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Memo: 5/1/91 To: Dr. John H. Reynolds IV From: B. Ingebrethsen, C. Lyman, W. Coleman, and P. Nelson Subject: Smoke nicotine "volatility" measurement methods. Motivation: We have evolved through several variations of mainstream WTPM nicotine "volatility" measurements as part of our investigations of evaporative deposition and sensory stimulation. The purposes of this memo are: to define, and prevent misinterpretations, of what we mean by nicotine "volatility; to describe the methods we have developed; and to discuss options for improved measurements. Definition nicotine "volatility": The fundamental smoke property controlling the rate of nicotine evaporative deposition during inhalation is the vapor pressure of nicotine in the vapor phase of the smoke. The vapor pressure of any compound is equivalent to its mass concentration in a gaseous system. In smoke, it follows, the vapor pressure of nicotine is equivalent to its mass concentration in the vapor phase of the aerosol. At equilibrium, the vapor pressure of nicotine in the gas phase of the smoke is the same as that at the surface of the smoke particles. The vapor pressure at the particle surface is, in turn, determined by the intrinsic vapor pressure of pure nicotine, a known quantity, and by the activity (related to the concentration) of nicotine in the particles, an unknown quantity. Calculation of the nicotine vapor 0 pressure in smoke requires significant assumptions due to the chemical complexity of the particles and is to be considered very approximate (seeC) memo to J. H. Reynolds, from B. Ingebrethsen, "Calculations of Evaporative Transfer Time Scales"). Direct measurement of the vapor pressure of C nicotine in smoke would be, if possible, experimentally complex. We choose, therefore, to measure a more accessible quantity that depends G directly on the vapor pressure of nicotine in smoke, but also depends on _ our measurement apparatus and operating parameters. We term this indirect measurement a "volatility" of nicotine measure and distinguish it from tner fundamental property, vapor pressure. ~ The "volatility" measures enable us to make valid comparisons among cigarettes regarding differences in nicotine vapor pressure. We can alsa~ make reasonable estimates from the volatility measures of the proportiona-~ magnitudes of differences among cigarettes with respect to nicotine vapor pressure. The limit of quantification comes when we attempt to estimate O the mass amount of nicotine transferred by evaporative deposition in the upper airways during inhalation. The latter estimate requires both a knowledge of the true vapor pressure of nicotine in smoke and other information about the syftem. With our present methods we can at best place some limits on the magnitude of the mass exchange within certain assumptions. Our early experimental results with "volatility" measurements are reported in a separate memo (to J. H. Reynolds, 4/22/91, "Evaporative deposition as a mechanism of sensory stimulation"). Our most reliable and informative results will be reported in a forthcoming memo. The following describes the evolution of methodologies and our experimental plans for the future. Syringe adsorption: our first measurements of nicotine "volatility" were with a model pharyngeal cavity adsorber a.k.a. a static denuder a.k.a. an internally wetted 50 cm^3 syringe. Our intent with this measurement was to create a

physical system in wbicts vapor adsorption would proceed with minimal particle deposition and the amount of nicotine deposited could be quantified. -The measurement apparatus is depicted in Figure 1. Mainstream smoke was drawn directly into a 50 cm"3 syringe by movement of the syringe piston with a programmable translation stage. The syringe contained 3 cm^3 distilled water which coated the inner walls of the syringe each time the piston was withdrawn from the closed position (Figure 1. A). Smoke was held in the syringe for periods ranging from 10 to 50 seconds. After the holding period the syringe was exhausted through a Cambridge filter pad placed in the cigarette's original position (Figure 1. B). After smoking a set number of puffs, the syringe-water and the filter pad were analyzed for nicotine and glycerol. The glycerol analysis was intended to serve as a particle marker to correct for particle deposition in the syringe and yield a better measure of nicotine vapor adsorption than the nicotine analysis alone. Separate smokings directly through filters (Figure 1. C) with this apparatus were made to establish the cigarette delivery with these puffing parameters. we originally intended to calculate the amount of vapor nicotine adsorbed by the difference between the pad analyses for direct smoking (onto pad, no syringe aging) and syringe aged smoking. We found that the amount of nicotine removed in the syringe, even at long aging times, was small and that the calculation of the amount adsorbed from the difference in the two pad analyses was unacceptable due to the errors in the pad measurements ;.• obscuring the small difference resulting from the amount adsorbed in the ~ syringe. The syringe-water analysis required method development, but waso required to get at the desired information. our syringe-water glycerol analysis did not work out, but this was a practical analytical matter thaQ could be resolved with sufficient time. CD The major shortcoming of this approach was the uncertainty that the inner~= walls of the syringe remained sufficiently wetted throughout the smoke aging to act as perfect sinks for nicotine vapor. A small amount of dead- volume was also unavoidable resulting in a small amount of smoke remainin~ in the syringe after exhausting. These shortcomings are addressed in our future plans described later. ,,,~ Pad Evaporation: C:) .The second type of nicotine volatility measurement was even more straightforward than the syringe adsorption method and is illustrated in C:) Figure 2. We simply flowed dry air through smoked filter pads and into a nicotine detector which gave a measurement of the vapor nicotine concentration in the air resulting from evaporation from the filter pad. We separately used two types of nicotine detectors, the TAGA mass spectrometer and a gas p:iase IR spectrophotometer. Additionally, we obtained a measure of nicotine lost from the filters by GC nicotine analysis of the pads after the air treatment and of duplicate smokings without air treatment. Initially we thought there was useful information to be derived from analysis of the vapor nicotine concentration vs. time curves derived from the IR measurements which were performed first. Two stages of nicotine evaporation appeared to be revealed from multiple nonlinear regression analysis of the concentration vs. time data. However, we knew that the IR absorbance measurement suffered from interferences from compounds other than nicotine and we could not be comfortable with our analysis. At this point we switched to the TAGA as a detector which yielded unambiguous

nicotine vapor conceatrations through monitoring of the nicotine molecular mass. Most of the differences in the shapes of the vapor nicotine vs. time curves that we thought we were observing with the IR measurements were not -present in the TAGA data. While we now attribute the disitinction of multiple nicotine source rates in the IR data to interferences, we did not perform the same detailed analysis of the TAGA results and cannot rule out the possibility that subtle differences among cigarettes may be revealed by closer examination of the TAGA curves. As opposed to the differential information referred to above, the integral measurements of total vapor nicotine concentrations from the TAGA and the GC pad analyses did show clear differences among cigarettes. We believe that nicotine volatility measured in this way gives some indication of how cigarettes may differ with respect to evaporative deposition during inhalation, but recognize that the physical state of the measurements differs in key respects from the system of interest. In other words, although we believe that the pad evaporation measurements reveal differences in the state of the nicotine in the WTPM, we cannot be convinced, from these measurements, that these differences will result in differences in evaporative deposition during inhalation. This recognition led us to our next measurement method. Bubbler adsorption: Mainstream smoke passing through the pharynx is exposed to wet surfaces ~= that readily adsorb water soluble vapors, but the path shape and size doe;~ not promote particle deposition (see memo, to J. H. Reynolds, "Evaporatibe deposition as a mechanism of sensory stimulation"). The pharynx is in C) effect a denuder tube for vapor phase smoke components and our preferred method of measuring nicotine volatility will be with denuder tubes as C discussed later. Smoke passing through an appropriately sized bubbler also mimics the key aspects of efficient vapor removal with minimal particle ^ deposition. Most of our measurements to date have been performed with such a bubbler adsorption apparatus shown in Figure 3. .~, Twenty-five cm^3 bubblers were used and the bubbling tips were cut back to eliminate particle impaction on the lower surface. Twenty-five cm"3 of ^• distilled water was used as the adsorption medium in the bubblers. Cambridge filter pads were placed down stream of the bubblers to collect`~ WTPM that passed through the bubblers. The air/smoke flow through the system was controlled by a valving system driven by a logic controller. nAt the start of a puffing/adsorption cycle solenoid 2 switches from bypass tte drawing air through solenoid 1, the bubbler, and filter. Two seconds after the start, solenoid 1 switches to puff on the cigarette for two seconds with the flow rate maintained throughout at 17.5 cm"3/second. After solenoid 1 switches to end the puff, 4 seconds into the cycle, solenoid 2 remains open for an additional 10 seconds to purge the smoke through the system. The cycle is repeated for a set number of puffs. We were concerned initially that the water's adsorption efficiency would change in the course of multiple cigarette smokings and smoked only one cigarette per run. Driven by a need to improve the reproducibility of the measurements, we determined that the pH of the water quickly achieved a value of 5.0-5.5 and remained in this range for the smoking of three cigarettes. We felt justified, therefore, in increasing the cigarettes per run to 3. We believe the pH effect is driven by C02 adsorption from the smoke and results in the bubbler being an acid adsorber for nicotine. Nicotine analyses were performed on the bubbler water and the filter for each run. Gravimetric measurements of the filter before and after the run were also performed.

In further attempts to improve the reproducibility of the measurements we modified the system as shown in Figure 4. We removed s,olenoid 1 to eliminate loss of smoke (revealed by deposits in the valve). Removing solenoid 1 eliminated the loss of smoke and also introduced fresher smoke into the bubbler, but it also complicated the smoking procedure. Without a means to automatically switch from puffing to purge air we had to adjust the cycle to take a two s3cond puff, stop the flow for 3 seconds to remove the cigarette and then open the purge for 10 seconds. This modification necessitates puff-by-puff interaction of the experimenter with the apparatus and also introduces a 3-second aging of the smoke over the bubbler water. We decided that these tradeoffs were worth the improved reproducibility. A second modification in the second bubbler adsorption configuration, not shown in Figure 4, was the positioning of the bubbler at an angle to the horizontal. The tilting produced more uniform bubbles and decreased the fraction of nicotine removed from the smoke. The reduction of the fraction of nicotine adsorbed as a result of tilting re-emphasizes the apparatus dependent, relative nature of the volatility measurements made with this procedure. The measurements made with the bubbler adsorption system showed that nicotine vapor adsorption differences among cigarettes could be verified in a system with roughly the same smoke residence time and adsorption surface area as that of the pharynx. What we cannot obtain from measurements with this system are absolute values of nicotine mass deposition rates from smoke to surface. The actual residence times and bubble surface area are•` not known sufficiently well with the bubblers to derive actual mass deposition rates. Our next step is to make measurements with a better O controlled and defined system which should overcome this limitation. C Spinning denuder (planned): C) C Denuders or denuder tubes are means to separate aerosol particles and vapors by taking advantage of the large difference in diffusion -- coefficients between particles and gases. Molecular species in the gas ~ phase diffuse rapidly compared to suspended aerosol particles; the ~• difference in diffusion coefficients usually being several orders of magnitude. Denuders are designed to pass aerosols through straight channels at flow rates under which diffusion to the walls of the channel is the predominant mechanism of deposition for both vapor phase molecules and aerosol particles. Effective denuders remove a large fraction of the vap6? of interest while removing a minimal fraction of the particles. Denuders are usually made selective for a particular class of vapor phase compoundp by coating the denuder surface with compounds with a chemical affinity for the target vapor phase species. The terminology usually employed is that the surface is made a perfect sink for the target compound meaning that if the target compound diffuses to the surface it is adsorbed. For example, acid coatings make the surface a perfect sink for vapor phase bases. All surfaces are generally considered to be perfect sinks for particles. Removal rates for "pure" particles and gases are theoretically well defined for denuders with simple geometries (cylinders, annular sections), perfect sink surfaces, and fully developed laminar flow profiles (these conditions can be approximated sufficiently in experiments to make use of the theory). By "pure" particles and gases we mean aerosol systems in which the vapor phase species of interest is neither supplied by evaporation from the particles nor condenses on the particles. The latter is clearly not the case for nicotine irn mainstream smoke. However, we can still conduct the experiments with mainstream smoke and extract from the deviations of the results from the theory (that assumes "pure" particles and gases)

information regarding the actual mechanisms of vapor mass tYansport. In fact one unique aspect of denuder theory may provide a direct experimental route to establish deviations from the "pure" particles and gases case. Theory predicts that when the above cited conditions are met for a cylindrical denuder, the removal rate of "pure" gases is independent of the tube diameter and depends only on the tube length and the volumetric flow rate through the tube. Qualitatively this can be understood by recognizing that at constant volumetric flow rate the aerosol in a small diameter tube has a shorter residence time but also a shorter average distance to the surface than in a larger diameter tube in which the residence time is longer and the average distance to the surface is greater. Mathematically these competing factors (residence time and distance from the surface) exactly cancel and the removal rate becomes independent of the tube diameter. This being the case, we can construct denuder tubes for which "pure" gas removal rates will be identical but which differ significantly in aerosol residence times and internal denuder surface areas. We have reason to believe that these latter two parameters may be important in determining the vapor removal rate volatile aerosol systems such as nicotine in cigarette smoke. Our plans are to use an array of nine denuder tubes spanning a range of diameters (11, 15, and 25 mm) and lengths (300, 450, and 600 mm). Measurements at constant volumetric flow rate with this set of tub sizes will provide ample data to test for deviations from the theory for °pure", particle and gas adsorption. The primary practical obstacle in the use of" denuders is creating a uniform surface coating of the adsorbent. Many C coating procedures have been devised. They are often dictated by intended field use. We have chosen to coat the surface with water which, from our C bubbler studies, will rapidly become acidified by C02 adsorption as smoke is passed. Coating of the inner surface will be maintained by spinning tFie denuder tube about its axis during the measurements. While spinning of tYV denuder may seem at first to be an overly complex solution to the coating`- problem, closer examination of the experiment reveals that several desirable ends are achieved through a small investment of time in constructing the spinning apparatus. The spinning approach ensures :~ complete surface coating, minimizes the opportunity for coating saturation by the adsorbing compounds, simplifies the chemistry of the surface (many ~ coating procedures employ a viscous stationary phase), and facilitates ,) recovery of the adsorbent. Properly executed measurements with the spinning denuder will almost certainly yield our best quantitative ~ measurements of nicotine vapor deposition rates from smoke. These measurements will enable us to start predicting the actual mass amounts of; nicotine deposited in the pharynx during inhalation. Additionally, we expect to derive at least a qualitative description of the mechanisms of nicotine transport from the smoke to the pharynx during inhalation.

FIGURE 1 SYRINGE ADSORPTION A B C CIG FILTER Q H2CY II 11 H20 CIG FILTER C) c c .., C:) C) 0 ~ A r

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FIGURE 3 BUBBLER ADSORPTION I CIGARETTE ~ AIR J, SOLENOID 1 H20 FILTER AIR I VALVE SOLENOID 2 YIBUBBLER I VACUUM cit c 0 c M c:) Co.

BUBBLER ADSORPTION II FIGURE 4 AIR VALVE VACUUM SOLENOID 2 C% V BUBBLER o 0 c 0-

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