PPFA 12 - Solution formulations and excipients

explain the different types of internal and external pharmaceutical solutions and their uses , identify commonly used excipients in solution formulations , describe their specific function, disscuss fcators affecting the stability of solutions and the packaging requirements for each type and compare advantaged and disadvantages of various pharmaceutical solution formulations.

What are pharmaceutical solutions ?

• Homogeneous mixtures — Uniform distribution of molecules or ions.

• Solute fully dissolved.

• Transparent and optically clear.

What are the types of pharmaceutical solutions ?

Types:

Internal: oral, parenteral, ophthalmic.

External: topical, nasal, ear.

What are excipients ?

Excipients are substances other than the drug, added to:

Enhance stability, bioavailability, and patient acceptability

Examples:

• Vehicles

• Solubility enhances or cosolvents

• Preservatives, antioxidants

• Sweeteners, flavours, colours

• Buffers, chelators

• Isotonicity & viscosity adjusters

What are the solvent types in Pharmaceutical solutions ?

• aqueous solvents

• nonaqueous solvents

What is a aqueous solvent ?

Aqueous solvents (Water-based)

• Most common solvent in pharmaceutical solutions.

• Purified Water: Produced by distillation, ion exchange, or reverse osmosis; used in non-parenteral formulations.

• Water for Injections: Further purified to remove pyrogens; used in parenteral preparations.

• ⚠ Tap (potable) water is not used due to dissolved impurities that can affect solubility and stability.

What makes a solvent good ?

• same/similar chemical properties 

What is a nonaqueous solvent ?

Examples of organic solvents

• Ethanol, Oils (e.g., arachis oil), Dimethyl sulfoxide (DMSO).

Applications: Intramuscular and topical solutions.

Disadvantages: potentially toxic or irritating, and may

not mix well with body fluids.

What can the size of the drug be in a solution ?

The drug in a solution can be:

• small molecule (e.g., citric acid)

• large biotherapeutic molecule (e.g., insulin, antibodies)- proteins and peptides

In solutions, the drug exists as molecules or ions, evenly distributed

throughout the solvent.

The concentration is kept well below saturation solubility.- why , to prevent precipitation during storage and temperature change

What can solubility in drugs be affected by ?

• Temperature

• Molecular structure

• Particle size

• pH

challenges - many. drugs have poor water solubility - requiring enhancement strategies 

How do you overcome poor solubility ?

• solubility enhancements

• add cosolvents  other chemicals 

the choice depends on - drug properties , route of administration , patient population

How do you enhance solubility by ph adjustment ?

Weak Acid:

HA⇌H++A−

(A weak acid partially dissociates to produce hydrogen

ions and its conjugate base.)

Solubility increases at increased pH ( more ionised)

Weak Base:

• A weak base combines with hydrogen ions to form its conjugate acid.)

• Solubility increases at decreased pH (more ionised)

How does adjusting Ph enhance solubility ?

Solubility principle:

• Ionised forms are more water-soluble than neutral forms.

• Use acids, alkalis, or buffers (e.g., citrate, acetate, phosphate) to achieve desired pH.

• Must avoid extreme pH to maintain physiological compatibility.

Key considerations:

pH must balance solubility, stability, and bioavailability.

pH affects:

Drug degradation rate (e.g., hydrolysis, oxidation).

Excipients' function (e.g., preservatives may lose activity at unsuitable pH).

Absorption, as unionized forms are better absorbed across membranes.

How do you enhance solubility using surfactants and micelles ?

Surfactants (amphiphiles): Molecules with a hydrophilic (water-loving) and hydrophobic (water- hating) part

• enhances solubility By lowering surface tension and providing a solubilizing environment for lipophilic drugs,

How micelles and surfactants work ?

1. Surfactants are "two-faced": They are amphiphilic, meaning each molecule has a water-loving head and a water-fearing tail.

2. Lowering Tension: Initially, surfactants break down the barriers (surface tension) between the drug and the water, helping them mix better.

3. Forming Micelles: Once enough surfactant is added (above the Critical Micelle Concentration), the molecules spontaneously group together to form tiny spheres called micelles.

4. Creating a "Hideout": In water, these spheres are structured with a non-polar, hydrophobic core (the tails pointing inward) and a water-soluble outer shell (the heads facing the water).

5. Drug Encapsulation: The poorly soluble drugs, being hydrophobic, are trapped within this internal "hideout" or core.

6. Increased Solubility: The micelle effectively "carries" the now-hidden drug through the water, drastically increasing its overall solubility and improving its absorption in the body (bioavailability).

What is the function of surfactants and micelles ?

Function:

• Accumulate at interfaces (e.g., water–air, water–oil), reduce surface tension.

• Form micelles above a specific concentration called the critical micelle concentration (CMC).

• Hydrophobic (non-polar) core: can trap and solubilize non-polar

(hydrophobic) drug molecules.

• Hydrophilic (polar) outer shell interacts with water ⟶micelle to stay dispersed

• When surfactant concentration > CMC, they self-assemble into micelles.

Examples: Polysorbates (e.g., Tween 80), Sodium lauryl sulfate , Bile salts

What is a cosolvent ?

Improve the solubility of nonpolar or poorly water-soluble drugs when

pH adjustment doesn’t work.

What is the principle of co solvents that allow it to enhance solubility ?

Principle: “Like dissolves like”

Polar drugs → dissolve in polar solvents (e.g., water)

Nonpolar drugs → dissolve in nonpolar solvents

Mechanism: Adding a water-miscible organic solvent reduces water polarity → increases solubility of nonpolar drugs.

Key point: Solubility ↑ as cosolvent fraction ↑, but limit concentration due to toxicity and formulation safety.

What Are some common co-solvents ?

Glycerol, Ethanol, Propylene Glycol

What is a cyclodextrins ?

• Cyclic glucose-based molecules with a hydrophilic exterior and hydrophobic cavity.

How do cyclodextrins work to enhance solubility ?

• Trap nonpolar drug molecules inside via non- covalent interactions ⟶ Improves drug solubility in water

• On administration, the drug is released from the cyclodextrin complex and then absorbed.

What are cyclodextrins most commonly used in ?

Used in:

• Eye drops – to improve delivery of corticosteroids

• Antiseptic gargles – to solubilise iodine

• Oral liquids – to enhance solubility of itraconazole (antifungal)

What happens when complex can form ?

• Adding a third substance can form an intermolecular complex with a solute.

• This complex can change (usually increase) the apparent solubility of the solute.

How It Works

The solute interacts with another molecule to form a complex.

The overall solubility depends on how soluble the complex is.

What are the requirements for solutions ?

• All solutions must be stable and acceptable to patients.

 Specific requirements vary by route of administration:

• Parenteral and ocular solutions: must be sterile.

• Oral solutions: must be palatable.

• Solutions in contact with body fluids (e.g. large volumes): should be

isotonic and at physiological pH.

• Multidose products require antimicrobial preservatives to prevent

microbial growth.

• These requirements are achieved by adding appropriate excipients (e.g.,

buffers, preservatives, stabilizers).

How do we choose excipients ?

Depending on the route of administration; for example:

Benzalkonium chloride is suitable for oral use but not for nebulizers

(causes bronchoconstriction).

Oral Route (e.g sucrose)

What are the different types of oral solutions ?

Syrups-

Contain a high concentration of sucrose or other sugars

(up to 85%).

Serve to:

Improve palatability (mask unpleasant tastes).

Act as a preservative by inhibiting microbial growth.

Can be used alone or as a vehicle in other preparations

(e.g., mixtures, elixirs).

May also contain active pharmaceutical ingredients.

Elixirs-

Typically clear, but may be coloured.

Formulated with:

• Alcohol: enhances solubility of certain drugs and serves as a preservative.

• Sugar (syrup): improves taste.

Suitable for drugs that require both aqueous and

alcoholic solvents.

Linctuses-

Example: Simple linctus

Viscous, sweetened preparations primarily used for cough relief.

Contain high sugar content; may also include alcohol.

Designed to soothe and coat the throat.

Oral Drops-

Example: vitamin drops

Concentrated oral solutions intended for administration

in small, precise volumes.

Useful for paediatric and geriatric patients or when a

accurate dosing is critical.

What are the advantages and disadvantages of oral solutions ?

ADVANTAGES -

• Easier to swallow

• Rapid absorption

• Uniform mixture

• More stable compared to suspensions

DISADVANTAGES -

• Less convenient to use

• Less stable overall

• May have an unpleasant taste

• Dosing accuracy may be lower

What are some excipients for oral solutions ?

• vehicle

• co solvent

• preservatives

• flavourings

• colouring agents

• sweeteners

• stabilisers

• thickeners

• buffers

What are the key components of  packaging ?

Plain amber glass/plastic bottles

• Click-locks

• Spoon Vs Syringe

 Expiry

• Some oral solutions will require a limited expiry date

once opened

• Example Sytron solution (Sodium feredetate for

anaemia): unopened expiry date 60 months, after

opening 3 months, affected by bacteria , contamination - drug degradation 

What are. key factors that effect degradation ?

• Hydrolysis

• Oxidation

• Reduction

• Dehydration

• Light-induced (photo-oxidation)

What are some stability strategies ?

• pH adjustment

• antioxidants & chelators

• light-protective packaging (e.g., amber bottles)

• nitrogen purging to reduce oxygen exposure

• preservatives for microbial protection in multidose products

What are the drop types ?

• aqueous 

• organic 

• alcoholic 

What are the different types of administration ?

• Eyes (occular) –

• Nose (nasal) –

• Ears (otic/aural) –

• Mouth (see oral drops)

What are key properties of eye drops ?

• usually aqueous solvent

• must be sterile

• packaging must protect form contamination

• once opened discard 28 days later

Possible excipients used :

Tonicity – should be isotonic 0.9%

• E.g. sodium hydroxide

Viscosity – increase viscosity can prolong contact with the eye

• Examples of viscosity enhancers include polyvinyl alcohol

pH – buffers to affect:

• Stability

• Therapeutic activity of the drug

• Comfort for patient (pH 7.2-7.4)

E.g. boric acid, sodium phosphate, citric acid, sodium hydroxide

Excipients eye drops part 2 

Oxidation – antioxidants to protect drug from oxidation

E.g. sodium metabisulphite

preservatives - may need more than 1

Benzalkonium chloride

• Most commonly used

• Broad spectrum anti-bacterial properties

• Not compatible with contact lenses

• Others include chlorhexidine

preservative free drops- 

• To be used after surgery or in hypersensitivity reactions

• Sterile single use vials, e.g. Minims

What packaging is used for eye drops ?

Single dose vials

• Injection moulded plastic with a sealed screw cap

• Sterilised by autoclaving

Plastic bottles

• Sterilised prior to filling

• Filled using aseptic technique

Glass bottles

• Mostly for extemp products

• 10ml ribbed amber bottles with dropper

• Must be sterilised after filling

Describe common characteristics/ requirements for nose , ear drops/spray?

Nose

• Solutions

• pH – 5.5-6.5

• Tonicity 0.9%

• Mostly local effect

• Congestion

• Inflammation

• Infection

• Some sprays can be used for

systemic effect

• E.g. Nicorette nasal spray

• Vehicles are usually aqueous

Describe common characteristics/ requirements for, ear drops/spray?

Ear

• Solutions

• Mostly local effect

• Softening ear wax

• Infection

• Inflammation

• Vehicles include

• Propylene glycol

• Oils

• Glycerol

• Water

What is the packaging used for nose and ear drops spray ?

• Nose and ear drops have similar packaging to eye drops

• Sprays

• Plastic Vs Glass

• Metered dose spray Vs squeezed bottle

• Age of patient

• Same stability issues as solutions

• Main issue is contamination resulting in a short shelf life once opened

What are the advantages and disadvantages of nose/ear drops ?

ADVANTAGES

• Convenient

• Reduced systemic side effects

• Local fast effects

• Sprays can be used for

systemic effects by passing 1st pass metabolism

• Drops can be administered in children

DISADVANTAGES

• Inaccurate dosing of drops and squeezed bottles

• Needs manual dexterity

• Patient preference

• Short shelf life once opened

What are some examples of external solutions ?

• Mouth wash and gargles - Concentrated solutions • Not to be swallowed Usually antiseptic - E.g. mouthwash

• Cleansers/antiseptics - Solutions

• Paints/tinctures • Concentrated aqueous/alcoholic solutions

• Evaporates after application

to deliver the drug E.g. Compound W

• Irrigations • Solution of 0.9% NaCl • For wound washing/cleansing

What are some excipients used for these external solutions ?

Excipients

• Similar to oral solution

• No flavourings or sweeteners

Stability

•Same as oral solutions

Packaging

• Similar to oral solutions

• Glass or plastic bottles

• Extemporaneous external liquids put in amber bottles

Summary 

• Different solution types vary by route of administration and require careful balance of solubility, excipients, and stability.

• Some excipients serve multiple roles across formulations.

•  Packaging and storage are vital for maintaining stability.

•  Overall, formulation design ensures product effectiveness and safety.