Aggregate Elasticity, Crystal Structure, and Tableting Performance for p-Aminobenzoic Acid and a Series of Its Benzoate Esters

Abstract

The tableting performance for p-aminobenzoic acid (PABA) and a series of its benzoate esters with increasing alkyl chain length (methyl-, ethyl-, and n-butyl) was determined over a broad range of compaction pressures. The crystalline structure of methyl benzoate (Me-PABA) exhibits no slip systems and does not form viable compacts under any compaction pressure. The ethyl (Et-PABA) and n-butyl (Bu-PABA) esters each have a similar, corrugated-layer structure that displays a prominent slip plane and improves material plasticity at low compaction pressure. The compact tensile strength for Et-PABA is superior to that for Bu-PABA; however, neither material achieved a tensile strength greater than 2 MPa over the compression range studied. Complementary studies with powder Brillouin light scattering (BLS) show the maxima of the shear wave, acoustic frequency distribution red shift in an order consistent with both the observed tabletability and attachment energy calculations. Moreover, zero-porosity aggregate elastic moduli are determined for each material using the average acoustic frequency obtained from specific characteristics of the powder BLS spectra. The Young's moduli for Et- and Bu-PABA is significantly reduced relative to PABA and Me-PABA, and this reduction is further evident in tablet compressibility plots. PABA, however, is distinct with high elastic isotropy as interpreted from the narrow and well-defined powder BLS frequency distributions for both the shear and compressional acoustic modes. The acoustic isotropy is consistent with the quasi-isotropic distribution of hydrogen bonding for PABA. At low compaction pressure, PABA tablets display the lowest tensile strength of the series; however, above a compaction pressure of ca. 70 MPa PABA tablet tensile strength continues to increase while that for Et- and Bu-PABA plateaus. PABA displays lower plasticity relative to either ester, and this is consistent with its crystalline structure and high yield pressure determined from in-die Heckel analysis. Overall the complementary approach of using both structural and the acoustic inputs uniquely provided from powder BLS is anticipated to expand our comprehension of the structure-mechanics relationship and its role in tableting performance.

Crystallographic and spectroscopic assessment of pharmaceutical material mechanics

“…For ethyl-and butyl-PABA those planes that bisected the oblique layers were found to have the lowest absolute attachment energies. 112 Assuming similar slip planes are operative for Me-, Cl-and Br-NBA, the lowest Py for Me-NBA is consistent with lack of any specific intermolecular interactions that connect oblique layers and thereby facilitating potential slip activation. Alternatively, for Br-NBA both C-H … O hydrogen bonds and Br … O short contacts act to stabilize oblique layers and subsequently increase Py.…”

“…For our studies, two interferometer mirror spacing values were required to clearly identify νL,max, νsep and νT,min, which are the characteristic frequencies used in our previous studies to calculate the aggregate elastic moduli. 112 which corresponds to stiffness along the c-axis, is considerably higher relative to the stiffness in the ab-crystallographic plane, as reflected by the lower C11 and C22 values. 118 The powder BLS spectrum, obtained at a 3 mm mirror spacing, is qualitatively similar to that displayed for 3-NBA, with both showing a clear, high-frequency tailing of the longitudinal frequency distribution.…”

“…Powder BLS was used to determine the aggregate elastic moduli for all NBA materials using our previously reported analysis of the powder BLS characteristic frequencies. 112 The BLS setup used for this study was reported in the previous chapters. The mirror spacing of the interferometer can be adjusted to tune the free spectral range (FSR) for clearly identifying all three characteristic frequencies of the powder BLS spectra.…”

“…For those materials with a quasi-isotropic distribution of intermolecular interaction strength, we expect an acoustic frequency distribution that resembles that displayed by polystyrene or PMMA, both amorphous materials. 64,112 For an elastically isotropic material, the scattering intensity rises sharply near νL,max to a peak intensity, followed by a decrease in intensity until νsep. The powder BLS spectrum for acetylsalicylic acid has been previously reported and qualitatively demonstrates similar features to that for Cl-and Br-NBA.…”

“…Similar features for observed for paraben esters in another study. 112 CAF: F-NBA by its layered structure is susceptible to slip. This direction is associated with weakest intermolecular interactions in its crystal structure and this is reflected in a lower νT,min relative to CAF and FNBA.…”