lectures1,2,3, 4.pdf

Chapter I: Pharmaceutical solutions

Pharmaceutical solutions defined as: liquid preparations in which the therapeutic agent and the

various excipients (known as solutes) are dissolved inaqueous or non –aqueous solvent (known as solvent).

Or it may be defined as a mixture of two or more componentsthat form a single phase which is homogenous down to themolecular level.

The solvent system (vehicle), is likely to be liquid The solute will be either a liquid, gas or a solid.

Solutions of gases in liquids are characteristic of aerosols, inwhich the propellant gas is dispersed or dissolved in thesolvent under pressure.


Advantages of pharmaceutical solutions for oral administration

Easily administered orally to individuals who have difficulty inswallowing, e.g. elderly patients, infants.

The therapeutic agent is dissolved in the formulation And therefore is therefore immediately available for

absorption.

Providing the drug does not precipitate within thegastrointestinal tract, the bioavailability ofpharmaceutical solutions is greater than that of oral solid-dosage forms.


Dis-advantages of pharmaceutical solutions for oral administration

They are unsuitable for therapeutic agents that are chemicallyunstable in the presence of water.

The poor solubility of certain therapeutic agents may prohibit theirformulation as pharmaceutical solutions. However, certaintechniques are available to improve drug solubility (will be discussedlater)

Pharmaceutical solutions are expensive to ship and are bulky forthe patient to carry due to the associated mass of the product.


Dis-advantages of pharmaceutical solutions for oral administration

Difficult to mask bad taste or odour.

They are liable to deterioration faster than solid dosage forms.

Has high possibility of bacterial growth.


Manufacture of solutions:

For small and large scale manufacture all what we need is dissolvingall ingredients in the solvent.

Equipment required for solutions preparation are: mixing vessels, ameans of agitation and a filtration system to ensure clarity of thefinal solution.

During manufacture, ingredients (solutes) are added to the solventin the mixing vessel and stirring is continued until dissolution iscomplete.



If solute is more soluble at elevated temperature, it may beadvantageous to apply heat. However, caution should be takenespecially if there are volatile or thermo-labile materials..

Size reduction is advantageous as it will increase the surface areaand speed up the solution process.

Solutes present in low concentrations particularly dyes are dissolvedin a small volume of the solvent then added to the bulk.



Volatile materials should be added last and after cooling to reduceloss due to evaporation.

Finally it is essential to make sure that there is no significant amountof any of the ingredients is adsorbed irreversibly onto the filtermedium used for final clarification


Pharmaceutical solutions may contain a range of excipients, each witha defined pharmaceutical purpose such as:

The vehicle, usually purified water

Co-solvents, e.g. propylene glycol, glycerin, alcohol

Agents specifically to enhance the solubility of the therapeutic agentin the vehicle, e.g. surface-active agents

Preservatives, e.g. parahydroxybenzoate esters(methylhydroxybenzoate and propylhydroxybenzoate), boric acidand borate salts, sorbic acid and sorbate salts, phenolics


Pharmaceutical solutions may contain a range of excipients, each witha defined pharmaceutical purpose such as:

Sweeteners, e.g. glucose, saccharin, aspartame

Rheology (viscosity) modifiers, e.g. hydrophilic polymers (cellulosederivatives, alginic acid, polyvinylpyrrolidone)

antioxidants, e.g. sodium formaldehyde sulphoxylate, butylatedhydroxyanisole, butylated hydroxytoluene

Colours

Flavours

Buffers to regulate the pH of the formulation, e.g. citrate buffer.


Classification of solution according to method of preparation:

Simple solution: prepared by dissolving solutes in solvent, it maycontain additives that help in solubilisation and stability of activemedicaments. E.g. calcium hydroxide topical solution, Iodinesolution

Solution by chemical reaction: formed by reacting 2 or moresolutes with each other in a suitable solvent. E.g. Aluminium sub-acetate topical solution

Solution by Extraction: Drugs or pharmaceutics obtained fromvegetables or animal source are extracted with a suitable solventsuch as water or water containing substances.


Classification of solution according to vehicle:

Aqueous solution

Non-aqueous solution

Aqueous solution: Water is the most widely used as a solvent.

Advantages: Inert (has no pharmacological effect). Palatable. Inexpensive. Safe (non-toxic when used internally and non-irritant when used

externally) Physiological compatible.



Disadvantages of Aqueous solution:Some drugs form unstable solutions when dissolved in water.

Types of pharmaceutical water:

(1) Potable water: It is water suitable for drinking. Salts often dissolve in potable water are undesirable. Contains less than 0.1% of total solids as dissolved and undissolved

organic matter and micro-organisms.

N.B. hard water contains calcium and magnesium cations.




(2) Purified water B.P.

Has been freshly boiled and cooled immediately before use to

destroy any vegetative microorganisms that might be present.

Purified Water is normally prepared by

Distillation of potable water: e.g Distilled water

Deionization of potable water: e.g demineralized water or de-

ionized.

Reverse osmosis





Distillation

Water is first heated to boiling. Then the water vapour passes

through a condenser where cooling water lowers the temperature

so the vapour is condensed, collected and stored.

Most contaminants stay behind in the liquid phase vessel.





Deionization:

Refer to water lacks ions present in tap water.

Tap water is usually full of ions from the soil (Na+, Ca2+), from the

pipes (Fe2+, Cu2+), and other sources.

Why de-ionize water? Because ions can interfere with chemical

processes.





Deionization:

Water is usually deionized by using an ion exchange process.

The ion-exchange equipment involves the passage of water

through a column of cation/anion exchangers, consisting of water-

insoluble, synthetic (resin).





Deionization:

These resins are mainly of two types;

The cation, or acid exchangers: permit the exchange

of the cations in solution (in the tap water) with

hydrogen ion from the resin

The anions or base exchangers: permit the removal ofanions.





Deionization:

These resins are mainly of two types;

The processes are indicated as follows, with M+ indicating the metal

or cation (as Na+) and the X-indicating the anion (as Cl-).

Cation ExchangeH-Resin + [M+ + X- + H2 O] ………M-Resin + H+ + X- + H2O

Anion ExchangeResin-NH2 + [H+ + X- + H2 O] ……… Resin-NH2.HX + H2O (pure)





Deionization:

N.B. Water purified in this manner is referred to as demineralized or

de-ionized water and may be used in any pharmaceutical preparation

or prescription required distilled water.

Advantages of ion exchange resins over distillation:No need for heat and hence, less cost and troublesome ofmaintenance.




The process of reverse osmosis:

Reverse osmosis is a filtration procedure typically used for water.

Removes many types of large molecules and ions.

It works by using pressure to force a solution through a membrane

retaining the solute on a side and allowing the solvent to pass

through the other side.





This is the opposite of nature osmosis process where solvent

moved from the region of low solute concentration to solute with

high concentration without applying an external pressure.

This process is commonly used in desalination of sea water to

produce fresh water. It is also used to purify fresh water for

industrial applications.





The pore size of semi permeable membranes can remove particlesdefined in the range of

Microfiltration (0.1 to 2 microns, e.g., bacteria) Ultrafiltration (0.01 to 0.1 microns, e.g., virus) Nano filtration (0.001 to 0.01 microns, e.g., organic compounds in

the Molecular weight range of 300 to 1000).

Reverse osmosis removes particles smaller than 0.001 microns;virtually all virus, bacteria, organic molecules, and 90-99% of allions should be removed.




Water for injection:

Used for parenteral solutions

As water for injection it should be sterile, pyrogen free and doesn’tcontain antimicrobial agent or other added substances.

Obtained by autoclave sterilisation of pyrogen free distilled waterimmediately after its collection.

Usually available in 1 L bottle. It is worth noting that this bottle isnot isotonic. Therefore, can’t be administrated intravenously.





This water is used as a solvent, vehicle, diluent for already sterilisedand packaged injectable medications.

Water for injection free from CO2 used for phenobarbitone sodiumor aminophylline which are sensitive to presence of CO2.

Water of injection free from O2 used for apomorphine andergotamine maleate that are sensitive to oxidation.





Both water of injection free from CO2 and O2 are prepared in asimilar manner to water for injection except they are boiled for 10minutes then cooled and sealed in their containers while excludingair and then sterilised by autoclaving.




Bacteriostatic water for injection:

It is sterile water for injection contains one or more of a suitableantimicrobial agent. The container label must state the name and% of antimicrobial agent.

The presence of antimicrobial agent allows flexibility of multipledose vials. i.e. if the first person to withdraw the first dosecontaminates the vial contents, the antimicrobial agents willdestroy the micro-organism.




Bacteriostatic water for injection:

Packed in prefilled syringe or as a 30 ml vial

Used for small volume injectable preparations.

Restricted use for large volume parenteral administration due to

excessive and perhaps toxic amounts of antimicrobial agents.

If vehicle volume is greater than 5 ml, sterile water for injection is

preferable to be used rather than bacteriostatic water for injection.




Sodium Chloride injection USP

It is a sterile isotonic solution of sodium chloride in water for

injection where Na+ and Cl- contents are around 15 mEq/ L.

It contains no antimicrobial agents.

Used for preparation of suspension and solutions for parenteral

administration.

Is frequently used as a catheter or IV line flush to maintain patency.



Non-aqueous solutions:

Advantage of Non-aqueous solutions: It is alternative to aqueous one in case the drug is unstable in

aqueous solution or it is difficult to ensure complete solution of theingredients at all storage temperatures.

Useful for Depot therapy. For example, Intramuscular injection ofdrugs in oil. In some cases more hydrophobic drugs are synthesizedto achieve depot therapy such as propionate and benzoate estersof Testosterone and Estradiol respectively.




Advantage of Non-aqueous solutions: Oily solution remains as a discrete entity within muscle tissues and

release the drug slowly into the surrounding tissue. Contrary toaueous solution that is miscible and diffuse readily with tissuefluids releasing the drug quicker.

It is essential to choose a solvent for non-aqueous solution thathave the following properties; non-toxic, non-irritant, reasonablecost, stable and compatible with other ingredients

This is commonly used for external applications rather thaninternally or parenterally.




Examples of solvent used for non-aqueous solutions

(2) Alcohols

Ethyl alc is the most widely used solvent particularly for external

application. Where it is rapidly evaporated after external

application and imparting a cooling effect e.g. salicylic acid lotions.

It has antimicrobial effect at a concentration 15%.

It is more selective than water for extraction of crude drugs.





(2) Alcohols

Ethyl alc is either (1) Diluted Alc: prepared by mixing equal volumes of alc USP and

purified water USP and used as a hydro-alcoholic solvent in pharmaceutical

preparation or

(2) Rubbing Alc: contains 70% alc by volume and the rest is water, denaturants,

might contain coloe or perfume oils and stabilizer. It is employed as a rubefacient

externally and as a soothing rub for bedridden patients (to improve blood

circulation and avoid bed sores). Also could be used as a skin cleaner prior injection

and a vehicle for topical preparations.





(2) Alcohols

Due to its toxicity, it is used only for parenteral and oral application at low

concentration.

According to FDA, Alc contents in OTC oral drug products should follow;

Children age < 6 Yr ….. Alc content limit is 0.5%

Children age 6- 12 Yr….. Alc content limit is 5%

Children >12Yr and adults … Alc limit is 10%

Isopropyl alcohol has similar properties to ethyl alc and it is used as a solvent for

diclophane. Isopropyl alc is less abused than ethyl alc.





(3) Polyhydric alcohol:

Alcohols contain 2 OH groups per a molecule are known as glycols.

Due to their toxicity, they are rarely used internally except

polypropylene glycol (PG). That is used in conjunction with water

as a co-solvent.





(3) Polyhydric alcohol: PG used in formulation of phenobarbital injections, digoxin

injection, Co-trimoxazole intravenous infusions and as a diluent forchloramphenicol Ear drops and in hydrocortisone Ear drops and insome oral preparation

PG is available in a wide range of viscosity grades that allow it to beused as a solvent for Clotrimazole topical solution or as a co-solvent with water or alcohol.

Glycerol is an alc with 3 OH groups and is widely used as a co-solvent with water for oral use.





(4) Dimethylsulphoxide:

It is a highly polar compound and is thought to aid penetration of

drugs through the skin.

It is used as a carrier for external application of idoxuridine, an

antiviral agent.





(5) Ethyl ether:

It is widely used for the extraction of crude drugs. Due to its own

therapeutic activity, it is not used for internal use but used as a co-

solvent with alcohol in some collodions.





(6) Liquid paraffin:

Its oily nature, make it unpleasant to be used externally. However,

it is used as a solvent for emulsion topical preparations.

Was used in one time as a solvent for nasal drops but currently it is

not used for this purpose due to the possibility of developing

lipoidal pneumonia if it is inhaled into the lungs.





(7) Miscellaneous solvents:

Isopropyl myristate and isopropyl palmitate are used for external

use in cosmotics due to low viscosity and lack of greasiness.

Dimethylformamide and Dimethylacetamide used as solvent in

veterinary formulations. Their toxicity renders them unsuitable for

human use.


Other formulations additives to solution:

Buffers

Density modifiers

Iso-tonicity modifiers

Viscosity enhancer

Preservatives

Reducing agents and Antioxidants

Sweeting agents

Flavours and Perfumes

Colors



Buffers

Buffers are employed to control the pH of the formulated product

and so optimise the physicochemical performance of the product.

Typically pH control is performed to maintain the solubility of the

therapeutic agent in the formulated product. The solubility of the

vast number of currently available drugs (they are either weak

acids or weak bases) is pH-dependent and, therefore, the solubility

of the therapeutic agent in the formulation may be compromised

by small changes in pH.



Buffers

Also they enhance the stability of final products where the

chemical stability of the active agent is pH-dependent.

The concentration (and hence buffer capacity) of buffer salts

employed in the formulation of oral solutions should be selected to

offer sufficient control of the pH of the formulation but yet should

be overcome by biological fluids following administration. This

latter property is particularly appropriate for parenteral

formulations to ensure absence of irritation or biological damage

following injection.



Examples of buffer salts used in pharmaceutical solutions include:

Acetates (acetic acid and sodium acetate): 1–2%

Citrates (citric acid and sodium citrate): 1–5%

Phosphates (sodium phosphate and disodium phosphate): 0.8–2%.

N.B. It must be remembered that the buffer system used in

solution formulations should not adversely affect the solubility of

the therapeutic agent, e.g. the solubility of drugs may be affected

in the presence of phosphate salts.



Density modifiers:

It is not common to control the density of solutions except for

those preparations for spinal anaesthesia.

Solutions of lower density than cerebrospinal fluid tends to rise

after injection and those with higher density tend to fall.

Careful control of these solutions density and position of injection

is highly important to control the area to be anaesthetized.



Density modifiers:

Isobaric, hypobaric and hyperbaric are terms used to describe the

density of solutions relative to spinal fluid and they means equal,

lower and higher density respectively.

Dextrose is the most commonly used density modifier



Iso-tonicity modifiers:

Solutions for injection as well as large volume solutions for

ophthalmic use must be isotonic to avoid pain and irritation.

Dextrose and sodium chloride are the most commonly used iso-

tonicity modifiers.

Iso-tonicity is adjusted after addition of all of others ingredients in

the preparation as these ingredients will contribute in the overall

osmotic pressure of a solution.



Viscosity enhancers:

The administration of oral solutions to patients is usually performed using a

syringe, a small-metered cup or a traditional 5-ml spoon.

The viscosity of the formulation must be sufficiently controlled in order to

ensure the accurate measurement of the volume to be dispensed.

Accordingly there is a viscosity range that the formulation should exhibit to

facilitate this operation. In addition, aqueous based topical solutions are difficult

to remain at the site of application (skin) due to low viscosity. Therefore addition

of viscosity enhancer is a requirement.



Viscosity enhancers:

Certain liquid formulations do not require the specific addition ofviscosity-enhancing agents, e.g. syrups, due to their inherentviscosity.

The viscosity of pharmaceutical solutions may be easily increased(and controlled) by the addition of non-ionic or ionic hydrophilicpolymers.

Non-ionic (neutral) polymersCellulose derivatives, e.g.:

methylcellulose hydroxyethylcellulose hydroxypropylcellulose polyvinylpyrrolidone

Ionic polymersSodium carboxymethylcellulose (anionic)Sodium alginate (anionic).



Preservatives:

Preservatives are included in pharmaceutical solutions to control the microbial

bio-burden of the formulation. Ideally, preservatives should exhibit the

following properties:

Possess a broad spectrum of antimicrobial activity encompassing Gram-

positive and Gram-negative bacteria and fungi

Be chemically and physically stable over the shelf-life of the product

Have low toxicity.



Preservatives:

A wide range of preservatives is available for use in pharmaceutical solutions for

oral use, including the following (values in parentheses relate to the typical

concentration range used in oral solutions);

Benzoic acid and its salts (0.1–0.3%)

Sorbic acid and its salts (0.05–0.2%)

Alkyl esters of parahydroxybenzoic acid, known as parabens (0.001–0.2%).

N.B. usually a combination of two members of this series is employed in

pharmaceutical solutions, typically methyl and propyl parahydroxybenzoates (in a

ratio of 9:1). The combination of these two preservatives enhances the

antimicrobial spectrum.



Preservatives:

Factors that directly affect the efficacy of preservatives in oral

solutions include:

(1) the pH of the formulation;

(2) the presence of micelles; and

(3) the presence of hydrophilic polymers.



Preservatives:


solutions include:


In some aqueous formulations the use of acidic preservatives, e.g. benzoic acid,

sorbic acid, may be problematic.

Organic acids, e.g. benzoic acid, sorbic acid, have pKa values around 4.2 and

therefore, in solution formulations whose pH is neutral, a high concentration of

preservative will be required to ensure that the required concentration of the

unionised species is obtained (will be explained later on)



Preservatives:

(2) The presence of micelles:

micelles are used for the solubilisation of lipophilic therapeuticagents. If the preservative exhibits lipophilic properties (e.g. theunionised form of acidic preservatives, phenolics, parabens), thenpartition of these species into the micelle may occur, therebydecreasing the available (effective) concentration of preservative insolution. An equilibrium is established as follows; To correct thisproblem, the preservative concentration must be increased toensure that the free concentration (those not associated withmicelles) in the formulation is ≥ MIC.

Factors that directly affect the efficacy of

preservatives in oral solutions include:



Preservatives:

Factors that directly affect the efficacy of preservatives in oral solutions include:

The presence of hydrophilic polymers:

The free concentration of preservative in oral solution formulations wasshown to be reduced in the presence of hydrophilic polymers, e.g.polyvinylpyrrolidone, methylcellulose.

This is due to the ability of the preservative to interact chemically with thedissolved polymer. This problem is addressed by increasing the concentrationof preservative in the formulation. In certain circumstances the preservativemay be incompatible with hydrophilic polymers in the formulation due to anelectrostatic interaction. Therefore, cationic hydrophilic polymers should notbe used in conjunction with acidic preservatives in oral solution formulations.



Preservatives:


solutions include:


The antimicrobial properties are due to the unionised form of the preservative;

the degree of ionisation being a function of the pH of the formulation.

The activity of the unionised form is due to the ability of this form to diffuse across

the outer membrane of the microorganism and eventually into the cytoplasm. The neutral

conditions within the cytoplasm enable the preservative to dissociate, leading to

acidification of the cytoplasm and inhibition of growth.



Preservatives:


solutions include:

(1) the pH of the formulation;The fraction of acidic preservative at a particular pH may be calculated using aderived form of the Henderson–Hasselbalch equation, as follows:

Fraction =

The importance of this equation will be illustrated as follows;



Preservatives:


solutions include:


Problem 1: Assuming that the MIC for the unionised form of an acidic preservative(pKa 4.2) is 0.0185 mg/ml, calculate the required concentration to preserve an oralsolution that has been buffered to pH 4.7. The Henderson–Hasselbalch equationmay be employed, as described above, to determine the fraction of unionised acidwithin the formulation.

Fraction = ర.ళషర.మ and therefore, the fraction = 0.24



Preservatives:


solutions include:


The required concentration is then calculated by dividing the MIC for the

unionised form of the preservative by the fraction of unionised preservative

present, i.e. 0.0185/0.24 = 0.07 mg/ml. In practice an excess is added and

therefore the actual concentration of preservative required would be 0.1–0.15

mg/ml.



Preservatives:


solutions include:


As you can observe, the pKa of the preservative is a vital determinant within the

above calculations. Organic acids, e.g. benzoic acid, sorbic acid, have pKa values

that are around 4.2 and therefore, in solution formulations whose pH is neutral, a

high concentration of preservative will be required to ensure that the required

concentration of the unionised species is obtained. If the above calculation is

repeated for an oral solution at pH 7.2, the following result is obtained:



Preservatives:


solutions include:


Fraction = 0.00001, Therefore, the required preservative concentration is 1850mg/ml. the latter could explains why use of benzoic acid/sorbic acid is problematicin certain formulations with neutral pH.

N.B. Alky esters of parahydroxybenozoic acid) and the phenolics are generally notaffected by formulation pH (within a pH range between 4.0 and 8.0) due to the highpKa of the organic hydroxyl group.



Reducing agents and Antioxidants:

Antioxidants are included in pharmaceutical solutions to enhance the stability

of therapeutic agents that are susceptible to chemical degradation by

oxidation.

Typically antioxidants are molecules that are redox systems that exhibit higher

oxidative potential than the therapeutic agent or, alternatively, are compounds

that inhibit free radical-induced drug decomposition.

Typically in aqueous solution antioxidants are oxidised (and hence degraded) in

preference to the therapeutic agent, thereby protecting the drug from

decomposition.



Reducing agents and Antioxidants:

Typically antioxidants are employed in low concentrations (0.2% w/w) and it is

usual for the concentration of antioxidant in the finished product to be

markedly less than the initial concentration, due to oxidative degradation

during manufacture of the dosage form.

Antioxidants may also be employed in conjunction with chelating agents, e.g.

ethylenediamine tetraacetic acid, citric acid, that act to form complexes with

heavy-metal ions, ions that are normally involved in oxidative degradation of

therapeutic agents.



Sweeting agents:

Sweetening agents are employed in oral solutions specifically to increase the

palatability of the therapeutic agent, mask the unpleasant taste and increase

the viscosity of the preparation.

Sucrose (has the following advantage; colourless, very soluble in water and

stable over pH 4-8), liquid glucose, glycerol, sorbitol, saccharin sodium and

aspartame are mainly used in oral preparations.



Sweeting agents:

The use of artificial sweetening agents (has a higher sweetener power than

sucrose, 100 to 1000 times more sweetener and used in lower conc 0.2%) in

formulations is increasing and, in many formulations, saccharin sodium is used

either as the sole sweetening agent or in combination with sugars or sorbitol to

reduce the sugar concentration in the formulation.

N.B. the artificial sweetener drawback is imparting a bitter/metallic taste.

Therefore, they always used with sugars. The most widely used artificial

sweetener is sodium and calcium salts of saccharin and less widely used is

aspartame.



Sweeting agents:

The use of sugars in oral formulations for children and patients with diabetes

mellitus has to be avoided.

Formulations for diabetic patients will be prepared with sorbitol, mannitol, and

to a lesser extent with glycerol but not sucrose.



Flavours and Perfumes:

Unfortunately the vast majority of drugs in solution are unpalatable and

therefore, the addition of flavours is often required to mask the taste of the

drug substance.

Taste-masking using flavours is a difficult task; however, there are some

empirical approaches that may be taken to produce a palatable formulation.

The four basic taste sensations are salty, sweet, bitter and sour. It has been

proposed that certain flavours should be used to mask these specific taste

sensations in particular:




Flavours that may be used to mask a salty taste include:

Butterscotch

Apricot

Peach

Vanilla

Wintergreen mint.

Flavours that may be used to mask a bitter taste include:

Cherry

Mint

Anise




Flavours that may be used to mask a sweet taste include:

Vanilla

Fruit and berry.

Flavours that may be used to mask a sour taste include:

Citrus flavours

Raspberry.




Usually a combination of flavours is used to achieve the optimal taste-masking

property.

Certain excipients may added to oral solution formulations, referred to as

flavour adjuncts (e.g. menthol, chloroform) that add flavour to the formulation

but, in addition, act to desensitise the taste receptors. Therefore, these agents

augment the taste-masking properties of conventional flavours.



Colors:

Colours are pharmaceutical ingredients that impart the preferred colour to the

formulation.

When used in combination with flavours, the selected colour should ‘match’

the flavour of the formulation, e.g. green with mint-flavoured solutions, red for

strawberry-flavoured formulations. Although the inclusion of colours is not a

prerequisite for all pharmaceutical solutions, certain categories of solution

(e.g. mouthwashes/gargles) are normally coloured.

Use of colour allows easy identification of the product by the patient.



Colors:

Types of colours;

(1) natural colouring agents: caramel, chlorophyll and carotenoids, they show

variations in chemical composition and availability as most natural products.

(2) synthetic colouring agents: dyes tend to give bright colours and are more stable

than natural colours. E.g. sodium salts of sulphonic acids


Approaches to improve aqueous solubility of active ingredients:

For poorly soluble drugs, one or more of the following methodsshould be used to improve aqueous solubility.

1- Co-solvency2- Influence of pH of the medium3- Solubilisation4- Complexation5- Chemical modification.6- Particle size control



(1) Co-solvency

Defined as water-miscible organic solvents that are used in liquid drug

formulations to increase the solubility of poorly water- soluble substances.

Most commonly used blend is water/ethanol blend.

Other suitable solvents are water/sorbitol or glycerol or propylene glycol.

A common example is the elixir, which by definition is a sweetened, hydro-

alcoholic solution intended for oral use.



(1) Co-solvency

Propylene glycol and water blend: is used to improve the solubility of co-

trimoxazole.

The choice of suitable co-solvents is somewhat limited for pharmaceutical use

because of possible toxicity and irritancy, particularly if required for oral or

parenteral use.



(2) Influence of pH of the medium:

Most of the drugs are weak electrolytes (weak acids and weak bases).

Weak acids and weak bases undergo ionization in solution.

Drugs are more soluble in water when they are in the ionized form, unionized drugs are

poorly water soluble.

Ionized drug is in the form of salt, or charged drug, the extent of ionization of drug in a

solution depends on the pH of the medium.



(2) Influence of pH of the medium:

For example:

Acidic drugs (phenobarbital) are more soluble in alkaline pH and begin to precipitate as

the pH decreases. (Increased pH leads to increased ionization leads to increased water

solubility).

Basic drugs (Procaine HCL) are more soluble in acidic pH and begin to precipitate at

alkaline pH due to decrease of drug ionization and formation of insoluble non-ionic form

of the drug.



(3) Solubilisation:

By the addition of a surface active agents (surfactants).

Surface active agents enhance the solubility of poorly water-soluble drugs due

to the formation of micelles. This phenomenon is known as micellar

solubilisation.

Surfactants have polar head and non-polar chain



(3) Solubilisation:

When surfactants are placed in water, at certain concentration (critical micelle

concentration) they will form a micelles by orienting themselves in a way where

the polar heads are exposed into the aqueous medium while the non-polar

chains are oriented towards each other forming the micelles. The poorly

soluble drug (hydrophobic drug) could be encapsulated inside the core of

micelles ended by increase drug solubility in the aqueous medium.



(3) Solubilisation:

The amount of surfactant must be carefully controlled:

A large excess of surfactant: is undesirable because of cost, toxicity, may also

reduce the bioavailability of a drug if it is strongly adsorbed into the micelles.

An insufficient amount of surfactant: may not fully solubilize the drug, or may

lead to precipitation either on storage or on dilution of the product.

Approaches to improve aqueous solubility ofactive ingredients:

(3) Solubilisation:

Surfactant chosen must be miscible with the solvent

system, compatible with the other ingredients, free

from disagreeable odour and taste and be non-

volatile.

Examples for solubilization.

Solubilization of fat soluble vitamins such as

phytomenadione using polysorbates.




(3) Solubilisation:

Examples for solubilization.

Antifungal drug such as griseofulvin, which has been formulated with

cetomacrogol.

Use of macrogol ethers with iodine to form iodophores. This product has

several advantages including improved chemical stability, reduced loss of active

ingredients, less corrosion of surgical instruments and enhanced activity.



(4) Complexation:

Interaction of a poorly soluble drug with a soluble material to form a soluble

intermolecular complex.

Examples:

Complexation of iodine with a 10-15% solution of polyvinylpyrrolidone

(PVP), to improve the aqueous solubility of the active agent.

Beta-cyclodexterin and nicotinamide used to increase the solubility of

poorly water soluble drugs.



(5) Chemical modification.

The drug may be chemically modified to produce a water soluble

derivative (usually salt form). Modification of chemical structure

of the drug molecule, by addition of polar groups like carboxylic

acids, ketones and amines. This can increase solubility by

increasing hydrogen bonding and the interaction with water.

Examples: Synthesis of the sodium phosphate salts of

hydrocortisone.



(6) Particle size control:

Decrease the particle size causes an increase in the solubility due to increasing

the surface area of the solid particles. High surface area allows a greater

interaction with the solvent.

The increase in the solubility ceases when the particle size attains very small

radius. Where any further decrease in particle size causes a decrease in

solubility rather than an increase Why? This is due to generation of

electrostatic charges on the particles that is predominant in small particles

leading to particle aggregations and clumps formation.


Types of pharmaceutical solutions:

1. Orally (Elixirs, Linctuses, Mixture and Draughts)

2. In mouth and throat (mouth washes, gargles, throat sprays)

3. External solutions (collodions, lotions, paints).

4. In body orifices (enemas, ear drops)

5. Intermediate solutions

6. Parenteral solutions

7. Rectal Solutions


Types of pharmaceutical solutions:Oral solution:

A- Elixirs:

An elixir is a liquid oral preparation that usually contains either potent or

unpleasant-tasting drugs.

The formulation is clear and generally contains a high proportion of sugar or

other sweetening agent, included to mask offensive or nauseating tastes.

Paediatric elixirs are usually formulated with fruity syrup as a base flavouring

agent.

In general, non-aqueous solvents (alcohol, glycerine or propylene glycol) form a

significant proportion of the vehicle used in elixirs, or alternatively solubilising

agents are included.



A- Elixirs:

Examples of Elixir:

Non-medicated Elixir: such as aromatic Elixir, compound

benzaldehyde Elixir and iso-alcoholic Elixir. This may be useful for

extemporaneous filling of prescriptions involving the addition of

therapeutic agent to a pleasant taste vehicle and dilution of an

existing medicated elixir.



A- Elixirs:

Examples of Elixir:

Medicated elixir:

Digoxin Elixir USP: Digoxin is a cardiotonic glycoside obtained from

the leaves of digitalis lanata. It is prepared to contain 0.25mg of

digoxin/ 5ml teaspoonful.

Phenobarbital Elixir USP: is a long acting barbiturates giving

sedation effect in treatment of children, infant and certain adult

patients it contains 20mh/ 5ml teaspoonful



B- Mixtures and Draughts:

Mixtures: Simple liquid preparations intended for oral use

containing dissolved medicaments may be described as oral

solutions or mixtures.

Draughts: A draught is an older term used to describe a liquid

preparation formulated as a single dose, in a volume which is

larger than generally utilised in traditional mixture formulations.

Each draught was usually supplied in a 50mL unit dose container.



(2) Mouthwashes and Gargles:

Gargles and mouthwashes are aqueous solutions that are

intended for treatment of the throat (gargles) and mouth

(mouthwashes) and are generally formulated in a concentrated

form.

Mouthwash contains 5 groups of excipients;

(1) Alcohols, (2) Humectants, (3) surfactants, (4) flavours, (5)

colouring agents.




(1) Alcohols (10-20%): It enhances the flavour, provide sharpness of

taste, aids in masking unpleasant taste of active ingredients, act as a

solubilizing agent for some flavouring agents and may act as a

preservatives.

(2) Humectants: e.g. Glycerine and sorbitol. Forms 5 - 20% of the

mouthwash. They increase the viscosity of the preparation,

enhances the sweetness of the product. Along with alcohol, they

improve the preservatives qualities of the product.




(3) Surfactants: non-ionic surfactant (0.1 – 0.5%) are used while

anionic surfactants such as sodium lauryl sulphate is occasionally

used. Surfactants are used because they aid in solubilisation of

flavours and in the removal of debris by providing foaming

(4) Flavours: used along with alcohol and humectants to overcome

the disagreeable taste. The main flavouring agents used are;

peppermint, cinnamon.




Gargles

They are aqueous solution contains antiseptic, antibiotics and/or

anaesthetic used for treating pharynx and nasopharynx by forcing

air from the lungs through the gargle that is held in the throat,

then gargles is expectorated. Many gargles must be diluted with

water prior use. E.g 7.5% povidone-iodine and 35%alc is used as

gargles or mouthwash after dilution with water.




Gargles

These preparations must be diluted before use and care should be

taken to ensure that appropriate instructions are included on the

label and that the container used will be easily distinguishable

from those containing preparations intended to be swallowed.



(3) External solutions:They are solutions developed for external application

Lotions:Lotions are solutions, but may also be suspensions or emulsions,that are intended to be applied to the skin without friction on acarrier fabric such as lint and covered with a waterproof dressing. Insome cases lotions are applied to the scalp, where the vehicle for themedication is alcohol based, allowing for rapid drying of the hair andthus making the product more acceptable to the patient (e.g.Salicylic Acid Lotion 2% BPC). In these cases, problems offlammability are addressed by suitable labelling.



(3) External solutions:They are solutions developed for external application

Liniments: A liniment is a liquid preparation intended to be rubbed

with friction and massaged onto the skin to obtain analgesic,

rubefacient or generally stimulating effects. Liniments should not be

used on a broken skin to avoid irritation. They are usually solutions

of oils, alcohols or soaps, but may be formulated as emulsions.

Usually Oleaginous liniments are less irritant than alcoholic liniment.


Types of pharmaceutical solutions:Oral solution:(3) External solutions:They are solutions developed for external application

Collodions: These are principally solutions of pyroxylin

(nitrocellulose) in a vehicle of ether and alcohol that are intended to

be painted onto the skin and left to dry. When dry, the collodion

leaves a flexible film of cellulose on the skin which may be used to

seal minor injuries or retain a dissolved drug in contact with the skin

for an extended period. Collodions are highly volatile and highly

flammable and care should be taken to label any preparation

appropriately.



Collodions:

E.g. Salicylic acid Collodion (10%): it is used for its keratolytic effect

to remove corns from toes. The product applied as a one drop at a

time onto the corn or wart allowing time to dry before the next drop

is added. Salicylic acid can be irritant to the normal skin. Therefore

the adjacent skin should be lined healthy with some white

petroleum prior product application.



Paints:

Liquids for application to the skin or mucous membranes in small

amounts and are usually applied with a small brush. The solvent is

normally alcohol, acetone, ether that evaporates quickly leaving a

film on the skin that contains the active ingredient. A viscosity

modifier (Glycerol) is added to ensure prolonged contact with the

skin.


Types of pharmaceutical solutions:Oral solution:(4) In body orifices:

A- Ear Preparations:

Known as Otic or aural products

Prepared for local use including antibiotics, antiseptics, cleansing

solutions and wax softners. Drugs are dissolved in a solvent that is

water, glycerol, propylene glycol or alcohol/water mixtures.

They applied to auditory canal as drops, sprays or washes.



B- Eye Preparations:

These are small volume sterile liquids designed to be instilled on to

eyeball or within the conjunctival sac for local effect.

C- Irrigations:

They are sterile, large volume aqueous solutions for the cleansing of

the body cavities and wounds.

They should be made isotonic with tissue fluid.



D- Nasal Products:

They are formulated as small volume solutions of an aqueous

vehicle. Oil are no longer used because the buffering capacity of

nasal mucus is low.

pH is necessary to be at 6.8.

Should be isotonic with nasal secretions. Isotonicity is adjusted by

sodium chloride.



E- Nasal Products:

Viscosity could be modified with cellulose derivatives

Antibiotics, Anti-inflammatory, decongestants are drugs

formulated as nasal products.



E- Douches:

They are an aqueous solution applied into a part or a cavity of the

body for cleansing or antiseptic purpose.

Eye douches: used to remove the foreign particles and discharges

from the eyes. It is directed gently at an oblique angle and

allowed to run from the inner to the outer corner of the eye.



E- Douches:

Pharyngeal douches: used to prepare the interior of the throat

for an operation and cleanse it

Vaginal douches: the most common type of douches and used for

irrigative cleansing of the vagina and for hygiene purposes. Liquid

concentrate or powders may be diluted in a warm water prior use


Types of pharmaceutical solutions:Oral solution:(4) In body orifices:E- Douches:

Vaginal douches:

Ingredients of vaginal douches include the following:

Antiseptic: e.g boric acid or sodium borate Astringents: zinc sulphate, ammonium alum Quaternary ammonium compounds: as benzalkonium chloride Detergents: sodium lauryl sulphate Oxidizing agents: sodium perborate Salts to alter pH such as sodium citrate, sodium bicarbonate Anaestics or antipruritics: eg. Phenol / menthol Aromatics as thymol/ menthol


Types of pharmaceutical solutions:Oral solution:(5) Intermediate products:A- Aromatic waters and Spirits:They are pharmaceutical solutions that are used during manufactureof other preparations.(1) Aromatic waters: are aqueous solutions of volatile materials thatare used mainly for their flavouring properties. Aromatic waters such as peppermint water and anise water

have carminative properties and chloroform water has apreservative action.

They manufactured as concentrated waters and are thendiluted, traditionally 1:40 in the final preparation.

(2) Spirits: Alcoholic solutions of volatile materials that are used as aflavouring agent.


Types of pharmaceutical solutions:Oral solution:(5) Intermediate products:B- Extracts, Infusions and Tincture:

They are terms used for concentrated solutions of active principles

from animal or vegetables sources

Infusions: They are prepared by extracting the drug using 25%

alcohol but without the application of heat, traditionally they are

diluted 1:10 in the final product.

Extracts: They are similar products to Infusions but they are

concentrated by evaporation



Tinctures: They are alcoholic extracts of the drug but they are

relatively weak compared to Extracts.

E.g. Iodine Tincture: prepared by dissolving 2% iodine crystals and

2.4% potassium iodide in an amount of alc equal to half the volume

of tincture to be prepared. Then dilution of the solution to the

required volume with water.



Tinctures:

Iodine react with potassium iodide to form tri-iodide (improved

water solubility) that prevents formation of ethyliodide that will be

accompanied by loss of the antibacterial activity.


Types of pharmaceutical solutions:Oral solution:(5) Intermediate products:C -Syrups:

Syrups are highly concentrated, aqueous solutions of one or more

sugar component or a sugar substitute that traditionally contain a

flavouring agent, e.g. cherry syrup, cocoa syrup, orange syrup,

raspberry syrup.

An unflavoured syrup is available that is composed of an aqueous

solution containing 85% sucrose.



Therapeutic agents may either be directly incorporated into these

systems or may be added as the syrup is being prepared. If the

former method is employed, it is important to ensure that the

therapeutic agent is soluble within the syrup base It should also

be remembered that the choice of syrup vehicle must match the

physicochemical properties of the therapeutic agent.



For example, cherry syrup and orange syrup are acidic and

therefore the solubility of acidic or some zwitterionic therapeutic

agents may be lowered and may result in precipitation of the drug

substance. Under these circumstances, the physical stability of the

preparation will have been compromised and the shelf-life of the

product will have been exceeded. The use of acidic syrups may

additionally result in reduced chemical stability for acid-labile

therapeutic agents.



The major components of syrups are as follows:

Purified water

Sugar (sucrose) or sugar substitutes (artificial sweeteners).



Traditionally syrups are composed of sucrose (usually between 60

and 80%) and purified water. Due to the inherent sweetness and

moderately high viscosity of these systems, the addition of other

sweetening agents and viscosity-modifying agents is not required.

In addition, the high concentration of sucrose and associated

unavailability of water (termed low water activity) ensures that

the addition of preservatives is not required.



As the concentration of sucrose is reduced from the upper limit

(e.g. through dilution), the addition of preservatives may be

required.

In some formulations, other non-sucrose bases may replace

traditional syrup.


Types of pharmaceutical solutions:Oral solution:(5) Intermediate products:

C -Syrups:

One of the most popular is Sorbitol Solution USP, which contains

64% w/w sorbitol (a polyhydric alcohol), although other

alternatives are available that are based on mixtures of sorbitol

and glycerin. These non-sucrose bases may be mixed with

traditional syrups, if required, in the formulation of oral syrups

that possess a low concentration of sucrose in comparison to

traditional syrups.



More recently, many products have been formulated as

medicated sugar-free syrups due to the glycogenetic and

cariogenic properties of sucrose.

For the afore-mentioned reasons, all medicinal products designed

for administration to children and to diabetic patients must be

sugar-free. Syrup substitutes must therefore provide an

equivalent sweetness, viscosity and preservation to the original

syrups.



C -Syrups:

To achieve these properties artificial sweeteners (typically

saccharin sodium, aspartame), non-glycogenetic viscosity

modifiers (e.g. methylcellulose, hydroxyethylcellulose) and

preservatives (e.g. sodium benzoate, benzoic acid and

parahydroxybenzoate esters) are included.



C -Syrups:Classification of Syrup:

(1) Simple Syrup,

(2) Medicated Syrup,

(3) Flavoured Syrup,

(4) Invert Syrup.



C -Syrups:

Simple Syrup: sucrose (65 – 85% w/w) in purified water with a

specific gravity 1.3.

Medicated syrup: Aqueous saturated solution of sugar contains

one or more medicinal agent.

Flavoured Syrup: contains aromatic or flavoured agents and has

no medicinal substance. Used as a vehicle or flavour for

prescription.



C -Syrups: Invert Syrup: According to BPC (British Pharmacopeia Codex), it is

formed by hydrolysis of sucrose by hydrochloric acid andneutralization with sodium or calcium carbonate. Invert syrupcontains 66.7% w/w sucrose. Levulose formed due to hydrolysishas more sweetener activity (1.23 times sucrose). Levuloase issensitive to heat and darken very fast. This explains why thesolution is darkened after hydrolysis of sucrose. The addition ofinverted syrup to the syrup, it prevents the sucrose crystaldecomposition during storage.

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