Abstract
The aim of this work was to survey how processing parameters affect the crystal growth of β-sitosterol in suspension. The process variables studied were the cooling temperature, stirring time and stirring rate during recrystallization. In addition, we investigated the effect a commonly used surfactant, polysorbate 80, has on crystal size distribution and the polymorphic form. This study describes the optimization of the crystallization process, with the object of preparing crystals as small as possible. Particle size distribution and habit were analyzed using optical microscopy, and the crystal structure was analyzed using X-ray diffractometry. The cooling temperature had a remarkable influence on the crystal size. Crystals with a median crystal length of ≈23 μm were achieved with a low cooling temperature (<10°C); however, a fairly large number of crystals over 50 μm appeared. Higher cooling temperatures (>30°C) caused notable crystal growth both in length and width. Rapid (250 rpm), continuous stirring until the suspensions had cooled to room temperature created small, less than 50 μm long (median <20 μm), needle-shaped crystals. The addition of surfactant slightly reduced the size of the initially large crystals. Both hemihydrate and monohydrate crystal forms occurred throughout, regardless of the processing parameters. By using an optimized process, it was possible to obtain a microcrystalline suspension, with a smooth texture.
Similar content being viewed by others
References
Mackellar AJ, Buckton G, Newton JM, Chowdhry BZ, Orr CA. The controlled crystallisation of a model powder. I. The effects of altering the stirring rate and the supersaturation profile and the incorporation of a surfactant (Poloxamer 188). Int J Pharm. 1994;112:65–78.
Mullin JW. Crystallization. Oxford, UK: Butterworth-Heinemann; 2000.
Florence AT, Attwood D. Physicochemical Principles of Pharmacy. Basingstoke, UK: Macmillan Press Ltd, 1998.
Myerson AS, Ginde R. Crystals, crystal growth and nucleation. In: Handbook of Industrial Crystallization. St Louis, MO: Butterworth-Heinemann; 1993:33–63.
Boistelle R, Astier JP. Crystallization mechanisms in solution. J Cryst Growth. 1988;90:14–30.
Schüth F. Nucleation and crystallization of solids from solutions. Curr Opin Solid State Mater Sci. 2001;5:389–395.
Zipp GL, Rodriguez-Hornedo N. The mechanism of phenytoin crystal growth. Int J Pharm. 1993;98:189–201.
Sunada H, Yamamoto A, Otsuka A, Yonezawa Y. Changes of surface area in the dissolution process of crystalline substances. Chem Pharm Bull. 1987;36(7):2557–2561.
Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.
Rasenack N, Hartenhauer H, Müller BW. Microcrystals for dissolution rate enhancement of poorly water-soluble drugs. Int J Pharm. 2003;254:137–145.
Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm. 1995;125:91–97.
Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18:113–120.
Mattson GM, Volpenheim FA, Erickson BA. Effect of plant sterol esters on the absorption of dietary cholesterol. J Nutr. 1997;107:1139–1146.
Christiansen LI, Rantanen JT, von Bonsdorff AK, Karjalainen MA, Yliruusi JK. A novel method of producing a microcrystalline β-sitosterol suspension in oil. Eur J Pharm Sci. 2001;15:261–269.
Christiansen LI, Lähteenmäki PLA, Mannelin MR, Seppänen-Laakso TE, Hiltunen RVK, Yliruusi JK. Cholesterol-lowering effect of spreads enriched with microcrystalline plant sterols in hypercholesterolemic subjects. Eur J Nutr. 2001;40:66–73.
von Bonsdorff-Nikander A, Karjalainen M, Rantanen J, Christiansen L, Yliruusi J. Physical stability of a microcrystalline β-sitosterol suspension in oil. Eur J Pharm Sci. 2003;19:173–179.
Jones AG, Mullin JW. Programmed cooling crystallization of potassium sulphate solutions. Chem Eng Sci. 1974;29:105–118.
Mullin JW, Raven KD. Nucleation in agitated solutions. Nature. 1961;190:251.
Dogua J, Simon B. Crystallization of sodium perborate from aqueous solution. J Cryst Growth. 1978;44:265–279.
Viaene J, Januszewska R. Quality function deployment in the chocolate industry. Food Quality and Preference. 1999;10:377–385.
Tyle P. Effect of size, shape and hardness of particles in suspension on oral texture and palatability. Acta Psychologica. 1993;84:111–118.
Mazzarotta B, Si Cave S, Bonifazi G. Influence of time on crystal attrition in a stirred vessel. AIChE J. 1996;42(12):3554–3558.
Gibaldi M. Biopharmaceutics. In: Lachman L, Lieberman HA, Kanig JL, eds. The Theory and Practice of Industrial Pharmacy. 2nd ed. Philadelphia, PA. Lea & Febiger; 1976: 78–140.
Bisrat M, Nyström C. Physicochemical aspects of drug release. VIII. The relation between particle size and surface specific dissolution rate in agitated suspensions. Int J Pharm. 1988;47:223–231.
Anderberg EK, Bisrat M, Nyström C. Physicochemical aspects of drug release. VII. The effect of surfactant concentration and drug particle size on solubility and dissolution rate of felodipine, a sparingly soluble drug. Int J Pharm. 1988;47:67–77.
Rauls M, Bartosch K, Kind M, Kuch S, Racmann R, Mersmann A. The influence of impurities on crystallization kinetics—a case study on ammonium sulfate. J Cryst Growth. 2000;213:116–128.
El-Bary AA, Kassem MAA, Foda N, Travel S, Badawi SS. Controlled crystallization of chlorpropamide from surfactant and polymer solutions. Drug Dev Ind Pharm. 1990;16(10):1649–1660.
Mackellar AJ, Buckton G, Newton JM, Orr CA. The controlled crystallization of a model powder. II. Investigation into the mechanism of action of poloxamers in changing crystal properties. Int J Pharm. 1994;112:79–85.
Kim CA, Choi HK. Effect of additives on the crystallization and the permeation of ketoprofen from adhesive matrix. Int J Pharm. 2002;236:81–85.
Luhtala S. Effect of sodium lauryl sulphate and polysorbate 80 on crystal growth and aqueous solubility of carbamazepine. Acta Pharm Nord. 1992;4(2):85–90.
Canselier JP. The effects of surfactants on crystallization phenomena. J Dispersion Sci Technol. 1993;14(6):625–644.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
von Bonsdorff-Nikander, A., Rantanen, J., Christiansen, L. et al. Optimizing the crystal size and habit of β-sitosterol in suspension. AAPS PharmSciTech 4, 44 (2003). https://doi.org/10.1208/pt040344
Received:
Accepted:
DOI: https://doi.org/10.1208/pt040344