ADR-12900; No of Pages 7

Advanced Drug Delivery Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Unintended and in situ amorphisation of pharmaceuticals☆

P.A. Priemel, H. Grohganz, T. Rades ⁎
Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Amorphisation of poorly water-soluble drugs is one approach that can be applied to improve their solubility and
Received 1 October 2015 thus their bioavailability. Amorphisation is a process that usually requires deliberate external energy input. Howev-
Received in revised form 28 November 2015 er, amorphisation can happen both unintentionally, as in process-induced amorphisation during manufacturing, or
Accepted 16 December 2015
in situ during dissolution, vaporisation, or lipolysis. The systems in which unintended and in situ amorphisation has
Available online xxxx
been observed normally contain a drug and a carrier. Common carriers include polymers and mesoporous silica par-
Keywords:
ticles. However, the precise mechanisms by which in situ amorphisation occurs are often not fully understood. In situ
Unintended and in situ amorphisation amorphisation can be exploited and performed before administration of the drug or possibly even within the gas-
Poorly water-soluble trointestinal tract, as can be inferred from in situ amorphisation observed during in vitro lipolysis. The use of in
Polymer situ amorphisation can thus confer the advantages of the amorphous form, such as higher apparent solubility and
Mesoporous silica particles faster dissolution rate, without the disadvantage of its physical instability.
Lipolysis © 2015 Elsevier B.V. All rights reserved.
Process-induced amorphisation

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Unintended and in situ amorphisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. Process-induced, unintended amorphisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2. Dissolution-mediated in situ amorphisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. Vapour-mediated in situ amorphisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4. In situ amorphisation during lipolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Challenges and benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction
Solid materials can exist in a crystalline state, where molecules are or-
dered in all three dimensions, or in an amorphous form with only short
range order [1]. The transformation from the crystalline to the amorphous
form, amorphisation, requires molecules to leave their place in the well-
ordered crystal structure [2]. This can be achieved via mechanical activa-
tion such as milling or via phase transitions from the solid to a liquid or
gaseous phase, i.e. either melting, dissolution, or vaporisation of the
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Amorphous
pharmaceutical solids.”
⁎ Corresponding author at: Department of Pharmacy, Universitetsparken 2, 2100
Copenhagen, Denmark. Tel.: +45 35 33 60 01.
E-mail address: thomas.rades@sund.ku.dk (T. Rades).
drug is necessary. The amorphous form has a higher apparent solubility
and therefore potentially a higher bioavailability than the corresponding
crystalline form. However, the amorphous form is thermodynamically
unstable and will eventually recrystallise [3]. The kinetics of the
recrystallisation process, i.e. how long does it take before recrystallisation
has a pronounced effect on pharmaceutically relevant properties, deter-
mines whether amorphisation is a suitable formulation approach for a
given poorly soluble drug or not. Amorphous products that have success-
fully been introduced into the market are mainly glass solutions
consisting of a drug and a polymer [4]. However, drug solubility in poly-
mers is normally low, and thus phase separation and recrystallisation
may occur if the solubility limit is exceeded [5–7]. If the kinetics of these
processes is slower than the shelf life of a pharmaceutical product, glass
solutions were shown to be a good formulation approach. Nevertheless,
the physical stability of these formulations has to be tested under various
conditions in order to be sure that no stability issues will arise [8].

http://dx.doi.org/10.1016/j.addr.2015.12.014
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Please cite this article as: P.A. Priemel, et al., Unintended and in situ amorphisation of pharmaceuticals, Adv. Drug Deliv. Rev. (2015), http://
dx.doi.org/10.1016/j.addr.2015.12.014
2 P.A. Priemel et al. / Advanced Drug Delivery Reviews xxx (2015) xxx–xxx
Unintended and in situ amorphisation can be understood as an
amorphisation process that happens without any deliberate external
energy input. If amorphisation can be induced just before the applica-
tion of a formulation or even happens in the body after administration,
it would allow the circumvention of stability issues of the amorphous
form. Unintended and in situ amorphisation has been mainly reported
in the fields of chemistry and physics and is also referred to as in situ
amorphisation. It may occur as ion-induced, electron beam-induced, an-
nealing-induced, or pressure-induced spontaneous amorphisation
[9–12]. The materials that are amorphised in this way are often alloys
and therefore they can endure harsh conditions under which small or-
ganic molecules such as drugs would degrade. In the pharmaceutical lit-
erature, unintended amorphisation has been mainly reported in case
studies of manufacturing processes. It is regarded as a disruptive event
in the supposedly well-planned and controlled manufacturing process
and can negatively affect product performance. In other cases, in situ
amorphisation was seen as a curious counterintuitive occurrence. In
general, in situ amorphisation has not yet been investigated and ex-
plored to the extent to make it a useful formulation approach. Hence
this review wants to provide an overview of unintended and in situ
amorphisation in the pharmaceutical setting with the hope of advanc-
ing further studies in this field.
2. Unintended and in situ amorphisation
In many cases of unintended or unexpected amorphisation, there is a
sudden change from an equilibrium state to a non-equilibrium state. For
example, a drug sometimes precipitates out in an amorphous form,
when a highly concentrated solution of a poorly water-soluble drug,
which is dissolved in a water-miscible organic solvent, is added to
water. It is important to note that such a change in the conditions in-
duces a highly non-equilibrium (amorphous) state. During the sudden
change in conditions, the amorphous form is the preferred form. How-
ever, when the conditions change again, e.g. after drying, this is of
course no longer the case. In this review, we use the expressions “unin-
tended” and “in situ amorphisation” if such a sudden change from an
equilibrium state to a non-equilibrium state leads to the formation of
an amorphous form, either unintended or intended. Unintended
amorphisation can happen during manufacturing processes where it is
an unintended event. However, recently, interest in intended in situ
amorphisation has increased. Several paths can be used to create the
amorphous form and similarly in situ amorphisation can also be
achieved through different routes. Fig. 1 depicts the main approaches
for intended in situ amorphisation
Fig. 1. Schematic of different approaches to achieve intended spontaneous amorphisation.
Please cite this article as: P.A. Priemel, et al., Unintended and in situ amorphisation of pharmaceuticals, Adv. Drug Deliv. Rev. (2015), http://
dx.doi.org/10.1016/j.addr.2015.12.014
2.1. Process-induced, unintended amorphisation
Process-induced solid state changes can occur in the manufacturing
processes of the pharmaceutical industry [13–15]. During manufacturing,
the drug and excipients experience heat, mechanical stress, and moisture
exposure. In all of the manufacturing steps, the solid state properties of
the drug or the excipients can change: one polymorph may convert to an-
other [16–18], hydrates may occur [19–21], amorphous material may
crystallise [22–26], or crystalline material may amorphise. These changes
in the solid state of a drug or excipient may have a substantial impact on
the performance of a dosage form with regard to dissolution behaviour,
degradation, and mechanical properties. Hence those changes have to
be monitored and evaluated for their potential risk. A good example illus-
trating various process-dependent solid state changes is a study on the-
ophylline tablets [27]. Theophylline can exist as stable anhydrate,
metastable anhydrate, or as monohydrate. In order to prepare a tablet,
the stable anhydrous form of the drug was mixed with microcrystalline
cellulose and wet granulated with polyvinylpyrrolidone (PVP) solution.
The granules were dried and compressed into tablets and stored at differ-
ent humidities. During wet granulation on a laboratory scale, the stable
anhydrous theophylline converted to the monohydrate form. In the sub-
sequent drying step, the crystal water was lost, resulting in a mixture of
both anhydrous forms. In order to avoid solid state transformations, the
manufacturing process was further investigated. When the granulation
step was performed in a fluid bed, the granules consisted only of the sta-
ble anhydrous form. However, after high shear granulation, a mixture of
stable and metastable theophylline was produced. When a mixture of
both anhydrous forms was stored over 33% relative humidity (RH), the
metastable drug transformed to the stable anhydrate which was accom-
panied by decrease in dissolution rate.
Unintended amorphisation during manufacturing processes can
lead to major changes in the performance of a product. The water ad-
sorption and the molecular mobility are higher in disordered or amor-
phous regions than in the respective crystalline counterparts [28–30].
Therefore, chemical or physical instabilities, promoted by humidity,
such as hydrate formation or hydrolysis, may be increased.
Asargan7016 is a commercial product containing acetylsalicylic acid
and is manufactured via roller compaction. Asargan showed a higher
water uptake between 10% and 80% RH in water vapour sorption anal-
ysis [31] than untreated crystalline acetylsalicylic acid [32]. Hancock
and Zografi [33] suggested possible reasons for this behaviour, namely
a very small particle size, an increase in microporosity, or partial
amorphisation. The first two possibilities are not very likely to occur in
the roller compaction process. However, amorphous material can ad-
sorb more water than crystalline material [34]. This increased water ad-
sorption into the amorphous regions leads to an increased interaction
with water. The increased water adsorption, together with the higher
molecular mobility of the amorphous from, resulted in faster hydrolytic
degradation of acetylsalicylic acid into salicylic acid and acetic acid via
ester cleavage. Hence process-induced solid state transformations
changed the degradation profile of the drug.
Another example for increased degradation due to amorphisation is
ABT-232. This drug can exist in a stable anhydrous form, a monohydrate,
and the amorphous form which is highly hygroscopic [35]. The pure
amorphous drug undergoes deliquescence and recrystallisation at ambi-
ent conditions within 10 min. ABT-232 in the stable anhydrous form
was wet granulated with excipients, dried, and compressed into tablets.
The monohydrate form converts rapidly to the anhydrate form at elevat-
ed temperatures. Therefore, after the drying step, the authors expected
that the solid state form in the final compacts would be the anhydrate
form. When these tablets were stored at high temperature and humidity,
an unexpected loss of potency was found. The granules did not display the
typical reflections of the drug when measured with X-ray powder diffrac-
tion (XRPD), indicating conversion of the drug to the amorphous form.
During storage for 5 months at room temperature and ambient condi-
tions, no recrystallisation occurred, even though the amorphous drug
 P.A. Priemel et al. / Advanced Drug Delivery Reviews xxx (2015) xxx–xxx
without excipients crystallised rapidly at ambient conditions. The authors
explain the stability of the amorphous granules as due to the anti-
plasticising or water scavenging effect of the excipients used in the gran-
ulation step. After storage at 40 °C and 75% RH for 1 month, reflections of
the drug reappeared in the diffractogram. Hence, the potency loss of the
ABT-232 formulations could be explained with amorphisation during
the manufacturing and degradation connected to it. When direct compac-
tion of a drug-excipient powder blend was used, no amorphisation took
place and the chemical degradation problem could be circumvented.
Albuterol sulphate is a β2 adrenergic receptor agonist, often used in in-
halation therapy for asthma and chronic obstructive pulmonary disease
by dry powder inhalation [36]. In order to deliver dry powder to the
lung, particle sizes between 5 and 1 μm are desired [37]. Ward and Schultz
[38] have investigated the effect of jet air milling on albuterol sulphate
with regards to the resulting solid state properties of the drug. XRPD
could not differentiate between micronised powders and those that
have not been micronised. However, in the micronised powder, addition-
al thermal events (a glass transition and recrystallisation event) occurred
in differential scanning calorimetry (DSC) measurements, indicating the
presence of small quantities of amorphous material. When the
micronised powder was stored at high temperature and humidity for
1 day, these events disappeared. In dynamic vapour sorption (DVS) mea-
surements, the micronised powder also had a higher water adsorption up
to 50% RH at which point the water content suddenly dropped. This drop
in water adsorption was also observed for amorphous lactose and thor-
oughly studied by Burnett et al [34]. Amorphous lactose was exposed to
increasing humidity in DVS; with increasing humidity, water was
adsorbed, increasingly plasticising the lactose. Once a certain humidity
threshold was exceeded, the particles gained enough mobility to
recrystallise. As the molecules subsequently reorganise into the crystal
lattice, water is expelled. For lactose, the drop in water adsorption was de-
termined to be at 58% RH at 25 °C. Hence the sudden drop in water ad-
sorption in the DVS measurement of the micronised albuterol sample is
another indicator for the presence of amorphous material. As a means
of evaluating the effect of this amorphisation on the drug performance,
the powder was stored at different conditions and the particle size was
measured. For micronised powder stored at room temperature and
under vacuum, 98% of the particles were smaller than 5 μm and 72%
smaller than 2 μm, while for the powder stored at high temperature
and humidity, these numbers decreased to 73% and 6%, respectively.
Hence the recrystallisation of the small amorphous fraction in the
micronised powder had a strong influence on the particle size, one of
the main critical quality attributes for dry powder inhaled formulations.
Gabapentin has three polymorphic anhydrate forms and a
monohydrate [39,40]. At elevated temperature, gabapentin degrades
under the formation of a lactam ring via intramolecular cyclisation in
aqueous solution [41]. To test the effect of manufacturing processes
on the degradation of gabapentin, the drug was milled for 15, 30, 45,
and 60 min [42]. The degradation product was measured directly after
milling and after storage at different humidities. The amount of degra-
dation product increased with increased milling time due to the forma-
tion of disordered regions during the milling. This may lead to higher
chemical degradation of the drug and loss of efficacy. After milling, no
amorphous phase was detected in XRPD and solid state NMR measure-
ments. However, the intensity of the reflections decreased with longer
milling time in XRPD and peak broadening was observed in NMR. This
indicated that crystal defects or small disordered regions had formed.
When milled samples were stored at 50 °C and low humidity, the deg-
radation rate was higher than for milled samples stored at humidity
above 30% RH. The authors found that the crystal defects and introduc-
tion of disordered regions by milling was reversed when the drug was
subjected to a highly humid environment. Hence the annealing of the
disordered region was a competitive event to chemical degradation in
the presence of humidity.
Process-induced unintended amorphisation had a negative effect in
most of the above examples. Either the rate of chemical degradation
Please cite this article as: P.A. Priemel, et al., Unintended and in situ amorphisation of pharmaceuticals, Adv. Drug Deliv. Rev. (2015), http://
dx.doi.org/10.1016/j.addr.2015.12.014
3
was higher, as in the case of Asargan and ABT-232, or the particle size
increased as in the case of the dry powder inhaler drug albuterol sul-
phate. However, process-induced disorder in the case of gabapentin
had a positive effect on the overall chemical stability when the milled
samples were stored at high humidity. In the following sections, the po-
tential of in situ amorphisation for drug delivery will be discussed.
2.2. Dissolution-mediated in situ amorphisation
Polyethylene oxide, PEO, is a polymer that contains crystalline la-
mellae and amorphous regions. When stored at high humidity, the
polymer undergoes deliquescence via absorption of water into the
amorphous regions of the polymer. Thus, lamellae are destabilised and
crystallinity decreases [43]. Marsac et al. [44] compressed PEO with
10% (w/w) crystalline drug and stored the compacts at room tempera-
ture and 94% RH. The selected drugs in this study (paracetamol, ibupro-
fen, ketoprofen, naproxen, felodipine, and ketoconazole) vary in their
molecular weight, melting point, aqueous solubility, heat, and entropy
of fusion. This study yielded three main findings. Firstly, after 14 days,
the paracetamol PEO compacts showed no signs of crystallinity of the
drug according to FT-Raman spectroscopy. This was confirmed with
XRPD, where only an amorphous halo was observed, indicating that
the paracetamol PEO mixture had completely amorphised. Interesting-
ly, the peaks of the polymer disappeared as well, probably due to deli-
quescence of the polymer. Secondly, compacts of PEO with ibuprofen,
ketoprofen, or naproxen lost some crystallinity during storage accord-
ing to Raman spectroscopy measurements. While reflections of the
crystalline drugs strongly decreased in intensity in the measured
XRPD diffractograms, those of PEO were still present. Thirdly, ketocona-
zole and felopdipine peaks in Raman spectroscopy and reflections in
XRPD measurements showed very little change after 28 days of storage
compared to the compacts at the start of the study. The physical appear-
ance of the compacts also changed during in situ amorphisation. Para-
cetamol PEO compacts were a “gelatinous mass” [44], the partly
amorphised compacts with ibuprofen, ketoprofen, and naproxen soft-
ened, whereas the felodipine and ketoconazole compacts changed
only slightly. A trend was observed that the degree of amorphisation
of the drug and its water solubility were correlated. Paracetamol has a
comparatively high water solubility and was completely amorphised.
Ibuprofen, ketoprofen, and naproxen have intermediate water solubility
and were partly amorphised. In contrast, felodipine and ketoconazole,
with very low aqueous solubility, did not show decreased crystallinity
after storage at high humidity. The authors suggest that several circum-
stances are required for in situ amorphisation of crystalline drugs in the
presence of PEO to occur. First, water is taken up into the amorphous
parts of the polymer. This decreases the viscosity of the polymer and
at the same time the crystalline areas in the polymer are reduced due
to deliquescence [43]. This way, a cosolvent of water and PEO is formed,
which then dissolves the drug molecules. This would explain why a
comparatively high aqueous solubility of the drug was beneficial for
its amorphisation.
In another study, the amorphisation behaviour of ibuprofen and in-
domethacin in the presence and absence of hydroxypropyl methyl cel-
lulose (HPMC) was investigated with regards to the influence of
milling and moisture/vapour [45]. Physical mixtures containing HPMC
with 20% drug were (i) milled under dry conditions for 3 h, (ii) sprayed
upon with either methanol or water and then milled for 3 h, (iii) kept in
saturated methanol vapour at room temperature for up to 16 h or
(iv) milled under saturated methanol vapour. The latter was achieved
with a tandem rotation mill (see Fig. 2), where one vessel contained
the physical mixture of drug and polymer and steel balls, while the sec-
ond vessel contained methanol and was heated to 50 °C. Both vessels
were connected with a tube and placed on a rotating roll.
The intensity of XRPD reflections of dry milled ibuprofen and HPMC
decreased, compared to the physical mixture of crystalline drug and
polymer, but reflections were still present. Samples that were sprayed
4 P.A. Priemel et al. / Advanced Drug Delivery Reviews xxx (2015) xxx–xxx
Fig. 2. Schematic of the tandem rotation mill, reprinted from [43] with permission from
Elsevier.
upon with methanol or water prior to milling showed a further decrease
in crystallinity; hence, the presence of solvents accelerated the
amorphisation process. Ibuprofen stored in a closed box with saturated
methanol vapour without further agitation and ibuprofen that was
milled under saturated methanol vapour both turned fully amorphous.
However, in the absence of methanol vapour, the weak stress of the tan-
dem rotation mill did not result in an amorphous material. Indometha-
cin did not turn amorphous when stored together with HPMC over
saturated methanol vapour. However, in this case, very mild milling in
the presence of methanol vapour led to a material that was mainly
amorphous with very small reflections remaining in the diffractograms.
Ibuprofen without HPMC stored in saturated methanol vapour absorbed
methanol and liquefied, whereas indomethacin did not. The authors
therefore explain the difference in in situ amorphisation behaviour as
due to the solubility of the drugs in methanol and the interactions of
drug and HPMC. The improvement in amorphisation behaviour for in-
domethacin was explained to be due to a better contact between drug
and polymer, facilitated by the mild mechanical stress of the tandem
mill.
Another study where dissolution of drug in the presence of polymer
led to in situ amorphisation was performed by Priemel et al [46]. The au-
thors of this article use the term in situ amorphisation because
amorphisation was planned with the idea of administering the drug to
the patient. Indomethacin was used as a model drug and Eudragit® E as
polymer. Both substances were mixed in either 3:1, 1:1, or 1:3 (w/w)
ratio and compacted, ensuring an intimate contact between drug and
polymer. When these compacts were immersed in phosphate buffer of
Fig. 3. Scanning electron microscopy images of indomethacin Eudragit® E compacts after amorphisation, (a) 3:1, (b) 1:1, (c) 1:3 drug to polymer ratios. Reprinted from [46] with
permission from Elsevier.
Please cite this article as: P.A. Priemel, et al., Unintended and in situ amorphisation of pharmaceuticals, Adv. Drug Deliv. Rev. (2015), http://
dx.doi.org/10.1016/j.addr.2015.12.014
pH 6.8 (in which the polymer is not soluble), their colour changed from
white to yellow indicating amorphisation. The colour change, which
was accompanied with swelling of the compact, was observed through-
out the whole compact for the 3:1 and 1:1 drug to polymer ratio. In the
1:3 ratio, only the surface that was exposed to the buffer showed a yellow
layer. Scanning electron microscopy of the cross-section of the 3:1 and 1:1
drug to polymer ratio compacts showed mainly smooth areas with some
individual crystals remaining. However, only the surface of the 1:3 drug to
polymer ratio compact that was exposed to the buffer had a smooth ap-
pearance (see Fig. 3). These observations were interpreted as indicator
for buffer penetration into the compact. After immersion of the compacts
in buffer, diffractograms showed small reflections superimposed on a
halo. Principal component analysis of Fourier transform attenuated total
reflection infrared (FT-ATR-IR) spectra was performed. The spectra of
in situ amorphised samples of all ratios clustered together with those of
conventionally prepared (quench cooling) glass solutions of the same
drug and polymer at their respective ratios. However, it should be noted
that FT-ATR-IR spectroscopy is a technique that mainly measures on the
sample surface. Especially for the 1:3 sample, this might overestimate
the effect of in situ amorphisation as only the amorphised layer on the ex-
posed surface of the compact was measured. The mechanism suggested
by the authors is based on the physico-chemical properties of drug and
polymer that must therefore be chosen accordingly to achieve the desired
amorphisation behaviour. At the pH at which in situ amorphisation oc-
curred, the drug is poorly soluble (but not completely insoluble) whereas
the polymer can be plasticised but will not dissolve. The penetrating
water dissolves some drug molecules that are now in close vicinity to
the plasticised polymer and interactions between both are favourable to
the formation of a glass solution. Interestingly, in situ amorphisation did
not lead to dissolution of the drug at this pH. In contrast, improved disso-
lution behaviour was observed upon transfer of the compacts to a low pH
environment, at which Eudragit® E dissolves. Additionally to the
amorphisation, the swelling of the polymer and hence the compact was
an important factor in the improved dissolution performance of in situ
amorphised compacts. This was most obvious for the compacts with 3:1
and 1:1 (w/w) drug to polymer ratios which displayed a high degree of
swelling and highly improved dissolution behaviour. The 1:3 (w/w)
ratio compact did not swell, reducing buffer penetration and therefore
restricting in situ amorphisation to the surface of the compact.
In situ amorphisation can also be a useful method for the production
of excipients with a high amorphous content. Cellulose is an abundant
source for fuel production and green chemistry [47,48]. Cellulose is a
biopolymer containing units of D-glucopyranose that are connected
via β-1,4 glycosidic bonds. In order to use cellulose, it needs to be bro-
ken down into smaller subunits via cleavage of the β-1,4 glycosidic
bonds. While methods such as steam explosion, ball milling, or ammo-
nia treatment are either energy expensive or consume a lot of ammonia,
another possible approach is dissolution–precipitation pre-treatment in
ionic liquids [49]. Microcrystalline cellulose is dissolved in an ionic liq-
uid, such as 1-butyl-3-methylimidazolium chloride or 1-ethyl-3-
methylimidazolium (EMIM) acetate. When water is added as an anti-
 P.A. Priemel et al. / Advanced Drug Delivery Reviews xxx (2015) xxx–xxx
solvent, the cellulose precipitates in a solid state form that is less crystal-
line than the starting material. Cellulose was added to EMIM acetate
that contained 5–50 (w/w) % water and dissolved cellulose was precip-
itated with water after 3 h, dried and investigated by XRPD [50]. The
crystallinity of the samples was calculated from the diffractograms
using an amorphous subtraction method. When the solvent mixtures
had up to 10% water content, the cellulose was completely dissolved
and resulted in an amorphous precipitate after addition of water. At
20% and 30% water content, only 4% and 1% cellulose dissolved, respec-
tively. Interestingly, at 20% water content, an amorphous content of 40%
was achieved. As only 4% of the cellulose had dissolved in the solvent,
this increase in amorphous content was not merely due to dissolution
of cellulose and precipitation thereafter. The degree of amorphisation
was also found to be dependent upon the ratio of added cellulose to sol-
vent. For 1% (w/w) added cellulose, 40% amorphisation was achieved.
However, when this was increased to 5% and 10% (w/w) cellulose,
only 35% and 24% amorphisation was achieved, respectively. The
amorphisation of the cellulose was observed with optical transmission
and second harmonic generation microscopy. Optical microscopy
showed swelling of the cellulose particles over 60 min. When the
same particles were imaged using second harmonic generation micros-
copy, the signal diminished strongly over the 60 min period indicating
loss of crystallinity. When cotton wool was used as alternative cellulose
source, a yield of 50% amorphous material from an EMIM acetate water
(20%) mixture could be achieved. The mechanism of this in situ
amorphisation is not yet understood. Nevertheless, this process might
become an alternative pre-treatment method for cellulose. It would
have the benefit of rendering the use of energy-intensive EMIM acetate
purification in the dissolution precipitation method unnecessary.
2.3. Vapour-mediated in situ amorphisation
In situ amorphisation does not necessarily require mobile molecules
in a liquid phase as described above, but may also occur via a gas phase.
Konno et al. described the amorphisation of drug and naphthalene in
the presence of adsorbent excipients [51]. Mixtures of crystalline drug
and excipient were stored in a desiccator and converted to the amor-
phous form after several weeks of storage. Acetylsalicylic acid or phen-
acetin were mixed with activated carbon or mesoporous silica and
stored together. Reflections of the crystalline drugs disappeared in the
measured XRPD diffractograms. The dissolution behaviour of these
amorphised mixtures did not improve significantly and acetylsalicylic
acid degraded faster in the presence of the excipients. When naphtha-
lene was mixed with activated carbon, it amorphised rapidly, but stayed
crystalline when stored with graphite, a polymorphic form of carbon
with a small surface area. Increase in temperature and reduction of
the pressure led to faster amorphisation. In all three cases, the authors
suggested amorphisation via the gas phase: Given time, the crystalline
model compounds (acetylsalicylic acid, phenacetin and naphthalene)
sublimed and molecules transferred into the gas phase from where
they adsorbed onto the porous excipients.
Qian et al. have further studied vapour-mediated in situ amorphisation
[52]. Naphthalene and silica were stored in a desiccator filled with nitro-
gen gas, under reduced pressure at 40 °C, but spatially separated from
each other. Naphthalene sublimed and molecules in the gas phase distrib-
uted in the desiccator and adsorbed onto the silica in an amorphous form.
The amorphisation capacity was determined to be 2:1 silica to naphtha-
lene. Alternatively, silicon dioxide and a model compound (naphthalene,
1-naphtoic acid, 1-naphtol, ibuprofen, or diflunisal) were mixed together
and stored in vials inside a container at 40 °C (or 80 °C for diflunisal). The
headspace of the vials and the container was filled with nitrogen gas.
While amorphisation took place in both cases, it took a shorter time in
the physical mixtures compared to spatially separated naphthalene and
silica. This was attributed to a shorter diffusion path in physical mixtures
compared to spatially separated compounds. However, complete
amorphisation still took several weeks for these drugs to occur and may
Please cite this article as: P.A. Priemel, et al., Unintended and in situ amorphisation of pharmaceuticals, Adv. Drug Deliv. Rev. (2015), http://
dx.doi.org/10.1016/j.addr.2015.12.014
5
take even longer for other drugs. Itraconazole was tested in this setup
and did not result in any adsorption onto the silica within a month [53].
In further studies [54], the effect of physico-chemical parameters of
drug and silica were investigated in order to determine the amorphisation
capacity of these systems. Mesoporous silica particles with different phys-
icochemical parameters are readily available [55–57], and therefore, the
effect of the silica on the amorphisation of naphthalene can be systemat-
ically studied. The silica particles were evaluated with regard to surface
area, pore volume, pore diameter, and hydrophilicity. No correlation
between surface area or pore volume and amorphisation capacity was
found. A positive correlation was found for pore diameter and
amorphisation, with a smaller diameter leading to higher amorphisation
due to capillary condensation. Amorphisation capacity was higher for hy-
drophilic silica compared to hydrophobic silica. Naphthalene is a non-
polar cyclic aromatic hydrocarbon and therefore hydrophobic silica was
expected to exhibit a higher amorphisation capacity. The higher
amorphisation observed with the hydrophilic version of the excipient
was explained with dipol induction of naphthalene by the silanol groups.
Due to these interactions, more naphthalene could be rendered amor-
phous. At a low naphthalene-to-silica ratio, the vapour pressure of the
compound was found to be the main determinant for the rate of
amorphisation, but overall, the amorphisation capacity was not easily de-
scribed by a single parameter. The enthalpy of condensation from vapour
to solid was found to be an indicator of amorphisation capacity. The
amorphisation capacity, however, decreased significantly in the presence
of water and water vapour [8]. Additionally, naphthalene, which was
amorphised at 0% RH and then stored at high humidity, recrystallised.
The authors argue that the adsorption of water onto silica is a competitive
process to the adsorption of the organic compound. The interaction be-
tween water and silicon dioxide is a more favourable one than the inter-
action between silica and naphthalene. Therefore, even already adsorbed
and amorphised compound desorbed and crystallised. While this com-
petitive effect of water is undesired in the case of storage, it is beneficial
in terms of dissolution, since the same competitive effect is responsible
for a very fast release of drug from the silica particles into the dissolution
medium. While supersaturation was achieved through this mechanism, it
was not sustainable and recrystallisation occurred during the dissolution
testing.
Vapour-mediated in situ amorphisation may not be suitable for
every drug as seen in the case of itraconazole for which no adsorption
was observed. Overall, this amorphisation approach is a scientifically in-
teresting avenue of study and several influencing factors were found,
but amorphisation was too slow for this method to be used in practice.
Therefore, other techniques are currently used to create amorphous
drug silica particles, such as solvent deposition or co-grinding [59,60].
2.4. In situ amorphisation during lipolysis
In the previous sections, several examples of in situ amorphisation
were described. While no deliberate energy input was required, the pro-
cesses still required some time. In the case of drug PEO compacts [44]
and in the case of vapour-mediated amorphisation [52,54,58], the
time frame of amorphisation during storage was up to several weeks.
Even amorphisation of indomethacin with Eudragit® E [46] and of cel-
lulose [50] described above still took 1–3 h. Amorphisation in the
body would be an ideal way to increase solubility without any storage
stability issues. While there are no examples for this in the literature,
in vitro experiments have shown that in situ amorphisation of some
drugs can occur during lipolysis of lipid-based oral formulations of poor-
ly water-soluble drugs. Lipolysis is an in vitro tool which mimics lipid di-
gestion in the body and thus provides understanding of the processes
that lipid formulations experience in the gastrointestinal tract. The dis-
solution medium contains lipase, phospholipids, and bile salts in addi-
tion to the buffer. The pH is kept constant by NaOH titration which
neutralises free fatty acids produced via lipolysis of triglycerides [61,
62]. The lipolysis products of lipid formulations together with the
6 P.A. Priemel et al. / Advanced Drug Delivery Reviews xxx (2015) xxx–xxx
components of the medium form different colloidal structures [63] that
can solubilise a drug. However, if the drug is supersaturated, it may
eventually precipitate. The kinetics of this precipitation is usually
tracked by taking samples at different time points and centrifugation
which leads to the formation of a pellet. The drug concentration in the
pellet is then determined via HPLC analysis. Recently, real-time
analytical tools such as Raman spectroscopy for quantification of drug
and for solid state analysis were also introduced into the lipolysis
model [64,65].
During lipolysis of self-microemulsifying drug delivery systems
(SMEDDS) containing cinnarizine, precipitation occurred. Previously,
precipitation during lipolysis has been considered undesirable as it
removes the dissolved drug from the medium. However, when Sassene
et al. investigated the nature of the pellet, they found that it was amor-
phous, i.e. in situ amorphisation had occurred during lipolysis [66].
When this pellet was exposed to new medium, it dissolved rapidly indi-
cating that in situ amorphisation during lipolysis might not be a problem
or perhaps even be advantageous for the delivery of the drug. Similarly,
amorphous precipitation during lipolysis was found for halofantrine
[67] and simvastatine [68] from self-nanoemulsifying drug delivery sys-
tems (SNEDDS). But not all drugs that precipitate during lipolysis do so
in an amorphous form. Both fenofibrate [69] and loratadine [70] were
found to precipitate in a crystalline form. Currently, the factors deter-
mining whether a drug precipitates into its amorphous or crystalline
form have not been defined but may be related to intrinsic properties
of the drug. Alternatively, the nature of the precipitate may be influ-
enced by the presence of components from the formulation such as
lipids, bile salts, partially digested formulation components, or the inter-
play between some or all of these factors. Carvedilol precipitated in its
crystalline form when dispersed into intestinal medium without en-
zymes. But when digestive enzymes and therefore lipid digestion prod-
ucts were present, i.e. under the normal conditions of lipolysis, the
precipitate was amorphous [70]. An important question that still
needs to be answered is the relevance and possible correlation of
in vitro precipitation to the in vivo performance of these formulations.
Several studies tried to correlate in vitro with in vivo data for lipid for-
mulations. For fenofibrate in vitro lipolysis results were unable to pre-
dict in vivo results in minipigs [69]. Furthermore, no correlation
between the solubility of drug in SNEDDS, the occurrence of precipita-
tion in lipolysis, or the droplet size of the created emulsion and in vivo
performance was found in a study of four different SNEDDS in dogs
[71]. It should also be noted that the adsorption step is missing in the
in vitro lipolysis model. Precipitation of drug may not occur in an
in vivo situation when drug molecules from supersaturated solutions
are absorbed.
3. Challenges and benefits
The field of in situ amorphisation is not yet well established and many
areas remain to be explored. Currently, understanding of the contributing
factors of in situ amorphisation needs to be developed. The physicochem-
ical properties that are required for drugs and excipients to undergo in situ
amorphisation or are prone to unintentional amorphisation need to be
studied. The role of water in the amorphisation process as well as possible
“preparation methods” for in situ amorphisation need to be identified.
More studies on in situ amorphisation may be able to fill the knowledge
gap and clarify the underlying mechanisms.
Nevertheless, in situ amorphisation would confer tremendous ad-
vantages as dosage forms could be developed in which the drug is
amorphised directly prior to administration. This would provide the ad-
vantages of the amorphous form, such as faster dissolution rate and
higher apparent solubility, while avoiding the disadvantage of potential
recrystallisation during storage. Another area of interest would be the
use of in situ amorphising formulations in preclinical or even clinical tri-
als. A batch of a suitable physical mixture of drug and polymer could be
produced under GMP environment and stored or shipped (for example
Please cite this article as: P.A. Priemel, et al., Unintended and in situ amorphisation of pharmaceuticals, Adv. Drug Deliv. Rev. (2015), http://
dx.doi.org/10.1016/j.addr.2015.12.014
to other trial centres) without the issue of physical instability. Just prior
to application in the trial, the formulation could be amorphised and that
way the same batch could be used for several studies.
4. Conclusions
This review attempted to give an overview of unintended and in situ
amorphisation in the pharmaceutical setting. If in situ amorphisation
can be achieved fast enough, it might be used to convert a formulation
into the amorphous form directly prior to application. By doing so, the ad-
vantages of both forms can be combined: the higher dissolution rate and
higher apparent solubility of the amorphous form and the storage stabil-
ity of the crystalline form. In situ amorphisation can be achieved via a dis-
solution or vaporisation process and via lipolysis. Amorphisation was
observed when certain drug polymer mixtures were stored at high hu-
midity, under methanol vapour or in physical mixtures of drugs and ab-
sorbents. However, the timeframes of the transformations were too
long to be of practical relevance. In situ amorphisation in water reduced
the required time from weeks to hours. Amorphisation during lipolysis
offers the advantage that the amorphisation process potentially happens
inside the body and therefore timeframes are short. A major problem
with in situ amorphisation is that it can also occur unintentionally during
manufacturing processes and may lead to changes in the physicochemi-
cal properties of the formulation. These property changes e.g. in hygro-
scopicity, aggregation behaviour of powders, or degradation of the drug,
may affect the pharmaceutical performance negatively. Overall, in situ
amorphisation is a promising field which requires further research to
make full use of its potential.
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