WEEK 4: DOSAGE FORMS, SOLUBILITY

The way we introduce a drug into the body:

• Liquids e.g. solutions: no delay, immediate release

• Solids: e.g. capsules and tablets: delay followed by rapid release

• Semi-solids: e.g. creams, ointments, gels and suppositories: no delay, but slow release

Solid dosage forms

• Powders

• oral powders – often effervescent (fizzy)

• topical powders

• Capsules

• hard capsule shells

• soft capsule shells

• Tablets

• immediate release

• not immediate release

• may or may not be coated

• e.g. enteric coated – polymer that prevents degradation

and release into stomach

Semi-Solid dosage forms

• Ointments: viscous, oily and difficult to remove from the skin, good for hydrophobic drugs

• Creams: water soluble emulsions (>2 liquids that are normally immiscible), easily removed from the skin, soft consistency, more appealing than ointments

• Pastes: differ from ointments that they contain a large amount of finely divided powdered solids (e.g. starch, zinc oxide)

• Gels/Jellies: transparent non-greasy preparations for external application to the skin

Solution dosage forms - terms

• Aqueous solution: water-based solution

• Syrups: concentrated, viscous, aqueous solutions containing sucrose or other sugars

• Elixirs: sweetened hydroalcoholic (water and alcohol) solutions for oral administration

• Spirits: alcoholic or hydroalcoholic solutions of aromatic volatile material

• Tinctures: alcoholic/hydroalcoholic solutions of plant materials

• Liniments: alcoholic or oleaginous (oily) solutions or emulsions intended to be used on the skin

Liquid dosage forms

• Most commonly these are water-based solutions

• called ‘aqueous’ solutions

• Can be classified by how they are administered (given in the body)

– oral solutions, topical solutions, injectable solutions, ophthalmic solutions

• May be suspensions (heterogenous mixture in which some particles settle out of the mixture upon standing) instead of solutions

• Properties of liquid dosage forms will depend on their use

– oral solutions must be palatable, injectables must be sterile

Liquid dosage forms - summary

• Solutions

– dissolved solute (active pharmaceutical ingredient (API) – minor component) in solvent (aqueous or non aqueous)

• Suspensions

– solute particle (e.g. insoluble solid) are dispersed in liquid  (aqueous or non-aqueous)

Can be:

• oral – (taste is a consideration)

• topical – (e.g. povidone iodine)

• injectable – (e.g. morphine)

NB: special conditions are required if a liquid dosage form is to be injected or applied topically to the eyes: isotonic with lachrymal secretions, buffered and particle free

What is in dosage forms?

• API

• active pharmaceutical ingredient i.e. ‘active’ drug

• Excipient/s

• inactive ingredients

• do not have a physiological effect in the body,

often include:

• diluent/solvent e.g. lactose in compressed tablets or water in solutions

• preservatives and anti-oxidants

• colours, flavours, viscosity agents

• additives to improve manufacturing process

Membrane permeability issues

Lipophilic functional groups:

• presence of aliphatic and aromatic structures

• absence of polar groups

Ionisation (increased polarity decreases permeability)

• Weak acids in intestines:

– are ionised in alkaline conditions

– are unionised in acidic conditions

• Weak bases in intestines:

– are unionised in alkaline conditions

– are ionised in acidic conditions

Surface area effects

Low Surface Area:

• eyes, nasal cavity, buccal cavity, rectum, stomach, large intestines

High Surface Area:

• small intestines, lungs

Blood flow effects

Low Blood Flow:

• eyes, stomach, large intestines, rectum,

subcutaneous tissue

High Blood Flow:

• small intestines, lungs, muscle, buccal cavity, nasal cavity

Blood flow effects: pharmacology

• Some drugs are vasoconstrictors

• Some drugs are co-administered with

vasoconstrictors

• Some drugs are vasodilators

Drug destruction at or near site of administration

• Liver

• hepatic enzymes

• ‘first pass’ effect

• Colon

• intestinal microflora

• Stomach

• digestive enzymes and acids

First pass effect

• Drugs that are absorbed via the GIT are circulated to the liver first via the hepatic portal vein

• Liver then acts as a filter

• Only part of the drug is circulated systemically

• The combination of processes is termed the 'first pass' effect

Drug administration

Method also depends on:

• Condition of the patient

– e.g. conscious/able to swallow?

• Advantages and disadvantages of various routes

– e.g. speed of absorption, degradation/removal from circulation

Routes of drug administration

1. Parenteral (injection into blood or tissues)

2. Enteral (via the GI tract)

3. Inhalation (e.g. lungs, throat)

4. Topical or local (e.g. skin, eyes, ears)

Apart from parenteral administration, all other routes require the drug to be absorbed. The length of time and the amount of drug that reaches the blood stream can vary significantly with each of these routes of administration.

Enteral

• Oral

•Sublingual

• Rectal

Parenteral

• Intravenous (IV)

• Intra-arterial (IA)

• Subcutaneous (SC)

• Intradermal (ID)

• Intramuscular (IM)

• Intraperitoneal (IP)

• Urethra

• Urinary bladder

• Intrathecal

• Epidural

• Directly Into target tissue

Topical

• Skin (Topical)

• Nose (Intranasal)

• Eye (Opthalmic)

• Ear (Otic)

• Vagina

• Inhalation

• Lungs

1. Enteral: e.g. Oral administration

• Common route drug has to survive the gastrointestinal tract (GIT)

• GIT consists of mouth, throat, stomach, and the small and large intestines

• GIT function - break down food and absorb nutrients (acids and enzymes)

• Drug has to survive gastric acid (HCI) in the stomach and digestive enzymes

• Tablet / capsule design can protect some drugs from stomach acids

Oral administration

• Drugs must pass through the cells lining the gut wall to reach the blood supply - (two fatty cell membranes)

• Very polar drugs are unlikely to cross fatty cell membranes (localised in the GIT - useful in designing drugs to treat gut infections)

• Very hydrophobic drugs are poorly absorbed - dissolve in fat globules from food resulting in poor surface contact with the gut wall

2. Inhalation - Respiratory System

• Respiratory system includes nose, airways, and lungs (trachea, bronchi, bronchioli, alveoli)

• Function of lungs - to exchange gases with blood supply (02 in, CO₂ out)

• Alveoli - air sacs with single cell walls surrounded by blood capillaries allowing fast efficient exchange of gases

• Surface area is 500 square feet (46.4 m²) dealing with 20 kg air per day

Inhalation

• Inhalation used for volatile gases (general anaesthetics) and anti-asthmatic aerosols (salbutamol or ventolin)

• Some inhaled drugs cross the cells lining the alveoli to access the blood supply required to cross two fatty cell membranes

• Very polar drugs are unlikely to cross cell membranes -useful property for anti-asthmatic drugs

• Drugs entering the blood supply through the lungs avoid the 'first pass effect'

3. Parenteral - e.g. injection

• Used for drugs which are poorly absorbed orally (e.g. morphine)

• Injected drugs may damage the area of injection causing localised inflammation and irritation

• Injected drugs have no cell membranes to cross in order to reach the blood supply - rapid distribution and fast effect

• No first pass effect through the liver

• High risk of toxicity or drug overdoses

• More difficult to counter toxic effects

Injection methods

• Intravenous - injection into veins

• Intramuscular - injection into muscle

• Subcutaneous - injection under the skin surface

• Intrathecal - injection into the spinal cord

• Intraperitoneal - injection into the abdominal cavity

• Intraocular - injection into the eye

• Intravenous method is fastest but riskiest

• Can lower the risk by using intravenous drips

4. Topical administration - local absorption

• Topical application of drugs for localised effect (e.g. menthol cream)

• Drugs act locally i.e. they do not reach the blood supply

• No first pass effect

Topical admin - transdermal absorption

• Used for topical application of drugs for systemic effect (e.g. nicotine patches)

• Drugs cross the skin to reach the blood supply

• No first pass effect

• Solvents may aid absorption of drugs

• Skin in different parts of body has variable porosity

• Chemicals are most easily absorbed where skin is thin (forearms)

• Chemicals that are soluble both in fat and water are most likely to be absorbed

• Absorption is increased if skin is moist or wet

Plasma concentration vs time: influence of route of administration

• Maximum (peak) plasma concentration and time taken to reach it depends on route of administration / rate of absorption

• After maximum plasma concentration is reached, it decreases with time (drug elimination)

Other routes of drug administration

Sublingual - rapid absorption

bypasses the liver

Rectal - great for patient that

• is vomiting or cannot (will not) swallow medication

Solute solvent interactions

• Solute molecules must interact with the solvent

• Solute-solute attractions need to break

• Solvent-solvent attractions need to break

• Solute-Solvent interactions must form

Solvent - solute interactions

• New attractions must form between solute and solvent

 • Essentially dipole forces

e.g: H-bonding or van-der-Waals

Buffer solution

• resists changes in pH when small quantities of weak acid or weak base are added

Composition of buffer solution

• a weak acid and its conjugate base

• a weak base and its conjugate acid

Tonicity: the capability of a solution to modify cell volume by altering water content

Clinical considerations:

Parenteral and ophthalmic preparations are isotonic with body fluids

• these solutions are prepared and buffered at an appropriate pH

• reduces irritation

• maintains the stability of products

• injections which are not isotonic should be administered slowly and in small quantities to minimise irritation, pain and fluid imbalance

Isotonic solutions

• A 0.9% NaCl is isotonic to blood cells

• it has same osmotic pressure as blood cells

• causes no swelling or contraction of contacting tissues

• causes no irritation in the eye, nasal tract, or other body tissues

• A 2.0% NaCl is hypertonic (shrinkage of cells)

• A 0.2% NaCl is hypotonic (swell, burst, haemolysis)

Calculations and solutions

• Concentration is denoted (C)

• Volume is (V)

• Amount of solute is (n)

In science the formula C =n/V used to calculate one of these variables when the other two are given

Amount can be in mass (g, mg, etc) or in moles (mol)

• Since C and V are related, if you change V of a solution but do not change the amount of substance (n) in the solution You 'dilute' a solution there is a formula to use for dilutions:

• C1V1 = C2V2

• C1 - is the starting conc (1st/initial conc)

• C2 - is the final concentration

• V2 - is the final volume (i.e. 'V' of the container or the 'V' you need to make)

• V1 - is the volume you need to move from one container to the other to create the final volume of the final concentration

Dosage forms: Controlled release

Additives (excipients)

Decrease Rate of Dissolution

• Binders

• Lubricants

• Coating agents

Increase Rate of Dissolution

• Disintegrants

Variable Effects on Rate of Dissolution

 • Diluents

• Coloring agents

• Flavoring agents

Dosage forms: Controlled release

Manufacturing parameters:

• tablet compression

• hard tablets dissolve more slowly

• tablet shape

• round tablets dissolve more slowly

• tablet size

• large tablets dissolve more slowly

Dosage forms: Controlled release

Delayed release preparations:

• enteric coating

• dissolve in intestines, not stomach

Sustained release preparations:

• reservoir diffusion products

• drug diffuses from pill core through membrane shell

• matrix diffusion products

• drug diffuses through matrix in which it is embedded

Dosage forms: Controlled release

• Sustained release preparations

• matrix dissolution products

• drug released as matrix dissolves

• osmotic tablets

• drug pumped out of tablet by osmotic forces

• ion-exchange products

• drug bound to resin exchanges with endogenous ions

Concentration

Pharmaceutical formulations:

• Solution

Suspension

Mixture of solid/semi-solid substances

• Common ways of expressing concentration:

• Volume-in-Volume (v/v)

• Weight-in-Weight (w/w)

• Weight-in-Volume (w/v)

• Molar concentration

• Other: mg/mL, Parts Per Million (ppm) and Parts Per Billion (ppb)

Volume-in-Volume (% v/v)

• Used to express concentration when both the solute and the solution are liquid (and both measured by volume) e.g. alcohol in water

• 70% v/v alcohol in water solution means that 70 mL of alcohol was dissolved in a sufficient quantity of water to make a total of 100 mL of solution.

Weight-in-Weight (% w/w)

• Used to express concentration when both the solute and the solution are expressed in units of weight.

• Also used to express the strength/concentration of some of the solid/semisolid products.

• 1% w/w hydrocortisone cream means each 100mg of the cream contains 1mg of hydrocortisone as the active ingredient.

Weight-in-Volume (% w/v)

• Used to express concentration when the solute is measured by weight and the final solution by volume.

• Since many drugs are solids dissolved in liquids, this is one of the most common expressions of pharmaceutical concentration.

• Sodium chloride 0.9% w/v IV solution means 9g of sodium chloride has been dissolved in 1000mL of solution 0.9% w/v). 9g/1000mL X 100 =0.9% w/v

NB: The units of measurement used for reporting w/v% are g for weight and mL for volume

Molar concentration (Molarity)

• Molar concentrations often expressed as millimoles per litre (mmol/L) and micromoles per litre (µmol/L or mcmol/L)

• Molar concentrations are sometimes used in expressions of clinical laboratory values and electrolytes

Other methods to express concentrations

• Parts Per Million (ppm) and Parts Per Billion (ppb):

• Used for extremely dilute solutions/ trace amounts.

• Parts per million (ppm): The number of parts of solute in a million (106) parts of solution

  • e.g. 20 ppm v/v alcohol → 20 mL of alcohol in 106 mL of a solution.

• Parts per billion (ppb): the number of parts of solute in a billion (109) parts of solution

  • e.g. 3 ppb w/v of sodium fluoride in drinking water → 3 g of sodium fluoride in 10 mL of drinking water

• Mainly used for environmental pollutants

Different drug salt forms

Manufacturers often combine an active drug into a salt form for different reasons such as:

• Produce better biopharmaceutical properties

• Increase solubility

• Increase stability

• Modify lipophilicity

• Modify absorption rate

• Rarely change drug's pharmacological properties

Different salt forms of drugs

• ~40% of oral active pharmaceutical ingredients exist as a salt with basic properties (e.g. hydrochloride, sulphate, acetate salts) → e.g. morphine sulphate, oxycodone hydrochloride

• ~10% of active pharmaceutical ingredients exist as a salt with acidic properties (calcium, magnesium, sodium, potassium salts) → e.g. Diclofenac sodium, diclofenac potassium

Different salt forms of drugs

Multiple salts of the same medication important when:

• Different salts may have different biopharmaceutical properties e.g. dissolution, absorption etc

• The strength of the drug on label is the mg of salt and not mg of the pure drug (e.g. 4 mg of perindopril erbumine salt contains 3.338 mg of perindopril.)

• When converting from one salt to another e.g. same amount of active ingredient in each salt may be different

• Different salt forms confer different therapeutic properties