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

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

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

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