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Solvent-Mediated Nonoriented Self-Aggregation Transformation: A Case Study of Gabapentin Songgu Wu,†,‡ Mingyang Chen,†,‡ Sohrab Rohani,§ Dejiang Zhang,†,‡ Shichao Du,†,‡ Shijie Xu,†,‡ WeiBing Dong,†,‡ and Junbo Gong*,†,‡,∥ †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, China ‡ The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, China § Department of Chemical and Biochemical Engineering, the University of Western Ontario, London, Ontario N6A 5B9, Canada ∥ The Key Laboratory Modern Drug Delivery and High Efficiency in Tianjin, Tianjin University, Tianjin 300072, China S Supporting Information *

ABSTRACT: 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 solventmediated 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.

1. INTRODUCTION Crystallization is a widely applied technique in the chemical, petrochemical, food, and pharmaceutical industries.1 Considerable effort has been invested to develop crystallization processes for the production of crystalline compounds with good powder performance, i.e., morphology, size, and size distribution. The crystal shape and size distribution of the powder not only play an important role in determining the product solid-state properties, such as separation, compaction, flowability, packing, and dissolution but also have a considerable impact on the bioavailability of the active pharmaceutical ingredients (APIs). However, so far, there is no a general method for controlling the powder properties, especially in the pharmaceutical industry.2 Many APIs display various crystal forms with different physicochemical characteristics.3,4 The problems of polymorphism and phase transformation have been of prime concern to the pharmaceutical industry for many years. Some researchers have studied the mechanism and process of phase transformation.3,5−7 The mechanism of phase transformation is a controversial topic.8 A two-step phase transformation has been proposed in the inorganic materials industry.9 The mechanism of crystal growth is oriented aggregation. Two types of phase transformation mechanisms have been reported © XXXX American Chemical Society

in the organic materials industry: solid-state phase transformation (SSPT) and solvent-mediated phase transformation (SMPT).10−13 Many studies have reported the diversity of transformations during the solution-mediated process.14,15 Although solution-mediated phase transformation is common in practical applications, the process involves a few incomprehensible phenomena such as the effect of solvents and solubility of APIs, induction time of phase transformation, and aggregation of particles.16,17 The driving force of phase transformation is the Gibbs free energy difference between the two forms, and this driving force can be estimated by the solubility difference of the two forms. The thermodynamic and kinetic factors are considered to be dependent on each other in determining the phase behavior.18 The kinetic and thermodynamic behaviors of phase transformation are important for modification of the physicochemical properties of a drug.19,20 The phase transformation rate is affected by many operating parameters, especially the solvent. Therefore, it is worth studying the mechanism of the phase transformation and the effect of solvent on the phase transformation. Phase transReceived: April 14, 2017 Revised: May 23, 2017 Published: June 16, 2017 A

DOI: 10.1021/acs.cgd.7b00529 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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temperature for 4 h, the suspension was filtered through a 0.45-μm filter. The residue of undissolved powder was separated and identified to be form II by PXRD, indicating that no phase transformation occurred during solubility experiments. Samples of the saturated solutions were dried at 60 °C until the solvent was completely evaporated. The solubility of form II in these solvents was determined from the mass of the remaining crystalline material. Suspending excess amounts of form I in the saturated solution of form II and then stirring the suspension for 0.5 h in methanol, 1 h in ethanol, 2 h in propanol, and 1 day in acetone, acetonitrile, and ethyl acetate, respectively. During the stirring period, the suspended solid must be identified to be form I or a mixture of form I and form II by PXRD, indicating that the solution is saturated with respect to form I. The suspension was filtered. Samples of the saturated solutions were dried at 80 °C until the solvent including water was completely evaporated. The remaining crystalline material in the beaker is solventfree. The solubility of form I, which removed the water content, was determined from the mass of the solvent-free crystalline material. 2.2.3. Phase Transformation Experiments. Excess amounts of form II powder were dissolved in 150 mL of methanol, ethanol, propanol, acetone, acetonitrile, and ethyl acetate, respectively. Then the suspension was filtered, and the saturated solution of form II was obtained. For each experiment, 110 mL of saturated solution was added to 150 mL scale crystallizer, and then 4.4 g of form I was added to the solution. The slurry was agitated by a propeller-type agitator at room temperature. Because form I is monohydrate, when it dissolves in solvent, it will release water. In order to reduce the influence of water on the experiment, we prepared the saturated solution with respect to form II in methanol, ethanol, propanol, acetone, acetonitrile, and ethyl acetate, respectively. And the phase transformation was investigated in these saturated solutions. The SMPT is characterized by the phase transformation time, induction time, and active phase transformation time. The phase transformation time refers to the whole process from the beginning of the experiment until the transformation is complete; induction time refers to the initial period during which no phase transformation product is observed, and the time from the point when the stable phase appears until the transformation has fully completed is called the active transformation phase time.27 All of these parameters can be influenced by the solvent. 2.2.4. Dissolution Rate Test. The dissolution rate profiles of the GBP rod-like product and aggregates were determined using a rotating paddle dissolution tester (Guoming RC-6, China). The dissolution conditions were 200 mL of water as medium, 37 ± 0.2 °C, and 100 rpm. Accurately weighed samples (40.0 g) were placed in the dissolution medium, and 5 mL aliquot samples were withdrawn at given time intervals (5, 10, 20, 30, 40, 60, 80, 100, 120, and 150 min) and filtered using a 0.25-μm membrane syringe filter. Filtered samples were analyzed for GBP concentration by a gravimetric method. Each test was performed in triplicate, and the data are expressed as the mean value.

formation is a powerful method to modify the particle properties, such as morphology, the particle size, and crystallinity of the APIs. The model compound used in the present study is gabapentin (GBP), which is a structural analogue of γaminobutyric acid. It is an effective anticonvulsant for treatment of postherpetic neuralgia and epilepsy, and for prevention of seizures.21 The drug is currently marketed as an adjunct therapy for partial seizures. Meanwhile, it is also widely recommended to alleviate pain, especially neuropathic pain and migraine headache. It has been found to provide benefits in relieving pain and improving the overall quality of life in patients with chronic radiculopathy.22,23 GBP is known to exist as a zwitterion in three solvent-free forms: II, III, and IV, with form II being the most stable and form IV the least stable.24 Form I is the monohydrate. A hemisulfate hemihydrate and two polymorphic chloride hemihydrates are also disclosed. More recently, cocrystals involving GBP with different carboxylic acids were also reported.25 Although there are many forms, form II is the most stable and is the commercial form. In a practical production process, the products are obtained from form I by phase transformation in solvent. In this paper we report the results of our studies on the phase behavior and the effect of solvent on the phase transformation. The solubility of form I and form II of GBP in methanol, ethanol, propanol, acetone, acetonitrile, and ethyl acetate was measured to estimate the kinetic driving force of the phase transformation. Raman and Fourier transformed infrared (FTIR) spectroscopy were used to monitor the phase transformation process to determine the induction time and phase transformation period.26 We find a new phase transformation mechanism. The products are single crystals in alcohols, and they are aggregates in acetone, acetonitrile, and ethyl acetate. The individual crystallites of the aggregates are nonoriented aggregates with micron size. The shape of individual crystallites is needle-like, plate-like, or even block. The dissolution rate profile of raw powder and aggregates is determined.

2. EXPERIMENTAL SECTION 2.1. Materials. Form I and form II powder of GBP, with a mass purity of 99%, were supplied by Zhejiang Chiral Medicine Chemicals Co., Ltd., China. Methanol, ethanol, propanol, acetone, acetonitrile, and ethyl acetate were purchased from Tianjin Kewei Chemical Technology Co., Ltd., China. The solvents were all analytical grades and used without further purification. 2.2. Methods. 2.2.1. Analytical Tools. Thermogravimetry (TG), with a model TGA 1/SF thermogravimetric analysis system (MettlerToledo, Switzerland), was used to determine the form I. Powder X-ray diffraction (PXRD, D/max -2500, Rigaku, Japan) was used to confirm the forms of the solid. The morphology of the powder was observed by an analytical scanning electron microscope (TM3000, HITACHI, Japan). A Raman spectrometer (RXN2-HYBRID, Kaiser Optical Systems, Inc., Ann Arbor, MI) was used in situ to monitor the forms in the solid state during the phase transformation process. Attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR, ReactIR 15, Mettler-Toledo, Switzerland) was used to monitor the concentration of the solution. The water content of the suspended solid was determined by a volumetric KF titrator (V20, MettlerToledo, Switzerland). 2.2.2. Solubility of GBP. The solubility of form II in methanol, ethanol, propanol, acetone, acetonitrile, and ethyl acetate at room temperature (24 ± 2 °C) was measured by the gravimetric method. An excess amount of form II powder was dissolved in 60 mL of solvent to saturate the solutions. After being stirred at 200 rpm and room

3. RESULT AND DISCUSSION 3.1. Identification of Form I and Form II of GBP. GBP, chemically called 1-(aminomethyl) cyclohexaneacetic acid (C9H17NO2, CAS Registry No. 60142-96-3), is a derivative of c-aminobutyric acid (GABA). The chemical structure of GBP is shown in Figure 1. On the basis of the morphological observation, GBP form I has a plate-like shape and form II has a rod-like habit (Figure 2). The size is about 280−350 μm for form I starting material

Figure 1. Molecular structure of GBP. B



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Figure 2. Crystal morphology: (A) plate-like form I and (B) rod-like form II.

and 300−500 μm for form II particles. It is observed that the PXRD patterns of form I crystals have a very intensive peak at 6° 2θ (Figure 3), suggesting that form I exhibits preferred orientation.

Figure 4. Raman spectra of form I (black line) and form II (red line) of GBP.

Table 1. Solubility of Form I and Form II solvent

Figure 3. PXRD patterns of form I (black line) and form II (red line) of GBP.

methanol ethanol propanol acetone acetonitrile ethyl acetate

The dehydration temperature of form I is from 58.5 to 110 °C. The weight loss is 9.65%, and it is equal to the weight of one water molecule in form I (Figure S1 in the Supporting Information). It also proves the form is monohydrate. There is no weight loss before decomposition for form II. Raman spectra of both forms studied in this work are clearly different and therefore suitable for the phase transformation experiments (Figure 4). The distinct peaks at 620−680 cm−1 and 540−580 cm−1 can be chosen as the characteristic peaks to characterize the form of the suspension solid during the phase transformation process. 3.2. Solubility of GBP and Kinetic Driving Force for the Phase Transformation. The solubility is the important thermodynamic property for selecting a proper solvent and determining the relative stability of the different forms. The solubility data at room temperature for form I and form II in methanol, ethanol, propanol, acetone, acetonitrile, and ethyl acetate were determined experimentally. The results are presented in Table 1. The solubility of form I was converted into solvent-free form, and the contents of water were deducted. It is a water free version. It is more effective to compare the solubility difference of two forms, because form II is a solvent-free form.

a

solubility of form Ia 6.2815 1.1994 0.7118 0.5170 0.0214 0.0145

± ± ± ± ± ±

0.0165 0.0188 0.0155 0.0056 0.0049 0.0024

solubility of form II

solubility difference

± ± ± ± ± ±

0.4291 0.4169 0.2764 0.2106 0.0062 0.0052

5.8524 0.7825 0.4354 0.3064 0.0152 0.0093

0.0155 0.0191 0.0044 0.0104 0.0013 0.0037

The unit of solubility is g/100 g of solvent.

The solubility of GBP in methanol is much higher than that in other solvents. It is almost insoluble in acetone, acetonitrile, and ethyl acetate. The solubility difference refers to the difference between the solubility of form I and form II. The solubility difference decreases with solvent pairs in methanol and ethanol, propanol and acetone, acetonitrile and ethyl acetate, respectively. GBP is a zwitterion, so it is more soluble in polar solvent. The kinetic driving force of phase transformation is the solubility difference of the two forms. Therefore, the kinetic driving force in alcohols is much higher than that in acetonitrile and ethyl acetate. Form I is a monohydrate, and form II is a solvent-free form. They are not polymorphs. So it is normal that the solubility difference between the two forms is a little larger. 3.3. Characterization of Solvent Meditated Phase Transformation. During the solvent-mediated phase transformation, qualitative analyses of the solid phase were performed using Raman, PXRD, and scanning electron C



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microscopy (SEM), while the solution concentration throughout the transformation was monitored using attenuated total reflectance Fourier transform infrared (ATR- FTIR) spectroscopy. Because of the low solubility and the detection limitations of in-line analysis tool, ATR-FTIR could not be applied in acetone, acetonitrile, and ethyl acetate. For the sake of clarity, only the results of the phase transformation process in methanol are discussed as the examples to describe and discuss in detail. The results of other in-line experiments are shown in the Supporting Information (Figures S2−S6). Figure 5 shows the change in the ATR-FTIR characteristic peaks of GBP. The peak intensity represents the concentration

Figure 6. Time-dependent evolution of Raman relative intensity of GBP during methanol-mediated phase transformation.

Figure 5. Time-dependent evolution of ATR-FTIR relative intensity of GBP during methanol-mediated phase transformation.

of GBP. In the methanol solution, GBP preserves the ionized form. The peak in the range 2344 cm−1 to 2361 cm−1 represents the vibration of N−H. When form I is added to the saturated solution of form II, initially the solute concentration moves up due to the dissolution of form I until it reaches the saturation point of form I (Figure 5(1)). Subsequently, a constant concentration process occurs. It appears that the dissolution of form I and nucleation and growth of form II take place simultaneously. The end point of the second step is the vanishing point at which the form I particle dissolves completely. The third phase starts with a decline in solution concentration owing to the growth of form II. Finally, the solution concentration approaches the solubility of form II. After the second step was completed, there was no particle of form I in the solution. At this point, the Raman peak intensity of form I approached the lowest value, and the Raman peak intensity of form II reached the highest value. The results of Raman spectroscopy coincide with those of ATR-FTIR spectroscopy. From the results of Raman spectroscopy, the induction time is estimated 6 min, and the active phase transformation time is about 62 min (Figure 6). Because of the nonexistence of the obvious Raman characteristic peak in acetone, the induction time and active phase transformation time in acetone were estimated from the off-line measurement, such as PXRD and SEM. The PXRD patterns of the suspended solid at different intervals are shown in Figure 7. The induction times and active phase transformation times in different solvents were measured and compared (Figure 8 and Table S1 in the Supporting Information). We see that active phase transformation time correlates to the induction time the longer the induction time, the slower the phase trans-

Figure 7. PXRD patterns of suspended solid at different times during the phase transformation in acetone.

Figure 8. Induction time and active phase transformation time of SMPT from GBP form I to form II at room temperature depending on the used solvent.

formation. The phase transformation rate and induction time depend on the solubility of the two forms. The solubility of GBP in alcohol is high, especially for methanol, which maybe favors the phase transformation. The nucleation and transformation rate are the highest in methanol. The induction time is very short and the phase transformation is completed in an hour. Because of the low solubility, the induction time is longer than 18 h in acetone, acetonitrile, and ethyl acetate. The D



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Figure 9. SEM images of form II product obtained by SMPT in the different solvents, (A) methanol, (B) ethanol, (C) propanol, (D) acetone, (E) acetonitrile, (F) ethyl acetate.

transformation and the quality of the products. It is known that form I exhibits plate-like morphology, while form II crystallizes in rod-like crystals. The distinct difference in the particle shape allowed phase transformation to be monitored by using the microscopy methods. The SEM images of the solid products reveal that the crystal habit of form II varies according to the solvent used (Figure 9). Although the aspect ratio is not the same, the particles are all rod-like in alcohols. The aspect ratio of the particle in ethanol is the largest and that in methanol is the smallest. The particles obtained from ethanol or propanol have good dispersion, and those in methanol slightly aggregate in methanol. A similar particle size of the observed form II crystals implies that they nucleated simultaneously or in a short time interval. On account that no obvious aggregation or breakage was observed, we believe that form II nucleated by homogeneous primary

solubility of form II is the lowest in ethyl acetate, and the nucleation and transformation rate should be the lowest in this solvent. However, it is contradicted by the fact that the nucleation and transformation rates in acetone are the lowest. The total phase transformation time in acetone is about 119 h, while the time in ethyl acetate is about 75 h. The counterintuitive result indicates that the solubility is not the only factor that determines the phase transformation time. The solute−solvent and solute−solute interactions should be taken into consideration because of their possible influence on the nucleation kinetics.16,28,29 Thus, the balance of the strength of these interactions and the solubility determines the total transformation time from form I to form II. 3.4. Morphology Characterization of the Product Obtained from SMPT. We used the SMPT method to study the phase behavior of GBP, thereby enabling us to explore the effect of a series of solvents on the phase E



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Figure 10. SEM images of single aggregate obtained in (A) acetone, (B) acetonitrile, (C) ethyl acetate. (D) The cross-section of aggregate prepared in ethyl acetate.

primary nucleation from solution because it needs very high supersaturation and energy barrier. Research has shown that surface nucleation dominates in most of SMPT.32 In our case, it is obvious that such behavior occurs in acetone, acetonitrile, and ethyl acetate. 3.5. Mechanism of Phase Transformation and Nondirectional Self-Aggregation Phenomenon. Surface nucleation and growth are a common phenomenon, but aggregation under the confinement of original particle without template is very rare. In our previous work, we proposed a solvent penetration-mediated phase transformation mechanism.33 In this case, the products are aggregates and can retain the initial size and shape of the metastable form particles. And then the well-defined aggregate can be obtained. But the individual crystallites are needle-like shape and can only aggregate from the surface to the interior of the metastable form particle. It takes only a few seconds to complete the whole process of solvent penetration-mediated phase transformation. The phase transformation mechanism in this work is different from the mechanism of solvent penetration-mediated phase transformation. There are a few obvious differences in the process. First, the individual crystallites have a needle-like, block or plate-like habit; second, the individual crystallites have no specific aggregate direction and can aggregate in any direction; and third, the phase transformation process needs a few days. Explanation is needed as to why the individual crystallites aggregate without specific direction and how the aggregates can retain their initial shape and size of the metastable form particles. In addition, the mechanism of the phase transformation in acetone, acetonitrile, and ethyl acetate needs to be unraveled.

nucleation from saturated solution. The form II particles grew significantly at the expense of disappearance of form I crystals. The result in acetone, acetonitrile, and ethyl acetate is totally different from that in alcohols. The products are all aggregates, and the morphology of the aggregates is a plate-like shape. Some breakage is due to the stirring or the sample preparation for testing. It is surprising that the morphology and size of the aggregates are startlingly close to those of form I particles. We speculate that the predecessor of one aggregate is one particle of form I. The size of the aggregates is about 300 μm (Figure 10). The individual crystallite in the aggregate obtained in acetone is totally different from that obtained from acetonitrile or ethyl acetate. The individual crystallite has a needle-like shape in acetone, and the length is about 40−80 μm, while the width is only a few microns (about 3−7 μm) (Figure 10A). The aspect ratio is very large. The individual crystallite is flake or block shape in acetonitrile and ethyl acetate (Figure 10B,C), and its size is about 15−30 μm. It is worth noting that the individual crystallites have no specific aggregate direction. They are disordered and can aggregate in any direction. It does not follow the spherulitic growth in which a single crystal grows along the direction of the spherical. It is also different from the spherical agglomeration. Because individual crystallites in spherical agglomeration are often needle-like. Plank-like (flattened needle) crystallite is not infrequent; plate-like crystallite is rare.30,31 Although the aggregates in our experiments are not spherical, the individual crystallites are plate-like or even block habit. The aggregation process is concomitant with SMPT. Because of the low solubility, there is almost no solute molecular diffusion into the solution. The form II could not nucleate by homogeneous F



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Figure 11. SEM images of intermittent sampling analysis in acetone (A) t = 0 h, (B) t = 26 h, (C) t = 42 h, (D) t = 84 h.

Table 2. Water Content of the Suspended Solid at Different Times during the Phase Transformation in Acetone time

0

1

2

3

5

24

water content (%)

9.5 ± 0.2

6.7 ± 1.1

4.9 ± 0.5

4.0 ± 1.2

1.5 ± 0.3

0.3 ± 0.2

large number of needle-like crystals (Figure 11D). The individual crystallites in the aggregate have no specific directional, and they can aggregate only in the limited spacethe space of the initial particle. We call this process a nondirectional self-aggregation under confinement during phase transformation. Refer to studies by Munroe et al. We use the online spot technique−polarizing microscope to observe this process, and the results are shown in the Supporting Information (Figure S7).34 To verify our speculation, we analyzed the water content of the suspended solid at different times. The result was shown in Table 2. The water content of the suspended solid decreases rapidly over with time. The induction time of phase transformation is more than 5 h; therefore, in the first 5 h the suspended solid could not contain the form II particles. When the form I particles were suspended in acetone, there was an obvious dehydration process, especially in the first 5 h. The loss of water does not change the crystalline structure, so the XRD of the suspended solid is the same as that of form I. But it causes a large number of defects and rough surfaces, which can be the nucleation sites of form II. The results confirmed our speculation. To compare the solvent-mediated nonoriented self-aggregation transformation, with solvent penetration-mediated transformation, spherical agglomeration and spherulitic growth, the schematic diagrams of these four processes are presented in Figure 12.

Take the case in acetone as an example. The results of intermittent sampling analysis in acetone indicate that there was no obvious dissolution after the form I particles were added into the solution (Figure 11). The surface and interior of the form I particle is smooth (Figure 11A). After suspending in solution for a period of time, the particle became very rough and some porosity appeared in the particles. The particles were superimposed by many small layers. We speculate that the form I particle is unstable in acetone solution due to the extremely low water activity. The molecules of water in form I particles will escape from the structure. This causes the self-cleaving in the particle and produces many small lamellae (Figure 11B). The structure of the particle is like sliced bread. But the escaping of water molecules does not destroy the structure of the crystal, so the X-ray diffraction (XRD) of these particles is the same as that of form I particles. One can imagine that this defective particle must be unstable. The rough surface and defects provide many nucleation sites for the stable form. A few hours later, a large number of nuclei appear on these small lamellae (Figure 11C). Owing to the very low solubility, the particles do not dissolve, and there are almost no molecules of GBP diffuse out into the solution. These nuclei only can grow along the lamellae, and the molecules of GBP are transferred from the lamellae to the nuclei. Because of the various locations of the nuclei and the stable form, crystals have a variety of growth directions. The whole process advances slowly. After it is completely over, the product is an aggregate composed of a G



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Figure 12. Schematic diagrams of (a) spherulitic growth, (b) spherical agglomeration, (c) solvent penetration-mediated transformation, and (d) solvent-mediated nonoriented self-aggregation phase transformation.

Although the products obtained from the four methods are all aggregates or agglomerates, the mechanisms of these are different. Branching is the key step in the spherulitic growth. The spherulite can only result from the successive branching of a nucleus.35 It allows spherulites to fill spherical volumes. And the spherulites grow as radial disks.36 Spherical agglomeration sometimes is realized by using a bridging solvent.37,38 The individual crystals form the aggregates by adhesion.39 Crystal growth or ripening transforms the aggregates into concrete agglomerates.40 In the solvent penetration-mediated phase transformation, the individual crystals only can be needle-like shape, and the growth direction of the individual crystals is from the surface to the inside of the metastable particle. But in the method of solvent-mediated nonoriented self-aggregation phase transformation, the individual crystals can be needle-like, plate-like, or even block shape. There is no fixed direction of the aggregation, but the size and morphology of the aggregates are confined by that of the metastable particles. A transition solid state obtained from desolvation is needed in this process. And the solubility of API in the solvent should be very small, and the dissolution rate is incredibly slow. So the stable aggregates can keep the same shape and size of the metastable form particles. In this method, a bridging agent or mixed solvent is not essential. 3.6. Dissolution Rate Analysis. The dissolution profiles of GBP rod-like raw powder and aggregates prepared in acetone are shown in Figure 13. The dissolution rate of aggregates is faster than that of raw powder, especially in the first 5 min. The equilibrium concentration of the two samples is the same. But the equilibration time of aggregates is only about 20 min, but

Figure 13. Dissolution profiles of GBP rod-like raw powder (black line) and aggregates prepared in acetone (red line).

that of raw powder is about 30 min. This was mainly because the particle size of individual crystallite in the aggregates is much smaller than that of the raw GBP particles.41 The size of the individual crystallite is about several microns but that of raw powder is a few hundreds microns. According to the Noyes− Whitney equation, with the size of particle decreasing, the surface area of the particles increases accordingly, thereby the contact area of the particles is increased and the dissolution of the particles is also improved accordingly.42 The product obtained from solvent-mediated nonoriented self-aggregation transformation has an advantage over raw powder in terms of dissolution rate. Because of the metastable of form II in water, there is a phase transformation process. The transormation rate of aggregates is faster than that of raw material. It suggests that H



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the dissolution rate of form II is the controlling step in this phase transformation process. A good dissolution performance is advantageous in rapidly achieving the equilibrium.

4. CONCLUSION Results demonstrated that nucleation of GBP form II in methanol, ethanol, and propanol is homogeneous primary nucleation from saturated solution, and the final crystallization products are well-grown single crystals. Form I particles undergo a dehydration process and cause a self-cleaving phenomenon in acetone, acetonitrile, and ethyl acetate. Many defects are produced on the particle and contribute to heterogeneous nucleation of the stable form. The growth of these new nuclei is confined by the initial particles, and the products are well-defined aggregates. The shape and size of these aggregates coincide exactly with that of the metastable particles. The concept of solvent-mediated nonoriented selfaggregation phase transformation is proposed. But the morphology of the individual crystallite can be needle-like, plate-like, or even block shape. The aggregates have good performance in the dissolution rate, and it is beneficial to improve the bioavailability.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00529. Figure S1: The TGA curve of form I of GBP; Figure S2: The time-dependent evolution of ATR-FTIR relative intensity of GBP during ethanol-mediated phase transformation; the time-dependent evolution of Raman relative intensity of GBP during ethanol (Figure S3), propanol (Figure S4), and acetonitrile (Figure S5), ethyl acetate (Figure S6) mediated phase transformation; Table S1: The induction time and active phase transformation time of SMPT from form I to form II at room temperature depending on the used solvent; Figure S7: The microscope images of intermittent sampling analysis in acetone (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: 86-22-27405754. Fax: +86-022-27374971. ORCID

Sohrab Rohani: 0000-0002-1667-1736 Junbo Gong: 0000-0002-3376-3296 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful for the financial support of National Natural Science Foundation of China (21676179, 21376164, and 91634117), National 863 Program (2015AA021002), major project of Tianjin (15JCZDJC33200), and Innovative Group Project 21621004.

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