Control of the physical form of salmeterol xinafoate

Article abstract of DOI:10.1021/op990160z

Two approaches to the generation of particles of the phenethanolamine, salmeterol xinafoate, are discussed. To produce particles with good flow properties a fast cooling crystallisation process was developed which delivered salmeterol xinafoate as spherical agglomerates of microcrystals which had good powder flow characteristics and could be micronised efficiently in a fluid energy mill. In a radically different approach, salmeterol xinafoate was crystallised using supercritical carbon dioxide in the SEDS (solution enhanced dispersion by supercritical fluids) process. By means of this technique the solid state form, crystal habit, and particle size of salmeterol xinafoate could be effectively controlled.

Full text of DOI:10.1021/op990160z

Organic Process Research & Development 1999, 3, 370−376
Control of the Physical Form of Salmeterol Xinafoate
†
,†
†
‡
,§
Steve Beach, David Latham,* Colin Sidgwick, Mazen Hanna, and Peter York*
Glaxo-Wellcome Research and DeVelopment, Medicines Research Centre, Gunnels Wood Road, SteVenage,
Hertfordshire, SG1 2NY, UK, Bradford Particle Design, 49 Campus Road, Listerhills Science Park,
Bradford, BD7 1HR, UK, and Drug DeliVery Group, School of Pharmacy, UniVersity of Bradford,
Bradford, BD7 1DP, UK
Abstract:
Two approaches to the generation of particles of the phen-
ethanolamine, salmeterol xinafoate, are discussed. To produce
particles with good flow properties a fast cooling crystallisation
process was developed which delivered salmeterol xinafoate as
spherical agglomerates of microcrystals which had good powder
flow characteristics and could be micronised efficiently in a fluid
energy mill. In a radically different approach, salmeterol
xinafoate was crystallised using supercritical carbon dioxide in
the SEDS (solution enhanced dispersion by supercritical fluids)
Figure 1. Structure of salmeterol xinafoate.
process. By means of this technique the solid state form, crystal
habit, and particle size of salmeterol xinafoate could be
effectively controlled.
in which the crystalline powder is driven by air pressure into
a cyclone. Impact of the drug particles with each other and
with the wall of the cyclone causes fracture and attrition to
give particles of the desired size range.
Salmeterol xinafoate drug substance generated by a
conventional crystallisation process has very poor powder
flow properties, making it unsuitable for size reduction
processes such as micronisation.
General Introduction
The development of a successful formulation for a new
pharmaceutical agent is highly dependent upon the physical
properties1 of the active ingredient, the drug substance.
These physical properties affect, for example, bioavailability,
powder flow, bulk handling, ease of compression, and
physical stability. Hence, control and management of the
physical properties of drug substances and the provision of
robust processes for their manufacture is an important factor
in drug development.
This paper presents two practical approaches to manage-
ment of the crystallisation of salmeterol xinafoate. In the
first approach (fast cooling crystallisation) the crystallisation
process is modified to produce spherical agglomerates of
small crystals which flow well and break up readily during
micronisation. In the second approach, micronisation may
be avoided altogether by a very rapid crystallisation process
using supercritical carbon dioxide. This technique, known
as SEDS (solution enhanced dispersion by supercritical
fluids), can produce particles in a single-stage process in the
required size range for delivery to the deep lung air passages.
,2
The phenethanolamine, salmeterol xinafoate (Figure 1)
is a long-acting beta 2 adrenoreceptor agonist used in the
treatment of bronchial asthma. The drug is delivered by
inhalation by means of either a metered-dose aerosol inhaler
or a dry powder delivery device. In the latter case the drug
is formulated as a blend with lactose.
Fast Cooling Crystallisation
Introduction. Crystallisation of salmeterol xinafoate from
organic solvents using the conventional technique of dis-
solution at elevated temperatures and natural cooling to
induce supersaturation provides the drug substance as stable
agglomerates of platelike crystals which are readily filtered
and washed. A scanning electron micrograph (SEM) of some
typical crystals is shown in Figure 2. The preferred solvent
for this procedure is 2-propanol and recoveries of >90% of
theory from pure salmeterol base and 1-hydroxy-2-naphthoic
acid (HNA) have been obtained routinely.
Observation of bulk samples of salmeterol xinafoate
prepared in this way shows that the material is highly
cohesive; the crystals adhere together and the resultant
formation of loose agglomerates inhibits smooth powder
flow. Attempted micronisation of this material resulted in
blockage of the input venturi of the microniser and failure
Before salmeterol xinafoate is formulated in the delivery
device the drug substance is micronised to a size range of
about 2-5 µm to enable a suitable respirable fraction of the
drug particles to be delivered to the bronchial region of the
3
4,5
lung. Micronisation is achieved using a fluid energy mill
*
Authors for correspondence.
Glaxo-Wellcome Research and Development.
Bradford Particle Design.
†
‡
§
University of Bradford.
(
1) The Theory and Practice of Industrial Pharmacy, 3rd ed.; Lachman, L.,
Lieberman, H. A., Kanig, J. L., Eds.; Lea & Febiger: Philadelphia, 1986.
2) Pharmaceutics, The Science of Dosage Form Design; Aulton, M. E. Ed.;
Churchill Livingstone: Edinburgh, 1988.
(
(3) Stahlhofen, W. et al. Am. Ind. Hyg. Assoc. J. 1980, 41(6), 385.
(4) Dobson, B.; Rothwell, E. Powder Technology 1969/70, 3, 213.
(5) Atkins, P. J.; Barker, N. P.; Mathisen, D. In The Design and DeVelopment
of Inhalation Drug DeliVery Systems in Pharmaceutical Aerosol Inhalation
Technology; Hickey, A. J., Ed.; Marcel Dekker Inc: New York, 1992.
3
70
•
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10.1021/op990160z CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry
Published on Web 08/12/1999

Figure 3. Scanning electron micrograph of granular salmeterol
xinafoate.
Figure 2. Scanning electron micrograph of crystalline salme-
terol xinafoate, exhibiting platelike habit.
Table 1. Typical physical properties of conventionally
crystallised and granular salmeterol xinafoate
quench solvent (14 volumes) an induction period before the
appearance of crystals of up to 4 min was observed after
complete mixing of the solutions. At the point at which
particles became visible in suspension the temperature was
below 20 °C, and the concentration was 4.25% w/v (solubil-
ity in 2-propanol is 0.17% w/v at 22 °C).
Bulk Physical Properties of “Granular” Salmeterol
Xinafoate. The bulk physical properties of granular salme-
terol xinafoate were dramatically different from typical
crystalline material. The data are summarised in Table 1.
Flow and handling were greatly improved, and micronisation
was efficient and reproducible from batch to batch. The size
of the spherical agglomerates was typically in the range 100-
250 µm and amounts of loose irregular crystals were
generally small. Residual solvent content was low (typically
about 0.1% w/w). A SEM of typical granular material
prepared by this method is shown in Figure 3.
conventionally
crystallized
physical property
granular
Bulk density (g‚ml-1)
a
0.16
40
82
26
1.9
0.30
9
b
Compressibility (%)
c
Cohesivity (%)
Mean particle size (µm)
1.34
156
9.6
d
Mean surface area (m ‚g-1)
e
2
a
Untapped.2,6 b Calculated from bulk density.2,6 c Determined by sieve analy-
sis. d Determined by laser diffraction analysis (Malvern Mastersizer). Deter-
mined by BET analysis.
e
of the size-reduction process. The measurement of bulk
2
,6
density and the calculation of the compressibility of the
drug substance gave values of >40%, consistent with other
7
poorly flowing materials. More detailed data on the flow
properties of salmeterol xinafoate are given in Table 1.
Crystallisation Procedures. To modify the crystallisation
process and produce a crystal habit with better flow proper-
ties, more aggressive crystallisation conditions were exam-
ined. A faster cooling regimen was investigated to produce
a high degree of supersaturation and rapid nucleation. This
was expected to produce smaller crystals, possibly with a
new crystal habit and with the potential to obviate the need
for micronisation.
The addition of salmeterol xinafoate in hot 2-propanol to
a chilled quench solvent induced crystallisation, but the
product was obtained as large spherical agglomerates of
microcrystals rather than as a microfine powder. A range of
solvents, temperatures, and addition methods was examined
to investigate the physical behaviour, yield, quality, and
throughput of the product. A delay in nucleation was
observed in this fast-cooling approach, even though the
solution was highly supersaturated, but once crystallisation
had begun the process was rapid. For example, using
Polymorphism of Salmeterol Xinafoate. Examination
of differential scanning calorimetry (DSC) scans of salme-
terol xinafoate (see Figure 4 for a typical example) showed
two major endothermic phase changes at about 125 and 139
°C, respectively. These events were assigned as the melting
8
points of two polymorphs in an enantiotropic system. The
higher melting form (form II) was produced by heating solid
samples of the lower melting form (form I) at about 100 °C
for prolonged periods. Comparison of X-ray powder dif-
fraction, infrared, and DSC data established clear differences
between the two polymorphs. The thermodynamic transition
temperature between the two forms was established by
infrared experiments to be about 80 °C. Nujol mulls
containing equal amounts of the two polymorphs were aged
at different temperatures, and the polymorphic ratio was
measured by infrared spectroscopy. A sample aged at 80 °C
for 20 h showed negligible change in polymorphic ratio,
whilst samples aged at 70 and 90 °C converted into forms I
8
and II, respectively.
2
-propanol as both dissolution solvent (9.5 volumes) and
Although form II has the higher melting point, it is
metastable with respect to form I at room temperature. Form
II is more soluble (e.g., 0.28% w/v in 2-propanol vs 0.17%
(
6) Carr, R. L. EValuating Flow Properties of Solids. Chem. Eng. News Jan,
1
965, 163.
(7) Brittain, H. G.; Bogdanowich, S. J.; Bugay, D. E.; DeVincentis, J.; Lewen,
G.; Newman, A. W. Pharm. Res. 1991, 8, 963.
(8) Reynolds, D. P.; Brush, P. W. Glaxo-Wellcome internal report.
Vol. 3, No. 5, 1999 / Organic Process Research & Development
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371

Figure 4. DSC profile of conventionally crystallised salmeterol xinafoate.
for form I at 22 °C) and crystallisation of salmeterol xinafoate
from a range of organic solvents and adding seeds of forms
I or II to the solution, always delivered form I. In all cases
the product crystallised at temperatures below 80 °C. The
fast-cooling crystallisation process described above gave, as
expected, exclusively form I of salmeterol xinafoate.
been recognised for some time in extraction procedures and
in chromatography, only recently has research demonstrated
the potential for SCF techniques in particle formation. A
supercritical fluid can be defined as a substance existing as
a single fluid phase above its critical temperature (T
c
) and
pressure (P ). At temperatures and pressures above the critical
c
conditions the single-phase domain defines the supercritical
region.
Crystallisation of Salmeterol Xinafoate using
Supercritical Carbon Dioxide
SCFs exhibit interesting physical and chemical properties
which can vary between liquidlike and gaslike characteristics.
Such features include large compressibility, high diffusivity,
lower surface tensions and viscosities than liquid solvents,
densities which can be varied between gaslike and liquidlike
values in a controlled manner by changing the temperature
and pressure conditions, and enhanced solvation power and
mass transfer rates compared with those of liquids. Carbon
dioxide, the most commonly used SCF (T ) 31.1 °C, P )
Introduction. Over recent years, increasing attention has
been directed to alternative approaches to particle formation
in an attempt to bypass and even eliminate the constraints
imposed by, as well as problems arising from, conventional
crystallisation and precipitation processes. The difficulties
of controlling final crystal/particle physical properties in
conventional processes, as well as the potential for batch-
to-batch variation, have to be overcome to minimise inef-
ficiency in downstream processing and potential product
malfunction. With increasing regulatory and environmental
demands on the preparation and specifications of pharma-
ceuticals and the desire for crystal engineering of materials
with preferred chemical and physical properties, new ap-
proaches which address these issues offer timely benefits.
This is especially the case for compounds delivered by
inhalation such as salmeterol xinafoate, where the direct
preparation of dry, 2-5 micrometer-sized particles for drug
delivery would avoid further size reduction operations
following particle generation and harvesting.
c
c
73.8 bar), provides the additional benefits of being relatively
inert, nonoxidising, and nondegrading, useful features when
handling sensitive compounds.
The processes which have previously been developed
where SCFs are used as a solvent or antisolvent in particle
formation are respectively termed rapid expansion of super-
critical fluid solutions (RESS) and gas antisolvent (GAS)
processes. In RESS the material of interest is packed into
an extraction vessel, and an SCF is passed through the vessel
under pressure. The SCF extracts (dissolves) some solid, and
the resultant supercritical solution is sprayed via a nozzle
into a particle formation vessel generally at ambient condi-
tions. The pressure reduction on spraying causes a rapid
A particularly attractive technique for particle formation
which has been considered for the past decade has been the
use of supercritical fluids (SCFs) both as solvents and
-
6
expansion (10 secs) causing high supersaturation, fast
nucleation, and the formation of fine particles. In the GAS
process, a solid, which is insoluble in the selected SCF, is
9
-12
antisolvents.
Whilst the benefits of this technology have
(9) Larsen, K.; King, M. Biotechnol. Progr., 1986, 2, 73.
(10) Supercritical Fluid Engineering Science; ACS Symposium Series 406;
American Chemical Society: Washington, DC, 1989, p 335.
(12) Yeo, S.-D.; Lim, G.-B.; Debendetti, P. G.; Bernstein, H. Biotechnol. Bioeng.
(11) Bleich, J.; Muller, B. W.; Wabmus, W. Int. J. Pharm. 1993, 97, 111.
1993, 41, 341.
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dissolved in a solvent which is miscible with the SCF. The
SCF is added to the solution, and as it dissolves in the
solvent, a rapid increase in volume occurs with a corre-
sponding drop in solvation power, an increase in supersatu-
ration, and the consequent nucleation of the solid. The
precipitated solid requires harvesting and isolation by
conventional filtration and drying. Modifications of the GAS
process, involving spraying the material or material:adjuvant
solution into a continuum of supercritical fluid, have also
been reported.
The GAS process requires the compound of interest to
be poorly soluble, or practically insoluble, in the SCF, which
is generally the case for pharmaceuticals with carbon dioxide.
RESS is restricted to the relatively few pharmaceutical
materials which are appreciably soluble in SCFs. However
for GAS recrystallisation, problems can occur with product
and solvent recovery when the system is depressurised and,
for both processes, the resultant size and morphology of
1
3
formed particles are not controlled or predictable.
Solution Enhanced Dispersion by Supercritical fluids
(SEDS). The SEDS process, developed in Pharmaceutical
Technology at Bradford University, builds on the benefits
of the RESS and GAS particle formation processes and
provides the major benefit of directed control over particle
properties such as particle size.14 A schematic diagram of
the SEDS equipment is illustrated in Figure 5.
In the SEDS process a solution of the material of interest
in an organic solvent and SCF carbon dioxide are fed into a
specially designed coaxial nozzle. The jet of drug solution
is broken by the high velocity jet of SCF carbon dioxide
and mixed with the SCF carbon dioxide, and the organic
solvent is immediately extracted and dissolved in the SCF
carbon dioxide. These mechanical, physical, and chemical
processes occur virtually instantaneously, leading to very
high supersaturation conditions and the rapid formation of
particles which are retained in the particle formation vessel.
The oven and back-pressure regulator control the selected
temperature and pressure of the experiment, respectively, in
the particle formation vessel. These factors, together with
the precise metering of the flow rates of the solution of
material and SCF carbon dioxide through the nozzle, provide
constant and uniform conditions and thereby control over
nucleation and particle generation.
The supercritical solution formed (i.e., SCF plus extracted
solvent) flows through the back-pressure regulator and
expands in a controlled manner so that the solvent and carbon
dioxide gas can be recovered and, if required, recirculated.
Advantages of Particle Formation by the SEDS Pro-
cess. Whilst the RESS and GAS processes offer benefits over
conventional precipitation and crystallisation methods, both
techniques are limited in achieving the goal of particle design
and crystal engineering due to the lack of control over the
size, size distribution, and morphology of the resulting
particles. In RESS, nozzle blockage is also frequently
encountered, whilst in GAS processes recrystallisation occurs
Figure 5. Schematic diagram of the solution enhanced disper-
sion by supercritical fluids (SEDS) process.
in bulk solution either by rapid (<1 min) or slow (>20 min)
introduction of SCF. In the former conditions, fine particles
9
10
are produced, while in the latter large particles are formed
with similar features to those associated with conventional
crystallisation from solution.
In SEDS, these aspects are avoided as the SCF is
introduced in a way which not only dissolves and extracts
the solvent rapidly, but also controls the dispersion of the
solution. By modification of the carefully controlled working
conditions it is possible to manipulate the characteristics of
the particles, including particles in the micrometer-sized
range.
It is also clear that in achieving this level of control of
the variables at the point of nucleation, a high level of
consistency and reproducibility is possible between batches.
Powders prepared by this process will also be (virtually) free
of retained solvent due to solvent transformation to the
supercritical state and removal in the SCF stream. These
features are coupled with the direct production of dry,
uncharged materials directly from a solution stream. Regula-
tory and environmental issues are addressed as the system
is a clean and closed process, avoiding atmospheric release
of impurities, solvents, and particulates and in-process
contamination. In addition, given the range of advantageous
properties provided by SCFs, it is likely that by probing the
supercritical domain, operating conditions which achieve
(
(
13) Bleich, J.; Kleinbudde, P.; Muller, B. W. Int. J. Pharm. 1994, 106, 77.
14) York, P.; Hanna, M. Respiratory Drug DeliVery V; Interpharm Press:
Illinois, 1996, 231.
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373

Figure 8. Effects of pressure and solution flow rate on particle
size of SEDS prepared salmeterol xinafoate, at 35 °C.
Figure 6. XRPD pattern of SEDS prepared salmeterol xin-
afoate at 60 °C and 350 bar.
Table 2. Particle size distribution data for two samples of
a
salmeterol xinafoate prepared by the SEDS process
mean spherical
diameter (µm)
% <5 µm
% <10 µm
sample 1
sample 2
7.2
7.7
31.6
28.3
67.8
64.5
a
Determined by laser diffraction analysis (Malvern Mastersizer). Working
conditions: 35 °C; 300 bar.
Figure 9. Scanning electron micrograph of SEDS prepared
salmeterol xinafoate from ethanol solution at 60 °C and 300
bar.
by HPLC, DSC, X-ray powder diffraction (XRPD), and
particle size analysis.
All salmeterol xinafoate products recovered from the
particle formation vessel were dry, uncharged, and easy
flowing. Samples were of high chemical purity and crystal-
linity when examined by HPLC and XRPD (see Figure 6),
respectively.
Control of Particle Size. Consistency of particle size and
particle size distribution in the 1-10 µm range between
batches prepared under the same working conditions is
impressive (see Table 2). Manipulation of the working
conditions provided controlled change in mean particle size
(see Figures 7 and 8). Clearly within the range of working
conditions employed in this study, it is possible to control
the mean particle size between 3 and 17 µm, with all of the
samples exhibiting a narrow particle-size distribution. As
expected, increased pressure and/or reduced solution flow
rate led to smaller mean particle sizes.
It is interesting to note that particle morphology was
modified by changing the solvent used to prepare the
salmeterol xinafoate solution. When prepared from ethanol
solutions, salmeterol xinafoate particles exhibited a thin,
bladelike habit (see Figure 9), whilst those from acetone
showed accretion forms (Figure 10).
Figure 7. Effects of pressure and temperature on particle size
of SEDS prepared salmeterol xinafoate, at constant solution and
SCF CO flow rates.
2
purity enhancement and even polymorphic separation may
be located.
In view of these factors, and in particular the opportunity
to obtain 2-5 micrometer-sized particles directly, the single-
step SEDS process is an alternative for the preparation of
salmeterol xinafoate particles for drug delivery by the
respiratory route.
Characterisation of Salmeterol Xinafoate Products
Prepared by the SEDS Process. Solutions of salmeterol
xinafoate, in ethanol and acetone, were introduced into the
SEDS apparatus under a range of working conditions (i.e.,
temperature, pressure, drug solution concentration, and
solution and supercritical carbon dioxide flow rates). The
particulate products were examined for residual solvent and
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Table 3. Residual solvent content in SEDS prepared
salmeterol xinafoatesamplesa
pressure
(bar)
temperature
residual solvent
(ppm)
sample
(°C)
Samples Prepared from Acetone Solutions
b
b
b
1
2
3
300
300
200
45
45
60
8
9
5
Samples Prepared from Ethanol Solutions
1
2
3
100
200
300
50
60
60
NDc
ND
ND
a
Typical solvent content in granular salmeterol xinafoate (methanol/2-
propanol) about 1000 ppm. Acetone content. c ND ) ethanol not detected.
b
Figure 10. Scanning electron micrograph of SEDS prepared
salmeterol xinafoate from acetone solution at 50 °C and 200
bar.
Figure 12. SEDS prepared salmeterol xinafoate form II: (a)
DSC profile; (b) XRPD pattern.
(expanded) profiles for samples obtained from different
regions of the supercritical domain, both prepared from an
acetone solution of salmeterol xinafoate. Identified pressure
and temperature conditions for form I preparation with
acetone as the drug solvent were 100-250 bar and 35-60
°C and above 250 bar and 70-100 °C for form II. Figure
11 shows characteristics of salmeterol xinafoate form I and
Figure 12 for form II. Interestingly, no interconversion
between the two forms is seen on the DSC trace for form I
(Figure 11a) which suggests a high purity sample of
polymorph I. Also no conversion of form I into form II was
seen when operating the DSC at heating rates up to 50
Figure 11. SEDS prepared salmeterol xinafoate form I: (a)
DSC profile; (b) XRPD pattern.
Control of Polymorphs. As discussed above, two poly-
morphic forms (I and II) of salmeterol xinafoate have been
identified, with melting points of about 125 and 139 °C,
respectively. Because of the potential for controlling the
particle formation process using SEDS, it was of interest to
carry out a study to explore different regions of the
supercritical domain which might provide “pure” polymorphs
I and II. Figures 11 and 12 show combined DSC and XRPD
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375

-
1
°
C‚min . Thus, the SEDS process appears to offer a means
crystallisation control have been successfully employed.
Given the poor flow and microniser mill feeding character-
istics of conventionally crystallised drug, a fast-cooling
crystallisation from a selected optimal solvent system was
developed to provide a granular form of salmeterol xinafoate.
This spherical, crystalline agglomerated form exhibited good
flow properties from which a milling process providing 2-5
µm-sized particles was possible.
An alternative and novel process, relying on using SCF
technologies and the SEDS process with SCF carbon dioxide
as an antisolvent, was studied. This process was able to
provide, directly without an extra milling operation, microfine
crystalline 2-5 µm-sized particles of salmeterol xinafoate
which were virtually free from retained solvent and easy
flowing. Of particular interest for preparing the polymorphic
forms of salmeterol xinafoate the SEDS process, unlike
conventional or modified conventional crystallisation pro-
cedures, was able to produce pure forms of the two
polymorphs, forms I and II and controlled mean particle sizes
between 2 and 17 µm by varying the working conditions.
for the production of pure polymorphic forms I and II of
salmeterol xinafoate. The absence of interconversion by DSC
and stability of the samples on storage is attributed to the
high degree of chemical and crystallographic purity achieved
using SEDS.
Solvent Removal. SEDS products of salmeterol xinafoate
prepared from acetone and ethanol solutions were examined
for residual solvent by a gas chromatographic method. Table
3
lists the results and data demonstrate the virtual absence
of acetone and nondetectable levels of ethanol in examined
samples. This factor provides considerable benefit over
conventionally crystallised material where retained solvent
levels were typically in the range of 500 to 1000 ppm. The
extremely low levels or absence of retained solvent in SEDS
prepared products is generally found and is thought to be a
contributing factor in the observed enhanced stability of such
materials with high chemical and crystallographic purity.
General Comments
The formulation requirement of microfine 2-5 µm
particles of salmeterol xinafoate for respiratory drug delivery
has presented opportunities for direct control of the physical
form of prepared particles. Two different approaches to
Received for review December 21, 1998.
OP990160Z
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