Pharmaceutical Aids and Necessities Topics included in pharmaceutical necessities o Preparation o Preservation o Storage of Pharmaceutical Products aids and

Major Subject Areas o Acids & Bases frequently employed in the conversion of drugs to chemical forms convenient to their product formulation o Buffers maintain the pH of various formulations within prescribed limits o Antioxidants prevent oxidative decomposition of pharmaceutically active components o Water primary solvent or liquid phase in most liquid pharmaceutical preparations o Glass used for storage and as dispensing container for most drug products. Official Inorganic Acids Boric Acid (H3BO3) (Boracid Acid, Hydrogen Borate, Orthoboric Acid) - must be 99.5%-100.5% in a solution - found in sea waters, certain plants, in nearly all fruits and in some volcanic stream - its native form is called sassolite - solid that is available in 3 forms o colorless, odorless, pearly scales o six-scaled triclinic crystals (more suitable for preparing aqueous solutions) o white, odorless powder, unctuous to touch (have a soapy feeling) - has a density of 1.46 - soluble in water and alcohol - freely soluble in glycerin, boiling water and boiling alcohol - its solubility is decreased by HCl - not absorbed through the intact skin but is highly toxic ingested orally - absorbed when applied over large areas of broken skin - constitute a portion of what would be required for a buffer solution but used alone it does not have such buffer capacity Sources of Boric Acid o Rasorite/ Kernite Na2B4O74H2O o Borax Na2B4O710H2O

o Borocalcite CaB4O74H2O Colemanite Ca3B6O105H2O o o Tincal - H3BO3Na2B4O72CaB4O718H2O Uses used in solutions, ointments and dusting powder as an antiseptic (weak bacteriostatic agent) used in eyewash (2.5-4.5% concentration) used as buffer in ophthalmic solutions, Aluminum acetate solution and Aluminum Subacetate Solution Combination with glycerin forms Boroglycerin Glycerite (C3H5BO3) (used as a suppository base) Hydrochloric Acid (HCl) (Muriatic Acid, Spirit of Sea Salt, Marine Acid, Espiritu de Sal Marina) - must be 35%-38% in a solution - colorless fuming liquid having a pungent odor and a density of 1.18 - pH of 12 M solution = -1.08 - capable of reacting with organic molecules usually forming water soluble hydrochloride salts - some hydrochloride formed are hygroscopic - capable of reacting with organic molecules which are weakly basic to form usually water soluble hydrochloride salts - highly ionized than most other strong acids and attacks many metals with evolution of hydrogen Non-fuming solution can be prepared by diluting HCl with 2 volumes of water Muriatic Acid from the latin word muria (meaning brine) technical grade of HCl containing 35%-38% and a number of impurities including Cl, As, HSO3 and Fe (it gives the yellow color) Diluted HCl exists in normal gastric juice (about 0.2%) aids in the conversion of pepsinogen into pepsin and proteids into peptones valuable in certain forms of indigestion usually given in doses of 1-10cc (diluted in water, intake using straw to avoid contact with the enamel of the teeth) Achlorhydria absence of hydrochloric acid Hypochlorhydria deficiency of hydrochloric acid Glutamic Acid Hydrochloride & Betaine Hydrochloride used to solve the reaction of diluted HCl with the enamel of the teeth

 crystalline and maybe administered in capsule form to liberate HCl in the stomach Uses acidifying agent Nitric Acid (HNO3) (Spirit of Nitre, Aqua Fortis, Agua Fuerte) - aqueous solution containing 68%-71% by weight - highly corrosive fuming liquid and has a highly irritating odor - has a boiling point of 120oC and specific gravity of 1.41 - produce a yellow stain on animal tissue due to nitration of the aromatic amino acids, phenylamine, tyrosine, and tryptophan found in the proteins of the skin (this is known as Xanthoproteic Test) - strong monoprotic acid, an oxidizing and nitrating agent - oxidizes all common metals except gold and platinum to produce the nitrate salt of the metal (used in nitrate toluene to produce trinitrotoluene or TNT) Uses used in the manufacture of sulfuric acid, coal tar dyes and explosives used as nitrating agent in Pyroxylin USP XVIII as a source of nitrate ion in the preparation of Milk of Bismuth used to destroy chancres and warts Phosphoric Acid (H3PO4) (Orthophosphoric Acid, Acido Orthofosforico) - contains 85%-88% by weight - colorless, odorless, syrupy liquid having a specific gravity of about 1.71 - non-volatile and has no oxidizing properties NF 21 categorizes phosphoric acid as a solvent in the preparation of Anileridine Injection NF XV Diluted H3PO4 contains 9.5g- 10.5g H3PO4 in 100 ml solutions used as tonic and stimulant to the gastric mucous membrane acts as synergistic to pepsin and aids in the formulation of peptones used in making pharmaceutical products Uses acidifying agent where its limitation will be primarily in the solubility of various phosphate salts produced

can be treated with NaOH at particular concentrations to produce mixtures of HPO42- and H2PO4-

Sulfuric Acid (H2SO4) (Oil of Vitriol, Vitriolic Acid, Aceite de Vitriolo) - colorless, odorless liquid of oily consistency containing 94%-98% in a solution - has a specific gravity of 1.84 - when strongly heated, vaporizes and gives off dense white fumes of sulfur trioxide - useful as dehydrating agent, oxidizing agent and sulfonating or sulfating agent Oleum/Nordhausen Acid (H2S2O7) commercial variety of sulfuric acid which contains about 10% of dissolved SO3 2 Industrial Process of Preparing H2SO4 o Contact of the Catalytic Process produces most of the commercial sulfuric acid can obtain a product of any desired strength vanadium or platinized product of silica gels are used as catalysts o Lead Chamber Process most concentrated obtained contains only 76% by weight of H2SO4 products from these process are mostly used in the manufacture of fertilizer, primary calcium phosphate, known as Superphosphate Uses Form salts of basic organic drug molecules. Utilized as a dehydrating agent in the preparation of Pyroxylin 26 Official Inorganic Bases Strong Ammonia Solution (NH4OH) (Ammonium Hydroxide, Stronger Ammonia Water) - contains 27%-30% by weight in a solution - it loses ammonia rapidly when exposed to air - clear, colorless liquid, having an exceeding pungent, characteristic odor - has a specific gravity of 0.90 - has caustic nature in solution form while irritating properties in vapor form (do not taste or inhale) - container should be cooled well before opening and the opening be covered with a cloth

can serve as a liquid in forming soluble complex ions with many metal cations (Cu, Ag, Au, Zn, Cd, Cr, Ni, Co, Mn, & Pt) - its insoluble salts/ hydroxides become soluble in Ammonia solution Diluted Ammonia Solution contains 9%-10% in each solution also known as Ammonia Water or Household Ammonia can be prepared by diluting Strong Ammonia Solution with the appropriate quantity of purified water occasionally employed as circulatory stimulant by inhalation of the vapors used as counter irritant Uses used as Bronsted Base in many applications to form ammonium salts of acids used in the manufactrure on nitric acid and sodium bicarbonate used in the preparation of Aromatic Ammonia Spirit NF XV, where its serves as a source of NH3 to stabilize the ammonium carbonate against hydrolysis and in the preparation of ammoniacal silver nitrate solution NF 21 Calcium Hydroxide [Ca(OH)2] (Slaked Lime, Calcium hydrate) - official as white powder having an alkaline and bitter taste - slightly soluble in water and very soluble in boiling water - soluble in glycerin and syrup but not in alcohol - has the ability to absorb carbon dioxide from air (which forms CaCO3 giving cloudy appearance of calcium hydroxide solution) - manufactured from lime (CaO) through slaking - characterized by the avid absorption of water by the oxide, accompanied by the evolution of much heat and swelling of CaO lumps and a final disintegration into fine powder. Slaking addition of water in limited amounts Ca(OH)2 Solution contains 140% of solute in a solution clear, colorless liquid having an alkaline taste and is alkaline to litmus

Uses medically used as fluid electrolyte and as topical astringent used in pharmaceutical preparations for its potentially high hydroxide ion concentration reacts with free fatty acids in various oils (e.g. oleic acid) to form calcium soaps (have emulsifying properties) combine with NaOH (Soda lime) used to absorb CO2 from expired air in metabolic function tests Potassium Hydroxide (KOH) (Caustic Potash, Potassa) - official as white or nearly white fused masses, small pellets, flakes or sticks that have a crystalline fracture - very delinquent and rapidly absorbs both moisture and carbon dioxide from air - very strong base having a caustic or corrosive effect on tissues. - It greatly destroys tissue so great care in handling should be exercised Delinquent absorbs moisture from air and liquefy Uses caustic principally in veterinary practice saponifying agent to hydrolyze esters of fatty acids into their constituent alcohols and the potassium salt. used as titrating acids and base or alkaline reagent Sodium Hydroxide (NaOH) (Caustic Soda, Soda Lye) - occurs in dry, hard, brittle, white sticks, in large fused, opaque, white stone-like masses, having a dense crystalline fracture - very delinquent and rapidly absorbs moisture and CO2 from air - 1 gram dissolves in 0.9 mL at 25oC - very soluble in alcohol, ether and glycerin - strongest base available - attacks soft glass, bottles which are use as containers should be made of hard glass using rubber stoppers - reacts with the salts of all metals except in alkali metals and ammonium - catalyze the hydrolysis of esters (saponifying agent) - capable of damaging tissues so great care in handling should be exercised

less deliquescent, milder and cheaper than KOH - extensively used in industrial purpuses Glass-stoppered bottles can be used as containers of NaOH if little petroleum or paraffin is spread aroung the stopper. Uses same as KOH Sodium Carbonate (Na2CO3H2O) (Monohydrated Sodium Carbonate) - official as a monohydrate is a colorless crystal or white crystalline powder - odorless and has a strong alkaline taste - absorbs small amounts of moisture from air but in warm, dry air at 50oC or above, it effloresces, becoming anhydrous at 100oC - 1 gram dissolves in 3 mL of water and in 1.8 mL of boiling water and in 7 ml of glycerin - insoluble in alcohol - should not be given internally because of its marked alkalinity and irritating properties - used for its basicity in pharmaceutical preparations where it will form sodium salts of acidic drugs Soda ash anhydrous form 3 Well Characterized Hydrates o Monohydrate Na2CO3H2O o Heptahydrate Na2CO37H2O o Decahydrate Na2CO310H2O (Sal Soda, Washing Soda) Solvay Process process used to manufacture Na2CO3 by saturating a thoroughly cooled concentrated solution of NaCl first with ammonia and then with Carbon dioxide Calcined Soda anhydrous sodium carbonate has a disadvantage of being hygroscopic and when exposed to air, it gradually absorbs about 15% or one mole of water forming then the more stable monohydrated sodium carbonate Nitromerasol Solution NF XV water insoluble formed from combination of Na2CO3 and NaOH Soda Lime - intended for use in metabolism tests, anesthesia and oxygen therapy - may contain as indicator which will not react with the common anesthetic gases and which will change color when the absorption capacity of soda lime for CO2 is exhausted

absorb CO2 which would otherwise accumulate in the system Components of Soda lime 75% Ca(OH)2 absorbs CO2 to form CO3 o react with Na2CO3 to form CaCO3 o 20% H2O o 3% NaOH pick up CO2, but its combining power is soon exhausted o 1% KOH Buffer controls the pH in solutions should neither contribute to nor detract from the pharmacological properties of the active ingredient Buffer systems pair of related chemical compounds capable of resisting large changes in the pH of a solution caused by the addition of small amounts of acid or base composed of a weak acid and its salt (conjugate base) and weak base and its salt (conjugate acid)(*weak bases are not widely employed because of stability problems) NH3 & CO3 volatile species that must be avoided since their loss will alter the pH Reasons for controlling pH o Chemical Stability o Solubility of the drug o Patients comfort Factors that alter pH o Alkali in the glass o Gases in air (e.g. CO2 & NH3) Buffer Pair should not: o Participate in oxidation-reduction reaction o Alter the solubility of other components o Form complexes with active ingredients 2 Important Inorganic Buffers (have particular advantages in pharmaceutical preparations) o Phosphate Buffer System (e.g. Sorensen Phosphate Buffer System) contains dihydrogen and monohydrogen phosphate ions (physiologically buffer pairs normally found in the body) insoluble with Ag, Zn and Al which supports microbial growth o Borate Buffer System used in preparations containing metals that would otherwise precipitate in the presence of phosphate toxic so it can only be used in external preparations (e.g.

ophthalmic and nasal solutions) but contraindicated in parentheral solutions 3 Primary Borate Buffer Systems presently recognized o Feldmans Buffer System (7-8.2pH) consists of boric acid and sodium chloride (to make it isotonic) and alkaline solution containing sodium borate o Atkins and Pantin Buffer System (7.6-11pH) consists of alkaline solution of sodium carbonate and acid buffer solution of boric acid and sodium chloride o Gifford Buffer System (6-7.8pH) similar to Feldmans Buffer System however in place of NaCl, KCl is used (to make it hypotonic) Sodium Borate (Na2B4O710H2O) (Borax, Sodium Pyroborate, Sodium Tetraborate, Tinkal) - occurs as colorless, transparent crystals or as a white crystalline powder - its compound is odorless and effloresces in warm, dry air often leaving the crystals coated with white powder - soluble in water and glycerin and insoluble in alcohol - its aqueous solutions are alkaline to phenolphthalein - used or formed in situ as the alkaline member of the borate buffer system - has the same toxicity as boric acid, in fact it is hydrolyzed to boric acid in aqueous solutions - weak bacteriostatic - one of the components of many mouthwashes and oral preparations and frequently applied in the form of powder to ulcers in the mouth Metal borates are insoluble in water (except Alkali metals) Zinc Borate/ Zinc Hydroxide may be precipitated due to the alkalinity of sodium borate solution (use Boric acid instead because acidic Zinc Borate is water soluble) Bacteriostatic prevents the growth of bacteria Bactericidal kills bacteria Use best eyewash when acids happen to enter the mucosa 1%-2% is used in collyria Forms borax soap which serves as an emulsifying agent in the preparation of ointments particularly Cold Cream USP and Rose Water Ointment NF

Antioxidants - are compounds which have the capability of functioning chemically as reducing agents - used in pharmaceutical preparations containing easily oxidizable substances (e.g. Iodide & Ferrous) in order to maintain these substances in their reduced forms. 2 Mechanism of Antioxidant o Antioxidant is oxidized in place of the active constituent o Antioxidant reduces back the active constituent to its normal oxidation state Factors considered in selecting a suitable antioxidant o Antioxidant should be physiologically inert o Possible toxicity of both reducing agent and its oxidized product must be assessed o Consider possible solubility problems between the antioxidant (reducing agent) and the drug o Very strong reducing agent will form explosive mixtures when combined in dry form or in concentrated solution with strong oxidizing agents Hypophosphorous Acid (HH2PO2) - colorless or slightly yellow, odorless liquid containing 30%-32% of solute in a solution - has a specific gravity of 1.13 at 25oC - its pure acid is a syrupy colorless liquid which becomes a solid at 17oC and melts at 25oC - its central phosphorous atom is 1+ making it a very powerful reducing agent - it can reduce many compounds to form phosphorous acid (H3PO3) having an oxidation state of 3+ and finally to phosphoric acid (H3PO4) having a oxidation state of 5+ - it decolorizes acidic solutions of potassium permanganate immediately Sodium Hypophosphite is present as preservatives in certain foods Ammonium Hypophosphite found in many preparations as a preservative Hypophosphite should never be triturated with oxidizing agents such as nitrates, chlorates or permanganates Uses including its salts, have no important pharmacological action used principally as an antioxidant serves to prevent the formulation of free iodine in diluted hydrochloric acid and syrup

present in Ferrous Iodide syrup NF XI where it prevent the formulation of both ferric ions and molecular iodine. Sulfur Dioxide - is a colorless, non-flammable gas possessing a strong suffocating odor characteristic of burning sulfur - contains 97% by volume - under pressure, it condenses to a colorless liquid which boils at -10oC - has a density of 1.5 - soluble in water forming a moderately strong acid (Sulfurous Acid) - contains sulfur in the 4+ oxidation state and functions as strong reducing agent - used in injectable preparations enclosed in single dose ampoules or multiple dose vials - when passed through an aqueous solution containing iodine, hydroiodic acid is formed while oxidized to sulfate when passed through an aqueous solution containing potassium permanganate Uses protect many susceptible compounds from oxidation by reducing the oxidized form back again or probably even more important, by reacting with O2 before the susceptible compounds do because of its gaseous nature, it is usually used in injectable preparations enclosed in single dose ampoules or multiple dose vials used in bleaching wood pulp, fumigating grains and arresting fermentation used in fumigating houses Sodium Bisulfite (NaHSO3) (Sodium Hydrogen Sulfite, Sodium Acid Sulfite, Leucogen) - described as a mixture of sodium bisulfate and sodium metabisulfatite (Na2S2O5) in varying proportions - the compound is white or yellowish white crystals or a granular powder having the odor of sulfur dioxide - yields 58.5%-67.4% of sulfur dioxide - its solid form is unstable in air, thus giving off SO2 Sodium Metabisulfite (Na2S2O5) - the compound is white or yellowish white crystals or a granular powder having the odor of sulfur dioxide - yields 66%-67% of SO2

converted to bisulfate when dissolved in water acidic enough to neutralize the stronger bases (e.g. Na2CO3 to form sulfite) Uses used almost exclusively as an antioxidant usually found in acidic solutions of drugs that contain the phenol or catechol nucleus to prevent oxidation of compounds to quinines maybe found in ascorbic acid injections as a reducing agent used to prepare water soluble derivatives of normally insoluble drugs (e.g. Menadione Sodium Bisulfite for preparing parentheral products. Its acitivity is maintained until regenerated in the tissues) Nitrogen (N2) - occurs as a colorless, odorless inert gas - non-flammable and does not support combustion - one volume dissolves in about 65 volumes of water and in 9 volumes of alcohol at 20oC and at 760mmHg - usually sold in black cylinders Uses used as an inert atmosphere to retard oxidation in oxidation sensitive products (e.g. cod liver oil, olive oil, multiple vitamin preparations) used to replace air in containers for parentherals and solutions for topical applications used to retard oxidation in the qualitative test for carbon monoxide Water - tasteless, odorless, clear liquid which is colorless in small quantities but greenish blue in deep layers - has the ability to form hydrogen bonds with other water molecules or other electronegative or positive ions or molecules - solid form (Ice) has lower density due to the partial collapse of hydrogen bonds in the ice crystals - has high dielectric constant (extremely important to its capacity as a solvent and stabilizer of structure) - predominant constituent of the body

its small molecular size allows it to penetrate into free space within a crystal and to break the ionic bond Dielectric Constant related to the separation of charge within the water molecule as a result of its non-linear bent shape high in this, allows the water to solvate ions readily and to stabilize macromolecules. Hardness of Water this property is due to the presence of various amounts of Ca, Fe and/or Mg salts which convert ordinary soap into water insoluble calcium, iron and/or magnesium salts of fatty acids (water insoluble curd) Zeolite sodium aluminum silicate (Na2OAl2O32SiO23H2O) with the symbol Na2Zeol NaCl restore the activity of inactivity of Zeolite Deionized water purified water 2 Types of Hardness of Water o Temporary Hardness (bicarbonate hardness) caused by the presence in the water of Ca(HCO3)2 or Mg(HCO3)2 and can be removed (softened) by boiling or addition of a source of hydroxide o Permanent Hardness caused by the presence in solution of sulfates, chloride, or hydroxide of calcium and/or magnesium which cannot be removed by boiling or addition of source of hydroxide Means of purifying water o Addition of Soluble Carbonates (e.g. washing soda) precipitate Ca and Mg as insoluble carbonates o Chelation by the Zeolite (Permutit) Process passing hard water through a Zeolite column (where an exchange of water hardening cations is made for nonhardening sodium cations) o Deionizer or Demineralizer makes use of certain synthetic resins which are endowed with removing both cations and anions from water o Polyphosphate Chelation uses basic phosphate and sodium metaphosphate to chelate the divalent calcium making it unavailable for further reaction Official Waters o Purified Water USP 31 water obtained by distillation or by ion exchange treatment occurs as a clear, odorless liquid

water of choice for extemporaneous compounding and preparation of most USP test reagents Water for Injection USP 31 water purified by distillation must meet all the specifications called for the purified water monograph must meet the requirement for pyrogen test using rabbits(because they have the same temperature with us humans) as test animals and bacterial endotoxin tests using Linulus Amebocytes Lysate reagent intended for use as a solvent for the preparation of parentheral solutions finished preparations should be sterilized Sterile Water for Injection USP 31 water for injection sterilized and suitably packaged most difficult to prepare maybe stored in single-dose containers of not larger than 1000mL size label must indicate that no antimicrobial substance has been added used for extemporaneous compounding of parentherals for either intravenous or intramuscular injection Sterile Water for Inhalation USP 31 prepared from water for injection that is sterilized and suitably packaged in glass (Type I or II) it contains no microbial agent (except when used in humidifiers or other similar devices and where liable to contamination over a period of time) intended for inhalation therapy and that it is not intended for parentheral administration Sterile Water for Irrigation USP 31prepared from water for injection that is sterilized and suitably packed in single-dose glass (Type I or II) or plastic containers with a volume of more than 1 liter and maybe designed to empty rapidly Bacteriostatic Water for Injection USP 31 sterile water for injection containing one or more suitable antimicrobial agents stored in single-dose or in multiple-dose containers of not larger than 30 mL size intended for compounding small volumes of extemporaneous parentherals for intramuscular injection not for intravenous administration

labels should include statement Not for Use in Newborns in boldface, capital letters printed in contrasting color preferable in red Benzyl alcohol common bacteriostatic agent Glass (Na2SiO3) (Sodium Silicate) - generic term referring to vitreous material - softens gradually over a temperature range rather than melting sharply Boron decrease the coefficient of expansion of pyrex glasses Potassium gives a brown light- resistant glass Rare Earth selectively absorb light of certain wavelength Aqueous solutions slowly become alkaline upon standing for prolonged time in soft glass containers 4 General Types of Glass o Type I highly resistant, borosilicate glass o Type II treated soda-lime glass o Type III soda-lime glass o Type NP general soda-lime glass Compendia usually specify the type of glass container or a suitable buffer if the drug is basesensitive Water for injection must be stored in glass type I & II 3 Types of Glass o Colorless o Opaque superior light-protective container (except for ointments) o Colored 3 Reasons why clear containers are preferred o The patient want to see what he is buying o The amount left in the bottle is seen o The ease of pouring 4 types of clear containers o Colorless o Green o Blue o Amber usually screen out ultraviolet light radiation very effectively and is usually the color recommended for protection from light