晶型与表面活性剂经典文献之四

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1、Effect of Additives on the Transformation Behavior ofL-Phenylalanine in Aqueous SolutionRajeev Mohan,Kee-Kahb Koo,Christine Strege,and Allan S.Myerson*,|Andrx Pharmaceuticals,Inc.,4955 Orange Drive,Fort Lauderdale,Florida 33314,Department of Chemical Engineering,Sogang University,Seoul 121-742,Korea

2、,Institut fur Verfahrenstechnik TVT,Martin-Luther-Universita t,Halle D-06099,Germany,and Department ofChemical Engineering,Illinois Institute of Technology,3301 S.Dearborn,Chicago,Illinois 60616The solution-mediated transformation of anhydrousL-phenylalanine in a saturated solution ofmonohydrateL-ph

3、enylalanine has been studied and the transformation rate quantified usingthe powder X-ray diffraction technique.It has been demonstrated that the anhydrous form isnot stable below 37 C(transition point)in the presence of additives,as previously reported(Sato,T.;Sano,C.European Patent 0703214A2,1995)

4、,and that the additives(ammonium sulfateand dextrose)affect only the transition rate but not the thermodynamic stability or the transitionpoint.1.Introduction and BackgroundPolymorphism is the phenomenon of a chemicalspecies having more than one possible crystal structure.Numerous organic materials

5、including amino acids andpharmaceutical and food substances are known to havepolymorphs.In addition,many of these materials cancrystallize as hydrates or solvates where solvent ispresent as an integral part of the crystal lattice.Solvatesand hydrates of a given compound are often calledpseudopolymor

6、phs.The crystallization of polymorphs/pseudopolymorphs occurs as a result of different mo-lecular conformations or packings.It is a function ofcrystal growth conditions such as temperature,pres-sure,impurity content,and growth rate,along withintra/intermolecular forces and interactions of the solute

7、with solvents and additives.In many cases,crystallization leads to the formationof a metastable polymorph,which will eventually trans-form into a more stable form.This transformation canoccur in solution or in a dry state.The transformationsfrom one polymorph to another are usually rapid whencrystal

8、s are suspended in solutions and are termedsolution-mediated transformations.Solution-mediatedtransformations have been reported for stearic acid,2,3magnesium phosphate hydrate,4L-glutamic acid,5theo-phylline,6carbamazepine,7ammonium nitrate,8calciumsulfate,9and calcium phosphates.10The phase trans-

9、formations of several organic and inorganic hydratesalts have been studied.11,12These studies indicate thatthe stable crystals grow,whereas the less stable crystalsdissolve.Typically,for a given substance,there existsa transition temperature below which one polymorphis stable and above which another

10、 form is stable.Reversible transformations between these forms can beeffected by temperature manipulations.Sometimestransformation is not certain even though a systementers a condition that will theoretically allow it.Transformation can only be ensured if a more stablesolid phase is already present,

11、is introduced(by seed-ing),or makes its appearance by nucleation.The rateof transformation can also be affected by the additionof additives or specific impurities.13Materials crystallizing in different polymorphs showa wide range of physical and chemical properties,including different melting points

12、,spectral properties,thermal conductivities,heat capacities,and densities.14-24For example,the most stable structure has the lowestsolubility and the lowest dissolution rate.Polymorphismis particularly important in pharmaceutical industries,where the polymorph present can alter the dissolutionrate,b

13、ioavailability,chemical stability,and/or physicalstability.Furthermore,during the manufacturing pro-cess of dosage forms or the storage of products,phasetransition has been frequently observed.19,25-27Becauseof the different properties of polymorphs,it is advanta-geous to choose the proper polymorph

14、 for the desiredapplication.Several factors need to be addressed,in-cluding the number of polymorphs;the solubilities ofthe different forms;the methods for preparing purestable forms;the methods for preventing the transfor-mation of forms during several unit operations such asdrying,grinding,or tabl

15、eting,etc.;and the chemical andphysical stabilities of each form.Haleblain and Mc-Crone17reviewed the numerous activities that requirethe consideration of polymorphism.Crystal habit playsan important role during downstream processing.Plate-like forms of tolbutamide cause powder bridging andcapping p

16、roblems during tableting.28In suspensions,ithas been shown that transformation of a material to astable form results in caking.This was due to thegrowth of crystals of the stable form with the concurrentdissolution of crystals of a less stable form.29Thedissolution and bioavailability due to differe

17、nt poly-morphs has been well-documented.30,31Therefore,it isnecessary to control conditions to obtain the desiredpolymorph and,more importantly,to prevent the trans-formation of the desired form to another polymorph.Several analytical methods have been used to studypolymorphism.17,20,32Infrared spec

18、troscopy,high-resolu-*Corresponding author.Tel.:+1-(312)-567-3163.Fax:+1-(312)-567-7018.E-mail address:myersoniit.edu.Andrx Pharmaceuticals,Inc.Sogang University.Martin-Luther-Universita t.|Illinois Institute of Technology.6111Ind.Eng.Chem.Res.2001,40,6111-611710.1021/ie0105223 CCC:$20.00 2001 Ameri

19、can Chemical SocietyPublished on Web 11/14/2001tion NMR spectroscopy,33Raman spectroscopy,34dif-ferential scanning calorimetry and differential thermalanalysis,19,35,36and X-ray diffraction methods37,38are themain approaches.The X-ray diffraction technique hasa high degree of accuracy and almost nev

20、er fails becauseof its outstanding ability to detect differences in crystalstructures.An important technique for measuring thedifferent amounts of polymorphs present in a system isquantitative X-ray diffraction.The quantitative X-raydiffraction technique has been applied in many areas,such as the an

21、alysis of mine dust,quartz,39,40heavymetal carbides,41inorganic compounds,42-44organiccompounds,45,46and pharmaceutical systems.7,38L-Phenylalanine,an essential amino acid and apharmaceutical and food intermediate,exhibits pseudo-polymorphism.It can exist in two different crystallinestates:a monohyd

22、rate(monoclinic,a)13.598,b)10.229,c)6.484,Z)4,space group P2221)andan anhydrous form(orthorhombic,a)13.598,b)14.468,c)9.169,Z)8,space group P2221).Thetransition point was reported to be 37 C in water.Theneedle-shaped monohydrate is stable below the transi-tion point,and the anhydrous form,which rese

23、mblesflakes,is stable above the transition point.The anhy-drous form ofL-phenylalanine is desirable for industrialpurposes because of its ease of downstream processingsuch as solid/liquid separation and drying.It has beenreported that the stable anhydrous form can be obtainedin the hydrate region th

24、rough the addition of certainadditives.1In this study,we report the results ofexperiments undertaken to elucidate the solution-medi-ated phase transformation of anhydrousL-phenylala-nine into monohydrate.Experiments were also per-formed to determine the effect of additives on thetransformation rates

25、 of anhydrate to monohydratebelow the transition point.The results could providesome insight into the process development ofL-phenyl-alanine crystallization from aqueous solution.2.Experimental Section2.1.Materials.L-Phenylalanine anhydrate(assay,formula 99%),purchased from Aldrich Chemical Co.,was

26、used without further purification.The monohydrateform ofL-phenylalanine was obtained by recrystalliza-tion.A saturated solution of anhydrate was preparedat 60 C and then quenched in a thermostat maintainedat 5 C.After 24 h,crystals of the monohydrateformed;47they were filtered using a mechanical vac

27、uumpump,dried for 24 h at 30 C,and then stored at roomtemperature.The crystal structure was confirmed usingpowder X-ray diffractometry(PXRD;Rigaku,Miniflex).Analysis of the X-ray pattern indicated that the dryingprocess did not result in any dehydration of the mono-hydrate crystals.Several additives

28、,both electrolytes andnonelectrolytes such as ammonium sulfate(NH4)2SO4,sodium chloride(NaCl),aluminum sulfate Al2(SO4)3,potassium aluminum sulfate dodecahydrate KAl(SO4)212H2O,dextrose(C6H12O6),and sucrose(C12H22O11),were selected to study their effects on both solubilityand the transformation rate

29、 ofL-phenylalanine anhy-drate to the monohydrate form.2.2.Solubility Measurements.The solubilities ofthe two forms ofL-phenylalanine in water,at differenttemperatures,were determined by a gravimetric tech-nique.A known amount ofL-phenylalanine was addedto 50 g of water in an equilibrium cell.A Scien

30、techmicrobalance,with a precision of(0.0001 g,was usedto weigh the samples.The equilibrium cell was placedin a double-jacketed cylinder maintained at the desiredtemperature by a thermostat(Polyscience).The solutionwas agitated using a magnetic bar for 5 h.The solidphase was later filtered using a me

31、chanical vacuumpump.The sample was dried in a vacuum oven at 30C for 24 h.The solubility was calculated by subtractingthe weight of the dried solid from the original weight ofL-phenylalanine added.The crystal structures of thesolid samples were examined using PXRD patterns toensure the no phase tran

32、sformation occurred.2.3.Transformation Kinetic Studies.The phasetransformation study of the anhydrate form ofL-phenylalanine into monohydrate was performed iso-thermally under ambient pressure at three differenttemperatures of 5,15,and 30 C.The experiments werecarried out using the following procedu

33、re:An excessamount of monohydrate was dissolved in distilled waterat the desired temperature for 24 h.The solution wasfiltered to prepare a saturated solution of monohydrate.The saturated solution was sealed in a 500-mL glasscylinder and was then heated to a temperature a fewdegrees higher than the

34、saturation temperature.Thesolution was maintained at this temperature for 30 minto ensure that any clusters or nuclei that might havebeen produced during filtration were dissolved.In eachexperimental run,10 glass test tubes(50 mL)containingthe saturated solution(40 g)of monohydrate withanhydrate pow

35、der(0.2 g)were prepared.These tubeswere immediately placed in a constant-temperaturebath maintained at the desired temperature and agi-tated(fixed speed)by a magnetic bar.Samples wereremoved at the desired time intervals,and the solidphase was filtered with a mechanical vacuum pump.The physically ad

36、sorbed water was removed by dryingthe sample for 24 h at 30 C.Finally,the crystalstructure of the dried sample was examined usingPXRD to enable the calculation of the degree of phasetransformation.The effect of the drying process on thetransformation rate was examined by wetting anhy-drous crystals

37、and drying them for 24 h at 30 C.Analysis of these samples by X-ray diffraction showedno measurable transformation.2.4.Powder X-ray Diffractometry.The PXRDtechnique was employed to quantify the relative amountsof the anhydrate and monohydrate forms present inmixtures.The method is based on the diffe

38、rencesbetween the powder diffraction patterns of the twoforms ofL-phenylalanine.Unlike the Karl Fischer anddrying methods,the X-ray method can distinguishbetween absorbed moisture and water of crystallization.The measurements were carried out under the followingconditions:Ni-filtered Cu KR()0.15418

39、nm)radia-tion;voltage,30 kV;current,15 mA;receiving slit,0.3mm;scan step,0.05;scanning speed,1/min;anddetector,scintillation counter.The areas of all peaks(2)4-40)of the anhydrate and the monohydrate wereutilized for calculation purposes.2.5.Optical Microscopy.Crystals ofL-phenylala-nine hydrate and

40、 anhydrate were observed using anoptical microscope(Nikon,F-II)and recorded with acamera(Nikon,FX-35A).Along with the crystal shapeand size,the microphotographs were useful for checkingthe crystal quality,including solvent inclusions.2.6.Calculation Curve for Degree of Transfor-mation.The anhydrate

41、conversion or the monohydrate6112Ind.Eng.Chem.Res.,Vol.40,No.26,2001content of the sample collected with time was measuredon the basis of the area ratio of the PXRD peaks of thetwo crystal forms.Known quantities of standard sampleswere prepared by physically mixing the anhydrate andmonohydrate forms

42、 ofL-phenylalanine in various ratiosin a mortar and pestle.The PXRD patterns of thestandard samples were measured for a number ofsamples.Figure 1 shows typical PXRD patterns for anumber of standard mixtures of different compositions(0,20,50,70,and 100 wt%of the anhydrous form).Ascan be seen in Figur

43、e 1,five peaks in the pure anhydratePXRD patterns(2)5.7,17.1,22.8,28.6 and 34.5)canbe separated from peaks of the pure monohydrate.Therefore,the ratio of the area of five characteristicpeaks for the anhydrate to the total area of all peaksfor a mixture of the two forms was chosen for use inthe const

44、ruction of a standard chart for determining theextent of phase transformation.In this way,a calcula-tion chart for the degree of anhydrate conversion intomonohydrate was prepared as shown in Figure 2.3.Results and Discussion3.1.Solubilities.The solubilities of the two forms ofL-phenylalanine in wate

45、r,in the temperature range of15-50 C,are shown in Figure 3.In the presentexperimental range,the data were regressed by theleast-squares method to the following equationswhere S is the solubility(g ofL-phenylalanine/100 g ofH2O)and T is the temperature(C).The averageFigure 1.Typical PXRD patterns for

46、 a number of standard mixtures of anhydrate(A)and monohydrate(H)forms.Figure 2.Calculation chart for the degree of conversion ofanhydrate(A)into monohydrate(H)form.S)2.043+2.394 10-2T+4.211 10-4T2(anhydrate)S)1.949+5.169 10-3T+9.900 10-4T2(monohydrate)Ind.Eng.Chem.Res.,Vol.40,No.26,20016113absolute

47、deviations between the experimental data andthe calculated values were 0.22%for the anhydrate and0.29%for the monohydrate.On the basis of the experi-mental data and regression,it was found that thesolubility curves showed an enantiotropic nature andthat the transition point between these two forms i

48、sabout 37 C,which quantitatively agrees with theprevious data.1The effect of additives on the solubility of the anhy-drate ofL-phenylalanine is shown in Figure 4.Theadditives used in the present experiments were chosenon the basis of previous research.1The amount ofadditives added was 10 g/100 g of

49、H2O.Some electro-lytes,such as ammonium sulfate and sodium chloride,tend to lower the solubility of anhydrate.Other elec-trolytes,such as aluminum sulfate and potassiumaluminum sulfate dodecahydrate,increase the solubilityto a large extent.In aqueous solutions,L-phenylalanineis doubly charged and is

50、 known as a zwitterion.Thecharges at the ends of the molecule form a strong dipole.Thus,complex interactions among zwitterions ofL-phenylalanine,water molecules,and ions of electrolytesseem to strongly affect the solubility.As expected,nonelectrolytes(dextrose and sucrose)were found tohave a negligi

51、ble effect on the solubility of the anhydratein water.3.2.Solution-Mediated Transformation.Trans-formation studies were carried out to determine whetherthe two forms could be crystallized in the temperatureregion where they are unstable(the anhydrous form isunstable below 37 C,and the monohydrate is

52、 unstableabove 37 C).A saturated solution ofL-phenylalaninein water at 40 C was cooled to 32.5 C(the region wherethe hydrate is stable).The solid was filtered and driedfor 12 h.It was found that the crystals were in the formof needles,indicating the presence of the monohydrateform.The experiments we

53、re repeated with ammoniumsulfate and dextrose as additives(additive concentrationof 10 g/100 g of water).The saturated solution wascooled from 40 C to 32.5 C in the first set of experi-ments and to 35.9 C in the second set of experiments.In all of the experiments,the precipitated crystals werefound

54、to be needles.AnhydrateL-phenylalanine,witha flakelike morphology,was precipitated when thesolutions were crystallized at temperatures above 37 C.Figure 5 shows typical microphotographs of anhy-drateL-phenylalanine transforming into the monohy-drate form after 5 and 20 h at a temperature of 26.5C.Af

55、ter 5 h,the monohydrate crystals began to formon the anhydrate(Figure 5,top).It can be seen thatthe process is completed after 20 h.This is confirmedby the presence of only the needlelike structure of themonohydrate in the bottom image in Figure 5.Thetransformation rates of anhydrate in the saturate

56、dsolution of monohydrate were measured for the puresystem at 5,15,and 30 C,as shown in Figure 6.Solution-mediated transformation proceeds so that thetwo processes,the dissolution of the metastable formand the recrystallization of the stable form,occursimultaneously.When the metastable phase is withi

57、nthe metastable zone width of the stable phase,there willbe an induction time of nucleation for the stable phase.If the metastable phase is outside the metastable zonewidth,the stable form will be produced without aninduction time.In this sense,the initial conditions ofall of our experimental runs s

58、eem to be within themetastable zone width of the stable phase.49At 30 C,the induction time was about 22 h,and thephase transformation process was completed in 60 h.At 15 C,the monohydrate crystals were formed afteran induction time of 3 h.The phase transformationprocess was completed in approximatel

59、y 10 h.It isinteresting to note that the induction time is muchlonger and the transformation rate is much slower at30 C than at 15 C.This result can be explained bythe fact that the free energy difference between the twocrystal structures,given by the solubility difference,plays a major role in phas

60、e transformation kineticsrather than the kinetic effect activated by increasingtemperature.Figure 7 illustrates the transformationprocess of the anhydrate form ofL-phenylalanine at 15C.The PXRD patterns of the samples obtained atdifferent times clearly indicate the transformation oc-curring in the s

61、olution.From Figure 3,the solubility differences between thetwo forms are approximately 0.25 g/100 g of H2O at 15C and 0.15 g/100 g of H2O at 30 C.This change insolubility differences(0.1 g/100 g of H2O)is expected tobe the major driving force for the phase transformation.Hence,it can be expected th

62、at,as the operating tem-perature of the transformation study approaches thetransition point,the system will achieve an equilibriumstate where the transformation rates of the two modi-fications will be equal to each other.The results at 5 and 15 C can be interpretedsimilarly.The solubility difference

63、s at 5 and 15 C seemto be almost the same,and the temperature effect onthe transformation kinetics is negligible.Therefore,thephase transformation kinetics at 5 and 15 C aresimilar,as shown in Figure 6.3.3.Effect of Additives on Phase Transformationat 15 C.Figure 8 shows the effect of additives on t

64、hephase transformation ofL-phenylalanine at 15 C.ThisFigure 3.Solubilities of the two forms ofL-phenylalaninesanhydrous and monohydrate.Figure 4.Effect of various additives on the solubility ofL-phenylalanine(anhydrate).6114Ind.Eng.Chem.Res.,Vol.40,No.26,2001figure clearly demonstrates that the addi

65、tives selectedin the present experiments,ammonium sulfate anddextrose,tend to lower the transformation rate ofL-phenylalanine.However,the interaction mechanismsof the additives in aqueous solutions ofL-phenylalanineseem to be quite different.When the electrolyte ammonium sulfate was addedin the amou

66、nt of of 0.5 g/100 g of H2O,the transforma-tion was not observed to take place until at least 9 hhad elapsed.In addition,the total time for the completeconversion of the anhydrate form was 19 h.Comparedwith the pure system,the induction time of nucleationincreased by a factor of 3,and the total transformationtime increased by a factor of 2.The reduction insolubility due to ammonium sulfate has been attributedto the inhibition of molecular interactions betweenL-phenylalanine and water molecules.T