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. 2004 Jun 19;5(3):57–64. doi: 10.1208/pt050344

Crystallo-co-agglomeration: A novel technique to obtain ibuprofen-paracetamol agglomerates

Atmaram P Pawar 1, Anant R Paradkar 1, Shivajirao S Kadam 2, Kakasaheb R Mahadik 2,✉
PMCID: PMC2750267  PMID: 15760077

Abstract

The purpose of this research was to obtain directly compressible agglomerates of ibuprofen-paracetamol containing a desired ratio of drugs using a crystallo-co-agglomeration technique. Crystallo-co-agglomeration is an extension of the spherical crystallization technique, which enables simultaneous crystallization and agglomeration of 2 or more drugs or crystallization of a drug and its simultaneous agglomeration with another drug or excipient. Dichloromethane (DCM)-water system containing polyethylene glycol (PEG) 6000, polyvinyl pyrollidone, and ethylcellulose was used as the crystallization system. DCM acted as a good solvent for ibuprofen and bridging liquid for agglomeration. The process was performed at pH 5, considering the low solubility of ibuprofen and the stability of paracetamol. Loss of paracetamol was reduced by maintaining a low process temperature and by the addition of dextrose as a solubility suppressant. The agglomerates were characterized by differential scanning calorimetry, powder x-ray diffraction (PXRD), and scanning electron microscopy and were evaluated for tableting properties. The spherical agglomerates contained an ibuprofen-paracetamol ratio in the range of 1.23 to 1.36. Micromeritic, mechanical, and compressional properties of the agglomerates were affected by incorporated polymer. The PXRD data showed reduction in intensities owing to dilution and reduced crystallinity. Thermal data showed interaction between components at higher temperature. Ethylcellulose imparted mechanical strength to the agglomerates as well as compacts. The agglomerates containing PEG have better comparessibility but drug release in the initial stages was affected owing to asperity melting, yielding harder compacts. The agglomeration and properties of agglomerates were influenced by the nature of polymer.

Keywords: crystallo-co-agglomeration, ibuprofen, paracetamol, drug combination, tableting properties

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References

  • 1.Nicholas G, Frampton CS. Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J Pharm Sci. 1998;87:684–693. doi: 10.1021/js970483d. [DOI] [PubMed] [Google Scholar]
  • 2.Alsaidan SM, Abdulhakeem AA, Eshra AG. Improved dissolution rate of indomethacin by adsorbents. Drug Dev Ind Pharm. 1998;24:389–394. doi: 10.3109/03639049809085635. [DOI] [PubMed] [Google Scholar]
  • 3.Wang H, Zhang R. Compaction behavior of paracetamol powders of different crystal shapes. Drug Dev Ind Pharm. 1995;21:863–868. doi: 10.3109/03639049509026651. [DOI] [Google Scholar]
  • 4.Kawashima Y, Okumara M, Takenaka H. The effect of temperature on the spherical crystallization of salicylic acid. Powder Technol. 1984;39:41–47. doi: 10.1016/0032-5910(84)85018-4. [DOI] [Google Scholar]
  • 5.Paradkar AR, Pawar AP, Chordiya JK, Patil VB, Ketkar AR. Spherical crystallization of celecoxib. Drug Dev Ind Pharm. 2002;28:1213–1220. doi: 10.1081/DDC-120015354. [DOI] [PubMed] [Google Scholar]
  • 6.Kawashima Y, Aoki S, Takenama H, Miyake Y. Preparation of spherically agglomerated crystals of aminophylline. J Pharm Sci. 1984;73:1407–1409. doi: 10.1002/jps.2600731021. [DOI] [PubMed] [Google Scholar]
  • 7.Pawar PH, Pawar AP, Mahadik KR, Paradkar AR. Evaluation of tableting properties of agglomerates obtained by spherical crystallisation of trimethoprim. Indian J Pharm Sci. 1998;60:24–28. [Google Scholar]
  • 8.Kawashima Y, Cui F, Takeuchi H, Niwa T, Hino T, Kiuchi K. Improvement in flowability and compressibility of pharmaceutical crystals for direct tableting by spherical crystallization with a two solvent system. Powder Technol. 1994;78:151–156. doi: 10.1016/0032-5910(93)02772-3. [DOI] [Google Scholar]
  • 9.Ueda M, Nakamura Y, Makita H, Kawashima Y. Preparation of microcapsules masking the bitter taste of enoxacin by using one continuous process of agglomeration and microencapsulation. J Microencapsul. 1993;10:461–473. doi: 10.3109/02652049309015323. [DOI] [PubMed] [Google Scholar]
  • 10.Kawashima Y, Lin SY, Naito M, Takenama H. Direct agglomeration of sodium theophylline crystals produced by salting out in liquid. Chem Pharm Bull (Tokyo) 1982;30:1837–1843. [Google Scholar]
  • 11.Kawashima Y, Lin Y, Ogawa M, Handa T, Takenada H. Prolonged release microcapsules of indomethacin through spherical crsstallization technique. J Pharm Sci. 1985;74:1152–1156. doi: 10.1002/jps.2600741104. [DOI] [PubMed] [Google Scholar]
  • 12.Kadam SS, Mahadik KR, Paradkar AR, inventors. A process for making agglomerates for use as or in a drug delivery system. Indian patent 183036. February 14, 1997.
  • 13.Kadam SS, Mahadik KR, Paradkar AR, inventors. A process for making agglomerates for use as or in a drug delivery system. Indian patent 183481. February 14, 1997.
  • 14.Morishima K, Kawashima Y, Takeuchi H, Niwa T, Hino T. Micromeritic characteristics and agglomeration mechanisms in the spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent diffusion methoss. Powder Technol. 1993;76:57–64. doi: 10.1016/0032-5910(93)80041-8. [DOI] [Google Scholar]
  • 15.Sethi PD. Quantitative Analysis of Drugs in Pharmaceutical Formulations. 2nd ed. Delhi, India: CBS Publication; 1993. Paracetamol, Ibuprofen. pp. 98–98. [Google Scholar]
  • 16.Shirakura O, Yamada M, Hashimoto M, Ishimaru S, Takayama K, Nagai T. Particle size design using computer optimization technique. Drug Dev Ind Pharm. 1991;17:471–483. doi: 10.3109/03639049109044257. [DOI] [Google Scholar]
  • 17.Jarosz PJ, Parrot EJ. Comparison of granule strength and tablet strength. J Pharm Sci. 1983;72:530–535. doi: 10.1002/jps.2600720513. [DOI] [PubMed] [Google Scholar]
  • 18.Heckel RW. Density—pressure relationships in powder compaction. Trans Mettall Soc AIME. 1961;221:671–675. [Google Scholar]
  • 19.Heckel RW. An analysis of powder compaction phenomena. Trans Mettall Soc AIME. 1961;221:1001–1008. [Google Scholar]
  • 20.Rubinstein MH, Musikabhumma P. A universal friability test for tablet granules. Pharm Acta Helv. 1978;53:125–129. [PubMed] [Google Scholar]
  • 21.Etman MA, Naggar VF. Thermodynamics of paracetamol solubility in sugar-water cosolvent systems. Int J Pharm. 1990;58:177–184. doi: 10.1016/0378-5173(90)90193-8. [DOI] [Google Scholar]
  • 22.Bodmeier R, Chen H. Preparation and characterization of microspheres containing the anti-inflammatory agents, indomethacin, ibuprofen and ketoprofen. J Control Release. 1989;10:167–175. doi: 10.1016/0168-3659(89)90059-X. [DOI] [Google Scholar]
  • 23.Paradkar AR, Maheshwari M, Ketkar AR, Chauhan B. Preparation and evaluation of ibuprofen beads by melt solidification technique. Int J Pharm. 2003;7427:1–10. doi: 10.1016/s0378-5173(03)00081-4. [DOI] [PubMed] [Google Scholar]
  • 24.Kawashima Y, Handa T, Takeuchi H, Okumura M. Effect of polyethylene glycol on size of agglomerated crystals of phenytoin prepared by the spherical crystallization technique. Chem Pharm Bull (Tokyo) 1986;34:3403–3407. doi: 10.1248/cpb.34.3403. [DOI] [PubMed] [Google Scholar]
  • 25.Kawashima Y, Handa T, Takeuchi H, Okumura M, Katou H, Nagata O. Crystal modification of phenytoin with polyethylene glycol for improving mechanical strength, dissolution rate and bioavailability by a spherical crystallization technique. Chem Pharm Bull (Tokyo) 1986;34:3376–3383. doi: 10.1248/cpb.34.3376. [DOI] [PubMed] [Google Scholar]
  • 26.Chow AHL, Leung MWM. A study of the mechanism of wet spherical agglomeration of pharmaceutical powders. Drug Dev Ind Pharm. 1996;22:357–362. doi: 10.3109/03639049609042001. [DOI] [Google Scholar]
  • 27.Lloyd GR, Craig DQ, Smith A. An investigation into the melting behavior of binary mixer and solid dispersion of paracetamol and PEG 4000. J Pharm Sci. 1997;86:991–196. doi: 10.1021/js970137w. [DOI] [PubMed] [Google Scholar]
  • 28.Wu C, McGinity JW. Influence of ibuprofen as a solid-state plasticizer in Eudragit RS 30 D on the physicochemical properties of coated beads. AAPS PharmSciTech. 2001;2:E24–E24. doi: 10.1208/pt020424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Dubernet C, Rouland JC, Benoit JP. Ibuprofen-loaded ethylcellulose microspheres: analysis of the matrix structure by thermal analysis. J Pharm Sci. 1991;80:1029–1133. doi: 10.1002/jps.2600801106. [DOI] [PubMed] [Google Scholar]
  • 30.Zubir S, Esezobo S, Pilpel N. The effects of interacting variables on the tensile strength, disintegration and dissolution of paracetamol tablets. J Pharm Pharmacol. 1988;40:278–281. doi: 10.1111/j.2042-7158.1988.tb05243.x. [DOI] [PubMed] [Google Scholar]

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