8 research outputs found
Transformations among the New Solid-State Forms of Clindamycin Phosphate
An
experimental study is undertaken to establish a transformation
screen for the solid-state forms of clindamycin phosphate. The experimental
study results in six novel crystalline forms: two solvates (with ethanol/water,
methanol/water), one hydrate (Form III), and three polymorph forms.
Further, all solid-state forms are characterized by various analytical
techniques such as X-ray diffraction, differential scanning calorimetry,
etc. Two polymorph forms (IV and VI) are selectively prepared by desolvation
of the solvates (I and V). The solid-state desolvation results in
the appearance of delamination of the 2D layers. Moreover, polymorph
IV shows a clear polymorphic transition to a new polymorph form (polymorph
II) above 165 °C. Phase transformations of the solid-state forms
were also established by slurry conversions at 25 °C. These experiments
suggest the reversible relationship between solvate I/V and hydrate
Form III at different solvent mixtures. Through the aqueous dissolution
test, it is also judged that polymorph II, IV, VI can transform to
Form III in water at 25 °C. The conversion relationships among
the six solid forms are illustrated
Multivariate Analysis of a Highly Effective Drug Combination Tablet Containing the Antiepileptic Drug Gabapentin to Enhance Pharmaceutical Properties with a Multicomponent Crystal Strategy
A thorough grasp of the relationship between the crystal
structure
and properties is necessary for the design of crystals with specific
properties using crystal engineering. Gabapentin (GBP), an analogue
of the neurotransmitter gamma-aminobutyric acid, is used to treat
partial seizures. GBP exhibits a fast dissolution rate. However, because
of being plastically and elastically deforming, which increases the
possibility of capping or laminating during compression, GBP exhibits
poor compaction behavior. The aim of the study was to address the
aforementioned issues, involving preparing and characterizing gabapentin
monohydrate (GBP·H2O) and cocrystals (GBP-PABA) with
p-aminobenzoic acid (PABA). Both the tablets of GBP·H2O and GBP-PABA can successfully slow down the dissolution rate of
the original drug and reduce the intrinsic dissolution rate. Additionally,
the multicomponent crystals of GBP have slip planes, demonstrating
very excellent compaction properties, according to a thorough study
on the mechanical properties of crystals. In terms of single-crystal
structure and intermolecular interaction, the compressibility assessment
of multicomponent crystals by analysis of relationships between mechanical
properties and bulk powder compaction behavior further proved its
plastic behavior and appropriateness for direct compression. Therefore,
the development of multicomponent crystals will effectively solve
the determination of the parent drug itself and become an efficient
oral combined formulation
Polymorphic Development Strategy for Rapid Pesticide Release: A Case Study of Spirotetramat
Spirotetramat has been utilized extensively in the world
for its
long-lasting effects. However, since form I has been reported with
the disadvantages of low solubility and poor pesticide release rate
in the literature, systematic crystal form screening is urgently required.
In this study, a new polymorph (form II) was discovered by melt crystallization,
and its single crystal grew in melt microdroplets. In comparison to
form I, form II is a metastable crystal form with a lower melting
point and enthalpy as well as higher lattice energy. Its solubility
is higher than that of form I. The increased solubility facilitates
the release of pesticides at an accelerated rate. Furthermore, a series
of stability experiments have shown that form II can maintain stability
at room temperature and ambient humidity for more than 3 months. The
form II crystals retain their stability even after grinding or heating.
Meanwhile, the phase transformations among three solid forms were
presented. Finally, a solution crystallization method was proposed
to prepare form II crystals with uniform particle size distribution
Polymorph Control by Investigating the Effects of Solvent and Supersaturation on Clopidogrel Hydrogen Sulfate in Reactive Crystallization
Reactive crystallization and polymorphic
transformation of clopidogrel hydrogen sulfate (CHS) in nine pure
solvents were studied at 313.15 K. It is found that thermodynamically
stable polymorphic form tends to be obtained in solvents with higher
solubility of CHS and the conversion rates from form I to form II
are also mainly increased with increasing solubility. The solvent
hydrogen bond donor ability is essential for determining the solvent
effects on solubility and polymorphic formation of CHS. Besides, the
reactive crystallization of CHS at different supersaturations in 2-propanol
and 2-butanol was monitored online by using ATR-FTIR and FBRM with
a calibration-based approach. The results indicate the nucleation
induction period is the kinetic-determining stage and supersaturation
is a direct factor to determine the polymorphic formation of CHS:
form II was obtained with <i>s</i> under 18 while form I
was produced when <i>s</i> increases above 21
Solvent-Mediated Nonoriented Self-Aggregation Transformation: A Case Study of Gabapentin
A good
powder performance is one of the essential targets for gabapentin
(GBP). However, the low bulk density and flowability of GBP are still
the industrial problems in practical production. The main purpose
of this paper is to investigate the phase transformation of GBP from
form I to form II in methanol, ethanol, propanol, acetone, acetonitrile,
and ethyl acetate and improve the powder properties. The results suggested
that there are two kinds of phase transformation mechanisms of GBP.
One is the classic solvent-mediated transformation in alcohols, and
the other is the solvent-mediated nonoriented self-aggregation transformation
in other solvents, which is proposed for the first time. On account
of the low water activity and solubility, there is a self-cleaving
phenomenon caused by the dehydration in the form I particles, and
then the unstable phase transforms into form II, but the growth of
the stable form is confined by the size and shape of the initial metastable
particle and the products are aggregates. These aggregates with a
well-defined shape and size have good performance in the dissolution
rate with improved bioavailability
Measurement and Correlation of the Solubility of Pyrimethanil in Seven Monosolvents and Two Different Binary Mixed Solvents
The solubility of pyrimethanil in
two binary solvents (water +
methanol and water + ethanol) and seven monosolvents (methanol, ethanol, <i>n</i>-propanol, isopropanol, <i>n</i>-butanol, isobutanol,
and cyclohexane) was measured by a gravimetric method within the temperature
range of 283.15 to 323.15 K at atmospheric pressure. In the investigated
temperature range, the solubility of pyrimethanil in all monosolvents
or mixed solvents increases with increasing temperature. The solubility
in the monosolvents was well-correlated using the NRTL model, the
Apelblat model, and the Wilson model. Furthermore, the NRTL model
and the modified version of the Jouyban–Acree model (the Apel-JA
equation) were employed to correlate the solubility in binary solvents.
The results showed that these models have a satisfactory correlation.
When we measured the solubility, we found that the solvent has a great
influence on the crystal habit. Therefore, these results can give
guidance for practical industrial processes such as the design of
the crystallization process and control of the crystal morphology
Solubility Correlation and Thermodynamic Analysis of Sorafenib Free Base and Sorafenib Tosylate in Monosolvents and Binary Solvent Mixtures
The
solubility of sorafenib free base (SFB) and sorafenib tosylate
(ST) in five monosolvents and binary solvents of 2-propanol + 1,4-dioxane
was measured over the temperature ranged from 283.15 to 333.15 K by
using a UV spectroscopy method. The solubility of SFB and ST in different
monosolvents increases with increasing temperature, while in the binary
solvents, the solubility shows the maximum value at 0.50 and 0.75
2-propanol mole fraction for SFB and ST, respectively. The Apelblat
model and the CNIBS/R-K model were applied to correlate the solubility
data, which shows that the two selected thermodynamic models could
give satisfactory results. Moreover, mixing thermodynamic properties
of enthalpy, entropy, and Gibbs free energy of SFB and ST were obtained
based on the nonrandom two-liquid model for further understanding
of the mixing behavior
Prediction and design of cyclodextrin inclusion complexes formation via machine learning-based strategies
This study reports a machine-learning (ML) method to develop multi-purpose prediction strategies for the formation of cyclodextrin inclusion complexes (ICs) in aqueous solutions. A balanced dataset of pharmaceutically relevant molecules was constructed using experimental verification. Three ML models (artificial neural network, support vector machine, and logistic regression) were established and optimized to predict IC formation. To provide more reliable approaches for different prediction requirements, ML-based linear, recall-first, and precision-first strategies were further established based on the ML models for the maximum recall or precision values. The proposed recall-first strategy identified all positive samples to avoid missing data in the prediction, and the precision-first strategy accurately identified positive samples to reduce the number of validation experiments. The ML-based prediction strategies for IC formation were first established and showed high accuracy and reliability. These strategies provide higher efficiency and lower processing cost solutions for IC screening