4 research outputs found
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 CH<sub>3</sub>···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