Gel Formation and Phase Transformation during the Crystallization of

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Gel Formation and Phase Transformation during the Crystallization of Valnemulin Hydrogen Tartrate Jinbo Ouyang,†,‡ Jingkang Wang,†,‡ Xin Huang,† Yuan Gao,† Ying Bao,†,‡ Yongli Wang,†,‡ Qiuxiang Yin,†,‡ and Hongxun Hao*,†,‡ †

School of Chemical Engineering & Technology, State Key Laboratory of Chemical Engineering and ‡Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin), Tianjin University, Tianjin 300072, P. R. China ABSTRACT: In this paper, the gel formation and its effect on the solution crystallization process of valnemulin hydrogen tartrate in a mixed solvent system were investigated. Some offline tools, such as differential scanning calorimetry (DSC) and Xray powder diffraction (XRPD), and online tools, such as FBRM and PVM, were used to monitor and analyze the process. It was found that the amorphous particles of valnemulin hydrogen tartrate were first observed and then gel formation followed and finally the amorphous state particles transformed into crystalline particles. To fully understand this process, the gel formation of this compound as well as the following transformation phenomenon were investigated in detail. It was concluded that gel was temporarily formed and acted as an intermediate phase during the transformation from an amorphous state to a crystalline state.

1. INTRODUCTION Crystallization is an important separation and purification process employed to produce a broad variety of materials in pharmaceutical, food, fine chemicals, and bulk chemical industries.1,2 In the pharmaceutical industry, the crystallization process is usually designed to obtain crystal products with high purity and ideal morphology.3 The crystallization process can be affected by many factors, such as types of solvent, temperature, cooling rate, dosing rate, additives, etc. For small molecule pharmaceuticals, the crystallization process is generally easy to control, and crystalline state products will normally be obtained. However, for large molecule pharmaceuticals, problems, such as formation of gels and phase separation, could be encountered if the crystallization processes are not well designed and controlled. The reasons for the gel formation are complicated, and many factors might affect the formation of gel.4,5 The phenomenon of gel formation is rarely studied in industrial crystallization but is well-known in the great industries of soap, leather, rubber, glass, and many others.6 A gel is a solid, jelly-like material that has a nonfluid colloidal network or polymer network that is expanded throughout its whole volume by a fluid.7 It will shrink when the pore liquid is removed or swell by adsorbing liquids.7 From a thermodynamic point of view, a gel is less stable than crystals, and it can transform into a crystal state in certain conditions.8,9 In the lipid−water system, depending on temperature and other variables, the gel can also exist for a long time.10 In the lipid−water system, the lipid is prone to self-assemble its structure into several states and the gel may be the transition phase during the transformation process from the liquid crystalline state to the stable coagel phase.11 In this transformation process, maybe the regional part of the lipid molecules trigger the phase transition of the gel to the subgel phase.12 In the lipid crystallization process, the lipid can undergo reversible gel−fluid phase transition upon heating and cooling.13 If the gel formation happens unexpectedly, it will change the medium and conditions of crystallization process © 2014 American Chemical Society

and prevent the nucleation and growth of compounds and consequently affect the crystallization process. As a result, the formation of the gel will affect the quality of the final product, such as purity, crystal size distribution, and even polymorphs in some cases.14−16 The gel formation is complicated, and two indispensable conditions are needed for gelation: (1) the presence of a gelator and (2) the interactions between gelators or between gelators and the solvents.4 Gelators could be nanometer or micrometer particles, low-molecular-mass gelators (LMWGs), and supramolecular polymers.4,17 In solution crystallization, nanometer or micrometer particles can serve as the gelators and lead to gelation.4 The interactions between gelators or between gelators and solvents could be hydrogen bonding, van der Waals forces, and electrostatic interactions which commonly exist between pharmaceutical molecules.18−23 Gel formation phenomena have been reported and studied by some researchers. Zhang24 has reported that, during the antisolvent crystallization of cefotaxime sodium (CTX), gelation occurs after certain amounts of antisolvent were added into the solution. Song25 and Zhu26 also found this phenomenon in the solution crystallization of clopidogrel hydrogen sulfate and tobracymin. However, most of these reports mainly focused on the phenomenon of gelation. The mechanism of the gelation and the transformation between gel and crystal is not well investigated. To fully understand the gelation and find a way to control it, it is of the utmost importance to investigate the transformation process and to understand the mechanism of the whole process. Valnemulin hydrogen tartrate is a new semisynthetic pleuromutilin derivative and it has been proposed for an oral administration to animals for the treatment and prevention of Received: Revised: Accepted: Published: 16859

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swine dysentery in the European Union.27 In the manufacturing processes of valnemulin hydrogen tartrate, crystallization is the final step which will directly determine the quality of the final products.28 It was found from our experiments that gel formation often occurs in the crystallization process of it. No literature about the gel formation and the subsequent transformation from amorphous to crystalline state of valnemulin hydrogen tartrate have been found and reported. To fully understand the crystallization process of valnemulin hydrogen tartrate and therefore find measures to control the quality of the final product, the gel formation and the transformation process was fully investigated in this work. The online tools, such as focused beam reflectance measurement (FBRM) and particle vision measurement (PVM), were used to in situ monitor the occurrence of gel. The offline tools, such as DSC and XRPD, were used to analyze and characterize the intermediate solid samples and the final products. It was found that the total crystallization process of valnemulin hydrogen tartrate undergo three steps.

acetate at 293.15 K. A clear solution was obtained by heating the suspensions to 338.15 K. Then 100 mL of butyl acetate was added into the clear solution at dosing rate of 2 mL/min. The solution was held at 338.15 K for 1 h with agitation speed of 300 rpm. At this stage, the solution was still clear. Then, the solution was cooled to 283.15 K at cooling rate of 0.2 K/min and held at 283.15 K for several hours until a lot of crystals emerged and equilibrium was achieved in solution. To investigate the gel formation and the following transformation, PVM and FBRM were used to in situ monitor the whole process. The probes were immersed into the solution when the temperature reached 333.15 K. The solid state of the product was identified by using XRPD and DSC analysis. In this study, in order to clearly observe the gel formation, the crystallization experiments were also carried out in a 10 mL glass vessel with the same concentration as above experiments. The glass vessel was inserted into a thermostat, the temperature of which was monitored and controlled by the CrystallinePV Reactor (Avantium, Netherlands) with temperature uncertainty of ±0.01 K. The experimental procedure was the same as the above experiments. The CrystallinePV Reactor can take real time images of the whole experimental process by using a microscope equipped with a camera. A polarizing microscope was also used to characterize the gel structure.

2. EXPERIMENTAL SECTION 2.1. Materials. Valnemulin hydrogen tartrate (supplied by Hubei Longxiang Chemical Co., Ltd. of China) was used without further purification. Its mass fraction purity is higher than 98%, which was determined by HPLC (Type Agilent 1100, Agilent Technologies, USA). Analytical-grade N,Ndimethylformamide and butyl acetate with mass fraction purity higher than 99.8% were purchased from Tianjin Kewei Chemical Co., Ltd. of China. 2.2. Solid-State Characterization Methods. In order to identify the solid state of valnemulin hydrogen tartrate used in the experiments, the X-ray powder diffraction (XRPD) patterns of the experimental samples were measured by the Cu Kα radiation (1.5405 Å) in the 2-theta range from 2° to 35°. The data collection was carried out on Rigaku D/max-2500 (Rigaku, Japan) with scanning rate of 1 step/s. In addition, the DSC data of amorphous and crystalline valnemulin hydrogen tartrate were measured by DSC (DSC 1/500, Mettler-Toledo, Switzerland) under protection of nitrogen. The sample amount was about 5.0 mg. The heating rate was set at 10 K/min. The measurement uncertainties were estimated to be approximately ±2%. 2.3. Process Analysis Tools. A laboratory scale FBRM (model G400) coupled with iC FBRM software from Mettler Toledo was applied to detect the particle size distribution with a interval of 10 s during the gel formation. Images of the transition process were taken by using a Lasentec PVM (model V819) with an update rate of 1 image per second. An optical camera (Canon 650d) and a polarizing microscope (OPTEC, BK5000, China) were used to observe the morphology of the crystals and gels. 2.4. Crystallization and Transformation Process. Crystallization experiments were performed in a 350 mL glass jacketed crystallizer. The temperature of the jacketed glass vessel was controlled by a thermostat (Julabo CF41, Germany) with temperature uncertainty of ±0.01 K. An overhead mechanical agitator was used to mix the solution. The cooling crystallization of valnemulin hydrogen tartrate was performed in 5% (volume) N,N-dimethylformamide/butyl acetate solvent with concentration of 5 g of valnemulin hydrogen tartrate/200 mL of solvent. At the beginning of the crystallization experiments, 5 g of valnemulin hydrogen tartrate was added into 10 mL of N,N-dimethylformamide and 90 mL of butyl

3. RESULTS AND DISCUSSION 3.1. Identification of Amorphous Form and Crystal Form of Valnemulin Hydrogen Tartrate. In this work, two forms of valnemulin hydrogen tartrate, namely amorphous form and crystalline form, were successfully prepared. The X-ray powder diffraction (XRPD) patterns of them are shown in Figure 1. The amorphous form has no apparent X-ray

Figure 1. X-ray powder diffraction patterns of the crystal form and the amorphous form of valnemulin hydrogen tartrate.

diffraction peaks while the crystalline form has many diffraction peaks. From the maximum of the broad scattering peak in Figure 1, the repeat distance of the amorphous phase was estimated. To estimate the repeat distance, the quasi-crystalline peak was chosen by XRD unimodal fitting and the residual error of the fitting is 7.61%. The value of the repeat distance calculated by the Bragg equation is 7.7780 nm. From this data, it can be deduced that the molecules in the amorphous phase are more likely to assemble regularly and finally form a stable crystal phase. The two forms of valnemulin hydrogen tartrate 16860

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confirmed by the third and fourth PVM images in Figure 4. When the solution temperature was further cooled after gel formation, there was a sharp increase in the counts of particles shown by FBRM data. At the same time, the fifth and sixth PVM images in Figure 4 showed that both particle amounts and particle sizes increased obviously. The form of the particles at this stage was determined to be crystalline state by XRPD and DSC, which are shown in Figures 1 and 2, respectively. 3.3. Gel Characterization. To further observe and verify the gel formation and the subsequent transformation during the crystallization of valnemulin hydrogen tartrate, the process is shown visually by pictures in Figure 5. During the cooling of the hot supersaturate solution, fiber-like aggregates appeared in the solution first, which were confirmed to be amorphous particles. Afterward, the aggregates intersected with each other until opaque gels were formed. The gel remained stable and stuck to the glass vessel wall and bottom tightly. In addition, the Tyndall effect which can confirm the existence of gel occurred in solution, as shown in the third images in Figure 5. Finally, crystalline particles with needle shapes were observed in the final picture of Figure 5. The polarizing microscope was also used to characterize gel and the results are shown in Figure 6. It can be found that the internal structure of the gel contains lots of pores filled with liquid. It can also been seen that there are many black lumps in the right photo in Figure 6, which indicates the existence of amorphous particles in the gel. 3.4. Transition Mechanism. Based on above results, a schematic presentation of the whole crystallization process of valnemulin hydrogen tartrate is depicted in Figure 7. Upon cooling the solution, nucleation take place like other common material. However, not like the common crystallization process, the nuclei formed here have no crystal structure. They assemble into the amorphous structure. Due to the instability of amorphous particles and its strong interactions with liquid, gels are formed subsequently. The gel can remain stable for about several hours if the temperature of the system is maintained at about 290−310 K. However, if the temperature of the system is decreased below 285 K, the structure of the gel will be destroyed step by step. The amorphous particles in the gel structure will transform into the crystalline state, which obeys the thermodynamic law because crystal is the most stable state of solid material. So in the transformation process, the gel serves as a medium state for valnemulin hydrogen tartrate. The whole transformation process can be divided into two steps: (1) after nucleation, the amorphous state particles were absorbed into the liquid to form gel structure and (2) as the temperature decreased, the network structure of gels was destroyed and the internal structure of the particles was rearranged into the crystalline state. As mentioned above, two indispensable conditions are needed for the gelation of valenmulin hydrogen tartrate. In this case, the amorphous particles act as the role of gelators. In addition, the intermolecular forces between valnemulin molecule and solvent molecule, N,N-dimethylformamide, are expected to be strong enough to maintain the temporary 3D-network structure of the gel. According to the structure of valnemulin, the valnemulin molecule contained many function groups, such as −NH2, −COO−, −OH, and −CONH−. They have the ability to form hydrogen bonds with solvent molecules, which might provide the necessary intermolecular forces for gel formation.29

are also characterized by using DSC analysis, as shown in Figure 2. The crystal form has an obvious melting peak at about

Figure 2. DSC plots of the crystal form and the amorphous form of valnemulin hydrogen tartrate.

375 K while the amorphous form has no apparent melting peak. The amorphous form undergoes glass transition at 330 K. Both of these two forms of valnemulin hydrogen tartrate will decompose at about 450 K. 3.2. Monitoring of Crystallization Process. The cooling crystallization of valnemulin hydrogen tartrate is performed in 5% (volume) N,N-dimethylformamide/butyl acetate solvent with concentration of 5 g of valnemulin hydrogen tartrate/200 mL of solvent. The gel formation and subsequent transformation were in situ monitored by FBRM and PVM. The FBRM data during the whole process are shown in Figure 3.

Figure 3. Change of FBRM data during gel formation and subsequent transformation of valnemulin hydrogen tartrate.

From all the data, the whole crystallization process of valnemulin hydrogen tartrate can be divided into three stages. When the solution was cooled, the first increasing of particle counts from FBRM data indicated the appearance of the amorphous particles, which can also be clearly seen in the first and second PVM images in Figure 4. The particles at this stage were determined to be the amorphous form by XRPD and DSC, which are show in Figures 1 and 2, respectively. Upon further cooling, the particle counts shown by FBRM decreased suddenly. It corresponded to the gel formation. This was also 16861

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Figure 4. PVM images of valnemulin hydrogen tratarte during the whole crystallization process.

conditions change and then the amorphous product will transform into the crystalline state product consequently. The total crystallization process of valnemulin hydrogen tartrate can be divided into three steps: (1) the formation of amorphous particles of valnemulin hydrogen tartrate, (2) the formation of gel, (3) the transformation from amorphous state to crystalline state valnemulin hydrogen tartrate. The gel formation is the intermediate or transitional stage during the whole crystallization process of crystalline state valnemulin hydrogen tartrate.

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Figure 5. Pictures of amorphous−gel−crystal transition process (the inlet of the third picture shows the Tyndall effect of the gel).

AUTHOR INFORMATION

Corresponding Author

*Tel: +86-22-27405754. Fax: +86-22-27374971. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research is financially supported by National Natural Science Foundation of China (No. 21376165) and Key Project of Tianjin Science and Technology Supporting Programme (No. 13ZCZDNC02000).

Figure 6. Optical and polarizing microscope photos of gel.

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REFERENCES

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Figure 7. Schematic presentation of the total crystallization process of valnemulin hydrogen tartrate.

4. CONCLUSIONS In this study, the crystallization process of valnemulin hydrogen tartrate was investigated in detail. It was found that amorphous state valnemulin hydrogen tartrate would crush out first and then the gel would be formed during the following further crystallization process of valnemulin hydrogen tartrate. However, since the amorphous state of valnemulin hydrogen tartrate is not stable, the gel structure will be destroyed when 16862

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