2000
`
`USP 24
`}[F T9
`
`I
`I
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pha¡macopeial
`Convention, Inc., meeting at Washington, D.C.,
`March 9-12, 1995. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official froq January I, 2000
`
`UNITED STATES PHARMAdOPBINI CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20952
`Argentum EX1040
`
`Page 1
`
`

`

`USP 24
`
`or as accurately prepared solutions in appropriate anhydrous
`solvents.
`Where the specimen is an insoluble solid, the water,may be ex-
`tracted using a suitable anhydrous solvent from which an appropri-
`ate quantity, accurately weighed, may be injected into the anolyte
`solution. Altematively an evaporation technique may be used in
`which water is released and evaporated by heating the specimen in
`a tube in a stream of dry inert gas, this gas being then passed into
`the cell.
`Procedure-Using a dry syringe, quickly inject the Test Prep-
`aration, accurately measu¡ed and estimated to contain 0.5 to 5 mg
`of water, into the anolyte, mix, and perform the coulometric titration
`to the electrometric endpoint. Read the water content of the ?er¡
`Preparation directly from the instrument's display, and calculate
`the percentage that is present in the substance. Perform a blank
`determination, and make any necessary corrections.
`
`METHÔD rr (AZEOTROPTC-TOLUENE
`DTSTTLLATTON)
`Apparatus-Use a 500-mL glass flask A connected by means of
`a lrap B to a reflux condenser C by ground glass joints (see figure).
`
`B+
`
`E+
`
`A_
`
`D
`
`Toluene Moisture Apparatus
`
`The critical dimensions of the parts of the apparatus are as fol-
`lows. The connecting tube D is 9 to 11 mm in intemal diameter.
`The trap is 235 to 240 mm in length. The condenser, if of the
`straight-tube type, is approximately 400 mm in length and not less
`than 8 mm in bore diameter. The receiving tube E has a 5-mL
`capacity, and its cylindrical portion, 146 to 156 mm in length, is
`graduated in 0.1-mL subdivisions, so that the error of reading is not
`greater than 0.05 mL for any indicated volume. The source of heat
`is preferably an electric heater with rheostat control or an oil bath.
`The upper portion of the flask and the connecting tube may be
`insulated.
`Clean the receiving tube and the condenser with chromic acid
`cleansing mixture, thoroughly rinse with water, and dry in an oven.
`Prepare the toluene to be used by first shaking with a small quantity
`of water, separating the excess water, and distilling the toluene.
`Procedure-Place in the dry flask,â quantity of ,the substance,
`weighed accurately to the nearest centigram, which is expected to
`yield 2 to 4 mL of water. If the substance is of a pasty character,
`
`Physical Tests / (9411 X-ray Diffraction 2005
`
`weigh it in a boat of metal foil of a size that will just pass through
`the neck of the flask. If the substance is likely to cause bumping,
`add enough dry, washed sand to cover the bottom of the flask, or
`a number of capillary melting-point tubes, about 100 mm in length,
`sealed at the upper end. Place about 200 mL of toluene in the flask,
`, connect the apparatus, and fill the receiving tube E with toluene
`poured through the top of the condenser. Heat the flask gently for
`15 minutes and, when the toluene begins to boil, distil at the rate
`of about 2 drops per second until most of the water has passed over,
`then increase the rate of distillation to about 4 drops per second.
`When the water has apparently all distilled over, rinse the inside of
`the condenser tube with toluene while brushing down the tube with
`a tube brush attached to a copper wire and saturated with toluene.
`Continue the distillation for 5 minutes, then remove the heat, and
`allow the receiving tube to cool to room temperature. If any droplets
`of water adhere to the walls of the receiving tube, scrub them down
`with a brush consisting of a rubber band wrapped around a copper
`wire and wetted with toluene. When the water and toluene háve
`separated completely, read the volume of water, and calculate the
`percentage that \¡/as present in the substance.
`METHOD III (GRAVIMETRIC)
`Procedure for Chemicals-Proceed as directed in the individual
`monograph preparing the chemical as directed under l,oss on Dry-
`ing \73r),
`Procedure for Biologics-Proceed as di¡ected in the individual
`monograph.
`Procedure for Vegetable Drugs-Place about 10 g of the drug,
`prepared as directed (see Vegetable Drugs-Methods of Analysis
`(561)) and accurately weighed, in a tared evaporating dish. Dry at
`105" for 5 hours, and weigh. Continue the drying and weighing at
`l-hour intervals until the difference bet',veen two successive weigh-
`ings corresponds to not more lhan O.25Vo.
`
`(e41> X-RAY DTFFRACTTON
`Every crystal form of a compound produces its own characteristic
`X-ray diffraction pattem. These diffraction patterns can be derived
`either from a single crystal or from a powdered specimen (contain-
`ing numerous crystals) of the material. The spacings between and
`the relative intensities of the diffracted maxirha can be used for
`qualitative and quantitative analysis of crystalline materials. Powder
`diffraction techniques are most commonly employed for routine
`identification and the determination of relative purity of crystalline
`materials. Small amounts of impurity, however, are not normally
`detectable by the X-ray diffraction method, and for quantitative
`measurements it is necessary to prepare the sample carefully to
`avoid preferred orientation effects.
`The powder methods provide an advantage over other means of
`analysis in that they are usually nondestructive in nature (specimen
`preparation is usually limited to grinding to ensure a randomly ori-
`ented sample, and deleterious effects of X-rays on solid pharma-
`ceutical compounds are not commonly encountered). The principal
`use of single-crystal diffraction data is for the determination of mol-
`ecular weights and analysis of crystal structures at the atomic level.
`However, diffraction established for a single crystal can be used to
`support a specific powder pattem as being truly representative of a
`single phase.
`Solids-A solid substance can be classified as being crystalline,
`noncrystalline, or a mixture of the two forms In crystalline mate-
`rials, the molecular or atomic species are ordered in a three-dimen-
`sional array, called a lattice, within the solid particles. This ordering
`of molecular components is lacking in noncrystalline material. Non-
`crystalline solids sometimes are referred to as glasses or amorphous
`solids when repetitive order is nonexistent. in all three dimensions.
`It is also possible for order to exist in only one or two dimensions,
`resulting in mesomorphic phases (liquid crystals). Although crys-
`talline materials are usually considered to have well-deñned visible
`external morphologies (their habits), this is not a necessity for X-
`ray difliaction analysis.
`The relatively rando¡n arangement of molecules in noncrystal-
`line substances makes them poor coherent scatterers of X-rays, re-
`sulting in broad, diff'use maxima in diffraction pattems. Their X-
`
`Page 2
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`

`

`2006 (941, X-ray Diffraction I Physical Tests
`
`. ray pattems afe quite distinguishable from crystalline specimens,
`which give sharply defined diffraction pattems.
`Many compotrnds are capable of crystallizing in more than one
`type of crystal lattice. At any particular temperature and pressure,
`only one crystalline form (polymorph) is thermodynamically stable.
`Since the rate of phase transformation of a metastable polymorph
`to the stable one can be quite slow, it is not uncommon to find
`several polymorphs of crystalline pharmaceutical compounds exist-
`ing under normal handling conditions.
`In addition to exhibiting polymorphism, many compounds form
`crystallíne solvates in which the solvent molecule is an integral part
`of the crystal strt¡cture. Just as every polymorph has its own char-
`acteristic X-ray pàtterhs, so does every solvate. Sometimes the dif-
`ferences in the diffraction pattems of different polymorphs are rel-
`atively minor, and must be very carefully evaluated before a
`definitive conclusiòn is reached. In some instances, these poly-
`morphs and / or solvates show varying dissolution iates. Therefore,
`on the time scale of pharmaceutical bioavailability, different total
`amounts of drug aÍe dissolved, resulting in potential bioinequival-
`ence of the several forms of the drug.
`Fundamental Principles-A collimated beam of monochro-
`matic X-rays is diffracted in various directions when it impinges
`upon a rotating crystal or randomly oriented powdered crystal. The
`crystal acts as a three-dimensional diffraction grating to this radi-
`ation. This phenomenon is described by Bragg's law, which states
`that diffraction (constructive interference) can occur only when
`waves that are scattered from diffeient regions of the crystal, in a
`specific direction, travel distances differing by integral numbers (n)
`of the wayelength (I). Under such circumstances, the waves are in
`phase. This condition is described by the Bragg equation:
`
`ntr
`
`z ,'rn e: d*'
`in which d* denotes the interplanar spacings and 0 is the angle of
`diffraction.
`A family of planes itr space can be indexed by three whole num-
`bers, usually rêferred to as Miller indices. These indices are the
`reciprocals, reduÒed to smallest integers, of the intercepts that a
`plane makes along the axes corresponding to three nonparallel
`edges of the unit cell (basic crystallographic unit). The unit cell
`dimensions are giveh by the lengths of the spacings along the three
`axes,a, b, c, and the angles between them, cr, B, and 1. The inter-
`planar spacing for a specific set ofparallel planes hkl is denoted by
`dnr,. Each such farnily of planes may show higher orders of diffrac-
`tion Where the d values for the related families of planes nh, nk, nL
`are diminished by the factor 7/n (nbeing an integer: 2,3,4, efc.).
`Every set of planes throughout a crystal has a corresponding Bragg
`diffraction angle associated with it (for a specific )r).
`The amplitude of a diffracted X-ray beam from any set of planes
`is dependent upon the following atomic properties of the crystal:
`(l) position of each atom in the unit cell; (2) the respective atomic
`scattering factors; and (3) the individual thermal motions. Other
`factors that directly influence the intensities of the diffracted beam
`are: (l) the intensity afld wavelength of the incident radiation; (2)
`the volume of crystalliñe specimen; (3) the absorption of the X-
`radiation by the specimen; and (4) the experimental arrangement
`utilized to record the intensity data. Thus, the experimental condi-
`tions are especially important for measurement of djffraction
`intensities.
`Only a limited numbet of Bragg planes are in a position to dif-
`fract when monochromatized X-rays pass through a single crystal.
`Techniques of recording the intensities of all of the possible dif-
`fracting hkl planes involve motion of the single crystal and the
`recording media. Recording of these data is accomplished by pho-
`tographic techniques (film) or with radiation detectors.
`A beam passing through a very large number of small, randomly
`oriented crystals produces continuous cones of diffracted rays from
`each set of lâttice planes. Each cone corresponds to the diffraction
`from various planes having a similar interplanar spacing. The in-
`tensities of these Bragg reflections are recorded by either film or
`radiation detectors. The Bragg angle can be measured easíly from
`a film, but the advent of radiation detectors has made possible rhe
`construction of diffractometers that read this angle directly. The
`intensities and d spacings are more conveniently determined with
`powder diffractometers employing radiation detectors than by fitm
`
`USP 24
`
`methods. Microphotometers are frequently used for precise intensity
`measurements of films.
`An example of the type of powder pattems obtained for four
`different solid phases of ampicillin are shown in the accompanying
`figure. These diffraction patterns were derived from a powder dif-
`fractometer equipped with a Geiger-Müller detector; nickel-ñltered
`Cu Kcr radiation was used.
`
`Noncry stal I i ne (an hyd rous )
`
`Trihydrate
`
`Anhydrous form I
`
`Anhydrous form 2
`
`5to
`
`15
`20
`20 +-
`
`25
`
`50
`
`Typical Powder Pattems Obtained for Four Solid Phases
`of Ampicillin
`
`Radiation-The principal radiation sources utilized for X-ray
`diffraction are vacuum tubes utilizing copper, molybdenum, iron,
`and chromium as anodes; copper X-rays are er4ployed most com-
`monly ,fór organic substances, For each õf these radiations there is
`an element that will filter off the Kp radiation and permit the Kcr
`radiation to pass (nickel is used, in the case of copper radiation).
`In this manner the radiation is practically monochromatized. The
`choice of radiation to be used depends upon the absorption'char-
`4cteristics of the material and possible fluorescence by atoms pres-
`lent in the specimen.
`
`tl
`
`Page 3
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`

`

`USP 24
`
`Caution-Care must be taken in the use of such radiation. Those
`not familiar with the use of X-ray equipment should seek expert
`advice. Improper use can result in harmful effects to the operator.
`Test Preparation-In an attempt to irnprove randomness in the
`orientation of crystallites (and, for fllm techniques, to avoid a grainy
`pattern), the specimen niay be ground in a mortar to a flne powder.
`Grinding pressure has been known to induce phase transformations;
`therefore, it is advisable to check the diffraction pattern of the un-
`ground sample.
`In general, the shapes of many crystalline particles tend to give
`a specimen that exhibits some degree of preferred orientation in the
`specimen holder. This is especially evident for needle-like or plate-
`like crystals whe¡e size reduction yields finer needles or platelets.
`Preferred orientation in the specimen influences the relative inten-
`sities of various reflections.
`Several specialized handling techniques may be employed to
`minimize prefe¡rdd orientation, but further reduction of particle size
`is often the best approach.
`Where very accurate measurement of the Bragg angles is nec-
`essary, a small amount of an internal standard can be mixed into
`the specimen. This enables the film or recorder tracing to be cali-
`brated. If comparisons to literature values (including compendial
`limits) of d are being made, calibrate the diffractometer. NIST stan-
`dards are available covering to a d-value of0.998 nm. Tetradecanolr
`may be used (d is 3.963 nm) for larger spacing.
`The absorption of the radiation by any specimen is determined
`by the number and kinds of atoms through which the X-ray beam
`passes. An organic matrix usually absorbs less of the diffracted
`radiation than does an inorganic matrix. Therefore, it is important
`in quantitative studies that standard curves relating amount of ma-
`terial to the intensity of certain d spacings for tHat substance be
`I Brindley, GW and Brown, G, eds., Crystal Structures of Clay
`Minerals and theír X-ray ldentification, Mineralogical Society
`Monograph No. 5, London, 1980, pp. 318 ff.
`
`Physical Tests / (941) X-ray Diffraction 2007
`
`determined in a mátrix similar to that in which the substance will
`be analvzed.
`In quântitative analyses of materials, a known amount of standard
`usuaÌly is added to a weighed amount of specimen to be analyzed.
`This enables the amount of the substance to be determined relative
`to the -amount of standard added. The standard used should have
`approximately the same density as the specimen and similar ab-
`sorption characteristics. More important, its diffraction pattem
`should not overlap to any extent with that of the material to be
`analyzed. Under these conditions a linear relationship between line
`intensity and concentration exists. In favorable cases, amounts of
`crystalline materials as small as l}Vo may be determined in solid
`matrices.
`Identiñcation of crystalline materials can be accomplished by
`comparison of X-ray powder diffraction pattems obtained for
`known2 materials with those of the unknown. The intensity ratio
`(ratio of the peak intensity of a particular d spacing to the intensity
`of the strongest maxima in the diffraction pattem) and the d spacing
`are used in the comparison. If
`SP Ref-
`erence Standard) is available, i
`primary
`reference pattem on the same
`the un-
`
`'?The Intemational Centre fo¡ Diffraction Data, Newtown Square
`Corporate Campus, 12 Campus Boulevard, Ne.#town Square, PA
`19073, maintains a file on more than 60,000 crystalline materials,
`both organic and inorganic, suitable for such comparisons.
`
`Page 4
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`
`
`meOZWWWDWEEWWM
`
`-
`
`I
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`Page 5
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`procedure-Place in the dry flask a quantity of the substance,
`s,eigled accur¿tely to the neáreÍ_centigram,îhich is
`rc yield ¿ to. 1 +! o[ water. If the substance is of a pasty
`"*peóiãã
`chaÍacter, wetgh it in a boat of metal foil of a size that witi jusi
`iass through the neck ofl the flask. If the substance is likel! to
`lause b-umping, add enough dry, washed sand to cover the botiom
`0f the ila.sk, or a. number of capillary melting-point tubes, about
`100 mm rn tength,-sealect at the upper end. place about 200 mL
`of toluene. ln the_ flask, connect the apparatus, and fill the re_
`ceiving tube E.witjr toluene. poured thióugh the top of the con-
`denser. Heat the flask gently for l5 minutes and, ivhen the tol-
`uene begins to boil, distil at the rate of about 2 drôps per second
`until most.of the water has passed over, then incräas'e the rate
`of distillation t9 aþ9u! 4 drops per second. When the water has
`npparently all distilled over, rinsè the inside of the condenser tube
`wi[h toluene while brushing down the tube with a tube brush
`attached.to.a copper ulire añd saturated with toluene. Continuã
`the distr.llatron lor 5 minutes, then remove the heat, and allow
`the receiving tube to_ cool t9 .ognl temperature. tf a'ny Oroliets
`of water .adhere to the walls of the reôeiving tube. sórub them
`down with a brush consisting.of a rubber bañd wrapped
`".o*O
`a copper wire and wetted with toluene. When thè^water and
`toluene have separated completely, read the volume of water, ànã
`calculate the percentage thàt wai present in the substance.
`
`METHOD rrr (cRAvrMETRrC)
`Procedure for Chemicals-Proceed as directed in the individual
`monograph preparing the chemical as directed under toii in
`Drying (731).
`Procedure for Biologics-Proceed as directed in the individual
`monograph.
`
`(94r> X-RAY DTFFRACTTON
`
`Physical Tests f X-ray Diffraction <941t 1843
`
`(
`
`nÀr
`2ri"0-
`iq ry.|ph d¡rr denotes the interplanar spacings and d is the angle
`of diffraction.
`
`uhkr'
`
`tectors.
`
`Page 6
`
`

`

`1844 (941) X-ray Diffraction f Physical Tests
`
`USP 23
`
`tized. The choice of radiation to be used depends upon the ab-
`
`operator.
`Test Prepâration-In an attsmpt to improve r¿ndomness in the
`orientation-of crystallites (and, for film techniques, to avoid a
`grainy pattern), the specimen may be ground in a mortar to a
`iine óoùder. GrindinÁ pressure has been known to induce phase
`trans'formations; thereTóre, it is advisable to check the diffraction
`
`et n t
`
`. noÍpf
`
`(
`tl
`cl
`
`analyses of materia
`dded to a weighed
`nables the amount
`to the amount of sta
`
`can be accomplished bY
`n patterns obtained for
`own. The intensitY raiio
`
`n(
`,IR
`is
`AT
`ef
`ge
`PI
`fo
`of
`in
`.$
`
`$:
`
`art
`Ut
`thr
`mi
`gal
`Ph
`me
`$:
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`sta
`0.1
`(
`cur
`the
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`ôtr
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`9ùr
`r¡rì¡
`
`Noncr y stal I i ne (an hyd rous )
`
`Tr ihydrate
`
`Anhydr.ous form I
`
`Anhydrous form 2
`
`510
`
`'t5
`20
`20 -->
`
`25
`
`30
`
`Typical Powder Patterns Obtained for Four Solid Phases of
`Ampicillin
`
`Ka radiation to pass (nickel is used, in the case of copper radia-
`tion). In this manner the radiation is practically monochroma-
`
`compailsons.
`
`Page 7
`
`

`

`22'70 (1241) Water-solid Interactions in Pharmaceutical Systems f General Informatiort
`
`u,sP 25
`
`ol
`af
`as
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`a flui
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`exces
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`many sl
`for iroJ
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`the effe
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`requirec
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`quitous to the aqueous environment and their exclusion would likelv
`require a sterilization process that would not be appropriate or feasi
`ble in many manufacturing scenarios. However, there are situations
`where they might not be tolerated: in topical products and in some
`oral dosage forms. It is, therefore, incumbent upon the manufacturer
`to supplement the general action guidelines to fit each particular man-
`ufacturing situation.
`
`(124r V/ATER-SOLID
`CTIONS IN
`PHARMACEUTICAL SYSTEMS
`
`Phannaceutical solids as raw materials or as dosage forms most
`
`hardness.
`'Wate¡ can associate with soUds in two ways. It can interact only at
`
`48 to 72 hours incubation at
`30'C to 35"C
`
`Identification of Microorganisms
`Identi$ing the isolates recovered from water monitoring meth-
`ods may be important in instances where specific water-bome micro-
`organisms may be detrimental to the products or processes in which
`the water is used. Microorganism information such as this may also
`be useful when identiffing the source of microbial contamination in a
`product or process.
`Often a limited group of microorganisms are continuously re-
`covered from a water system. After repeated charactenzatron, an ex-
`perienced microbiologist rnay become proficient at their identification
`based on only a few t¡aits such as colonial morphology and staining
`characterìstics. This level of characteizalion is adequate for most si-
`tuations.
`
`Alert and Action Levels
`The individual rnonographs for Purifed Water and Ilaterfor In-
`jection do not include specific microbial limits. These were purpose-
`fully omitted since most current microbiological techniques available
`require at least 48 hours to obtain definitive results. By that time, the
`water f¡om which the sample was taken has akeady been employed in
`the production process, Failure to.meet a compendial specification
`would require rejecting the product lot involved, and this is not the
`intent of an alert or action guideline. The establishment of quantita-
`tive microbiological guidelines for water for pharmaceutical purposes
`is in order because such guidelines will establish procedures that are
`to be implemented in the event that significant excursions beyond
`these limits occur.
`Water systerns should be microbiologically monitored to con-
`firm that tbey continue to operate within their design specifications
`and produce wate¡ of acceptable quality. Monitoring data may be
`compared to established process parameters or product speciûcations.
`A refinement to the use ofprocess parameters and product specifica-
`tions is the establishment of Alert and Action Levels, which signal a
`shift in process performance. Aiert and Action Levels are distinct
`from process parameters and product specifications in that they are
`used for monitoring and control ¡ather than accept or reject decisions.
`Alert Levels are levels or ranges that, when exceeded, indicate
`that a process may have drifted from its normal operating condition.
`Alert Levels constitute a waming and do not necessarily require a cor-
`rective action.
`Action Levels are levels or ranges that, when exceeded, indicate
`that a process has drifted from its normal operating range. Exceeding
`an Action Level indicates that corrective action should be taken to
`bring the process back into its normal operating range.
`Alert and Action Levels are established within process and pro-
`duct specification tolerances and are based on a combination oftech-
`nical and product related considerations. Consequently, exceeding an
`Alert or Action Level does not imply that product quality has been
`compromised.
`Technical considerations used to establish Alert and Action Le-
`vels should include a review of equipment design specifications to
`ensure tbat the purification equipment is capable of achieving the re-
`quired level ofpurity. In addition, samples should be collected and
`analyzed over a period of time to develop data reflecting normal water
`quality trends, Historical or statistically based levels can be estab-
`lished using the above data. Levels established in this way measure
`process performance and are independent ofproduct concems.
`Product related Alert and Action Levels should represent both
`product quality concems and the ability to effectively manage the
`puriflcation process. These levels are typically based on a review of
`p¡ocess data and an assessment ofproduct sensitivity to chemical and
`microbiological contamination. The assessment of product suscept-
`ibility might include preservative efficacy, water activity, pH, etc.
`The levels should be set such that, when exceeded, product quality
`is not compromised.
`Monitoring data should be analyzed on an ongoing basis to en-
`sure that the process continues to perform within acceptable limits.
`An analysis of data trends is often used to evaluate process perfor-
`
`Page 8
`
`

`

`USP 25
`
`General Information I \1241) Water-solid Interactions in Pharmaceutical Systems 2211
`
`weighing. Studies u
`balance to measure
`the nurnber of samp
`to measure amount
`
`an electro-
`but reduce
`so Possible
`imetricallY
`
`the effects ofmoisture on solids before strategies are developed for
`ieces of
`(a) total
`and ab-
`specific
`of crys-
`
`a thermogravimetric
`t with these possible
`of water content bY
`gas chromatograPhY
`
`(
`
`ditions dissolution will take place.
`
`metric mole: mole ratio of water to solid. In some cases, however,
`
`RH, is defined as:
`
`RH=(¿)/(P,) x 100,
`where P. is the pressur
`vapor pressure of pure
`P"l P. is referred to as
`the use of saturated sa
`
`forthe surface available.
`
`to the amorphous regions.
`
`lative humidities above that exhibited by a saturated solution of that
`solid will spontaneously dissolve via deliquescence and continue to
`
`Page 9
`
`€
`

`

`2272
`
`(1251) weighing on an Analytical Balance f General Inforntation
`
`USP 25
`
`dissolve over a long time period. The rate of water uptake in general
`fepends on a number of pàrameters not found to be óritical in"equili_
`bnum measurements because rates of sorption are primarily mass_
`transfer controlled with some contributions ÍÌom hèat-tranifer me_
`chanisms. Thus, factors such as vapor diffusion coefficients in air
`and in the solid, convective airfl_ow, ãnd the surface area and geome_
`try of the solid bed and surrounding environment, can play un"irnpã._
`ta-nt role. Indeed, the method used to make such measurements can
`often be the rate-determining factor because ofthese environmental
`and geometric factors.
`Physical States of So¡bed Water-The key to understanding the
`effects water can have on the properties of solids, and vice v"ersa,
`rests with an understanding of thê location of the water molecule
`an-d_its physical state. MoJe specifically, water associated with
`solid.s.can exist in a highly immobile staie, as well as in a state of
`mob.ility approaching that of bulk water. This difference in mobility
`has been observed.through such measurements as heats of sorptior¡
`fieezing point, nuclear magnetic.resonance, dielectric propertiei, and
`,diffusion. Such changes in-.mobility have been interpreteå as aúsing
`because of changes in the thermodynamic state of wãter as more anã
`more water is sorbed. Thus water bound directly to a solid is often
`thought of as "tightly" bound and unavaiíable to affect the
`properties of the solid, whereas larger amounts of sorbed water
`.tend to become more clustered anã form water more like that
`exhibiting solvenr pr-opeties. In rhe case of crystal hyd.ai"r, ihe
`combination of intermolecular forces (hydrogen boîding.¡'and
`crystal packing can produce very strong'wateriolid interaõíions.
`!I9w9ve1, there are r,eported situations where hydration and
`dehydration of crystals occur quite easily at low iemperatures.
`More recently the concept of .,tiÈhtly" bound water in Jmorphous
`systems has been questioned. Recógnizing that the preseice of
`water ln an amorphous solid can affect the elass transition
`temperature_and hence the physical state of the sõlid, it is argued
`that at low levels of water môst polar amorphous ,ó1ids ure'in u
`hìghly viscoul glpry srare because of their high vaiues oÌ îg.
`Hence, water is "frozen" into the solid structurã and is renderêâ
`immobile-by, the high viscosity; e.g., l0ra poise. As the amount of
`water sorbed increases and Tg deðreases ànd approaches ambient
`temperature,s, the glassy state approaches that ofa ..fluid" state and
`waterrnobilify_along with tne Àdti¿ itself increases significantly. Àt
`hig^I RH the degree of water plasticization of thisolid caî be
`sufficiently high so that water and the solid now can assume
`significant amounts of mobility. In general, therefore, this picture ål
`the nature of sorbed water help-s to eiplain tfie rather sígnifr*nt éii""i
`moisture can have on a number of bult properties of'solids such as
`c-hemical reactivity and mechanical deformaiion. It suggests strongly
`that methods of e^valuating chemical and physical staãîity of soli"ds
`and solid dosage forms should take into acèoúnt the effectõ water can
`have on the solid when it is sorbed, particularly when it enters the
`solid structure and acts as a plasticizer. Much résearch still remains
`to be done in assessing the underlying mechanisms involved in
`\¡/ater-sohd rnteractions of pharmaceutical impofance.
`
`(r2s1) wErcHrNG ON AN
`ANALYTICAL BALANCE
`
`Weighing is a frequent step in anal¡ical procedures, and the bal_
`Tge rs^a1 essential piece of laboratory equipment in most analyses. In
`splre orÌnls, welghlng ts a cornmon source of error that can be diffi-
`cult to detect in the final anal¡ical results. The procedure described
`here applies directly to electronic baìances; therefore, tertain portions
`of'the procedure are not applicable to other types'of balance. The
`weigling procedure can beìèparated into th¡ee bäsic steps: planning,
`checking the balance, and weìghing the material.
`
`PLANNING
`
`tainers ror
`The iniri
`proper size
`
`tti.:"tp",':ffi:tÀ:Ëif,il"å¡
`ofsucï ,irê tt íttËe foãJing
`
`capacity ofthe balance is not exceeded. Make sure that the contain"^
`selected to receive theweßhed material are clean and dry. err"-mUi.
`the necessary chemicals if solutions or reagents are required.
`Preparation of the mate¡ial to be weighed is often necessary. Jþs
`material rnay require_ grinding.or drying. Some materials m"í frai.
`been heated or stored in a refi:igeratór. Materials must be U.oún-lrii"
`the temperature ofthe balance before they are weighed. fo uuoiióàni
`densation of moisture, refügerated materials must be aflowed to cóme
`to room tempe¡ature before the container is opened.
`
`CHECKTNG THE BALANCE
`
`Balance Environment
`
`Calibration
`
`Balance Uncertainties
`
`DRIFT RTDUCTION
`Drift is one of the most conìmon errors, and it is also one of the
`easiest to reduce or eliminate. Balance drift can be prespnt without the
`operator being aware of the problem. Check the sämpie, the balance,
`and the labo¡atory environmènt for the following caujes of enors, and
`eliminate them:
`(l) A balance door is open.
`(2) Temperatures of the balance and the material to be weighed are
`not the same.
`
`M¡cu.q¡ltcll HYSTERESIS
`Hysteresis in the balance is cau
`springs, and it is primarily due to
`dropping ofan object onto the pan.
`
`e stretching ofthe
`to the accidental
`are very sensifive
`
`USP
`
`þ ove
`the ret
`the wt
`hyster
`weigh
`excesl
`of ele'
`tues i
`
`QUAI
`
`(
`day v
`regrrlz
`been
`shoul,
`lhatn
`balan,
`whosr
`the b¿
`balan
`storec
`
`1
`
`1
`
`the pr
`(1) l
`(2) |
`Þr
`tume
`prior
`(3)
`
`Ar
`mass
`to rei
`struc
`on th
`the b
`the v
`feren
`of in
`place
`weig
`chan
`at thr
`iatior
`with
`the t
`read
`[Nor
`sentl
`not c
`anae
`purp
`toler
`M
`use Í
`Ple, r
`load
`ultra
`kno,
`cbec
`cord
`The
`to th
`er th
`
`Page 10
`
`