Download production of crystalline powders for inhalation drug delivery

PRODUCTION OF CRYSTALLINE POWDERS FOR
INHALATION DRUG DELIVERY USING
SUPERCRITICAL FLUID TECHNOLOGY
B. Y. Shekunov *a, M. Rehman b, A. H. L. Chow c, H. H. Y. Tong c and P. York a,b
a
Drug Delivery Group, School of Pharmacy, University of Bradford, BD7 1DP, UK
Bradford Particle Design Ltd, 69 Listerhills Science Park, Bradford, BD7 1HR, UK
c
Department of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., China
b
*Corresponding author: Ferro Corporation, Pharmaceutical Technologies, 7500 E. Pleasant
Valley Road, OH 44131; E-mail: [email protected], Fax: +44 1 216 750-6953
The present study involves typical asthmatic drugs such as salmeterol xinafoate,
terbutaline sulphate and fenoterol hydrobromide and represents an approach by which the
direct preparation of powders for respiratory formulations using crystallization in supercritical
CO2 is optimised on the basis of product material properties. Comparative analysis between
micronised and supercritically-produced powders was carried out to define the surface and
aerodynamic particle characteristics responsible for performance of these compounds in
aerosol tests. Particle size measurements were carried out using laser diffraction and time-offlight measurements, powder surface energetics was determined using inverse gas
chromatography (IGC) and analysis of fine particle fraction was performed using a cascade
impactor technique. It is shown that reduced surface energy of supercritically-produced
particles, related to their low adhesion, plays an important role in the superior performance of
these particles in the dry-powder formulation.
1. INTRODUCTION
The manufacturing of particles with suitable properties for formulation into dry powder
inhalers (DPI) continues to present a major challenge to pharmaceutical technology. Drugs
are rarely crystallised directly to meet the criterion of particle size (1-5 µm) to reach the
respiratory airways, therefore additional processing steps usually include re-crystallization,
filtering, drying, micronisation or high-energy milling and may also involve granulation
before the micronisation and solid-state or surface conditioning after the micronisation stage.
This processing sequence only provides limited opportunity for control over particle
characteristics such as size, shape and morphology and introduces uncontrolled structural
variations (decreased crystallinity, polymorphism) and surface modifications (increased
surface free energy, adhesion, cohesiveness and charge) which have an adverse effect on drypowder formulation and may even render the formulation ineffective.
An alternative is to use supercritical fluid (SCF) processing which enables formation of
micron sized particulate products in a single step operation, with a significant benefit of
selective crystallization, separation of impurities and control of crystalline forms, leading to a
potentially clean and recyclable technology [1]. The benefits of SCF-processed particles in
both dry-powder (DPI) and multi-dose (MDI) inhaler formulations have been demonstrated
for particles of several steroid drugs [2,3]. An increase of fine particle fraction (FPF) for
steroid formulations prepared with lecithin was observed. The SEDS method (Solution
Enhanced Dispersion By Supercritical Fluids) [4] has an added advantage of very fast,
homogeneous nozzle mixing between supercritical antisolvent and drug solution leading to
consistent production of micron-sized particulate products [5]. The present work represents a
comparative study of the micronised and supercritically-processed powders of salmeterol
xinafoate (SX), terbutaline sulphate (TBS) and fenoterol hydrobromide (FHBr), in which the
processing conditions for production of respirable particles of these drugs are directed on the
basis of analysis of particle size distribution, combined with surface analysis by an inverse
gas chromatography (IGC) and powder deposition in a cascade impactor.
2. EXPERIMENTAL METHOD
2.1. SCF CRYSTALLIZATION PROCESS
The SEDS method was employed to prepare the drug powders. This technique [4] is based
on mixing between supercritical CO2 antisolvent and a drug solution using a twin-fluid
nozzle. The particle formation vessel of 0.5 L volume was used in all cases. Several solvents
including methanol, ethanol, acetone and tetrahydrofurane were tested in this work, after
which methanol (for SX and FHBr) and ethanol (for TBS) were selected for further studies
because of the high yield (>95%) and suitable particle size distribution (PSD) (x99 < 10 µm) of
the products. Typical flow rate of CO2 was 5 kg/hour. Process optimisation was achieved by
controlling the solution flow rate and solution concentration as described in the Results.
Pressure and temperature were selected to produce the most stable crystalline (polymorphic
and solvate) forms of these materials.
2.2. ANALYTICAL STUDIES
PSD measurements were performed using firstly, AeroSizer time-of-flight instrument
equipped with AeroDisperser (TSI Inc., Minneapolis, USA) and secondly, laser diffraction
sensor HELOS with dry-powder air-dispersion system RODOS (Sympatec GmbH, Germany).
The volume mean particle diameter, VMD, was obtained for both instruments using software
options. In the general case of non-spherical particles, these instruments cannot provide the
exact value of VMD, however, the time-of-flight technique gives an aerodynamic-equivalent
particle diameter, whereas the laser diffraction method provides the geometric projectionequivalent diameter. These diameters afford the complementary information on PSD and
therefore can be used for comparative size analysis.
For SX powders, IGC was performed using a Hewlett Packard Series 5890 Gas
Chromatograph equipped with an integrator and flame ionization detector. For TBS and FHBr
powders, IGC was done using a Hewlett Packard Series 6890 instrument which was
specifically modified for IGC measurements by Surface Measurement Systems Ltd
(Manchester, UK). The IGC method is described in details elsewhere [6]. The principle
involves analysis of interaction between polar or non-polar vaporised solvents with the
surface of powder under investigation. Triplicate measurements in separate packed columns
were made. Differences in surface energetics were reflected in the calculated dispersive
component of the surface free energy, γsD; specific component of surface free energies of
adsorption, ∆GA; the acid-base parameters, KA and KD. and the total (Hildebrand) solubility
parameter, δ, which reflects the adhesion work between particles. In this paper, the γsD and
∆GA values obtained at temperature 303K are reported.
Finally, the deposition behaviour of micronised and supercritically-produced powders were
evaluated using an Andersen-type cascade impactor (Copley Scientific Limited, Nottingham,
UK). This device is designed to imitate particle deposition in the lungs; the control criterion is
that the high fine particle fraction (FPF) of a respirable drug to be delivered to the defined
stages (from 1 to 5) of the cascade impactor. The drugs were blended with inhalation grade,
DMV Pharmatose 325M α-lactose monohydrate, with 3.8% w/w of drug typical for such
formulation. The airflow through the apparatus, measured at the inlet to the throat, was
adjusted to produce a pressure drop of 4 kPa over the inhaler under test (Clickhaler)
according to compendial guidelines, consistent with the flow rate 49 L/min.
3. RESULTS AND DISCUSION
3.1. OPTIMISATION OF THE PARTICLE SIZE DISTRIBUTION
Prior to crystallization experiments, an on-line dynamic solubility method [7] was used to
determine the equilibrium solubility, c0, of SX and FHBr in methanol/CO2 and TBS in
ethanol/CO2 mixtures at different mole fractions of the solvents. On this basis, the solution
flow rate was optimised to achieve maximum supersaturation in the flow.
supersaturation, σ
6
5
4
3
0
0.02
0.04
0.06
0.08
solvent mole fraction, x
Fig. 1. Dependency of supersaturation of SX on the relative methanol - CO2 flow rate,
expressed in methanol mole fraction, at T=313K, P=200 bar. Concentration is 3% w/v.
For very low concentrations of the non-volatile solutes in the anti-solvent crystallization,
supersaturation during the initial precipitation stage is characterised by the maximum
attainable supersaturation, σ. This corresponds to the ideal case of CO2/solvent/solute fresh
feed being completely mixed on a molecular level and is calculated as [8]:
σ = ln
cA f A
c0 ( f A + f )
(1)
where fA and f are the flow rates (mol/s) of the solution and CO2 respectively, and cA is the
molar concentration of a drug in the feed solution. An example shown in Fig. 1 represents the
level of supersaturation σ calculated as a function of relative rate of methanol to CO2 flow.
volume mean diameter, VMD
This dependence has a maximum at about fA/f ≈ 0.025 and reflects a competition between the
antisolvent and diluting effects of CO2. This maximum corresponds to the minimum particle
size, in terms of VMD, as shown in Fig.2. From eq.(1) is to be expected that the
supersaturation should progressively increase with the increase of solution concentration, cA,
and also result in a continuously decreasing particle size with increasing cA, as expected from
the theory of homogeneous nucleation and previous experimental data [5,8]. In Fig. 2, the
minimum VMD changes non-progressively: the minimum is achieved at an intermediate
solution concentration 3% w/v. This effect was studied and related to particle aggregation at
the large particle number concentration which corresponds to high supersaturation. Therefore,
for a given nozzle and vessel geometry, there is an optimal concentration of the feed solution
as well as an optimum solution feed rate.
6
5
4
2% w/v
3% w/v
5% w/v
3
0
0.02
0.04
0.06
solvent mole fraction, x
Fig. 2. Dependency of the volume mean diameter, VMD, of SX powders produced at different
solution concentrations as a function of the relative methanol - CO2 flow rate, expressed in
methanol mole fraction, at T=313K, P=200 bar.
3.2. COMPARISON OF PARTICULATE AND SURFACE PROPERTIES
Several batches of particulate material of respirable size, with cumulative PSD for all batches
x99 < 10 µm, were consistently prepared at the conditions optimised, with batch quantities
between 1 and 10 g. VMD of powders obtained using different techniques are shown in Table
1. These data indicate that, although both the aerodynamic (a) and geometric (b) diameters for
the micronised particles are smaller than the correspondent VMD for supercritically-produced
materials, the FPF deposited in the cascade impactor is significantly larger for the
supercritically-produced powders. Therefore the powder dispersion rather than the particle
size distribution defines the deposition profile of the drug particles in this aerosol test.
Dispersability of powders in the air flow is defined by the balance of forces generated by the
aerodynamic stresses and the inter-particulate forces. The theoretical tensile strength of the
particle aggregate, required to separate primary particles, is proportional to the work of
particle adhesion [9] and can be associated with the specific surface energy defined by the
IGC method. Table 2 represent the surface–energy related parameters which reflect the
interaction of the non-polar (γSD) and polar (-∆GA) nature.
Table 1. Summary of the volume mean diameters, VMD, obtained by (a) time-of-flight and (b)
laser diffraction measurements and the fine particle fraction, FPF, in the % emitted dose for
micronised (M)- and supercritically-produced (S)- materials.
Compound
(M)-SX
(S)-SX
(M)-TSB
(S)-TSB
(M)-FHBr
(S)-FHBr
VMD(a),
µm
1.2(0.1)
1.6 (0.1)
2.7 (0.2)
3.4(0.9)
1.7(0.2)
1.7 (0.1)
VMD(b),
µm
1.69(0.03)
3.56(0.03)
3.04(0.02)
3.43(0.1)
2.34(0.02)
3.55(0.02)
FPF, %
25.1
57.8
30.7
38.6
17.4
41.7
Table 2. The dispersive component of surface free energy, γSD and the free energies of
adsorption of polar probes, -∆GA; of micronised (M)- and supercritically-produced (S)materials. The standard deviations are shown in the brackets.
Substance
(M)-SX
(S)-SX
(M)-TSB
(S)-TSB
(M)-FHBr
(S)-FHBr
γ S D,
mJ/m2
40.49
(1.96)
34.55
(0.16)
58.61
(0.30)
55.05
(0.43)
48.53
(0.46)
49.87
(0.25)
−∆GA, kJ/mol
Diethyl
toluene
ether
14.20
(0.11)
12.65
(0.44)
3.42
(0.01)
2.85
(0.01)
4.77
(0.04)
3.86
(0.03)
acetone
15.24
(0.08)
14.4
(0.33)
12.57
(0.06)
10.42
(0.16)
*
ethyl
acetate
17.46
(0.06)
15.87
(0.42)
16.01
(0.05)
13.76
(0.07)
*
13.15
(0.25)
17.48
(0.19)
chloroform
14.78
(0.24)
14.03
(0.75)
1.79
(0.01)
1.21
(0.03)
0.69
(0.01)
0.63
(0.05)
dioxane
15.96
(0.23)
14.20
(0.13)
*
15.32
(0.10)
* - probe is retained in column
The reduced magnitude of γSD for the supercritically-produced powders implies that the
surfaces of these particles are less energetic for non-polar, dispersive surface interactions than
the micronised materials. The largest changes are however observed for the polar interactions
(∆GASP) which are significantly smaller, by a factor of 1.5 on average, for the supercriticallyproduced powders. In general, the enhanced powder dispersion always correlated well with
the reduced surface energy of these materials.
4. CONCLUSIONS
By changing the working conditions of pressure, temperature, solution concentration and flow
rates, it is possible to control the size, morphology and crystal form of the micron-sized
particles, therefore supercritical fluid crystallization provides an attractive alternative for the
direct production of powders for dry powder respiratory formulations. The main factor
responsible for superior performance of supercritically-processed materials in the cascade
impactor tests is the improved deaggregation of these powders. The IGC method serves as a
reliable technique for assessing particle interactions and adhesion.
5. ACNOWLEDGEMENTS
SX, TBS and FHBr substances in the form of starting and micronised materials were
generously supplied by GlaxoSmithKline, AstraZeneca and Boehringer Ingelheim
correspondingly. The authors would like to thank Talbir Austin (AstraZeneca) for her help
with IGC analysis and Jane Feeley for cascade impactor measurements of SX powders. We
gratefully acknowledge the financial support of AstraZeneca and the Engineering and
Physical Sciences Research Council (UK) in the form of PhD studentship for Mahboob
Rehman.
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