Influence of Excipients in Comilling on Mitigating
Milling-Induced Amorphization or Structural Disorder of
Crystalline Pharmaceutical Actives
PRASHANT N. BALANI,1 WAI KIONG NG,2 REGINALD B.H. TAN,2,3 SUI YUNG CHAN1
1
Department of Pharmacy, National University of Singapore, Block S4, 18, Science Drive 4, Singapore 117543, Singapore
2
Crystallisation and Particle Sciences, Institute of Chemical and Engineering Sciences, Agency for Science,
Technology and Research, 1 Pesek Road, Jurong Island, Singapore 627833, Singapore
3
Department of Chemical and Biomolecular Engineering, National University of Singapore
4
Engineering Drive 4, Singapore 117576, Singapore
Received 6 April 2009; revised 22 September 2009; accepted 22 September 2009
Published online 9 November 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21998
ABSTRACT: The feasibility of using excipients to suppress the amorphization or structural
disorder of crystalline salbutamol sulphate (SS) during milling was investigated. SS was
subjected to ball-milling in the presence of a-lactose monohydrate (LAC), adipic acid (AA),
magnesium stearate (MgSt), or polyvinyl pyrrolidone (PVP). X-ray powder diffraction, dynamic
vapor sorption (DVS), high sensitivity differential scanning calorimetry (HSDSC) were used to
analyze the crystallinity of the milled mixtures. Comilling with crystalline excipients, LAC, AA,
and MgSt proved effective in reducing the amorphization of SS. LAC, AA, or MgSt acting as seed
crystals to induce recrystallization of amorphous SS formed by milling. During comilling, both
SS and LAC turned predominantly amorphous after 45 min but transformed back to a highly
crystalline state after 60 min. Amorphous content was below the detection limits of DVS (0.5%)
and HSDSC (5%). Comilled and physical mixtures of SS and ALM were stored under normal and
elevated humidity conditions. This was found to prevent subsequent changes in crystallinity and
morphology of comilled SS:LAC as compared to significant changes in milled SS and physical
mixture. These results demonstrate a promising application of comilling with crystalline
excipients in mitigating milling induced amorphization of pharmaceutical actives. � 2009
Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2462 2474, 2010
Keywords: milling; stability; crystallinity; excipients; X-ray powder diffractometry
INTRODUCTION the surface. Solid-state amorphizations induced by
milling have been reported in many cases such as
Milling or comminution is a common unit operation piroxicam,5 budesonide,6 and sucrose.7 These amor-
employed for particle size reduction, which forms an phous regions or crystal defects created are unstable,
integral part of pharmaceutical secondary manufac- can migrate, transform, and change their number and
turing.1 3 When milling crystalline active pharma- nature.8 During postmilling storage, these amor-
ceutical ingredients (APIs), the mechanical stress phous regions, not being at thermodynamic equili-
inherent to the process often produces structural brium, may transform back to the crystalline state
changes on the crystal.4 Milling is often accompanied and affect long-term stability in terms of powder
by a disorder in the crystalline structure leading to properties such as particle size distribution, specific
the formation of amorphous regions, particularly at surface area, chemical and physical reactivity, dis-
solution, and finally the drug product performance.9
Batch-to-batch reproducibility of the materials with
Associate Professor.
Correspondence to: Sui Yung Chan (Telephone: 65-65162646; different degrees of crystalline disorder is another
Fax: 65-67791554; E-mail: phacsy@nus.edu.sg)
major concern in the pharmaceutical industry.8
Correspondence to: Reginald B.H. Tan (Telephone: 65-65166360;
In order to stabilize the unstable amorphous form,
Fax: 65-67791936; E-mail: chetanbh@nus.edu.sg)
comilling or co-grinding with amorphous excipients
Journal of Pharmaceutical Sciences, Vol. 99, 2462 2474 (2010)
� 2009 Wiley-Liss, Inc. and the American Pharmacists Association such as polyvinyl pyrrolidone (PVP), magnesium
2462 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010
STRUCTURAL DISORDER OF CRYSTALLINE PHARMACEUTICAL ACTIVES 2463
aluminometasilicate (Neusilin US2), etc., has been and diluent, especially in the formulation of powder
employed.10,11 Several authors11 14 have studied the mixtures for inhalation.19 Fine lactose has been
physical stabilization of amorphous indomethacin by reported as improving the aerosolization properties
co-grinding with silicates. The effect of mass ratios of of a cohesive drug and controlling drug dispersion
indomethacin to Neusilin US2 (magnesium alumino- from drug lactose mixtures of inhalation.20 21 AA is
metasilicate) and processing humidity on stabilizing selected because it is a single polymorph22 and a
the amorphous form of indomethacin were studied by common pharmaceutical excipient, used as an acidu-
Bahl and Bogner.11 Plasticization of amorphous drug lent in effervescent tablets or lubricant in tablets.
to allow mechanical transfer of drug to silicate, vapor- Being a single polymorph, there is no need to consider
phase mass transfer, and the role of water in particle any influence of polymorphic transformation on
particle surface migration of the drug to the silicate milling. MgSt is selected because it is crystalline in
have been put forward as possible explanations for nature and is most widely used lubricant in tablets.23
the formation of the stable indomethacin silicate PVP is selected because it is an amorphous excipient,
alloy.11 However, there has been no reported attempt tolerated physiologically, widely used as a carrier for
to avoid the formation of the amorphous state during solid dispersions to increase the dissolution rate while
milling, as amorphization is conventionally consid- suppressing recrystallization.24 28
ered as an often undesirable but also unavoidable Several methods have been used to assess amor-
side-effect of milling. Therefore, this work is aimed at phous content such as XPRD. Differential Scanning
using comilling to minimize amorphization of crystal- Calorimetry (DSC) with limits of detectability down
line APIs. The authors first observed there was to 5% and dynamic vapor sorption (DVS) which can
retention of some crystallinity in a milled API in the detect extent of disorders as low as 0.5%.29 DVS was
X-ray powder diffraction (XPRD) patterns of urso- recently reported as the method for producing the
deoxycholic acid comilled with various additives, but best correlation for amorphous content in lactose
the effect was not discussed and amorphous content among seven techniques.30 In the present study,
was not quantified in the report.15 A recent report the amorphous contents of the individual milled
revealed that some form of recrystallization or defect components, physical, and comilled mixtures were
rearrangement can take place by heating below the analyzed using XRPD, DVS, and DSC. Amorphous
glass transition temperature of griseofulvin.4 There- content analysis in case of DVS, was based on a
fore, the objective of this research work is to evaluate reported method31 where the change in mass of
the feasibility of retaining the crystalline form of micronized SS at a given relative humidity was used
milled salbutamol sulphate (SS) by comilling with to determine the amorphous content. Besides these
crystalline excipients lactose (LAC) or AA or magne- methods, changes in particle morphology were
sium stearate (MgSt). Comilling with an amorphous studied using scanning electron microscopy (SEM)
excipient, PVP, is also carried out as a comparison to for comilled mixtures kept under ambient and
investigate the effect of the crystallinity of the elevated humidity conditions (75% RH) to observe
excipient on the comilled mixture. Comilling was any accompanying particle agglomeration and mor-
carried out by milling different ratios of SS and phological changes. It is hoped that providing an in-
excipients using a planetary ball mill. Finally, to test depth understanding of retention of the crystallinity
out the usefulness of the new comilling technique, a of substances on comilling could open up new
stability study was conducted to monitor the physical strategies to minimize amorphous phase formation
stability of comilled SS after 1-week storage at 75% during milling, stabilize the properties of a crystalline
RH compared to those of the milled SS alone and the drug during storage, and improve the batch-to-batch
physical mixture of SS with LAC. reproducibility.
SS is selected as the model compound as it is
physically not stable after milling. It readily converts
from the crystalline to the amorphous form on ball-
milling. During storage, it has been reported that the
MATERIALS AND METHODS
particle size of milled SS increases over time.16 18
Pfeiffer et al.17,18 proposed that the particle size
Materials
enlargement of SS resulted from the moisture
sorption-mediated recrystallization of amorphous SS ( 99% purity) was purchased from Junda Phar-
surfaces leading to agglomeration. Such shift in maceutical Co. Ltd (Jiangsu, PR China). a-Lactose
particle size is detrimental for inhalation drugs like monohydrate (LAC, Mw ź 360.31, 99% purity), adipic
SS because it has a direct impact on the aerosolization acid (AA, Mw ź 146.14, 99% purity), MgSt (Mw ź
performance and therapeutic effect.17 LAC is selected 591.24, 90% stearic and palmitic acid basis), and
as one of the crystalline excipients as it has been PVP (Mw range 29000 55000, 99% pure,) were pur-
widely used in the pharmaceutical industry as carrier chased from (Sigma Aldrich, Singapore, Singapore).
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010
2464 BALANI ET AL.
Methods Preparation of Cryo-Comilled Mixture
Milling of SS and Excipients The physical mixture of cSS and mLAC (1:1 w/w) was
cryo-comilled using a mixer mill (Retsch Mixer mill
Sieved fractions of crystalline (nonmilled) SS
MM 301, Rheinische Stra�e) equipped with a stain-
(75 250 mm, cSS), crystalline LAC (less steel jar and a grinding ball (diameter 20 mm).
crystalline AA (250 500 mm, cAA) were prepared
Two grams of the mixture and the grinding ball
using Retsch Sieve Shaker (Retsch GmbH, Rhei-
placed inside the jar were precooled in liquid nitrogen
nische Stra�e, Haan, Germany) set at amplitude of
for a few min and milled for a duration of 5 min at
2.5 mm for 10 min. Crystalline MgSt (cMgSt) and PVP
10 Hz. The cryo-comilled mixture was characterized
were used as received. Milling of cSS and all
immediately after extracting the sample from the
excipients except PVP was carried out using Fritsch
milling jars at the end of the milling process.
Pulverisette 5 (FRITSCH GmbH, Idar-Oberstein,
Germany), a planetary ball mill equipped with
X-Ray Powder Diffraction
stainless steel jar and balls (diameter 10 mm). As
PVP is amorphous in nature, no prior milling was XRPD patterns of cSS, mSS, mLAC, mAA, mMgSt,
required. The mass ratio of ball to sample was kept at PVP, comilled mixtures of cSS and mLAC, comilled
50:1. The rotation speed was set at 300 rev min 1 and mixtures of cSS and mAA, comilled mixtures of cSS
a milling duration of 60 min at room temperature was and mMgSt, comilled mixtures of cSS and PVP,
used for all samples. The milled form of drug (mSS) physical mixtures of mSS and mLAC, physical
and excipients (mLAC, mAA, mMgSt) were charac- mixtures of mSS and mAA, physical mixtures of
terized immediately after extracting the sample from mSS and mMgSt, and physical mixtures of mSS and
the milling jars at the end of the milling process. PVP were obtained using an X-ray powder diffract-
Immediate characterization was needed due to the ometer (D8 Advance, Bruker AXS GmbH, Karlsruhe,
unstable nature of the milled form of the materials. Germany) equipped with PSD Vantec-1 detector.
Measurements were performed with CuKa radiation
over the reported32 angular range for SS from
Preparation of Comilled Mixtures 2 < 2u < 408 in step scan mode (step width 0.0178,
scan rate 1 8/min). Crystalline structures of the
Freshly milled excipients (mLAC, mAA, mMgSt) and
samples were verified by comparing to the standard
PVP was used for comilling. The different drug to
reported in the Cambridge Structural Database.
excipient ratios prepared for the study were: 1:1, 1:2,
1:3, 1:4, 2:1, 3:1 (w/w) of cSS with mLAC and 1:1, 1:2,
Dynamic Vapor Sorption
1:3, 2:1, 3:1 (w/w) of cSS with mAA, mMgSt, and PVP,
respectively. Different drug (cSS) excipient (i.e., Sorption isotherms of mSS, mLAC, mAA, mMgSt,
mLAC, mAA, PVP, mMgSt) ratios were mixed in a comilled mixtures of cSS and mLAC, comilled
turbula mixer at 49 rpm for 20 min and the resultant mixtures of cSS and mAA, comilled mixtures of cSS
mixtures were subsequently comilled at room tem- and mMgSt, physical mixtures of mSS and mLAC,
perature (258C) in the planetary ball mill at condi- physical mixtures of mSS and mAA, physical
tions mentioned in the previous section of   Milling of mixtures of mSS and mMgSt were obtained using
SS and excipients.  The comilled mixtures were DVS (Advantage, Surface Measurement Systems,
characterized immediately after extracting the sam- Alperton, UK). The humidity range was varied from
ple from the milling jars at the end of the milling 0% to 90% RH in steps of 10% RH at 228C. The
process. instrument was runned in dm/dt mode to decide when
equilibrium had been reached, with a reported33 dm/
dt set at 0.002%/min within an interval of 5 min. All
sample weights were approximately 10 12 mg.
Preparation of Physical Mixtures
High Pressure Liquid Chromatography
The physical mixtures of drug with all excipients
except PVP were prepared by mixing freshly milled The SS contents in cSS-mLAC comilled mixtures
drug (mSS) and freshly milled excipients (i.e., mLAC, were analyzed by HPLC using the method developed
mAA, mMgSt) in a turbula mixer at 49 rpm for by Zhu et al.34 The measured retention time for SS
20 min. The procedure was repeated in preparation of was approximately 3.9 min. Standard solutions were
physical mixtures of freshly milled drug (mSS) and prepared for drug concentrations ranging from 0.5 to
PVP. Drug to excipient ratios used were similar to 15 mg/mL, in order to construct a calibration curve of
those for comilled mixtures. The physical mixtures drug concentration against the peak area. The
were characterized immediately after sample was calibration was considered to be acceptable when
obtained from turbula mixer. R2 > 99.9%.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010 DOI 10.1002/jps
STRUCTURAL DISORDER OF CRYSTALLINE PHARMACEUTICAL ACTIVES 2465
Spectroscopy Scientific Instruments, Inc., Watford, UK), prior to
analysis.
Fourier transformed infra-red spectroscopy (FTIR)
absorbance spectra of cSS, mSS, comilled mixtures
of cSS and mLAC (1:1), and physical mixture of
Physical Stability of Stored Samples
mSS:mLAC (1:1) (w/w) were obtained on a FTIR
Milled SS, comilled, and physical mixtures of
spectrometer (Perkin-Elmer 2000, Massachusetts,
cSS:mLAC and mSS:mLAC, respectively, at ratios
USA). Samples were prepared as a pellet in a KBR
of 1:1 and 1:3 (w/w) were stored in desiccators at
matrix. Thirty-two scans were collected for each
approximately 228C for 7 days. Storage humidity
sample with a spectral resolution of 4 cm 1.
conditions of 15% and 75% RH were prepared using
phosphorus pentoxide and standard hygrostatic NaCl
High Sensitivity Differential Scanning Calorimetry
solutions.35 XRPD and SEM analyses of the comilled
(HSDSC)
and physical mixtures prior and after storage were
conducted to evaluate changes in crystallinity and
HSDSC thermograms of mSS, mLAC, mAA, mMgSt,
morphology.
PVP, comilled mixtures of cSS and mLAC, comilled
mixtures of cSS and mAA, comilled mixtures of cSS
and mMgSt, comilled mixtures of cSS and PVP,
RESULTS AND DISCUSSION
physical mixtures of mSS and mLAC, physical
mixtures of mSS and mAA, physical mixtures of
Effect of Comilling on Crystallinity of SS
mSS and mMgSt, physical mixtures of mSS and PVP
were analyzed using a Micro-DSC (Setaram, Caluire,
In Figure 1, the XRPD of cSS comilled with mLAC
France). Approximately 20 mg of each sample was
was compared with those of milled and crystalline SS,
loaded into Hastelloy-made vessels (1 cm3). Scanning
milled LAC, physical mixture of mSS and mLAC. As
was performed from 40 to 1108C at a heating rate of
agreed with previous reports,36,37 milling reduced the
1 8C/min.
characteristic peaks of cSS (Fig. 1b) at 10.508, 17.678,
and 18.328 2u and gave rise to a broad halo confirming
the X-ray amorphous state (Fig. 1a). The character-
Scanning Electron Microscopy
istic peaks of crystalline LAC at 19.618 and 19.988 2u
The particle morphology was examined by high (Fig. 1c) though reduced in intensity, were still
resolution SEM (JSM-6700F, JEOL Ltd, Tokyo, present in milled LAC. This agrees with a recent
Japan) operating at 10 keV under secondary electron study showing that at least 12 h of ball-milling was
imaging (SEI) mode. Each sample was mounted on a required to fully amorphize LAC.38 Interestingly, the
carbon sticky tab and platinum coated for 1 min by a characteristic peaks of crystalline SS at 17.678 and
sputter coater (Cressington 208HR, Cressington 18.328 2u were observed when cSS was comilled with
Figure 1. Powder X-ray diffractograms of (a) mSS, (b) cSS, (c) mLAC, (d) physical
mixture of mSS:mLAC 1:1, (e) comilled mixture of cSS:mLAC 1:1.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010
2466 BALANI ET AL.
mLAC (Fig. 1d). The retention of characteristic peaks used as reference points for 0% and 100% amorphous
suggested that the degree of amorphization has been contents, respectively. The contribution of varying
reduced in the presence of LAC. When the mass ratio excipient contents to the isotherms has been
of SS:LAC was greater than 1, no crystalline peaks of deducted.
SS were seen, suggesting a minimum ratio of LAC
Dmms 1
Amorphous content ź 100% (1)
was needed in retaining the crystalline form of SS on
md Dm100
comilling (data not shown). In comparison, these
characteristic peaks of SS were also absent in all where by Dm is the difference in change in mass
physical mixtures including mSS:mLAC 1:1 (Fig. 1e). between first sorption and second sorption cycle at
The use of other grinding techniques such as cone or 30% RH [%], ms the sample mass [kg], md the dry
hammer mill with shorter milling durations could mass of SS [kg], and Dm100 the difference in change in
result in achieving same level of particle size and with mass between first sorption and second sorption cycle
less potential amorphization. of milled X-ray amorphous SS at 30% RH [%]. As
To quantify the amorphous content in milled and indicated in Table 1, the comilled ratio (cSS:mLAC
comilled samples, the individual components, physi- 1:1) still contained significant amorphous content
cal mixtures, and comilled mixtures were analyzed with small difference of 19% in comparison with the
using DVS. The moisture sorption isotherms of cSS physical mixture (mSS:mLAC 1:1) The additional
with mLAC at comilled ratios 1:1, 1:3, and 1:4 were water sorption, which provides a % amorphous of
measured and plotted in Figure 2. As expected, a greater than 100, is probably due to amorphous
mass loss was observed between the first and second lactose. The standards used are pure SS and do not
sorption isotherms of milled SS with a steep mass loss contain lactose. Hence, the amorphous content
between 60% and 70% RH39 due to the recrystalliza- quantification by DVS may not be precise. On the
tion of amorphous regions. Interestingly, this hyster- other hand, no detection of amorphous content below
esis occurrence was clearly absent in comilled the reported detectable limit (<0.5%) could be seen in
mixtures at mass ratios of 1:3 and 1:4, which suggests the comilled ratios of cSS with mLAC at 1:3 and 1:4.
the absence of amorphous content. Physical mixtures To verify the absence of amorphous content in
of mSS with mLAC and comilled mixture (cSS:mLAC comilled mixture at 1:3 and 1:4 mass ratios, another
1:1) showed mass loss similar to mSS. It should be highly sensitive technique, HSDSC, was applied to
noted that in order to improve the clarity in Figures 2 probe the amorphous content. Figure 3 shows the
and 7, second sorption isotherms of all samples except HSDSC thermograms of milled SS, milled LAC,
milled SS were excluded. Using the method reported physical and comilled mixtures of SS with LAC.
by Matthias et al.,31 the amorphous content was The HSDSC thermograms of milled SS (Fig. 3a),
estimated using Eq. (1) and shown in Table 1. physical (Fig. 3c), and comilled (Fig. 3d) mixtures
Crystalline SS and milled X-ray amorphous SS were except comilled ratios (cSS:mLAC 1:3 (Fig. 3e) and 1:4
Figure 2. Sorption isotherms of mSS, comilled mixtures of cSS:mLAC (1:1, 1:3, and
1:4), and comilled mixture of mSS:mLAC 1:1.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010 DOI 10.1002/jps
STRUCTURAL DISORDER OF CRYSTALLINE PHARMACEUTICAL ACTIVES 2467
Table 1. Amorphous Contents of SS, Physical Mixture, and Comilled SS with Excipients
Difference in Mass Loss Between
Components First and Second Cycle (% w/w) Amorphous Content (% w/w)
cSS 0.0 0a
mSS 3.6 100a
Comilled cSS:mLAC (1:1) 3.8 106
Physical mixture mSS:mLAC (1:1) 4.5 125
Comilled mSS:mLAC (1:1) 0.1 0.1
Comilled cSS:mLAC (1:3) 1.0 0
Physical mixture mSS:mLAC (1:3) 2.4 66
Comilled cSS:mLAC (1:4) 0.7 0
Physical mixture mSS:mLAC (1:4) 3.1 106
Comilled cSS:mAA (1:1) 1.9 54
Physical mixture mSS:mAA (1:1) 5.1 91
Comilled cSS:mMgSt (1:1) 0.5 0
a
Reference values.
(Fig. 3f)) showed an expected glass transition between drug amorphization below detectable limits ( 0.5%
60 and 658C. A recrystallization exotherm was also and 5%).
observed but at a higher temperature range of 100
1058C instead of 828C reported previously.18 The
observation of Tg and recrystallization is attributed to
Understanding Behind Amorphization Reduction
the amorphous content generated by milling. Neither
Tg nor crystallization exotherms were observed for H-bonding interactions have been well studied upon
the comilled ratios of cSS:mLAC 1:3 (Fig. 3e) and 1:4 mechanical activation with polymers and inorganic
(Fig. 3f). Both the DVS and HSDSC data provided additives such as silicates.40 H-bonding interactions
evidence to support the notion that comilling of cSS have also contributed in confirming co-crystal forma-
with mLAC at mass ratios of 1:3 and 1:4 reduced the tion after co-grinding.41 To decipher the mechanism
Figure 3. HSDSC thermograms of (a) mSS, (b) mLAC, (c) physical mixture of
mSS:mLAC 1:1, (d) comilled mixture of cSS:mLAC 1:1, (e) comilled mixture of
cSS:mLAC 1:3, (f) comilled mixture of cSS:mLAC 1:4.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010
2468 BALANI ET AL.
Figure 4. FTIR spectra of (a) mSS, (b) cSS, (c) mLAC, (d) physical mixture of
mSS:mLAC 1:1, (e) comilled mixture of cSS:mLAC 1:1.
behind the retention of crystalline SS on comilling; One of the processes involving transformation from
spectra of individual components, physical mixtures, crystal to crystal on milling could involve an inter-
and comilled mixtures were recorded using FTIR. mediate stage of transient amorphization followed by
Figure 4 shows the FTIR of milled SS, milled LAC, a rapid recrystallization process. It has been difficult
physical mixtures, and comilled mixtures of SS with to analyze this transient amorphous fraction because
LAC (1:1). FTIR of cSS (Fig. 4b) has been well amorphization ceases when milling is stopped but,
studied and is characterized by the presence of peaks recrystallization does not and by the time the sample
corresponding to secondary amine salt (C N) stretch is analyzed using DSC or XRPD, the amorphous
at 1616 and 1509 cm 1 apart from phenolic C O fraction is not present.46 The presence of transient
stretching and secondary alcoholic C O stretching at amorphous fraction has been difficult to observe
1209 and 1085 cm 1, respectively.42,43 After milling, directly but suspected in observations such as
these peaks decreased in intensity as seen in spectra polymorphic transformation of sorbitol47 induced on
of milled SS (Fig. 4a). Milled LAC (Fig. 4c) displayed milling. In that case, the microstructural analysis by
low intensity reported44 peaks within 1040 XRPD indicated an increase in crystallite size of the
1160 cm 1 attributed to the asymmetrical stretching milled product. To investigate the possibility of the
vibrations of C O C ether unit bonds (glucose and formation of a transient amorphous fraction during
galactose). The peaks in the range of 1600 and comilling of cSS and mLAC, samples at ratio of 1:1
1700 cm 1 around 1654 cm 1 correspond to the were taken at different milling durations of 15, 30, 45,
stretching vibrations of water from crystallization and 60 min. The mixtures at the end of each time
of O H bonds and of water adsorbed to the surface of interval were analyzed using XRPD and plotted in
milled LAC.45 The peaks did not shift to higher or Figure 5. Little change in crystallinity was observed
lower wave numbers as seen in spectra of both after 15 min (Fig. 5b). An increase in peak counts for
comilled cSS:mLAC (Fig. 4e) and physical mixtures SS and LAC in comilled mixture after 30 min (Fig. 5c)
(Fig. 4d) of mSS:mLAC at 1:1 ratio. At the same time, suggesting crystallinity increased as seen in case of
no significant change in absorbance of principal sorbitol.47 Interestingly, after 45 min, the amorphous
peaks of SS and LAC could be noted. The presence halo in XRPD pattern (Fig. 5d) indicated an almost
of H-bonding was also not detected with no significant complete crystalline amorphous transition, which
shift in N H and O H stretching broad peaks reverted back to the crystalline state after 60 min
(>3000 cm 1) to a lower wave number. Thus, FTIR (Fig. 5e). The data showed that amorphization of SS
results suggested that intermolecular interactions did take place during the initial phase of comilling
between APIs and crystalline excipients are not with LAC. Only upon comilling (>45 min) that SS
likely to account for the appearance of the char- amorphous phase underwent recrystallization. This
acteristic SS crystalline peaks in the comilled confirmed the presence of a transient amorphous
mixtures. phase followed by recrystallization after 60 min.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010 DOI 10.1002/jps
STRUCTURAL DISORDER OF CRYSTALLINE PHARMACEUTICAL ACTIVES 2469
Figure 5. Effect of milling time [(a) cLAC, (b) 15 min, (c) 30 min, (d) 45 min, (e)
60 min], temperature [(f) cryo-comilled mixture of cSS:mLAC 1:1], (g) comilled mixture
of mSS:mLAC 1:1.
Thus, recrystallization was evident in the presence of grinding has been reported.48 Acceleration of poly-
residual crystalline peaks of LAC (as seen in Fig. 1d) morphic transformation from one form to another
unaffected by mechanical activation. This observa- form was observed in the presence of seed crystals of
tion aligns with a recent study on fananserine where particular form.
partially amorphous sample produced on milling The readily accepted hypothesis behind   amorphi-
tended to revert to the stable crystalline state in zation  upon milling of a single compound suggests
presence of residue crystalline particles of the same the creation of local hot points due to an increase in
material.46 temperature induced by collisions of the milling balls.
To verify whether the role of   residue  crystalline These local hot points may exceed the melting
particles of LAC enhanced the process of recrystalli- temperature of the compound. The rapid return to
zation or minimize amorphization during comilling, a room temperature after the impact would then act as
mixture of milled amorphous SS and milled LAC was a quench mechanism. The amorphization process is
comilled at 1:1 ratio for 1 h. Characteristic crystalline thus believed to be governed by local   melt/quench 
peaks of SS were clearly visible in the XRPD of the events.46 However, this hypothesis is debatable as
comilled mixture (Fig. 5g), showing that the amor- suggested in milling studies with compounds such
phous SS has been recrystallized. XRPD results were as fanaserine,46 glucose,49 lactose,50 and indometha-
also supported by DVS results (Fig. 2) with amor- cin.51 These compounds underwent amorphization
phous content below the detection limits (Tab. 1). This when milled at temperatures lower than their
scenario leads to the certainty that crystalline LAC melting points, increasing the gap between the
served as seed crystals to recrystallize any form of milling and melting temperatures. Although, differ-
starting API (i.e., crystalline or amorphous) upon ent results make it difficult to understand the process
comilling for 1 h. Supporting this hypothesis, Pfeiffer of amorphization, milling temperature is certainly
et al.18 have also suggested that possible recrystalli- one of the crucial factors governing the nature of the
zation could occur during prolonged milling, account- milled product. To understand whether the   milling
ing for the increase of particle size and the temperature  plays a role in mitigating the amorphi-
agglomeration of SS. The possible role of nucleation zation process during comilling, cryogenic comilling
seeds (seed crystals) in suppressing complete amor- was carried out at cSS:mLAC ratio of 1:1. Cryomilling
phization of comilled indomethacin with Aerosil 200 is a cryogenic comminution technique that grinds
was also suggested by Watanabe et al.,12 which was at liquid nitrogen temperatures.37 If recrystallization
supported by theoretical calculations of the lowest n of amorphous SS was indeed the mechanism for
value for the co-ground mixture in Kolmogoro mitigating amorphization, comilling at temperatures
Johnson Mehl Avrami (KJMA) equation. In addi- far below the Tg would suppress the recrystallization
tion, the role of seed crystals in polymorphic process leading to an amorphous sample. As shown in
transformation of chloramphenicol palmitate during Figure 5f, characteristic crystalline peaks of SS were
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010
2470 BALANI ET AL.
not observed on cryo-comilling. At room temperature, ents (AA, MgSt), amorphous PVP were separately
recrystallization of amorphous SS during comilling comilled with SS under similar conditions. Results in
was probably facilitated by localized heating in the Figure 6 showed that the characteristic crystalline
ball mill as seen with fanaserine.46 In previous peaks of SS were also retained on comilling with mAA
reports, the temperature of the mill container has (Fig. 6c) and mMgSt (Fig. 6g), respectively. A distinct
been correlated to temperature rise in metallic observation was that all AA:SS ratios (not shown)
powder at collision site of balls and has been found displayed similar peak counts of SS suggesting that a
to be less than 1508C under normal milling condi- low ratio of AA:SS may have been sufficient for SS to
tions.52 High energy ball-milling could lead to the rise retain some degree of crystallinity on comilling.
of average environmental temperature of more Comilling of SS with PVP showed an amorphous
than 1008C, that is beyond the Tg of SS (60 mixture in Figure 6i. It could be said that the
658C).53 Descamps et al.54 explained that when amorphous nature of PVP was unable to minimize
milling at temperatures above Tg, where an amor- amorphization of SS during comilling. Additionally,
phous state can exist as a metastable liquid, the the glass transition of amorphous mixtures of SS
molecular mobility is known to be much higher and with LAC or PVP calculated theoretically using the
increases rapidly with temperature. Because of this Gordon Taylor equation are 778C for SS:LAC (1:1)
higher mobility, the restoration of a crystallographic and 928C for SS:PVP (1:1). These results strongly
order upon milling is expected to be more efficient. supported the notion that the crystallinity of the
Thus, the presence of nucleation seeds along with a excipient along with milling temperature were
temperature rise of powder (above Tg of SS) during important factors in minimizing amorphization dur-
room temperature milling could have been the ing comilling. Using the same method described by
plausible mechanism behind retention of crystalline Matthias et al.,31 the amorphous content of comilled
SS on comilling. It should be further noted that the mixtures of SS with AA and MgSt, the physical
increase in temperature did not lead to drug degra- mixtures and the individual components were esti-
dation as suggested by drug content of 93 2% (assay mated by DVS. Results in Figure 7 and Table 1
by HPLC; n ź 3) and absence of any additional peak in showed that comilling of cSS with mAA resulted in
HPLC chromatogram of comilled cSS:mLAC at the minimizing the amorphous content of SS, to a lesser
ratio of 1:3. extent than with mLAC. On the other hand, comilling
As an excipient for comilling, LAC has been shown with mMgSt at a lesser excipient ratio (1:1) in
to be effective in mitigating the amorphization of SS. comparison to mLAC (1:3) was found to be the most
To further support the role of crystalline seeds in effective in reducing amorphous content below
inducing recrystallization of mSS, crystalline excipi- detection limits.
Figure 6. Powder X-ray diffractograms of (a) mAA, (b) cSS, (c) comilled mixture of
cSS:mAA 1:1, (d) physical mixture of mSS:mAA 1:1, (e) mMgSt, (f) physical mixture
of mSS:mMgSt 1:1, (g) comilled mixture of cSS:mMgSt 1:1, (h) physical mixture of
mSS:PVP 1:1, (i) comilled mixture of cSS:PVP 1:1.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010 DOI 10.1002/jps
STRUCTURAL DISORDER OF CRYSTALLINE PHARMACEUTICAL ACTIVES 2471
Figure 7. Sorption isotherms of mSS, physical mixture of mSS:mAA 1:1 and comilled
mixture of cSS:mAA 1:1, comilled mixture of cSS:mMgSt 1:1.
Stability Studies physical mixture of mSS:mLAC (1:1) (Fig. 8f) and
comilled mixture of cSS:mLAC (1:1) (Fig. 8d), which
To evaluate the feasibility of this comilling method in also showed the occurrence of recrystallization under
improving the physical stability of milled SS, milled the chosen storage conditions.
SS, comilled, and physical mixture of SS:LAC at Apart from XRPD, SEM has served as a useful
ratios (1:1 and 1:3 w/w) were stored for 7 days (at technique for visualizing changes in particle shape
228C, 15% RH or 75% RH). The samples were and surface with respect to milling time55 and length
analyzed in terms of crystallinity and morphology of storage of the milled material.56 Figure 9a f
prior to and after storage. Figure 8 shows the XRPD illustrates the SEM images of milled SS, physical
patterns. Milled SS remained amorphous at 15% RH mixtures, and comilled samples under both storage
(Fig. 8a). Presence of crystalline peaks in the XRPD conditions. Milled SS (Fig. 9a), which has similar
pattern of milled SS at 75% RH (Fig. 8b) showed morphology reported for spray dried SS57 appeared
recrystallization behavior. At 75% RH, the increase in close to spherical on storage at 15% RH for 7 days.
peak counts in the diffractograms was observed in Spherical-like shape of milled SS (Fig. 9b) was not
Figure 8. Powder X-Ray diffraction patterns of stability samples (a) mSS (228C/15%
RH), (b) mSS (228C/75% RH), (c) comilled mixture of cSS:mLAC 1:1 (228C/15% RH), (d)
comilled mixture of cSS:mLAC 1:1 (228C/75% RH), (e) physical mixture of mSS:mLAC
1:1 (228C/15% RH), (f) physical mixture of mSS:mLAC 1:1 (228C/75% RH).
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010
2472 BALANI ET AL.
Figure 9. SEM images of stability samples (a) mSS (228C/15% RH), (b) mSS (228C/
75% RH), (c) comilled mixture of cSS:mLAC 1:1 (228C/15% RH), (d) comilled mixture
of cSS:mLAC 1:1 (228C/75% RH), (e) physical mixture of mSS:mLAC 1:1 (228C/15% RH),
(f) physical mixture of mSS:mLAC 1:1 (228C/75% RH).
retained after storage at 75% RH for 7 days. Fines 1:3 and 1:4 ratios was effective in minimizing the
appeared to agglomerate on irregularly shaped amorphization below the detection level of DVS
blocklike structures, which tallied with the occur- (0.5%), DSC (5%), and XRPD (5%). As a control,
rence of recrystallization shown in earlier XRPD physical mixture did not improve the crystallinity of
results. The SEM photomicrograph of comilled milled SS. To the best of our knowledge, the use of
mixture of cSS and mLAC (1:1) stored under 15% crystalline excipients to mitigate the amorphous
RH (Fig. 9c) showed particle agglomeration with some content of an API to such low levels by comilling
of the SS particles retaining the spherical-like shape has not been reported before. By investigating the
rather similar to milled SS (Fig. 9a). Particle agglo- effects of the nature of excipients, milling time and
meration and subsequent recrystallization was evi- temperature, it was found that the presence of
dent in the SEM photomicrograph of comilled mixture crystalline excipient aided by the temperature rise
of cSS:mLAC (1:1) stored under 75% RH (Fig. 9d). As during milling (>Tg) led to recrystallization of SS
expected, spherical shape of the SS was relatively upon comilling for 1 h. Comilled cSS:mLAC at 1:3
well retained in the physical mixtures of mSS:mLAC ratio showed no change in crystallinity nor mor-
(1:1) (Fig. 9e) stored at 15% RH, while no retention of phology upon storage at 75% RH (elevated humidity
the spherical shape was seen in the sample stored level) for 7 days as compared to both milled SS
under 75% RH (Fig. 9f). They bore resemblance to and physical mixture. The results reveal that
(Fig. 9b) with particles in agglomerated form. This comilling with a crystalline excipient has potential
absence of fused spherical SS particles agrees with a in achieving a crystalline form of a milled API. As
recrystallization process towards a stable state that milling alone leads to dynamical stationary state
had undergone before storage, during the milling often amorphous and thermodynamically unstable,58
process itself. No significant changes in the XRPD this application poses a novel solution to tackle the
and SEM analyses of the comilled mixtures challenges of handling the unstable amorphous state
cSS:mLAC (1:3) and higher was observed. (having residual mobility) in milled pharmaceutical
materials.
CONCLUSIONS
ACKNOWLEDGMENTS
The work sets out to investigate the effect of various
excipients in mitigating amorphization in SS. The This work was supported by the Research Scholar-
results indicate that comilling of cSS with mLAC at ship of the National University of Singapore awarded
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010 DOI 10.1002/jps
STRUCTURAL DISORDER OF CRYSTALLINE PHARMACEUTICAL ACTIVES 2473
to Mr. Prashant Balani and the Science and Engi- 16. Ward GH, Shultz RK. 1995. Process-induced crystallinity
changes in albuterol sulfate and its effect on powder physical
neering Research Council of AMSTAR (Agency for
stability. Pharm Res 12:773 779.
Science, Technology and Research), Singapore. The
17. Pfeiffer KB, H�usler H, Grab P, Langguth P. 2003. Condition
authors would like to thank Mr. Lim Seng Chong, Mr.
following powder micronization: Influence on particle growth of
Benjamin Ang, Mr. Ng Junwei, Miss Tok Ai Tee, Miss
salbutamol sulfate. Drug Dev Ind Pharm 29:1077 1084.
Goh Xue Ping, Mr. Kwek Jin Wang, Mr. Gary Liu, 18. Pfeiffer KB, Langguth P, H�usler H, Grab P. 2003. Influence of
mechanical activation on the physical stability of salbutamol
and Miss Angeline Seo of the Institute of Chemical
sulphate. Eur J Pharm Biopharm 56:393 400.
and Engineering Sciences, Singapore, and Miss Wong
19. Tee SK, Marriott C, Zeng XM, Martin GP. 2000. The use of
Shi Yin of the Department of Pharmacy, the National
different sugars as fine and coarse carriers for aerosolized
University of Singapore, for their contribution in
salbutamol sulphate. Int J Pharm 208:111 123.
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