Control Of Diameters Of Microspheres

According to Table 1, for any medical applications tailoring of diameters of biodegradable particles would be of great importance. We noticed that the size

FIG. 4 SEM image of poly(d,d + l,l-lactide) microspheres. Dn = 2.71 |lm, Dw/Dn = 1.03. Conditions of polymerization: [d,d + l,l-lactide]0 = 0.28 g/L, [stannous octoate]0 = 5.0 X 10-3 mol/L, P(DA-CL) 1.6 g/L [Mn(CL)/Mn(DA-CL) = 0.25], 1,4-dioxane/heptane (1:4 v/v) medium, polymerization temperature 95°C, time of polymerization 2 h.

FIG. 4 SEM image of poly(d,d + l,l-lactide) microspheres. Dn = 2.71 |lm, Dw/Dn = 1.03. Conditions of polymerization: [d,d + l,l-lactide]0 = 0.28 g/L, [stannous octoate]0 = 5.0 X 10-3 mol/L, P(DA-CL) 1.6 g/L [Mn(CL)/Mn(DA-CL) = 0.25], 1,4-dioxane/heptane (1:4 v/v) medium, polymerization temperature 95°C, time of polymerization 2 h.

of microspheres is related to the initial monomer and initiator concentrations. Smaller microspheres could be obtained by stopping dispersion polymerization of lactide at the earlier stages. For example, for polymerizations l,l-lactide with initial monomer concentration equal 0.29 mol/L, initiated with 2,2-dibutyl-2-stanna-1,3-dioxepane ([2,2-dibutyl-2-stanna-1,3-dioxepane]0 = 8.0 x 10-3 mol/ L), diameters of microspheres formed at monomer conversion 90%, 71%, and 31% were 2.55, 2.37, and 1.76 pm, respectively. The increased initial initiator concentration also leads to particles with smaller diameters. Polymerization of lactide with the same initial monomer concentration as in experiments described above ([l,l-lactide]0 = 0.29 mol/L) but with much higher concentration of initiator ([2,2-dibutyl-2-stanna-1,3-dioxepane]0 = 1.02 x 10-2 mol/L) yielded particles with Dn = 1.14 pm even for monomer conversion exceeding 99% [51].

Whereas synthesis of poly(lactide) particles with diameters ranging from about 1 to 4.0 pm was rather easy and could be accomplished by proper adjustment of monomer and initiator concentrations, obtaining larger particles during polymerization posed considerable difficulties. It is well known that radical dispersion and/or emulsion polymerizations with lower concentrations of surfactants (added or produced in situ) often yield microspheres with larger diameters. This is due to aggregation of the less stabilized primary particles at the earlier stages of the polymerization. A similar phenomenon has also been observed for dispersion polymerization of l,l-lactide ([l,l-lactide]0 = 0.278 mol/L) initiated

FIG. 5 Dependence of diameter polydispersity of poly(l,l-lactide) microspheres and percent of poly(l,l-lactide) in form of microspheres on concentration of poly(dodecyl acrylate)-g-poly(e-caprolactone) (P(DA-CL)) surfactant. Conditions of polymerization: [l,l-lactide]0 = 0.277 mol/L, [stannous octoate]0 = 4.9 X 10-3 mol/L, 1,4-dioxane/heptane (1:4 v/v) medium, polymerization temperature 95°C, time of polymerization 2 h. (Based on data from Refs. 44 and 50.)

FIG. 5 Dependence of diameter polydispersity of poly(l,l-lactide) microspheres and percent of poly(l,l-lactide) in form of microspheres on concentration of poly(dodecyl acrylate)-g-poly(e-caprolactone) (P(DA-CL)) surfactant. Conditions of polymerization: [l,l-lactide]0 = 0.277 mol/L, [stannous octoate]0 = 4.9 X 10-3 mol/L, 1,4-dioxane/heptane (1:4 v/v) medium, polymerization temperature 95°C, time of polymerization 2 h. (Based on data from Refs. 44 and 50.)

with stannous octoate ([stannous octoate]0 = 4.9 x 10-3 mol/L). Figure 6 shows that for polymerizations with concentration of P(DA-CL) decreasing from 1.6 g/L to 0.1 g/L the diameters of microspheres CDn) increased to 4.8 pm. Unfortunately, as follows from Fig. 5, in polymerizations with lower concentrations of surfactants the fractions of polymer in the form of microspheres significantly decreases, making such approach somewhat impractical.

It has been noted that with increased monomer conversion diameters of microspheres increased gradually [51]. Thus, it was reasonable to expect that for higher initial monomer concentrations it might be possible to obtain larger particles. Unfortunately, limited solubility of l,l-lactide in 1,4-dioxane/heptane (1:4 v/v) mixture (maximal concentration about 0.35 mol/L) did not allow for this apparently straightforward approach. The above-mentioned problem has been solved by a stepwise monomer addition to the polymerizing mixture [52]. The first step was carried out with initial l,l-lactide concentration equal 0.35 mol/L ([stannous_octoate]o = 5.70 x 10-3 mol/L, [poly(DA-CL)] = 1.67 g/L, (P(DA-CL) with Mn(CL)/Mn(DA-CL) = 0.18). After 1.5 h a new monomer portion was added, making the overall concentration of introduced lactide equal to 0.624

FIG. 6 Dependence of diameters of poly(l,l-lactide) microspheres and percent of poly-(l,l-lactide) in form of microspheres on concentration of poly(dodecyl acrylate)-^-poly(e-caprolactone) [P(DA-CL)] surfactant. Conditions of polymerization: [l,l-lactide]0 = 0.277 mol/L, [stannous octoate]0 = 4.9 X 10-3 mol/L, 1,4-dioxane/heptane (1:4 v/v) medium, polymerization temperature 95°C, time of polymerization 2 h. (Based on data from Refs. 44 and 50.)

FIG. 6 Dependence of diameters of poly(l,l-lactide) microspheres and percent of poly-(l,l-lactide) in form of microspheres on concentration of poly(dodecyl acrylate)-^-poly(e-caprolactone) [P(DA-CL)] surfactant. Conditions of polymerization: [l,l-lactide]0 = 0.277 mol/L, [stannous octoate]0 = 4.9 X 10-3 mol/L, 1,4-dioxane/heptane (1:4 v/v) medium, polymerization temperature 95°C, time of polymerization 2 h. (Based on data from Refs. 44 and 50.)

mol/L. A third portion of l,l-lactide was added, raising the concentration of introduced monomer to 0.90 mol/L. After each step a sample of polymerizing mixture was withdrawn and diameters of microspheres were determined from the SEM images. Figure 7 shows relations between the number averaged diameters and volumes of microspheres and the total monomer concentration after each step. The average volume of microsphere was calculated using the following equation:

In Eq. (1), N denotes number of microspheres in the analyzed SEM picture. Indeed, according to Fig. 7, Dn increased following each monomer addition, reaching a value 6.36 pm. It is also worth noting that the dependence of the average volume of microspheres (Vn) on total monomer concentration could be represented by a straight line. This suggests that each new added monomer portion was converted to polymer in the already existing particles, without lead-

FIG. 7 Dependence of the number averaged diameters and volumes of poly(l,l-lactide) microspheres and total concentration of added monomer. Conditions of polymerization: [stannousoctoate]0 = 5.70 X 10-3 mol/L, [poly(DA-CL)] = 1.67 g/L, [P(DA-CL) with Mn(CL)/Mn(DA-CL) = 0.18]. (Based on data from Ref. 52.)

FIG. 7 Dependence of the number averaged diameters and volumes of poly(l,l-lactide) microspheres and total concentration of added monomer. Conditions of polymerization: [stannousoctoate]0 = 5.70 X 10-3 mol/L, [poly(DA-CL)] = 1.67 g/L, [P(DA-CL) with Mn(CL)/Mn(DA-CL) = 0.18]. (Based on data from Ref. 52.)

ing to formation of new ones. Taking into account this assumption, the dependence of Dn on total concentration of l,l-lactide introduced into polymerizing mixture [(l,l-lactide)0] was fitted with the function Dn = aV[l,l-lactide]0 - b reflecting a linear dependence of Vn on [l,l-lactide]0. Both lines, for Dn and Vn, intersected abscissa at a concentration of l,l-lactide equal to 0.18 mol/L. Therefore, below this monomer concentration microspheres apparently could not be formed. Polymerization of lactides is a reversible process; even after long polymerization times residual monomer was always detected in polymerizing systems (regardless of whether polymerizations were carried out in solution or in dispersion). It is worth noting that the equilibrium monomer concentration evaluated from dependencies of Dn and Vn on [l,l-lactide]0 was close to the value found in separate studies in which the remaining monomer concentration was measured by GPC (0.14 mol/L) [43,44]._

From the slope of the dependence of Vn on [l,l-lactide]0 it was also possible to estimate concentration of microspheres in polymerizing mixture expressed as number of particles per liter of suspension. From mass balance it follows that nd(yn)dpoly(LWactide) = FWL,L-lactide d([l,l-lactide]0)1012

where N denotes number of microspheres, d(Vn) change of the average volume of microsphere (in pm3), dpoiy(L,L-iactide) density of polymer (1.25 and 1.28 g/cm3 for amorphous and crystalline poly(l,l-lactide), respectively), FW^L-Me formula weight for monomer (144.13), d([l,l-lactide]0) change of monomer conversion, and coefficient 1012 is due to unification of units. Rearrangement of Eq. (2) gives

in which d(Vn)/d([l,l-lactide]0) is a slope in the Vn _/([l,l-lactide]0) plot.

This slope was equal to 220 pm3 • L/mol (cf. Fig. 7), and taking the density of poly(l,l-lactide) at 1.28 g/cm3 the concentration of microspheres in the above-described three-step polymerization was estimated at 5.24 x 1011 parti-cles/L.

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