Pharmaceutical aids and necessities

OBJECTIVES At the end of the unit, the students should be

able to:

Identify the different pharmaceutical aids and necessities

Describe the properties of different pharmaceutical aids

Discuss the importance and application of pharmaceutical aids and necessities to pharmaceutical preparations/

Overview Pharmaceutical aids and necessities are

agents important to

Preparation Preservation Storage of pharmaceuticals.

Classification Acids and bases Buffers Antioxidants Water Glass

NO therapeutic value For making dosage forms

ACIDS, BASES, AND BUFFERS Bronsted-Lowry theory is the acid base

theory we use in the pharmacy because physiologic functions and pharmaceuticals are often times dispensed as an aqueous solution.

General chemical expression:HA + B = A + ˉ HB˖

Acid + Base = conjugate base + conjugate acid

Electrolytes Strong acids and bases are strong

electrolytes Weak acids and bases are weak electrolytes

Relation The stronger the acid, the weaker its

conjugate base, and vice versa. The stronger the base, the weaker its

conjugate acid, and vice versa.

OFFICIAL INORGANIC ACIDS

Boric acid (H3BO3) Synonym: boracic acid, hydrogen borate, orthoboric acid Occurrences: found in seawaters, certain plants, in

nearly all fruits and in some volcanic stem jets. The nativ boric acid is called sassolite.

Properties: available in three crystalline forms: a) colorless,odorless, pearly scalesb) Six-sided triclinic crystalsc) White, odorless powder with a soapy feel

Uses: antiseptic because it is a weak bacteriostatic agent; in 2% w/c concentration as eyewash and as buffer in opthalmic solutions*the toxicity of boric acid makes it unfit to he taken orally.

Hydrochloric acid (HCl) Synonym: chlorhydric acid, spirit of sea

salt, muriatic acid Use: a pharmaceutical aid as an

acidifying agent

Diluted Hydrochloric acid Diluted HCl exists in the normal gastric

juice aiding in the conversion of pepsinogen into pepsin and of proteins into peptones and serving as a gastric antiseptic. It is also used in the management id gastric achlorhydria, the absence if HCl in the stomach; and hypochlorhydria, the deficiency of HCl production of the stomach.

Nitric acid (HNO3) Synonym: spirit of nitre, aquafortis, aqua fuerte Properties: nitric acid will produce a yellow stain on

animal tissue due to the nitration of the aromatic amino acid, phenylamine, tyrosine and tryptophan found in the proteins of skin. This reaction is known as xanthoproteic test. It oxidizes common metals except gold and platinum to produce the nitrate salt of the metal.

Uses: the manufacture of sulfuric acid, coal tar dyes and explosives; a nitrating agent in pyroxylin USP XVIII; a source of nitrate ion in the preparation of milk of bismuth; externally, the elimination of chancres and warts.

Phosphoric acid(H3PO4) Synonym: orthophosphoric acid, acido

orthofosforico Use: acidifying agent

Diluted phosphoric acid Uses: a tonic and stimulant to the

gastric mucous membranes; a synergistic substance to pepsin and acids to the formulation of peptones

Sulfuric acid (H2SO4) Synonym: oil of vitriol, vitriolic acid, aceite de

vitriole Preparation: there are two ways to prepare

sulfuric acid: contact pr catalytic process and the Lead chamber process. Blth have the same principle, that is, the oxidation of the sulfur dioxide to sulfur trioxide by adding enough water to form sulfuric acid. In the catalytic process, vanadium and platinized silica gels are catalyst.

Use: dehydrating agent in the preparation of pyroxylin USP XX

Acetic acid (CH3COOH) Synonym: glacial acetic acid Use: irrigation solution with some

bacteriostatic properties

Official Inorganic Bases

1. Strong Ammonia Solution2. Diluted Ammonia Solution3. Calcium Hydroxide4. Potassium Hydroxide5. Sodium Hydroxide6. Sodium Carbonate7. Soda Lime8. Potassium Bicarbonate9. Sodium Bicarbonate

Strong Ammonia Solution (NH4OH) USP38/NF33

Other Names: Ammonium Hydroxide Stronger Ammonia WaterPrecautions:

Use care in handling (caustic nature and irritating properties of its vapor)

Cool the container well before opening Cover the closure with cloth while opening Do not taste or inhale the vapors

Bronsted baseManufacture of nitric acid and sodium bicarbonatePreparation of aromatic spiritPreparation of ammoniacal silver nitrate solution

Tollens' reagent is an alkaline solution of ammonia cal silver nitrate and is used to test for aldehydes

Diluted Ammonia Solution (NH4OH) USP38/NF33 Prepared from strong ammonia solution Known as ammonia water or household

ammonia Employed as circulatory stimulant

through inhalation of vaporsUSES When used externally, it is counter-

irritant

Calcium Hydroxide Ca(OH)2 USP38/NF33 Other Names:

Slaked lime Calcium hydrate

Preparation: Manufactured from lime or Calcium Oxide

by slaking process.

Medicinally used as fluid electrolyte and topical astringentUtilized for its high hydroxide ion concentration in pharmaceutical preparations.Its alkalinity reacts with free fatty acids in various oils to form calcium soaps which have emulsifying properties.Due to its ability to absorb CO2 from expired air, it is combinedwith NaOH or KOH in a mixture known as soda lime

Potassium Hydroxide (KOH) USP38/NF33Other Names:

Caustic potash Potassa

Properties: Deliquescent Very strong base with caustic/ corrosive

effect on tissues (handle carefully)

Uses: As a caustic in veterinary practice As a saponifying agent to hydrolyze esters of

fatty acids into their constituent alcohols and potassium salt

Sodium Hydroxide (NaOH) USP38/NF33Other Names:

Caustic soda Soda lyeProperties:

It attacks soft glass (containers should be made of hard glass with rubber stoppers

Glass-stoppered bottles can be used if a liitle petroleum or paraffin is spread around the stopper

Not borosilicate, a soft glass has high coefficients of thermal expansion; thus it does not require a high temperature to make them soft.

Uses: same as potassium hydroxide but has

more advantage since it is less deliquescent, milder, and cheaper.

Sodium Carbonate (Na2CO3.H2O) USP38/NF33

Other Names:Monohydrated sodium carbonate

Use:In pharmaceutical preparations,

its basicity forms sodium salts of acidic drugs

Soda Lime USP38/NF33Uses: A mixture of Ca(OH)2 and NaOH or KOH

or both intended for metabolism tests, anesthesia, and O2 therapy.

Potassium Bicarbonate USP38/NF33Other Names:

Potassium Hydrogen CarbonatePotassium Acid Carbonate

Use:Buffering agent for

pharmaceutical preparations

Sodium Bicarbonate USP38/NF33

Other Name: Sodium Hydrogen Carbonate

Use: Preferred in preparation of effervescent

mixtures containing sodium bicarbonate and organic acids such as tartaric or citric. These additives react to liberate CO2 that acts as a disintegrator producing effervescence when in water.

BUFFERS

A buffer is a solution of a weak acid and its salt or the salt of its conjugate base or a weak base and its salt or the salt of its conjugate acid that resists drastic changes in pH when small amounts of acid or base are added to it. Buffers control the pH of pharmaceutical products within certain specified limits for these reasons:A. Chemical StabilityB. Solubility of the drugC. Patient’s comfort Some factors which can produce alterations in pH include:A. Alkali in certain inexpensive containersB. Gases present in air such as CO2 and NH3

MECHANISM OF ACTION When small amounts of hydrogen ion are

introduced into the medium, they will react with the conjugate base and basic members of the buffer to form a weak acid.

Similarly,when small amounts of hydroxide ion are introduced into the medium, they will react with the weak acid or acidic member of the buffer pair and form water and the conjugate base.

Hence,each component of the buffer pair will react with either acid or base to form the other component

If base (OH) is added, it will react with the acid to neutralize the base, forming acetate ion and water

H2C3O2 + OH → C2H3O2 + H2O

The selected buffer should not:A. Participate in oxidation-reduction reactionB. Alter the solubility of other componentsC. Form complexes with active ingredients

EXAMPLES:ACETIC ACID AND ITS CONJUGATE BASE, ACETATE ION:

HC2H3O2 (acid) + H20 → H3O + C2H3O2 (conjugate base) If acid (H3O) is added, it will react with the conjugate base to neutralize the acid, forming acetic acid and water

C2H3O2 + H3O → HC2H3O2 + H2O

Consider the following when choosing a buffer:1. Volatile species should not be used as buffers2. It should not have any influence on the

pharmacological activity of the API3. The use of the pharmaceutical should be

considered in choosing a buffer for a product. If it is to be ingested, buffers containing borates should not be used as they are toxic systemically.

TWO INORGANIC BUFFER SYSTEMSA. PHOSPHATE BUFFER SYSTEM ADVANTAGE: it contains dihydrogen and monohydrogen phosphate ions which are found normally in the body DISADVANTAGE: The insolubility of the phosphate salts of such metals such as Ag, Zn, and Al support microbial growthB. BORATE BUFFER SYSTEM It contains metals that would precipitate in the presence of phosphate. They are toxic and it is suitable in external preparations, ophthalmic, and nasal solutions but is contraindicated in parenteral solutions.

THREE PRIMARY BORATE BUFFER SYSTEMS:

1. FELDMAN’S BUFFER SYSTEM - pH of 7.6 – 8.2 - consists of : BORIC ACID, NaCl ( to make it isotonic), and Sodium Borate

2. ATKINS AND PANTIN BUFFER SYSTEM - pH of 7.6 – 11 - consists of: Sodium carbonate, Boric acid, and NaCl

3. GIFFORD BUFFER SYSTEM: - pH of 6 – 7.6 - similar to Feldman’s Buffer System but NaCl is replaced by KCl to make it hypotonic

STANDARD BUFFER SOLUTIONSBuffer systems in pharmacy can be roughly categorized into:1. Standard buffer systems – designed to provide a

solution having a specific pH for analytical purposes.2. Actual pharmaceutical buffers – designed to

maintain pH limits in drug preparations

Standard buffer solutions having pH ranges between 1.2 and 10.00 can be prepared by appropriate combinations of:- BORIC ACID AND POTASSIUM CHLORIDE, 0.2M- HYDROCHLORIC ACID, 0.2M- POTASSIUM CHLORIDE, 0.2M

- POTASSIUM PHOSPHATE, MONOBASIC 0.2M- POTASSIUM BIPHTHALATE, 0.2M- SODIUM HYDROXIDE, 0.2M- ACETIC ACID, 2N

All the crystalline reagents except boric acid should be dried at 110 – 120 degrees Celsius for an hour before use.The water should also be CO2-free.The solution should be stored in Type 1 glass bottles and the solutions used within 3 months.The solutions, prepared and standardized, will later be combined in specific quantities to make the following standard buffer solutions to achieve a certain pH.

F

BUFFER pH COMPOSITIONHYDROCHLORIC ACID 1.2 -2 50ml KCl solution with a

specified volume of 0.2 HCl and water

ACID PHTHALATE BUFFER 2.2-4.O 50 ml of potassium biphthalate solution with a specified volume of 0.2 HCl and water

NEUTRALIZED PHTHALATE BUFFER 4.5-5.8 50 ml of potassium biphthalate with a specified volume of NaOH and water

PHOSPHATE BUFFER 5.8-8.0 50 ml of monobasic potassium phosphate with NaOH and water

ALKALINE BORATE BUFFER 8.0-10.0 50ml of boric acid and KCl with NaOH and water

ACETATE BUFFER 4.1-5.5 Specified amount of sodium acetate with acetic acid and water

Antioxidants

• REDUCING AGENTS • Pharmaceutical necessity

MECHANISM OF ACTION OF ANTIOXIDANTS• Either the antioxidant oxidizes in place of the

active constituent or inversely, the antioxidant reduces the already oxidized active constituent back to its normal oxidation state.

• In selecting a suitable antioxidant, the following factors should be considered:

a) An antioxidant in a pharmaceutical preparation should be PHYSIOLOGICALLY INERT

b) The possible TOXICITY of both the reducing agent and its oxidized product must be assessed

c) One should consider possible SOLUBILITY problems between the reducing agent and the drug

d) VERY STRONG reducing agent will form explosive mixtures when combined in dry form or in concentrated solution with strong oxidizing agents

HYPOPHOSPHOROUS ACID (HPH2O2)

USES:• The formation of free iodine is prevented in

diluted hydriodic acid and syrup.• Its presence in ferrous iodide syrup ensures the

non-formation of both ferric ions and molecular iodine.

• Salts of hypophosphorus acid are antioxidants.• Sodium hypophosphite is a preservative in

certain foods.• Ammonium hypophosphite is likewise a

preservative in many preparations.

Sulfur dioxide (So2

SYNONYM : Sulfurous anhydride

USES:• It will protect many susceptible compounds

from oxidation by reducing oxidized forms back to their original compounds or by reacting with oxygen before the susceptible compounds do.

• It is usually in injectable preparations in ampules or vials.

• It is used in industry to bleach wood pulp, to fumigate grains and to arrest fermentation

Sodium bisulfite (NaHSO3) or SODIUM METABISULFITE(Na2S2O5)

SYNONYMS: SODIUM HYDROGEN SULFITE, SODIUM ACID SULFITE AND LEUCOGEN

USES:• It prevents oxidation of the compounds

of phenol or catechol nucleus to quinones.

• Bisulfite may also be found in ascorbic acid injections as a reducing agent.

• It prepares water-soluble derivatives of normally insoluble drugs.

• Metabisulfite is an ascorbic acid injections as reducing agent.

Nitrogen(n2)

Uses:• As an inert atmosphere, it retards

oxidation in oxidation-sensitive products, and replaces air in containers for parenterals and solutions for topical applications.

Sodium thiosulfate

Uses:• Contains sulfur in two different oxidation

states.• The oxidized sulphur atom is in a +6 state

resisting further oxidation, whereas the remaining sulphur atom is in a zero oxidation state. This oxidation polarity allows the compound to act as a reducing agent. Also, sodium thiosulfate acts as an antidote for cyanide poisoning.

Sodium nitrite

Uses:• Nitrites can act as both a reducing and oxidizing

agent. Reduction of compounds with sodium nitrite results in formation of nitrates.

• It is an antidote for cyanide poisoning.• Nitrites in brine solutions are curing ingredients

of meats and fish for they are excellent color developer, enhance flavor production, and prevent microbial growth. However, nitrite ions remain in cured meats and react with organic amines to form potentially carcinogenic N-nitrosamines.

Glass

Red or Pink

Substance added Color imparted

Copper(I) oxide Opaque red, green, blueTin (IV) oxide Opaque

Calcium Fluoride Milky whiteManganese (IV) oxide Violet

Cobalt (II) oxide BlueFinely divided gold Red, Purple, Blue

Uranium compounds Yellow, GreenIron (II) compounds Green

Iron (III) compounds) YellowChromium Green

Cadmium sulfide YellowSelenium Red or Pink

• Glass is the container material of choice for most small volume infusions. It is composed chiefly of silicon dioxide, with varying amounts of other oxides like sodium, potassium, calcium, magnesium, aluminum, boron and iron.

• The following are added to imaprt color to the glass

• Glass is formed by the silicon oxide tetrahedron. Though boric oxide will enter into this structure, most of the other oxides do not.

• Glass types are determined from the result of two USP tests: the powdered glass test and water attack test. The latter is used for type II glass.

• Selecting the appropriate glass composition is critical facet of determining the overall specifications for each parenteral formulation.

• Source or cause of leachables/extractables, adsorption formulation components, especially proteins, and cracks or scratches.

• Leachability- is a property in which ions from the glass container will leach out and interact with the product, thereby reducing the stability of the product.

Delamination or glass particulate formation- is caused by the chemical attack on the glass matrix by the formulation solution, resulting in the weakening of the glass and eventual dislodgement of flakes from the glas surface.

GLASS TYPES

TYPE I – Borosilicate glass• Composed principally of silicon dioxide

and boric oxide, with low levels of the non-network-forming oxides, it is a chemically resistant glass (low leachability) with low thermal coefficient of expansion.

• This type of container is suitable for all products although sulfur dioxide treatment sometimes is added to further increase its resistance.

TYPE II – Soda-lime treated glass• The relatively high proportions of

sodium oxide and calcium oxide makes this glass type chemically less resistant.

• Type II melts at lower temperature, rendering it easier to mold into various shapes; and has a higher thermal coefficient of expansion than Type I.

• It has a lower concentration of the migratory oxides than Type III.

• This type is treated under controlled temperature and humidity conditions with sulfur dioxide or other dealkalizers to neutralize the interior surface of the container.

• Type II glasses may be suitable for a solution that is buffered, has a pH below 7, or is not reactive with glass.

TYPE III – Soda-lime glass• These glasses are composed of relatively

high proportions of sodium oxide and calcium oxide, a combination that renders the glass chemically less resistant.

• They melt at lower temperature, are easier to mold into various shapes, and have a higher thermal coefficient of expansion than Type I.

• Type III glasses are suitable principally for anhydrous liquids or dry substances.

• 4. NP – Soda- lime glass not suitable for containers for parenterals

Water

Reagents added to modify the characteristics/appearance of glass

Special addition/Composition

Desired Property

Large amounts of PbO with SiO2 and Na2CO3

Brilliance, Clarity, Suitability for optical structures; crystals or flint glass

SiO2, B2O3, and small amounts of Al2O3

Small coefficient if thermal expansion; borosillicate glass

One part SiO2 and four parts PbO

Ability to stop (absorb) large amounts of X-rays and gamma rays: lead glass

Large concentrations of As2O3

Transparency to infrared radiation

Water acts as a primary solvent for most substances due to its properties: small size, string permanent dipole,high dielectric constant and availability for protons for hydrogen bonding.

Pure water is a tasteless, odorless, clear liquid which is colorless in small quantities and greenish blue in deep layers.

Due to solvent powers and physiological inertness, water is an extremely important pharmaceutical agent.

Natural water Alkaline water- usually contain appreciable

quantities of sodoum and magnesium sulfates Carbonated waters- charged with carbon dioxide

under pressure while in earth. Chalybdate waters- have iron in solution or in

suspension and are characterized by a ferrigenous taste.

Lithia waters- occur in the form of carbonate or chloride

Saline waters- also known as "purgative waters" , hold relatively large amount of magnesium and sodium sulfates with sodium chloride.

Sulfur waters- have hydrogen sulfide siliceous waters- include very small amounts of

soluble alkali silicates.

Official USP waters Most liquid injections are quite dilute; the

component present in the highest proportion

1.) Purified water 2.) Water for injectionDescription: clear colorless odorless liquid purified by distillation or reverse osmosis and contains no added substances.Use: pharmaceutic aid as a vehicle or solvent

• 3.) Bacteriostatic water for injectionDescription : it is prepared from water for injection that is sterilized and packaged in prefilled syringes or in vials containing not more than 30 mL. It also has one or more suitable antimicrobial agents.Use: sterile vehicle for parenteral preparationsNOTE: label should state: "NOT FOR USE IN NEONATES" as there were problems encountered with neonates and the toxicity of the bacteriostat, benzyl alcohol.

• 4.) Sterile water for injection• Description: clear colorless odorless liquid for

parenterals; sterilized; no antimicrobial agent or other added substances

• 5.)Sterile water for irrigationDescription: clear, Colorless, odorless liquid; water for injection that has been sterilized; no antimicrobial agent or other substances Use: an irrigating solutionNOTE: label must say "For irrigation only and not for injection"

6.) Sterile water for inhalationDescription: it is prepared from water for injection, sterilized and packaged,with no added antimicrobial agents.

Heavy water is isotopes of hydrogen (deuterium and tritium)

END