`
`Solutions, Emulsions, Suspensions and Extracts
`
`
`
`JG Nairn, PhD
`Professor of Pharmacy
`Faculty of Pharmacy
`University of Toronto
`Toronto, Canada M55 1A4
`
`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 pharmaceutically or therapeutically acceptable solvents) in
`am 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 formsare 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 anomnlves 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-
`orsand 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 orderthat it has the proper palatability for an oral
`preparation and to have the appropriate suspending proper-
`ties if itis 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 use of buffers and solubilization, is dis-
`cussedin Chapters 16and17. 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-
`ageforms.
`Inassessing the bioavailability of drugs in tablets
`and capsules, many researchersfirst 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
`reasonsfor formulating drugs in forms in which the drugis not
`in the molecular state. These are improved stability,
`im-
`proved taste, low water solubility, palatability and ease of
`administration.
`It.becomes apparent, then, that each dosage
`form will have advantages and disadvantages. ©
`Liquid preparations may be dispensed in oneof three ways.
`The pharmacist may dispense the productin 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 mannerindicated.on the prescription or,
`in specific instances, may require the incorporationof 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 effi-
`cacy by evaluating their products in a scientifically acceptable
`mannerbut, in some.instances, such efficacy is relative. For
`example, cough mixtures marketed by two different manufac-
`turers may contain the sameactive 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 on_product acceptability and prefer-
`ence which includes suchfactors as color, odor, taste, pourabil-
`ity, uniformity and packaging. Two additional importantfac-
`tors which mustbe considered in formulations are the stability
`of active and other ingredients, and the prevention of micro-
`bial contamination.
`Thestability of the active ingredient in the 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 andit 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
`ingredient-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
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`CHAPTER 86
`
`Y
`
`when the ingredient(s) in the product react with oxygen but
`without drastic external interference. Such reactions first
`must be initiated by heat, light (including ultraviolet radiant
`energy), peroxides or other labile compoundsor 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* + O, — RO,* (peroxy radical)
`
`RO,* + RH — ROOH + R*
`
`The free radical thus is regenerated and reacts with more
`oxygen. This propagation step is followed by the termina-
`tion reactions.
`
`RO,* + ROg* — inactive product
`RO,* + R* — inactive product
`
`R* + R* — 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 radi-
`calsformed inthe product. Examples of antioxidants are the
`propyl, octyl and dodecyl esters of gallic acid, butylated hy-
`droxyanisole (BHA) and the tocopherols or vitamin. E.
`.Fora
`more detailed approachto the prevention of oxidative deterio-
`ration in pharmaceuticals, the information provided by Con-
`nors ef alt should be consulted. A description of many anti-
`oxidants is given in Chapter 80,
`.
`i
`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 products as baby lotions and milk of
`magnesia have been recalled from the market because 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 Pseudomonas aeruginosa. The aerobic plate
`count ranged from less than 100 to 9,300,000 organisms/g.
`Kurup and Wan? 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-
`nas sp, including P aeruginosa, and Staphylococcus aureus.
`Bruch? describes the types of microorganisms foundin vari-
`ous products and attempts to evaluate the hazards associated
`with the use of nonsterile pharmacéuticals. Coates? in a
`seriés of papers describes various interactions which must be
`considered when preservativesare 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 mineral
`products, for freedom from Salmonella sp; oral solutions and
`suspensions, for freedom from FE colt; articles applied topi-
`cally, for freedom from P aeruginosa and S aureus and
`articles for rectal, urethral or vaginal administration, for yeasts
`and molds.
`’
`:
`Products may become contaminated for a number of rea-
`sons.
`-
`74
`
`The raw materials used inthe 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 inthenooks and ¢revicesofpharmaceu-
`tical equipment (and in the simple equipment used in the dispensary).
`Such equipment should be cleaned theroughly priorto use.
`- Environment and personnel can contribute to product contamination.
`
`Finally, consumer use may result in the introduction of
`microorganisms as a source of contamination, and this is of
`particular concern if the organism is pathogenic. The con
`sumershould be instructedin the proper technique in ordert,
`minimize contamination, and the manufacturer shoulq 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 manufactuyin
`practice. However, the formulator should adda preservative
`to the product and decrease the probability of product
`contamination.
`If the product contains water, which is an
`important requirementfor microbial growth, it almost is man.
`datory to include a preservative in the formulation. Nearly
`all products described in this chapter contain water and, thys
`with certain exceptions, eg, aqueousacids, will support micro.
`bial growth. Microbes will grow in an aqueoussolution, anq
`inthe aqueous phase of multiphase systemssuch as emulsions
`and suspensions.
`It must be stressed that the addition of an
`appropriate preservative in no way replaces good manufactur.
`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 thereag.
`ter.
`:
`The majorcriteria 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 andessentially 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.
`Thesite of use, eg, 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 takesplace.
`5. _ Adsorption onto the solid phase of a suspension, thereby reducing
`the concentration in the aqueous phase.
`6. Processing and packaging variables such as heat, order of addition
`of the ingredients,stirring or container materials. °
`,
`7. Typeof dosage form,eg, solution, emulsion or suspension.
`Preservatives®® may be grouped into a numberof 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.
`Alcohols—Ethanol 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 higha concentration may result in
`incompatibilities in suspension and emulsion systems: Propylene glycol
`also is used as a solventin oral solutions and topical preparations, and it
`can function as a preservative in the range of 15 to 30%.
`It is notvolatile
`like ethanol andis used frequently not only in solutions but also in suspen-
`sionsand emulsions. Other alcohols used in lower concentrations, about
`1%, for preservative action, include chlorobutanol and phenylethyl alco-
`hol.
`|
`.
`Acids—Benzoic¢ acid has a low solubility in water, about 0.34% at
`25°. The concentration range usedfor 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 alow
`solubility in water, 0.3% at 30°. Suitable concentrations for preservative
`action are in the range of 0.05 to 2%.
`Its preservative action is due to the
`nonionized form; consequently,
`it
`is only effective in acid media.
`Becauseof the double bond inits structure, it is subject to oxidation.
`Esters—Parabensare 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 compoundsare used widely in phar-
`maceutical products andare effective and stable over a pH range of4 to 8.
`
` 000002
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`SOLUTIONS, EMULSIONS, SUSPENSIONS AND EXTRACTS
`
`1497
`
`Quaternary Ammonium Compounds—Benzalkonium chloride is a
`pixie consisting principally of the homologs C,2H25 and C,Hes. 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 optimalactivity over the pH range of4to 10 andis quite
`stable at room. température. Because ofthe cationic nature ofthis type of
`reservative, it is incormpatible with many anionic compounds such as
`surfactants 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-
`enses OF 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 self-evident. Stock should
`pe 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 ofinstability. 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 butif they break (ie, there is a separa-
`
`tion of an oil phase) the productis considered to be unstable.
`Sedimentation and caking are primary indications of instabil-
`ityinsuspensions. The presence of large particles may mean
`that excessive crystal growth has occurred.
`The USP states that if the product must be repackaged, care
`andthe container specified by the compendium must be used.
`For example, a suitably opaque plastic container should be
`usedif a light-resistant containeris specified.
`Ifa 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 chemicalstability 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 timeit must be used by the patient.
`Because of the numberof 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 whenthese 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 particlesize. 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 des-
`ignated as Water, Aromatic Waters, Aqueous Acids, Solu-
`tions, Douches, Enemas, Gargles, Mouthwashes, Juices,
`Nasal Solutions, Otic Solutions andIrrigation Solutions.
`
`has been shown that P aeruginosa (and other microorgan-
`isms) can grow in the distilled water produced in hospitals.
`The implications of this are obvious. Sterile watcr may be
`sterile at the time of production but may lose this characteris-
`tic if itis stored improperly. Hickman et al,” by regrouping
`the components of conventional distillation equipment, have
`described a methodfor the continuous supplyofsterile, ultra-
`pure water. Quality-control procedures for monitoring the
`microbiological quality of water should be performed in the
`pharmaceutical manufacturer’s productionfacilities.
`The major impurities in water are calcium, iron, magne-
`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.
`7
`Jon-exchange (deionization, demineralization) processes
`will remove most of the major impurities in water efficiently
`and economically. A cation exchanger, HR, first converts
`bicarbonates, sulfates and chloridesto their respective acids,
`es)
`
`The major ingredient in most ofthe dosage forms described
`herein ig water.
`It is used both as a vehicle and as a solvent
`for the desired flavoring or medicinal ingredients.
`Tts taste-
`lessness, freedom from irritating qualities and lack of pharma-
`cological activity make it ideal for such purposes. There is,
`Ca
`CaSO,
`however, a tendency to assume that its purity is constant and
`that it can be stored, handled and used with a minimum of
`MgSO,|+ H.R > Mg! R + H,SO,
`care. While it is true that municipal supplies must comply
`Na,SO,
`Nay
`with Environmental Protection Agency (EPA) regulations (or
`comparable regulations in other countries), drinking water
`Ca(HCO)s
`Ca
`must be repurified beforeit can be used in’ pharmaceuticals.
`Mg(HCO;)o) + H»R > Mg|R + 2H,CO3
`Forfurther information on water, see Chapter 23:
`Five of the six solvent waters described in the USP are used
`2NaHCO; :
`-
`Nag
`in the preparation of parenterals, irrigations or inhalations.
`Carbonic acid decomposes to carbon dioxide (which is re-
`Purified Water must be used for all other pharmaceutical
`moved by aeration in the decarbonator) and water.
`operations, dosage forms and, as needed, in all USP tests and
`The anion exchanger may contain either a weakly basic or a
`assays.
`It must meet rigid specifications for chemical purity.
`strongly basic anion resin. These adsorb sulfuric, hydrochlo-
`Such water may be prepared by distillation, by use of ion-
`ric and nitric acids. Chemical reactions may involve com-
`exchange resins or by reverse osmosis.
`plete adsorption or an exchange with some other anion.
`A wide variety of commercially available stills are used to
`
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`4
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`1498
`
`CHAPTER 86
`
`Weakly dissociated carbonic andsilicic acids can be removed
`only by strongly basic anionresins.
`H,Si0, + 2AOH > A,SiO, + 2H,0
`Unit capacity varies with the nature ofthe installation, butit is
`possible to process as much as 15,000 gal of water/min.
`Deionization processes do not necessarilyproduce Purified
`Water which will comply with EPA requirements for drinking
`water. Resin columns retain phosphates and organic debris.
`Either aloneor 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, 10° organisms/mL. Columns can be
`cleaned partially of pseudomonadsby recharging, but.a0.25%
`solution of formaldehyde will destroy most bacteria. The
`column must be washed thoroughly and checked for theab-
`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 in water. The latter method employs membranefilters
`and can be used to removebacteria from heat-labile materials
`as described under membranefilters in Chapter 84.
`The phenomenon of osmosis involves the passage of water
`from a dilute solution across a sernipermeable 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 polymerhas 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
`bondingsite 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 higher-valent ions being repelled to a greater
`extent, thus causing a separation of ions from the water.
`Organic moleculesare 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
`2.00 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
`between5 and 100A. Viruses and bacteria larger than 100A
`are rejected if no imperfections exist inthe 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
`themembrane.
`Improvementsin 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.
`,
`
`prepared. They are used principally as flavored or Perfume
`vehicles. Aromatic Waters may be preparedbydistillation 0
`solution of the aromatic substance with or without the use of :
`dispersing agent such as talc. Peppermint Water USP ang
`Stronger Rose Water USP are examples of aromatic waters
`Other methods have been suggested for preparing aromatic
`waters based on the useof soluble concentrates or on incorpo,
`ration of solubilizing agents such as polysorbate 20.
`Concentrated waters eg, peppermint, dill, cinnamon 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 50g ofsterilized purified tal.
`shake occasionally for several hours andfilter.
`:
`
`The aromatic water is prepared by diluting the concentrate
`with 39 timesits volume of water.
`The chemical composition of many of the volatile oils js
`known and suitable synthetic substances may be used in pre.
`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 combination, can be used in nonofticial
`preparations. Additional information regardingthe appropri-
`ate preparation of aromatic waters is provided in RPS-18
`Chapter 83, and RPS-17, Chapter84.
`The principal difficulty experienced in compounding pre-
`scriptions containing aromatic watersis 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 thanthat of a vehicle.
`Preservation—Aromatic 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 official 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—Manyofthe more importantinor-
`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 thesolubility and
`stability of the solute in water and on the manufacturing
`process. Thus, the official Hydrochloric Acid contains from
`36.5 to 38% by weight of HCl, whereas Nitric Acid contains
`from 69 to 71% by weight of HNO.
`Because the strengthsofthese concentratedacidsare stated
`in terms of % by weight, it is essential that specific gravities
`also be providedif oneis.to be able to calculate conveniently
`the amountof absolute acid containedin a unit volumeofthe
`solution as purchased. The mathematical relationship in-
`volved is given by the equationM = V x S x F, where Mis the
`mass in g of absolute acid contained in VmLofsolution having
`a specific gravity S$ and a fractional percentage strength F.
`As an example, Hydrochloric Acid containing 36.93% by
`weight of HCl has a specific gravity of 1.1875. Therefore,
`the amount of absolute HCl supplied by 100 mL ofthis solu-
`tionisgivenby:
`
`M = 100 x 1.1875 x 0.3693 = 43.85 g HCl
`Incompatibilities—Although many of the reactions char-
`acteristic of acids offer opportunities for incompatibilities,
`only a few are of sufficient importance to require more than
`
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`SOLUTIONS, EMULSIONS, SUSPENSIONS AND EXTRACTS
`
`1499
`
`soluble, the organic acid will be precipitated.. Thus, salicylic
`acid and benzoic acid are precipitated from solutionsof salicy-
`lates 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-
`yerted 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
`in preparing solublesalts of these substances.
`It should be borne in mind that certain solutions, syrups,
`elixirs 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—tThediluted acids in the USP are aqueous
`solutions of acids, of a suitable strength (usually 10% w/v but
`Diluted Acetic Acid is 6% w/v) forinternal administration or
`for the manufacture of other preparations.
`The strengthsofthe official undiluted acids are expressed
`as percentages w/w, whereas the strengths of the official
`diluted acids are expressed as percent w/v.
`It, therefore,
`becomes necessary to consider the specific gravities of the
`concentrated acids when calculating the volumerequired to
`make a given quantity of diluted acid. The following equa-
`tion will give the numberof mL required to make 1000 mL of
`diluted acid:
`
`
`Strengthof diluted acid x 1000
`Strength of undiluted acid x sp gr of undiluted acid
`Thus, if one wishes to make 1000 mLof Diluted Hydrochloric
`Acid USP using Hydrochloric Acid which.assays 37.5% HCl
`(sp gr 1.18), the amount required is
`-10 x 1000
`37.5 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 describedlater in the chapter.
`Solvents, solubility and general methods for the incorpora-
`tion of a solute ina solvent are discussed in Chapter 16.
`So-
`lutions are usually bottled automatically with equipment of
`the type shown in Fig. 1.
`Preparation—Aspecific 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.
`
`OH- + CO, > HCO,"
`
`OH- + HCOQ,7 > CO,2- + B20
`Calcium Hydroxide Topical Solution, therefore, should be preserved in
`well-filled, tight containers, ata temperature not exceeding 25°.
`Strong Iodine Solution contains, in each 100 mL, 4.5-5.5 g of iodine,
`and 9.5-10.5 g of potassium iodide.
`Itis prepared by dissolving 50 g of
`iodine in 100 mL ofpurified water containing 100 g of potassium iodide.
`Sufficient purified water then is added to make 1000 mL of solution.
`One g ofiodine dissolves in 2950 mL of water. However, solutions of
`iodides