In this work, the thermodynamics of theophylline anhydrate and monohydrate were investigated. The solubilities of theophylline anhydrate and monohydrate in methanol–water and isopropanol–water mixtures were measured from 278.15 K to 303.15 K. Then the solubility data were correlated with the combined nearly ideal binary solvent/Redlich–Kister (CNIBS/R–K) model and the modified Jouyban–Acree model, respectively. The water activity aT that corresponds to the transformation between hydrate and anhydrate forms of theophylline was investigated. The water activity was accurately calculated by the Wilson equation and correlated by the van’t Hoff equation. The transformation enthalpy and entropy were calculated as well. The ternary phase diagrams of the theophylline–methanol–water system and theophylline–isopropanol–water system thus were obtained.

•The dissolution rates of NaLAS and Na2CO3 are time-dependent.•NaLAS belongs to IDR, whereas Na2CO3 follows DDR and IDR for type 1 and type 2.•The dissolution heterogeneity is influenced by the type and content of binder.•The two types of detergent agglomerates follow different dissolution mechanisms.In this work, the dissolution mechanisms of detergent agglomerates with different binders were investigated in aqueous solution. The dissolution processes of detergent agglomerates were online monitored by using in situ UV–VIS spectrophotometer and electric conductivity probe. Dissolution profiles were correlated by Weibull model to evaluate the time-dependent dissolution rate coefficient and to classify the type of dissolution rate function kt(t). The Kullback-Leibler information distance dK-L was proposed to assess the degree of dissolution heterogeneity. The results indicate that the sodium linear alkylbenzene sulfonates (NaLAS) and sodium carbonates (Na2CO3) in detergent agglomerates have different dissolution behaviors, and their dissolution rates are influenced by the type and content of binders. Moreover, detergent agglomerates using semi-solid NaLAS paste or liquid linear alkylbenzene sulfonic acid (HLAS) as binders in granulation processes follow different dissolution mechanisms in water.Download high-res image (63KB)Download full-size image

•A study relates to the gelation.•The presence and the interaction of gelators induce the formation of gel.•Gel can transform to crystal under certain condition.•No polymerization reaction between water and Moxidectin during the gelation process.•The formation of gel is the adsorption and cementation of Moxidectin particles.The gel formation and transformation to crystal of moxidectin (Form I) during the anti-solvent crystallization was studied in this paper. Several characterization techniques were used to monitor and identify this process, including online and offline instruments, such as X-ray powder diffraction (PXRD), polarizing microscope(POM), differential scanning calorimetry (DSC), focused beam reflectance measurement (FBRM) and On-line Forier transform infrared (FTIR). The results demonstrated that tiny crystal nucleus could be found after certain amount water was added into the solution, and then the tiny crystal nucleuses served as gelators and induced the system to form gel through the hydrogen bonds between moxidectin and water molecules. Finally, the gel would transform to form I due to the instability of gel.

In this work, the dissolution behaviors of a series of sodium alkylbenzenesulfonates (NaLAS) tablets with different moisture contents and neutralization degrees were investigated in aqueous solution. The ANOVA-based, model-independent and model-dependent methods were employed to perform comparison analyses on dissolution profiles. The measurements of powder X-ray diffraction patterns and mechanical properties elucidate distinct differences in each formula. The results show that ANOVA provides a possibility for finding the source of differences among different variables, and the model-independent methods including the k values and mean dissolution time are easy to interpret and perform comparison analyses. The Hixson–Crowell model gives satisfactory correlation results for the dissolution data and the dissolution kinetics parameters are obtained. The inhibition effects of neutralization degree and moisture content on NaLAS dissolution were examined, which reveals that the increase in lamellar phase proportion leads to the reduction of dissolution rate. The comparison analyses performed in this work form part of a methodology for dissolution profile prediction and comparison.

In this work, the solvent-mediated phase transformation of the metastable form (Form II) to the stable form (Form I) of ethenzamide–saccharin cocrystal in isopropanol was investigated. Solubility of Form I and Form II in pure isopropanol was also measured. The transformation mechanism from Form II to Form I was analyzed by some online and off-line tools including attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Raman spectroscopy, and polarizing microscopy. The results demonstrate that the transformation process consists of three steps, involving the dissolution of Form II, the nucleation of Form I, and the following growth of Form I. The ATR-FTIR and Raman results show that the polymorphic transformation from Form II to Form I is controlled by the nucleation and growth of Form I. Furthermore, the microscope photographs clearly reveal that the Form I preferably nucleates and grows on the (100) surface of Form II. The molecular simulation results indicate that higher adsorption energy and the exposure of more activity groups make the molecule adsorbed more strongly on the (100) surface, which is in agreement with the experimental observation. The results drawn in this work will be of great significance to control the formation of a desired polymorphic final product of ethenzamide–saccharin cocrystal.

•The solubility of ethenzamide in different pure solvents was experimentally determined.•The experimental solubility of ethenzamide was correlated by five models.•The studies of molecular modeling were carried out.•The mixing thermodynamic properties of ethenzamide of ethenzamide were calculated.The solubility of ethenzamide in methanol, ethanol, 1-propanol, isobutanol, ethyl acetate and acetonitrile was determined via the gravimetric method in the temperature range from 288.15 K to 323.15 K at atmospheric pressure. Five thermodynamic models were employed to correlate the experimental solubility data. The correlated results were analyzed and compared with the experimental results. It was found that all the thermodynamic models give satisfactory correlation results, in which the modified Apelblat model shows the best fitting result. In addition, the molecular modeling studies were carried out to give the explanation for the sequence of solubility in various solvents. The dissolution enthalpy and entropy of ethenzamide were obtained by using the Van't Hoff equation. Furthermore, the mixing thermodynamic properties of ethenzamide, including the mixing Gibbs energy, the mixing enthalpy and entropy, as well as the infinite-dilution activity coefficient and the infinitesimal concentration reduced excess enthalpy, were also obtained by using the Wilson model and the experimental solubility values.

•The phase diagrams for ethenzamide-saccharin cocrystals were measured.•The effects of temperature and solvents on the phase diagram were investigated systemically.•The solubility of ethenzamide-saccharin cocrystals was correlated by using a deduced mathematical model.•The solubility of ethenzamide-saccharin cocrystals as a function of saccharin concentration was calculated.The phase equilibrium for ethenzamide (EA) and saccharin (SAC) in ethanol, isopropanol and ethyl acetate were determined at 298.15 and 308.15 K under atmospheric pressure in this work. In ethanol and isopropanol, the two solutes dissolve incongruently and the diagrams are asymmetric, so excessive EA is required to isolate cocrystals. However in ethyl acetate, EA and SAC exhibit similar dissolution behavior, resulting in larger and more symmetric regions for EA-SAC cocrystal, which would be beneficial to enhance the control of EA-SAC cocrystallization process. In addition, the solubility of EA-SAC cocrystal was correlated by using a mathematical model based on both solubility product and solution complexation. The solubility of EA-SAC cocrystal as a function of SAC concentration was calculated. These new findings are of great importance to control the cocrystallization process of EA-SAC.

This paper seeks to extend the screening methods for cocrystal incongruent systems by using siloxane self-assembled monolayers (SAMs). The theophylline (THE)–saccharin (SAC)–methanol incongruent system was chosen as a case study. The results of cocrystallization experiments showed that siloxane SAMs with exposed Cl groups can act as templates for the selective growth of THE–SAC cocrystal on the monolayer surface with relatively high purity, which was confirmed by Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The observed selectivity is rationalized on the basis of two-dimensional geometric matching and chemical interactions at the SAM/crystal interfaces using a molecular modeling method.

Moxidectin is a single-component and semisynthetic macrocyclic lactone antibiotic, which has been widely used in the prevention and treatment of parasites in farm animals. In this paper, the transformation of ethanol solvate to form I of moxidectin in an ethanol–water mixture was studied. Offline methods and online instruments were used to monitor and identify the transformation process, and the influences of water content and temperature were discussed. It is noted that the transformation kinetics are highly sensitive to both the solvent composition and temperature and the transformation rate is a function of the ethanol content in aqueous ethanol mixtures. The solvent-mediated polymorphic transformation mechanism from ethanol solvate to form I was suggested, and the process is controlled by the nucleation and growth rate of the stable form. Understanding these effects can aid optimization and improve process control in the crystallization of moxidectin.

Understanding the salting effects on the solubility and transformation kinetics of amino acid solvates in aqueous solutions is important for a rational design of the industrial isolation and purification conditions of amino acid. We report measurements of l-phenylalanine anhydrate and monohydrate solubility as a function of temperature in aqueous NaCl, KCl, Na2SO4, and (NH4)2SO4 solutions with concentrations of 4 g/100 g of H2O in this work. It is found that salts play an important role in determining solubility reduction and solvated behavior, which had not been elucidated. This comparison has provided important insight into the dependence of l-phenylalanine solvates on temperature. The dependence of the l-phenylalanine anhydrate/monohydrate transformation kinetics on temperature in the presence of NaCl, as a typical salt, is discussed. It is noted that NaCl can markedly increase the rate of the transformation of l-phenylalanine between anhydrate and monohydrate compared with pure water. A simple model for the transformation kinetics based on the salt effect between anhydrate and monohydrate is established, which can quantitatively provide the observed experimental dependence of the transformation rate on time. This work can provide important instruction for optimum process control during industrial production of l-phenylalanine.

The water activity aT[H2O] that corresponds to the transformation between hydrate and anhydrate forms of a drug is important to pharmaceutical process development; however, the traditional method for measuring aT[H2O] can be time-consuming. A thermodynamic model derived from the thermodynamic equilibrium in this study provides an easy way to predict the value of aT[H2O] at different temperatures through the solubility ratio of hydrate to anhydrate. The model also provides a new way to determine the solubility of the metastable form with accessible accuracy and offers a tool to study the activity coefficient of the solute. Experimental validation of the model was performed using the compounds theophylline and carbamazepine. The results illustrate that this new method is acceptably accurate and reproducible.

In this paper, the influence of polymorphs on the transformation water activity that corresponds to the transformation between hydrate and anhydrate of theophylline was investigated. Theophylline is known to exist either as anhydrates or a monohydrate. The transformation water activities of theophylline form II and IV were determined respectively, and the solubility data of these two forms in methanol, ethanol, acetonitrile, and acetone was also determined. The following thermodynamic derivation indicates that the transformation water activity ratio of theophylline forms II to IV can be correlated with the solubility ratio. According to the above study, the stability and intercoversion of theophylline polymorphs is discussed. This work will be useful in understanding the transformation process and benificial for industrial process control.

This paper focuses on developing an experimental method, which combines mathematic models, to evaluate complexation behavior in a saturated cocrystal solution. 1:1 and 2:1 urea–oxalic acid (U-OA) cocrystals were chosen as a model. The 2:1 U-OA cocrystal solubility was first explained by mathematical models which took into consideration the solubility product (Ksp) and solution complexation. The 1:1 U-OA cocrystal solubility was also analyzed by considering 1:1 solution complexation. To test the suitability of these models and evaluate complexation behavior, the aqueous solutions of U-OA with five different stoichiometric compositions which were located on solubility curves in different cocrystal regions were measured by in situ attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) (ReactIR). The spectra of complexes were obtained by the FT-IR absorbance subtraction method. The IR spectroscopy of crystalline 1:1 and 2:1 U-OA cocrystals was also discussed in comparison with those of complexes in solution. The absorbance of complexes in these five systems did not increase with free OA concentration. The tendency between the calculated concentration of 1:1 complex based on mathematic models and its absorbance was also against the Bouguer–Lambert–Beer law. These phenomena appear because the solution complexation changes from 2:1 and 1:1 complexation to 1:1 and higher order complexation.

Racemic tartaric acid (TA) exists in the solid state as an anhydrate and a monohydrate. In this paper, a method to obtain the anhydrate at lower temperature by adjusting the water activity, aw, through introduction of ethanol is proposed. The influence of aw on the phase conversion temperature of TA was investigated by the determination of the ternary phase diagrams for the system of water–ethanol–TA at varying temperatures. The result shows that the anhydrous TA can be obtained at ambient temperature by lowering the water activity and that the conversion rate from monohydrate to anhydrate appears to increase with decreasing water activity. The result can be extended to the application of other anhydrate and hydrate systems. Meanwhile, the process of anhydrous TA crystal formation from ethanol–water solution was investigated by using microscopy and HPLC.

The solid–liquid phase equilibrium of d- and l-tartaric acid (TA) was investigated in this work. Based on the solubility data, the dissolution enthalpy and entropy of the monohydrate racemic tartaric acid (race-TA) and enantiomer were calculated using van't Hoff plots. Binary melting point phase diagrams of d- and l-TA and ternary phase diagrams of d-TA/water/l-TA were also described. The results show that TA exhibits a racemic compound behavior. Furthermore, the influence of temperature on the eutectic points between enantiomer and racemic compounds was investigated. Finally, the importance of solid–liquid equilibrium on the purification and separation of enantiomers was discussed.

•There existed an optimal layer thickness in microwave thin layer drying process.•Optimal thickness was determined by the balance between heat and mass transfer.•An integrated kinetics equation for microwave thin layer drying starch was given.•Effective diffusivities reduced with the increase of surface area under microwave.Absolutely dried starch is widely used in cooking and other industries. However, the prolonged drying time during falling rate drying period and low energy efficiency limit the application of traditional hot air drying. Microwave energy is the alternative choice considering the ‘volumetric heating’ mechanism. Then, investigations on microwave thin layer drying of starch were conducted by experimental studies and mathematical modeling. Results show that drying time can be reduced significantly with the increase in microwave power density. And there exists an optimal layer thickness, both greater and less than the value will result in a lower drying rate. This phenomenon is completely different from hot air dying and has not been reported in literature before. Explanations are given from the perspective of heat and mass transfer. Data fitting shows that ‘Midilli–Kucuk’ model is the best one to describe drying behavior of starch. An integrated ‘Midilli–Kucuk’ model is also given after considering the effect of operating variables on model parameters. Effective diffusivities vary from 6.08 × 10−7 to 6.10 × 10−5 m2/s, and increase with the increase of microwave power density, decrease with the increase of surface area per unit mass, values are higher when compared with other materials dried under microwave in literature. Finally, nonlinear surface fitting was conducted in order to give a systematic prediction for effective diffusivities.Download high-res image (182KB)Download full-size image

•A new model was developed and validated to simulate microwave drying.•Moisture diffusion along material layer was ignored under intensive microwave.•An optimal layer thickness exists in microwave thin layer drying.•The temperature gradient has different orientation in hot air and microwave drying.Various methodologies have been proposed in literature on modeling microwave drying process. However, in these methodologies moisture diffusion is normally considered in the presence of intensive microwave energy. In the present study, a new theoretical model was developed to simulate microwave drying of thin layer particulate solids, based on the consideration that moisture diffusion along material layer could be ignored due to rapid evaporation under intensive microwave energy. The model was solved numerically by using finite difference method and validated against experimental data. Results indicated good agreement between the model and experimental data, thus providing confidence in the modeling approach. For the system investigated in this study, it was demonstrated that an 80% reduction in drying time was achieved with approximately fivefold increase in microwave power (109–543 W). Furthermore, it was also demonstrated that the drying rate was the maximum corresponding to the optimal layer thickness in microwave thin layer drying process. Qualitative analysis explained the optimal thickness phenomenon using principles of heat and mass transfer. Finally, the validated model was used to predict moisture and temperature distributions along the entire material layer.

•Droplet-based microchannels were used to investigate polymorphs of l-gluatamic acid.•l-glutamic acid has different nucleation behavior under droplet-based microchannels.•Easy to realize rapid control of the crystallization temperature in the droplets.Supersaturation is an important controlling factor for crystallization process and polymorphism. Droplet-based microchannels and conventional crystallization were used to investigate polymorphs of l-gluatamic acid in this work. The results illustrate that it is easy to realize the accurate and rapid control of the crystallization temperature in the droplets, which is especially beneficial to heat and mass transfer during crystallization. It is also noted that higher degree of supersaturation favors the nucleation of α crystal form, while lower degree of supersaturation favors the nucleation of β crystal form under droplet-based microchannels for l-gluatamic acid. In addition, there is a different nucleation behavior to be found under droplet-based microchannels both for the β form and α form of l-glutamic acid. This new finding can provide important insight into the development and design of investigation meanings for drug polymorph.