Solubility

What is a solution?

A mixture of two or more components forming a homogenous molecular dispersion. A solution can be a solid dissolved in another solid, a liquid or a gas (same being true for liquids and gases) e.g. NaCl dispersed in water, nanoparticle dispersed in wat

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What is the difference between solubility and rate of solution

Solubility (inherent property affected by temperature, pH etc, can be modified by various methods). Solubility rate (rate of solution/dissolution, depends on factors - particle size, size distribution, surface properties, dissolution media)

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What does solubility depend on? (1)

The solvation energy of the solute in the solvent overcoming both the crystal lattice energy of solid and energy to create space in solvent for solute

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What does solubility depend on? (2)

Solubility of compound depends not only on properties of drug molecule itself (polarity, lipophilicity, ionisation potential, size) but also on properties of solvent and solid (crystal packaging, presence of solvates)

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What is the significance of solubility in formulation?

Amount of time the product remains in the stomach can vary – directions on medicines label (take before/after meals)

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Poor solubility/bioavailability can affect what?

HTS assays, ability to achieve efficacious and toxicologically relevant exposures in animals. Bioavailability of drug from formulation. Possibility of increased food effect. Inability to provide liquid formulations e.g. IV, paediatric/geriatric forms

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Give examples of drugs where solubility/dissolution affect bioavailability (1)

Digoxin (different particle size, mixed with different excipients, generate CR), penicillin V, phenytoin (low dose – ataxia, high dose – seizures). Digoxin/phenytoin (narrow therapeutic index). Quinidine, tetracycline.

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Give examples of drugs where solubility/dissolution affect bioavailability (2)

Getting the right amount in the right location at the right time

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Outline the process for the dissolution test

Drug in dissolution medium at different pH values, analyse samples (environment not similar to the stomach)

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What does the rate of solution/dissolution depend on? (1)

Inherent physicochemical properties of the drug, degree of agitation of solid/droplet, formation of saturated solution at solid/liquid interface, viscous properties of that saturated solution

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What does the rate of solution/dissolution depend on? (2)

Diffusion from this through stationary layer of solvent surrounding the particle

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Which factors affect dissolution? (1)

Intrinsic dissolution, volume of dissolution medium, dose:solubility ratio (lab/stomach/intestine/injection site), SA of solid, particle size/size distirbution, SA (internal porosity not just external surface)

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Which factors affect dissolution? (2)

Amount of liquid in contact with surface area of drug – varied (polymorphic structures). Porous material, high internal SA

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What are the other solution considerations? (1)

Potential for re-crystallisation/precipitation (change of form). Solution during granulation (tablets, capsules). Solution in suspensions during storage. Formulation drug/excipient dissolution. Bioavailability (tablets, capsules, aerosols)

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What are the other solution considerations? (2)

High chance of drug precipitating out, recrystallise into a different form

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Outline the steps for the drug to dissolve and enter systemic circulation

Tablet/capsule, dissolution (drug in solution). Disintegration (granule/aggregate), deaggregation (fine particle), dissolution (drug in solution), absorption (drug in systemic circulation), precipitation (fine particle - can enter back into solution)

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Give examples of pharmaceutical preparations as solutions

Oral solutions (gargles, liquid drops/medicines). Externally applied solutions. Syrups. Elixir/tincture/spirits. Parenteral injections. Alcohol tincture (issue for some countries)

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Which factors influence solubility?

Solvent, temperature, pH, hydrophilicity: hydrophobicity, particle size, size distribution, SA

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What are solvents used in?

Aqueous and non-aqueous solvents. Used in oral formulations, external formulations, injections, manufacturing processes

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Which solvents are used in oral and external formulations?

Aqueous and non-aqueous. Water, ethyl alcohol, glycerin, propylene glycol, arachis oil, ethyl oleate, liquid paraffin

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Which solvents are used in external formulations?

Industrial methylated spirit, isopropyl alcohol, benzyl alcohol, PEG, hexylene glycol, ethyl, isopropyl, butyl esters of palmitic, myristic, sebacic acids

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Which solvents are used in injectable formulations?

Water for injections, ethyl oleate, arachis oil, propylene glycol, benzyl alcohol, (fatty acids more suitable for SC/IM depot)

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Which solvents are used in manufacture?

Methy/ethyl/isopropyl alcohol, industrial methylated spirit, glycols, ethyl ether and higher ethers, acetone, acetic acid, (petroleum ether), (benzene), (chloroform)

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Describe features of temperature and solubility

For most substances, solubility increases with temperature. For some (e.g. potassium nitrate), the increase is quite fast. For others (NaCl), there is only a small change in solubility with temperature (graphs)

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Describe features of eutectic mixtures

Salt and water ratio, temperatures to form different states vary e.g. ice and salt solution, salt solution, solid salt and salt solution, solid salt and ice (freeze-drying) - graph

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What is the effect of pH on solubility for weak electrolytes? (1)

pHp= pKa + log (S-So/So). pHp (pH below which drug precipitates from solution as undissociated acid). S (total solubility). So (molar solubility of undissociated acid). Assume ionised form is freely soluble but not always true e.g. COOH has pKa of ~4

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What is the effect of pH on solubility for weak electrolytes? (2)

Acid (solubility increases with pH). Base (solubility decreases with pH). Both have sigmoidal shaped graphs

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What is hydrophilicity and hydrophobicity?

Hydrophilicity (polar, water loving). Hydrophobicity (non-polar, water hating). Ratio. Wettability (measure contact angle). Able to change hydrophilicity: hydrophobicity by using surfactants

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What do ionisable substances depend on?

pH (for solubility). Non-ionisable substances are usually hydrophobic (pH not needed)

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What are the methods to improve solubility/rate of solution? (1)

Solid state modification (particle size/distribution, new salt, polymorph). Liquid systems (co-solvents, lipid based systems, solution, emulsion). Additives/complexes (surfactants, polymers, cyclodextrins)

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What are the methods to improve solubility/rate of solution? (2)

Carrier mediated systems (liposomes, nanoparticles, solid dispersions)

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How does particle size and SA affect solubility/rate of solution?

Increased SA, more contact with liquid, improve solubility and increase rate of solution

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Describe features of solid state modification - effect of particle size and size distribution? (1)

Particle size and size distribution determines SA exposed to solvent. Rate of solution (under conditions of constant agitation/temperature) is proportional to SA of solid in contact with solvent

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Describe features of solid state modification - effect of particle size and size distribution? (2)

During dissolution, rate of solution will decrease due to a decrease in SA. Internal and external surfaces. Unless solid is fabricated - to expose a greater SA as dissolution proceeds

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What are the causes of poor solubility?

High crystallinity/high m.p (zwitterion, insoluble salts, H2 bonding networks). Hydrophobicity/high log P (lack of ionisable group, high mwt)

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Describe features of solid state modification - alter structure of molecule (1)

E.g. addition of polar groups like COOH, ketones and amines (can increase solubility by increasing H bonding and interaction with water). E.g. reduce intramolecular forces. Methyl dopa (solubility ~ 10 mg/mL)

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Describe features of solid state modification - alter structure of molecule (2)

and prodrug methyl dopate (solubility 10-300 mg/mL depending on pH)

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Give examples of salts and esters used in solid state modification (1)

Sulphate, bromide (S/E in body), phosphate, citrate, nitrate, tartrate, succinate, maleate, stearate, benzoate, silicate, acetate, lactate, proprionate, cinnmate, benzoate, hezanoate, phthalate, valerate, gluconate, mesylate, tosylate, besylate

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Give examples of salts and esters used in solid state modification (2)

Chloride, hydrochloride, napsylate

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Give examples of cations used in solid state modification

Na, K, Ca, Mg, Li, Zn, Al, choline, diethanolamine

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State features of solid state modification - crystal engineering (1)

Amorphous to crystalline. Crystalline to more soluble polymorph. E.g. polymorphs of riboflavin, graph, different crystal asymmetry/lattice energy, molecular forces

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State features of solid state modification - crystal engineering (2)

Generics - type of polymorphic form determines bioavailability, not the amount of API in formulation

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State features of dipolar (zwitterion) compounds

E.g. L-alanine, simple amino acid. At very low pH (acidic), proton donated to amino acid. At high pH, COOH ionised into COO-. Zwiterions have high solubility in water due to charged groups and poor solubility in most organic solvents

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Which co-solvents are used in pharmaceuticals?

Propylene glycol, PEG, ethanol, sorbitol

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Describe features of lipid based systems

(Olive oil), oleic acid, oleyl alcohol, isopropyl myristate, (silicones). Phospholipids (lecithin, phosphatidyl choline). No oxidation (e.g. oleic acid). Liposomes formed

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Describe the use of surfactants (1)

Surfactants used to enhance solubility. A surfactant or surface active agent is amphipathic (polar end/head and non-polar end/tail). When surfactant is placed in water it will form micelles

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Describe the use of surfactants (2)

A non-polar drug will partition into hydrophobic core of micelles and polar tails will solubilise complex

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Give examples of surfactants

Anionic (SLS), cationic (cetyl trimethyl ammonium bromide), non-ionic (polysorbate 80, Tween 80). Used to increase wettability/dissolution. Solubilisation, micelles (diagrams), liposomes

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Describe features of complexation (1)

Complexation relies on relatively weak forces such as London forces, H bonding, hydrophobic interactions. As concentration of complexing agent is increased, so is solubility, up to a point

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Describe features of complexation (2)

In some cases, complex can precipitate out of solution as the concentration of complexing agent is increased

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Describe features of complexation (3)

Solid solutions/solid dispersions/comelts. E.g. PEG (dissolve/disperse drug in heated PEG, comelt then cool/freeze, then subdivide into particulates). E.g. excipient of co-crystals (complex of drug/excipient co-crytallised, solvated/polymorphic)

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What is the effect of converting dextrin into cyclodextrin?

Solubility is increased (e.g. digoxin placed in cyclodextrin for drug delivery)

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What are the three types of carrier mediated systems?

Liposomes, nanoparticles, solid dispersions

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State features of liposomes

Micellar structures, used for drug delivery e.g. anti-cancer drugs (antibodies bound to surface), stealth

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State features of co-crystallisation

E.g carbamazepine, forms supramolecular complexes with other excipients. Carbamazepine: saccharin

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State features of nanoparticles

Drug in solution, supercritical fluid crystallises droplet, evaporation, production of minute sized particles. Large SA – enter solution instantly. E.g. gold incorporated into structure, application of heat, kill tumours in the body

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Solubility

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