Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 21:08 ... [… · The pycnometric density, as measured by gas pycnometry, a sealed test cell with an empty cell volume of V c

USP 35 Physical Tests / ⟨698⟩ Deliverable Volume 289

Typically, this temperature change in an electronic form is desiccant, preferably containing an indicator of effective-measured at precisely defined time intervals to produce ness. If crystallinity–humidity studies are to be carried out,temperature–time data that are collected, analyzed by a the solid sample should be stored in a sealed chamber con-computer, and then plotted. A blank run without addition taining a saturated salt solution to provide a defined relativeof the solid solute to the solvent should show no discernible humidity at 25.0 ± 0.1°.change in the slope of the temperature–time plot.

For isoperibol solution calorimeters, response is relativelyrapid, but any heat losses to or heat gains from the bathreduce the accuracy and contribute to noise. Therefore,isoperibol solution calorimeters are more advantageous thanisothermal solution calorimeters when the solution process isrelatively fast. For all measurements of enthalpy of solution ⟨698⟩ DELIVERABLE VOLUMEusing isoperibol solution calorimeters, the choice of solventand solid is critical. The nature and weight of the solventand the weight of the solid sample allow the total heat

The following tests are designed to provide assurance thatchange, corresponding to total dissolution of the solid, tooral liquids will, when transferred from the original con-proceed to completion within 10 minutes under vigoroustainer, deliver the volume of dosage form that is declaredstirring at a constant rotational speed within the range ofon the label of the article. These tests are applicable to400 to 600 revolutions per minute. The rotational speed isproducts labeled to contain not more than 250 mL, whetherchecked with a stroboscope.supplied as liquid preparations or liquid preparations thatare constituted from solids upon the addition of a desig-

Isothermal Solution Calorimetry nated volume of a specific diluent. They are not required foran article packaged in single-unit containers when the mon-

In the isothermal (constant temperature) solution calorim- ograph includes the Uniformity of Dosage Units ⟨905⟩ test.eter, the heat change during the solution process is com-pensated for by an equal but opposite energy change, such

TEST PREPARATIONSthat the temperature of the solvent–solute system (i.e., solu-tion) remains constant. This equal but opposite energy

For the determination of deliverable volume, select notchange is measured and, when its sign is reversed, providesfewer than 30 containers, and proceed as follows for thethe enthalpy of solution. For isothermal calorimeters, re-dosage form designated.sponse is relatively slow, but the compensation process

eliminates the effects of heat losses to or heat gains from Oral Solutions, Oral Suspensions, and Other Oralthe bath. Therefore, isothermal calorimeters are more ad- Liquid Dosage Forms—Shake the contents of 10 containersvantageous than isoperibol calorimetry when the solution individually.process is relatively slow. Powders that are Labeled to State the Volume of Oral

Liquid that Results when the Powder is Constituted withthe Volume of Diluent Stated in the Labeling—ConstituteCALORIMETER CALIBRATION 10 containers with the volume of diluent stated in the label-ing, accurately measured, and shake individually.To ensure the accuracy of the calorimeter, chemical cali-

brations must be performed daily. For an endothermic solu-tion process, the calibration of the calorimeter is checked by PROCEDUREmeasuring the heat absorbed during the dissolution of po-tassium chloride in distilled water at 298.15 K (25.0°). The Being careful to avoid the formation of air bubbles, gentlyestablished enthalpy change in this endothermic process is pour the contents of each container into separate dry grad-235.5 J/g or 4.196 kcal/mol. For an exothermic solution uated cylinders of a rated capacity not exceeding two and aprocess, the calorimeter is checked by measuring the heat half times the volume to be measured, and calibrated “toevolved during the dissolution of 5 g per L of tromethamine contain”. Allow each container to drain for a period not to[tris(hydroxymethyl)aminomethane, THAM] in a 0.1 mol/L exceed 30 minutes, for multiple-unit containers and 5aqueous hydrochloric acid solution at 298.15 K (25.0°). The seconds for single-unit containers, unless otherwise specifiedestablished heat for the aforementioned process is –29.80 in the monograph. When free from air bubbles, measure thekJ/mol or –7.12 kcal/mol. volume of each mixture. Alternatively, in the case of prod-

The effective heat capacity of the calorimeter cell and its ucts of low volume packaged in single-unit containers, thecontents is determined for every calorimeter run. This deter- volume can be computed as follows: (1) discharge the con-mination is accomplished by electrical heating of the container contents into a suitable tared container (allowingtents of the calorimeter cell. The effective heat capacity is drainage for not more than 5 seconds); (2) determine thedetermined according to one of two protocols—either by weight of the contents; and (3) compute the volume aftermaking one determination after ampul breakage or by mak- determining the density.ing one determination before and a second determinationafter ampul breakage and then averaging the two results.The accuracy and reliability of the electrical heating are es- ACCEPTANCE CRITERIAtablished by the accuracy and reliability of the aforemen-tioned chemical calibrations. Use the following criteria to determine compliance with

this test.For Multiple-Unit Containers (see Figure 1)—The aver-SAMPLE HANDLING age volume of liquid obtained from the 10 containers is not

less than 100%, and the volume of no container is less thanThe thermodynamic stability of solids decreases with de- 95% of the volume declared in the labeling. If A, the aver-creasing crystallinity. In particular, solids of low crystallinity, age volume is less than 100% of that declared in the label-especially amorphous solids, tend to sorb water vapor from ing, but the volume of no container is less than 95% of thethe atmosphere, leading to crystallization and a correspond- labeled amount, or B, the average volume is not less thaning gain in crystallinity. For these reasons, anhydrous solid 100% and the volume of not more than 1 container is lesssamples whose crystallinity is to be determined must be than 95%, but is not less than 90% of the labeled volume,stored at zero humidity in sealed chambers containing a perform the test on 20 additional containers. The average

Official from May 1, 2012Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.

Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 21:08:38 EST 2011

290 ⟨698⟩ Deliverable Volume / Physical Tests USP 35

Figure 1. Decision scheme for multiple-unit containers. (AV = Average volume. LV = Labeled volume)

volume of liquid obtained from the 30 containers is not less container is outside the range of 95% to 110%, or if B, thethan 100% of the volume declared in the labeling; and the average volume is not less than 100% and the volume ofvolume of liquid obtained from not more than 1 of the 30 not more than 1 container is outside the range of 95% tocontainers is less than 95%, but not less than 90% of that 110%, but within the range of 90% to 115%, perform thedeclared in the labeling. test on 20 additional containers. The average volume of liq-

uid obtained from the 30 containers is not less than 100%For Single-Unit Containers (see Figure 2)—The averageof the volume declared in the labeling; and the volume ob-volume of liquid obtained from the 10 containers is not lesstained from not more than 1 of the 30 containers is outsidethan 100%, and the volume of each of the 10 containersthe range of 95% to 110%, but within the range of 90% tolies within the range of 95% to 110% of the volume de-115% of the volume declared on the labeling. clared in the labeling. If A, the average volume is less than

100% of that declared in the labeling, but the volume of no



USP 35 Physical Tests / ⟨698⟩ Deliverable Volume 291

Figure 2. Decision scheme for single-unit containers. (AV = Average volume. LV = Labeled volume)



292 ⟨699⟩ Density of Solids / Physical Tests USP 35

ple schematic of one type of gas pycnometer is shown in⟨699⟩ DENSITY OF SOLIDS Figure 1.

TERMS AND DEFINITIONS

Density refers to the average spatial distribution of massin a material. The density of solids typically is expressed in gper cm3, in contrast to fluids, where the density is com-monly expressed in g per mL at a stated referencetemperature.

The density of a solid particle can assume different valuesdepending on the method used to measure the volume ofthe particle. It is useful to distinguish among three differentpossibilities.

The true density of a substance is the average mass perunit volume, exclusive of all voids that are not a fundamen-tal part of the molecular packing arrangement. It is a prop-erty of a particular material, and hence should be indepen- Figure 1. Schematic of gas pycnometer.dent of the method of determination. The true density of aperfect crystal can be determined from the size and compo-sition of the unit cell. The sample, with mass w and volume Vs, is placed inside

The pycnometric density, as measured by gas pycnometry, a sealed test cell with an empty cell volume of Vc. The sys-is a convenient density measurement for pharmaceutical tem reference pressure, Pr, is determined at the manometerpowders. In a gas pycnometer, the volume occupied by a while the valve that connects the reference volume with theknown mass of powder is determined by measuring the vol- test cell is open. The valve is closed to separate the refer-ume of gas displaced by the powder. The quotient of the ence volume, Vr, from the test cell. The test cell is pres-mass and volume is the pycnometric density. The pycno- surized with the measurement gas to an initial pressure, Pi.metric density equals the true density unless the material Then the valve is opened to connect the reference volume,contains impenetrable voids, or sealed pores, that are inac- V r, with the test cell, and the pressure drops to the finalcessible to the gas used in the pycnometer. pressure, Pf. If the measurement gas behaves ideally under

The granular density includes contributions to particle vol- the conditions of measurement, the sample volume, Vs, isume from open pores smaller than some limiting size. The given by the following expression:size limit depends on the method of measurement. A com-mon measurement technique is mercury porosimetry, wherethe limiting pore size depends upon the maximum intrusionpressure. Because of the additional contribution from porevolume, the granular density will never be greater than thetrue density. A related concept is the aerodynamic density,which is the density of the particle with a volume definedby the aerodynamic envelope of the particle in a flowing The density, ρ, is given by the equation:stream. Both the closed and open pores contribute to thisvolume, but the open pores fill with the permeating fluid.The aerodynamic density, therefore, depends on the densityof the test fluid if the particle is porous.

For brevity, the pycnometric density and the true densityare both referred to as density. If needed, these quantities Details of the instrumental design may differ, but all gasmay be distinguished based on the method of measure- pycnometers rely on the measurement of pressure changesment. as a reference volume is added to, or deleted from, the test

The density of a material depends on the molecular pack- cell.ing. For gases and liquids, the density will depend only on The measured density is a volume-weighted average oftemperature and pressure. For solids, the density will also the densities of individual powder particles. The density willvary with the crystal structure and degree of crystallinity. If be in error if the test gas sorbs onto the powder or if vola-the solids are amorphous, the density may further depend tile contaminants are evolved from the powder during theupon the history of preparation and treatment. Therefore, measurement. Sorption is prevented by an appropriateunlike fluids, the densities of two chemically equivalent choice of test gas. Helium is the common choice. Volatilesolids may be different, and this difference reflects a differ- contaminants in the powder are removed by degassing theence in solid-state structure. The density of constituent par- powder under a constant purge of helium prior to theticles is an important physical characteristic of pharmaceuti- measurement. Occasionally, powders may have to becal powders. degassed under vacuum. Two consecutive readings should

Beyond these definitions of particle density, the bulk den- yield sample volumes that are equal within 0.2% if volatilesity of a powder includes the contribution of interparticulate contaminants are not interfering with the measurements.void volume. Hence, the bulk density depends on both the Because volatiles may be evolved during the measurement,density of powder particles and the packing of powder the weight of the sample should be taken after theparticles. pycnometric measurement of volume.

GAS PYCNOMETRY FOR THE MEASUREMENT MethodOF DENSITY

Ensure that the reference volume and the calibration vol-ume have been determined for the gas pycnometer by anGas pycnometry is a convenient and suitable method forappropriate calibration procedure. The test gas is helium,the measurement of the density of powder particles. A sim-unless another gas is specified in the individual monograph.



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Accessed from 128.83.63.20 by nEwp0rt1 on Fri Dec 02 21:08 ... [… · The pycnometric density, as measured by gas pycnometry, a sealed test cell with an empty cell volume of V c