within (±15%) of the average value obtained for the repli-RUGGEDNESS
cate measurements of the Standard solution . The average value of the replicate measurements of Spiked sample solu-Perform the Repeatability analysis over three independent tion 2 must provide a signal intensity or value less than that events using the following events or combinations thereof:
of the Standard solution . [N OTE —Correct the values obtained 1.on different days, or
for each of the spiked solutions using the Unspiked sample 2.with different instrumentation, or solution .]
3.with different analysts.Acceptance criteria
Relative standard deviation:NMT 25% for each Target Precision for Instrumental Methods
Element
(Repeatability)
[N OTE —Non-instrumental precision is demonstrated by Specificity
meeting the Detectability requirement above.]
Sample solutions:Six independent samples of the mate-The procedure must be able to unequivocally asss (e rial under test, spiked with appropriate reference materials Validation of Compendial Procedures 〈1225〉) each Target Ele-for the Target Elements at the Target Concentration .ment in the prence of components that may be expected Acceptance criteria
to be prent, including other Target Elements , and matrix components.
Relative standard deviation:NMT 20% for each Target Element .
Limit of Quantitation, Range, and Linearity
Specificity
Demonstrated by meeting the Accuracy requirement.
s 2S (USP35)
The procedure must be able to unequivocally asss (e Validation of Compendial Procedures 〈12
25〉) each Target Ele-ment in the prence of components that may be expected to be prent, including other Target Elements , and matrix components.
Physical Tests and QUANTITATIVE PROCEDURES
Determinations
The following ction defines the validation parameters for the acceptability of alternative quantitative procedures.Meeting the requirements must be demonstrated experi-mentally, using an appropriate system suitability procedure 〈616〉 BULK DENSITY AND and reference materials. Meeting the requirements dem-onstrates that the procedure is equivalent to the compendial TAPPED DENSITY OF POWDERS
procedure for the purpo of quantifying the Target Elements .
Accuracy
Change to read:西红柿怎么吃
Standard solutions:Prepare solutions containing the Tar-get Elements at concentrations ranging from 50% to 150%of J , using appropriate reference materials.
BULK DENSITY
动物剪纸Test samples:Prepare samples of the material under test spiked with appropriate reference materials before any sam-This general chapter has been harmonized with the corre-ple preparation steps (digestion or solubilization) at concen-sponding texts of the European Pharmacopoeia and/or the trations ranging from 50% to 150% of J for each Target Japane Pharmacopoeia . 3The portion that is not harmo-Element .
nized is marked with symbols (33) to specify this fact.3
Acceptance criteria
The bulk density of a powder is the ratio of the mass of Spike recovery:70%–150% for the mean of three rep-an untapped powder sample and its volume including the licate preparations at each concentration
contribution of the interparticulate void volume. Hence, the bulk density depends on both the density of powder parti-cles and the spatial arrangement of particles in the powder Precision
bed. The bulk density is expresd in grams per mL (g/mL)although the international unit is kilogram
s per cubic meter (1g/mL = 1000kg/m 3) becau the measurements are
made using cylinders. It may also be expresd in grams per REPEATABILITY
cubic centimeter (g/cm 3). The bulking properties of a pow-der are dependent upon the preparation, treatment, and Test samples:Six independent samples of material under
storage of the sample, i.e., how it was handled. The parti-test (taken from the same lot) spiked with appropriate refer-cles can be packed to have a range of bulk densities; how-ence materials for the Target Element(s) at the indicated ever, the slightest disturbance of the powder bed may result level.
in a changed bulk density. Thus, the bulk density of a pow-Acceptance criteria
der is often very difficult to measure with good reproducibil-ity and, in reporting the results, it is esntial to specify how Relative standard deviation:NMT 20% for each Target the determination was made. The bulk density of a powder Element
is determined by measuring the volume of a known weight of powder sample, that may have been pasd through a s sieve s 2S (USP35), into a graduated cylinder (Method I ), or by
measuring the mass of a known volume of powder that has Procedure—Allow an excess of powder to flow through been pasd through a volumeter into a cup (Method II) or the apparatus into the sample receiving cup until it over-
a measuring vesl (Method III).flows, using a minimum of 25 cm3 of powder with the Method I and Method III are favored.square cup and 35 cm3 of powder with the cylindrical cup.
Carefully scrape excess powder from the top of the cup by
smoothly moving the edge of the blade of a spatula perpen-Method I—Measurement in a Graduated dicular to and in contact with the top surface of the cup,
Cylinder taking care to keep the spatula perpendicular to prevent
packing or removal of powder from the cup. Remove any
material from the sides of the cup, and determine the Procedure—Pass a quantity of material sufficient to com-
weight, M, of the powder to the nearest 0.1%. Calculate plete the test through a sieve with apertures greater than or
the bulk density, in g/mL, by the formula:
equal to 1.0 mm, if necessary, to break up agglomerates
that may have formed during storage; this must be done
(M)/(V0)
gently to avoid changing the nature of the material. Into a
dry graduated 250-mL cylinder (readable to 2 mL) intro-
in which V0 is the volume, in mL, of the cup. Record the duce, without compacting, approximately 100g of test
average of three determinations using three different pow-sample, M, weighed with 0.1% accuracy. Carefully level the
der samples.
powder without compacting, if necessary, and read the un-
ttled apparent volume (V0) to the nearest graduated unit.
Calculate the bulk density in g/mL by the formula m/V0.Method III—Measurement in a Vesl Generally, replicate determinations are desirable for the de-
termination of this property. If the powder density is too
Apparatus—The apparatus consists of a 100-mL cylindri-low or too high, such that the test sample has an untapped
cal vesl of stainless steel with dimensions as specified in apparent volume of either more than 250 mL or less than
Figure 2.
150 mL, it is not possible to u 100g of powder sample.
Therefore, a different amount of powder has to be lected
as the test sample, such that its untapped apparent volume
is 150–250 mL (apparent volume greater than or equal to
60% of the total volume of the cylinder); the weight of the
test sample is specified in the expression of results. For test
samples having an apparent volume between 50 mL and
100 mL, a 100-mL cylinder readable to 1 mL can be ud;
the volume of the cylinder is specified in the expression of
results.
有仓
Figure 2.
教小孩画画
Method II—Measurement in a Volumeter
Procedure—Pass a quantity of powder sufficient to com-
plete the test through a 1.0-mm sieve, if necessary, to break Apparatus—The apparatus (Figure 1) consists of a top
up agglomerates that may have formed during storage, and funnel fitted with a 1.0-mm s sieve s2S(USP35).1 The funnel is
allow the obtained sample to flow freely into the measuring mounted over a baffle box containing four glass baffle
vesl until it overflows. Carefully scrape the excess powder plates over which the powder slides and bounces as it
from the top of the vesl as described for Method II. Deter-pass. At the bottom of the baffle box is a funnel that
mine the weight (M0) of the powder to the nearest 0.1% by collects the powder and allows it to pour into a cup of
subtraction of the previously determined mass of the empty specified capacity mounted directly below it. The cup may
measuring vesl. Calculate the bulk density (g/mL) by the be cylindrical (25.00 ± 0.05 mL volume with an inside diam-
formula M0/100, and record the average of three determina-eter of 30.00 ± 2.00 mm) or s cubical s2S(USP35) (16.39 ± 0.2
tions using three different powder samples.
mL volume with inside dimensions of s25.400s2S(USP35)±
0.076 mm).
Change to read:
TAPPED DENSITY
The tapped density is an incread bulk density attained
after mechanically tapping a container containing the pow-
der sample. Tapped density is obtained by mechanically tap-
ping a graduated measuring cylinder or vesl containing a
powder sample. After obrving the initial powder volume
or weight, the measuring cylinder or vesl is mechanically
擎着
tapped, and volume or weight readings are taken until little
further volume or weight change is obrved. The mechani-
cal tapping is achieved by raising the cylinder or vesl and
allowing it to drop under its own weight a specified dis-
tance by either of three methods as described below. De-
vices that rotate the cylinder or vesl during tapping may
be preferred to minimize any possible paration of the
mass during tapping down.
Figure 1.
1The apparatus (the Scott Volumeter) conforms to the dimensions in ASTM
32990.
Figure 3.
作文比赛Method I Method III
Apparatus—The apparatus (Figure 3) consists of the Apparatus and Procedure—Proceed as directed in following:Method III—Measurement in a Vesl for measuring bulk den-•A 250-mL graduated cylinder (readable to 2 mL with a sity using the measuring vesl equipped with the cap mass of 220±44 g)shown in Figure 2. The measuring vesl with the cap is •A ttling apparatus capable of producing, in 1 min,lifted 50–60 times per min by the u of a suitable tapped either nominally 250±15 taps from a height of 3±0.2density tester. Carry out 200 taps, remove the cap, and mm, or nominally 300±15 taps from a height of carefully scrape excess powder from the top of the measur-14±2 mm. The support for the graduated cylinder,ing vesl as described in Method III—Measurement in a Ves-with its holder, has a mass of 450±10 g.l for measuring the bulk density. Repeat the procedure
using 400 taps. If the difference between the two mass Procedure—Proceed as described above for the determi-
obtained after 200 and 400 taps exceeds 2%, carry out a nation of the bulk volume (V0). Secure the
cylinder in the
test using 200 additional taps until the difference between holder. Carry out 10, 500, and 1250 taps on the same pow-
succeeding measurements is less than 2%. Calculate the der sample and read the corresponding volumes V10, V500,
tapped density (g/mL) using the formula M F/100, where M F and V1250 to the nearest graduated unit. If the difference
is the mass of powder in the measuring vesl. Record the between V500 and V1250 is less than s or equal to s2S(USP35) 2
average of three determinations using three different pow-mL, V1250 is the tapped volume. If the difference between
der samples. The test conditions including tapping height
V500 and V1250 exceeds 2 mL, repeat in increments such as
are specified in the expression of the results.
1250 taps, until the difference between succeeding meas-
urements is less than s or equal to s2S(USP35) 2 mL. Fewer taps
may be appropriate for some powders, when validated. Cal-MEASURES OF POWDER COMPRESSIBILITY culate the tapped density (g/mL) using the formula m/V F, in
持球突破
which V F is the final tapped volume. Generally, replicate Becau the interparticulate interactions influencing the determinations are desirable for the determination of this bulking properties of a powder are also the interactions that property. Specify the drop height with the results. If it is not interfere with powder flow, a comparison of the bulk and possible to u a 100-g test sample, u a reduced amount tapped densities can give a measure of the relative impor-and a suitable 100-mL graduated cylinder (readable to 1tance of the interactions in a given powder. Such a com-mL) weighing 130±16 g and mounted on a holder weigh-parison is often ud as an index of the ability of the pow-ing 240±12 g. The modified test conditions are specified in der to flow, for example the Compressibility Index or the
the expression of the results.Hausner Ratio as described below.
The Compressibility Index and Hausner Ratio are measures
of the propensity of a powder to be compresd as de-Method II
scribed above. As such, they are measures of the powder’s
ability to ttle, and they permit an asssment of the rela-Apparatus and Procedure—Proceed as directed under tive importance of interparticulate interactions. In a free-
Method I except that the mechanical tester provides a fixed flowing powder, such interactions are less significant, and
drop of 3±0.2 mm at a nominal rate of 250 taps per min.the bulk and tapped densities will be clor in value. For
poorer flowing materials, there are frequently greater in-In reality, a powder probably contains particles with dif-terparticle interactions, and a greater difference between the ferent degrees of crystallinity, just as it may contain particles bulk and tapped densities will be obrved. The differ-with varying sizes and shapes. The lower the crystallinity of ences are reflected in the Compressibility Index and the a solid, the greater its enthalpy and entropy. The increa in Hausn
er Ratio .
enthalpy is never totally compensated by the increa in en-tropy; therefore, the Gibbs free energy, which reflects the Compressibility Index—Calculate by the formula:
balance between them, actually increas. Hence, the lower the crystallinity of a material (powder), and conquently 100(V 0 − V F )/V 0
the greater its amorphous character, the greater its apparent intrinsic solubility and dissolution rate, but the lower its V 0 = unttled apparent volume thermodynamic stability. Becau of the great relevance of V F = final tapped volume the properties, crystallinity is also an important property Hausner Ratio—
and requires measurement by a suitable method.
In the following chapter, the crystallinity or the content of V 0/V F
amorphous parts of a powder are measured by calorimetric methods such as microcalorimetry or solution calorimetry,Depending on the material, the compressibility index can although other methods could be ud (e.g., e general be determined using V 10 instead of V 0. [N OTE —If V 10
is ud,chapter Characterization of Crystalline and Partially Crystalline it will be clearly stated in the results.]
Solids by X-ray Powder Diffraction (XRPD) 〈941〉).
Many substances are capable of crystallizing in more than one type of crystal lattice, which is known as polymorphism.If water or a solvent is incorporated in the crystal lattice, the crystals are termed hydrates or solvates. Becau of the dif-ferent crystal packing, and/or molecular conformation and lattice energy, they usually exhibit different physical proper-ties. For simplicity, calorimetry measurements for degree of Change to read:
crystallinity determination discusd here assume only one solid crystalline form prent in the material of interest. The theory and experimental technique can be easily expanded s
〈696〉 CHARACTERIZATION OF to polymorphic systems with proper consideration of the enthalpy differences among the polymorphs.
CRYSTALLINE SOLIDS BY MICROCALORIMETRY AND METHOD 1—MICROCALORIMETRY (DETERMINATION OF AMORPHOUS
SOLUTION CALORIMETRY
CONTENT)
Most chemical, physical, and biological process are as-For the purpo of this chapter, crystalline material, partially sociated with the exchange of heat. Microcalorimetry is a crystalline material, and amorphous material are considered as highly nsitive technique to monitor and quantify both ex-solids.
othermic (heat producing) and endothermic (heat absorb-ing) changes associated with tho process. The technique allows the determination of the rate and extent of chemical INTRODUCTION—THE CONCEPT OF
reactions, changes of pha, or changes of structure.
CRYSTALLINITY
Thermal events producing only a fraction of a microwatt can be obrved using microcalorimetry. This means that The perfectly ordered crystal lattice with every molecule temperature differences less than 10-6 K must be detectable.in its expected lattice position is an ideal that is ldom, if Micro
calorimetry typically us the heat flow (heat leakage)ever, achieved. The other extreme is the amorphous state,principle, where, in a thermally defined vesl, the heat pro-in which a solid contains the maximum possible density of duced (or absorbed) flows away from (or into) the vesl in imperfections (defects of various dimensionalities), such that an effort to re-establish thermal equilibrium with its sur-all long-range order is lost while only the short-range order,roundings. Exceptional thermal stability with its surrounding impod by its nearest neighbors, remains. Real crystals lie has to be achieved either by a heat sink or an electronically somewhere between the two extremes. A crystal’s position regulated surrounding.
on a scale bounded by the two extremes is termed Heat energy from an active sample in the reaction vesl crystallinity .
运维工程师面试is channeled typically through Peltier elements; they act as All real crystals, even in the pure state, posss some lat-thermoelectric generators using the Seebeck effect. The heat tice imperfections or defects, which increa both the en-energy is converted into a voltage signal proportional to the ergy (enthalpy under conditions of constant atmospheric heat flow.
pressure) and the disorder (expresd as the entropy) of the Results are typically prented as a me
asure of the thermal crystal lattice. A crystal with a relatively low density of im-energy produced per unit of time (Watt) as a function of perfections is said to be highly crystalline and to posss a time.
high crystallinity. By contrast, a particle with a relatively high density of imperfections is said to be partially amor-phous and to posss a low crystallinity. In ideal terms, a Apparatus
totally amorphous particle corresponds to zero crystallinity.Amorphous particles may contain somewhat ordered do-Microcalorimeters are typically designed as twin systems mains that can act as nuclei for crystallization; such so-called with a measuring vesl and a reference vesl. Vesls are amorphous particles are said to posss a low-level, but fi-typically made of glass or stainless steel. For certain applica-nite, crystallinity.
tions, specially designed vesls that allow the addition of a The ability to detect and quantify the amount of amor-gas, a liquid, or a solid material may be ud.
phous material within a highly crystalline substance is of great importance during the development and subquent manufacture of a pharmaceutical preparation.
