Experimental and Modeling Studies on the Solubility of d‑Pantolactone in Four Pure Solvents and Ethanol–Water Mixtures

The solubility of d-pantolactone in water, ethanol, methanol, ethyl acetate, and ethanol–water mixtures was determined at temperatures between (278.15 and 318.15) K using a digital densitometer by a static method. The measured solubility data were correlated with Apelblat equation, van’t Hoff equation, nonrandom two liquid model, and Wilson model. The results indicate that the Wilson model is the most suitable model in pure solvents and the Apelblat model is the best model in ethanol–water mixtures

Determination and Correlation of Solubility of Quetiapine Fumarate in Nine Pure Solvents and Two Aqueous Binary Solvents

A gravimetric method was used to determine the solubility of quetiapine fumarate (QF) in nine pure solvents and two aqueous binary solvents (water + methanol/ethanol) at different temperatures from 283.15 to 323.15 K. The solubility of QF increases with the increase of temperature in nine pure solvents, and it is in the order DMF > methanol > ethanol >1-butanol > isopropyl alcohol > (acetone > ethyl acetate > isobutyl alcohol) > water at low temperature, and in the order DMF > methanol > ethanol >1-butanol > isopropyl alcohol > (acetone > isobutyl alcohol > ethyl acetate) > water at relatively high temperature at a given temperature. The solubility of QF in the binary solvents also shows temperature dependence, while at a given temperature the solubility is mainly influenced by the solvent composition with the presence of maximum, reflecting cosolvency. Also the solubility of QF increases with the increase of temperature in binary solvents in a given composition. The Hansen solubility parameters were used to explain the cosolvency and maxima shift, confirming that for large values (>25 MPa^1/2) of solute, the solubility shows a peak in the range of 35 to 31 MPa^1/2 of solubility parameters of alcohol mixtures. The experimental solubility of QF in pure and binary solvents is well correlated by modified Apelblat equation, the nonrandom two-liquid model, and the CNIBS/R-K equation, respectively

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

Solubility of Benzoin in Six Monosolvents and in Some Binary Solvent Mixtures at Various Temperatures

The solubility of benzoin in monosolvents (acetone, ethyl acetate, methanol, ethanol, 1-propanol, and 1-butanol) and binary solvent mixtures (ethyl acetate + methanol, ethyl acetate + ethanol) was measured using UV–vis spectroscopy at temperatures ranging from 283.15 K to 323.15 K. It can be seen from the data that the solubility of benzoin increases expectedly as temperature increases in a given solvent or solvent mixture, the solubility in acetone is maximum among six monosolvents which could be well explained by the existence of strong H-bonds, rather than the “like dissolves like” rule. In binary solvent mixtures, the solubility reaches maximum when the mole fraction of methanol is 0.1 in ethyl acetate + methanol mixed solvents, while the maximum exhibits at 0.2 of mole fraction of ethanol in ethyl acetate + ethanol. The solubility parameter was interpreted as the cosolvency of benzoin solubility in binary solvent mixtures. The solubility data were correlated by modified Apelbalt equation, CNIBS/R-K equation, λ<i>h</i> equation, Jouyban–Acree model, and Van’t–JA equation. Mixing thermodynamic properties were further calculated and discussed regarding their roles in dissolution and solubility

Measurement of Solubility of Thiamine Hydrochloride Hemihydrate in Three Binary Solvents and Mixing Properties of Solutions

Data on (solid + liquid) equilibrium of thiamine hydrochloride hemihydrate (HH) in {water + (ethanol, acetone, or 2-propanol)} solvents will provide essential support for industrial design and further theoretical studies. In this study the solid–liquid equilibrium (SLE) was experimentally measured over temperatures ranging from 278.15 to 313.15 K under atmospheric pressure by a dynamic method. For the temperature range investigated, the equilibrium solubility of thiamine hydrochloride hemihydrate (HH) varies with temperature and the composition of the solvents. The experimental solubility was regressed with different models including the modified Apelblat equation, λ<i>h</i> equation, as well as NRTL equation. All the models gave good agreements with the experimental results. On the basis of the solubility data of HH, the thermodynamic properties of mixing process of HH with mixed solvents were also discussed. The results indicate that the mixing process of HH is exothermic. Besides, the model outwardly like the Arrhenius equation was employed to quantitatively exhibit the relationship between solubility and solvents mixtures polarity of solvents mixtures

Controlled Recrystallization of Tubular Vinpocetine Crystals with Increased Aqueous Dissolution Rate and <i>In Vivo</i> Bioavailability

Vinpocetine was a BCS II drug, whose clinical applications had suffered from low oral bioavailability because of its inefficient dissolution in the GI tract. As the dissolution rate depended on the surface area of the drug crystals, we herein explored shape-controlled recrystallization via antisolvent process as an excipient-free strategy to improve the bioavailability of VIN. By adjusting the water/ethanol ratio, initial VIN concentration, and temperatures, morphologies of the crystalline products could be finely tuned from three-dimensional cubes and tubes, to two-dimensional frizzled plates, and finally to zero-dimensional microparticle clusters. Morphology analysis and in situ FBRM surveillance of the growing process suggested that a diffusion-limited crystal growth mechanism was responsible for the shape variation of VIN products. Finally, we tested the <i>in vitro</i> dissolution efficiency as well as the <i>in vivo</i> bioavailability of recrystallized VIN crystals. Results manifested that the tubular crystal showed a faster dissolution behavior as compared with the raw VIN, achieving an increased AUC_0‑t of 484.0 ± 24.6 ng/mL·h, which was 1.3-fold that of the raw VIN product (386.6 ± 22.8 ng/mL·h). To the best of our knowledge, this was one <i>in vitro</i> to <i>in vivo</i> report for bioavailability improvement of BCS II drug by applying the shape-controlled recrystallization strategy

Seed-Assisted Effects on Solution-Mediated Phase Transformation: A Case Study of l‑Histidine in Antisolvent Crystallization

In this study, the effects of crystal nucleation–growth on subsequent solvent-mediated phase transformation experiments of l-histidine (l-his) in antisolvent crystallization were performed at 298.15 K. The unexpected acceleration of the overall transformation rate in antisolvent crystallization with solution-mediated phase transformation was found for a methanol volume fraction of 0.35 < <i>x</i>₂ < 0.60. Interestingly, concomitant polymorphs were obtained for a methanol volume fraction of 0.30 ⩽ <i>x</i>₂ ⩽ 0.65 in antisolvent crystallization, whereas only form B was observed for other volume fractions of methanol, which indicated that the concomitant polymorphic phenomenon was the main reason for the accelerated transformation rate in antisolvent crystallization. Furthermore, seed-assisted experiments and suspended solution-mediated phase transformation experiments were designed to uncover the role of the nucleation of form A accompanying with form B in the subsequent transformation process

Effects of Additives on the Morphology of Thiamine Nitrate: The Great Difference of Two Kinds of Similar Additives

The growth of thiamine nitrate, in supersaturated aqueous solutions in the absence and presence of sodium alkyl sulfates CH₃(CH₂)_<i>n</i>SO₄Na and sodium alkyl sulfonates CH₃(CH₂)_<i>n</i>SO₃Na was studied by a single seed crystal growth experiment. It was surprisingly found that the growth of the <i>a</i>-axis of thiamine nitrate is significantly inhibited by CH₃(CH₂)_<i>n</i>SO₄Na, thus reducing the aspect ratio of thiamine nitrate, while the aspect ratio of thiamine nitrate in the presence of CH₃(CH₂)_<i>n</i>SO₃Na remains almost constant. Furthermore, the mechanism of additives to modify the crystal morphology is proposed: both additives can inhibit the growth of thiamine nitrate by hindering the solute diffusion. However, their unusual behavior is due to the selective adsorption, which was caused by electrostatic and hydrogen bond interactions between solute and additive molecules. In particular, the anionic groups exposed at the end of the additives demonstrate an interesting case in which a small variation in the charge density and hydrogen bonding ability can lead to a marked difference in modifying the crystal growth behavior. The results obtained from this study should be helpful in the performance evaluation and selection of the morphology modifiers for thiamine nitrate crystals