Oral solutions - formulations

define oral solution

Oral liquids containing one or more active ingredients dissolved in a suitable vehicle

is a solution homogenous

A solution is homogeneous, i.e. colour, density is the same throughout

is a solution filtered

When a solution is filtered, no residue particles are left on the filter paper

does the solution seperate from the solvent

When a solution is left to stand, the solute does not separate from the solvent

is a suspension homogenous

A suspension is not homogeneous, i.e. it is heterogenous; particles >100 nm

when a suspension is left to stand do the patricles settle

When a suspension is left to stand, the insoluble solids settle to the bottom of the container

what is a colloidal dispersion

Particles intermediate in size between those found in solutions and suspensions can be mixed in such a way that they remain evenly distributed without settling out.

how are particles held in suspension

they are held in suspension due to brownian motion

what is the particle size like

Particles range in size from 10-9 m (1 nm) to 10-6 m (1000 nm) in size and are termed colloidal particles or colloids.

what are the components of a solution

The components of a solution are atoms, ions, or molecules, making them 10-9 m (1nm) or smaller in diameter

is a solution homogenous

yes

is a colloid hoogenous

no

is a suspesion homogenous

no

what is the paricle size for a solution

0.01-1 nm

atoms ions or molecules

does a solution sperate on standing

no

can a solution be seperated by filtratrion

no

does a solution scatter light

no

is a colloid homogenous

no

-it is heterogenous

colloid particle size

1-1000 nm

dispersion

large molecules/aggregates

do colloids seperate on stabdig

yes

can a colloid be seperated by filtration

yes

does a colloid scatter light

yes

is a suspension homogenous

no

-heterogenous

particle size of a suspension

1000nm

do particles seperate on standing

yes

can a suspension be seperated by filtration

yes

does a suspension scatter light

may scatter light or be opague

what is the ideal solvent

water

why is water an ideal solvent

Freely available, cheap, non-toxic

- Purified water

are all drugs soluble in water

no

what are some stability issues with a drug and water

- some drugs are not stable in aqueous solution

what do you always assume in the case of stability

assume that the drug is not stable in water for a long period of time

what does solubility and stability depend on

H dependent solubility and stability

-ph dependent solubiloity

An acidic drug will have max solubility at a high pH

-ionised form of the drug is the more soulbule form of the drug

how can you increase the solubility of a drug

cosolvency

pH control

solubilisation

complexation

chemical modification

what is cosolvency

the use of liquids such as - Ethanol, glycerol, propylene glycol to increase the solubility of a drug in water

PH control

most drugs are weak acids and weak bases

you can optimise the solubility of the drug by changing the pH

weak acids are more soluble in high pH

pH control and preservitives

water is a breeding ground for bacteria

-many preservitives that are added to a solution are pH dependent

solubilisation

you can increase the solubility of the drug by solubilising the drug in micelles

complexation

when two different molecules associate or attach to each other

of a substance which is used to increase solubility

cyclodextrins [cyclic oligosaccharides]

they are cyclic in their arrangement with a cavity into which a poorly soluble drug can be attached

chemical modification

(e.g. salt formation)

Salt form will have a better tendency to ionise and a better solubility

what are some formulation additives

-buffers

-colours

-flavours

-preservitves

antioxidants

thicking agents

what are some buffer examples and what are they used for

Citrate, carbonate, phosphate, lactate, gluconate, tartrate

keep the pH constant

what are colours used for

important for pedatric compliance

what is a dye

a colouring agent which is soluble in wataer

what is a pigment

a colouring agent that is soluble in inorganic solvents

why are flavours important

-hide any nasty taste as a result of the API

what can you use to mask a salty taste

apricot

butterscotch

liquorice

peach

vanilla

what can you use to mask a bitter taste

anise

chocolate

mint

passion fruit

wild cherry

what can you use to mask sweet

vanilla fruits berries

what can you use to mask sour taste

citrus fruits

liquorice

rasberry

Name 5 commonly used sweetening agents found in pharmaceutical oral solution preparations.

Syrup (~20% v/v - 60% v/v)

- Orange syrup (~10 - 20% v/v)

- Raspberry syrup (~10 - 20%v/v)

- Conc. raspberry juice (~2.5 - 5% v/v)

- Concentrated peppermint emulsion (~2.5% v/v)

- Sorbitol (or

what is the point of a preserivite

prevent any growth of bacteria

-very important if the vehicle is aqueous based

why are anti-oxidants

used if the drug is susceptable for oxidation

what are syrups used in

used in exemeprous preperation

-high levels of sucrose therefore not good for the teeth

-not used in commercial

what is a pharmaceutical syrup

produced by mixing purified water, sweeteners, active ingredients (API), aromas, flavors and other ingredients (thickeners) etc

It works as an expectorant. So the bacteria are removed along with the mucus.

what is tincture

a solution in which the solvent is alcohol

why do you include a preservitive

Every oral liquid preperation shoukd include a preservitive

If there is no preservitives in the formulation there is chance for a bacterial growth

The bacteria may not harm the patient however the patient may not want to take the formulation

The bacteria could cause a change in ph and it may cause

-solubiloity if the API

-stability of the API

what is a preservitive

Chemical agents that prevent growth of microorganisms in the product, thereby rendering it safe in use and increasing its shelf life.

what are preservitves used in

Preservatives are typically used in liquid products that do not have extreme pH values or a high concentration of surfactants.

E.g., products with a pH between 3 and 10 generally require preservative(s) to avoid growth.

what are the options used for preservitives

-chloroform water

-chloroform spirit

-doublestrength chloroform water

-alcohol compounds

what should the final conc of chloroform in the preperation

Appropriate volumes should be used such that final concentration of chloroform in the preparation is 0.25% v/v

what is chloroform spirit

- Chloroform 50ml

- Ethanol (90%) to 1000ml

what is chloroform water

Chloroform 2.5ml

- Water to 1000ml

what is double strength chloroform water

- Chloroform 5ml

- Water to 1000m

what are the alcohol compounds that can be used as preservitives

-ethanol

-benzyl alcholohl

-glycerol

-propylene glycol

ethanol as a presivites

Ethanol >10% v/v

Mainly used as a cosolvent but it can have a dual function

what is benzyl alcohol

-%v/v

-ph optimim

-who should you not give it to

2.0% v/v

(N.B. don't use in newborns - fatal adverse reactions).

Optimum activity at pH less than 5

what %v/v should u use for glycerol

20% w/v

what is propelene glycol conc

15-30 %w/v

how does the martindale describe of paracetamol

"Sparingly soluble in water; freely soluble in alcohol; very slightly soluble in dichloromethane."

what is sparingly soluble in water

1 in 30 to 1 in 100

-at best I gram of paracetamol will dissolve in 30g of solvent

At worst 1 gram will dissolve in 100g of solvent

what solubility should you assume

the worst solubility

what is the solubility of paracetamol in alchol

Freely soluble:

1 in 1 to 1 in 10

what is to note about alcholol in preperations for children

• Children are more sensitive than adults to some of the effects of ethanol. Relatively small amounts of ethanol can produce hypoglycaemia, especially in infants and young.

• Signs of coma, hypoglycaemia and hypothermia may occur when the blood alcohol content (BAC) exceeds 50-100 mg/100 ml.

how are the limits of ethanol set

It is desirable that no ethanol be included in paediatric medicines because the safety implications are not well understood. However, if ethanol is unavoidable, the concentration should be kept as low as possible.

• The amount of ethanol contained in any medicine should not be able to produce a blood concentration greater than 25 mg/100 ml after a single dose, and appropriate dosing intervals should be prescribed to prevent accumulation of blood alcohol

how does the EMA set limits on the use of ethanol

the presence of ethanol should be based on each dose of a medicinal product, rather than related daily exposure.

In all cases, the amount of ethanol contained in a dose or volume of a medicinal product must be given.

what is the acceptable dose of alcohol for children

he amount of ethanol contained in any medicine should not be able to produce a blood concentration greater than 25 mg/100 ml after a single dose, and appropriate dosing intervals should be prescribed to prevent accumulation of blood alcohol.

what is an elixer

-likely to have ethanol/propelyne glycol as cosolvents

bezoic acid as a preservitive

Oral solns & susps: 0.01 - 0.1% w/v

Slightly soluble in water, freely soluble in EtOH Greatest activity at pH 5

Benzoic acid solution B.P.

what is glycerol used for

a preserivitve

Used as sweetening and thickening agent in alcoholic elixirs (up to 20%)

what is propelyne glycol used for

a preservitve

Also used as solvent/co-solvent and thickening agent

list other common preservitives

sodium benzoate

scorbic acid

potassium sorbate

What are the "parabens" preservatives and why are they widely used?

Parabens are a family of related chemicals that are commonly used as preservatives in cosmetic products.

to prevent the growth of harmful bacteria and mold,

As a group effective over wide pH range (4-8) and have broad antimicrobial activity

solubility of the parabins

• Often used in combination - activity may be improved - additive effects (e.g. Nipasept) •

Poor solubility - often used as sodium salt

what are examples of parabens used for preservitives

Butylparaben 0.006-0.05% w/v for oral solns. and susps.

• Ethylparaben 0.01-0.05% w/v for oral solns. and susps.

• Methylparaben 0.015-0.2% w/v for oral solns. and susps.

• Propylparaben 0.01-0.02% w/v for oral solns. and susps.

what are antioxidants

Typically in aqueous solution antioxidants are oxidised (and hence degraded) in preference to the therapeutic agent, thereby protecting the drug from decomposition

give 4 examples of antioxidants

Ascorbic acid and sodium ascorbate • Sodium metabisulphite • Sodium sulphite • Sodium formaldehyde sulphoxylate

why are thickeners used

Patients may perceive a thick liquid to have a stronger effect than a "watery" liquid -

Thickeners may enhance the sensory impact of a cough medicine by prolonging the residence of the preparation in the mouth and prolonging the duration of any sweet taste,

- Some thickeners, e.g. glycerol, have demulcent properties that help to soothe an inflamed throat/pharynx

what is a demulent property

forms soothing film over irritated or inflamed internal tissue

examples of thickening agents

o Glycerol

o Propylene glycol

o Hydroxyethylcelulose,

o Carmellose sodium

o Xanthan gum

define a mixture

are oral liquids, usually aqueous preparations, containing one or more active ingredients dissolved or suspended in a suitable vehicle.

define an elixer

a clear, flavoured oral liquids containing one or more active ingredients dissolved in a vehicle that usually contains a high proportion of Sucrose or a suitable polyhydric alcohol or alcohols and may also contain Ethanol (96 per cent) or a Dilute Ethanol.

define a linctus

are viscous oral liquids that may contain one or more active ingredients in solution.

The vehicle usually contains a high proportion of Sucrose, other sugars or a suitable polyhydric alcohol or alcohols.

what is a linctus used to treat

Linctuses are intended for use in the treatment or relief of cough, and are sipped and swallowed slowly without the addition of water