Solution-Mediated Polymorphic Transformation: From Amorphous to

Article

Solution-Mediated Polymorphic Transformation: From Amorphous to Crystals of Disodium Guanosine 5#-Monophosphate in Ethanol Fengxia Zou, Qiao Chen, Pengpeng Yang, Jingwei Zhou, Jinglan Wu, Wei Zhuang, and Hanjie Ying Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b01190 • Publication Date (Web): 21 Jun 2017 Downloaded from http://pubs.acs.org on June 29, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Industrial & Engineering Chemistry Research is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Industrial & Engineering Chemistry Research

Solution-Mediated Polymorphic Transformation: From Amorphous to Crystals of Disodium Guanosine 5′-Monophosphate in Ethanol Fengxia Zoua,1, Qiao Chena,1 , PengPeng Yanga, Jingwei Zhoua,c, Jinglan Wua,c,, Wei Zhuanga,c,*, Hanjie Yinga,b,c,*

a

College of Biotechnology and Pharmaceutical Engineering, National Engineering

Research Center for Biotechnology, Nanjing Tech University, Nanjing 210009, China b

State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing 210009, China

c

Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University, Nanjing 211816, China

1

To whom contributed equally to this article

*To whom correspondence should be addressed. Contact information: Dr. Wei Zhuang E-mail: [email protected] Prof. Hanjie Ying E-mail: [email protected]

1 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract Solvent-mediated transformation of disodium guanosine 5′-monophosphate (5′-GMPNa2) from amorphous to hydrated crystal phases was studied. The SMT process is dominated by the dissolution of the amorphous form and nucleation and growth of the crystal polymorph. The kinetic estimation based on population balance equation was carried out according to experimental data, including polymorphic fraction in the solid phase, solute concentration, and crystal size distribution. Furthermore, independent seeded batch experiments were carried out to estimate the kinetic parameters. The experimental data showed that the nucleation and growth of the crystal polymorph occurred shortly after the dissolution of the amorphous form. The estimated growth, nucleation, and dissolution rates indicated that the solution-mediated transformation was governed by the nucleation and growth of crystal polymorph. We believe that the results hold great importance toward understanding the transformation process of 5′-GMPNa2, which provides theoretical guidance for producing its specific forms, and possibly those for other pharmaceuticals and chemicals as well. Keywords: disodium guanosine 5′-monophosphate, solution-mediated transformation, kinetic estimation, nucleation and growth determined transformation


Page 2 of 36

Page 3 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1. Introduction Crystallization has been widely used as an important purification method for solid products in chemical, pharmaceutical and food industries. In food and pharmaceutical manufacturing, crystallization of an active pharmaceutical ingredient (API) in the correct form is vital, since the ingredient will remain in this form in the final product and during its shelf-life 1, 2. Therefore, polymorphs have attracted much attention from chemical and pharmaceutical researchers

3, 4

. As you know, different

polymorphic cocoa may have different melting point, as as to have different flavor. Polymorphism is a kind of widespread phenomenon of solid compound to crystallize in different crystalline forms. Different polymorphs often have different functions and physical properties, such as bioavailability, stability, melting point, structural energy, and particle morphology. Different polymorphic cocoa butter may have different melting point, only β-form has melting point about 36.4℃, which is near people’s body temperature, so as to have a good flavor just for melting in mouth. 5

As a result, it is essential to investigate the properties of all polymorphic forms of

the compound in detail, and the mechanism of their inter-conversion when developing the manufacturing process

6, 7

. A good understanding of the mechanism and kinetics

of the polymorphic transformation is of great help in obtaining the desired form of crystals in the industrial crystallization process. Based on different medium, the common mechanism of polymorphic transformation can

be divided into solid-solid

transformation (SST) and



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 36

solution-mediated transformation(SMT). Like crystallization in solution, the presence of solvent surrounding often promotes the phase transition. So this kind of transformation in solvent surrounding is called SMT. During anti-solvent crystallization, the transformation process should be considered as SMT. Extensive research has focused on the mechanism of polymorph transformation 8, including the following three main mechanisms: solid-state 9, 10, solution-mediated 1, 11, 12

, and interface-mediated transformations

13, 14

. The crystallization of polymorphs

from solutions generally involves three stages: dissolution of the metastable phase, nucleation of the stable phase, and growth of the stable phase 15. It follows Ostwald’s rule of stages

16

, which indicates that the initially formed crystals will be the least

stable owing to their smallest reduction in free energy, and that crystals have a thermodynamic tendency to convert to a more stable form via solution-mediated transformation 7. In recent years, some particle analysis technique (PATs) have been widely used to monitor and control the transformation process during crystallization, especially in pharmaceutical ,fine chemical and food industries

17, 18

. Off-line techniques such as

powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermo gravimetric analysis (TGA), and scanning electron microscopy (SEM) are often used to identify the polymorphs to qualitatively analyze this process

15, 19

techniques including focused beam reflectance measurement (FBRM) spectroscopy

. In situ

20

, Raman

7, 21

, attenuated total reflection-Fourier transform infrared spectroscopy

(ATR-FTIR) 22, and near-infrared (NIR) spectroscopy 23 can be applied to analyze the 4 ACS Paragon Plus Environment

Page 5 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


transformation kinetics quantitatively. Particle vision measurement (PVM)

24

can be

used to follow the evolution of crystal morphology during the process. Both the off-line and on-line techniques can provide valuable information about the polymorphic transformation. Disodium guanosine 5′-monophosphate (5′-GMPNa2), is an important substrate used for preparing RNAs, also is a kind of drug intermediate and food additives. It is produced by fermentation, from a mother liquid that contains many impurities and unknown ingredients. Furthermore, it is known in at least four polymorphs plus an amorphous form.25-28. Understanding its polymorphic transformation will improve the quality of the final product and facilitate the scale up process. The amorphous and I forms are stable, when improper processing conditions are used, the amorphous form is easily obtained, which is undesirable since it prolongs the operation time and lowers the product quality. The transformation of 5′-GMPNa2 in methanol-water binary solution has been studied

29-31

; however, there was no explanation of the

mechanism or kinetic estimation. Our group had previously examined the metastable zone and induction time of the amorphous form 32, 33. In this study, our first goal is understanding the process and mechanism of the transformation of 5′-GMPNa2 from the amorphous to the stable I-form hydrate crystal in ethanol-water aqueous solution under different crystallization conditions, using both on-line and off-line techniques. Then, the next question is how to transform the amorphous form into a specific crystal form, such as certain metastable forms that



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

sometimes have strong pharmaceutical effects. Also, the associated kinetics was studied to determine the key step. Three important factors like dissolution of metastable phase, nucleation and growth of stable phase, that are crucial in the transformation process were compared, based on the transformation time from FBRM data. Last but not the least, we proposed a mechanism for this transformation process, and utilized it to obtain the target polymorph (I) experimentally.

2. Material and methods 2.1 Materials 5′-GMPNa2 in the amorphous form with a purity of ≥95% was obtained by crystallization from fermentation feed liquid (supplied by Tongkai Biotechnological Co. Ltd.). The I-form crystals (purity ≥ 99.5%, supplied by XJTIDE Co. Ltd.) were used as seed during the transformation process. Reagent-grade ethanol (≥ 99.7%, supplied by Shanghai Chemical Reagent Co., China) was used as the anti-solvent. De-ionized water was generated by an ultra-pure water system (YPYD Co., China).

2.2 Transformation Experiments The experiments were implemented in a 1 L jacketed glass crystallizer equipped with an impeller and a thermostat controlled by periodic water bath. The agitation speed was kept at 150 rpm for all operations. The GMPNa2 under-saturation solution in water was prepared by dissolving a certain amount of amorphous crystal in 250 mL of water at a given temperature. After 1 h of dissolution time, a given amount of ethanol was added into the jacket, followed by the addition of a certain amount of I-form


Page 6 of 36

Page 7 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


crystal seeds, and the time of the seed addition was recorded. An FTIR probe was also inserted into the crystallizer for on-line monitoring of the solute concentration in the mother liquid, and a FBRM probe was used to monitor the whole transformation process and obtain on-line data of the chord length of the crystal in different forms. The PVM images were taken at intervals of 1 min to monitor the morphological change during the SMT process. About 6 samples were taken at different transformation stages. After filtration, the solid was dried at 303.15±0.01 K for about 2 h, and then analyzed with PXRD and microscopy to obtain the off-line transformation data. After transformation, an additional 400 mL of ethanol was also added into the crystallizer until the concentration of mother liquid would not changing. At the end of the experiment, the suspension was filtered and the solid was dried at 303.15 K. The size distribution of the obtained crystals was measured with a Beckman S3500 laser diffraction particle size analyzer.

2.3 On-Line monitoring of liquid concentration ATR-FTIR spectroscopy was used to monitor the solute concentration in the liquid phase during all the experiments. An ATR-FTIR ReactIR15 system (Mettler-Toledo, Switzerland) was used, equipped with a 9.5 mm×1.5 m fiber, a DiComp immersion probe, and a diamond as ATR crystal. The spectra were collected with a resolution of 977 cm-1 and averaged over 256 scans. A multivariable model was used to estimate the solute concentration, using a calibration curve developed that includes different variables such as the temperature, anti-solvent content, and solute



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

concentration. The spectra data information and the calibration curve were shown in Figure S1 and Figure S2, respectively.

2.4 Off-line powder X-ray diffraction The PXRD methods used to measure the polymorphic content during the transformation process were based on the literature, with ex situ calibration using prepared polymorphic mixtures (either in suspension or as dry powder). No influence of the crystal size on the calibrated signal has been reported. In this work, we have calibrated the polymorphic content of 5′-GMPNa2 in a similar way. In the first step, a series of dry powder samples with different mass ratios ranging from 0-1 of amorphous and crystalline particles were measured in the off-line PXRD system. The PXRD data was disposed by software JADE to calculate the degree of crystallinity of each sample and fitted by suitable line to calculate the standard curve. The details of standard curve was shown in S3. Then, the polymorphic compositions of 16 samples obtained at different steps during the crystallization process were determined with this standard curve. The patterns were recorded in the 2 range of 5–60° with steps of 0.01° and dwelling time of 2 s/step.

2.5 Solubility measurement The solubility of amorphous and crystalline 5′-GMPNa2 in water and mixed solvents (10, 20, 30, and 40 mol% ethanol in water (E-W)) was determined at temperatures ranging from 298.15 to 318.15 K. The measurement process has been described in a previous work.34

2.6 TG-DSC measurement 8 ACS Paragon Plus Environment

Page 8 of 36

Page 9 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The thermal properties of the amorphous and crystalline products were determined by DSC and TGA using a NETZSCH STA 449F3 system. Samples were accurately weighted into aluminum pans and sealed with a crimper. The sealed aluminum pans were heated to 30–600 °C at a heating rate of 10 ℃/min under a dry nitrogen purge (20 cc/min).

2.7 Kinetic experiments A series of experiments were implemented to estimate the dissolution rates of the hydrate crystal form at 30 ℃ in 250 g saturated solution. Then, 25–40 g of the amorphous form was sieved to a narrow particle size distribution, and added to the solution. The concentration of the solute was detected by ATR-FTIR in order to estimate the parameters of dissolution kinetics of the amorphous form. Also, several batch crystallization experiments seeded with hydrate crystals were carried out to estimate the growth kinetics of these crystals. The experimental process is similar to that described in Section 2.2. Furthermore, FBRM was employed to identify that no significant nucleation counts occurred during the desupersaturation experiments. Such nucleation would be evidenced by a sudden increase in the number of small chord lengths (1-10 µm), which was never observed in this study.

3. Mathematical model 3.1 Population balance model A mathematical model of the crystallization of 5′-GMPNa2 and the solvent-mediated transformation (from the metastable amorphous to the stable hydrate 9 ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 36

crystal form) is presented in this section, based on population balance equations. These equations are widely used to estimate the parameters in Table 2 by combining equations of nucleation, growth, and dissolution obtained from different experiments. Assuming a perfectly mixed batch process during all anti-solvent crystallization, size-independent growth, and the absence of agglomeration and breakage, the population balance equations (PBEs) can be written as 35:

+

+ = 0

(i = amorphous and crystalline polymorphs

(1)

where t is the time, L is the crystal size, ( is the number density of particles, is the growth rate of the corresponding polymorph, and V is the solution volume. The driving force of crystallization is supersaturation ratio, ) , which in the case of two different polymorphs is regarded as the ratio between the actual solute concentration c and the solubility of the corresponding polymorph *∗ : ,

) = , ∗

(i = amorphous and crystalline polymorphs)

(2)

The mass balance is also important in solving PBEs by the moment method. The value of c can be obtained through material balance in the following equation： ./ .

=∑

1, 1

= ∑ −345, 7 ( 89 :8

(3)

where 7 and 45, are the solid density and the volume shape factor of the i-th polymorph, respectively. From previous work ,the value of volume shape factor here is 0.56.32 The densities of crystalline polymorph is 1560 kg/m3, while for amorphous form is 1340 kg/m3 . The following initial and boundary conditions apply: 36 10 ACS Paragon Plus Environment

Page 11 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


c;0) = *

(6)

?

where @ is the nucleation rate and (,< represents the initial particle size distribution of the polymorph i.

3.2 Crystallization kinetics A more accurate study of the crystallization kinetics can be carried out using on-line and off-line measurements of the solid-state polymorph content, solute concentration, and crystal chord length distribution. In this study, the in-situ experimental data combined with parameter estimation algorithms were used to estimate the kinetics of the hydrate crystal polymorph including nucleation and growth, as well as the rate of the transformation from amorphous to hydrate crystal polymorphs. Since the amorphous phase was produced by burst nucleation, and the seeds were added within 30 min, the nucleation and growth of the amorphous form can be neglected. Hence, in this work we only consider the dissolution of the amorphous form, and the nucleation and growth of the hydrate crystal. 3.2.1 Dissolution rate of amorphous form In SMT process, the dissolution of the metastable polymorph becomes a dominant phenomenon with time. The measured solute concentration and solubility of



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 36

the amorphous form were used to estimate its dissolution rate according to the following Sherwood-based equation 36: ABCDEFGDHI = 4J ;)BCDEFGDHI − 1)

(7)

where D is the dissolution rate and 4J is the dissolution parameter. When the supersaturation of the amorphous form was above that of the hydrate crystal, the growth rate of the crystalline polymorph was substituted by the dissolution rate of crystalline polymorph. 3.2.2 Nucleation parameter estimation for hydrate crystal polymorph In this study, the nucleation of hydrate crystals occurs in the presence of amorphous form, and seeds of the hydrate crystal were used. Therefore, a typical secondary nucleation process is discussed here for seeds were added in such system. In addition, during the transformation, the solute concentration remains at the solubility of the amorphous form, so the effect of supersaturation could not be studied here. A simplified expression for the nucleation rate of the hydrate crystal polymorph can be written as .11 P

QR S̅PQU @,EKIBL = 4MN OBCDEF

(8)

where B is the nucleation rate , OBCDEF is the mass of the amorphous form, and 4MN , 4M9 , and 4MV are empirical parameters. S̅ is the mean specific power input, which can be estimated using a power number correlation method 37:

S̅ =

Z WX 1YX [U

(9)


Page 13 of 36

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


where \F is the power number for the type of stirrer used, :CF is the impeller diameter, (I is the stirring rate, and V is the reactor volume. For a two-half-moon blade impeller, the estimated power number is 0.6. 3.2.3 Growth parameter estimation for hydrate crystal polymorph The growth of hydrate crystal polymorph was studied through seeding with the crystal polymorph in the absence of any amorphous seeds. The resulting supersaturation can be used to either grow the existing crystal seeds or form new crystalline and/or amorphous nuclei. The following equation was applied to the growth of crystals 37: ,EKIBL = 4?N ;),EKIBL − 1)P]R ^ ;P]U⁄_`ab[cde fN)

(10)

where G is the growth rate and 4?NfV are growth kinetic parameters. In Eqn. 10, supersaturation is the key parameter for the growth of particles, and it can be measured by using FTIR. Also, the solution of material balance equations gives the solute concentration which can be easily obtained from FTIR data. Based on the transformation experiments and kinetic experiments, all kinetic parameters were estimated by solving PBE, mass balance equation and polymorphic kinetics with the method of moment by using the Matlab programming language

4. Results and discussion 4.1 Characterization of 5′-GMPNa2



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 36

The amorphous and crystalline solids have quite different molecular packing arrangements, due to their different crystallinity. Each packing can be detected through vibrational spectra and thermodynamic measurements. Figure S3 shows the typical PXRD patterns of the two polymorphs. The amorphous product displays three diffraction peaks with a crystallinity of 7.98%, while the hydrate crystal form has a crystallinity of 99.7%.The calculation of crystallinity was shown in Figure S4. Figure 1 shows the DSC-TGA data for the two polymorphs. Based on the weight loss data, a total of seven crystal water molecules are lost in four steps during heating (in the order of 3–2–0.5–1.5 molecules). The melting points and heats of fusion for the two polymorphs are determined from the DSC data and shown in Table 1. The amorphous product has a higher melting temperature and larger heat of fusion than the hydrate crystal. The transition between the two forms follows a monotropic relationship, according to the “heat of fusion rule” of Burger and Ramberger

38

. The

heat of transition rule is also consistent with a monotropic transition, since an exothermic transition of amorphous product to hydrate crystal was indicated in Table 1.


Page 15 of 36

120

endo 2.5

a 1.5

100

DSC TG

Tm=263.13℃ ℃

1.0

80

0.5

Weight(%)

Heat flow(mW/mg)

2.0

60 0.0 -0.5

0

100

200

300

400

500

600

40

Temperature/°C 120

endo 1.6

b

1.2

100 Tm=287.99℃ ℃

0.8

DSC TG

80 0.4

Weight(%)

Heat flow (mW/mg)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


60

0.0 -0.4 0

100

200

300

400

500

600

40

Temperature/°C Figure 1 DSC-TG of the amorphous product and hydrate crystal of 5′-GMPNa2. (a) is hydrate crystal. (b) is amorphous product.



Table 1 Melting Points and Heats of Fusion Established for different forms. Amorphous product

Hydrate crystal

hi ;℃)

269.48 ± 6.17

254.32 ± 2.46

∆qrst ;uv/wxy)

95.18 ± 2.97

57.84 ± 3.02

4.2 Solubility curves

24

20

C(g/L)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 36

hydrated crystal amorphous second-order polynomials fitting

16

12

8 295

300

305

310

315

320

T/K Figure2 Solubility for two polymorph in 20% mole fraction of ethanol-water binary solution with error bars. The lines are fitted by a second-order polynomials. The solubility curves of 5′-GMPNa2 in different polymorphs are shown in Figure 2. The maximum error bar (at the temperature of 318.75 K) of

Solution-Mediated Polymorphic Transformation: From Amorphous to

Recommend Documents