Solvent-mediated Transformation Research Articles

Polymorphs of praziquantel–succinic acid cocrystal: Crystal structure, thermodynamic relationship, and improved pharmaceutical performance

Polymorphism is a ubiquitous phenomenon of critical significance for the pharmaceutical industry, yet reports on cocrystal polymorphs are scarce. This study elucidates the crystal structure of the praziquantel (PZQ)-succinic acid (SUC) cocrystal polymorph, α-PZQ-SUC. The dominant supramolecular interaction in the cocrystal polymorph is the O − H···O hydrogen bond between SUC and PZQ, consistent with the supramolecular interaction in the previously reported β-PZQ-SUC polymorph. Comprehensive analysis, including thermal analysis, theoretical calculations, and solvent-mediated polymorphic transformation experiments, established a monotropic relationship between the two polymorphs, with α-PZQ-SUC demonstrating greater stability than β-PZQ-SUC. Both α-PZQ-SUC and β-PZQ-SUC enhance the solubility and dissolution behavior of PZQ, indicating their suitability for pharmaceutical applications based on improved pharmaceutical performance.

The Solid-Phase Transition of Carbapenem CS-023 Polymorphs and the Change in Helicity Observed in the Transition

Anti-solvent crystallization of carbapenem CS-023 was performed at 25 °C. The following results were obtained: (1) A solvate crystal, Form A (5/2 Ethanol·1/2 H2O), was recovered from 80 v/v% ethanol solution; (2) Form A transformed to Form H (4H2O) through solid-phase transition through the solvate-free polymorph, Form A-2, and Form A also transformed into Form C (1Ethanol·3H2O) through solvent-mediated transformation. In the present study, we found that Form C also transforms to Form H through the solid-phase transition through the solvate-free polymorph Form C-2. The three polymorphs, Forms A, H, and C, were composed of helical chain structures. However, there was an incomprehensible affair in the solid-phase transition among the three polymorphs. Namely, Form A comprised a left-handed helix. On the other hand, Form C’s and Form H’s helix chains were in a left- and right-handed helix complex, respectively. The solid-phase transition of Form A into Form H suggested a switch in helicity in the solid. We attempted to explain the helicity change in the solid-phase transition. As a result, we suggest that the over-absorption of water by Form A-2 at high humidity plays a vital role in the helicity change.

Crystallographic and Compositional Dependence of Thermodynamic Stability of [Co(II), Cu(II), and Zn(II)] in 2-Methylimidazole-Containing Zeolitic Imidazolate Frameworks.

We report the first systematic study experimentally investigating the effect of changes to the divalent metal node on the thermodynamic stability of three-dimensional (3D) and two-dimensional (2D) zeolitic imidazolate frameworks (ZIFs) based on 2-methylimidazolate linkers. In particular, the comparison of enthalpies of formation for materials based on cobalt, copper, and zinc suggests that the use of nodes with larger ionic radius metals leads to the stabilization of the porous sodalite topology with respect to the corresponding higher-density diamondoid (dia)-topology polymorphs. The stabilizing effect of metals is dependent on the framework topology and dimensionality. With previous works pointing to solvent-mediated transformation of 2D ZIF-L structures to their 3D analogues in the sodalite topology, thermodynamic measurements show that contrary to popular belief, the 2D frameworks are energetically stable, thus shedding light on the energetic landscape of these materials. Additionally, the calorimetric data confirm that a change in the dimensionality (3D → 2D) and the presence of structural water within the framework can stabilize structures by as much as 40 kJ·mol-1, making the formation of zinc-based ZIF-L material under such conditions thermodynamically preferred to the formation of both ZIF-8 and its dense, dia-topology polymorph.

Dissolution thermodynamics and polymorphic transformation behaviors of glutathione

Glutathione (GSH) is a bioactive oligopeptide which was widely used in sports, pharmaceutical and food industry. This paper compared the properties of two crystalline forms of GSH (Form α and Form β) in thermodynamics and explored the transformation of corresponding polymorph. The solubility data of GSH were determined by using the dynamic method in binary mixed solvents (methanol + water, ethanol + water, isopropanol + water, ethylene glycol + water) at temperatures ranging from 278.15 to 313.15 K. The solubilities of the two forms both increased with the increasing of mole fraction of water and temperature. The modified Apelblat equation, the CNIBS/R-K model and the Jouyban-Acree model were used to correlate the experimental solubility. The mixing thermodynamic properties of GSH in the binary mixed solvents were calculated by Van’t Hoff equation. Form β was supposed to be the stable crystalline form based on the thermodynamics analysis, which corresponded to the solvent-mediated transformation from Form α to Form β.

Design of Montelukast Nanocrystalline Suspension for Parenteral Prolonged Delivery.

BackgroundMontelukast (MTK), a representative leukotriene receptor antagonist, is currently being investigated as a potential candidate for treating Alzheimer’s disease. For potent and effective dosing in elderly patients, a parenteral prolonged delivery system is favored, with improved medication adherence with reduced dosage frequency.PurposeThis study aimed to design a nanocrystalline suspension (NS)-based MTK prolonged delivery system and evaluate its pharmacokinetics profile and local tolerability following subcutaneous administration.MethodsTo decelerate the dissolution rate, the amorphous MTK raw material was transformed into a crystalline state using a solvent-mediated transformation method and subsequently formulated into NS using a bead-milling technique. The MTK NSs were characterized by morphology, particle size, crystallinity, and in vitro dissolution profiles. The pharmacokinetic profile and local tolerability at the injection site following subcutaneous injection of MTK suspension were evaluated in rats.ResultsMicroscopic and physical characterization revealed that the amorphous MTK powder was lucratively transformed into a crystalline form in acidic media (pH 4). MTK crystalline suspensions with different diameters (200 nm, 500 nm, and 3 μm) were uniformly prepared using bead-milling technology, employing polysorbate 80 as suspending agent. Prepared crystalline suspensions exhibited analogous crystallinity (melting point, 150°C) and size-dependent in vitro dissolution profiles. MTK NSs with particle sizes of 200 nm and 500 nm provided a protracted pharmacokinetic profile for up to 4 weeks in rats, with a higher maximum drug concentration in plasma than the 3 μm-sized injectable suspensions. Histopathological examination revealed that MTK NS caused chronic granulomatous inflammation at the injection site, which resolved after 4 weeks.ConclusionThe MTK parenteral NS delivery system is expected to be a valuable tool for treating Alzheimer’s disease with extended dose intervals.

Baloxavir Marboxil Shows Anomalous Conversion of Crystal Forms from Stable to Metastable through Formation of Specific Solvate Form

Baloxavir marboxil is a novel cap-dependent endonuclease inhibitor of influenza. This study aimed to identify its polymorphs and their relationship with crystal engineering. Polymorph screening by evaporation gave forms I–III and solvate forms IV and V. Heating enabled the conversion of form III to form II, but did not enable that of forms I and II. The solvent-mediated transformation of the forms I–III by magnetic stirring in various solvents resulted in the formation of form I. These results indicate that form I is the stable form. However, all crystal forms transformed to form II after magnetic stirring in a 50% acetonitrile aqueous solution, which was not obtained from water or acetonitrile. The suspension in a 50% acetonitrile aqueous solution exhibited a novel X-ray diffraction pattern as shown in form VI. The measurement of the suspension by solid-state 13C-nuclear magnetic resonance revealed that the spectra of forms II and VI were similar. From these results, we conclude that the drug forms a solvate with both water and acetonitrile and spontaneously transforms to form II upon rapid desolvation under ambient conditions. This study elucidates the mechanism of unexpected convergence to a metastable form in a specific solvent and contributes to the crystal engineering of baloxavir marboxil.

Solvent-Mediated Polymorphic Transformations in Molten Polymers: The Account of Acetaminophen.

Solvent-mediated polymorphic transformations (SMPTs) employing nonconventional solvents (polymer melts) is an underexplored research topic that limits the application of polymer-based formulation processes. Acetaminophen (ACM), a widely studied active pharmaceutical ingredient (API), is known to present SMPTs spontaneously (<30 s) in conventional solvents such as ethanol. In situ Raman spectroscopy was employed to monitor the induction time for the SMPT of ACM II to I in polyethylene glycol (PEG) melts of different molecular weights (Mw, 4000, 10 000, 20 000, 35 000 g/mol). The results presented here demonstrate that the induction time for the SMPT of ACM II to I in PEG melts is driven by its diffusivity through the polymer melts. Compared to conventional solvents (i.e., ethanol) the mass transfer (diffusion coefficient, D) in melts is significantly hindered (Dethanol = 4.84 × 10-9 m2/s > DPEGs = 5.32 × 10-11-8.36 × 10-14 m2/s). Ultimately, the study proves that the induction time for the SMPT can be tuned by understanding the dispersant's physicochemical properties (i.e., η) and, thus, the D of the solute in the dispersant. This allows one to kinetically access and stabilize metastable forms or delay their transformations under given process conditions.

Counter Anion Effects on the Formation and Structural Transformations of Mo(vi)-Hydrazone Coordination Assemblies: Salts, Solvates, Co-Crystals, and Neutral Complexes

Complex salts [1H]X and [1H](XA)0.5·2MeOH, and co-crystals [1H]X·0.5VA (X = chloride or bromide, XA = chloranilate or bromanilate, VA = o-vanillin azine), comprising [MoO2(HL)(MeOH)]+ ([1H]+) cation (H2L = 3-methoxysalicylaldehyde isonicotinoyl hydrazone), were prepared either by solution-based synthesis or by mechanochemical synthesis. Whereas [1H]X salts were extremely sensitive to humidity, their stability could be reinforced by the azine incorporation into the complex network. Solvent-mediated transformations of [1H]X led to methanol co-ligand replacement and afforded complexes [MoO2(HL)X] (2Cl·MeOH, 2Cl, and 2Br·0.5MeCN). However, solvates [1H](XA)0.5·2MeOH, under the same conditions, gave stable complexes [1H](XA)0.5 in which methanol remained coordinated. The differences in the assembly’s behavior were attributed to the packing arrangements, the relative orientation of cations and anions, and interactions between them. Polymorph [MoO2(L)(MeOH)] (1), not attainable by other routes, was the only product when compounds [MoO2(HL)X] were treated with a weak base at low temperatures. Tetranuclear [MoO2(L)]4 and polynuclear [MoO2(L)]n (2) supramolecular isomers, concomitantly crystallized when the reaction was conducted solvothermally. All of the complexes were characterized using X-ray diffraction methods (SCXRD and PXRD), spectroscopic methods (ATR-IR and solution-state and solid-state MAS NMR), and elemental and thermal analyses. The cytotoxicity of the different types of compounds against THP-1 and HepG2 cells was also evaluated.

Inclusion of cyclodextrins in a metallosupramolecular framework via structural transformations

The inclusion of α-cyclodextrin and both α- and γ-cyclodextrins in a multilayer framework composed of d-penicillaminato AuI3CoIII2 complex anions and aqua sodium(i) cations via solvent-mediated structural transformations are reported.

Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile.

A new cocrystal of Norfloxacin, a poorly soluble fluoroquinolone antibiotic, has been synthetized by a solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. The new cocrystal exists in both anhydrous and monohydrate forms with the same (1:1) Norfloxacin/resorcinol stoichiometry. The solubility of Norfloxacin and the hydrated cocrystal were determined by the shake-flask method. While Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, the cocrystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher. The dissolution rate was tested at four biorelevant pH levels of the gastrointestinal tract: 2.0, 4.0, 5.5, and 7.4. In a first set of comparative tests, the dissolution rate of Norfloxacin and the cocrystal was determined separately at each pH value. Both solid forms showed the highest dissolution rate at pH 2.0, where Norfloxacin is totally protonated. Then, the dissolution rate decreases as pH increases. In a second set of experiments, the dissolution of the cocrystal was evaluated by a unique dissolution test, in which the pH dynamically changed from 2.0 to 7.4, stepping 30 min at each of the four biorelevant pH values. Results were quite different in this case, since dissolution at pH 2 affects the behavior of Norfloxacin at the rest of the pH values.

Solvent-Directed Transformation of the Self-assembly and Optical Property of a Peptide-Appended Core-Substituted Naphthelenediimide and Selective Detection of Nitrite Ions in an Aqueous Medium.

This study vividly displays the different self-assembling behavior and consequent tuning of the fluorescence property of a peptide-appended core-substituted naphthalenediimide (N1) in the aliphatic hydrocarbon solvents (n-hexane/n-decane/methyl cyclohexane) and in an aqueous medium within micelles. The N1 is highly fluorescent in the monomeric state and self-aggregates in a hydrocarbon solvent, exhibiting "H-type" or "face-to-face" stacking as indicated by a blue shift of absorption maxima in the UV-vis spectrum. In the H-aggregated state, the fluorescence emission of N1 changes to green from the yellow emission obtained in the monomeric state. In the presence of a micelle-forming surfactant, cetyl trimethylammonium bromide (CTAB), the N1 is found to be dispersed in a water medium. Interestingly, upon encapsulation of N1 into the micelle, the molecule alters its self-assembling pattern and optical property compared to its behavior in the hydrocarbon solvent. The N1 exhibits "edge-to-edge" stacking or J aggregates inside the micelle as indicated by the UV-vis spectroscopic study, which shows a red shift of the absorption maxima compared to that in the monomeric state. The fluorescence emission also differs in the water medium with the NDI derivative exhibiting red emission. FT-IR studies reveal that all amide NHs of N1 are hydrogen-bonded within the micelle (in the J-aggregated state), whereas both non-bonding and hydrogen-bonding amide NHs are present in the H-aggregated state. This is a wonderful example of solvent-mediated transformation of the aggregation pattern (from H to J) and solvatochromism of emission over a wide range from green in the H-aggregated state to yellow in the monomeric state and orangish-red in the J-aggregated state. Moreover, the J aggregate has been successfully utilized for selective and sensitive detection of nitrite ions in water even in the presence of other common anions (NO3-, SO42-, HSO4-, CO32-, and Cl-).

Ultrasound-assisted theophylline polymorphic transformation: Selective polymorph nucleation, molecular mechanism and kinetics analysis

In this paper, the ultrasound-assisted solvent-mediated polymorphic transformation of theophylline was explored in detail. The induction time and reconstruction time were significantly decreased by ultrasound, thereby decreasing the total transformation time and promoting the transformation process. The ultrasound-promoted efficiency of nucleation was different in three alcoholic solvents, which was difficult to explain by traditional kinetic effects. To resolve the above confusion, binding energies calculated by Density Functional Theory were applied to explore the relationship between the ultrasound-promoted efficiency of nucleation and solute–solvent interactions. Then, a possible molecular self-assembly nucleation pathway affected by ultrasound was proposed: the ultrasound could change and magnify the crucial effect of the specific sites of solute–solvent interactions in the nucleation process. Finally, the transformation kinetics with different effective ultrasonic energies was quantitatively analyzed by Avrami-Erofeev model, indicating that the dissolution element in the rate-limiting step was gradually eliminated by higher ultrasonic energy. Fortunately, the elusive crystal form V could be easily obtained by the ultrasound-assisted polymorph transformation. This proved to be a robust method to produce high purity form V of theophylline. The outcome of this study demonstrated that the proper ultrasonic irradiation had the potential to produce specific polymorphs selectively.

Phase transformation among multiple hydrates of creatine phosphate sodium in solution and in the vapor: A distinction between solution- and solvent- mediated transformation

Understanding transformation pathway and mechanism in multiple-hydrates-system is essential for controlling hydrate forms in the manufacture. In this work, the investigation of thermodynamic stability, transformation pathway and mechanism of creatine phosphate sodium (CPS) hydrates was performed in the water–methanol solvent and vapor environment with different relative humidity (RH) via in-situ Raman, ATR-FTIR, DVS, PXRD, and SEM. Results show that, a novel ternary phase diagram was presented, where seven phase regions are included but without an anhydrate form’s region. The stability of CPS·2H2O, CPS·4.5H2O, and CPS·7H2O depends on the water activity and temperature. Phase transformation can be achieved between any two CPS hydrates in solution, influenced by water content, temperature and solid loading. Meanwhile, phase transformation in the vapor environment was found to carry on via three types of mechanism, solid-state transformation, solvent-mediated transformation, and solution-mediated transformation, the concepts of which were frequently confused before. This work elaborates on the concept and reveals the mechanism of solvent- and solution-mediated transformation, as well as provides guides for controlling hydrate forms in multiple-hydrates-system.

Thermodynamic and kinetic studies on the polymorphic transformations of puerarin hydrates

Puerarin (PUE), a bioactive flavonoid from the plant Pueraria lobata, exists in two hydrated forms: monohydrate (PUEMH) and dihydrate (PUEDH). The aim of the present work was to explore the thermodynamic and kinetic mechanism of the polymorphic transformation of PUE, including the solvent-mediated polymorphic transformation (SMPT) of PUEMH to PUEDH and the solid-state polymorphic transformations (SSPTs) of PUEMH and PUEDH. PUEMH and PUEDH were identified as isolated and channel hydrate, respectively. The thermodynamic parameters (ΔG < 0, ΔH < 0, and ΔS < 0) indicated that the SMPT was a spontaneous, exothermic and entropy-decreased reaction. The facilitating roles of stirring rate and temperature on the SMPT were favored by the primary and secondary nucleation process of PUEDH. In addition, the results of SSPTs suggested that PUEMH and PUEDH would transform to two different anhydrates (PUEAH-I and PUEAH-II) upon heating, respectively. The dehydration rate of PUEMH was slower than that of PUEDH due to the stronger hydrogen bond interactions. The rate-limiting step for the dehydration of PUEMH was the diffusion of water molecules, resulting in the increased dehydration activation during the dehydration process, while the dehydration activation energy of PUEDH showed opposite trend due to the complicated crystallization process of PUEAH-II.

Crystal forms and phase transformation of 1,5-pentanediamine-terephthalate: a bio-based nylon 5T monomer.

Nylon 5T is one of the bio-based nylons, its raw material 1,5-pentanediamine is derived from biomass resources and produced by biological methods. 1,5-pentanediamine-terephthalate (PDA-TPA) is the monomeric salt for nylon 5T polymerization, and its own product quality has a significant impact on the performance of nylon 5T. PDA-TPA was prepared by anti-solvent crystallization in this study. It exists in two solid forms, a monohydrate [form (I)] and an anhydrous phase [form (II)]. The transition temperature of the two phases was around 65°C in the given ethanol-water binary (7:1) mixture. The characterization of monohydrate and anhydrate phases regarding structures and stabilities was carefully carried out using powder X-ray diffraction, single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy and Fourier transform infrared spectroscopy. The relationship between the molecular interactions of monohydrate and anhydrate phases under different packing architectures and their thermal behaviours was analysed and established. In addition, the relationships between the structures and thermal behaviours for the two solid forms were analysed and established. In addition, the effect of solvent on phase conversion, the relationships between the temperature and water activity, as well as the relative stability of monohydrate and anhydrate phases under different thermodynamic conditions, were investigated by solid-solid transformation and solvent-mediated transformation experiments. It was obvious that the transition temperature of monohydrate and anhydrate phases of PDA-TPA was significantly influenced by water activity, and the larger the value of water activity is, the higher is the transition temperature. These studies give insight into the transformation of nylon 5T monomer salt and contribute to the control of target crystal preparation.

The mechanism of solvent-mediated desolvation transformation of lenvatinib mesylate from dimethyl sulfoxide solvate to form D.

In this work, the mechanism of solvent-mediated desolvation transformation of lenvatinib mesylate (LM) was investigated. Two new solid forms of LM, a dimethyl sulfoxide (DMSO) solvate and an unsolvated form defined as form D, were discovered and characterized using powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, polarized light microscopy and Raman spectroscopy. To investigate the thermodynamic mechanism of solvent-mediated desolvation transformation (SMDT) from LM DMSO solvate to form D, solubilities of LM DMSO solvate and form D in binary solvent mixtures of DMSO and water at different water volume fractions and temperatures (293.15-323.15 K) were measured and correlated by non-random two liquids model. The solubility data were used to evaluate the thermodynamic driving force of the SMDT process from DMSO solvate to form D and the effect of the activities of water and DMSO on the transformation process. Raman spectroscopy was used to monitor in situ the solid phase compositions during the SMDT process from LM DMSO solvate to form D while the solution concentration was measured by the gravimetric method. The overall desolvation transformation experiments demonstrated that the SMDT process was controlled by the nucleation and growth of form D. Moreover, effects of operating factors on the SMDT process were studied and the results illustrated that water activity in solution was the paramount parameter in the SMDT process. Finally, a new SMDT mechanism was suggested and discussed.

Process intensified anti-solvent crystallization of o-aminobenzoic acid via sonication and flow

Process intensification via flow and ultrasound can make crystallization much more efficient, economic, reproducible and safe. However, successful application requires obtaining substantial knowledge on the effect of these techniques on process parameters and product properties. Investigation of such effects on polymorphism is still limited. In this work, batch and flow anti-solvent crystallization of o-aminobenzoic acid (o-ABA – 3 polymorphs) was conducted in silent and sonicated conditions. A new type of continuous flow sono-crystallizer was also demonstrated. In batch experiments, form – I nucleated at low anti-solvent volume and form – II at high anti-solvent volume. However, differences in mixing led to a significant change in the nucleated polymorph in flow experiments where concomitant nucleation of form – II and III was observed for all cases. Ultrasound did not affect the polymorph in either systems but did enhance the process by reducing induction time and increasing yield. Ultrasound in flow with a residence time of mere 2.5 s, provided a yield of nearly 50 %, which was 2.4 times more than silent conditions. Ultrasound can be considered as a useful technique for continuous production of metastable polymorphs as it provides high yield at low residence time thus, alleviating risk of solvent-mediated transformation.

Sequential structural transformations via pseudohalide-anion exchange reactions in Cu(II) supramolecular complexes

We report here the first example of sequential post-synthetic structural transformations via pseudohalide anion exchanges. Assembly of a rigid angular ligand 3-phenyl-5-(2-pyridyl)-4-(4-pyridyl)-4H-1,2,4-triazole (L240) with CuBr2 results in a 1D crystalline material {[Cu(L240)(Br)2](DMF)(H2O)}n (1). Immersing the green microcrystalline sample of 1 into an aqua solution of NaN(CN)2 (Na(dca)), the partly exchanged blue species {[Cu(L240)(dca)Br](H2O)}n (2) is obtained after ca. a week. Then, the fully exchanged green [Cu(L240)(dca)2]n (3) occurs after about ten days and 2 gradually disappears. Further immersing 1 or 3 into the solution of NaN3, a new deep green material defined as [Cu(L240)(N3)2]2 (4) can be obtained. These structural transformations can be ascribed to the solvent-mediated structural transformation, accompanied the change of crystallinity, shape, size, and color. Notably, 2–4 cannot be synthesized by direct assembly of L240 and Cu salts with those pseudohalide (dca– or N3–).

Thermodynamic and population balance models for solvent-mediated phase transformation of lansoprazole

In this work, two new polymorphs (monohydrate and ethanol solvate) of lansoprazole were first discovered and fully characterized. The transformation between two polymorphs of lansoprazole was investigated both experimentally and theoretically. The ternary phase diagram of the two polymorphic forms of lansoprazole in the binary solvent mixtures of ethanol and water at 15 °C, 25 °C and 35 °C was determined and the thermodynamic model was established. Raman spectroscopy was used to in situ monitor the solvent-mediated transformation from monohydrate to ethanol solvate of lansoprazole, while the solution concentration was measured by UV spectroscopy. The population balance models were established to analyze and compare the dissolution, nucleation and crystal growth process during polymorphic transformation. By combining the experimental and simulation results, the rate-controlling step, the changing profiles of the suspension density and the solid compositions of both polymorphs were investigated and discussed. Furthermore, the effect of temperature on the transformation process was also analyzed.

Solvent-Mediated Polymorphic Transformation of Famoxadone from Form II to Form I in Several Mixed Solvent Systems

This paper discloses six polymorphs of famoxadone obtained from polymorph screening, which were characterized by XRPD, DSC, and SEM. A study of solvent-mediated polymorphic transformation (SMPT) of famoxadone from the metastable Form II to the stable Form I in several mixed solvent systems at the temperature of 30 °C was also conducted. The transformation process was monitored by Process Analytical Technologies. It was confirmed that the Form II to Form I polymorphic transformation is controlled by the Form I growth process. The transformation rate constants depended linearly on the solubility difference value between Form I and Form II. Furthermore, the hydrogen-bond-donation/acceptance ability and dipolar polarizability also had an effect on the rate of solvent-mediated polymorphic transformation.