lecture 1 and 2

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:


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 oral solution that has

been buffered to pH 4.7. The Henderson–Hasselbalch equation may be employed, as

described above, to determine the fraction of unionised acid within 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.



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.

lecture 1 and 2

Documents

solutions preparation

solutions of gases

ingredients solutes

aqueous solvent

oral soliddosage forms

oral administration

solvent system vehicle

solid dosage forms