CHAPTER 66
`
`Solutions, Emulsions, Suspensions and Extracts
`
`
`J G Nairn. PhD
`Professor of Pharmacy
`Faculty of Pharmacy
`University of Toronto
`Toronto. Canada M55 1A1
`
`The dosage forms described in this chapter may be pre-
`pared by dissolving the active ingredient(s) in an aqueous or
`nonaqueous solvent, by suspending the drug (if it is insoluble
`in pharmac eutically or therapeutically acceptable solvents) in
`an appropriate medium or by incorporating the medicinal
`agent into one of the two phases of an oil and water system.
`Such solutions, suspensions and emulsions are further de-
`fined in subsequent paragraphs but some, with similar proper—
`ties, are considered elsewhere. These dosage forms are use-
`ful for a number of reasons. They can be formulated for
`different routes of administration:
`oral use, introduction into
`body cavities or applied externally. The dose easily can be
`adjusted by dilution, and the oral liquid form readily can be
`administered to children or people unable to swallow tablets
`or capsules. Extracts eliminate the need to isolate the drug
`in pure form, allow several ingredients to be administered
`from a single source (eg, pancreatic extract) and permit the
`preliminary study
`of
`drugs
`from natural
`sources.
`Occasionally, solutions of drugs such as potassium chloride
`are used to minimize adverse effects in the gastrointestinal
`tract.
`.
`The preparation of these dosage forms involves several
`considerations on the part of the pharmacist: purpose of the
`drug, internal or external use, concentration of the drug,
`selection of the liquid vehicle, physical and chemical stability
`of the drug, preservation of the preparation and use of appro-
`priate excipients such as buffers, solubilizers, suspending
`agents, emulsifying agents, viscosity controlling agents, col-
`ors and flavors. Oral preparations require that consideration
`be given to improving patient compliance by making an accept—
`able product; consequently, color, odor and taste must be
`considered. These organoleptic factors are described in
`Chapter 80. The viscosity of a product also must be consid-
`ered in order that it has the proper palatability for an oral
`preparation and to have the appropriate suspending proper-
`ties if it is an emulsion or suspension. The theory pertaining
`to these systems is provided in Chapters 21 and 22. The
`theory of solutions, which involves solubility, ionization, pH
`control through the Lise of buffers and solubilization, is dis-
`tilssed in Chapters 16 and 17. Because of the complexity of
`some manufactured products, compounding may be carried
`out with the aid of linear programming models in order to
`obtain the optimal product. Chapters (87 to 89) should be
`consulted for information on the preparation and characteris-
`tics of those liquid preparations that are intended for ophthal-
`mic or parenteral use.
`Much has been written during the past decade about the
`biopharmaceutical properties of, in particular, the solid dos—
`age forms.
`In assessing the bioavailability of drugs in tablets
`and capsules, many researchers first have studied the absorp-
`tion of drugs administered in solution. Since drugs are ab-
`sorbed in their dissolved state, frequently it is found that the
`absorption rate of oral dosage forms decreases in the follow-
`
`tors which may influence the bioavailability and pharmacoki—
`netics of drugs in solution include concentration of the drug,
`volume of liquid administered, pH, buffer capacity and
`viscosity. Emulsions and suspensions are more complex sys-
`tems and consequently the extent of absorption and pharma—
`cokinetic parameters may be affected by a number of addi-
`tional formulation factors such as surfactants, type of viscosity
`agent, particle size and particle-size distribution, polymor-
`phism and solubility of drug in the oil phase. Specific ex-
`amples are provided in Chapter 19. There are a number of
`reasons for formulating drugs in forms in which the drug is not
`in the molecular state. These are improved stability,
`im—
`proved taste, low water solubility, palatability and ease of
`administration.
`Itbecomes apparent, then, that each dosage
`form will have advantages and disadvantages. '
`Liquid preparations may be dispensed in one of three ways.
`The pharmacist may dispense the product in its original con-
`tainer, buy the product in bulk and repackage it at the time
`a prescription is presented by the patient or compound
`the solution, suspension or emulsion in the dispensary.
`Compounding may involve nothing more than mixing mar-
`keted products in the manner indicated on the prescription or,
`in specific instances, may require the incorporation of active
`ingredients in a logical and pharmaceutically acceptable man-
`ner into the aqueous or nonaqueous solvents which Will form
`the bulk of the product.
`The pharmacist, in the first instance, depends on the phar-
`maceutical manufacturer to produce a product that is effec-
`tive, elegant and stable when stored under reasonably adverse
`conditions. Most manufacturers attempt to guarantee eifi-
`cacy by evaluating their products in a scientifically acceptable
`manner but, in some instances, such efiicacy is relative. For
`example, cough mixtures marketed by two different manufac-
`turers may contain the same active ingredients and it becomes
`difficult to assess the relative merits of the two products.
`In
`such instances the commercial advantage gained by one over
`the other may be based onproduct acceptability and prefer-
`ence which includes such factors as color, odor, taste, pourabil-
`ity, uniformity and packaging.
`TWO additional important fac~
`tors which must be considered in formulations are the stability
`of active and other ingredients, and the prevention of micro-
`bial contamination.
`The stability of the active ingredient inthe final product is of
`prime concern to the formulator.
`In general, drug sub-
`stances are less stable in aqueous media than in the solid
`dosage form and it is important, therefore, to properly stabi-
`lize and preserve, in particular those solutions, suspensions
`and emulsions that contain water. Certain simple chemical
`reactions can occur in these products. These may involve an
`ingre dient-ingredient interaction which implies a poor formu-
`lation, a container-product interaction which may alter prod-
`uct pH and thus, for pH—sensitive ingredients, be responsible
`for the subsequent formation of precipitates or a direct reac-
`
`Exhibit 1149
`IPR2017-00807
`ARGENTUM
`
` 000001
`
`

`

`1496
`
`CHAPTER 86
`
`V
`
`when the ingredient(s) in the product react with oxygen but
`without drastic externai interference. Such reactions first
`must be initiated by heat, Light (including ultraviolet radiant
`energy), peroxides or other labile compounds or heavy metals
`such as copper or iron. This initiation step results in the
`formation of a free radical (R*) which then reacts with oxygen.
`
`R* + 02 4» R02* (peroxy radical)
`
`R053 + RH —> ROOH + R“
`
`The free radical thus is regenerated and reacts with more
`oxygen. This propagation step is followed by the termina-
`tion reactions.
`
`ROZ’K + R05? —> inactive product
`R02* + R* a inactive product
`
`R* + R* a inactive product
`
`The effect of trace metals can be minimized by using citric acid
`or EDTA ie, sequestering agents. Antioxidants, however,
`may retard or delay oxidation by reacting with the free India
`cals formed in the product. Examples of antioxidants are the
`propyl, octyl and dodecyl esters of gallic acid, butylated hy-
`droxyanisole (BHA) and the tocopherols or vitamin E.
`.For a
`more detailed approach to the prevention of oxidative deterio-
`ration in pharmaceuticals, the information provided by Con-
`nors at all should be consulted. A description of many anti—
`oxidants is given in Chapter 80.
`.
`-
`The problem of drug stability has been well-defined by
`pharmaceutical scientists, but during the past few years a
`secondary and, in some respects, more serious problem has
`confronted the manufacturer of liquid preparations: Such
`pharmaceutically diverse pro ducts as baby lotions and milk of
`magnesia have been recalled from the market bedause of
`microbial contamination.
`In a survey of retail packages of
`liquid antacid preparations containing magnesium hydroxide,
`it was found that 30.5% of the finished bottles were contami-
`nated with Pseudomoncts aemginosa. The aerobic plate
`count ranged from less than 100 to 9,300,000 organisms/g.
`Kurup and “fan2 describe many preparations that are not
`preserved adequately and thus are not able to resist microbial
`contamination. Other examples could be cited but the range
`of microorganisms which can contaminate the liquid prepara-
`tion includes the Salmonella sp, E coli, certain Pseudomo-
`nos sp, includingPaemtginosct, and Staphylococcm (Lu/raw.
`Brucha describes the types of microorganisms found in vari-
`ous products and attempts to evaluate the hazards associated
`with the use of nonsterile pharmaceuticals. Coates’1 in a
`series of papers describes various interactions which must be
`considered when preservatives are selected.
`'-
`The'USP recommends that certain classes of products be
`tested for microbial count and for specified indicator micro-
`bial contaminants, eg, natural plant, animal and some'inineral
`products,'for freedom from Salmonella, sp ; oral solutions and
`suspensions, for freedom from E coli; articles applied topi-
`cally, for freedom from, P aemginosa and S (Lure/us and
`articles forrectal, urethral orvaginal administration, for yeasts
`and molds.
`-
`‘
`Products may become contaminated for a' number of rea—
`sons.
`'
`.
`'
`
`The raw materials used in the manufacture of solutions, suspensions and
`emulsions are excellent growth media for bacteria. Water, in particular,
`must be handled with care but substances such as gums, dispersing agents,
`surfactants, sugars and flavors can be the carriers of bacteria which
`ultimately contaminate the product.
`'
`'
`'
`Equipment. Bacteria grow well in the hooks and crevices ofpharmaceu-
`tical equipment (and in the simple equipment used in the dispensary).
`Such equipment should be cleaned thoroughly prior to use.
`Envirorunent and personnel can contribute to product contamination.
`
`Finally, consumer use may result in the introducuOn of
`microorganisms as a source of contamination, and this is Of
`particular concern if the organism is pathogenic. The mm
`sumer should be instructed in the proper technique in Ordertc;
`minimize contamination, and the manufacturer should en.
`sure, through the use of suitable challenge tests, that the
`. product is preserved appropriately and will reduce a SEVEre
`microbial challenge.
`Most factors cited above relate to good manufacturin
`practice. However, the forrnulator should add a preservativE
`to the product and decrease the probability of product
`contamination.
`If the product contains water, which 13 an
`important requirement for microbial growth, it almost is man.
`datory to include a preservative in the formulation. Nearly
`all products described in this chapter contain water and, thus
`with certain exceptions, eg, aqueous acids, will support micro.)
`bial growth. Microbes will grow in an aqueous solution, and
`inthe aqueous phase of multiphase systems such as emulsions
`and suspensions.
`It must be stressed that the addition of an
`appropriate preservative in no way replaces good manufactup
`ing practice but merely provides further assurance that the
`product will retain its pharmaceutically acceptable character.
`istics until it is used by the patient and for sometime thereaf.
`ter.
`.
`
`The major criteria that should be considered in selecting a
`preservative are as follows:
`it should be effective against a
`Wide spectrum of microorganisms, stable for its shelf life,
`nontoxic, nonsensitizing, compatible with the ingredients in
`the dosage form inexpensive and essentially relatively free of
`taste and odor.
`_
`in addition to the above discussion, there are a number of
`specific factors which should be taken into account when a
`preservative is selected:
`1. The site of use, cg, external, internal or ophthalmic.
`2. The pH of the liquid, as it may affect both the ionization of the
`preservative and its stability.
`-
`3. The solvent, as this will affect the solubility of the preservative.
`4. Partitioning into the oil phase of an emulsion, thereby reducing the
`concentration in the aqueous phase Where preservative action takes place.
`5. _, Adsorption onto the solid phase of a suspension, thereby reducing
`the concentration in the aqueous phase.
`5. Processing and packaging variables such as heat, order of addition
`of the ingredients, stirring or container materials. "
`,
`7. Type of dosage form, eg, solution, emulsion or suspension.
`
`PreservativesfilE may be grouped into a number of classes
`depending upon their molecular structure and only a few Will
`be discussed. The reader shouldconsult Chapter 80 or se-
`lected texts in the bibliography for further description.
`Alcoho‘lsiEthanol is useful as a preservative when it is used as a
`solvent; however, it does need a relatively high concentration, somewhat
`greater than 10%, to be effective. Too high a concentration may result in
`incompatibilities in suspension and emulsion systems; Propylene glycol
`also is used as a solvent in oral solutions and topical preparations, and it
`can function as a preservative in the range of 15 to 30%.
`It is not volatile
`like ethanol and is used frequently not only in solutions but also in suspen-
`sions and emulsions. Other alcohols used in lower concentrations, about
`1%, for preservative action,_inc1ude chlorobutanol and phenylethyl alco-
`hol.
`'
`'
`AcidseBenzoic acid has a low solubility in water, about 0.34% at
`25“. The concentration range used for inhibitory action varies from 0.1%
`to 0.5%. Only the nonionized form is effective and therefore its use is
`restricted to preparations with a pH below 4.5.
`Sorbic acid also has a low
`solubility in water, 0.3% at 30°. Suitable concentrations for preservative
`action are inthe range of 0.05 to 2%.
`Its preservative action is due to the
`nonionized form; consequently,
`it
`is only efiective in acid media-
`Because of the double bond in its structure, it is subject to Oxidation.
`EstersflParabens are esters ofp-hydroxybenzoic acid and include the
`methyl, ethyl, propyl and butyl derivatives. ' The solubility in water de'
`creases as the molecular weight increases from 0.25% for the methyl ester
`to 0.02% for the butyl ester. These compounds are used widely in phar-
`maceutical products and are effective and stable over a pH range of 4 to 8.
`
` 000002
`
`

`

`SOLUTIONS, EMULSIONS, SUSPENSIONS AND EXTRACTS
`
`149?
`
` Quaternary Ammonium CompoundsrBenzalkonium chloride is a
`
`mixture consisting principally of the homologs C,2Hg.r, and CMHZQ. This
`reservative is used at a relatively low concentration, 0.002 to 0.02%,
`depending on the nature of the pharmaceutical product. This class of
`compounds has an optimallactivity over the pH range of 4 to 10 and is quite
`stable at room temperature. Because of the cationic nature ofthis type of
`reservative, it is incompatible with many anionic compounds such as
`Smfactants and can bind to nonionic surfactants.
`It is used generally in
`preparations for external use or those solutions which come in contact
`with mucous membranes.
`'
`It now should be obvious that when the pharmacist dis—
`penses or compounds the various liquid preparations respon-
`sibility is assumed along, with the manufacturer, for the main—
`tenance of product stability. The USP includes a section on
`Stability considerations in dispensing, which should be stud-
`ied in detail. Certain points are se1f~evident. Stock should
`be rotated and replaced if expiration dates on the label so
`indicate. Products should be stored in the manner indicated
`in the compendium; eg,
`in a cool place or a tight, light-
`resistant container. Further, products should be checked for
`evidence of instability. With respect to solutions, elixirs and
`syrups, color change, precipitation and evidence of microbial
`or chemical gas formation are major signs of instability.
`Emulsions may cream but if they break (ie, there is a separa-
`
`tion of an oil phase) the product is considered to be unstable.
`Sedimentation and caking are primary indications of instabil-
`ity in suspensions. The presence of large particles may mean
`that excessive crystal growth has occurred.
`The USP states that if the product must be repackaged, care
`and the container specified by the compendium must be used.
`For example, a suitably opaque plastic container should be
`used if a light-resistant container is specified.
`If a product is
`diluted, or where two products are mixed, the pharmacist
`should use his or her knowledge to guard against incompatibil-
`ity and instability. Oral antibiotic preparations constituted
`into liquid form should never be mixed with other products.
`If the chemical stability of extemporaneously prepared liquid
`preparations is unknown, their use should be minimized and
`every care taken to insure that product characteristics will not
`change during the time it must be used by the patient.
`Because of the number of excipients and additives in these
`preparations, it is recommended that all the ingredients be
`listed on the container to reduce the risks which confront
`hypersensitive patients when these products are administered.
`Finally, the pharmacist should inform the patient regarding
`the appropriate use of the product, the proper storage condi»
`tions and the time after which it should be discarded.
`
`Solutions
`
`Aqueous Solutions
`
`A solution is a homogeneous mixture that is prepared by
`dissolving a solid, liquid or gas in another liquid and repre-
`sents a group of preparations in which the molecules of the
`solute or dissolved substance are dispersed among those of
`the solvent. Solutions also may be classified on the basis of
`physical or chemical properties, method of preparation, use,
`physical state, number of ingredients and particle size. The
`narrower definition in this subsection limits the solvent to
`water and excludes those preparations that are sweet and/or
`viscid in character and nonaqueous solutions. This section
`includes, therefore, those pharmaceutical forms that are dese
`ignated as Water, Aromatic Waters, Aqueous Acids, Solu—
`tions, Bunches, Enemas, Gargtes, Mouthwashes, Juices,
`NasalSolutions, Otto Solutions andlrrigoiion Solutions.
`
`The major ingredient in most ofthe dosage forms described
`herein is water.
`It is used both as a vehicle and as a solvent
`for the desired flavoring or medicinal ingredients.
`Its taste-
`lessness, freedom from irritating qualities and lack of pharman
`cological activity make it ideal for such purposes. There is,
`however, a tendency to assume that its purity is constant and
`that it can be stored, handled and used with a minimum of
`care. While it is true that municipal supplies must comply
`With Environmental Protection Agency (EPA) regulations (or
`comparable regulations in other countries), drinking water
`must be repurified before it can be used in'pharmaceuticals.
`For further information on water, see Chapter 28.
`Five of the six solvent waters described in the USP are used
`in the preparation of parenterals, irrigations or inhalations.
`Purified Water must be used for all other pharmaceutical
`operations, dosage forms and, as needed, in all USP tests and
`assays.
`It must meet rigid specifications for chemical purity.
`Such water may be prepared by distillation, by use of ion-
`EXchange resins or by reverse osmosis.
`A wide variety of commercially available stills are used to
`
`has been shown that P oemginosct (and other microorgan-
`isms) can grow in the distilled water produced in hospitals.
`The implications of this are obvious. Sterile water may be
`sterile at the time of production but may lose this characteris-
`tic if it is stored improperly. Hickman et ctl,7 by regrouping
`the components of conventional distillation equipment, have
`described a method for the continuous supply of sterile, ultra-
`pure water. Quality—control procedures for monitoring the
`microbiological quality of water should be performed in the
`pharmaceutical manufacturer’s production facilities.
`The major impurities in water are calcium, iron, magno
`sium, manganese, silica and sodium; The cations usually are
`combined with the bicarbonate, sulfate or chloride anions.
`“Hard” waters are those that contain calcium and magnesium
`cations. Bicarbonates are the major impurity in “alkaline”
`waters,
`'
`.
`Ion-exchange (deionization, demineralization) processes
`will remove most of the major impurities in water efliciently
`and economically. A cation exchanger, HgR, first converts
`bicarbonates, sulfates and chlorides to their respective acids,
`eg,
`
`CaSO4
`
`Ca
`
`Mgso4 + HER a Mg R + st04
`
`NaZSO4
`
`camcopg
`
`'
`
`Na2
`
`Ca
`
`Mg(HCO,,)2 + _H2R r; Mg R + ziizco3
`2Ncho3r
`-
`Nag
`Carbonic acid decomposes to carbon dioxide {which is re-
`moved by aeration in the decarbonator) and water.
`The anion exchanger may contain either awealdy basic or a
`strongly basic anion resin. These adsorb sulfuric, hydrochlo-
`ric and nitric acids. Chemical reactions may involve com-
`plete adsorption or an exchange with some other anion.
`
` 000003
`
`

`

`1498
`
`CHAPTER 86
`
`W
`
`Weakly dissociated carbonic and silicic acids can be removed
`only by strongly basic anion resins.
`
`HZSiOS + ZAOH —> Azsro2 + 211120
`
`Unit capacity varies with the nature of the installation, but it is
`possible to process as much as 15,000 gal of water/min.
`Deionization processes do not necessarily'produce Purtfied
`Water which will comply with EPA requirements for drinking
`water. Resin columns retain phosphates and organic debris.
`Either alone. or- in combination, these substances can act as
`growthmedia for microorganisms. Observations have shown
`that deionized water containing 90 organisms/mL contained,
`after 24-hour storage, 105 organisms/mL. Columns can be
`cleaned partially of pseudomonads by recharging, buta 0. 25%
`solution of formaldehyde will destroy most bacteria. The
`column must be washed thoroughly and checked for the. ab«
`sence of aldehyde (with a Schiffs Reagent) before it can be
`used to generate deionized water..
`Ultraviolet radiant energy (240—280 nm), heat or filtration
`can be used to limit the growth, kill or remove microorga-
`nisms inwater. The latter method employs membrane filters
`and can be used to remove bacteria from heat-labile materials
`as described under membrane filters in Chapter 84.
`The phenomenon of osmosis involves the passage of water
`from a dilute solution across a semipermeable membrane to a
`more concentrated solution. Flow of water can be stopped
`by applying pressure, equal to the osmotic pressure, to the
`concentrated solution. The flow of water can be reversed by
`applying a pressure, greater than the osmotic pressure. The
`process of reverse osmosis utilizes the latter principle; by
`applying pressure, greater than the osmotic pressure, to the
`concentrated solution, eg, tap water, pure water may be ob-
`tained (see Reverse Osmosis in Chapter 37).
`_
`Cellulose acetate is used in the manufacture of semiperme-
`able membranes for purifying water by reverse osmosis.
`This polymer has functional groups that can hydrogen«bond
`to water or other substances such as alcohol. The water
`molecules which enter the polymer are transported from one
`bonding site to the next under pressure. Because of the thin
`layer of pure water strongly adsorbed at the surface of the
`membrane, salts, to a large extent, are repelled from the
`surface, the highenvalent ions being repelled to a greater
`extent, thus causing a separation of ions from the water.
`Organic molecules are rejected on the basis of a sieve mecha-
`nism related to their size and shape. Small organic mol-
`ecules, with a molecular weight smaller than approximately
`200, will pass through the membrane material. Since there
`are few organic molecules with a molecular weight of less than
`200 in the municipal water supply, reverse osmosis usually is
`sufficient for the removal of organic material. The pore sizes
`of the selectively permeable reverse-osmosis membranes are
`between 5 and 100 A. Viruses and bacteria larger than 1 00 A
`are rejected if no imperfections exist in the membrane. The
`membranes may and do develop openings which permit the
`passage of microorganisms. Because of the semistatic con-
`ditions, bacteria can grow both upstream and'downstream of
`the membrane.
`Improvements in membranes are being made
`continually in type and manufacturing process such as the use
`of polyamide materials.
`It is expected that the preparation
`ofwaterwith negligible or no bacteria present will be achieved
`by this process.
`The selection of water—treatment equipment depends upon
`the quality of water to be tested, the quality of water required
`and the specific pharmaceutical purpose of the water.
`Frequently, two or more methods are used to produce the
`water desired, for example, filtration and distillation, or filtra-
`tion, reverse osmosis and ion exchange.
`'
`
`Aromatic Waters
`
`prepared. They are used principally as flavored or perfljmed
`vehicles. Aromatic Waters may be prepared by distillation 0
`solutiorr of the aromatic substance with or without the use of:
`dispersing agent such as talc. Peppermint 1Water USP and
`Stronger Rose Water USP are examples of aromatic waters
`Other methods have been suggested for preparing aromas,
`waters based on the use of soluble concentrates or on meal-pm
`ration of solubilizing agents such as polysorbate 20.
`Concentrated waters eg, peppermint, dill, cinnamcm and
`caraway, may be prepared as follows:
`
`Dissolve 20 mL of the volatile oil in 600 mL of 90% ethanol. Add
`sufficient purified water in successive small portions to produce 1000 ml.
`Shake vigorously after each addition. Add 50 g of sterilized purified tale
`shake occasionally for several hours and filter.
`’
`
`The aromatic water is prepared by diluting the concentrate
`with 39 times its volume of water.
`The chemical composition of many of the volatile oils is
`known and suitable synthetic substances may be used in pm,
`paring pharmaceuticals and cosmetics.
`Similarly, many syn.
`thetic aromatic substances have a characteristic odor; eg
`geranyl phenyl acetate has a honey odor. Such substances}
`either ”alone or in cembinati'on, can be used in nonofficiai
`preparations. Additional information regarding the appropfi.
`ate preparation of aromatic waters is provided in RPS-18
`‘
`Chapter 83, and RPS-17, Chapter 84.
`The principal difficulty experienced in compounding pre-
`scriptions containing aromatic waters is due to a “salting out"
`action of certain ingredients, such as very soluble salts, on the
`volatile principle of the aromatic water. A replacement of
`- part of the aromatic water with purified water is permissible
`when no other function is being served than that of avehicle.
`PreservationeAromatic waters will deteriorate with time
`and should, therefore, be made in small quantities and pro-
`tected from intense light, excessive heat and stored in airtight,
`light‘resistant containers.
`
`'AqueousAcids
`The ofiicial inorganic acids and certain organic acids, al-
`though of minor significance as therapeutic agents, are of
`great importance in chemical and pharmaceutical manufac-
`turing. This is especially true of acetic, hydrochloric and
`nitric acids.
`-
`‘
`'
`Percentage Strengths—Many of the more important inor-
`ganic acids are available commercially in the form of concen-
`trated aqueous solutions. The percentage strength varies
`from one acid to another and depends on the solubility and
`stability of the solute in water and on the manufacturing
`process. Thus, the ofiicial Hydrochloric Acid contains from
`36.5 to 38% by weight of H01, whereas Nitric Acid contains
`from 69 to 71% by weight ofl-l'N03.
`Because the strengths of these concentrated acids are stated
`in terms of % by weight, it is essential that specific gravities
`also be provided if one is to be able to calculate conveniently
`the amount of absolute acid centained in a unit volume of the
`solution as purchased. The mathematical relationship in-
`volved is given by the equationM : V X S x F, whereM is the
`mass in g of absolute acid contained in VmL of solution having
`a specific gravity S and a fractional percentage strength F-
`As an example, Hydrochloric Acid containing 86.93% by
`weight of HCl has a specific gravity of'1.1875. Therefore:
`the amount of absolute HCl supplied by 100 mL of this solu-
`tion is given by:
`'
`
`M : 100 X 1.1875 x 0.3693 = 43.85 gHCl
`
`Incompatibilities-Although many of the reactions chair
`acteristic of acids offer opportunities 'fOr incompatibilities
`only a few are of sufficient importance to require more this“1
`
` 000004
`
`

`

`SOLUTlONS, EMULSIONS, SUSPENSlONS AND EXTRACTS
`
`1499
`
`soluble, the organic acid will be precipitated. Thus, salicylic
`acid and benzoic acid are precipitated from solutions of salicy-
`laws and benzoates. Boric acid likewise is precipitated from
`concentrated solutions of borates. By a similar reaction,
`Certain soluble organic compounds are converted into an
`insoluble form. Phenobarbital sodium, for example, is con-
`verted into phenobarbital which will precipitate in aqueous
`solution.
`.
`‘
`.
`The ability of acids to combine with alkaloids and other
`organic compounds containing a basic nitrogen atom is used
`m preparing soluble salts of these substances.
`It should be borne in mind that certain solutions, syrups,
`efixirs and other pharmaceutical preparations, may contain
`free acid, which causes these preparations to exhibit the incom—
`patibilities characteristic of the acid.
`Acids also possess the incompatibilities of the anions which
`they contain and,
`in the case of organic acids, these are
`frequently of prime importance. These are discussed under
`the specific anions.
`.
`Diluted Acids—The diluted acids in the USP are aqueous
`sclutions of acids, of a suitable strength (usually 10% w/o but
`Diluted Acetic Acid is 6% w/u) for internal administration or
`for the manufacture of other preparations.
`‘
`The strengths of the ofiicial undiluted acids are expressed
`as percentages w/w, whereas the strengths of the official
`diluted acids are expressed as percent w/u.
`It, therefore,
`becomes necessary to consider the specific gravities of the
`concentrated acids when calculating the volume required to
`make a given quantity of diluted acid. The following equa-
`tionwili give the number of mL required to make 1000 ml, of
`diluted acid:
`'
`'
`
`
`Strength of diluted acid X 1000
`
`Strength of undiluted acid >< sp gr of undiluted acid
`
`Thus, if one Wishes to make 1000 mL of Diluted Hydrochloric
`Acid USP using Hydrochloric Acid which assays 37.5% H01
`(Sp gr 1.18), the amount required is
`- 10 X 1000
`87.5 X 1.18
`
`: 226 mL
`
`Diluted Hydrochloric Acid USP has been used in the treat-
`ment of achlorhydria. However, it may irritate the mucous
`membrane of the mouth and attack the enamel of the teeth.
`The usual dose is 5 mL, well-diluted with water.
`In the treat-
`ment of achlorhydria no attempt is made to administer more
`than a relief-producing dose.
`
`Solutions
`
`A solution, in the present context, is a liquid preparation
`that contains one or more soluble chemical substances dis-
`solved in water. The solute usually is nonvolatile.
`Solu-
`tions are used for the specific therapeutic effect of the solute,
`either internally or externally. Although the emphasis here
`is on the aqueous solution, certain preparations of this type
`such as syrups, infusions and decoctions have distinctive charac-
`teristics and, therefore, are described later in the chapter.
`Solvents, solubility and general methods for the incorpora-
`tion of a solute in a solvent are discussed in Chapter 16.
`So—
`lutions are usually bottled automatically with equipment of
`the type shown in Fig. 1.
`Preparation—A specific method of preparation is given in
`the compendia for most solutions. These procedures fall
`into three main categories.
`Simple Solutions—Solutions of this type are prepared by dissolving
`the solute in most of the solvent, mixing until dissolved, then adding
`sufficient solvent to bring the solution up to the proper volume, The
`
`ously 3 g of calcium hydroxide with 1000 mL of cool, purified water. Ex-
`cess calcium hydroxide is allowed to settle out and the clear, supernatant
`liquid dispensed.
`An increase in solvent temperature usually implies an increase in solute
`solubility. This rule does not apply, however, to the solubility of calcium
`hydroxide in water, which decreases with increasing temperature. The
`official solution is prepared at 25°,
`'
`Solutions containing hydroxides react with the carbon dioxide in the
`atmosphere.
`
`our + co2 —> Hco;
`
`on- + HCClg’ —> 0032* + H20
`Calcium Hydroxide Topical Solution, therefore, should be preserved in
`well-filled, tight containers, at a temperature not exceeding 25”.
`Strong Iodine Solution contains, in each 100 mL, 4.5—5.5 g of iodine,
`and 91.5—10.5 g of potassium Iodide.
`It is prepared by