4 research outputs found
Iso-Structurality Induced Solid Phase Transformations: A Case Study with Lenalidomide
Lenalidomide (LDM) is a thalidomide
analogue known for its immunomodulation,
antiangiogenic, and antineoplastic properties. However, to date, only
two forms of lenalidomide [Form-1 (anhydrous) and Form-2 (hemihydrate)]
are reported in the literature. Through a comprehensive polymorph
screening herein, we report five forms of lenalidomide [Form-3 (DMF-solvate),
Form-4 (anhydrous), Form-5 (DMSO solvate), Form-6 (acetone solvate),
and Form-7 (dihydrate)]. Single crystal structures (for all forms)
are established to provide potential knowledge about the intermolecular
interactions, three-dimensional structures, and the nature of solvent/water
within the lattice. Thermodynamic stability investigations revealed
unusual solid state phase transformations which are relatively unexplored
to date. It is noteworthy that all solvates upon desolvation convert
to Form-1 (thermodynamically stable anhydrous form), whereas all hydrates
upon dehydration convert to a metastable Form-4 (novel anhydrous form)
which, upon further heating, converts to more stable Form-1. Correlation
of results from modeling, single crystal analysis, and nonambient
studies established “isostructurality” as one of the
major factors leading to such bifurcated phase transformations. Mechanisms
of desolvation and dehydration in different forms of LDM are explained
by utilizing various analytical techniques such as variable temperature
Fourier transform infrared spectroscopy, variable temperature powder
X-ray diffraction, differential scanning calorimetry, and hot stage
microscopy. A thorough understanding of the relationships between
structure and thermodynamic properties is deemed a prerequisite which
is considered vital in selecting the most suitable form for drug product
development
Development of Pharmaceutically Acceptable Crystalline Forms of Drug Substances via Solid-State Solvent Exchange
In
the pharmaceutical industry, solid form screening plays an important
role to discover forms that exhibit desired physicochemical properties
for drug product development. This work describes an approach to meet
this objective by the transformation of undesirable solvates to hydrates
or cosolvates with water via solid-state solvent exchange. Case studies
of two drug substances, imatinib mesylate and linagliptin, are discussed,
where linaglipitin methanol/ethanol solvate was converted to an iso-structural
hydrate and, similarly, imatinib mesylate methanol–water cosolvate
was converted to a predominantly water-containing cosolvate. Through
quality by design based optimization, temperature and relative humidity
were identified as critical process parameters that impacted the rate
of solvent exchange during humidification. In addition, crystallization
parameters that impacted the crystal size were found to play a key
role in determining the extent of solvent exchange. This unexpected
effect of crystal size was investigated through single crystal structure
elucidation and molecular modeling, which showed the solvent to be
residing in channels oriented along the length of the crystal. The
dimensions of these channels determined the ease of solvent exchange
by controlling the rate and extent of diffusion of solvent molecules.
With these case studies, this paper provides insight on robust process
development for solid-state solvent exchange with an in-depth understanding
of molecular level phenomena and critical process parameters
Second Harmonic Generation Guided Raman Spectroscopy for Sensitive Detection of Polymorph Transitions
Second harmonic generation
(SHG) was integrated with Raman spectroscopy
for the analysis of pharmaceutical materials. Particulate formulations
of clopidogrel bisulfate were prepared in two crystal forms (Form
I and Form II). Image analysis approaches enable automated identification
of particles by bright field imaging, followed by classification by
SHG. Quantitative SHG microscopy enabled discrimination of crystal
form on a per particle basis with 99.95% confidence in a total measurement
time of ∼10 ms per particle. Complementary measurements by
Raman and synchrotron XRD are in excellent agreement with the classifications
made by SHG, with measurement times of ∼1 min and several seconds
per particle, respectively. Coupling these capabilities with at-line
monitoring may enable real-time feedback for reaction monitoring during
pharmaceutical production to favor the more bioavailable but metastable
Form I with limits of detection in the ppm regime
Triboluminescence from Pharmaceutical Formulations
Triboluminescence
(TL) is shown to enable selective detection of
trace crystallinity within nominally amorphous solid dispersions (ASDs).
ASDs are increasingly used for the preparation of pharmaceutical formulations,
the physical stability of which can be negatively impacted by trace
crystallinity introduced during manufacturing or storage. In the present
study, TL measurements of a model ASD consisting of griseofulvin in
polyethylene glycol produced limits of detection of 140 ppm. Separate
studies of the particle size dependence of sucrose crystals and the
dependence on polymorphism in clopidogrel bisulfate particles are
both consistent with a mechanism for TL closely linked to the piezoelectric
response of the crystalline fraction. Whereas disordered polymeric
materials cannot support piezoelectric activity, molecular crystals
produced from homochiral molecules adopt crystal structures that are
overwhelmingly symmetry-allowed for piezoelectricity. Consequently,
TL may provide a broadly applicable and simple experimental route
for sensitive detection of trace crystallinity within nominally amorphous
materials