Vapor pressure and volatility

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In general, absorption of inhaled drug is dependent upon the physical characteristics of the drug, including particle size, lipid solubility, and volatility. Clearly, a drug's volatility would play an important role in determining its inhalation potential. Drug volatility is determined by many factors, including boiling point, melting point, and vapor pressure. Since many abused substances are less volatile than organic solvents and are smoked at very high pV = nRT

temperatures, effects of melting and boiling points on the volatilization would be negligible. On the other hand, vapor pressure may serve as a good indication of volatility.

Based on the ideal gas law, equation 1

where p is the partial pressure of the gas, R is the gas constant, n is the number of molecules, V is the volume of the gas phase of the compound, and T is the temperature in kelvin, the partial pressure of the gas becomes the vapor pressure (Pv) when the gas and liquid phases of the compound reach equilibrium at a particular temperature. Then, equation 1 can be expressed as equation 2

where C = n/V and is the concentration of the compound in the gas phase and is directly proportional to the vapor pressure. This relationship suggests that the vapor pressure of a compound is P = CRT

positively Pv = CRT

correlated with volatility; the higher concentration of the gas, the more volatile it is. Therefore, the volatility of a drug at a certain temperature is determined by its vapor pressure and the volatilization temperature.

Due to a lack of information on vapor pressure for a variety of drugs of abuse and related compounds, the authors determined this parameter by an indirect method based on a system using gas chromatography and relative retention times. This approach is a modification those described by others (Hamilton 1980; Westcott and Bidleman 1981; Bidleman 1984). The original method is based on in the relationship between solid vapor pressure and GC column retention time (or volume retention time, VR), and has been used in determination of vapor pressures for herbicides, pesticides, and a variety of nonpolar organic compounds. The vapor pressure (Pv) of two substances at the same temperature (as well as their latencies of vaporization, LV) are related by equation 3

and the fact that vapor pressure has been shown to be related to column retention volumes by equation 4

The relationship between vapor pressure and column retention times can be determined from the combination of equations 3 and 4: equation 5

Therefore, a plot of ln [(VR)1/(VR)2] versus ln P2 should yield a straight line with either a positive or negative correlation coefficient depending on the ratio of (VR)1/(VR)2 . The value of (L1/L2) can be calculated from the slope and thus P1 determined from equation 3. If substances 1 and 2 are the unknown and standard compounds, respectively, then the vapor pressure of the unknown at a given temperature can be determined. The relationship between vapor pressure and temperature can be simply described by the Clausius-Clapeyron equation: equation 6

Therefore, the vapor pressure at any temperature can be extrapolated by the linear regression between ln P and 1/T.

Since this technique has primarily been used for estimating vapor pressures of pesticides, these chemicals were utilized to establish a working model to determine the vapor pressures of drugs of abuse. The authors' strategy was to determine the vapor pressure of drugs of abuse by employing a pesticide with known Pv values as a standard. A GC/MS was equipped with a 4-meter capillary column. The helium carrier gas was adjusted to a 1.11 milliliter per minute (mL/min) flow rate and a 78.26 mL/min split for a split ratio of 79:1. The injector port was kept at 200%C, detector port at 225%C, and the source of the MS at 200%C. The oven temperature was kept constant during any given analysis. All test compounds were dissolved in hexane or ln P1= (L1/L2) ln P2 - C (Vt)yRVi,R)Vjt)2P2^&1-(L1/L2)] ln P2 -

chloroform at 0.5 to 4.0 milligrams per mL (mg/mL) in order to obtain a substantial peak from a 1 microliter (L) injection. Since eicosane and octadecane are commonly used as standard compounds in determining the vapor pressure of other pesticides, both compounds were used to standardize the GC column. Various pesticides (nonpolar organic compounds), such as naphthalene, phenanthrene, pyrene, and benzo[a]pyrene were then injected and retention times obtained for 5 to 8 temperatures at 10%C increments, ranging from 40%C to 190%C. The natural logs of the ratios of the retention times of the standard and test compounds were then plotted against the natural log of the vapor pressure of the standard at each temperature.

Both octadecane and eicosane standardization yielded vapor pressures of the pesticides very close to published values. Of these two compounds, the values obtained with eicosane exhibited a higher correlation coefficient. Thus, eicosane appeared to be the better standard for approximating the values of various drugs of abuse. However, the plot of relative retention time ratios of several of the drugs of abuse to the published vapor pressure of eicosane (equation 5) correlated poorly (table 1). This result eliminated eicosane as a standard for measuring the vapor pressures of drugs of abuse. In the search for another standard, dibutyl phthalate proved to be a good candidate. Using eicosane as a standard, the vapor pressure of dibutyl phthalate, at 25%C, was determined as 6.89 x 10-5 torr, which fell within the published vapor pressure range of 1.2 x 10-6 to 4.4 x 10-5 torr (Small et al. 1948). By the same method, the vapor pressures of dibutyl phthalate at different temperatures were then determined against eicosane. Equation 6 was then solved for dibutyl phthalate: ln P = A + B/T where A = 25.179, B = -10,364, P is in torr and T is in kelvins. Using dibutyl phthalate as a standard, the natural log of the relative retention time ratios plotted against the natural log of its vapor pressures at the respective temperatures yielded a high correlation for various drugs of abuse (figure 1). Thus, vapor pressures at 25%C could be approximated for drugs representing a variety of classes (table 1).

Vapor pressures of selected compounds are listed in table 1. In comparing different classes of drugs, the opioids appear to have relatively low vapor pressure, suggesting that they are less volatile than other drugs. As can also be seen in table 1, nicotine exhibited relatively high volatility, which is consistent with the fact that cigarette smoking is the most popular method of nicotine administration. Vapor pressures for methamphetamine and amphetamine appeared to be higher than that of nicotine at 25%C, but their vapor pressures could not be determined by the present method since their volatility exceeded the range of the standard at the temperatures that were

TABLE 1. Determining the vapor pressures of drugs of abuse using dibutyl phthalate as the standard.

Correlation coefficient of

TABLE 1. Determining the vapor pressures of drugs of abuse using dibutyl phthalate as the standard.

Correlation coefficient of

Drugs (Free base)

Eicosane

Dibutyl phthalate

Vapor pressures (Torr, at 25%C)

Nicotine

A

0.871

2.61x10-2

MDMA

0.997

4.47x10-3

Caffeine

0.997

8.56x10-4

PCP

0.984

1.49x10-4

Secobarbital

0.996

5.72x10-5

Pentalbarbital

0.948

4.16x10-5

Methaqualone

0.751

0.896

1.60x10-5

Cocaine

0.748

0.996

9.79x10-6

Morphine

0.943

9.49x10-7

9-THC

0.986

1.01x10-7

Heroin

0.981

0.983

5.71x10-8

Fentanyl

0.982

2.41x10-8

KEY: A = Values were not determined.

KEY: A = Values were not determined.

studied. Compounds with high vapor pressures are predicted to be much more volatile and consequently more likely to be smoked than those possessing low vapor pressures.

Vapor Pressure And Volatility

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