Abstract
Purpose. The purpose of this study was to evaluate a novel in situ micronization method avoiding any milling techniques to produce nano- or microsized drug particles by controlled crystallization to enhance the dissolution rate of poorly water-soluble drugs.
Methods. Ibuprofen, itraconazole, and ketoconazole microcrystals were prepared by the association of the previously molecularly dispersed drug using a rapid solvent change process. The drug was precipitated in the presence of stabilizing agents, such as hydrocolloids. The obtained dispersion was spray-dried. Particle size, morphology, dissolution rate, specific surface area, and wettability were analyzed. Physicochemical properties were characterized using differential scanning calorimetry and X-ray diffractometry.
Results. The obtained dispersions showed a homogeneous particle size distribution. Drugs are obtained in a mean particle size of approximately 2 μm and below. A high specific surface area was created and in situ stabilized. Different stabilizers showed differences in protecting the precipitated drug from crystal growth. The surface was hydrophilized because of the adsorbed stabilizer. Thus, a drug powder with markedly enhanced dissolution rate was obtained.
Conclusions. In situ micronization is a suitable method for the production of micro-sized drugs. This technique can be performed continuously or discontinuously and uses only common technical equipment. Compared to milled products drug properties are optimized as all particle surfaces are naturally grown, the particle size is more uniformly distributed and the powder is less cohesive.
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REFERENCES
J. R. Robinson. Recent advantages in formulation of poorly absorbed Drugs. In Current Status on Targeted Drug Delivery to the gastrointestinal tract, Capsugel Library, 1993 pp. 59-63.
Y. Kawashima. Nanoparticulate systems for improved drug delivery. Adv. Drug Deliv. Rev. 47:1–2 (2001).
E. L. Parrott. Comminution. In J. Swarbrick, J. C. Boylan (eds.), Encyclopedia of Pharmaceutical Technology, Vol. 3., Marcel Decker Inc., New York, 1990 pp. 101–121.
L. Mackin, R. Zanon, J. M. Park, K. Foster, H. Opalenik, and M. Demonte. Quantification of low levels (< 10%) of amorphous content in micronised active batches using dynamic vapour sorption and isothermal microcalorimetry. Int. J. Pharm. 231:227–236 (2002).
M. D. Ticehurst, P. A. Basford, C. I. Dallman, T. M. Lukas, P. V. Marshall, G. Nichols, and D. Smith. Characterisation of the influence of micronisation on the crystallinity and physical stability of revatropate hydrobromide. Int. J. Pharm. 193:247–259 (2000).
L. Mackin, S. Sartnurak, I. Thomas, and S. Moore. The impact of low levels of amorphous material (< 5%) on the blending characteristics of a direct compression formulation. Int. J. Pharm. 231:213–226 (2002).
J. C. Feeley, P. York, B. S. Sumby, and H. Dicks. Determination of surface properties and flow characteristics of salbutamol sulphate, before and after micronisation. Int. J. Pharm. 172:89–96 (1998).
G. H. Ward and R. K. Schultz. Process-induced crystallinity changes in albuterol sulfate and its effect on powder physical stability. Pharm. Res. 12:773–779 (1995).
R. J. Roberts, R. C. Rowe, and P. York. The relationship between indentation hardness of organic solids and their molecular structure. J. Mater. Sci. 29:2289–2296 (1994).
C. Jacobs, O. Kayser, and R. H. Müller. Nanosuspensions as a new approach for the formulation for the poorly soluble drug tarazepide. Int. J. Pharm. 196:161–164 (2000).
R. H. Müller, C. Jacobs, and O. Kayser. Nanosuspensions as Particulate Drug Formulations in Therapy. Rationale for Development and what We Can Expect for the Future. Adv. Drug Deliv. Rev. 47:2–19 (2001).
R. H. Müller, H. L. Böhm, and M. J. Grau. Nanosuspensionen-Formulierungen für schwerlösliche Arzneistoffe mit geringer Bioverfügbarkeit; 1. Herstellung und Eigenschaften. Pharm. Ind. 61:74–78 (1999).
E. Shalaev, M. Shalaeva, and G. Zografi. The effect of disorder on the chemical reactivity of an organic solid, tetraglycine methyl ester: change of the reaction mechanism. J. Pharm. Sci. 91:584–593 (2002).
J.-O. Waltersson and P. Lundgren. The effect of mechanical comminution on drug stability. Acta Pharm. Suec. 22:291–300 (1985).
V. Joshi, S. Dwivedi, and G. H. Ward. Increase in the specific surface area of budesonide during storage postmicronization. Pharm. Res. 19:7–12 (2002).
R. H. Müller, K. Peters, R. Becker, and B. Kruss. Nanosuspensions for the i.v. administration of poorly soluble drugs-stability during sterilization and long-term storage. Proc. Intern. Symp. Control. Rel. Bioact. Mater. 22:574–575 (1996).
P. Ga?mann, M. List, A. Schweitzer, and H. Sucker. Hydrosols-Alternatives for the parenteral application of poorly watersoluble drugs. Eur. J. Pharm. Biopharm. 40:64–72 (1994).
D. Horn. Preparation and characterisation of microdisperse bioavailable carotenoid hydrosols. Angew. Makrom. Chem. 166:139–153 (1989).
H. Auweter, H. Bohn, H. Haberkorn, D. Horn, E. Luddecke, and V. Rauschenberger. Production of carotenoid preparations in the form of coldwater-dispersible powders, and the use of the novel carotenoid preparations, US patent no. 5,968,251, October 19, 1999.
H. Steckel, J. Thies, and B. W. Müller. Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide. Int. J. Pharm. 152:99–110 (1997).
J. Kerc, S. Srcic, Z. Knez, and P. Sencar-Bozic. Micronization of drugs using supercritical carbon dioxide. Int. J. Pharm. 182:33–39 (1999).
N. Rasenack, and B. W. Müller. Verfahren zur Herstellung und Anwendung von Mikro-und Nanoteilchen durch aufbauende Mikronisation, German Patent Application No. 102 14 031.6 (2002).
B. L. Pedersen, A. Müllertz, H. Brondsted, and H. G. Kristensen. A comparison of the solubility of danazol in human and simulated gastrointestinal fluids. Pharm. Res. 17:891–894 (2000).
V. P. Shah, J. J. Konecny, R. L. Everett, B. McCullough, A. C. Noorizadeh, and J. P. Skelly. In vitro dissolution profile of waterinsoluble drug dosage forms in the presence of surfactants. Pharm. Res. 6:612–618 (1989).
H. Schott. Colloidal Dispersions Gennaro A.R., Chase G.D., Gibson, M.R., Granberg, C.B., Harvey, S.C., King, R.E., Martin, A.N., Medwick, T., Swinyard, E.A., and Zink, G.L. (eds.). In: Remington's Pharmaceutical Sciences; The Philadelphia College of Pharmacy and Science, 1985, pp. 286–289 Philadelphia, Pennsylvania.
S. A. Chang and D. G. Gray. The surface tension of aqueous hydroxypropyl cellulose solutions. J. Colloid. Interface Sci. 67: 255–265 (1978).
R. Daniels and A. Barta. Pharmacopoeial cellulose ethers as oil-in-water emulsifiers. I. Interfacial Properties. Eur. J. Pharm. Biopharm. 40:128–133 (1994).
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Rasenack, N., Müller, B.W. Dissolution Rate Enhancement by in Situ Micronization of Poorly Water-Soluble Drugs. Pharm Res 19, 1894–1900 (2002). https://doi.org/10.1023/A:1021410028371
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DOI: https://doi.org/10.1023/A:1021410028371