Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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. 6. REFERENCES [1] SHEKUNOV, B. Y. AND YORK, P. J. Crystal Growth Vol. 211, 2000, p. 122. [2] STECKEL, H., THIES, J. AND MÜLLER, B. W. Int. J. Pharm. Vol. 152, 1997, p. 99. [3] STECKEL, H. AND MÜLLER, B. W. Int. J. Pharm. Vol.173, 1998, p.25. [4] YORK, P. AND HANNA, M. Proceedings of the Conference on Respiratory Drug Delivery, Phoenix, Arizona, Vol. V, 1996, p. 231. [5] SHEKUNOV, B. Y., BALDYGA, J AND YORK, P. Chem. Eng. Sci. Vol. 56, 2001, p. 2421. [6] TONG H. H. Y., SHEKUNOV, B. Y. YORK, P., CHOW, A. H. L. Pharm. Res. Vol. 18, 2001, p. 852. [7] BRISTOW, S., SHEKUNOV, B. Y. AND YORK, P. Ind. Eng. Chem. Res. Vol 40, 2001, p. 1732. [8] BRISTOW, S., SHEKUNOV, T., SHEKUNOV, B. Y. AND YORK, P. J. Supercritical Fluids Vol. 21, 2001, p. 257. [9] KENDALL K. AND STAINTON, K. Powder Technology Vol.121, 2001, p. 223.