The chemical structures of the tested drugs (Cl, Pr and Vi) are presented in Figure 1. Photographs of an undoped porous silica xerogel and a Pr-doped silica matrix are shown in Figure 2(a). The cylindrical xerogels obtained after doping with drug molecules remained unbroken and without visual inhomogeneities.

Two important aspects in the design and testing of a delivery system is whether or not the drug molecule can be detected in the carrier matrix and whether or not there is interaction between the two. In the present work, the gels were first examined to determine the best method of detecting the absorbed species. The assignments of the Raman bands observed for SiO₂ xerogel, in Figure 2(b), are presented in Table 1. Of these bands, those around 430, 490 and 600 cm^–1 assigned to the network Si-O-Si bending vibration, and to the symmetric stretching modes of Si-O bonds in 4- and 3-membered silica rings, respectively, are the most important signals of the silica matrix. In the micro-Raman spectra of Figure 2(c), test results obtained using primaquine diphosphate before (A) and

after (B) doping are presented. These spectra, obtained with an excitation at 632.8 nm, show the fluorescence interference often encountered with colored samples. However when excited with UV excitation at 266 nm, the spectrum (C) shows a fluorescence-free signal, which unfortunately can be assigned uniquely to carbon thus demonstrating that the high laser energy resulted in a calcination of the samples. Using the characteristic vibrational frequencies for Pr which are presented in Table 2, it can be seen that in spite of the fluorescence, all the bands characteristic of Pr are detected in the doped gel (spectrum B of Figure 2(b)). In the region of 463 cm^–1, one can see the contribution of the Si-O-Si matrix. The fact that no frequency changes are observed between A and B, indicates that there is no interaction between Pr and SiO₂. As the molecule is not affected by the matrix, when it is released, it will still be in its normal active form.

In a similar way, the spectrum of Cl-Si, in Figure 2(d), shows bands characteristic of Cl (See Table 3: 1008, 1161 and 1460 cm^–1). In this case, as the drug is colorless, there is no problem with fluorescence and the spectrum of the gel is clearly obvious (430, 492 and 815 cm^–1). Similarly, Vi could be identified in the spectra of Vi-Si samples.

These data show that micro-Raman spectroscopic investigation of doped silica matrices can detect the presence of doping species and can also indicate whether or not there is an interaction between the carrier matrix and the drug molecule. Obviously, an interaction would imply a structural modification of the drug molecule and hence a possible change in its mechanism of interaction.

The porosity of the drug-incorporated matrix also plays an important role in release kinetics. For determination of the texture (porous volume, pore size distribu-

Table 1. Assignments of Raman bands of silica xerogel.

Table 2. Assignments of Raman bands of primaquine diphosphate powder.

Table 3. Assignments of Raman bands of clotrimazole powder.

tion and pore interconnection), the nitrogen adsorptiondesorption technique was used. The shape of the adsorption-desorption isotherms and the type of hysteresis loops were described using the Brunauer et al. model and the de Boer correlations, respectively [12,13]. The specific surface areas were determined using the Brunauer-Emmett-Teller (BET) method [14]. The pore-size distributions were thus given by the Barett-Joyner-Hal-enda (BJH) formula which determines the derivative of the desorbed volume as a function of the pore diameter [15]. For the following sections, only results concerning primaquine diphosphate will be presented.

As can be seen in Figure 3(a), the isotherms for undoped and Pr-doped xerogels show reversible sections at low pressures and hysteresis loops at higher pressures. These loops of the type IV isotherms are characteristic of mesoporous samples with interconnected pores. Com-

parison of the two curves shows an increase in total pore volume after doping with Pr (from 0.62 (SiO₂) to 0.94 cm³×g^–1 (Pr-Si)). The corresponding specific surface area increases from 375 to 671 m²×g^–1. Determination of the pore diameters shows that the mean pore diameter (Figure 3(b)) decreases with doping, from 6 nm for SiO₂ to 4.7 nm for Pr-Si.

These results demonstrate that the doping has a marked effect on the porous structure of this carrier matrix. Remembering that these materials are porous gels and not glasses, the data suggest that during post-doping, the gel behaves like a sponge, with inflation of pore volume and specific surface. The apparent decrease in pore size after doping could be due to the occupation of space within the pores by the primaquine diphosphate molecules, which would limit access of the infiltrating nitrogen gas.

Another important aspect of these results is that these porous gels can be adapted to the use with a multitude of drug molecules. For, as the carrier pores apparently expand during soaking procedures, it can be deduced that the size of the matrix pores does not pose rigid limitations on the size of the molecules to be inserted.

Release properties of the SiO₂ matrix were studied by soaking the Pr-doped gels in distilled water in order to test the discharge of the drug molecules into the surrounding liquid. In order to quantify the amount of drug eluted, UV-visible absorption spectra were first measured for standard solutions of primaquine diphosphate in order to establish a Beer-Lambert curve (See Figure 4(a)).

UV-visible absorption spectra were then measured of the liquid used for soaking the samples at various times up to 10 days of elution (Figure 4(b)). The drug release pattern for Pr-Si, presented in Figure 4(c), shows a biphasic behavior. There is an initial “burst” of 3.5 mg per gram of SiO₂ gel, released on the first day. The amount of primaquine diphosphate molecules diffused from the gel decreases to 0.40 mg per gram of SiO₂ gel after 4 days. A sustained diffusion of this amount of primaquine continues up to 10 days.

As the samples were consistently washed before elution measurements, all molecules released were issue of the inner pores of the xerogel, not from its surface. The decreased rate of diffusion of the drug from the matrix with time might be due to the lesser driving force for diffusion which is proportional to the availability of entrapped drug molecules.

In general, in the case of an insoluble porous carrier, in which the release is governed by diffusion of the drug from the matrix, release kinetics follows a conventional Higuchi relationship (variation of drug vs. square root of time). Accordingly, the plot of Figure 4(d) shows a two-step release profile. Since our Raman studies have shown that there are no chemical interactions between the drug and the matrix, this behavior must be attributed to physical entrapping and the elution is, in fact, therefore diffusion controlled.

These release properties show that a porous silica matrix can be effectively post-doped by immersion in a drug solution. Moreover, the resulting systems act as effective carriers for drug delivery making it possible to maintain a sustained release of the drug molecules.