Calculate the quantity, in mg, of thiamine hydrochloride (C
12
H
17
外交英语ClN
4
OS·HCl) in the assay material on the basis of the ali-
quots taken. Where indicated, the quantity, in mg, of thiamine mononitrate (C
12
H
17
N
5
O
4
S) may be calculated by multiplying
the quantity of C
12
H
17
ClN
4
OS·HCl found by 0.9706.
á541ñ TITRIMETRY
Direct Titrations—Direct titration is the treatment of a soluble substance, contained in solution in a suitable vesl (the titrate), with an appropriate standardized solution (the titrant), the endpoint being determined instrumentally or visually with the aid of a suitable indicator.
The titrant is added from a suitable buret and is so chon, with respect to its strength (normality), that the volume added is between 30% and 100% of the rated capacity of the buret. [N OTE—Where less than 10 mL of titrant is required, a suitable microburet is to be ud.] The endpoint is approached directly but cautiously, and finally the titrant is added dropwi from the buret in order that the final drop added will not overrun the endpoint. The quantity of the substance being titrated may be calculated from the volume and the normality or molarity factor of the titrant and the equivalence factor for the substance given in the individual monograph.
Residual Titrations—Some Pharmacopeial assays require the addition of a measured volume of a vo
lumetric solution, in excess of the amount actually needed to react with the substance being assayed, the excess of this solution then being titrated with a cond volumetric solution. This constitutes a residual titration and is known also as a “back titration.” The quantity of the substance being titrated may be calculated from the difference between the volume of the volumetric solution originally added, corrected by means of a blank titration, and that consumed by the titrant in the back titration, due allowance being made for the respective normality or molarity factors of the two solutions, and the equivalence factor for the substance given in the individual monograph.
Complexometric Titrations—Successful complexometric titrations depend on veral factors. The equilibrium constant for formation of the titrant-analyte complex must be sufficiently large that, at the endpoint, very clo to 100% of the analyte has been complexed. The final complex must be formed rapidly enough that the analysis time is practical. When the analytical reaction is not rapid, a residual titration may sometimes be successful.
In general, complexometric indicators are themlves complexing agents. The reaction between metal ion and indicator must be rapid and reversible. The equilibrium constant for formation of the metal-indicator complex should be large enough to produce a sharp color change but must be less than that for the metal-titrant complex. Indicator choice is also restricted by the pH range within whic
h the complexation reaction must be carried out and by interference of other ions arising from the sample or the buffer. Interfering ions may often be masked or “screened” via addition of another complexing agent. (The masking technique is also applicable to redox titrations.)
Oxidation-Reduction (Redox) Titrations—Determinations may often be carried out conveniently by the u of a reagent that brings about oxidation or reduction of the analyte. Many redox titration curves are not symmetric about the equivalence point, and thus graphical determination of the endpoint is not possible; but indicators are available for many determinations, and a redox reagent can often rve as its own indicator. As in any type of titration, the ideal indicator changes color at an endpoint that is as clo as possible to the equivalence point. Accordingly, when the titrant rves as its own indicator, the difference between the endpoint and the equivalence point is determined only by the analyst's ability to detect the color change. A common example is the u of permanganate ion as an oxidizing titrant since a slight excess can easily be detected by its pink color. Other titrants that may rve as their own indicators are iodine, cerium (IV) salts, and potassium dichromate. In most cas, however, the u of an appropriate redox indicator will yield a much sharper endpoint.
It may be necessary to adjust the oxidation state of the analyte prior to titration through u of an appropriate oxidizing or reducing agent; the excess reagent must then be removed, e.g., through pre
蜘蛛侠卡通cipitation. This is nearly always the practice in the determination of oxidizing agents since most volumetric solutions of reducing agents are slowly oxidized by atmospheric oxy-gen.
Titrations in Nonaqueous Solvents—Acids and bas have long been defined as substances that furnish, when dissolved in water, hydrogen and hydroxyl ions, respectively. This definition, introduced by Arrhenius, fails to recognize the fact that prop-erties characteristic of acids or bas may be developed also in other solvents. A more generalized definition is that of Bröns-ted, who defined an acid as a substance that furnishes protons, and a ba as a substance that combines with protons. Even broader is the definition of Lewis, who defined an acid as any material that will accept an electron pair, a ba as any material that will donate an electron pair, and neutralization as the formation of a coordination bond between an acid and a ba.
The apparent strength of an acid or a ba is determined by the extent of its reaction with a solvent. In water solution all strong acids appear equally strong becau they react with the solvent to undergo almost complete conversion to oxonium ion and the acid anion (leveling effect). In a weakly protophilic solvent such as acetic acid the extent of formation of the ace-tate acidium ion shows that the order of decreasing strength for acids is perchloric, hydrobromic, sulfuric, hydrochloric, and
nitric (differentiating effect).
Acetic acid reacts incompletely with water to form oxonium ion and is, therefore, a weak acid. In contrast, it dissolves in a ba such as ethylenediamine, and reacts so completely with the solvent that it behaves as a strong acid. The same holds for perchloric acid.
This leveling effect is obrved also for bas. In sulfuric acid almost all bas appear to be of the same strength. As the acid properties of the solvent decrea in the ries sulfuric acid, acetic acid, phenol, water, pyridine, and butylamine, the bas become progressively weaker until all but the strongest have lost their basic properties. In order of decreasing strength, the strong bas are sodium 2-aminoethoxide, potassium methoxide, sodium methoxide, and lithium methoxide.
Many water-insoluble compounds acquire enhanced acidic or basic properties when dissolved in organic solvents. Thus the choice of the appropriate solvent permits the determination of a variety of such materials by nonaqueous titration. Further-more, depending upon which part of a compound is the physiologically active moiety, it is often possible to titrate that part by proper lection of solvent and titrant. Pure compounds can be titrated directly, but it is often necessary to isolate the active ingredient in pharmaceutical preparations from interfering excipients and carriers.
The types of compounds that may be titrated as acids include acid halides, acid anhydrides, carboxylic acids, amino acids,enols such as barbiturates and xanthines, imides, phenols, pyrroles, and sulfonamides. The types of compounds that may be titrated as bas include amines, nitrogen-containing heterocyclic compounds, oxazolines, quaternary ammonium com-
pounds, alkali salts of organic acids, alkali salts of weak inorganic acids, and some salts of amines. Many salts of halogen acids may be titrated in acetic acid or acetic anhydride after the addition of mercuric acetate, which removes halide ion as the unionized mercuric halide complex and introduces the acetate ion.
For the titration of a basic compound, a volumetric solution of perchloric acid in glacial acetic acid is
花费preferred, although perchloric acid in dioxane is ud in special cas. The calomel-glass electrode system is uful in this ca. In acetic acid sol-
vent, this electrode system functions as predicted by theory.
For the titration of an acidic compound, two class of titrant are available: the alkali metal alkoxides and the tetraalkylam-monium hydroxides. A volumetric solution of sodium methoxide in a mixture of methanol and toluene is ud frequently, al-
though lithium methoxide in methanol-benzene solvent is ud for tho compounds yielding a gelatinous precipitate on titra-
tion with sodium methoxide.
The alkali error limits the u of the glass electrode as an indicating electrode in conjunction with alkali metal alkoxide ti-trants, particularly in basic solvents. Thus, the antimony-indicating electrode, though somewhat erratic, is ud in such titra-
tions. The u of quaternary ammonium hydroxide compounds, e.g., tetra-n -butylammonium hydroxide and trimethylhexade-
cylammonium hydroxide (in benzene-methanol or isopropyl alcohol), has two advantages over the other titrants in that (a)the tetraalkylammonium salt of the titrated acid is soluble in the titration medium, and (b) the convenient and well-behaved calomel-glass electrode pair may be ud to conduct potentiometric titrations.
Becau of interference by carbon dioxide, solvents for acidic compounds need to be protected from excessive exposure to the atmosphere by a suitable cover or by an inert atmosphere during the titrat
ion. Absorption of carbon dioxide may be deter-mined by performing a blank titration. The blank should not exceed 0.01 mL of 0.1 N sodium methoxide VS per mL of sol-vent.
The endpoint may be determined visually by color change, or potentiometrically, as indicated in the individual monograph.If the calomel reference electrode is ud, it is advantageous to replace the aqueous potassium chloride salt bridge with 0.1 N lithium perchlorate in glacial acetic acid for titrations in acidic solvents or potassium chloride in methanol for titrations in basic solvents.
Where the or other mixtures are specified in individual monographs, the calomel reference electrode is modified by first removing the aqueous potassium chloride solution and residual potassium chloride, if any, by rinsing with water, then elimi-nating residual water by rinsing with the required nonaqueous solvent, and finally filling the electrode with the designated nonaqueous mixture.
In nearly all cas, except tho where silver ion might interfere, a silver-silver chloride reference electrode may be substitu-ted for the calomel electrode. The silver-silver chloride electrode is more rugged, and its u helps to eliminate toxic mercury salts from the laboratory. Generally, a salt bridge may be ud to circumvent interference by silver ion.
水政监察
The more uful systems for titration in nonaqueous solvents are listed in Table 1
.
Table 1. Systems for Nonaqueous Titrations
Type of
Acidic (for titration
of bas and their
salts)
Relatively Neutral
(for differential
titration of bas)
Basic (for titration
of acids)
Relatively Neutral
(for differential
titration of acids) Solvent1Glacial Acetic Acid Acetonitrile Dimethylformamide Acetone
Acetic Anhydride Alcohols n-Butylamine Acetonitrile
Formic Acid Chloroform Pyridine Methyl Ethyl Ketone
Propionic Acid Benzene Ethylenediamine Methyl Isobutyl Ketone
Sulfuryl Chloride Toluene Morpholine tert-Butyl Alcohol
Chlorobenzene
Ethyl Acetate
Dioxane
Indicator Crystal Violet Methyl Red Thymol Blue Azo Violet
Quinaldine Red Methyl Orange Thymolphthalein Bromothylmol Blue灰雀图片
p-Naphtholbenzein p-Naphtholbenzein Azo Violet p-Hydroxyazobenzene
Alphezurine 2-G o-Nitroaniline Thymol Blue
Malachite Green p-Hydroxyazobenzene
Electrodes Glass–calomel Glass–calomel Antimony–calomel Antimony–calomel
Glass–silver–silver chloride Calomel–silver–silver
chloride
Antimony–glass Glass–calomel
Mercury–mercuric acetate Antimony–antimony2Glass–platinum2
Platinum–calomel
Glass–calomel
1 Relatively neutral solvents of low dielectric constant such as benzene, toluene, chloroform, or dioxane may be ud in conjunction with any acidic or basic solvent in order to increa the nsitivity of the titration end-points.
2 In titrant.
Indicator and Potentiometric Endpoint Detection—The simplest and most convenient method by which the equivalence point, i.e., the point at which the stoichiometric analytical reaction is complete,
may be determined is with the u of indica-tors. The chemical substances, usually colored, respond to changes in solution conditions before and after the equivalence point by exhibiting color changes that may be taken visually as the endpoint, a reliable estimate of the equivalence point.
A uful method of endpoint determination results from the u of electrochemical measurements. If an indicator electrode, nsitive to the concentration of the species undergoing titrimetric reaction, and a reference electrode, who potential is in-nsitive to any dissolved species, are immerd in the titrate to form a galvanic cell, the potential difference between the elec-trodes may be nd by a pH meter and ud to follow the cour of the reaction. Where such a ries of measurements is plotted correctly (i.e., for an acid-ba titration, pH versus mL of titrant added; for a precipitimetric, complexometric, or oxida-tion-reduction titration, mV versus mL of titrant added), a sigmoid curve results with a rapidly changing portion (the “break”) in the vicinity of the equivalence point. The midpoint of this linear vertical portion or the inflection point may be taken as the endpoint. The equivalence point may also be determined mathematically without plotting a curve. However, it should be no-ted that in asymmetrical reactions, which are reactions in which the number of anions reacting is not the same as the number of cations reacting, the endpoint as defined by the inflection of the titration curve does not occur exactly at the stoichiometric equivalence point. Thus, potentiome
tric endpoint detection by this method is not suitable in the ca of asymmetric reactions, examples of which are the precipitation reaction,
2Ag+ + CrO
4
–2
and the oxidation-reduction reaction,冷冻温度
5Fe+2 + MnO
4
–.
All acid-ba reactions, however, are symmetrical. Thus, potentiometric endpoint detection may be employed in acid-ba ti-trations and in other titrations involving symmetrical reversible reactions where an indicator is specified, unless otherwi direc-ted in the individual monograph.
Two types of automatic electrometric titrators are available. The first is one that carries out titrant addition automatically and records the electrode potential differences during the cour of titration as the expected sigmoid curve. In the cond type, titrant addition is performed automatically until a pret potential or pH, reprenting the endpoint, is reached, at which point the titrant addition ceas.
Several acceptable electrode systems for potentiometric titrations are summarized in Table 2.
Table 2. Potentiometric Titration Electrode Systems
Titration Indicating Electrode Equation 1Reference Electrode Applicability 2
Acid-ba Glass E = k + 0.0591 pH Calomel or silver–silver chloride
Titration of acids and bas
Precipitimetric (silver)Silver E = E° + 0.0591 log [Ag +]Calomel (with potassium ni-trate salt bridge)Titration with or of silver in-
volving halides or thiocya-
nate
Complexometric Mercury–mercury(II) E = E° + 0.0296(log k ¢ − pM)Calomel Titration of various metals
(M), e.g., Mg +2, Ca +2 Al +3,
Bi +3, with EDTA
Oxidation–reduction Platinum E = E° + (0.0591/n) × log [ox]/[red]Calomel or silver–silver chloride Titrations with arnite, bro-
mine, cerate, dichromate,
exacyonoferrate(III), iodate,
nitrite, permanganate, thio-
sulfate
1 Appropriate form of Nernst equation describing the indicating electrode system: k = glass electrode
constant; k ¢ = constant derived from Hg–Hg(II)–EDTA equi-librium; M = any metal undergoing EDTA titration; [ox] and [red] from the equation, ox + n e ®¬
red.
2
Listing is reprentative but not exhaustive.
Blank Corrections—As previously noted, the endpoint determined in a titrimetric assay is an estimate of the reaction equiv-alence point. The validity of this estimate depends upon, among other factors, the nature of the titrate constituents and the
concentration of the titrant. An appropriate blank correction is employed in titrimetric assays to enhance the reliability of the伤仲永的故事
endpoint determination. Such a blank correction is usually obtained by means of a residual blank titration , wherein the required procedure is repeated in every detail except that the substance being assayed is omitted. In such instances, the actual volume
of titrant equivalent to the substance being assayed is the difference between the volume consumed in the residual blank titra-tion and that consumed in the titration with the substance prent. The corrected volume so obtained is ud in calculating
the quantity of the substance being titrated, in the same manner as prescribed under Residual Titrations . Where potentiometric
endpoint detection is employed, the blank correction is usually negligible.
á551ñ VITAMIN E ASSAY
INTRODUCTION
The following liquid chromatographic procedures are provided for the determination of vitamin E as an active pharmaceutical ingredient, as a dietary supplement ingredient, or as a component in compendial dosage forms in the forms of alpha toco-pherol (C 29H 50O 2), alpha tocopheryl acetate (C 31H 52O 3), or alpha tocopheryl acid succinate (C 33H 54O
5).
九层妖塔演员表Throughout this assay, protect solutions containing, and derived from, the test specimen and the Reference Standard from the atmosphere and light, preferably by the u of a blanket of inert gas and low-actinic glassware.
Where vitamin E (alpha tocopherol, alpha tocopheryl acetate, or alpha tocopheryl acid succinate) is specified in the following procedure, u the chemical form prent in the formulation and the relevant USP Reference Standard.
ASSAY
• P ROCEDURE 1
•This procedure can be ud to determine vitamin E in:
•Oil-Soluble Vitamins Tablets
•Oil-Soluble Vitamins Capsules
•Oil-Soluble Vitamins with Minerals Tablets
•Oil-Soluble Vitamins with Minerals Capsules
•Oil- and Water-Soluble Vitamins Tablets
•Oil- and Water-Soluble Vitamins Capsules
•Oil- and Water-Soluble Vitamins with Minerals Tablets
•Oil- and Water-Soluble Vitamins with Minerals Capsules
•This is a neutral procedure that involves the u of dimethyl sulfoxide to dissolve the excipients in the sample, fol-lowed by a liquid–liquid extraction of vitamin E with hexane. The hexane extract is then evaporated in vacuum to
dryness, and the residue is reconstituted in methanol prior injection into the chromatograph.
•Unless specified in the individual monographs, the System suitability solution , Standard solution , Sample solutions , and reagent solutions are prepared as follows.
Solution A:Phosphoric acid solution (1 in 100) in water
Mobile pha: Methanol and Solution A (19:1)
