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Micronization of anti-inflammatory drugs for pulmonary delivery by a controlled crystallization process
Norbert Rasenack1, Hartwig Steckel, Bernd W Müller
1Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University Kiel, Gutenbergstr 76, D-24118 Kiel, Germany.
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), betamethasone-17-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 microm in most cases and consequently in the respirable range. Whereas the fine particle fraction (<5 microm, 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.
Insights
Controlled crystallization offers a superior alternative to jet-milling for drug micronization, yielding respirable particles with enhanced fine particle fractions for improved pulmonary drug delivery.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Drug Delivery
Background:
- Jet-milling, a common drug micronization technique, presents limitations for pulmonary applications.
- Effective pulmonary drug delivery necessitates not only small particle size but also good deagglomeration properties.
Purpose of the Study:
- To develop an alternative micronization method for anti-inflammatory drugs.
- To achieve respirable drug particles with improved fine particle fractions compared to jet-milling.
Main Methods:
- Controlled crystallization via solvent change precipitation using hydroxypropylmethylcellulose as a stabilizer.
- Spray-drying of the resulting drug-hydrocolloid dispersion.
- Particle size analysis and fine particle fraction determination for various anti-inflammatory drugs.
Main Results:
- Micronized drug powders with mean particle sizes below 5 micrometers were produced.
- Significantly higher fine particle fractions were achieved compared to jet-milled counterparts (e.g., 78.2% for ECU-R2 vs. 13.1%).
- Drug load reached up to 98% for beclomethasone dipropionate (BDP) and betamethasone valerate (BV).
Conclusions:
- Controlled crystallization followed by spray-drying is an effective method for producing respirable drug particles.
- This technique enhances fine particle fraction, crucial for efficient pulmonary drug delivery.
- Drug hydrophilicity, influenced by partition coefficient, is a key factor limiting particle size in this method.