Effect of Hydrophobic Coating on the Behavior of a Hygroscopic Aerosol Powder in an Environment of Controlled Temperature and Relative Humidity

A. J. HICKEY**’, I. GONDA*, W. J. IRWIN*, AND F. J. T. FILDES’ Received July 5, 1989, from the *University of Aston in Birmin ham, Pharmaceutical Sciences Institute, Aston Trian le, Birmingham, 84 7ET, U.K., the §University of Sydney, Department of Pharmacy, Sygey, N.S. W. 2006, Australia, and nlCl Pharmaceuticag, Hurdsfield lndustrial Estate, Macclesfield, Cheshire. SKI0 ZNA, U.K. ‘Present address: University of Illinois at Chicago, College of Pharmacy, Department of Pharmaceutics (MIC 880), 833 South Wood Street, Chicago, IL 60612.

Accepted for publication January 2, 1990.

Abstract 0 Powders of uncoated disodium fluorescein (DF) and DF coated with various amounts of lauric or capric acids were generated as aerosols in an environment of controlled temperature and relative humidity. The particle size and distribution of these powders were characterized using a cascade impactor and a computerized data inversion method of analysis. Disodium fluorescein exhibited a hygro- scopic growth ratio of 1.5 at a relative humidity of 97%. This growth was reduced to 1.3 by coating with 0.1 5 g of lauric acid or 0.8 g of capric acid per gram of DF, and was eliminated with 0.2 g of lauric acid or 0.1 8 g of capric acid per gram of DF. The reduction in hygroscopic growth probably reflects an inhibition of the growth rate. In the time following generation and prior to deposition in the collection device, -40 s, the coated aerosol powders do not seem to reach their equilibrium droplet diameter. These studies indicate that these combinations of DF and fatty acid would result in larger equilibrium droplet diameters than that of the dye alone.

The water-soluble nature of most therapeutic aerosols brings about the increased deposition of particles in the respiratory tract as a result of hygroscopic growth. Under- standing and controlling this phenomenon may result in improved inhalation aerosol formulations. An extensive re- view of this subject was published recently.1

Upon entry into the respiratory tract, the aerosol will be conditioned to reach the lung temperature of 37°C and relative humidity of 99.5%.1 This latter value can be derived from the osmotic pressure or from the lowering of the freezing point of blood.2

Experimental and theoretical investigations of the hygro- scopic growth of a variety of aerosols have been performed. Pure acids and salts,3-5 pharmaceutical compounds,G-12 and household products’3J4 have all been examined.

Sodium chloride has been used as a standard aerosol1”ls for comparison with the growth rates of pharmaceutical aero- sols.4.5 Assuming ideal solution behavior, the growth ratio for sodium chloride at 99.5% relative humidity has been esti- mated as 4.1.3 Experimentally, a growth ratio of 3.7, at 98% relative humidity and 37 “C, has been observed.8 This differ- ence may be explained by the assumption of ideal solution behavior for the estimated values.12 It was shown that for a number of pharmaceutical compounds, the assumption of ideal solution behavior would lead to erroneous growth predictions.12J9

A number of both predictivelV5J2 and experimental7-11 investigations of the hygroscopic growth of pharmaceutical aerosols have placed the growth ratio for these compounds in the range of 2 to 3. Martonen et a1.s have suggested that isoprenaline hydrochloride particles reach a maximum growth ratio of between 1.2 and 2.0, for particles ranging from 5 to 2 pm, respectively, by the first airway generation. Thus, hygroscopic growth in the respiratory tract is likely to

influence the deposition of pharmaceutical aerosols, as sug- gested by analyses of other workers.20-23 Correctly formulat- ing and accounting for these effects may permit pharmaceu- tical aerosols to be selectively deposited at target sites within the lung and thus improve clinical aerosol therapy.16

Surfactants are included in aerosol formulations as emul- sifiers and as valve lubricators.24~25 Both increases13.26 and reductions2628 in the association of water with hygroscopic particles have been attributed to the presence of surfactants. It seems that some control of hygroscopic growth might be achieved by careful application of surfactants to hygroscopic aerosol powders.

In order to study the particle size distribution and the growth of an aerosol a method of assessment is required. The aerodynamic diameter is the most appropriate size parameter to measure since the complicating factors of shape and density are incorporated in this measurement. The devices most commonly used for measuring this parameter are inertial samplers,29-36 particularly those which sample by inertial impaction.34--36 An inertial device, such as a cascade impactor, permits direct determination of the drug mass distribution in different aerodynamic size intervals. Chemical, or radiochem- ical, assays account specifically for the drug distribution, excluding any excipients in the aerosol.37 Furthermore, mea- surements can be carried out under conditions of temperature and relative humidity extrapolated from those in the human respiratory trad.12,37-39 The disadvantage of these methods is that the aerosol is sized after a longer exposure time to high relative humidity than the typical inspiration time in vivo. Therefore, except for very slow growth, inertial impaction is only suitable for studying the equilibrium size.

Throughout the studies reported here, the distribution of “drug” mass based on aerodynamic measurements will be used. Thus, the appropriate term for describing the size is drug mass median aerodynamic diameter.37 The aerosol can be characterized by this parameter and the width of the distribution, the geometric standard deviation, up.

Experimental Section Preparation of Coated Powders-Powders of disodium fluores-

cein associated with a fatty acid (lauric or capric acid) were prepared by an adsorption coacervation technique. Quantities (0.25 g) of disodium fluorescein were weighed into flasks containing fatty acid dissolved in 25 mL of dichloromethane. After 6 h, 5 mL of chloroform were added to promote the association of the fatty acid with the dye. The total time allowed for equilibration was 72 h.40 The extent of association between the fatty acid and disodium fluorescein was established by gas chromatography and spectrofluorimetry.40 The nominal concentrations of the coating materials relative to fluores- cein refer to the total amounts in the powder; some of the coating material may exist in the free (unadsorbed) form.

Aerosol Generation-The aerosol generator employed was a ver-

0022-3549/90/1100- 1009$0 1 .OO/O 0 7990, American Pharmaceutical Association

Journal of Pharmaceutical Sciences I 1009 Vol. 79, No. 11, November 1990

tical spinning disc device (Nebulet, Nottingham, U.K.) capable of generating small quantities of dry powder. This is a battery operated generator with a small electric motor which drives a rotating disc vertically through the substance (powder, liquid) to be aerosolized. The patient’s breathing, or a n air supply in the laboratory, provide a carrier gas. The device has been described in detail elsewhere.41 The uncoated and coated powders were aerosolized under identical con- ditions.

Particle Size-The Delron DCI-6 cascade impactor (Delron Re- search Products Company, Powell, OH) was employed. This is a vertically oriented, stacked, six-stage instrument. The presence of a filter at the outlet gives the impactor seven levels of measurement of particle size. The nominal cut-off points for each stage, based on 50% collection efficiency, were 11.2, 5.5, 3.3, 2.0, 1.0, 0.5, and 0.2 pm aerodynamic diameter. Situated at each of the stages were silicone fluid-coated glass slides.12

Air was drawn through the apparatus by a vacuum pump at a rate of 12.45 Umin. The glass slides used to collect the aerosol particles were coated with silicone fluid by dropping a 0.2-mL sample of a 10% solution (in benzene) onto the slide and rotating the slide to effect an even coverage. Following deposition of the aerosol, the slides were subjected to an extraction procedure to remove the coating material and the disodium fluorescein. The slides were placed in 5 mL of benzene and sonicated for 5 min. A volume of 5 mL of Sorensen’s glycine buffer, pH 12.0 (AR Grade glycine, Fisons Scientific Appara- tus, Loughborough, UK; sodium hydroxide and sodium chloride, BDH Chemicals Limited, Poole, Dorset, UK), were added to the benzene extracts and to the fiber glass filter from the last stage. These samples were also sonicated for 10 min. The aqueous solution was then filtered (0.22 pm Swinnex, Millipore Corporation, Bedford, MA), diluted, and assayed by spectrofluorimetry (Aminco-Bowman, Type 4-8202) at an emission wavelength of 516 nm and an excitation wavelength of 486 nm. The percentage deposition data obtained by assaying each stage of the cascade impactor was fitted to a theoretical particle size distribution by a computer-assisted iterative technique using a least mean square analysis.1~~42-43 Calibration data for the cascade impac- tor were utilized.12

Controlled Temperature and Relative Humidity Studies- Temperature and relative humidity were kept at 37 * 0.1 “C, and at either 20 * 5% or 96.6 t 1.2% relative humidity. The degree of control required to allow differences in growth ratio to be detected was validated for these studies. 1238 The aerosol, produced by the spinning disc generator, with conditioned carrier air was introduced into the “growth chamber” from which it passed into the cascade impactor. The residence time in the growth chamber was -40 s (equilibrium “growth chamber”vo1ume = 7.85 L, volume flow rate = 12.45 Llmin). Replicate studies were performed on each formulation at each humidity.

Vapor Pressure Osmometry-This technique was employed to derive theoretical growth ratios for aerosol particles based on the water activity of solution droplets. A calibration curve was prepared using solutions of sodium chloride for which water activities were known.44

Six concentrations of disodium fluorescein were used to check the previously obtained data4 and thus validate their use. The additional water activities measured were for the following concentrations: 0.07, 0.14,0.7,1.0, and 1.02 movkg. This information was used to evaluate the data from the direct hygroscopic growth experiments in the impactor (see Appendix for theory).

Dissolution Experiments-A rotating wire-mesh basket method of dissolution, similar to the USP Apparatus l,46 was employed at a stir rate of 50 rpm and temperature of 37 t 0.5 “C. A 200-mL volume of citrate phosphate buffer, pH 7.45,2 was placed in the vessel. Discs of -0.3 gwerepreparedofO.O,O.O7,0.12,0.15,0.2, and0.23 goflauric acid per gram of disodium fluorescein. A second series of experiments using 0.0, 0.06, 0.08, and 0.16 g of capric acid per gram of disodium fluorescein was performed.

The experiment was initiated by lowering the basket containing the powder to -2 cm below the surface of the buffer. Samples were taken using a microsyringe (Hamilton, Melbourne, Australia) at 30-s and 1-min intervals for 9.5 min, then at 12 and 15 min and subsequently every 5 min until total dissolution had occurred. Each 1-mL sample was replaced with buffer from the reservoir. The samples were examined by UV spectroscopy at a wavelength of 420 nm.

Results and Discussion Preparation of Coated Powders-The samples employed

have been identified according to their fatty acid content in Table I.

Particle Size--Figure 1 shows an example of the plot of the particle size on a logarithmic scale against the cumulative percent undersize for a capric acid-coated disodium fluores- cein aerosol powder, using data collected from the cascade impactor. A linear plot on this scale is indicative of a single, log-normal, particle size distribution. This preliminary tech- nique of establishing the unimodality and apparent log- normality of the data is a useful screening method for validity prior to using a computer method.

Controlled Temperature and Relative Humidity Appa- ratu-The results of the best fits, the MMAD, and ug obtained from the experimental data for disodium fluorescein, and lauric acid- and capric acid-coated disodium fluorescein at the two relative humidities are presented in Tables 11-IV. The growth ratio of disodium fluorescein alone at 97% relative humidity is 1.45 4 0.18. Marked reductions in hygroscopic growth of disodium fluorescein occurred with the addition of both lauric and capric acids. The lowest surface coverage at which the reduction in hygroscopic growth occurred was 0.11 g/g for capric acid and 0.2 glg for lauric acid, the growth ratios being 1.07 and 1.0, respectively.

We may hypothesize that the fatty acids could have the following opposing effects: (1) retardation of the rate of hygroscopic growth by formation of a hydrophobic coat around the fluorescein particle or droplet, and (2) increase in the capacity to absorb water in order to form droplets whose vapor pressure is the same as that in the cascade impactor. This latter effect comes about through the lower molecular weight of the fatty acid compared with that of fluorescein (see Appendix). Therefore, we would expect a possible increase in the growth ratio a t low levels of fatty acids due to the “thermodynamic” effect of the dissolved acids, and a reduction in the growth ratio due to the “kinetic” effect of the hydro- phobic acids on the rate of entry of water into the fluorescein particles and droplets. It should be noted that the present experiments are unable to distinguish unambiguously be- tween “kinetic” and “thermodynamic” effects because only a single residence time in the growth chamber was employed. Future studies could employ several residence times in conjunction with more rapid sizing techniques.’

Examination of the lauric acid growth data shows that these samples exhibit a range of effects on hygroscopic growth. The 0.07-g/g sample of lauric acid-coated powder gives a growth ratio of 1.5 which is equal to that of disodium fluorescein alone, within the range of experimental error. The 0.12-glg sample gives a growth ratio of 1.68, suggesting that growth beyond that of disodium fluorescein occurred. This may be due to penetration of the water molecules into the particle with the subsequent “thermodynamic” effects on its hygroscopic growth. The 0.15-g/g sample gives a growth ratio

Table I-Amount of Fatty Acid Associated with Dlsodium Fluorescein Powders.

Amount of Fatty Acid, g/g

Capric Acid Lauric Acid Sample Number

0.08 0.08 0.1 1 0.14 0.16 0.18

0.07 0.12 0.15 0.20 0.24 0.23

a Reference 40.

1010 I Journal of Pharmaceutical Sciences Vol. 79, No. 77, November 7990

Table IV-Effect of Relative Humidity on Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (a ) for Fluorescein Powder Coated with Various Amounts of kapric Acid"

X . O I /

0.01 0.1 10 50 90

C U M U L l T I V E % U N D C l 5 I Z t

Figure 1-Example of a plot of the logarithm of the particle size (pm) against cumulative percentage undersize for capric acid (0.08 gig)- coated disodium fluorescein generated at ambient (20%) relative hu- midity and 37 "C.

Table ICEffect of Relative Humidity on Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (ag) for Uncoated Fluorescein Powder"

Ambientb 3.8 f 0.24 1.5 f 0.13 1.45 f 0.18 HighC 5.5 f 0.60 1.4 f 0.12

a Temperature remained constant at 37.0 f 0.1 "C; n = 4. * 20 f 5%. c97 f 1%.

Table ill-Effect of Relative Humidity on Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (a ) for Fluorescein Powder Coated with Various Amounts of lauric Acid"

Amount of Lauric Relative Mean MMAD Mean ua Growth Ratio Acid, gig Humidity f SD f SD

0.07 Ambientb

0.12 Ambient

0.15 Ambient

0.2 Ambient

0.24 Ambient

0.23 Ambient

HighC

High

High

High

High

High

4.2 f 0.08 1.3 f 0.14 1 S O f 0.04 6.3 f 0.25 1.8 f 0.05 4.1 f 0.18 1.3 2 0.17 1.68 f 0.08 6.9 f 0.15 1.6 f 0.1 4.4 f 0.26 1.3 f 0.05 1.33 f 0.13 5.9 f 0.46 1.6 f 0.17 4.0 f 0.33d 1.4 f 0.05 1 .OO f 0.1 1 4.0 f 0.26d 1.2 f 0.15 4.1 f 0.42 1.4 f 0.05 1.05 f 0.13 4.3 2 0.32 1.6 t 0.15 4.1 * 0.25 1.5 ? 0.08 1.05 f 0.07 4.3 f 0.1 5 1.5 f 0.08

a Temperature remained constant at 37.0 f 0.1 "C; n = 4. 20 f 5%. c 97 +- w0. d n = a.

of 1.33, which suggests a reduction in the growth ratio of disodium fluorescein. Finally, the 0.2-, 0.23-, and 0.24-glg samples eliminated growth over the period that the aerosol was allowed to grow, having growth ratios of 1, within experimental error. The explanation for this range of effects was the presence of too little surfactant a t a concentration of 0.07 g/g to influence the growth ratio of the disodium fluo- rescein and, a t a concentration of 0.12 gig, to prevent the entry of water into the particle. In the latter case, the presence of surfactant effected an increase in the growth of disodium

Amount of Capric Relative Mean MMAD Mean ug Growth Ratio Acid, gig Humidity f SD f SD

0.08 Ambientb

0.08 Ambient

0.1 1 Ambient

0.14 Ambient

0.16 Ambient

0.18 Ambient

HighC

High

High

High

High

High

4.4 f 0.32 5.6 f 0.35 4.4 f 0.36 6.0 f 0.53 4.1 f 0.15 4.4 * 0.13 4.0 f 0.06 4.4 * 0.16 4.2 f 0.17 4.7 f 0.38 4.3 f 0.36 4.4 f 0.10

1.5 2 0.1 1.27 f 0.12 1.8 f 0.29 1.3 f 0.14 1.36 f 0.16 1.6 f 0.08 1.4 f 0.06 1.07 f 0.05 1.2 2 0.06 1.3 2 0.06 1.10 f 0.04 1.4 2 0.15 1.3 f 0.08 1.12 f 0.10 1.2 f 0.13 1.4 * 0.13 1-02? 0.09 1.3 f 0.05

a Temperature remained constant at 37.0 f 0.1 "C; n = 4. 20 f 5%. =97 f 1%.

fluorescein for "thermodynamic" reasons. From studies of the nature of the association between the fatty acids and disodium fluorescein42 it would seem that the sodium salt of the fatty acid is formed upon association with water from the atmo- sphere. The 0.15-glg sample probably reflected a reduction in the rate of hygroscopic growth as a critical value for the surface coverage, with respect to the dominance of "kinetic" over "thermodynamic" factors. The 0.2-, 0.23-, and 0.24-glg samples exhibit a further reduction, and eventual elimina- tion, of hygroscopic growth on the time scale of residence in the impactor.

There was no observed increase in the growth ratio com- pared with uncoated fluorescein when capric acid was used (Table IV). In fact, on a weight basis, capric acid seems to be more effective in reducing the rate of hygroscopic growth than lauric acid; the 0.08-glg samples show a growth ratio of 1.27 and 1.33, respectively. The 0.11-, 0.14-, 0.16-, and 0.18-glg samples exhibit eliminated growth over the period of aerosol equilibration, having growth ratios approaching 1, within the range of experimental error. The selection of two samples with the same (0.08 glg, Table IV) or similar (0.23 and 0.24 g/g, Table 111) fatty acid concentrations was an internal control study. Each of these samples was taken from different points on the adsorption isotherm of fatty acid with disodium fluorescein.40 By examining their hygroscopic growth behav- ior, the possibility of structural differences related to the equilibrium concentration of surfactant in solution was elim- inated. There were no significant differences in the growth ratio of samples taken at similar points of the isotherm, suggesting that the total amount of fatty acid per powder is the important parameter.

Vapor Pressure Osmometry-The use of vapor pressure osmometry as a tool in the prediction of the hygroscopic growth of pharmaceutical aerosol powders has been described in the literature.12.45 A calibration curve using sodium chlo- ride solutions of known water activity (a,)44 at a given temperature was prepared [instrumental response = 1709.4(-1n a,) - 3.611. Using this calibration curve, the instrumental responses obtained for several solutions of disodium fluorescein were converted to water activities and are shown in Table V. These data are plotted in Figure 2 with previously obtained values45 for the same system. These results may be used in conjunction with particle densities to calculate the growth ratio for formulations containing lauric and capric acids, assuming ideal solution behavior as shown in the Appendix. According to these calculations, the maxi- mum (equilibrium) growth ratio with lauric acid would be

Journal of Pharmaceutical Sciences 101 1 Vol. 79, No. 11, November 1990

Table V-Concentrations of Disodium Fiuoresceln Solutions and Respective Water Activities Obtained from the Calibration Curve.

Disodium Fluorescein, mol/kg

~~ ~

Water Activity

0.07 0.14 0.4 0.7 1 .o 1.02

0.9995 0.9988 0.9938 0.9829 0.9673 0.9658

* n = 3.

0 1 2 3

M D L I L I T ~ I M D L ~ ~ K;')

Figure 2-Water activity (a,.,) of aqueous disodium fluorescein solution versus concentration (mollkg) showing current (0) and previous (0) data (ref 45).

-1.47 a t the highest concentration of the acid used. However, because the rate of growth is inhibited at this high coverage, the highest growth ratio observed experimentally is 1.68 2 0.08 a t the lauric acid concentration of 0.12 g/g. The expected equilibrium growth ratio would be a little less a t this coverage (1.46). This discrepancy is reasonable in view of the low precision of growth ratio of uncoated fluorescein. The maxi- mum growth ratios for capric acid (0.18 g/g) would be 1.48. Because of the inhibition of the growth rate, the maximum growth ratio found experimentally was -1.3 a t 0.08 g/g. This indicates that capric acid-coated powders do not equilibrate in the dynamic growth measurement experiments.

Dissolution Experiments-The purpose of these studies was to investigate the possibility that reduced hygroscopic growth might be reflected in retarded dissolution. It is also important that once an aerosol deposits in the respiratory tract the active ingredient is released and available for absorption, or for local action, in order t o achieve its thera- peutic effect. In vitro dissolution of aerosol particles has been correlated with in vivo dissolution in the lower respiratory tract after inhalation.47 It would be difficult to examine the dissolution of the coated disodium fluorescein particles since the size and wetting properties lead to floating if directly added to an aqueous medium. By preparing compacts of the powder, the dissolution becomes a function of the surface area and mass of the compact, as well as those factors attributable to the original powder. However, by comparing the dissolution of disodium fluorescein alone with the coated powders, this technique might indicate differences attributable to coating.

The trend in the lauric acid samples, shown in Figure 3, was towards a slower dissolution with increased surface coverage. The most marked reduction occurred between consecutive

I

< x

0 10 20 30 40 50

c T I M E ~ ~ I N U T C S I

Figure 3-Dissolution of lauric acid-coated disodium fluorescein pow- ders prepared as compacts. The concentrations (g/g) of lauric acid employedwere:0(0);0.07(0);0.12(V);0.15 (V);0.2(@);and0.23(~).

samples taken from lauric acid isotherms a t 0.12 and 0.15 g/g which exhibited reduced growth in dynamic growth experi- ments. Capric acid shows similar reductions in the rate of dissolution (Figure 4).

Observations of both increased and reduced hygroscopic growth of aerosols have been commented on by Martin et a1.39 Otanyi and Wang27.28 have carried out aerosol growth studies using saline droplets with surfactant; the surfactant used was cetyl alcohol. The growth rate of the surfactant-covered droplets following the initial period was slightly faster than that of the droplets in the absence of the surfactant. The equilibrium droplet size was, however, the same for both the surfactant-coated and uncoated sarnples.z*

Chikazawa et a1.26 measured the amounts of adsorbed water and the isosteric heats for water vapor adsorption on fine crystals of potassium bromide treated with various amounts of potassium oleate. A small amount of pre-adsorbed potassium oleate prevented water adsorption on potassium bromide. Conversely, this effect disappeared with increasing

0 10 t o

T X M C ( n I N U T L I )

Figure 4-Dissolution of capric acid-coated disodium fluorescein pow- ders prepared as compacts. The concentrations (glg) of capric acid employed were: 0 (0); 0.06 (0); 0.08 (+); and 0.16 (@).

101 2 I Journal of Pharmaceutical Sciences Vol. 79, No. 11, November 1990

potassium oleate content, while the hygroscopicity of the sample increased markedly. The increase in hygroscopicity was explained by assuming penetration of the adsorbed water molecules into potassium oleate films on the surface of the potassium bromide. Other authors47 also suggest that this may occur. Note, however, that the relative molecular weights of the compounds also affect the capacity for water uptake (hygroscopicity), as shown in the Appendix.

The publication describing potassium bromide is of some significance in the interpretation of the aerosol hygroscopic growth studies presented here and of the physicochemical analyses of the coated powders.42 It has been suggested42 that these powders may be coated with sodium salts of fatty acids formed at the surface of the disodium fluorescein by the presence of the free fatty acid. This would seem to suggest some similarity to the system of Chikazawa and co-workers.26 The observed reduction in growth with increased surface coverage of disodium fluorescein with fatty acids, although contradicting the observations of Chikazawa et al., are not entirely inconsistent with them. The time scale of the gen- eration of the aerosol powders may not be long enough to allow the coated powders to equilibrate with the environment and, as a consequence, the growth appeared to be reduced. This follows the pattern of initially retarded growth observed by Otanyi and Wang.27.28 If all of the powders were allowed adequate time to equilibrate, then some similarity to the observations of Chikazawa et a1.26 might be expected. There is some evidence for this conclusion in the behavior of the 0.12-g/g lauric acid sample.

Conclusions Disodium fluorescein powder coated with lauric or capric

acids was generated in an environment of controlled temper- ature and relative humidity. The hygroscopic growth was reduced or eliminated over the period prior to deposition in the cascade impactor in all but one case. The reduction in growth is paralleled by a reduction in in vitro rate of dissolution from compacts of these coated powders.

The control of hygroscopic growth may be employed to develop desirable deposition characteristics and thus enhance the therapeutic effect of a drug. These studies also indicate that targeting drugs by controlling their hygroscopic growth may be a possibility in the future.

Appendix This section is a theoretical treatment of the effect of dissolved

excipients on the hygroscopic growth ratio of a drug. This theory assumes that equilibrium is attained between the surrounding atmosphere and the droplets of the composite .solution.

Consider a droplet of solution containing nD moles of drug which can give rise to k species (i.e., ions assuming complete ionization) and nE moles of excipients giving rise to 1 Bpecies. The osmolality of the solution, c (osmolkg) will be:

where g, is the mass of the solvent in the droplet in grams. The number of moles can be calculated from the mass of the drug, g,, or excipient, g,, and their molecular weights, MD and ME, respectively:

g D g E n D = -and n E = -

M D M E

The droplet weight is G

(A2)

The ratio of excipients to drug mass is expressed as follows:

(A41

(A51

Therefore:

From eqs A1 and A2, the following relationship is derived:

Therefore; eq A6 becomes:

(A71

The diameter of the droplet, D, is:

I-

D = (A91

where pc is the density of the droplet solution. The diameter of the original particle, d, is:

where ps is the mean density of the solid consisting of the drug and the excipient.

The growth ratio (GR) of the droplet relative to the diameter of the initial dry particle is:

Substituting for GlgD from eq AS we obtain:

In the dynamic growth experiments, the growth ratio (GR,J is measured in terms of aerodynamic diameters of the droplet (D,) and the solid particle (d,,). Ignoring the slip correction factor,Iz the following relationships can be written:

DA = D G a n d d a = D G (A131

Journal of Pharmaceutical Sciences I 1013 Vol. 79, No. 11, November 1990

Table VCCalculated Growth Ratlo (GRJ of Aerodynamic Dlameters of Droplets Origlnatlng from Dry Partlcles Contalning Various Ratlor (R) of Fatty Acid:Fluorescelnd

Additive:Fluorescein R GR,”

None:F Lauric acid:F

Capric acid:F

0 0.05 0.10 0.15 0.20 0.25 0.05 0.10 0.15 0.20 0.25

1.45 1.454 1.458 1.461 1.465 1.468 1.458 1.465 1.471 1.476 1.482

~~

a Calculated using eq A14, with pc = 1 g/cm3, ps = 1.49 g/cm3, k = 3, M, = 376.3,l = 2, R = 0.00-0.25, ME = 200.31 (lauric acid) or 172.26 (capric acid), and c = 2.9296 osmol/kg.

Therefore:

In the dynamic growth experiments, a mean GR, of 1.45 was found for the uncoated fluorescein powder. Taking k = 3, 1 = R = 0, MD = 376.3, pr = 1 g/cm3, and pa = 1.49 g/cm3,’s we obtain c = 2.9296 osrnol/kg. In other words, if we assume equilibration of the vapor pressure of the droplet at the relative humidity of the dynamic growth experiments (97%), then the fluorescein solution of osmolality 3.072, ormolality, (m = c/k = c/3) 0.977 mol/kg, should have a water activity, a,, of 0.97 (relative humidity = 100 x a,).12 This is indeed so, as shown in Table V. In view of the large particle and droplet size, the Kelvin effect was ignored in these calculations.

We assume for simplicity that the fatty acids, when dissolved, will contribute to the water activity in the same colligative fashion as the fluorescein molecules, except that the number of ions for each fatty acid molecule, I , is two. This is equivalent to the approximation that the deviation from ideality, caused by the fatty acid ions, will be the same as the deviation of fluorescein solutions of the same osmolality. Then, the osmolality of the droplets containing the fatty acids which would equil- ibrate at relative humidity of 97% would also be c = 3.072 osmolflrg.

Further, it can be assumed that neither the solution, nor the composite solid, will have densities much different from the pure fluorescein. With these assumptions, the growth ratio GR, for various compositions offatty acid and fluorescein can be calculated from equation A14 (Table W. It can be seen that the presence of the fatty acids can actually increase the growth ratio when compared with the uncoated powder if the equilibrium cornpition of the solution is attained (i.e., the “thermodynamic” effect of the excipient applies). Note that a greater increase in the growth ratio in the preaence of the fatty acids would be observed at higher relative humidities because the value of the equilibrium osmolality in eq A14 would be lower.

1. 2.

3. 4.

5. 6.

7. 8.

9. 10.

11.

References and Notes Morrow. P. E. Phvsiol. Rev. 1986.66.330-376. Diem, K., ScientEfic Tables, Sixth ed., Geigy Pharmaceutical: Ardslev, U.K., 1968. Ferroi,G. A. J. Aerosol Sci. 1983.14, 196199. Sundarajan, A. R.; Mitra Gotri, D. S.; Mukunda Rao, S. R. J . Nucl. Sci. Technol. 1982,19, 151-157. Martonen. T. B. Bull. Math. Biol. 1982,44, 425-442. Martonen, T. B.; Patel, M. J . Toxicol. Environ. Health 1981, 8,

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Acknowledgments The authors wish to recognize the contribution of Dr. C. V..Groom

in the initial stages of this work. We wish to ex rees our gratitude 40 Drs. A. F.A. El Khalik, A.R. Clarke, and $.R. Byron for their assistance, and to Hilal Malem for the extended loan of the Nebulet vertical spinning disc aerosol generator. This work was sup rted by a Science and Engineering Research.Counci1 Co-o erative rward in Science and Engineering in conjunction with I. C. f. plc, Pharmaceu- ticals Division.

101 4 / Journal of Pharmaceutical Sciences Vol. 79, No. 1 1, November 1990