Caffeine Co-Crystal Mechanics Evaluated with a Combined Structural and Spectroscopic Approach

In this report caffeine (CAF) co-crystallization with a fluoro-nitrobenzoic acid (F-NBA) yields a new solid form with superior tableting performance. A primary N···H–O synthon connects the basic nitrogen of CAF with the carboxylic acid of F-NBA to result in a layered structure with supportive CH₃···O interactions. Over the entire compaction pressure range of nominally 50–300 MPa, the co-crystal displayed improved tensile strength relative to the individual co-formers that demonstrated tensile strengths consistently below 2 MPa. Qualitatively we interpret this tableting improvement for the co-crystal a result of increased plasticity manifested from the layered co-crystal structure, an observation consistent with previous co-crystal studies on modified material mechanics that suggest facile slip plane activation supports improved tableting. Powder Brillouin light scattering (BLS) is further introduced as a novel tool to rapidly evaluate elastic anisotropy to complement our structural interpretation of tableting performance. Each powder BLS spectra revealed two acoustic frequency distributions that we assign as longitudinal and transverse and permits rank-order of the elastic anisotropy. The shear mode distribution revealed an increasing population of low-velocity modes that mirrored the rank-order tableting performance of CAF:F-NBA > CAF > F-NBA. With further experimental support, we anticipate powder BLS may be utilized as a complementary tool to quantify and discriminate the mechanical properties of co-crystals and polymorphs for relation to their processing performance

Aggregate Elasticity, Crystal Structure, and Tableting Performance for <i>p</i>‑Aminobenzoic Acid and a Series of Its Benzoate Esters

The tableting performance for <i>p</i>-aminobenzoic acid (PABA) and a series of its benzoate esters with increasing alkyl chain length (methyl-, ethyl-, and <i>n</i>-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 <i>n</i>-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

Compression–decompression modulus (CDM) – an alternative/complementary approach to Heckel’s analysis

The novel modulus-based approach was developed to characterize the compression behavior of the materials and how it results into tablet mechanical strength (TMS) of the final tablet. The force–displacement profile for the model materials (Vivapur® 101, Starch 1500®, Emcompress®, and Tablettose® 100) was generated at different compression pressures (100, 150, and 200 MPa) and speeds (0.35, 0.55, and 0.75 m/s) using compaction emulator (Presster™). A generated continuous compression profile was evaluated with Heckel plot and the proposed material modulus method. The computed compression parameters were qualitatively and quantitatively correlated with TMS by principal component analysis and principal component regression, respectively. Compression modulus has negatively correlated, while decompression modulus is positively correlated to TMS. Proposed modulus descriptors are independent of particle density measurements required for the Heckel method and could overcome the limitations of the Heckel method to evaluate the decompression phase. Based on the outcome of the study, a two-dimensional compression and decompression modulus classification system (CDMCS) was proposed. The proposed CDMCS could be used to define critical material attributes in the early development stage or to understand reasons for tablet failure in the late development stage.</p

Factorial Design Based Multivariate Modeling and Optimization of Tunable Bioresponsive Arginine Grafted Poly(cystaminebis(acrylamide)-diaminohexane) Polymeric Matrix Based Nanocarriers

Desired characteristics of nanocarriers are crucial to explore its therapeutic potential. This investigation aimed to develop tunable bioresponsive newly synthesized unique arginine grafted poly­(cystaminebis­(acrylamide)-diaminohexane) [ABP] polymeric matrix based nanocarriers by using L9 Taguchi factorial design, desirability function, and multivariate method. The selected formulation and process parameters were ABP concentration, acetone concentration, the volume ratio of acetone to ABP solution, and drug concentration. The measured nanocarrier characteristics were particle size, polydispersity index, zeta potential, and percentage drug loading. Experimental validation of nanocarrier characteristics computed from initially developed predictive model showed nonsignificant differences (<i>p</i> > 0.05). The multivariate modeling based optimized cationic nanocarrier formulation of <100 nm loaded with hydrophilic acetaminophen was readapted for a hydrophobic etoposide loading without significant changes (<i>p</i> > 0.05) except for improved loading percentage. This is the first study focusing on ABP polymeric matrix based nanocarrier development. Nanocarrier particle size was stable in PBS 7.4 for 48 h. The increase of zeta potential at lower pH 6.4, compared to the physiological pH, showed possible endosomal escape capability. The glutathione triggered release at the physiological conditions indicated the competence of cytosolic targeting delivery of the loaded drug from bioresponsive nanocarriers. In conclusion, this unique systematic approach provides rational evaluation and prediction of a tunable bioresponsive ABP based matrix nanocarrier, which was built on selected limited number of smart experimentation