Micronization of Anti-Inflammatory Drugs for Pulmonary Delivery by a Controlled Crystallization Process

Micronization of Anti-Inflammatory Drugs for Pulmonary Delivery by a Controlled Crystallization Process ¨ LLER NORBERT RASENACK, HARTWIG STECKEL, BERND W. MU Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany

Received 1 May 2002; revised 21 June 2002; accepted 18 July 2002

ABSTRACT: Jet-milling as the common way for micronization of drugs shows several disadvantages. Drug powder properties are decisive for pulmonary use because, besides a small particle size, a good deagglomeration behavior is required. In this study, several anti-inflammatory drugs [beclomethasone-17,21-dipropionate (BDP), betamethasone17-valerate (BV), triamcinolone acetonide, ECU-R2, budesonide, and prednisolone] were micronized by controlled crystallization without any milling processes. First the drug is dissolved in an organic solvent (BDP/BV: 4%; ECU-R2: 1% in acetone) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as stabilizing hydrocolloid. By rapid pouring the solution of hydroxypropylmethylcellulose in water (BDP/BV: 0.005%; ECU-R2: 0.025%) into the drug solution under stirring in a relationship (v/v) of 1:16 (BDP/BV), 1:4 (ECU-R2), the previously molecularly dispersed drug was associated to small particles and stabilized against crystal growth simultaneously. This dispersion was spray-dried, resulting in a drug powder with a uniform particle-size distribution and a drug load of up to 98% (BDP, BV). The mean particle size of the drug was lower than 5 mm in most cases and consequently in the respirable range. Whereas the fine particle fraction (<5 mm, measured without excipients and without an inhalation device) of jet-milled drugs is 9.5 (BDP) or 13.1 (ECU-R2), fine particle fractions of 25.6% (BDP) resp. 78.2% (ECU-R2) are obtained with the spray-dried powders. As the formation of the small crystals requires a rapid solvent change process, the affinity of the hydrocolloid, and a high difference between the solubility in the solvent and nonsolvent, the drug’s partition coefficient limits the method as drugs which are more hydrophilic form larger particles. ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:35–44, 2003

Keywords: micronization; anti-inflammatory drug; pulmonary drug delivery; dry powder inhaler; controlled crystallization

INTRODUCTION Pulmonary drug delivery has an important role in the treatment of pulmonary diseases. Because of several advantages—such as avoidance of the first-pass effect or degradation in the gastroin-

Correspondence to: Bernd W. Mu¨ller (Telephone: 431-8801333; Fax: 431-880-1352; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 92, 35–44 (2003) ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

testinal tract, a high and well blood-supplied surface area—pulmonary dosage forms are also suitable for systemic drug delivery. Most commonly, metered-dose inhalers or dry powder inhalers (DPIs) are used for drug application. The efficiency of pulmonary drug delivery is still a problem because, in some cases, only approximately 10% of the inhaled drug powder reaches the alveoli.1 The performance of a DPI is influenced by both the device and the powder formulation. Because of high particulate cohesion forces of micronized powders,2 they require a rapid inspiratory flow generated by the patient. The

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powder flow affects the dispensation from the bulk reservoir.3 Consequently, an effort needs to be made to optimize the properties of the drug powder. For pulmonary drug delivery, the drug powder should have a tight particle-size distribution and a mean particle size of 5 mm with nearly no particles larger than 10 mm. However, besides the size of the single particles, the agglomeration behavior of the powder is important. For a good DPI formulation, drug particles with low agglomeration tendency, sufficient flow properties, and good batch-to-batch conformity are required.4 The common way to reduce the particle size into the respirable range is micronization by jet-milling or milling in pearl-ball mills. Air-jet-milling as the traditional method provides only limited opportunity for the control of important product characteristics such as size, shape, morphology, surface properties, and electrostatic charge.5 The micronization process using mills is described as extremely inefficient6 because of the high energy input which decreases crystallinity7 and which can affect chemical degradation.8,9 As a thermodynamically activated surface10,11 is created, the surface properties and thus the drug substance properties are altered. The conversion of crystalline solid surfaces into partially amorphous solid surfaces leads to a ‘‘dynamic nature’’ of the micronized drug.12 Thus, disordered structures in the material influence the performance in formulations13,14 and processing properties such as the powder flow, because micronized powders with a higher energetic surface show poorer flow properties.15,16 Not only the surface properties but even the particle size can change during storage after micronization because of stress-relaxation processes.17 Besides the creation of a thermodynamically activated surface that can recrystallize uncontrolled, there exist further problems concerning the newly created surfaces. These are not naturally grown as the crystal cleaves at the crystal face with the smallest attachment energy.18 Therefore, this surface will dominate the milled particles and the micronized powder is characterized by their surface properties. Besides these problematic properties, a further disadvantage, especially of jet-milling processes, is a broad size distribution.19 Because these milling techniques show several disadvantages, new techniques that produce the drug directly in the required small particle size are the focus of interest. Micronized spherical particles can be prepared by spray-drying a solution of the drug. Spray-dried drugs, which are amorJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 1, JANUARY 2003

phous, show a smaller and more homogeneous particle size and a higher respirable fraction than mechanically micronized drugs.20,21 However, this technique is rarely used for water-insoluble drugs because organic liquids are required which necessitate high machine expenditure and causes environmental problems. Micronized drugs can also be prepared using supercritical carbon dioxide.22,23 Steroids for pulmonary delivery can be micronized by the ASES process,24,25 in which a drug that is insoluble in supercritical carbon dioxide is precipitated out of an organic solution that is sprayed into the supercritical fluid. The organic solvent can be regained. A disadvantage of this technique is the high machine expenditure. An example of nano-sized drugs for intravenous application are the so-called hydrosols26 which are colloidal suspensions containing amorphous drug nanoparticles of poorly water-soluble drugs prepared by a precipitation process in the presence of stabilizing agents such as poloxamer and modified gelatins. Because of the high surface that needs to be created, the established methods need high amounts of stabilizing excipients leading to amorphous products. The aim of this study was to prepare micro-sized drug particles of different anti-inflammatory drugs without any size reduction techniques. Different steroids [mainly steroids important for pulmonary use such as beclomethasone-17,21dipropionate (BDP), budesonide, triamcinolone acetonide (TCA)] and a new anti-inflammatory drug for pulmonary use (ECU-R2) were used as drug examples. All drugs are soluble in organic solvents and poorly water-soluble. Micro-sized drug particles were prepared by a solvent change process that precipitates and stabilizes the drug in small particle size by the use of hydroxypropylmethylcellulose (HPMC). Because HPMC shows surface activity,27 it can be adsorbed onto the newly created surface of the precipitated drug to lower the interfacial tension. Especially cellulose ethers containing methoxyl or hydroxypropyl groups are adsorbed onto hydrophobic solid surfaces as described for hydrophobic silicon dioxide.28 So the precipitated drug is sterically stabilized29 against crystal growth by adsorbed polymer. Accordingly, the molecularly dispersed drug is associated to particles in the required size and simultaneously stabilized in the formed dispersion by HPMC. After drying this dispersion, a drug powder with a high drug load is obtained. The preparation method is easy to handle and needs only common equipment.

MICRONIZATION OF ANTI-INFLAMMATORY DRUGS

MATERIALS AND METHODS

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would occur when pure water or other additives are used. In the first step, the drug was dissolved in an organic solvent that is miscible with water (acetone; in the case of prednisolone ethanol). The chosen concentration depends on the solubility of the drug. A solution of HPMC in water was used as nonsolvent. Concentrations used and the relation of solvent to nonsolvent were previously determined preparing different dispersions (data not shown). By batch-wise mixing the two liquids, a dispersion is formed (experimental data, see Table 1). The nonsolvent was poured rapidly (200 mL/30 s) from a beaker into the drug solution under stirring using a magnetic stirrer. After the precipitation process, the drug concentration in the resulting dispersion was (nearly) the same in all cases. After spray-drying the prepared dispersion under standardized conditions (Bu¨chi 190 Mini Spray-Dryer; Bu¨chi Labortechnik AG, Flawil, Switzerland) (temperatureinlet: 1288C; temperatureoutlet: 558C; air flow 600 Nl/h; 0.5-mm nozzle; aspirator stream 40 m3/h), a micro-sized drug powder was obtained. In this study, the spray-drying process was not used to form particles as if solutions are spray-dried, but only to dry previously formed particles. As in the case of prednisolone, no stable dispersion but large crystals were precipitated, this drug was not dried. In the case of BDP, a further experiment with a lower drug load and a more rapid precipitation (2500 mL/ min) was performed (solution of the drug: 4.0 g/ 100 mL acetone; 0.02% HPMC solution; resulting product: 92.59% drug load).

Materials The drugs BDP (Sicor, Milan, Italy), betamethasone-17-valerate (BV), TCA (both Diosynth, Oss, Netherlands), ECU-R2 (a poorly water-soluble low molecular peptidomimetic enzyme inhibitor for pulmonary application belonging to the chemical class of glyoxylic acid amides with antiinflammatory properties which is in a clinical state of development; Pharmatech, Flintbek, Germany), budesonide (Polfa, Poznan, Poland), and prednisolone (Merck KG, Darmstadt, Germany) were supplied jet-milled and used as received in this study for comparison. Acetone and ethanol (both from Merck KG) were of analytical grade. Water was used in double-distilled quality. The stabilizing agent used was HPMC (type 2910, USP; Metolose1 60 SH 50; Shin Etsu, Tokyo, Japan). Crystallization Procedure Controlled crystallization was performed using the solvent change method by instantaneously mixing two liquids in the presence of HPMC as stabilizing agent as described by Rasenack and Mu¨ller.30 The process was performed at room temperature. HPMC was chosen as the stabilizing agent in this study because it has shown to be the best prevention of particle growth in a screening of many stabilizers (such as gelatine, different cellulose ethers, alginate, dextran, pectin, agar, PVA, PVP, HES) (Rasenack and Mu¨ller31). Further, a minimum necessary amount of stabilizer could be detected (Rasenack and Mu¨ller31). Below this concentration, particle growth occurs. However, the use of a higher amount of HPMC does not result in smaller particles. HPMC controls the crystallization process because it prevents a crystal growth that

Particle Characterization Scanning Electron Microscopy (SEM) Scanning electron micrographs were taken using a Philips XL 20 (Philips, Eindhoven, Nether-

Table 1. Experimental Data of the Crystallization Process

Drug BDP BV TCA Budesonide Prednisolone ECU-R2

Drug Solution (g/100 mL)

HPMC Solution (g/100 mL)

Relation (v/v) Solvent/Nonsolvent

Drug Load in Product (%)

4.0 4.0 1.3 1.3 3.0 1.0

0.005 0.005 0.030 0.030 0.100 0.025

1:16 1:16 1:6 1:6 1:12 1:4

98.04 98.04 87.84 87.84 Not dried 90.91

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lands). Samples were fixed on an aluminum stub with conductive double-sided adhesive tape (LeitTabs; Plano GmbH, Wetzlar, Germany) and coated with gold in an argon atmosphere (50 Pa) at 50 mA for 50 s (Sputter Coater; Bal-Tec AG, Liechtenstein). X-Ray Diffractometry Powder X-ray diffraction patterns were collected in transmission using an X-ray diffractometer with a rotating anode (Stoe and Cie GmbH, Darmstadt, Germany) with Cu Ka radiation (monochromator: graphite) generated at 200 mA and 40 kV. Powder was packed into the rotating sample holder between two films (PETP). Particle Size The volume particle-size distribution was measured using a laser diffractometer (Helos; Sympatec GmbH, Clausthal Zellerfeld, Germany). The dispersions were diluted with water and measured in a cuvette. As a second determination method, microcrystals were measured in dry powder form after dispersing in air using compressed air (Helos Rodos). Particle-size distribution is characterized by the X10 (10% below this size), the X50, and the X90 value. Aerodynamic Particle-Size Analysis The aerodynamic particle size was evaluated using a multi-stage liquid impinger (MLI) (Erweka, Heusenstamm, Germany). The pure drug (2 mg) was delivered to the impinger by using a deviceless application system. The powder was put on an applicator (Fig. 1) and then fed into the air stream. The flow rate was adjusted to a pressure drop of 4 kPa as typical for the inspiration by a patient32 resulting in a flow of 82 L/min. No inhaler and no excipients were used because the pure powder characteristics were to be analyzed. The drug deposition in the throat, the

Table 2.

Figure 1. Application system for deviceless drug application into the MLI. The powder is dispersed into the airstream by rotating the fill cavity from the ‘‘fill’’ to the ‘‘feed’’ position.

four stages, and the filter (stage 5) were determined by high-pressure liquid chromatography (HPLC) analysis. All samples were analyzed in triplicate. HPLC The HPLC system consisted of a Gynkotek High Precision Pump Model 300 (Gynkotek, Munich, Germany), a Kontron HPLC Autosampler 360, a Kontron HPLC Detector 430 (Kontron Instruments, Milano, Italy) and LiChrospher 100 RP18 columns (5 mm, 125 mm; Merck KG). Peak integration was performed using a computercontrolled software (Data System 450; Kontron Instruments). Samples of 100 mL were injected. For the mobile phase, acetonitrile/water-mixtures were used (Table 2). Acetonitrile and glacial acid (both Merck KG) were of HPLC quality; water was used in double-distilled quality. The amount of drug was calculated using an external standard.

RESULTS AND DISCUSSION Micronizing drugs using the new controlled crystallization process without any milling processes leads to a product with a homogeneous and

Experimental Settings of the HPLC

Mobile Phase ECU-R2 BDP TCA Budesonide

Acetonitrile/water (48:52) Acetonitrile/water (60:40) Acetonitrile/water/glacial acid (43:56.8:0.2) Acetonitrile/water (45:55)

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Flow (mL/min)

Detector Wavelength (nm)

1.0 1.2 1.0

267 237 241

1.2

254

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tight particle-size distribution. When a hydrophobic substance is precipitated in an aqueous environment, the energy of the system increases because of the formation of a hydrophobic surface. Thus, a stabilizing agent, provided that it has at least some affinity to the surface, covers the newly formed surface spontaneously. Thereby, the surface energy and consequently the enthalpy of the system is lowered. The small particles, which normally would aggregate because of their hydrophobic surface in order to lower the surface energy, are stabilized sterically against crystal growth by a layer of protective polymer.29

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Figure 3. SEM photograph of jet-milled BV.

Characterizing the Precipitated Dispersion Immediately after precipitation, a homogeneous dispersion with a mean particle size of about 1 mm is formed in both cases, when using pure water or HPMC solution. When precipitating the drug with a solution containing HPMC as stabilizing agent, this dispersion is stable during storage because no significant crystal growth occurs (Fig. 2). However, when the crystallization process is performed with pure water, 60 min after precipitation, large crystals are formed (Fig. 2). This shows the effect of HPMC to stabilize the small particles formed by the rapid crystallization. Similar results were obtained for all other drugs. Characterizing the Spray-Dried Drug Powders SEM Jet-milled drugs consist of fine and broad particles with irregular particle shapes as exemplarily

Figure 2. Volume particle-size distributions of ECUR2 in dispersion (60 min and 24 h after precipitation with HPMC solution; 60 min after precipitation with pure water).

shown for BV (Fig. 3). In contrast, the controlled crystallized drug powders show uniform particle shapes and sizes (Fig. 4a,b,d) for each drug. Different crystal habits can be observed, as the controlled crystallized drugs show the crystal habit that is formed naturally under the crystallization conditions. ECU-R2 is needle-plateshaped, BDP is needle-shaped, and BV is spherical-shaped. All drug powders are crystalline as powder X-ray diffraction showed. Amorphous BDP that is obtained if a higher amount of HPMC is used and if precipitation is performed more rapidly consists of spherical particles, which are droplet-like (Fig. 4c). X-Ray Diffractometry An important property of the drug is its stability during storage and use. Because of the thermodynamic instability of amorphous drugs, crystalline solids are preferable. The preparation method used in this study results in crystalline drug powders. The jet-milled drug and the drug obtained by the controlled crystallization process are isomorphic. Because the drug powder contains amorphous HPMC, an amorphous content can be observed in the X-ray patterns of the controlled crystallized drug. However, amorphous drugs can also be prepared using this technique. When a higher amount of stabilizer is used and the precipitation is performed more quickly, an amorphous drug is obtained as shown for BDP. If stored under stress conditions (408C/75% RH), the drug recrystallizes during 3 months. However, the aim of this study was to develop a method for the production of microcrystals by JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 1, JANUARY 2003

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Figure 4. SEM photographs of the controlled crystallized drugs: (a) ECU-R2; (b) BDP; (c) BDP, amorphous; and (d) BV.

association and controlled crystallization avoiding any milling techniques. Particle Size The particle-size distribution measured in compressed air (Table 3) is tighter for controlled crystallized ECU-R2 (Fig. 5) and BV than for the jet-milled drugs. In the case of controlled crystallized BDP, the particle-size distribution seems to be broad. However, this is attributable to the needle-shaped crystal habit (Fig. 4b). Because the used precipitation technique requires a hydrophobic drug with poor water-solubility, more hydrophilic substances are not stabilized well. In the case of TCA, some coarse particles crystallize. However, compared with the jet-milled drug, this powder is preferable, because the jet-milled drug is more agglomerated and shows much larger particles. Especially budesonide, which has a lower partition coefficient, shows a particle growth; 20% of the crystals are larger than 10 mm as confirmed by particle-size measurement and by SEM (not shown). With prednisolone, a more hydrophilic steroid, no stable dispersions are obtainable. Immediately after precipitating JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 1, JANUARY 2003

the drug, a sediment of large crystals is formed. No difference between the precipitation with pure water (mean particle size X50 ¼ 17 mm) or with a solution of HPMC (X50 ¼ 16 mm) can be observed. In the case of budesonide, the drug is only partially stabilized against crystal growth. A relationship between the hydrophilicity, which is described by the partition coefficient (log P value),33 and the ability to stabilize the small crystal germs is obvious (Table 4). The solubility profile during the precipitation process, the supersaturation, and the solubility in the resulting solvent/nonsolvent mixture depends on the hydrophilic/hydrophobic behavior of the drug that is characterized by its partition coefficient. The higher the log P value for a drug, the higher the lipophilicity and the earlier supersaturation is achieved in the solvent change process. However, log P values describe the phase equilibrium concentrations in octanol and water. In this study, acetone was used as organic solvent. Thus, the solubility in acetone and water is decisive for the precipitation process. For the chemically similar steroids, the log ratio of the saturation solubility in acetone [cs(acetone)] and water [cs(water)] correlates with the tabulated log P values. Because the

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Table 3. Particle Size Distribution (Compressed Air)a X(10)/X(50)/X(90) (SD) [mm] Drug ECU-R2

BDP

BV

TCA

Budesonide

Jet-Milled

Controlled Crystallization

0.53 (0.01) 2.21 (0.12) 5.08 (0.32) 0.47 (0.01) 1.45 (0.06) 3.19 (0.18) 0.66 (0.04) 2.96 (0.33) 9.48 (0.33) 1.54 (0.26) 6.07 (0.18) 11.47 (0.19) 0.48 (0.01) 1.50 (0.06) 3.76 (0.24)

0.76 (0.01) 2.61 (0.06) 4.71 (0.16) 0.72 (0.00) 3.07 (0.06) 8.25 (0.40) 0.56 (0.04) 2.04 (0.07) 4.48 (0.14) 0.77 (0.01) 3.86 (0.04) 9.10 (0.14) 0.58 (0.02) 2.11 (0.07) 19.45 (1.82)

Controlled Precipitation

0.56 (0.01) 1.78 (0.04) 3.61 (0.15)

a

Results are the mean of three measurements.

chemically dissimilar ECU-R2 is less soluble in octanol than in acetone, here the log P coefficient cannot be used to characterize the precipitation process. The good processability of ECU-R2 using the controlled crystallization process is explainable by its highly different saturation solubility (cs) in acetone (1 g/100 mL) and water (0.05 mg/ 100 mL) which corresponds to a log (cs(acetone)/ cs(water)) of 4.3. This also fits into the hypothesis that the feasibility of controlled crystallization is dependent on the solubility of the drug in the solvent and nonsolvent and thus dependent on its hydrophilicity, affecting the supersaturation in the precipitation process. Aerodynamic Particle Size Besides the particle size of a drug, the deagglomeration behavior in an air stream is important

for pulmonary drug delivery. The aerodynamic behavior analyzed in a multi-stage liquid impinger for the pulmonary drugs used in this study is shown in Table 5. The fraction <5 mm can be increased by preparing the drug according to the controlled-crystallization technique. A dramatic increase in the respirable amount can be achieved as shown for ECU-R2 and BDP. The jet-milled drugs are agglomerated and electrostatically charged, increasing the aerodynamic particle size. The controlled crystallized drugs are not electrostatically charged and are less cohesive and adhesive. They show a homogeneous particle size and a modified surface with changed properties attributed to adsorbed HPMC.31 The six-fold increase in respirable amount of ECU-R2 can be explained by the small crystals which are loosely packed (Fig. 4a). Because of the needle-shaped crystals, the increase in the case of BDP is ‘‘only’’ approximately 2.5-fold. TCA and budesonide show a slight increase in the respirable fraction Table 4. Partition Coefficients (Modified from Hansch et al.33)

Figure 5. Volume particle-size distributions of jetmilled and controlled crystallized ECU-R2.

BDP BV TCA Budesonide Prednisolone

of

the

Steroids

log P

Stabilizing of Micro-Sized Particles?

4.30 4.20 2.70 2.31 1.60

þ þ þ/
(
)


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Table 5.

Fine Particle Fraction of Pulmonary Drugs (MLI) Fraction <5 mm (%) (m/m)a (SD)

Drug

Jet-Milled

Controlled Crystallization

ECU-R2 BDP TCA Budesonide

13.1  2.6 9.5  3.5 7.3  0.1 9.9  1.8

78.2  0.9 25.6  0.2 10.4  0.7 13.2  0.7

Controlled Precipitation 33.0  3.1

a

Results are the mean of three measurements.

because of the larger particles formed. However, even for these drugs, the jet-milled drug is disadvantageous. The in vitro deposition profiles (Fig. 6) show a high deposition of the jet-milled drugs in the applicator, throat, and stage 1. Controlled crystallized ECU-R2 settles down mainly in lower stages of the impinger (Fig. 6a). BDP, which is prepared by controlled crystallization or controlled precipitation, also shows a decrease in deposition on the first stages and an increase on the lower stages (Fig. 6b). In the case of TCA, which shows only a slight increase of the fine particle fraction (<5 mm), a shift to smaller particles was also observed as an increase in

stages 1 and 2 could be observed for the controlled crystallized drug. However, even if this does not relate to a higher lung deposition, it shows a shift to smaller effective particle size. General Aspects Besides the deposition patterns, another aspect needs to be considered. Before the drug can be absorbed in the lung, it has to be dissolved because only dissolved molecules can permeate the membrane. Because of the hydrophilized surface by adsorbed HPMC, the drugs obtained by controlled crystallization are dissolving faster. In the case of drugs for oral use, an increase in drug dissolution was observed.31 Thus, the bioavailability of a drug given via DPI can be expected to be increased by two effects, the increased respirable drug amount and the increase in drug dissolution. Because the drug powders micronized using the controlled crystallization technique are prepared directly in the micronized state during the particle formation without any further size reduction, this technique can be described as an in situ micronization technique. This technique requires a suitable stabilizer as described above. HPMC was found to show the best stabilizing properties. HPMC is a common excipient for oral, dermal, and ophthalmic use. However, because it is not yet used for inhalation, no toxicological data on inhaled HPMC are available, but toxic effects are expected to be low.

CONCLUSIONS

Figure 6. Drug deposition in vitro. (a) ECU-R2 and (b) BDP. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 92, NO. 1, JANUARY 2003

Microcrystals of hydrophobic drugs for pulmonary use can be prepared using a controlled crystallization technique in the presence of HPMC as protective hydrophilic polymer followed by

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spray-drying. Compared with jet-milled drugs, the respirable fraction is increased. Thus, side effects caused by drug deposition in the throat are avoided and the administered amount of drug can be lowered. This technique offers a relatively easy process for the production of micro-sized drugs which are characterized by a homogeneous particle-size distribution. Critical effects resulting from milling processes are avoided. Preparation of the microcrystals can be performed discontinuously or continuously using a static mixer. The in situ production of microcrystals is possible as a one-step process and only requires common equipment.

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