Lecture 47: Liquid dosage forms for oral administration- solutions

what are the advantages of pharmaceutical oral solutions?

1. easier to swallow(old ppl, patients)

2. faster therapeutic response(drug instantly available for absorption)

3. homogenous system, uniform distribution, no issues with phase separation such as with emulsions and suspensions

4. reduced irritation, immediately diluted by gastric contents

5. masks taste of bitter therapeutic agents

what are the disadvantages of pharmaceutical oral solutions?

1. problems associated with manufacture, transport(breaking container), administration

2. growth of microorganism

3. poorer stability of excipients in aq sol vs a solid dosage form(ie surfactants, preservatives, colours, flavours)

4. shorter shelf life

5. less dose accurate (can fix by using 5ml spoons)

6. taste

7. unsuitable for drugs which are chemically unstable in presence of water

8. expensive to ship, bulky for patient to carry(weight)

what are some challenges to making oral solutions?

• Homogeneity in the formulation, being all the same composition

how does the aqueous solubility of the drug affect the formulation at specific pH’s?

• high solubility at selected pH: drug is readily incorporated into the vehicle

• Moderate solubility at selected pH: drug solubility in the formulation needs to be enhanced using co-solvents, related methods

• low solubility at selected pH: alternative dosage form should be used: e.g. suspension

what are the features of the vehicles used in oral solutions?

they are made from purified water USP

• low cost and toxicity

• tap water shouldnt be used as it has chemical incompatibilities

• cant be used for parenteral formulations as they have to be sterile

how is purified water prepared?

• distillation

• ion exchange methods

• reverse osmosis

the solid residue obtained after evaporation <1mg/100ml of evaporated sample

How can we increase the solubility of drug within formulation?

use cosolvents:

• glycerol can be used and it has cosolvency properties due to 3 OH groups

• alcohol: ethanol can be used

• propylene glycol USP

• poly(ethylene glycol): repeating units of ethylene oxide

  • lower MW grades (PEG200, 400) are preferred in pharmaceutical solutions

surface active agents and complexation can be used too

what are the different types of excipients in pharmaceutical oral solutions?

• Buffers

• sweetening agents

• viscosity enhancing agents

what are buffers used for plus examples:

• control pH

• acetates(1-2%), citrates(1-5%), phosphates(0.8-2%)

what are sweetening agents used for plus examples:

• they increase the palatability of drugs

• eg. sucrose, glycerol, sorbitol, aspartame

what are viscosity-enhancing agents used for plus examples:

non-ionic: methylcellulose(cellulose derivatives)

ionic hydrophilic polymers: sodium carboxymethylcellulose(anionic)

some liquid formulations dont need viscosity inhancing agents(syrups: inherent viscosity)

what are antioxidants?

• redox systems that exhibit increased oxidative potential than drug OR

• compounds that inhibit free radical induced drug decomposition

how are antioxidants used?

some drugs are susceptible to chemical degradation by oxidation, so we add antioxidants to them

• they increase the stability of the drug

• they are oxidised(degraded) instead of the drug which protects the drug from decomposition

• they can be water soluble or water insoluble

what are preservatives and what are their properties?

preservatives control the microbial bioburden of the formulation

properties:

• they have a broad spectrum of antimicrobial activity( G+, G-, bacteria, fungi)

• chemically and physically stable over the shelf life of the product

• low toxicity

what are examples of preservatives we use?

• benzoic acid and salts (0.1-0.3%)

• sorbic acid and its salts(0.05-0.2%)

• alkyl esters of parahydroxybenzoic acid(0.001-0.2%); combination enhancement of the antimicrobial spectrum

why is the preservative efficacy in oral solutions important and how can it be affected?

the correct form of preservative needs to be available at the required conc to inhibit microbial growth. This is known as the Minimum inhibitory concentration: MIC(minimum conc to inhibit microbial activity)

• the conc of preservative may be affected buy other excipients and formulation pH:

  • the pH of formulation

  • the presence of micelles

    • the presence of hydrophilic polymers

the unionised form of the preservative is the one with the antimicrobial properties.

the preservatives diffused across the outer membrane of the microorganism and eventually into the cytoplasm. the cytoplasm has neutral conditions which allow the preservatives to dissociate which acidifies the cytoplasm and inhibits microbial growth

• the fraction of acidic preservative at a particular pH can be calculated with the henderson-hasselbalch eq

how does the presence of micelles affect preservatives?

micelles solubilise lipophilic drugs

• the lipophilic properties(unionised form of acid preservatives) may partition into the micelle which then decreases the available and effective conc of preservative in solution

• they will be in equilibirum

• so therefore increasing the conc of preservative means the conc of free preservative in the formulation is > or = to the MIC of the preservative

why does the conc of free preservatives decrease in the presence of hydrophilic polymers?(methylcellulose)

may have a chemical interaction between the preservative and the dissolved polymer

• to fix that problem , we just need to increase the conc of preservative in the formulation

what are the different flavours for the 4 different taste sensations?

4 basic taste sensations: salty, sweet, bitter and sour

- a salty taste: butterscotch, apricot, peach, vanilla, wintergreen mint

- a bitter taste: cherry, mint, anise

- a sweet taste: vanilla, fruit and berry.

- a sour taste: citrus flavours, raspberry.

flavour adjuncts (methanol and chloroform) add flavour and act to desensitise the taste receptors

preferred colour to formulation; in combination with flavours, colour should match flavour (green with mint-flavoured solutions); not prerequisite for solutions

how do we prepare and manufacture these solutions?

•Simply dissolving the solutes (actives, inactives) in solvent or solvent mixture then pass through Filtration system

•Industrial scale: large mixing vessels with ports for mechanical stirrers; vessels thermostatically controlled (maintain a certain temperature); order of addition of components is fixed (product development and scale-up)

what are the types of pharmaceutical oral solutions

• oral solutions

• oral syrups

• oral elixirs

what are features of oral solutions

•systemic absorption of the drug

into the SI then to the blood

•formulated over a broad pH range

•usual pH:~ 7.0 (unless issues regarding solubility or stability of drug)

•All components of the formulation should be soluble, with no evidence of precipitation.

what are features of oral syrups?

• highly concentrated, aqueous solutions of sugar or sugar substitute; flavouring agent (cherry syrup)

• unflavoured syrup: aqueous solution containing 85% sucrose.

• drugs: directly incorporated into these systems or added as the syrup is being prepared.

•choice of syrup vehicle: physicochemical properties of drug. i.e. orange syrup: acidic therefore solubility of acidic drugs may decrease [precipitation of the drug].

what are the oral syrup components?

1. purified water

2. sugar(sucrose) or sugar substiutes(artificial sweeteners)(60-80%)

   • for syrups, already have inherent sweetness and moderately high viscosity so theres no addition of sweetening agents or viscosity modifying agents

   • in syrups, we have a high conc of sucrose so not a lot of available water so no microbial growth so we dont use preservatives

   • non sucrose bases can also be used: sorbitol solution USP(64% w/w)

   • sugar free syrups: for children and diabetic patients

what are the oral syrup components?

3. flavours:

   • natural origin (peppermint, herbs, lemon, spices)

   • synthetic flavours

   • some flavours have mild therapeutic activity: e.g. lots of antiacids contain mint due to its carminative properties

4. colours

what are oral elixirs?

clear, hydroalcoholic solution formulated for oral use

• the conc of alcohol is sufficient enough to ensure that all of the other components remain in solution>10% v/v; other polyol co-solvents may be incorporated

• however the presence of alcohol may be a problem for paediatric formulations or adults who wish to avoid alcohol or cant consume it

• preservatives are not needed for elixirs with >12%v/v alcohol as they have enough antimicrobial properties

theophylline elixir

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