The Effect of Polymeric Excipients on the Physical Properties and Performance of Amorphous Dispersions: Part I, Free Volume and Glass Transition

Abstract

Purpose

To investigate the structural effect of polymeric excipients on the behavior of free volume of drug-polymer dispersions in relation to glass transition.

Methods

Two drugs (indomethacin and ketoconazole) were selected to prepare amorphous dispersions with PVP, PVPVA, HPC, and HPMCAS through spray drying. The physical attributes of the dispersions were characterized using SEM and PXRD. The free volume (hole-size) of the dispersions along with drugs and polymers was measured using positron annihilation lifetime spectroscopy (PALS). Their glass transition temperatures (Tgs) were determined using DSC and DMA. FTIR spectra were recorded to identify hydrogen bonding in the dispersions.

Results

The chain structural difference-flexible (PVP and PVPVA) vs. inflexible (HPC and HPMCAS)-significantly impacts the free volume and Tgs of the dispersions as well as their deviation from ideality. Relative to Tg, free volume seems to be a better measure of hydrogen bonding interaction for the dispersions of PVP, HPC, and HPMCAS. The free volume of polymers and their dispersions in general appears to be related to their conformations in solution.

Conclusions

Both the backbone chain rigidity of polymers as well as drug-polymer interaction can impact the free volume and glass transition behaviors of the dispersions.

Appendix

Specific Volume and Fractional Free Volume from P-V-T [24, 26]

After simplification, the SS equation of state can be expressed as the following:

$$ V\left( p, T\right)={V}^{*}* exp\left({a}_0+{a}_1{\left(\frac{T}{T^{*}}\right)}^{\frac{3}{2}}+\left(\frac{p}{p^{*}}\right)\left[{a}_2+\left({a}_3+{a}_4\left(\frac{p}{p^{*}}\right)+{a}_5{\left(\frac{p}{p^{*}}\right)}^2\right)*{\left(\frac{T}{T^{*}}\right)}^2\right]\right) $$

(1)

Where a₀ = 0.0921, a₁ = 4.892, T*, P*, and V* are the conditions at the material’s critical point. The data shown is found using a Tate extrapolation to 0 MPa, allowing the reduction of the above equation to

$$ \ln \left(\mathrm{V}\right)= \ln \left({V}^{*}\right)-{a}_0+{a}_1*{T}^{\frac{3}{2}}*{\left(\frac{1}{T^{*}}\right)}^{\frac{3}{2}} $$

(2)

Occupied volume, V_occ, was calculated using the following equation where y_occ is the occupied fraction, $\overset{\sim }{P},\overset{\sim }{T}$, and $\overset{\sim }{V}$ are reduced parameters:

$$ \overset{\sim }{P}=\frac{P}{P^{*}}\kern0.5em \overset{\sim }{T}=\frac{T}{T^{*}}\kern1em \overset{\sim }{V}=\frac{V}{V^{*}} $$

$$ \frac{\overset{\sim }{P}\overset{\sim }{T}}{\overset{\sim }{V}}={\left[1-\mathrm{y}*{\left({2}^{\frac{1}{2}}*{\mathrm{y}}_{occ}*\overset{\sim }{V}\right)}^{\frac{1}{3}}\right]}^{-1}+\frac{{\mathrm{y}}_{occ}}{\overset{\sim }{T}}\left[2.002*{\left({\mathrm{y}}_{occ}*\overset{\sim }{V}\right)}^{-4}-2.409*{\left({\mathrm{y}}_{occ}*\ \overset{\sim }{V}\right)}^{-2}\right] $$

(3)

$$ {V}_{occ}={V}_{sp}*{y}_{occ} $$

(4)

Fractional free volume, FFV, can be calculated using:

$$ FFV=1-{y}_{occ} $$

(5)