'^'^ N*Sc!l»'?'"'^' o^^P Understanding the Mechanism of p-form Nucleation m Cooling Crystallization of L-glutamic Acid Dang Tmong Giang. K h n . Chan Qnang, Trinh Thi Thanh Huyen", Ngnyen Anh Tuan
Institute OfChemical Technology. Vietnam Academy ofScience and Technology Received 25 Febniary 2016: Accepted for publication 12August 2016 Abstract
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WKi explored, where die p-fonn nuclei was favombW c r l s S i d T l ?no^""!, ° ' '•«=«'e™"» P-fonn nucleation surfece of n-fomi crystal during die phas^trmsfonnaZ Th , ' ° " " ' ' <"' " ' ' ^ ' " " "">""'»" * ' d H ) which die taed»ial groups ofLlecu"™ ^ i r ' S c e ^ ^ ^ ^ 1 " " " f " " " " , « » <^' -olecular simulation, in matching (E) between the a-fomi substrate spaces Mfrl ^ 1 , ^ ' "•"= '''"^=""'' '" * ' "=8""= "f lattice TO> (011) > (111), meaning dia, the n u c l e a t ^ X t — o r ' i T ^ ^ ^ ^
suriiices compared to dia, on the (111) surface of a-fo™ c^fa" ' ° ° " " " ™ " ' ' ™ *= (001) and (011) K.,,.rds. Ciystallizalion, co-stallography, polymoiphism. nucleation, ciystal growth.
I. INTRODUCTION
Crystallization is veiy important separation purification imd particle symhesis process usTd widely m phannaceutical, chemical, and food mdustiies, etc [IJ. In the phannaceutical industiy here are more dian 90% of all phannaceuticai i ^ ^ r . T , * ^ ' " ' " ^ "•= ^"'^^ pharmaceutical mgiedicnts (API) i„ ciystalline fonns. As such erystallization process is certainly required to make
*e phase transition of molecules ftom the solution L?M-' . -f"- ""'• *= "^rly 'l™«"ed ciyflallme facilitates impurity rejection from the Mild product, so the purity of phannaceutical product IS significantly enhanced via the S f J T " '^"^^'^- ^^'"^ '" particularly mportam because tiie purity of this kind product is always required at least 98%. Moreover, during the oystallization, die solid product can adopt more man one crystal stiuctiire due to the different packing anangement and confonnation of molecules l» die crystal latiice, and this phenomenon is known as the polymoiphism, which is very common in organic compounds. Generally, there is more than 50/. of API compounds having the polymorphism and smce the different polymorphic cryslal has marked dilferences in the physico-chemical properties such as bio-availability, solubility, hardness, chemicai slability, etc, contiol of polymorphism becomes a vital issue in any
phannaceutical crystiillizalion process [2 3) Ammo acid L-glutamic has a wide application in the phannaceutical, chemical and food industries L- glutamic acid has two kinds of polymorphic crystal mcluding metastable a-fonn and stable B-fonn where the mechanism of polymorphic nucleation is' veiy complicated and elusive because it depends on so many ciystallization conditions. For example Tahr, et al [4] reported tiia, nuclei of a-fonn J p ' fonn were both generated under the stinina condition, while the only p-form nuclei a p p S under die stiignanl condition, meaning diat the fluid hydrodynamic condition in ciystallizcr is significant factor as It directly impacts on the mechanism of polymorphic nucleation. Lai e, al [5] also reported
hat die a.fonn nuclei crystallized a, a low temperature as 25°C, while the only p.fonn nucW perfonned at a high temperature as 45 "C in ihe continuous MSMPR ciystallizer. According to Florence et al [6], in order to initiate ,he p - ^ i "
nuclei a, a low lemperature as 25 "C, the seeding ciysal ,s a valuable method whe; using hf continuous Oscillatoo-baffles cryslallizer
f.i:r;iii:;^:S-:-^-:::;
acid was dp,nlv P ™ L-glutam c deeply investigated during phase
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transfonnation via die experimental and molecular simulation in stining cooling crystiilHzation, so die mechanism of p-form nucleation would be more understood.
2. EXPERIMENTAL
The standard Stirred tank crystallizer was designed by Tuan et al [3]. The L-glutamic acid material (>98% purity) was bought from Sigma Aldrich company. The concentiation of feed solution was 18.5(g/L), which was prepared by dissolving the material into die distilled water at 50 "C. Initially, die ciystallizer was fiilly filled with the feed solution, and tiien operated as the batch mode in the cooling crystallization at 4.0 °C/min of cooling rate and 360rpm of agitation speed. Here, tiie temperanire and agitation speed of crystallizer were continued via the circulating coolant flxim die chiller and motor, respectively.
The suspensions were periodically taken fitim die crystiillizers and quickly filtered by nsing a vacuum pump. The crystal samples were dien dried in a desiccator and analyzed to define die shape, stiucture and crystal fraction of P-fonn. Here, tiie shape and stiuctiire of crystal product were monitored and confumed by Video microscope and XRD pattems (M18XHF-SRA, Japan), respectively Meanwhile, die molecular simulation was canied out via die crystiillographic softwares including Encifer, Mercuiy, Diamon and Grace [7-9].
-I. RESULTS AND DISCUSSION 3.1. Crystallography of a-form and P-form
The parameters and position of each molecule in unit cell of a-fonn and p-fonn were collected from the Cambridge Stiuctiiral Database [9J. Although the crystal system of two polymorphs is orthorhombic wid, space group P2,2,2,, die a-fonn ciystal has a unit cell parameters as a = 7.068 b = 10 277 c = 8.755 A, while the P-fonn ctystal has a unit cell parameters as a = 5.159, b = 17.300, c = 6 948 A From diese raw datii, die Cif file was coded via the Encifer software, and dien the molecules and unit cell were simulated via die Mereuiy software, as hown in Fig.l. Here, die crystallographic data showed distinction in tenns of the unit cell parameters packing anangement and confonnation of molecule of two polymorphs (Fig. I). The difference of co-stiil stiucture of two polymorphs was also confinned via tiie powder XR^ p a S a ! reflective angles 29 of 10°, 15°, 16°, 18", 21° 23°
26.5 , 27.5°, as depicted in Fig.2. Moreover, die
Trinh Thi Thanh Huye etal distinguished morphology of a-form and p-form crystals was clearly observed via the prism shape of a-form and needle shape of P-form, respectively, as shown in Fig. 2.
Figure 1: O
parameters oi a-iorm ana p-torm ctystal
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Figure 2: Stmctine and moiphology of a-fonn add P-foim
3.2. Heterogeneous nucleation of p-form dilHri the phase transformation
In cooling crystallization, the a-fonn was initially crystallized (Fig. 3(a)) and then tile P-fonn was generated after 5h of crystallization tbA (l-ig.3(b)) through die solvent-mediated phaw transformation of unstable a-forai to stable p-fcnn [10]. The phase tiansfonnation of a-form into f- form was completed after 40 h of ciystallizattoh time, as shown in Fig.3(c). According to our previous result [10], die nucleation of P-fonn was considered as an important factor impacting on die phase transfonnation time, where die phase transfonnation time would be significantly reduced If the nucleation rate of p-fonn was promoted Thus, die mechanism of P-fonn nucleation durinn die phase tiansfonnation should be clearly understood
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L S ^ i T ™ " * " * • *= °>«=taism of p-fom,
^ T t h o T f " ^ " ^ ""-^ As s h o ^ in 2 ^ f t e ^form crystal obviously appeared on fc^*ce of a.f„nn crysbU. meaning diat a »
•MMOOO Ot p-fonn was heterogeneous nucleation
• • J vras epitaxial growdi on the suifice of a-fonn gjBUl. As such, die a-fonn crystals were known as fcM^ae which provided die nucleation shes for
» P-«lnn ciystal. It was well known diat tiie rilslrate provided a lower free energy banier to JKleation dmiugh die favourable intinactions liet«ieen die snbstiate and solute molecules
^WCgate, hnplying diat die nucleation of P-fonn lappeoed on die a-fonn substiatc was more WBtale dian riiat occuned in die bulk solution.
Moreover, smce die ephaxial oidering of tile p-form molecules on the a-fonn snbstiate directiy depended 00 die fiuictional groups of molecules on die a-fonn Mbsh* surface and die lattice matchmg between tej-fotm and P-fonn crystal, die distinguished Itmamti group of molecules on each a-fonn snhsttale surface and die degree of lattice matching between two polymorphs played a key role to generate die p-fonn nuclei.
CtystaBogrt^hy: Deep understandmg the mechantsn: . of a-fom crystal including (OOI), (011) and (111) (hkl Miller planes) were clarified, as shown in Fig 4. Acconhng to Fig.3(b), it was confinned tiiat die P-form crystal was epitaxial growtii on the (001) and (011) surfaces of a-fonn crystal, while it had no any P-fonn crystals observed on tiie (111) surface of a- form crystal even tiiough tiie experiment was repeated more tiian 100 times. This result implied tiiat tiiere was a selective nucleation of P-fonn on a specific surface of a-fonn crystiil, where die P-fonn nuclei was tivoiable crystallized on die (001) and (Oil) surfaces radier tiian die ( U l ) surface of a-form crystal.
Figure 4: Schematic surfaces of a-fonn crystal
figure 3: Heterogeneous nucleation of p-fonn and phase tiansfonnation of a-fonn to P-fonn In Ofder to understand die mechanism of P-fonn niKlealian on die a-fonn crystal sorfice, die surfaces
For deep understanding, tite fimctional group of molecules on various surface of a-fonn ctystal was estimated via die molecular simulation. Here die tiinctional groups of molecules including COQ- OH' via die Diamon software, as depicted in Fig.5 Tlie molecular simulation result indicated diat diere was significant difference witii respect toa"
anangement of fimctional groups on Uiese surf-aces, n a t IS die fimctional groups C-O and O-H was was Uie COO on tiie (Oil) surface (Fig 5(b))
o"Tfm\*%''""T^ «'<""' ~"^*"- ""-te^-
on tfie (111) surface of a-fonn crystal (Fig.5(c)) As such, die different fimctional Iroup of iSiou surfaces of a-fonn ciystiil were a reason whyTere nuclei. Tins hypodiesis was Anther investigat^ Z t j T ? ° '"""=' •""="'"8 (E) betweeltiieT fonn molecules aggregate and surface of a-form crystal as using tiie Grace software [7]. Here Z Giace ^iftware (global real-space analysis of crystal epitaxy) was used to calculate tiie depee of l a S « match between two contacting a-fonn c ' s S surface and overiayer p-fonn lattice planes wl*
vaned 8 azimutfi angle, where die 6 azimutf, angle was defined die relative orientation between Se surface lattice of a-fomi co.stal and p-fo™
molecules aggregate. H-'oim As shown in Fig.6, tfie largest value of E on
vanous surfaces of a-fonn cry^l mcluding (M™
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(Oil) and (111) were 1.37, 0.68 and 0.69 respectively, meaning diat tiie (001) surface had a highest probability for tiie epitaxial growing of p- fonn nuclei. In case of tiie (011) and (111) surfaces, aldiough die largest value of (E) on Uiese surfaces was vety competitive (0.68 and 0.69), die density of value E as E > 0.56 on die (011) surface was higher tiian that of (111) surface in a wide range of 9 azimudi angle, where die (111) surface had only one predominant peak at 9 - 7°. That means tiie optimum epitilxial configuration of various surface of a-form crystal for the P-form nuclei was ordered as (001) > (011) > (111). This result was consistem with the experimentiil result as described in Fig.3(b), where die P-forai nuclei was preferably perfonned on die (001) and (011) surfaces instead of die (111) surface of a-form crystal.
Trinh Thi Thimh t'u. lot be mentioned diat die crystitllization in ; work was canied out under stirring conditio .milarity to tile industiial prtxluction, while die r - lOus study operated the crystallization under st^^ • '-t condition [11], so Uie mass/heat transfer and iir .biiity of solute molecules in solution of tfiis case were definitely different
Figure 5: Fmictional group of various surfaces of a-fonn crystal: (aHOOl), (bHOl 1) and (cMl 11)
The present sttidy had a contiovereial result to die previous sttidy [11], where Uie (011) and (111) surfaces was predominant for die p-fonn nucle compared to die (001) surface. However, it should
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•saoo «too .3000 otn aaoo
Thot<(Degl
i!k I *
•sftoo «uxi .3100 aoo saoo moo at The(a(Deg}
Figure 6: Degree of lattice matching between various o-fonn substtate surface and p-fonn
molecules aggregate 518
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VJC, 54(4)2016 4. CONCLUSION
The present study explored a new mechanism of P * ™ nucleation occnmng on the suhsOale a-fiinn OJ""! during tiie phase tnoisliinnition of L- gtatamn: acid m die stining coolmg ciystallization.
Ihe experimental result showed that the P-fonn mcki was selectively peifotmed on the (OOI) and (Oil) snr&ces radier dian die (111) suriace of o- fimn ciystaL This result mabihed witfi die molecules simulation resuh, where die effect of different anfices of a-fomi crystal oo tfie selective nucleation of P-fonn crystal was origmal fiom die distinguished ftnetional group of molecules on various surface of o-fonn and degree of lattice matehuig (E) between the a-lbnn substtate surface and p-fonn molecules
• f f i i ^ . HeiB, die degree of lattice matehing tetireen die a-fonn substtate surface and P-fonn molecules aggregate was ordered as (001) > (011) >
(111), meaning tfiat tfie p-fonn nucleation on tfie (001) and (Oil) surfaces was more ftcilhated Uian diat on die (111) surface of a-fonn crystal.
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(2om"°" ' ^ ' ^ """"^ ° " - " • ^"^-^'os
atahor. Trinh Thi Thanh Huyen histitiite OfChemical Technology Vietnam Academy ofScience and Technology
