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Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox

Yıl 2019, Cilt: 23 Sayı: 5, 851 - 859, 27.06.2025

Tuğba Gülsün Yagmur Akdag , Nihan Izat Levent Öner , Selma Şahin

Öz

Deferasirox is an oral iron chelator used for the treatment of chronic iron overload in blood transfusions. Deferasirox is a BCS Class II drug with low solubility and high permeability. In the formulation development stage for BCS Class II compounds, one of the main approaches is solubility enhancement to achieve better dissolution profiles, increased bioavailability and in some cases, dose reduction. The aim of the study was to investigate the effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. Ball milling method was used to reduce the particle size of deferasirox. Pluronic F127 or sodium lauril sulfate (SLS) were selected as surfactants at different concentrations. The maximum increase in the solubility was obtained with 10% SLS at pH 1.2 (from 0.9 µg/mL to 333.7 µg/mL), and with 5% Pluronic F127 at pH 6.8 (from 46.8 µg/mL to 334.2 µg/mL). Dissolution studies revealed that time to dissolve 85% of deferasirox was decreased as a function of ball milling time and particle size. Permeability studies showed that, in 100 µM concentration, deferasirox permeability was significantly enhanced by all concentrations of SLS (p<0.05). With an increase in Pluronic F127 concentration, permeability of deferasirox was not altered (p>0.05). All these results clearly demonstrated that surfactant addition to the formulations was effective for solubility enhancement of deferasirox, and surfactant type in optimized concentrations was very crucial. Particle size reduction can be used as a promising approach to improve dissolution, and hence bioavailability of deferasirox.

Anahtar Kelimeler

Deferasirox dissolution particle size distribution permeability solubility surfactant

Kaynakça

  • [1] Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: Provisional BCS classification of the world’s top oral drugs. AAPS J. 2009; 11(4): 740-746. [CrossRef]
  • [2] Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, Cho JM, Yun G, Lee J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J Pharm Sci. 2014; 9(6): 304-316. [CrossRef]
  • [3] Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutics drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995; 12(3): 413-420. [CrossRef]
  • [4] Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005; 22(1): 11-23. [CrossRef]
  • [5] Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, Files B, Hassell K, Kelly P, Wilson F. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol. 2007; 136(3): 501-508. [CrossRef]
  • [6] Hosey CM, Chan R, Benet LZ. BDDCS predictions, self-correcting aspects of BDDCS assignments, BDDCS assignment corrections, and classification for more than 175 additional drugs. AAPS J. 2016; 18(1): 251-260. [CrossRef]
  • [7] Guidance for industry. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. U.S. Department of health and human services food and drug administration center for drug evaluation and research (CDER). 2017. https://www.fda.gov/downloads/Drugs/Guidances/ucm070246.pdf (accessed March 16, 2019).
  • [8] Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, Porter CJ. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013; 65(1): 315-499. [CrossRef]
  • [9] Chaudhary A, Nagaich U, Gulati N, Sharma V, Khosa R, Partapur M. Enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: A recent review. J Adv Pharm Educ Res. 2012; 2(1): 32-67.
  • [10] Hetal T, Bindesh P, Sneha T. A review on techniques for oral bioavailability enhancement of drugs. Health. 2010; 4(3): 033.
  • [11] Kumar A, Sahoo SK, Padhee K, Kochar P, Sathapathy A, Pathak N. Review on solubility enhancement techniques for hydrophobic drugs. Pharm Glob. 2011; 3(3): 001-007.
  • [12] FDA, Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system guidance for industry. https://www.fda.gov/downloads/drugs/guidances/ucm070246.pdf (accessed March 1, 2019).
  • [13] Shaikh M, Derle ND, Bhamber R. Permeability enhancement techniques for poorly permeable drugs: A review. J Appl Pharm Sci. 2012; 2(6): 34-39. [CrossRef]
  • [14] Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897; 19(12): 930-934.
  • [15] 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(1): 91-97. [CrossRef]
  • [16] Lee J, Lee S-J, Choi J-Y, Yoo JY, Ahn C-H. Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion. Eur J Pharm Sci. 2005; 24(5): 441-449. [CrossRef]
  • [17] Niwa T, Miura S, Danjo K. Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies–development of particle design method. Int J Pharm. 2011; 405(1-2): 218-227. [CrossRef]
  • [18] O'Hara T, Dunne A, Butler J, Devane J. A review of methods used to compare dissolution profile data. Pharm Sci Technolo Today. 1998; 1(5): 214-223. [CrossRef]
  • [19] Ozturk N, Kaynak MS, Sahin S. Comparison of dissolution profiles of commercially available lamivudine tablets. Dissolut Technol. 2015; 22(4): 38-43. [CrossRef]
  • [20] FDA, Dissolution methods. https://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_searchresults.cfm (accessed March 1, 2019).
  • [21] Sun J, Wang F, Sui Y, She Z, Zhai W, Wang C, Deng Y. Effect of particle size on solubility, dissolution rate, and oral bioavailability: Evaluation using coenzyme q10 as naked nanocrystals. Int J Nanomedicine. 2012; 7: 5733. [CrossRef]
  • [22] Hecq J, Deleers M, Fanara D, Vranckx H, Amighi K. Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine. Int J Pharm. 2005; 299(1-2): 167-177. [CrossRef]
  • [23] Sharma D. Solubility enhancement strategies for poorly water-soluble drugs in solid dispersions: A review. Asian J Pharm. 2007; 1(1): 9-19.
  • [24] Shokri J, Azarmi S, Sabouri A, Shokri M. Enhancement of oxazepam dissolution rate using oxazepam-surfactant solid dispersions. Pharm Sci. 2006; (4): 35-45.
  • [25] Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P, Van den Mooter G. Physicochemical characterization of solid dispersions of the antiviral agent uc-781 with polyethylene glycol 6000 and gelucire 44/14. Eur J Pharm Sci. 2000; 10(4): 311-322. [CrossRef]
  • [26] Yüksel N, Karataş A, Özkan Y, Savaşer A, Özkan SA, Baykara T. Enhanced bioavailability of piroxicam using gelucire 44/14 and labrasol: In vitro and in vivo evaluation. Eur J Pharm Biopharm. 2003; 56(3): 453-459. [CrossRef]
  • [27] Goswami D, Vitorino HA, Alta RYP, Silvestre DM, Nomura CS, Machini MT, Espósito BP. Deferasirox-tat(47–57) peptide conjugate as a water soluble, bifunctional iron chelator with potential use in neuromedicine. BioMetals. 2015; 28(5): 869-877. [CrossRef]
  • [28] Yee S. In vitro permeability across caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man—factor myth. Pharm Res. 1997; 14(6): 763-766.
  • [29] Huang X-P, Spino M, Thiessen J. Transport kinetics of iron chelators and their chelates in caco-2 cells. Pharm Res. 2006; 23(2): 280-290. [CrossRef]
  • [30] Debebe Z, Nekhai S, Ashenafi M, Lovejoy DB, Kalinowski DS, Gordeuk VR, Byrnes WM, Richardson DR, Karla PK. Development of a sensitive HPLC method to measure in vitro permeability of E-and Z-isomeric forms of thiosemicarbazones in caco-2 monolayers. J Chromatogr B. 2012; 906: 25-32. [CrossRef]
  • [31] https://www.ema.europa.eu/en/documents/scientific-discussion/exjade-epar-scientific-discussion_en.pdf (accessed on April 3, 2019).
  • [32] Anandakumar K, Chinthala R, Subhash V, Jayamariappan M. Development and validation of newer analytical methods for the estimation of deferasirox in bulk and in tablet dosage form by UV spectroscopy and RP-HPLC. J Pharm Res. 2011; 4: 2998-3000.

Yıl 2019, Cilt: 23 Sayı: 5, 851 - 859, 27.06.2025

Tuğba Gülsün Yagmur Akdag , Nihan Izat Levent Öner , Selma Şahin

Öz

Kaynakça

  • [1] Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: Provisional BCS classification of the world’s top oral drugs. AAPS J. 2009; 11(4): 740-746. [CrossRef]
  • [2] Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, Cho JM, Yun G, Lee J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J Pharm Sci. 2014; 9(6): 304-316. [CrossRef]
  • [3] Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutics drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995; 12(3): 413-420. [CrossRef]
  • [4] Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005; 22(1): 11-23. [CrossRef]
  • [5] Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, Files B, Hassell K, Kelly P, Wilson F. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol. 2007; 136(3): 501-508. [CrossRef]
  • [6] Hosey CM, Chan R, Benet LZ. BDDCS predictions, self-correcting aspects of BDDCS assignments, BDDCS assignment corrections, and classification for more than 175 additional drugs. AAPS J. 2016; 18(1): 251-260. [CrossRef]
  • [7] Guidance for industry. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. U.S. Department of health and human services food and drug administration center for drug evaluation and research (CDER). 2017. https://www.fda.gov/downloads/Drugs/Guidances/ucm070246.pdf (accessed March 16, 2019).
  • [8] Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, Porter CJ. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013; 65(1): 315-499. [CrossRef]
  • [9] Chaudhary A, Nagaich U, Gulati N, Sharma V, Khosa R, Partapur M. Enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: A recent review. J Adv Pharm Educ Res. 2012; 2(1): 32-67.
  • [10] Hetal T, Bindesh P, Sneha T. A review on techniques for oral bioavailability enhancement of drugs. Health. 2010; 4(3): 033.
  • [11] Kumar A, Sahoo SK, Padhee K, Kochar P, Sathapathy A, Pathak N. Review on solubility enhancement techniques for hydrophobic drugs. Pharm Glob. 2011; 3(3): 001-007.
  • [12] FDA, Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system guidance for industry. https://www.fda.gov/downloads/drugs/guidances/ucm070246.pdf (accessed March 1, 2019).
  • [13] Shaikh M, Derle ND, Bhamber R. Permeability enhancement techniques for poorly permeable drugs: A review. J Appl Pharm Sci. 2012; 2(6): 34-39. [CrossRef]
  • [14] Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897; 19(12): 930-934.
  • [15] 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(1): 91-97. [CrossRef]
  • [16] Lee J, Lee S-J, Choi J-Y, Yoo JY, Ahn C-H. Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion. Eur J Pharm Sci. 2005; 24(5): 441-449. [CrossRef]
  • [17] Niwa T, Miura S, Danjo K. Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies–development of particle design method. Int J Pharm. 2011; 405(1-2): 218-227. [CrossRef]
  • [18] O'Hara T, Dunne A, Butler J, Devane J. A review of methods used to compare dissolution profile data. Pharm Sci Technolo Today. 1998; 1(5): 214-223. [CrossRef]
  • [19] Ozturk N, Kaynak MS, Sahin S. Comparison of dissolution profiles of commercially available lamivudine tablets. Dissolut Technol. 2015; 22(4): 38-43. [CrossRef]
  • [20] FDA, Dissolution methods. https://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_searchresults.cfm (accessed March 1, 2019).
  • [21] Sun J, Wang F, Sui Y, She Z, Zhai W, Wang C, Deng Y. Effect of particle size on solubility, dissolution rate, and oral bioavailability: Evaluation using coenzyme q10 as naked nanocrystals. Int J Nanomedicine. 2012; 7: 5733. [CrossRef]
  • [22] Hecq J, Deleers M, Fanara D, Vranckx H, Amighi K. Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine. Int J Pharm. 2005; 299(1-2): 167-177. [CrossRef]
  • [23] Sharma D. Solubility enhancement strategies for poorly water-soluble drugs in solid dispersions: A review. Asian J Pharm. 2007; 1(1): 9-19.
  • [24] Shokri J, Azarmi S, Sabouri A, Shokri M. Enhancement of oxazepam dissolution rate using oxazepam-surfactant solid dispersions. Pharm Sci. 2006; (4): 35-45.
  • [25] Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P, Van den Mooter G. Physicochemical characterization of solid dispersions of the antiviral agent uc-781 with polyethylene glycol 6000 and gelucire 44/14. Eur J Pharm Sci. 2000; 10(4): 311-322. [CrossRef]
  • [26] Yüksel N, Karataş A, Özkan Y, Savaşer A, Özkan SA, Baykara T. Enhanced bioavailability of piroxicam using gelucire 44/14 and labrasol: In vitro and in vivo evaluation. Eur J Pharm Biopharm. 2003; 56(3): 453-459. [CrossRef]
  • [27] Goswami D, Vitorino HA, Alta RYP, Silvestre DM, Nomura CS, Machini MT, Espósito BP. Deferasirox-tat(47–57) peptide conjugate as a water soluble, bifunctional iron chelator with potential use in neuromedicine. BioMetals. 2015; 28(5): 869-877. [CrossRef]
  • [28] Yee S. In vitro permeability across caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man—factor myth. Pharm Res. 1997; 14(6): 763-766.
  • [29] Huang X-P, Spino M, Thiessen J. Transport kinetics of iron chelators and their chelates in caco-2 cells. Pharm Res. 2006; 23(2): 280-290. [CrossRef]
  • [30] Debebe Z, Nekhai S, Ashenafi M, Lovejoy DB, Kalinowski DS, Gordeuk VR, Byrnes WM, Richardson DR, Karla PK. Development of a sensitive HPLC method to measure in vitro permeability of E-and Z-isomeric forms of thiosemicarbazones in caco-2 monolayers. J Chromatogr B. 2012; 906: 25-32. [CrossRef]
  • [31] https://www.ema.europa.eu/en/documents/scientific-discussion/exjade-epar-scientific-discussion_en.pdf (accessed on April 3, 2019).
  • [32] Anandakumar K, Chinthala R, Subhash V, Jayamariappan M. Development and validation of newer analytical methods for the estimation of deferasirox in bulk and in tablet dosage form by UV spectroscopy and RP-HPLC. J Pharm Res. 2011; 4: 2998-3000.
Toplam 32 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Farmasotik Kimya, İlaç Dağıtım Teknolojileri
Bölüm Articles
Yazarlar

Tuğba Gülsün

Yagmur Akdag

Nihan Izat

Levent Öner

Selma Şahin

Yayımlanma Tarihi 27 Haziran 2025
Yayımlandığı Sayı Yıl 2019 Cilt: 23 Sayı: 5

Kaynak Göster

APA Gülsün, T., Akdag, Y., Izat, N., Öner, L., vd. (2025). Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. Journal of Research in Pharmacy, 23(5), 851-859.
AMA Gülsün T, Akdag Y, Izat N, Öner L, Şahin S. Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. J. Res. Pharm. Temmuz 2025;23(5):851-859.
Chicago Gülsün, Tuğba, Yagmur Akdag, Nihan Izat, Levent Öner, ve Selma Şahin. “Effect of Particle Size and Surfactant on the Solubility, Permeability and Dissolution Characteristics of Deferasirox”. Journal of Research in Pharmacy 23, sy. 5 (Temmuz 2025): 851-59.
EndNote Gülsün T, Akdag Y, Izat N, Öner L, Şahin S (01 Temmuz 2025) Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. Journal of Research in Pharmacy 23 5 851–859.
IEEE T. Gülsün, Y. Akdag, N. Izat, L. Öner, ve S. Şahin, “Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox”, J. Res. Pharm., c. 23, sy. 5, ss. 851–859, 2025.
ISNAD Gülsün, Tuğba vd. “Effect of Particle Size and Surfactant on the Solubility, Permeability and Dissolution Characteristics of Deferasirox”. Journal of Research in Pharmacy 23/5 (Temmuz 2025), 851-859.
JAMA Gülsün T, Akdag Y, Izat N, Öner L, Şahin S. Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. J. Res. Pharm. 2025;23:851–859.
MLA Gülsün, Tuğba vd. “Effect of Particle Size and Surfactant on the Solubility, Permeability and Dissolution Characteristics of Deferasirox”. Journal of Research in Pharmacy, c. 23, sy. 5, 2025, ss. 851-9.
Vancouver Gülsün T, Akdag Y, Izat N, Öner L, Şahin S. Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. J. Res. Pharm. 2025;23(5):851-9.