D1: Introduction to Formulation and Excipients Flashcards
Describe blood plasma concentration versus time graph
ONE NOTE
Describe oral drug delivery
-Non-invasive
-Painless
-Often associated with improved compliance i.e. the extent to which a patient correctly follows a drug scheme.
-Cost effective manufacturing
-Most extensively utilised route for drug administration. Around 80 % of drugs are preferentially administered orally1.
-Most medicines delivered to children are administered orally2.
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Describe the importance of drug dissolution
-Only substances in the molecularly dispersed form, i.e. in solution, are transported across biological membranes and are absorbed into the systemic circulation
-The rate and extent to which this happens is influenced by the excipients present
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Aqueous solutions vs solid dosage forms?
-Providing that no precipitation occurs, solution administration bypasses dissolution, and unlike following administration of a solid dosage form, there is no disintegration step.
-Because of the difference in number of intervening steps, bioavailability of a drug tends to obey the following:
aqueous solutions > aqueous suspensions > solid dosage forms.
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What is the Noyes-Whitney Equation?
The rate at which drug particles become individual drug molecules dispersed within a solvent, e.g. the gastrointestinal fluids, is known as the dissolution rate. The rate of dissolution is described by the Noyes-Whitney equation.
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What do we want when using the Noyes-Whitney equation?
-We want the dissolution rate to be a large number (meaning the rate is high, and dissolution is fast).
-This means that we want all the terms on the top of the fraction, i.e. the numerators, to be high. k, A, and (Cs – C) should be as big as possible. To make (Cs – C) as big as possible, we should make Cs large and C small.
-We want h, i.e. the denominator, to be small.
what is surface area of undissolved solid affected by?
-size of particles (smaller particles= bigger surface area)
-porosity of solid particles
what is the saturation solubility in diffusion layer affected by?
-temperature
-molecular structure
-crystalline form
-presence of other compounds
What is the concentration of drug in solution affected by?
Volume of dissolution medium (increase V, decrease C)
What is the diffusion coefficient affected by?
viscosity of the medium
what is the thickness of diffusion layer affected by?
degree of agitation of medium
role of excipients?
-aid preparation of the dosage form
-enhance patient acceptability
-enhance the functioning of the dosage form
what are the tablet excipients?
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Polymorphism?
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Describe salt forms
-The conversion of a weak acid to its sodium salt leads to a much greater degree of ionic dissociation of the compound when it dissolves in water, and the solubility consequently rises. This changes Cs in Noyes-Whitney.
-An example of this effect is found by a comparing the aqueous solubility of salicylic acid (1 in 550) and that of its sodium salt (1 in 1).
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Describe drug solutions
-Homogenous, molecular mixture of two or more components. The drug in solution is already in a molecular form and thus is available for absorption.
-It is the fastest acting oral dosage form, limited only by gastric emptying.
-In the neonatal, infant, and toddler age groups, peroral formulations are often solution based such as syrups, or may be suspensions1…
what are the possible limitations of drug solutions?
-Acidic drugs as salt form can precipitate in stomach…However, precipitate usually dissolves easily in small intestine
-Poorly water-soluble acidic drugs, e.g. Phenytoin, may have better bioavailability as a well formulated suspension of free acid
ONE NOTE
Describe suspensions
-The solid material (usually the drug) does not dissolve in the vehicle to any appreciable extent.
-Drugs are formulated as suspensions for oral delivery because they show limited aqueous solubility related to their target dose, and hence an aqueous solution formulation is not feasible.
Suspensions are almost as efficient as solutions. Typically, poorly water-soluble drugs show dissolution rate-limited absorption, therefore all physicochemical related factors apply especially:
-Particle size (A in Noyes Whitney).
-Wetting agents (A in Noyes Whitney since these result in an increase in total surface area in contact with the gastrointestinal fluids).
-Crystal form (Cs in Noyes Whitney).
-Viscosity (k in Noyes Whitney).
Describe parental drug delivery
-The parenteral route involves the injection of the formulation into the body at various sites. The three main parenteral routes are subcutaneous, intramuscular, and intravenous. When the intravenous route is used, drugs have 100 % bioavailability, since the entire dose is entering the circulation.
-Other parenteral routes exist, such as the intracardiac and intrathecal routes, but these are used less frequently
Issues with parental drug delivery?
Issues with patient acceptance include pain and inconvenience, but the parenteral route may be required when drugs are poorly absorbed following oral administration, when rapid absorption is needed, or when a patient is unconscious.
ONE NOTE
components of parental drug delivery?
-Injectables are usually sterile solutions or suspensions. Absorption is more rapid from solutions since the drug is already in the molecularly dispersed form.
-Drug may be in water or other vehicles. Alcohols, such as ethanol and propylene glycol, are common co-solvents in solutions delivered by the parenteral route.
-Oily vehicles can be used to provide a ‘depot’ of drug for slower absorption, since bodily fluids are aqueous. These are administered by the intramuscular route, and examples include penicillin injections.
-Common vehicles for intramuscular injections include esters such as ethyl ethanoate and benzyl benzoate.
-Other common excipients include substances which render the preparation isotonic, adjust the pH, and increase stability.
ONE NOTE
Describe vaginal drug delivery
-Vaginal suppositories (pessaries) are solid, single-dose preparations for vaginal insertion.
-Can be prepared in various shapes, usually ovoid, with a volume and consistency suitable or insertion into the vagina. Typically, they weigh around one gram.
-Contain one or more active substances dissolved or dispersed in a suitable base that may be soluble or dispersible in water or may melt at body temperature.
-Base should be non-irritating, physically and chemically stable, and pharmacologically inert.
-Leakage is less likely to be problematic if the viscosity of the vehicle after melting or dispersing is high.
Common bases for vaginal drug delivery?
-Hydrophobic Waxes Fats, Witepsols
-Hydrophilic Waxes Macrogols, PEG
-Gelatin (Hydrophilic),Glycerogelatin
-Hydrophilic bases are water miscible and mix with secretions. Choice of base depends on drug properties - no single ideal suppository base
Describe topical and transdermal drug delivery
-Ointments, creams, and pastes consist of a drug in a semi-solid base
-The base can be either hydrophobic or hydrophilic; this is important because the nature of the base governs release characteristics. Ointments are hydrophobic, whereas creams are semi-solid emulsions. Pastes are stiffer in consistency because they contain more solids.
Describe excipients in topical and transdermal drug delivery
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