Journal of Crystal Growth 235(2002)471–481
Stabilization of a metastable polymorph of sulfamerazine by
structurally related additives
Chong-Hui Gu a,c ,Koustuv Chatterjee a ,Victor Young Jr.b ,David J.W.Grant a,*
a
Department of Pharmaceutics,College of Pharmacy,University of Minnesota,Weaver-Densford Hall,308Harvard St.S.E.,
Minneapolis,MN 55455-0343,USA
b
Department of Chemistry,University of Minnesota,207Pleasant St.S.E.,Minneapolis,MN 55455,USA
c
Bristol-Myers Squibb Co.,1Squibb Drive,P.O.191,New Brunswick,NJ 08903,USA
Received 30April 2001;accepted 8October 2001
Communicated by A.A.Chernov
Abstract
The influence of structurally related additives,namely N4-acetylsulfamerazine (NSMZ),sulfadiazine (SD)or sulfamethazine (SM),on the rate of the solvent-mediated polymorphic transformation (I -II)of sulfamerazine in acetonitrile (ACN)at 241C was studie d.Thetransformation rateis controlle d by thecrystallization rateof themore stable Polymorph II.All three impurities exhibit inhibitory effects on the crystallization of Polymorph II and hence stabilize the metastable Polymorph I in ACN suspension.The rank order of the inhibitory effect (NSMZ b SD>SM)is thesameas therank orde r of thebinding e ne rgy of theimpurity mole culeto thesurfaceof thehost crystal.The relationship between the concentration of the impurity and the inhibitory effect was fitted to various models and was found to be best described by a model bad on the Langmuir adsorption isotherm.r 2002Published by Elvier Science B.V.
Keywords:Al.Adsorption;A1.Computer simulation;Al.Crystal structure;A1.Impurities;A1.Nucleation;A2.Growth from solutions
1.Introduction
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Polymorphs arecrystallinesolids with thesame chemical composition but with different arrange-ments
and/or conformation of the molecules in a crystal lattice.The discovery and characterization of polymorphs areimportant in various fie lds,becau different polymorphs exhibit significantly
different physicochemical properties.In the phar-maceutical field,for example,the sudden appear-anceof a morestablepolymorph,that was not discovered at the early stage of pharmaceutical development,can cau loss of time and resources [1].Solvent-mediated polymorphic transformation is an efficient method to prepare more stable polymorphs [2,3].Traceamounts of a structurally related impurity may exert significant effects on thekine tics of dissolution [4]and crystallization [5],leading to changes in the polymorphic transformation rate in solution.Such effects may delay the discovery of a more stable polymorph.
*Corresponding author.Tel.:+1-612-624-3956;fax:+1-612-625-0609.
E-mail address:grant001@tc.umn.edu (D.J.W.Grant).
0022-0248/02/$-e front matter r 2002Published by Elvier Science B.V.PII:S 0022-0248(01)01784-5
On the other hand,the prence of an impurity or additivemay assist thepre paration of theme ta-stab
lepolymorph,which may othe rwirapidly transform to themorestablepolymorph [6].To exploit the superior properties of a metastable polymorph,additives may be ud to stabilize kinetically the metastable polymorph by inhibiting the formation of more stable polymorphs.There-fore,it is important to understand the effects of impurities or additives on the polymorphic trans-formation ratein solution.
Thetransformation from theme tastablePoly-morph I of sulfamerazine (SMZ)to the more stablePolymorph II at 241C (room temperature)was chon as the model system,while N4-acetylsulfamerazine (NSMZ),sulfadiazine (SD),and sulfamethazine (SM)were each chon in turn as theimpurity (Sche me1).
2.Materials and methods 2.1.Materials
Sulfamerazine (SMZ,4-amino-N-[4-methyl-2-pyrimidinyl]benzenesulfonamide,Lot #47H0114,purity >99.9%),SD,and SM were purchad from Sigma Co.(St.Louis,MO).Polymorphs I and II of SMZ were prepared as described in a previous paper [3].HPLC grade acetonitrile (ACN)was purchad from Fischer Scientific (Pittsburgh,PA).Residual water in ACN was
minimized by adding molecular sieves and anhy-drous calcium sulfate (Drierite,Hammond,Xenia,
OH).
N4-acetylsulfamerazine (NSMZ,4-acetamido-N-[4-methyl-2-pyrimidinyl]benzene-sulfonamide)was synthesized as described by Roblin and Winneck [7].The starting materials,namely acetylsulfanilyl chloride and 2-amino-4-methyl-pyrimidine,were purchad from Aldrich Chemi-cal Co.(Milwaukee,WI).The final precipitated product was recrystallized twice from tetrahydro-furan.The water content of NSMZ,determined by Karl Fischer titrimetry,was 6.3%(w/w),which corresponds to the monohydrate [theoretically 5.6%(w/w)water].Dehydration was achieved by storing at zero humidity for 2weeks.The anhydrate form of NSMZ (water content o 0.5%,w/w)was ud in the later experiments.2.2.Solvent-mediated polymorphic transformation
Thetransformation from theme tastablePoly-morph I to Polymorph II at 241C was studied in ACN [3].Polymorph I was suspended in its presaturated solution containing a known amount of an impurity at 241C.Thewe ight/volumeratio of suspended solid to solvent was 20mg/ml.The suspension was shaken by a wrist-action shaker (Model 75,Burrell,Pittsburgh,PA)at B 300strokes/min.A portion of the suspension was withdrawn and filtered at designated times and the polymorphic composition of thesolid phawas
S NH
O
O
N
N
C H
3
NH 2
C H 3
S N H
O
O
N
N NH 2
S NH
O
O N N
C H 3
C H 3
衣架英文
C ONH
上海交大附中
sulfamerazine (SMZ)
N4-acetylsulfamerazine (NSMZ)
sulfamethazine (SM) sulfadiazine (SD)
Scheme 1.Molecular structure of the host molecule,SMZ,and the impurity molecules,NSMZ,SD,SM.
C.-H.Gu et al./Journal of Crystal Growth 235(2002)471–481
472
determined by powder X-ray diffractometry (PXRD,Siemens D5005,Germany),which was described in detail in the previous reports[3,8]. Meanwhile,the concentration of SMZ in the solution during thetransformation proce ss was determined at l¼307nm with a spectrophot-ometer(DU7400,Beckman,Irvine,CA)[9].The standard solution contained the same concentra-tion of theimpurity as thesolution in which SMZ was suspended.
To determine the crystal growth rate of Form II, 270mg(90%)of Polymorph I and30mg(10%)of Polymorph II were geometrically mixed and were suspended in the solutions described above,to determine the polymorphic transformation rate. This high proportion of eds(10%of II)obviated the primary nucleation step in the transformation. Thepolymorphic transformation rateso de te r-mined corresponded to the crystal growth rate of themorestablePolymorph II in solution[3].
2.3.Scanning electron microscopy(SEM) Themorphology was analyze d by SEM(S-800, Hitachi,Tokyo,Japan)at an accelerating voltage of10kV.The samples were sputter-coated with platinum to a thickness of50(A.
2.4.Calculation of the impurity–surface binding energy
Theinte raction of theimpurity with a growing surfacemay becalculate d,assuming that the solvent has no effect on the available conforma-tions of the impurity molecule[10].Commercial software(Ce rius2t,Molecular Simulation Inc. San Diego,CA)was employed to calculate the binding energy of the impurity molecule to the crystal surface.The Dreiding2.21forcefield was ud to minimize the structure and to calculate the energy.For purpos of comparison,the binding energy of one molecule of each impurity to afixed and defined crystal face was calculated according to the procedure described by Jang and Myerson [10].The binding energy was obtained by sub-tracting the energy of the impurity molecule in the corresponding conformation from the minimum total energy of the surface bound with a single impurity molecule.
3.Results and discussion
3.1.Inhibitory effect of impurities on the transformation of SMZ Polymorph I to Polymorph II in ACN s
uspension
Solvent-mediated transformation consists of three concutive steps:dissolution of the less stablepolymorph;nucle ation of themorestable polymorph;and crystal growth of themorestable polymorph.Theimpurity may affe ct any or all of the three steps.It was found in a previous study that thetransformation ratein pureACN is controlled by the crystallization rate of SMZ Polymorph II[3].To determine the rate-limiting step in the prence of the impurity,the concen-tration of SMZ in thesolution was monitore d.The concentration vs.time profile(Fig.1)indicated that thetransformation ratein thepre nceof impurity is still controlled by the crystallization rate of Polymorph II,becau the concentration of SMZ was cloto thesolubility of theme tastable Polymorph I until all Polymorph I in thesuspe n-sion had transformed to Polymorph II.In the prence of impurity,both the nucleation rate and crystal growth rate(Table1)were reduced significantly.However,the effect of NSMZ is 0
1
horny2
3
4
5
6
0102030
Time (h)
C
o
n
c
.
o
f
S
M
Z
i
n
s
o
l蔬菜英语
yearu
t
i
o
n
(
m
g
/
m
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)
Fig.1.SMZ concentration–time profile during polymorphic transformation(I-II)in ACN solution containing the impurity,NSMZ(E)or SM(’)or SD(m),at molefraction 1.71Â10À5.
C.-H.Gu et al./Journal of Crystal Growth235(2002)471–481473
much greater than that of SM and SD.The morphology of SMZ Polymorph II grown from solutions containing each of the impurities is shown in Fig.2.Themorphology of SMZ grown in the prence of SM or SD is similar to that grown in its abnce.However,in the prence of NSMZ at a molefraction as low as3.43Â10À6, themorphology is change d to a plateshapewith dominant\001\faces.The results indicate that all three impurities inhibit the crystallization of SMZ Polymorph II and that therank orde r of the inhibitory effect is NSMZ b SD>SM.
The rank order of the inhibitory effect of the impurity may be explained by examining the crystal structureof SMZ Polymorph II,which is shown in Fig.3[11].Theamino group on the phenyl ring rves as a hydrogen bond donor in thecrystal of Polymorph II.If a NSMZ mole cule substitutes for a SMZ molecule in the crystal lattice,the acetyl group of NSMZ,which has replaced a hydrogen atom in SMZ,will hence disrupt the hydrogen bond interaction with incoming SMZ molecules(Scheme1).Therefore, the rate of molecule ,the crystallization rate,will be reduced.In addition, at the nucleation stage,the incorporated impurity molecule may destabilize the molecular aggregates and facilitate the dissolution of the aggregate, resulting in a reduction of the nucleation rate.In this way,the nucleation and crystal growth process can be greatly disrupted by NSMZ.However,SM and SD differ from SMZ only in the methyl group on thepyrimidinering,which doe xxt
s not participate in the hydrogen bonding interaction.Therefore, SM and SD are less effective in inhibiting the crystallization process than is NSMZ.
The inhibitory effect of the impurity does not follow therank orde r of themole cular sizeof the impurity.The molecular volumes and mole-cular surface areas of the impurity
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molecules, Fig.2.Morphologies of the crystals of SMZ Polymorph II grown from ACN in the prence of impurities,NSMZ,SM,and SD.The molefraction of theimpurity in thesolution is1.71Â10À5.
C.-H.Gu et al./Journal of Crystal Growth235(2002)471–481475
respectively,are:NSMZ,244.6(A
3,295.4(A 2;SM,225.1(A
试用期自我评价范文3,275.2(A 2;SD,196.3(A 3,233.4(A 2.3.2.Surface–impurity binding energy
The effects of impurities on crystallization kinetics are related to the strength of the inter-molecular interaction between the impurity and the terraces,steps,and kinks of the nuclei or crystals.Becau crystal growth of SMZ in ACN follows theBCF me chanism,theimpurity inhibits crystal growth mainly by being adsorbed on to the steps and kinks.Chernov found that the decrea in step rate is proportional to the time when the kinks are free of impurities [12–14].If the lifetime of adsorbed molecules at kinks,steps,and terraces is shorter than the time required for the step to cover the interstep distance,impurities with great-
er adsorption energy at kinks and steps are more likely to be adsorbed and thereby to inhibit the crys
tal growth.The adsorption energy at kinks and steps includes the adsorption energy on the terrace,which is proportional to the calculated solute–surface binding energy.The calculated solute and solvent binding energies (kcal/mol)to the crystal faces (001),(100),and (110),respec-tively,of SMZ Polymorph II are:NSMZ,À23.0,À20.4,À19.8;SM,À8.1,À14.5,À18.4;SD,À21.8,À17.6,À19.0;SMZ (host molecule),À19.5,À13.9,À12.2;ACN (solvent),À6.52,À6.13,À5.28.The greater the absolute value of the surface–impurity binding energy,the stronger the binding of impurity molecule to the surface,indicating higher probability of absorption on theste ps or kinks.The results show that all three impurities have greater binding energies to the individual
crystal
Fig.3.Crystal structure of SMZ Polymorph II [11].The dotted lines reprent the hydrogen bonds.
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