Particle Design of Drugs via Spherical Crystallization: A Review from Fundamental Aspects to Technology Development

In the pharmaceutical industry, the production process of most active pharmaceutical ingredients involves at least one crystallization step. Design of drug spheres via various spherical crystallization technologies can impart crystals with certain superior attributes including high flowability and compressibility as well as excellent mechanical properties. Some new spherical crystallization approaches and design principles have been proposed in recent years. This review aims to review the up-to-date design principles and preparation technologies of drug spheres, providing a guide for design, preparation, and performance evaluation of the drug spheres. Herein, we review the mechanisms and design principles of the spherical crystallization first, and subsequently various technologies reported in the literature are reviewed with the critical process parameters being analyzed. Lastly, the challenges facing the development of spherical crystallization for drugs are discussed

Investigation of the Crystallization of Disodium 5′-Inosinate in a Water + Ethanol System: Solubility, Nucleation Mechanism, and Crystal Morphology

In this work, the solubility of IMP in a water + ethanol system was measured by a gravimetric method at the temperature range from 283.15 to 323.15 K. To explain the solubility behavior of IMP in this system, a model was applied to quantitatively describe the effect of dielectric constants on the solubility of IMP. Then, the induction time was determined to be related to the supersaturation level for analysis of the nucleation mechanism, indicating that homogeneous nucleation dominated the nucleation process at higher supersaturation, while heterogeneous nucleation was more important mechanism at lower supersaturation. Finally, the molecular modeling was carried out to understand the effect of supersaturation on the crystal habits of IMP: the rodlike products preferred to form at high supersaturation, while flakelike products formed at low supersaturation, as shown in the microscopy images. In summary, supersaturation should be considered in the process of optimizing IMP crystallization operation conditions

Interplay between Kinetics and Thermodynamics on the Probability Nucleation Rate of a Urea–Water Crystallization System

In this contribution, by employing the Poisson distribution combined with the regular solution theory in the classical nucleation theory (CNT) framework, we construct a new model to uncover the relationship between induction time (<i>t</i>_ind) and supercooling (Δ<i>T</i>) and saturation temperature (<i>T</i>₀) at different specific probabilities. By choosing the urea aqueous solution as a benchmark system, we show that the value of ln­(1/<i>t</i>_ind) follows a reasonable linear relationship with (<i>T</i>₀/Δ<i>T</i>)²/(<i>T</i>₀ – Δ<i>T</i>), except the probability value tends to be 0 or 1. Furthermore, we also shed new light on the role of chemical potential difference and nucleation temperature in determining the nucleation rate; namely, although the chemical potential difference is the driving force for the crystallization process, it does not always favor the nucleation process. We demonstrated that when the chemical potential difference increases as the nucleation temperature decreases (Δ<i>T</i> gradually increases), in this case, the kinetic factor overwhelms the thermodynamic factor thus leading to a faster nucleation rate by employing the CNT theory. However, when the chemical potential difference decreases as the nucleation temperature increases, we found that increasing the nucleation temperature favors the nucleation process both in kinetic and thermodynamic aspects

Correlation of Solubility and Prediction of the Mixing Properties of Ginsenoside Compound K in Various Solvents

The solubilities of ginsenoside compound K in pure solvents and binary mixture solvents were determined at several temperatures from 278.15 K to 318.15 K by a static analytical method. The experimental solubility data in pure solvents were correlated by the van’t Hoff plot, the modified Apelblat equation, the λ<i>h</i> (Buchowski) equation, the Wilson model, and the NRTL model, with the Wilson model giving the best correlation results. Based on the Wilson model and experimental data, the mixing Gibbs free energies, enthalpies, and entropies of solutions and activity coefficients in pure solvents were predicted, and other thermodynamic properties (infinite-dilution activity coefficients and excess enthalpies) were calculated as well. In addition, the solubility was maximal at a certain water mole fraction in acetone + water mixture and acetonitrile + water mixture, whereas in a methanol + water system, the solubility decreases as the water concentration increases monotonically. The solubilities in mixture solvents were correlated by the solvent components using the Wilson model. The partial molar Gibbs free energies with negative values were obtained, which indicates the changing of the solubility

Selective Crystallization of Racemic Polymorph <i>via</i> Native Enantiomer Inhibition: dl-Methionine

Crystallization of chiral compounds is dictated by chiral recognition and molecular self-assembly in solution. However, their interplay remains elusive. The reason for the considerably reduced polymorphism in chiral molecules than that of nonchiral molecules remains unclear. Herein, we use a combination of experimental and computational techniques to show that excessive enantiomer functioning, as a native crystallization inhibitor, selectively suppresses the crystallization of racemic polymorphs, affording preferential crystallization of the metastable α polymorph of dl-methionine. Bulk crystallization assays show concomitant crystallization of the α and β polymorphs of racemic dl-methionine in the solution with no enantiomeric excess. However, when the solution contains excessive d-/l-methionine enantiomer, only the metastable α form can be crystallized. Crystal growth experiments, fluoresce confocal microscopy, and atomic force microscope surface topology measurements reveal the growth inhibition of both polymorphs with preferential suppression of the β form by excess native enantiomer. Binding energy calculations and molecular dynamic simulations further demonstrate the preferential adsorption of excessive enantiomers on the (0 0 2) facet of the β form over the α form. Overall, our results uncover a unique chiral self-positioning mechanism where the excess enantiomer solutes serve as a native growth inhibitor to disrupt the kinetics of racemic polymorphic crystallization, affording selective crystallization of only one polymorph of dl-methionine. Our results highlight the important effect of excess enantiomer in a solution on the polymorph occurrence of chiral molecules

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

Determination of the Solubility, Dissolution Enthalpy, and Entropy of Pioglitazone Hydrochloride (Form II) in Different Pure Solvents

The solubility of pioglitazone hydrochloride (Form II) in <i>N,N</i>-dimethylacetamide, methanol, dimethyl sulfoxide, and acetic acid was determined at temperatures ranging from 283.15 to 323.15 K. The experimental data were correlated with the modified Apelblat equation, <i>λh</i> equation, van’t Hoff equation, ideal model, Wilson model, and nonrandom two-liquid model. Calculation results show that the <i>λh</i> equation, van’t Hoff equation, and the ideal model are more suitable in determining the solubility of pioglitazone hydrochloride (Form II) compared with the other three models. By using the van’t Hoff equation, the dissolution enthalpy, entropy, and molar Gibbs free energy of pioglitazone hydrochloride (Form II) are predicted in different solvents

Correlation of Solubilities of Hydrophilic Pharmaceuticals versus Dielectric Constants of Binary Solvents

In this paper, the polarity of binary solvents was studied by the sum law of cube roots of the dielectric constant. During the antisolvent crystallization process, the composition of the binary solvents and their dielectric constants changed simultaneously. These results demonstrated that variation of the solubility is dependent on the polarity of the binary solvents. On the basis of experiments, a new model was put forward to quantitatively describe the relationship between the solubility of hydrophilic pharmaceuticals and the dielectric constants of the binary solvents. Furthermore, this model was tested and verified by solubility data of other pharmaceuticals published in the literature with high accuracy

Determination and Correlation of Dipyridamole p‑Toluene Sulfonate Solubility in Seven Alcohol Solvents and Three Binary Solvents

The solubility of dipyridamole p-toluene sulfonate in seven monosolvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, 2-butanol) and three different binary solvents (methanol + ethanol, methanol + 1-propanol, methanol + 1-butanol) was measured by a gravimetric method at temperatures ranging from 288.15 to 328.15 K. The experimental results indicate that the solubility of dipyridamole p-toluene sulfonate increases with increasing temperature while showing negative correlation with the mole fraction of organic solvents (ethanol, 1-propanol, 1-butanol) at a given temperature in binary solvents. The Apelblat model, the CNIBS/R-K model, and the modified version of Jouyban-Acree models (the Apel-JA equation) were used to correlate the experimental data, and the calculated results of above models were found to agree well with the experimental data

Determination and Correlation of Dipyridamole p‑Toluene Sulfonate Solubility in Seven Alcohol Solvents and Three Binary Solvents

The solubility of dipyridamole p-toluene sulfonate in seven monosolvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, 2-butanol) and three different binary solvents (methanol + ethanol, methanol + 1-propanol, methanol + 1-butanol) was measured by a gravimetric method at temperatures ranging from 288.15 to 328.15 K. The experimental results indicate that the solubility of dipyridamole p-toluene sulfonate increases with increasing temperature while showing negative correlation with the mole fraction of organic solvents (ethanol, 1-propanol, 1-butanol) at a given temperature in binary solvents. The Apelblat model, the CNIBS/R-K model, and the modified version of Jouyban-Acree models (the Apel-JA equation) were used to correlate the experimental data, and the calculated results of above models were found to agree well with the experimental data