pilosebaceous duct.
Retention hyperkeratosis (increased adherence and production of follicular epithelial cells)
• Presence of Propionibacterium acnes
P. acnes lipases break triglyceride to fatty acids, which are irritating, cause comedones, and result in inflammation.
Acne Tx Strategies………
• Increased sebum production (decrease the sebum production)
Androgens regulate sebum production. Testosterone converted to DHT, which induces sebaceous glands to increase in size and activity, resulting in increased amount of sebum.
The result of direct contact with a contact allergen, such as poison ivy and nickel. Allergic contact dermatitis is considered a T-cell mediated delayed-response immune reaction, because elicitation of an allergic reaction typically takes 48 to 72 hours to occur after reexposure to the same allergen.
Allergic CD
One of the most common dermatological conditions encountered in clinical practice.
1. Hapten contacts skin epidermis2. Hapten complexes with protein3. Hapten-protein enters lymphatic systems4. Generation of specific Th1 CD4+ and CD8+ T cells.5. Re-exposure6. Dermatitis responses
Hapten = small molecules that are only antigenic when combined with a carrier protein.
Urushiol oil is presented in the roots, stems, leaves, and fruit. Burning plants can cause droplets of the oil carried by smoke to enter the respiratory system. Can even remain in toilet seat!
• Severe eruptions: systemic corticosteriods• Less severe eruptions:
Relieve itching
Local anesthetics (benzocaine)
Antihistamines (oral or topical, mainly sedative effect)
Topical hydrocortisone
Treatment
Topical hydrocortisone.
For information about the transdermal drug delivery section, please see previous exams. You do not need to remember the equations for Log P and log S calculations. Do not need to remember the polymeric composition of different transdermal patches. Peneration enhancers (DMSO, water, Azone. Do not need to remember the types of transdermal device the transdermal patches mentioned.
Pay attention to Fick's Law and parameters in the equation (Koct/H2O diffusion coefficient, permeability coefficient, solubility and the relationship between them.
