Surface Active Agents (SAA) / Surfactants

Surface Active Agents (SAA) / Surfactants

• Solutes or molecules get adsorbed at a liquid's surface or the interface between two liquids
• They reduce surface or interfacial tension

Composition of Soluble Surfactants

• Lipophilic/hydrophobic groups consist of long carbon chains with low affinity for aqueous solvents
• Hydrophilic/lipophobic groups consist of polar groups like -COOH or -OH with affinity for polar solvents
• Surfactants with polar and nonpolar groups that have affinity for both aqueous and non-aqueous solvents are termed "amphiphils"

HLB System Formula Definition

• Balance between hydrophilic and lipophilic nature of surfactants is given by the HLB system
• The HLB system consists of an arbitrary scale of values used to describe surfactants
• Formula: HLB = 20 x (Mh / Mt)
• Mh is the molecular weight of the hydrophilic group, Mt is the molecular weight of the whole molecule
• Each surfactant in the HLB system has a number between 1 and 20, showing the relative proportions of lipophilic and hydrophilic parts of the molecule
• Higher number means more hydrophilic
• Lower number means more lipophilic

HLB Values Example

• HLB value of Tween 20 (polyoxyethylene (20) sorbitan monolaurate) calculation:
  • HLB = 20 x (1044 / 1226) = 17
• HLB Calculation for Merj 49 (polyoxyethylene)21 stearate knowing that the total m.w is 1024 and Oxyethylene m.w is 44 Da:
  • HLB = 20 x (924 / 1024) = 18

HLB Scale Surfactant Uses

• HLB value is used to determine different uses for each surfactant
• HLB values and their uses are
  • 1: Oleic acid
  • 3.8: Glyceryl monostearate
  • 4.3:Sorbitan monooleate
  • 4.7:Sorbitan monostearate
  • 6.7:Sorbitan monopalmitate
  • 8: Glyceryl monostearate
  • 8.6: Gum acacia
  • 12: Sorbitan monolaurate
  • 15: Triethanolamine oleate
  • 16: polyoxyethylene sorbitan monooleate
  • 17: Polyoxyethylene sorbitan monolaurate
  • 40 Sodium lauryl sulphate

Classification of Surfactants

• Anionic
• Cationic
• Nonionic
• Amphoteric

Anionic Surfactants

• Release long chain anion upon dissociation, giving surface activity
• These feature a general formula of sulfate (OSO3-) while the cationic part is inactive
• Anionic surfactants are unsuitable for oral use due to unpleasant taste and irritant action

Anionic Examples

• Alkali soaps: Unstable below pH 10, incompatible with acids like potassium and sodium stearate
• Amine soaps: Triethanolamine oleate produced from reactions of amines with fatty acids
• Metallic soaps: Salts of divalent or trivalent metals with long-chain fatty acids
• Alkyl sulfates and phosphates: Esters formed by the reaction of fatty alcohols with sulfuric or phosphoric acid, e.g., sodium lauryl sulfate
• Alkyl sulfonate: Includes Dioctyl sodium sulfo succinate

Cationic Surfactants

• These must be ionized or dissociated to be effective
• Form +ve cations in aqueous solutions, providing surface activity with a general formula of trimethyl ammonium N(CH3)3+
• They're used as antiseptic, emulsifiers, and preservatives

Cationic examples

• Quaternary ammonium compounds like cetrimide (cetyl trimethyl ammonium bromide) and benzalkonium chloride (benzyl trimethyl ammonium chloride)

Ampholytic (Amphoteric) Surfactants

• Substances whose ionic characters depend on the pH of the system
• Below a certain pH (acidic) → cation, above the defined pH (alkaline) →anion
• At intermidiate pH → zwitterions
• Lecithin and N-dodecyl-alanine are examples

Non-Ionic Surfactants

• Constitute biggest group used in pharmaceutical preparations
• Advantages: compatible with anionic and cationic S.A.A., resist pH changes, resist effects of electrolytes, less irritant
• Disadvantage: Tend to inactivate preservation of phenolic or carboxylic groups
• Examples: Brij & merj 2, Spans, Tweens, Macrogol esters or polyethylene glycol (PEG), Glycerol monostearate

Micelle Formation

• Important property of surfactants where they have the capacity to aggregate in solution
• The aggregation process depends on the surfactants and condition of the system they are dissolved in
• Abrupt change in physicochemical properties is seen when specific concentration is exceeded will result in formation of oriented colloidal aggregates

How Micelles are Formed

• Surfactant molecules (monomers) orient at liquid-air interface upon addition of surfactants to water
• Monomers adsorbed at the surface become crowded with more surfactants until the interface is occupied. The surfactant is compressed at the surface and monomers become crowded
• Molecules of surfactant aggregate into micelles with further surfactant additions.

Micelle Shapes and Progression

• Monomers --> Spherical Micelle --> Cylindrical Micelle --> Lamellar Micelle
• Changes in surfactant concentration impacts micelle shape and structure

Why Micelles Are Formed

• To achieve a state of minimum free energy (more stability).
• To remove hydrophobic group form aqueous solution.

Critical Micelle Concentration (CMC)

• The concentration at which micelles are formed
• Surfactant concentration above which it migrates to the bulk, forms micelles and shows minimum surface tension value
• Surface tension goes down until CMC, at which point micelles form.

Factors Affecting CMC

• Molecular structure of surface active agent
  • Hydrocarbon chain (hydrophobic part)
    • Chain length: As chain length increases, micelle size increases, so CMC decreases
    • Branched hydrocarbon chain: Branching increases CMC since chain must come together in the micelle
    • Unsaturation: CMC increases by 3-4x with double bonds present

Factors Affecting CMC, Hydrophilic Group

• Hydrophilic group:
  • Type of hydrophilic group: Complete ionic dissociation leads to small effect on CMC
  • Number of hydrophilic groups: CMC increases in solubility as the number increases
  • Position of hydrophilic group: CMC increases when polar groups move from the terminal position to middle

CMC Additives

• Electrolytes: Addition of salts decreases CMC
• Alcohols: Decreases CMC facilitating micelle formation
• Hydrocarbons: Decreases CMC, facilitates micelle formation
• Other surfactants: Decreases or increases CMC

Temperature Effect of CMC

• Non-ionic surfactants: The CMC value first decreases with increasing temperature to a certain minimum, then increases with further temperature increase
• As temperature increases, hydrogen bonding weakens which facilitates micellization (lowers CMC)
• Rising temperature distorts water structure reducing micellization (higher CMC)
• Overall CMC increase or decrease relies on temperature related effects
• Ionic surfactants: Temperature has a small effect on the micelle property

Medical Applications of Surface Active Agents

• Antimicrobials: Quaternary ammonium compounds like benzalkonium chloride are antibacterial, used as disinfectants for instruments, and as antimicrobial agents in eye drops and creams
• Expectorants: Reduces the viscosity of bronchial mucus through inhalation of sprays with surfactants in cases of acute and chronic respiratory infections
• Cleansing agents: Surfactants have detergent properties

Pharmaceutical Applications of Surface Active Agents

• Solubilizing agents: SAAs extensively used as solubilizing agents for poorly soluble drugs like oil soluble vitamins, volatile oils, and hormones
• Also used as solubilizers for disinfectants like cresol or chloroxylenol
• This increases disinfectant property due to permeability changes in the cell membrane of microoganisms
• Wetting agents: Surfactants adsorbed at solid/liquid interface between powder particles and solvent increases affinity of hydrophobic powder of water
• Flocculating agents: Surfactants enable controlled flocculation for suspension powder particles
• Emulsifying agents: Reduce interfacial tension between oil and water phases by forming stable interfacial film
• Additives in semisolid preparations: Modify release characteristic of incorporated drug increasing skin absorption
  • For example: Tween and Span

State of Matter

• State depends on temperature and pressure of a given substance
• Five states of matter: solid, liquid, gas, plasma, super critical fluid (state of matter in which the matter behaves like a fluid without viscosity and with infinite thermal conductivity.)

Solids

• Particles are tightly packed, vibrating in a fixed position.
• Solids have a definite shape and a definite volume

Liquids

• The particles are tightly packed, but far enough apart to slide over one another to flow
• Liquids have an indefinite shape and a definite volume

Gas

• Particles of gases are very far apart and move freely
• Gases have an indefinite shape and indefinite volume

Plasma

• Plasma is an electrically charged gas
• Plasma particles have an electrical charge, and are affected by electrical and magnetic fields

Properties Differentials Across States

Boyle's Law

• States for a fixed amount of gas at constant temperature, the volume of the gas increases as its pressure decreases
• Formula: P1V1 = P2V2

Charles' Law

• States that for a fixed amount of gas at a constant pressure, the volume of the gas increases as the temperature of the gas increases.
• Formula: V1/T1 = V2/T2

Ideal Gas Law

• Combines Boyle's and Charles' laws forming a single equation
• PV=nRT, where P is pressure, V is volume, n is number of moles, R is universal gas constant= 8.314 J mol-1k-1 and T is temperature
• One mole of substance contains 6.023x 10^23 particles of that substance

Phase Changes

• The transfers between solid, liquid, gas, and plasma
• Transfers between the states are solid to liquid (melting), liquid to solid (freezing),  solid to gas (sublimation), liquid to gas (vaporization), gas to liquid (condensation) and gas to solid (deposition)
• These transfers increase (melting) or decrease (freezing) heat within the system

Heat Directionalities of Phase Changes

• Heat is required for: melting (solid → liquid), vaporization (liquid → vapour), sublimation: solid → vapour
• Heat is released by: condensation (vapour → liquid), freezing (liquid → solid), and deposition (vapour → solid)

Phase Diagram

• Shows what phases exists at equilibrium
• Allows to expect phase transformations expected when one changes parameters of the system
• A relationship between the temp, composition and quantities of phases at equilibrium
• Triple point: The point at which all the three curves meet. Here, the substance will be in a state of equilibrium between the three states and minor variations cause it to shift between them.
• Critical point: the point at which the Vaporization curve "ends". The pressure at this point is called the "critical pressure" and the temperature, the "critical temperature."

Crystalline and Amorphous Solids

• Solids are split into these two types
• Crystalline Solids: their structural units are arranged in fixed geometric patterns or lattices, exhibit a definite shape and an orderly arrangement of units, and have a sharp melting point (e.g.- quartz, sugar, table salt etc)
• Amorphous Solids: their structural units of are arranged in a random manner, do not have a sharp melting point, generally are more soluble than crystalline solids (e.g.- glass, woods, plastics, rubber etc)

Crystal Structure Attributes

• Constructed from repeating units known as unit cells
• Specific crystal unit cells share a size and number of molecules/ions arranged in the same way
• Has cubic, tetragonal, orthorhombic, rhombohedral, monoclinic, triclinic and hexagonal cells

Seven Basic Unit Cells

• Crystal forms divided into basic 7 units based on symmetry
• Simple cubic NaCl
• Tetragonal Urea
• Orthohombic Iodine
• Rhombohedral Quartz
• Monoclinic Sucrose
• Triclinic Boric Acid
• Hexagonal Iodoform and Beryl

Polymorphism Definition

• Polymorphism is the ability of a substance to exist in more than one crystal structure
• Also the ability of any compound or element to crystallize as one or more distinct crystal species with different internal lattice.
• Polymorphs of the same drug show different X-ray diffraction patterns, DSC, IR, may have different melting points, solubilities and bioavilability & also usually exist in different habits

Polymorph Stability

• The polymorphic form with the lowest free energy will be the most stable.
• The other polymorphs will tend to transform into

Crystal Habit Influence

• Impacts the ability to inject a suspension containing a drug in crystal form,
• Also impacts the flow properties and compressibility of a drug
• Crystal habit depends on conditions of crystallization that include solvent used, temperature, the concentration and presence of impurities and surfactants
• Conditions increase crystal growth through absorbption onto growing faces

Polymorphism Types

• Polymorph 1- Salt is a counter ion, Solvate is a solvent, Hydrate is water, Co-crystal is an excipient/API
• Polymorph 2- API is an excipient
• Enantiotropic has stable ↔ Metastable and reversible change, is affect by temperature, Moisture and grinding and has an examplenof sulphar
• Monotropic (Metastable) has Metastable → stable and irreversible change, not has affected by temp. moisture and grounding and has glyceryl stearate as an example.

Polymorphism Influencing Factors

• Temperature
• Pressure
• Solvents
• Agitation
• Milling
• Rate of crystallisation

Pharmaceutical Implications

• Formulation problems include: Polymorphs with specific crystal habits are hard to inject in suspensions or formulate as tablets
• Transformation changes lead to changes crystal size causing caking
• Crystal growth results in gritty creams
• Changes can cause produce different and unacceptable results
• Impacts Bioavailability Differences, crystal and Pseudopolymorphic solvates,
• Impacts solid form properties:
  • Dissolution
  • Stability
  • Processing