Hydrate Formation Wet Granulation Taylor LS

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In-Line Monitoring of Hydrate Formation during WetGranulation Using Raman Spectroscopy

HAKAN WIKSTRO ¨ M, PATRICK J. MARSAC, LYNNE S. TAYLOR

Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, Indiana 47907

Received 5 April 2004; revised 30 July 2004; accepted 13 September 2004

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20241

ABSTRACT: Process-induced transformations are very important to control during

pharmaceutical manufacturing because they may change the properties of the activepharmaceutical ingredient in the drug product, compromising therapeutic efficacy. Oneprocess that may facilitate a process-induced transformation is high-shear wetgranulation. In this study, the feasibility of Raman spectroscopy for in-line monitoring of the transformation of theophylline anhydrous to theophylline monohydrate during high-shear wet granulation has been evaluated. The midpoint of conversion occurred

3 min after the binder solution was added. The effects of several processing parameterswere also examined,includingmixing speed andmonohydrateseeding. Mixingspeed hadthe greatest effect on the transformation, where an increase in mixing speed shortened

the onset time and increased the rate of transformation. In contrast, seeding withmonohydrate or changing theway in which thebinderwas incorporatedinto thegranulesdid not affect the transformation profile. The transformation kinetics observed during wet granulation were compared with those generated by a simple model describing thesolvent-mediated transformation of theophylline in solution. In conclusion, these studiesshow that Raman spectroscopy can be used for in-line monitoring of solid-state trans-

formations during wet granulation. In addition, for this particular compound, a simplesolvent-mediated transformation model has been shown to be useful for estimating the time scale for hydrate formation during high-shear wet granulation.ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:209–219, 2005

Keywords: transformation; hydrate; granulation; Raman spectroscopy

INTRODUCTION

Process-induced transformations (PITs) occur asa result of mechanical or thermal stress imposed

upon a system during processing or after exposureto solvent. PITs are well documented and includeproduction of amorphous regions, crystallizationof amorphous material, polymorphic transforma-tions, change in size and shape of materials,

dehydration of crystalline hydrates, and hydra-tion of anhydrous crystals.1

PITs are important because they may alter theproperties of the final dosage form such as the

solubility, dissolution rate, hygroscopicity, stabi-lity, solid-state reactivity, and ultimately bioavail-ability. One processthat may facilitate a PIT is wetgranulation in which the blended components of aformulation are agitated as water is added leading to granule formation and growth due to mobile-liquid bonding between primary particles. Thequantity of water needed to achieve good granulesvarieswith formulationand processingconditions,but can be up to 50% (w/w) of the dry powders.

Although techniques such as differential scanning calorimetry, X-ray powder diffraction, solid-state

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 1, JANUARY 2005 209

Correspondence to: Lynne S. Taylor (Telephone: 765-496-6614; Fax: 765-494-6545;E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 94, 209–219 (2005)ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association



nuclear magnetic resonance, and microscopy canbe helpful in identifying PITs off-line, an in-linetest, that is, in situ monitoring in real-time, thatminimizes disturbance of the process and elim-inates artifacts associated with sample prepara-tion is obviously advantageous to improve processunderstanding and control. To date, it seems thatthe only technique that has been used to monitorphase transformations in-line during wet granula-tion is X-ray powder diffraction,2 although bothRaman and near infrared (NIR) spectroscopy havebeen used at-line for this purpose.3

Raman spectroscopy is emerging as a usefultechnique for pharmaceutical process monitoring,particularly during the synthesis and productionof drug substance. Svensson et al.4 demonstratedthat Raman spectroscopy combined with chemo-metric analysis could be used for reaction monitor-

ing. Raman spectroscopy has also been used tomonitor the solvent-mediated polymorphic trans-formation of progesterone5 and in the identifica-tion and quantitation of three polymorphic formsof a developmental drug compound during a slurryconversion.6

Given the well-documented ability of Ramanspectroscopy to discriminate between solid-stateforms, even in the presence of excipients,7– 9 andthe availability of commercial process spectro-meters with suitable sampling configurations, it isof interest to investigate whether this technique

can be used for in-line monitoring of phasetransformations during high-shear wet granula-tion. In this study, theophylline was selectedas the model compound and the kinetics of trans-formation were monitored using in-line Ramanspectroscopy. The mechanism of theophyllinetransformation to the hydrate in an aqueous en-vironment has been extensively investigated.10,11

The monohydrate form is the most stable formbelow 608C and heterogeneously nucleates fromthe surface of the anhydrate in water.

In this investigation, we were interested inprobing the transformation during wet granula-

tion in the presence of excipients. The effects of mixing speed, changes to the active pharma-ceutical ingredient (API), including seeding andball-milling, and changes to binder solutionwere examined. Finally, we attempted to predictthe timescale for transformation during wetgranulation using a simple model for solvent-mediated transformations, which assumes Noyes-

Whitney dissolution,12 a screw dislocation-mediated growth-rate equation,10 and a simplemass balance.

EXPERIMENTAL

Materials

Theophylline anhydrous (AT) was purchasedfrom Rhodia (Cranbury, NJ) and placed in an

oven at 1008C for at least 1 h before use to ensurethat no monohydrate was present and usedimmediately after cooling. The surface area of

AT was measured using a Micromeritics ASAP2010 BET (Micromeritics Instrument Company,Norcross, GA) with nitrogen gas. Eight hundredmilligrams of AT was placed in a round-bottomflask and the material was degassed overnight at1008C. Analyses were performed in triplicate.Theophylline monohydrate (MT) was supplied byMallinckrodt Chemical Works (St. Louis, MO)and placed in a desiccator with 100% relative

humidity for a week before use to ensure that noanhydrate was present. Avicel-PH-101 microcrys-talline cellulose (MCC) was obtained from FMCCorporation (Newark, DE). Mannitol was ob-tained from Ruger Chemical Company (Irvington,NJ) and screened through a 20-mesh screen toreduce agglomeration before used. Polyvinylpyrrolidone K-29/32 (PVP) was obtained fromISP Technologies, Inc. (Wayne, NJ). The bindersolution was prepared by slowly adding 100 g of PVP to 800 mL of double-distilled water.

Slurry ExperimentsSlurry conversion experiments were conducted intriplicate using a jacketed vessel and a NeslabRTE-111 circulated water bath (Neslab Instru-ments, Inc., Newington, NH). Five grams of ATwas placed in 40 mL of doubly distilled watermaintained at 25Æ 18C and the slurry wasagitated with a magnetic stir bar.

Wet Granulation

Dry material was weighed and placed in a Diosna

P 1/6 high-shear mixer-granulator (Dierks &Sohne GmbH, Osnabruck, Germany) equippedwith a 2-L stainless steel bowl. All granulationswere performed according to Table 1, unlessotherwise noted. The binder solution was sprayedonto the mix using a Masterflex Quick Load model7021-24 pump (Cole-Parmer Instrument Co.,

Vernon Hills, IL) and the amount of bindersolution added was determined gravimetricallyusing a Mettler PC 8000 balance (Mettler Toledo,Inc., Hightstown, NJ).

210 WIKSTROM, MARSAC, AND TAYLOR

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 1, JANUARY 2005



Raman Spectroscopy

Raman spectra were collected using an RXN1-785 Raman spectrometer (Kaiser Optical Sys-tems, Inc., Ann Arbor, MI) equipped with a 1/4 00

MultiRxn stainless steel immersion probe with aflat sapphire window. A 10–400 mW diode laserat 784.8 nm was used for excitation and the powerat the sample was measured to be around 100 mW using a LaserCheck power meter (Coherent, Inc.,

Auburn, CA). Each spectrum was composed of twoscans with a minimum integration time of 5 s perscan. Spectra were obtained every 15–30 s overthe duration of the experiments. For wet granula-tion experiments, the immersion probe was placedin the mixing bowl just above the impeller andangled toward the movement of the bed to reducethe risk of sample adhesion. For some experi-

ments, a round-tipped probe from Matrix Solu-tions, Inc. (Seattle, WA), designed by Brian J.Marquardt, was used to further minimize the riskof sample adhesion to the probe. Repeat runs wereperformed using both probes to verify that theprobe design did not influence the results.

NIR Spectroscopy

In-line NIR experiments were performed using a NIR-250L-1.7T2 NIR spectrometer (ControlDevelopment, Inc., South Bend, IN) equipped

with a 35-W tungsten halogen light source witha gold reflector mounted on a lamp fixture with afocusing lens mounted in front of an optical fiber.The spectrometer was calibrated against a 50-mmHalon/Albrillon white reflectance reference (Con-trol Development) before use. Spectra were con-tinuously accumulated over the range of 1100– 2200 nm using an integration time of about0.025 s. Only data from 1100 to 1850 nm wasused because of saturation of the detector atlonger wavelengths.

Calibration

Calibration samples were prepared in triplicateby geometrically mixing AT with MT in 10% (mol/ mol) increments with a total of 4 g of material persample. In addition, 5 and 15% (mol/mol) levels of

both forms were also included to better describethe extremes of the calibration range. To mini-mize particle size differences, AT was preparedfrom MT by placing it in an oven at 1008C forseveral days to ensure complete transformation.

To minimize the effect of sub-sampling, anautomatic sampling device was constructed con-sisting of an electrical motor that rotated thesample vial. The flat-faced immersion probe wasfitted with a blade and inserted into the samplebed. An additional blade was inserted into the vial,positioned so that it cleaned the sides of the vial

from sticking material. The blade fitted to theimmersion probe was positioned so that it movedmaterial from the bottom of the vial. With thissetup, an adequate calibration curve was obtainedfrom triplicate sample preparations, each mea-sured three times.

Software

HoloGRAMS software (version 3.0; Kaiser OpticalSystems) was used to control the Raman spectro-meter. Spec32 software (version 4.0; ControlDevelopment) was used to control the NIR

spectrometer. Excel (build 9.0.2720; MicrosoftCorporation, Seattle, WA) was used for calibra-tion calculations and graph plotting. SIMCA-Pþ(version 10.0.4; Umetrics AB, Umea, Sweden) wasused for partial least squares (PLS) data analysis.Raman spectra from HoloGRAMS software weretransferred to Excel via SIMCA as SPC files(Thermo Galactic, Salem, NH) and NIR spectrafrom the Spec32 software were imported toSIMCA as ASCII text files. Sigma Plot (version8.02; SPSS, Inc., Chicago, IL) was used for curvefitting, and Polymath (version 5.1; CACHE Cor-

poration, Austin, TX) was used for the modeling calculations.

RESULTS

Calibration

To determine the amount of theophyllinetransformed at each time point during the wetgranulation experiments, a calibration curve wasgenerated from powder blends of known ratios of

Table 1. Typical Batch Components and

Operating Conditions

AT 90 g MCC 105 g Mannitol 105 g PVP (added in water solution) 14.5 g

Water 115 g Mixing speed 100 rpmChopper speed 1200 rpmDry mixing time 2 min

Binder solution addition time 0.6 min Wet massing time 10 min

IN-LINE MONITORING OF HYDRATE FORMATION 211




AT and MT. As can be seen from Figure 1, AT hasdistinct peaks at 1664 and 1707 cmÀ1 and MThas a distinct peak at 1686 cmÀ1, all related tocarbonyl vibrations in the theophylline molecule.Because the excipients used in these studies havelittle or no Raman response in this region, thesepeaks were chosen to construct the calibrationcurve. Because there is slight overlap betweenthese peaks, a calibration model for overlapping peaks was used to determine the ratio of AT andMT in the samples.13 The observed-versus-pre-dicted plot was fitted to a linear regression linewith the equation y¼ 0.9937xÀ 5.431 and exhi-bits sufficient linearity with a correlation coeffi-cient ( R2) value of 0.988, thus indicating thatRaman spectroscopy can discriminate betweenthe anhydrous and hydrate forms of theophyllineover the entire concentration range.

The NIR calibration was calculated using a PLSregression model and the NIR spectra of AT andMT can be seen in Figure 2. The data matrix waspretreated using a standard normal variate trans-formation,14 mean centered, and fit to a twoprincipal component PLS regression model. The

R2 and Q2 values were 0.994 and 0.994, respec-tively, indicating that the model had a good fitand predictability. The root mean square error of prediction was determined to be 4.4 by predict-ing known samples at 20, 40, 60, and 80% MT(mol/mol).

Wet Granulation

It has been well documented that theophyllineundergoes a solvent-mediated phase transfor-

mation from the anhydrate to the monohydrateduring wet granulation.11 Because off-line ana-lyses have several disadvantages, including sam-pling issues and time delays between sampling and analysis, we were interested in assessing thefeasibility of in-line Raman and NIR spectroscopyas methods to monitor the transformation inreal time during the granulation experiment.NIR spectroscopy has been interfaced with many

processing operations; however, the reported useof Raman spectroscopy for pharmaceutical for-mulation unit operations seems to be limited toat-line analyses.

Before interfacing the sampling devices withthe process, the mass of binder solution necessaryto produce acceptable granules was determin-ed. The mean volume diameter of the resultantgranules was 350 mm, with 80% of the particlesbeing within 100 mm of the average particle size.The Carr’s index was determined to be 18%and attrition was negligible. When the sampling devices were present in the mixing bowl, there was

no visually discernible change in the quality of thegranules, that is, the devices did not appear tocause noticeable disruption of the granulationprocess.

Figures 3 and 4 show examples of Raman andNIR spectra collected at various time intervalsduring wet granulation and the zero time pointcorresponds to the beginning of binder addition.From Figure 3, it is apparent that peaks char-acteristic of AT at 1664 and 1707 cmÀ1 disappearand the peak corresponding to MT at 1686 cmÀ1

Figure 1. Raman spectra of anhydrous (AT) and

monohydrate (MT) theophyllinefrom 1500 to 1750 cmÀ1.

Figure 2. NIR spectra of AT and MT from 1100 to

1850 nm.





appears during wet massing indicating that it ispossible to follow the transformation with Ramanspectroscopy. Furthermore, because there is nosignificant interference from either water or ex-cipients in this spectral region, thechanges in peakheight ratios could be converted to percentagetransformed using calibration data. The resulting time profile of hydrate formation is shown inFigure 5. In contrast, the main differences inthe NIR spectra between the two forms of theo-phylline arise because of the presence of the water

molecule, which results in increased absorptionat 1450 nm, as seen in Figure 2. Thus, it is notpossible to follow the transformation kinetics withNIR spectroscopy because of the drastic changeswater addition has to these regions, even if the

wavelength regions used for the calibration modelwere selected so that the influence from the watersignal was minimal. However, it is possible togain information about binder addition. The NIRdata show changes in the water content whereasRaman data provide information about the kine-tics of theophylline hydrate formation. Because wewere primarily interested in investigating trans-formation kinetics, only Raman spectroscopy wasused for more extensive investigations.

Having established that Raman spectroscopy

could be used to monitor the transformation, threebatches of identical composition were prepar-ed using the same granulation conditions (seeTable 1) in order to evaluate the repeatability of this methodology. For this particular formulationsubject to these process variables, the time takenfor 50% of the theophylline to transform was 3 minafter initiating binder solution addition with arelative standard deviation of 6.0%. This level of repeatability provides an indication that it shouldbe possible to study the effect of process variableson the transformation.

Influence of Mixing Speed

Differences in mixing speed are, among otherparameters, likely to affect the rate of water dis-tribution, wetting, and the shear forces experi-enced by particles. To investigate the influence of this parameter on the transformation kinetics,granulations were performed using different mix-ing speeds. As a way of comparing the differentgranulation conditions, data obtained at mixing speeds of 100, 200, and 400 rpm (corresponding to

Figure 3. Waterfall plot of Raman spectra collectedduring granulation showing the transformation of ATwith characteristic peaks at 1664 and 1707 cmÀ1 to MTwith a characteristic peak at 1686 cmÀ1.

Figure 4. Waterfall plot of NIR spectra collected

during a granulation run highlighting the dominating effect of the water peak at 1450 nm.

Figure 5. Effect of mixing speed on kinetics of transformation of AT to MT monitored with Raman

spectroscopy during wet granulation. Binder additionwas initiated at t¼0 and data before this point wereacquired during dry mixing.





tip speeds of 0.9, 1.8, and 3.6 m/s, respectively)were fit to the empirical eq. (1). This equation waschosen because it fit the data well and allowed usto compare granulations with different processing conditions.

C MT ¼ minþ maxÀmin

1 þ t=midÀ Á k

ð1Þ

where C MT is the fraction of monohydrate, min isthe initial level of C MT (i.e., 0), max is the finallevel of C MT (i.e., 1), mid is the time when 50% hasbeen transformed, k is related to the rate of trans-formation, and t is time in minutes.

The mean midpoint (n¼ 3) was reached at 2.9,2.1, and 1.2 min after the beginning of bindersolution addition for the mixing speeds of 100, 200,and 400 rpm, respectively (see Table 2). These

results indicate that mixing speed influences thetransformation kinetics, and that for the 100– 400 rpm range of mixing speeds, transformationtime decreases with increasing mixing speed. A plot of the transformation profiles for differentmixing speeds is shown in Figure 5.

In addition to the experiments described above,granulations at lower mixing speeds (30 and50 rpm, i.e., tip speeds of 0.27 and 0.45 m/s) werealso performed. Very large granules were pro-duced, which interfered with data collection. Off-line measurements were made after the granula-tion was complete and it seems likely that the

distribution of water was inhomogeneous becausethe extent of transformation measured at differ-ent locations in the granulation bowl variedsignificantly.

At higher mixing speeds (600þ rpm or at tipspeeds >5.4 m/s), mixing was so rigorous that itincreased the temperature of the granules, result-ing in an increase in transformation time, prob-ably due to the decrease in supersaturation athigher temperatures. In addition, at 600 rpm, thebatch quickly became overgranulated causing material to stick to the probe, which prevented

representative sampling.

Effect of API Properties

A granulation was prepared in which 5% (mol/ mol) of monohydrate seeds were substituted for

AT powder. The rate of transformation was simil-ar to that obtained without seeding. The effect of

increasing the concentration of theophylline inthe formulation was also investigated. The theo-phylline loading was increased by 50% from 30 to45% (w/w), keeping the ratio of mannitol to micro-crystalline cellulose constant at 1:1 (w/w). Theamount of water was decreased slightly to bettersuit this formulation. No differences between thetransformation rate in the formulation consisting of 45% (w/w) API and the formulation consisting of 30% (w/w) API could be seen.

Finally, ball-milled theophylline was substi-tuted for unprocessed theophylline to investigate

the effect of initial surface area and surface pro-perties on the rate of transformation. Althoughsuccessful in-line monitoring of granulation wascompletely impossible because of excessive stick-ing to the probe, periodic sampling indicated thatthe transformation was completed in <3 min com-pared with only 50% being transformed in thattime during identical process condition withunprocessed AT.

Effect of Changes to Binder Addition

The effect of adding the binder as a dry powder

instead of as an aqueous solution was also inves-tigated. No significant changes occurred withrespect to the rate of transformation; however,adding binder as a dry powder significantlychanged the granules’ properties.

DISCUSSION

Interfacing the Raman spectrometer to thewet granulation process proved to be relativelystraightforward for the lab-scale equipment usedin these studies yielding spectra of sufficient

quality in a reasonable time interval such that

Table 2. Effect of Mixing Speed on Transformation Midpoint, Confidence Interval

(CI) About the Midpoint, and Slope of AT to MT Conversion Profile

Mixing Speed Midpoint Lower CIa Upper CIa Slope

100 rpm 2.93 min 2.50 min 3.37 min À5.7200 rpm 2.06 min 1.55 min 2.57 min À7.7400 rpm 1.18 min 0.86 min 1.50 min À11.3

a95% CI.







terms of the initial concentration in solution andthe initial and final CSDs of each solid phase.

Clearly, the wet granulation environment is amuch more complicated system andmeasuring thefinal CSD and the solution phase concentrationduring wet granulation would be a difficult, if notimpossible, task. Raman spectroscopy only pro-vides information about the percentage of eachsolid phase. However, it is possible to predict thetimescale of the transformation based on a fewsimple equations in order to identify whether asolvent-mediated transformation would pose apotential problem during wet granulation. Forexample, Davis et al.2 predicted the polymorphictransformation of flufenamic acid by calculating the solubility of each phase, the growth rateconstant, assuming first-order kinetics, and fitting the dissolution rate constant to on-line X-ray data

collected during wet granulation. Taking a similarapproach, assuming Noyes-Whitney dissolutionand second-order growth with respect to super-saturation,10 we have attempted to predict therate of theophylline hydrate formation during wetgranulation. This model does not take into accountthe induction period. The surface area availablefor dissolution and nucleation of MT was esti-mated by fitting the model to slurry data using published rate constants and solubilities.

Dissolution of AT

AT is assumed to follow Noyes-Whitney dissolu-tion and is expressed in terms of the degree of undersaturation according to eq. (2).

dA

dt¼ kd A A

C sol À S A

S A

ð2Þ

where kd is the dissolution rate constant, A A is thesurface area of AT, C sol is the concentration of theophylline in solution, and S A is the solubility of

AT.The dissolution rate constant was measured by

de Smidt et al.18 to be 0.043 mg/s using a rotating

disk method at 160 rpm. The intrinsic dissolutionrate constant was calculated to be 0.0146 mg/ mm2 Ámin by dividing the dissolution rate con-stant by the surface area of the rotating disk.19 Theinitial external surface area of AT was estimatedto be 0.14 m2 /g by fitting the model to a slurryexperiment and compares well with the surfacearea measured by nitrogen gas adsorption:0.46 m2 /g. The lower value can be explained bythe fact that AT tends to form agglomerates, asshown in Figure 6 and it has been shown that

surface area for dissolution decreases with forma-tion of agglomerates.20,21 Next, the solubility of the

AT was taken tobe 12.3mg/mLat 258C as reportedpreviously11 and the change in surface area withtime was estimated from the change in mass of thedissolving phase, assuming constant crystal shapefactors.22

Growth of MT

It has been shown that the growth of MT onto MTseeds is proportional to the square of the super-saturation with a temperature-dependent growth

Figure 6. Scanning electron microscopy pictures of AT crystals highlighting the presence of agglomerates.a) 400Â magnification, b) 6000Â magnification.





rate constant.10 From these results, we estimate agrowth rate constant of 16.3 mm/min at 258C.

Assuming that this growth rate constant can beapplied to our system and multiplying the growthrate constant by the density as measured byEbisuzaki et al.,23 an intrinsic growth rate con-stant of 0.0246 mg/mm2 /min is obtained. Thesolubility of MT was taken to be 5.96 mg/mL at258C10 and the rate of monohydrate growth wasmodeled with eq. (3).

dM

dt¼ kG AM

C sol À SM

SM

2

ð3Þ

where kG is the growth rate constant, AM is thesurface area of MT, and SM is the solubility of MT.It was then assumed that AM remained constantthroughout the process. This is a reasonableassumption because growth of MT is linear andnucleation can be assumed to occur as an initialburst implying constant surface area during growth.10

Mass Balance

To complete the model, the total mass must beconserved as shown in eq. (4), such that the sum of the changes in mass in the solution phase, theanhydrous phase, and the monohydrate phasemust be zero.

V dC soldt ¼ À dAdt þ dM dt

ð4Þ

where V is the volume of binder solution.

Modeling Wet Granulation

A comparison of the model described in the pre-vious section to the data collected during granu-lation is given in Figure 7. The observedtransformation time for the granulation is welldescribed by the model, particularly for mixing speeds of 200 and 400 rpm. This observation, in

conjunction with the results of the differentgranulation experiments, provides insight intosome of the factors controlling the transforma-tion. First, although the water/theophylline ratiois much greater for the slurry compared with thegranulation, the transformation kinetics are com-parable, thus the quantity of water used in wetgranulation is clearly not a limiting factor. Fur-thermore, any hydrodynamic differences betweenthe slurry conversion experiments and the gran-ulations seem to have a minimum effect on the

transformation. Additionally, seeding with mono-hydrate had no effect on the induction or trans-formation time, suggesting that nucleation is notthe limiting factor (note that the amount of wateradded at the beginning of the process was notenough to dissolve more than a fraction of theseeds added). Although the origin of the inductionperiod has not been elucidated (Fig. 5), likely it isassociated with water distribution, wetting of theophylline, and the initial dissolution stage. It

is also interesting to note that the excipients usedin this study had no perceivable influence on thetransformation kinetics. The two factors that didexert an influence were impeller speed and ball-milling. It is likely that both of these can influencethe growth of monohydrate. A higher impellerspeed would be expected to provide more shearforce, which in turn would lead to better waterdistribution. This effect was not as dramatic asball-milling AT. For this sample, the transforma-tion time was practically instantaneous. It islikely that milling the powder changed the sur-face properties and resulted in an increased

number of high-energy sites (including the possi-ble formation of amorphous regions) for nuclea-tion of MT and an increased surface areaavailable for dissolution.

CONCLUSIONS

In-line Raman spectroscopy was successfullyinterfaced to high-shear wet granulation of aformulation containing AT and used to monitor

Figure 7. Comparison between modeled transforma-

tion profile of AT to MT and transformation profile afterthe onset of transformation monitored using Ramanspectroscopy during wet granulation for various mixing speeds.





the solvent-mediated psuedopolymorphic conver-sion of the API. NIR spectroscopy could not beused to monitor the phase transformation in thissystem because of the large absorbance of bulkwater, which hid spectral information relating to the transformation. Because the conversionoccurred over a relatively short time period(<5 min), using an in situ method enabledprofiling of the transformation kinetics. Theconversion rate to MT was found to be similarfor high-shear wet granulation and a simpleslurry system. The ability to follow the transfor-mation allowed considerable insight into thecritical parameters determining the conversionrate. Raman spectroscopy shows considerablepotential as an advanced in-line monitoring tech-nique particularly for the understanding andcontrol of process-induced solid-state transitions,

although advances in instrumentation need to beprogressed to realize this potential.

ACKNOWLEDGMENTS

Dr. Jukka Rantanen and Francis E. Rhea aregratefully acknowledged for assistance with dataanalysis and experimental support. The authorsare grateful to Mary A. Albrecht at SSCI, Inc. forobtaining the scanning electron microscopy pic-tures. Brian J. Marquardt and Matrix Solutions,

Inc. are acknowledged for the design and use of the round-tip immersion probe used for someRaman experiments. Xiaomin Lui of Illinois Insti-tute of Technology is thanked for helpful discus-sions on modeling. Finally, AstraZeneca R & DMolndal is acknowledged for financial supportand Kaiser Optical Systems, Inc. is acknowledgedfor assistance with instrumentation.

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Hydrate Formation Wet Granulation Taylor LS

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