Transformation of Pharmaceutical Compounds

upon Milling and Comilling: The Role of Tg

M. DESCAMPS, J.F. WILLART, E. DUDOGNON, V. CARON

Laboratoire de Dynamique et Structure des Matériaux Moléculaires. UMR. CNRS 8024.

University of LILLE1. Bat P5 - 59655 Villeneuve d’Ascq CEDEX, France

Received 9 October 2006; revised 19 December 2006; accepted 22 December 2006

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20939

ABSTRACT: Milling is a usual process used in the course of drug formulation, which
however may change the physical nature of the end product. The diversity of the
transformations of organic compounds upon milling has been widely demonstrated in
the pharmaceutical literature. However, no effort has still been devoted to study the
correlation between the nature of the transformation and the milling conditions. Results
clarifying such transformations are shortly reviewed with special attention paid to the
temperature of milling. The importance of the position of the glass transition
temperature compared with that of milling is demonstrated. It is shown that decreasing
the milling temperature leads to an increase of the amorphization tendency whereas
milling above Tg can produce a crystal-to-crystal transformation between polymorphic
varieties. These observations contradict the usual suggestion that milling transforms the
physical state only by a heating effect which induces a local melting. Equilibrium
thermodynamics does not seem appropriate for describing the process. The driven alloys
concept offers a more rational framework to interpret the effect of the milling
temperature. Other results are also presented, which demonstrate the possibility for
milling to form low temperature solid-state alloys that offer new promising ways to
stabilize amorphous molecular solids. ß 2007 Wiley-Liss, Inc. and the American Pharmacists
Association J Pharm Sci 96:1398–1407, 2007
Keywords: amorphous; X-ray powder diffractometry; solid state; solid solutions;
polymorphism; physical stability; milling; materials science; glass; calorimetry (DSC)

INTRODUCTION involve classical thermodynamic variables such

as temperature and pressure but also external
In the course of the solid drugs formulation, dynamical forcing. Typical examples of dynami-
molecular compounds are submitted to a large cally driven systems are provided by irradiation,
variety of possible perturbations. These perturba- milling, extrusion. . . Usual phase transforma-
tions may result in phase transformations or tions are properly addressed by thermal equili-
amorphizations of the material. Such physical brium states, equilibrium, and irreversible
transformations have direct influence on the thermodynamics. However, a general framework
stability and solubility of the compounds.1 Con- that would allow describing and predicting the
sequently, bioavailability of the drug is prone to nature of the end product of dynamically forced
changes. Not only these perturbations may pharmaceuticals, is not available.
Contrary to metallurgy,2–6 systematic investi-
Correspondence to: M. Descamps (USTL-UFR de physique, gations of mechanically induced transformations
Bat P5 59655 Villeneuve d’Ascq, France. Telephone: 00-33-3- of molecular compounds have not yet been
20-43-68-34; Fax: 00-33-3-20-43-68-57;
E-mail: [email protected])
done. Over and above the interest to get a
Journal of Pharmaceutical Sciences, Vol. 96, 1398–1407 (2007)
better understanding of these transformations
ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association for practical reasons in pharmaceutical science,1

1398 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

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MILLING OF PHARMACEUTICAL COMPOUNDS 1399

there are also fundamental reasons to consider the decrease and a broadening of the X-ray diffraction
effect of milling molecular solids to get a better peaks. No polymorphic transformation was thus
insight in the physics of this kind of process in observed. On the contrary, form I of sulfamerazine
general. There are several specific properties is completely converted to the metastable form II
of molecular compounds which have special upon a 120 min milling. Form II thus appears to be
relevance in mechanical activation.1,7,8 Their the result of milling whatever the initial product
molecular and crystalline symmetry are generally with no sign of amorphization. Another example is
low, the kinetics of crystallization are often very the milling of the different polymorphic varieties of
slow and molecular compounds often show an easy indomethacin (g stable form or a metastable) at
ability to vitrify. Moreover their melting and glass room temperature (i.e., close to the glass transi-
transition temperatures are low and the inter- tion, which is Tg
428C). It has been found to
molecular interactions are week. The evolutions of induce a transformation to the same final state
the transport coefficients in the amorphous composed of 50% of the form a and 50% of the
state often exhibit a strongly nonArrhenius tem- amorphous state. The same experiments per-
perature behavior with a dramatic evolution on formed at 48C have been found to induce a total
approaching the glass transition temperature (Tg) amorphization.12 Recent cryo-milling experiments
(‘‘fragile glass formers’’).9 All these specificities on indomethacin13 also lead to fast amorphization
lead to expect a strong sensitivity of molecular independently of the starting crystalline state.
compounds to the temperature of milling. From a Sometimes more stable states can even be obtained
fundamental point of view molecular compounds as exemplified by caffeine.14 A recent study of the
certainly offer new interesting situations, which factors influencing the complexation of ursodeoxy-
allow testing theoretical approaches. cholic acid with phenanthrene or with anthrone
In this article we present some selected results has clearly revealed the influence of the tempera-
that may help clarifying the behavior pattern of ture of grinding.15 The results indicate that
molecular compounds under milling. We have complexation is only possible above some grinding
used the interesting opportunity provided by temperature while milling at temperature much
molecular compounds to have their glass transi- lower than room temperature prevent the com-
tion temperature not far from room temperature to plexation process and results in the amorphization
test the importance of the milling temperature of the ursodeoxycholic acid. Moreover, the idea
with respect to Tg. There are several suggestions that milling may drive the crystallites to sizes
found in the literature that milling induces an below the critical radius of nucleation cannot fully
amorphization because it simply results from a explain transformation to other polymorph. By
local thermal melting followed by a rapid quench. changing the milling temperature we can check
Molecular compounds which are chemically very whether the amorphization tendency is amplified
sensitive to a high temperature excursion allow or not. By milling above the glass transition
getting better insight in this aspect. Indeed they temperature of the compound we are in position
may provide an indirect test of the real tempera- to test whether the transformation still occurs
ture reached upon milling through their possible toward an amorphous state which would be that
degradation. An other suggestion is that amorphi- time either rubbery or even fluid.
zation can result from a huge accumulation of Milling experiments were performed on
defects10 in the crystal resulting in an increase of series of molecular compounds having their glass
its Gibbs free enthalpy. In these conditions the transition temperature above (trehalose, lactose,
highly defective crystalline phase can become budesonide) or below (sorbitol and mannitol)
physically less stable than the metastable liquid milling temperature (room temperature). Results
state so that it amorphizes spontaneously at the of experiments in which compounds with very
temperature of milling. However, the pharmaceu- different values of Tg were milled together are then
tical literature reveals that milling crystals may presented. This offers one more possibility to check
just as well induce amorphization or transforma- the effect of indirectly changing the glass transi-
tions to other crystal polymorph. The investigation tion temperature by changing the composition.
of the effect of milling on the two polymorphic
varieties of sulfamerazine by Grant and co- EXPERIMENTAL
workers11 is particularly illustrative from this
point of view. They have shown that milling the Crystalline anhydrous a-lactose was obtained by
metastable form II only produces an intensity dehydration of crystalline a-lactose monohydrate.

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
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1400 DESCAMPS ET AL.

The dehydration was performed by blowing dry stage of particle size reduction and it is useful to
gaseous methanol through 20 g of a-lactose know the physical behavior under milling for
monohydrate during 3 h. The remaining traces practical purpose.
of methanol were then removed by placing the At room temperature (i.e., about 1008C
sample under vacuum (103 mmHg) at 208C below their glass transition temperature), using
during 12 h. Thermogravimetric and NMR16 a O value of 400 rpm, these two sugars are
measurements have indicated respectively that completely amorphized after a few hours of
the a-lactose thus obtained was free of any solvent milling. Figures 1 and 2 demonstrate that not only
(water or methanol), and anomer b of lactose. the compounds are X-ray amorphous, but also
Crystalline a–a anhydrous trehalose, mannitol, really glassy since a glass transition at Tg is found
and G-sorbitol were purchased from Fluka. Their to occur on the DSC scans upon heating the milled
purity are 99.9%, 99.9 %, and 99.5 %, respectively materials. The Tg values (1208C for trehalose and
and they were used without further purification. 1118C for lactose) are found to be similar to
Crystalline budesonide (purity: 99.5%) was that obtained when undercooling the melt. It is
kindly provided by AstraZeneca. important to note that the glassy states which are
Ball-milling experiments were performed in a obtained do not show any trace of caramelization
high-energy planetary micro-mill (Pulverisette 7; as would be obtained when quench cooling the melt
Fritsch, Idar-Oberstein, Germany) at room tem- of sugars. It must also be noted that amorphous
perature. Samples were sealed in Zirconium vials of lactose obtained by the milling route is free of
45 cm3 volume with seven balls (Ø 15 mm) of the the anomer b.18 This is not the case for any
same materials. The vials are fixed onto a rotation other amorphization routes (melt-quenching,
disc and rotate with the same rotation speed O on the lyophilization, spray drying. . .) involving dissolu-
opposite direction to the disc, the important feature tion or heating stages that induce unavoidably
is thus that the intensity of the mechanical treat- a strong mutarotation process giving rise to
ment is an increasing function of O. The apparatus b-lactose concentrations as large as 50%.
was specially modified to grind hygroscopic samples There is thus no indication that the amorphiza-
in a controlled atmosphere. Prior to the milling tion is the result of a local heating above the
procedure, the vials were flushed with dry nitrogen compound melting point which would be followed
gas in order to prevent hydration of the powder by a temperature quench. Milling is really able to
during the experiments. To avoid any overheating of promote a direct low temperature crystal to glass
the samples, milling periods were alternated with transformation.
pause periods. The analyses of the milled samples
were performed by X-ray diffraction and DSC. Milling of Crystalline Budesonide
The budesonide (22RS 16a,17a-Butylidenedioxy-
MILLING OF PURE CRYSTALLINE pregna-1,4-diene-11b,21-diol-3,20-dione) is a drug
COMPOUNDS WELL BELOW THE Tg OF used as an anti-inflammatory corticosteroid.19
THEIR CORRESPONDING LIQUID

Milling of Crystalline Anhydrous Disaccharides

Trehalose and Lactose
These two disaccharides are highly important
excipients in drug formulation.17,18 Trehalose
has the very specific character to protect the
labile biological molecules both from temperature
variations—heating or cooling—and from dehy-
dration effects. Compare to other disacharides
these two sugars have both unusually high glass
Figure 1. X-ray diffraction patterns of trehalose
transition temperature (Tg > 1008C). They offer recorded at room temperature before milling (a) and
the possibility to explore the effect of milling well after 20 h of milling treatment with O ¼ 400 rpm (b). DSC
below Tg. Their Tg value is similar to that of heating curves (58C/min) of crystalline trehalose before
number of polymers for which milling would milling (c) and after 20 h of milling treatment with
present a risk to affect the molecular integrity. O ¼ 400 rpm (d). The inset shows a close up view of the
Furthermore, their formulation often involves a glass transition domain of curve d.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
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MILLING OF PHARMACEUTICAL COMPOUNDS 1401

amorphous budesonide is obtained ((b) curve).

Upon heating, this glassy system undergoes a
glass transition at 908C (see the inset of (d) curve)
and then re-crystallises at 1168C. Since it has been
shown that there is no noticeable temperature
increase upon milling,18 milling well below their
glass transition thus appears to be a very inter-
esting way to obtain amorphous molecular
compounds without thermal degradation.
Figure 2. X-ray diffraction patterns of lactose
recorded at room temperature before milling (a) and MILLING OF PURE CRYSTALLINE
after 30 h of milling treatment with O ¼ 400 rpm (b). DSC COMPOUNDS ABOVE THE Tg OF THEIR
heating curves (58C/min) of crystalline lactose before CORRESPONDING LIQUID
milling (c) and after 30 h of milling treatment with
O ¼ 400 rpm (d). The curve in inset is a close up view of Milling of Crystalline D-Sorbitol
the glass transition temperature domain of curve d.
Figure 4 shows that milling the G crystalline form
This crystalline material has been found to be of D-Sorbitol during 10 h at room temperature
almost insoluble in water (20 mg  mL1) at (i.e., above Tg which is 08C) promotes a pro-
physiological pH (log P ¼ 3.2).20 To enhance its gressive conversion to the metastable crystalline
bioavailability, it is interesting to investigate form A.21 The X-ray analysis of the nanostructure
possibilities to formulate it in its amorphous evolution upon milling has shown a clear recon-
state since it is known that the solubility can be struction of the ultimate crystallites. In the first
significantly increased in this latter state. Amor- stage of milling (t < 1 h) a broadening of the
phous budesonide can be obtained by quench from diffraction peaks reveals a stage of nanostruc-
the liquid state. The glass transition temperature turation of the crystallites. This is confirmed by
is then observed at about 908C. However, as many the decrease of the melting temperature of the G
other pharmacological compounds, budesonide
undergoes a thermal degradation before the
melting temperature (Tm ¼ 2508C) is reached. It
is thus interesting to search for other amorphiza-
tion routes for this compound. The effect of
milling budesonide at room temperature, that is,
well below Tg was thus investigated.
Figure 3 shows that, after a 15 h milling at
room temperature (O ¼ 400 rpm), a completely

Figure 3. X-ray diffraction patterns of budesonide

recorded at room temperature before milling (a) and
after 15 h of milling treatment with O ¼ 400 rpm (b). DSC
heating curves (58C/min) of crystalline budesonide
before milling (c) and after 15 h of milling treatment Figure 4. Evolution of the X-ray diffraction patterns
with O ¼ 400 rpm (d). The inset shows a close up view of sorbitol (G crystalline form) in the course of a 10 h
of the glass transition domain appearing on the MDSC milling process. It shows the progressive conversion of
‘‘in-phase’’ flow (modulation of 0.7968C/min). the G phase toward the A phase.

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1402 DESCAMPS ET AL.

phase which is an indirect proof of the crystallite

size reduction. This behavior (Gibbs Thomson
effect22,23) predicts a depression (DTm) of the
melting point (Tm) for a decreasing crystallite
size (d) which is given by:
4sTm
DTm ¼ ð1Þ
dDHm rs
where s is the solid–liquid interfacial energy,
DHm the bulk energy of melting, and rs the
density of the solid. Then, in the second stage,
the peaks of the new polymorph appear (t > 2 h)
and are also broad. After a long enough milling,
the Bragg peaks of the appearing new form
progressively become very sharp. This shows that
milling is able at that time to promote a total
reconstruction of the new long-range order on a
large microstructural scale. It is not totally clear
whether a very transient stage of amorphization
mediates between these two polymorphs. This is
suggested by the fact that some transport of
matter is necessary for the crystalline reconstruc-
tion to operate. However, there is no direct
Figure 5. X-ray diffraction patterns of mannitol
evidence of such a stage through the appearance recorded at room temperature: (a)–(c) corresponds
of an amorphous halo in the X-ray pictures or respectively to mannitol b before milling, after milling
through a glass transition event in the thermo- (3 h), and after a RT storage (8 days). The milling of the
grams. This is certainly a very important point to form b induces a conversion toward the form a which
elucidate in order to know if a direct solid-state reverses toward the form b during the subsequent
reconstruction induced by milling is possible. If storage. (d)–(f) corresponds respectively to mannitol d
not, a mechanism of nucleation and growth of before milling, after milling (3 h), and after a RT storage
crystals in the metastable liquid would prevail. In (1 day). The milling of the form d induces a conversion
such a case it would be necessary to accommodate toward the form a which reverses toward the form b
the very small fraction of liquid that may be during the subsequent storage.
assume from experiments with the slowness of
the kinetics of the process.
using the same milling parameters (temperature
and intensity) but starting with different physical
state, the milling process leads to a stationary
Milling of Crystalline Mannitol
state which is independent of the physical state of
A similar polymorphic transformation was the initial material.
observed when milling the crystalline form of
another polyol: the mannitol at room temperature
(i.e., above Tg which is 138C).24 The X-ray DISCUSSION
diffraction patterns on Figure 5a,b show that
upon milling, the stable crystalline form b of Most often it is the amorphization induced by
mannitol undergoes a polymorphic transforma- milling that is discussed. Over and above the
tion toward the metastable form a. The X-ray hypothesis of an induced local heating, it is often
diffraction patterns in Figure 5d,e reveal that the suggested that the introduction of defects in
polymorphic form b of mannitol undergoes the the crystal induces a progressive destabilization
same transformation upon milling. However, in of the latter with respect to the liquidlike
both cases the form d obtained by milling slowly structure.25 Eventually an amorphous solid is
reverses toward the stable crystalline form a produced when milling is performed below Tg.
during a RT annealing following the milling Above Tg this way of reasoning predicts a melting
process (Fig. 5c,f). These results thus reveal that, to a liquid. Our results show that milling a crystal

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
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MILLING OF PHARMACEUTICAL COMPOUNDS 1403

above Tg repetitively produces a polymorphic temperature under milling becomes higher than
transformation. We have other results, to be the equilibrium melting temperature. This may
published, which show that a slight milling of a explain that the lower the temperature of milling
glass just below Tg induce crystallization.26 In the the easier the amorphization.
cases presented in this article, the polymorphic
transformations which are observed drive
the crystal to a more metastable state. This could COMILLING AND MANIPULATION OF
suggest that milling automatically pushes THE AMORPHOUS STATE
the system toward states that have higher free
enthalpy. However, there are published results— In this series of milling experiments we have
in particular caffeine14—where the reverse situa- comilled individual crystalline compounds having
tion has been observed: milling transforms the different values of their Tg in the amorphous
compound in a more stable crystalline phase. state. As model systems we have taken lactose/
This situation is similar to that of milling- mannitol and lactose/budesonide mixtures
induced crystallization mentioned above. Milling whose thermodynamic characteristics and beha-
is certainly expected to induce a disorder by vior upon milling were described above. The
shearing a compound. However, to explain practical objective of this investigation is to test
the full pattern of observed behaviors a more the possibility to directly prepare molecular alloys
universal approach is necessary. A simple at low temperature. This is particularly impor-
thermodynamic equilibrium picture does not tant for pharmaceutical compounds which are
seem satisfying. From the results described above unstable at high temperature and would not
it looks as if temperature is unable to restore a support a high temperature alloying. Lactose is
crystalline equilibrium when milling proceeds in a good representative of such a temperature
the low temperature domain of the sample where sensitive excipient even if possible reactions with
large amplitude molecular motions are essentially the amine functionality have to be considered
frozen. On the other hand, at temperature when formulating in the amorphous state. A more
above Tg where an amorphous state can exist as fundamental objective is to further investigate
a metastable liquid, the molecular mobility is the effect of temperature on the end product
known to be much higher and to increase rapidly of milling by changing the fractions of the
with temperature. Because of this higher mobility compounds and thus the expected value of Tg of
the restoration of a crystallographic order upon a possible glassy alloy with regard to room
milling is expected to be more efficient. temperature.
This set of observations suggests that the
results can be interpreted in the framework of
Mixed Compounds (Lactose)1  x (Mannitol)x
the driven material concept of Martin and Bellon.6
According to this model the full process involves a Figure 6 shows the DSC scans recorded upon
competition between ballistic disordering process, heating of quenched liquid mannitol (a), milled
which is independent of temperature (T), and a lactose (c), and comilled lactose/mannitol crystal-
thermally activated restoration. It has thus been line mixture (molar fraction of mannitol: x ¼ 0.39)
proposed by Martin and Bellon6 that the state (b). It must be noticed that, contrary to lactose,
reached upon milling, is identical to the equili- the glass transition of mannitol (Tg ¼ 138C) is
brium state of the nonmilled material at an located below the milling temperature. The first
effective temperature Teff given by the following event in the last thermogram is a Cp jump
relation: characteristic of a glass transition located at Tg
  (x ¼ 0.39) ¼ 658C, that is, between those of pure
Dbal
Teff ¼ T 1 þ ð2Þ mannitol and pure lactose. Absolutely no sign of
Dth
glass transition corresponding to pure mannitol
where Dbal is the ballistic diffusion coefficient or pure lactose can be detected at 138C and 1118C
which depends on the forcing intensity and not on (see run (a) and run (c) corresponding to the pure
temperature. Dth is the thermal diffusion coeffi- compounds for comparison). This single glass
cient possibly modified by the occurrence of transition indicates that the amorphous mixed
created defects. sample obtained by milling is characterized by a
At low enough temperature, thermal diffusion single relaxation process. The mixing of the two
is expected to be low enough so that the effective kinds of molecules has thus really been performed

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
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1404 DESCAMPS ET AL.

Figure 6. DSC scans recorded upon heating (58C/

Figure 7. DSC scans recorded upon heating (58C/
min) of (a) quenched liquid mannitol. (b): lactose/
min) of: (a) initially crystalline a-lactose after a 12 h
mannitol crystalline mixture (mannitol fraction
milling process. (b): lactose/budesonide crystalline mix-
x ¼ 0.39) after a 12 h milling process. (c): initially
ture (budesonide weight fraction ¼ 0.5) after a 15 h
crystalline a-lactose after a 30 h milling process.
milling process. (c): initially crystalline budesonide after
a 15 h milling process. The inset presents the ‘‘in-phase’’
at the molecular level, giving rise to a true flow of the corresponding MDSC scans (modulation of
molecular alloy formed in nonequilibrium condi- 0.7968C/min).
tions. Upon heating, crystallization is observed
followed by two endotherms corresponding
respectively to the melting of the eutectic and a one is located at 1258C and the second one at
lactose rich solid solution. 1628C. These temperatures almost correspond
to the crystallization temperatures of pure com-
pounds. Investigations are actually in progress to
Mixed Compounds (Lactose)1  x (Budesonide)x
analyze the exact nature of the recrystallization
Figure 7 presents the DSC scans recorded process with respect to the complex melting
upon heating (at 58C/min) of milled lactose (a), pattern.
milled budesonide (c) and comilled lactose/
budesonide crystalline mixture (budesonide Composition Dependence of the Glass Transition
molar fraction x ¼ 0.44) (b). At room temperature,
these materials are amorphous. The Cp jumps The possibility to form molecular alloy has been
that are characteristic of the glass transition can investigated in the whole range of concentrations
clearly be observed on the ‘‘in phase’’ flow of the for both lactose/budesonide and lactose/mannitol
MDSC scan (modulation of 0.7968C/min) (inset mixtures. For lactose/budesonide the molecular
of Fig. 7). The glass transition of the comilled alloy was found to be formed whatever the
mixture appears at 1028C. The finding of a single molar fraction x of budesonide. This behavior
glass transition located between those of pure was consistent with the fact that the two
milled budesonide ((c) scan) and pure milled compounds can be fully amorphized when sepa-
lactose ((a) scan) indicates that the comilling of rately milled. The evolution of the glass transition
budesonide and lactose blends leads to the temperature of the alloy against the budesonide
formation of a molecular alloy with a unique glass concentration x is reported in Figure 8. It obeys
phase. As in the case of comilled compound the Gordon Taylor law,27 which generally
lactose/mannitol, it emphasizes that the mixing describes the concentration dependence of the
of the two molecular species has really been glass transition in the alloys obtained by thermal
performed at the molecular level so that the quench:
mixture is characterized by a unique relaxation xTgbud þ Kð1  xÞTglact
process and thus behaves as a single amorphous Tg ðxÞ ¼ ð3Þ
x þ Kð1  xÞ
phase.
At higher temperatures, two crystallization where K is a fitting parameter. In this case K is
peaks can be seen on the DSC scan (b). The first found to be equal to 0.69  0.02.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
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MILLING OF PHARMACEUTICAL COMPOUNDS 1405

mannitol a. The extrapolation of the Tg(x) curve

in Figure 9 indicates that for x > 0.50 the glass
transition temperature of the alloy becomes close
to the milling temperature. In these conditions,
the molecular mobility of the alloy becomes high
enough to trigger the crystallization of the chemi-
cal component, which is responsible for the
plastization of the alloy during the milling process.
When the Tg of the alloy reach the milling
temperature, further amorphization of mannitol
is thus probably counterbalanced by a rapid
recrystallization toward the form a leading to a
steady state concentration of mannitol in the glass
solution. This mechanism is coherent with the fact
Figure 8. Evolution of the glass transition tempera- that the phase a is known to arise systematically
ture of the comilled mixture of lactose/budesonide from the recrystallization of the undercooled liquid
versus the budesonide content (&). The solid line mannitol.
represents the Gordon’s fitting law. The dot-line is a Milling devices generally operate at room
guide for the eyes. temperature or at the liquid nitrogen temperature.
It is thus really difficult to perform systematic
investigations of the effects of milling with
Contrary to the lactose/budesonide mixtures, temperature. It is in particular difficult to decide
lactose/mannitol mixtures cannot form molecular whether the duality ‘‘amorphization/polymorphic
alloys upon RT milling in the whole range of transformation’’ upon milling is driven or not by
concentration in mannitol. Molecular alloy can the position of the milling temperature with
only be obtained for mannitol fraction x lower than respect to the glass transition of a given compound.
0.44. Figure 9 shows that in this concentration In our investigations, this difficulty has been
range the evolution of Tg with the mannitol overcome by milling at room temperature a binary
concentration is well described by the Gordon mixture whose glass transition temperature can
Taylor law (1) with a fitting parameter K close to be tuned on either side of the milling temperature
0.65  0.02. For larger mannitol fraction the state by changing the concentration of the two chemical
obtained after milling is in fact a mixture of components. Our investigations of the lactose/
lactose/mannitol glass solution and crystalline mannitol mixtures for which the Tg can be
tuned from 120–138C clearly show that the
amorphization process upon milling is replaced
by a polymorphic transformation when the Tg of
the mixture becomes lower than the milling
temperature.

SUMMARY

Transformations of molecular crystals induced

by milling are reported in this article. Specific
attention is paid to the position of Tg with respect
to the temperature of milling. It should be under-
lined that we took care to use a milling procedure
which includes long pause periods in order to keep
the milling temperature close to the room tem-
perature and limit overheating. The two main
Figure 9. Evolution of the glass transition tempera- tendencies which emerge from this work are the
ture of the comilled mixture of lactose/mannitol following:
versus the mannitol content (&). The solid line repre-
sents the Gordon’s fitting law. The dot-line is a guide for (i) Milling crystalline compounds well below
the eyes. the glass transition temperature of the

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007
 15206017, 2007, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jps.20939 by Institute Of Chemical Technology, Mumbai, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1406 DESCAMPS ET AL.

corresponding liquid induces a direct far below Tg (at high enough intensity), and
solid state vitrification (cases of lactose,18 polymorphic transformations (if any) when the
trehalose,17 and budesonide19). This amor- milling is performed above Tg. In the glass
phization process is fundamentally differ- transition range both transformations can occur
ent from the usual thermal quench of the depending on the milling intensity. These observa-
melt as proved, for example, by the total tions may have interesting consequences con-
absence of caramelization and mutarota- cerning the definition of operative procedure of
tion in amorphous lactose obtained by formulation. For instance, a process which leads to
milling. decreasing the glass transition temperature may
(ii) Milling crystalline compounds above Tg hinder the amorphization tendency under milling.
may induce polymorphic transformations This is true for milling under humidity and
which generally place the system in a probably the reason which makes that propellant
metastable states (cases of sorbitol,21 man- milling is able to promote crystal reconstruction.
nitol,24 sulfamerazine11). A conventional thermodynamical approach is
thus not sufficient to justify the whole pattern
It is however necessary to qualify the effect of of observed transformations. A nonequilibrium
the relative position of Tg with respect to the approach such as that proposed for irradiation-
milling temperature on the nature of the induced transformations6 should be appropriate
end product. A first reason is associated to to provide a satisfying description of all of the
the definition of the glass transition itself. It is observations.
basically not a thermal equilibrium event but the
manifestation of the change from an ergodic
(above Tg) to a nonergodic (below Tg) situation.
The position of the Cp jump which marks the glass
ACKNOWLEDGMENTS
transition is thus dependent on the temperature
The authors thank Dr. Thomas Larsson for very
scanning rate: for a given compound, the higher
useful discussions concerning lactose and binary
the cooling rate, the higher the Tg. In that sense,
phase diagrams of molecular compounds. The
the comparison of the milling temperature with Tg
authors also thank Dr. G. Martin and Prof. P.
is only a way to locate it with regard to the
Bellon for very useful discussions concerning
transformation range. The width of this zone is
driven materials. This work was performed in
itself very dependent of the fragility, the non-
the framework of an INTERREG network (‘‘Ther-
exponentiality and the nonlinearity of the
apeutic Materials’’) between Nord-Pas de Calais,
dynamics of the glass former. Another point to be
Haute Normandie and Kent (financially sup-
noted is that when not far below Tg the nature of
ported by the FEDER). We also thank F. Danède
the transformation upon milling depends on the
and F. Capet for their technical management of
intensity of milling.26 For example, milling the g
the present work.
form of indomethacin at room temperature (i.e.,
Tg208C) may either induce an amorphization at
high intensity or a polymorphic transformation at
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JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI 10.1002/jps
 15206017, 2007, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jps.20939 by Institute Of Chemical Technology, Mumbai, Wiley Online Library on [07/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007