Objective: Cefdinir is a poorly- water-soluble drug, it belongs to Biopharmaceutical Classification System class IV, which shows that it may have limited therapeutic effects due to its low solubility and poor bioavailability. The aim of the present work was to design a pH-modified solid dispersion (pHM-SD) that can improve the dissolution rate of cefdinir and subsequently its bioavailability.
Materials and Methods: pHM-SDs of cefdinir were prepared at different drug-to-carrier ratios by the spray-drying technique. The solid dispersions were investigated by dissolution studies at different pH media, drug release kinetics were studied, and their solid-state characterizations were performed by FTIR spectrophotometer, Scanning electron microscopy (SEM), Differential scanning calorimetry (DSC), and Powder X-ray diffraction (PXRD).
Results: PVP- based and HPMC- based pHM-SDs exhibited a marked improvement in the dissolution behavior when compared with crystalline cefdinir powder, whereas Eudragit L100-based pHM-SDs showed lower dissolution at pH 1.2 and 4.5.
FTIR results may indicate a formation of a salt between cefdinir and the alkalizer. Solid-state characterization may indicate a change in crystallinity of cefdinir into an amorphous state. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsmeyer–Peppas model and the drug release kinetics primarily as Fickian diffusion.
Conclusion: According to these observations, pHM-SD in the presence of an alkalizer for a poorly water-soluble acidic drug, cefdinir, appeared to be efficacious for enhancing its dissolution rate.
Wise R, Andrews JM, Thbornber D. The in-vitro activity of cefdinir (FK482), a new oral cephalosporin. J Antimicrob Chemother 1991; 28(2): 239-48. https://doi.org/10.1093/jac/28.2.239
Guay DRP. Cefdinir: An advanced-generation, broad-spectrum oral cephalosporin. Clin Ther 2002; 24(4): 473-89. https://doi.org/10.1016/S0149-2918(02)85125-6
Perry CM, Scott LJ. Cefdinir: a review of its use in the management of mild-to-moderate bacterial infections. Drugs 2004; 64(13): 1433-64. https://doi.org/10.2165/00003495-200464130-00004
Aleem O, Kuchekar B, Pore Y, Late S. Effect of β-cyclodextrin and hydroxypropyl β-cyclodextrin complexation on physicochemical properties and antimicrobial activity of cefdinir. J Pharm Biomed Anal 2008; 47(3): 535-40. https://doi.org/10.1016/j.jpba.2008.02.006
Bassi P, Kaur G. pH modulation: a mechanism to obtain pH-independent drug release. Expert Opin Drug Deliv 2010; 7: 845-57. https://doi.org/10.1517/17425247.2010.491508
Sawant KK, Patel MH, Patel K. Cefdinir nanosuspension for improved oral bioavailability by media milling technique: formulation, characterization and in vitro-in vivo evaluations. Drug Dev Ind Pharm 2015; November: 1-11. Available from: https://pubmed.ncbi.nlm.nih.gov/26548349/
Patil OA, et al. Formulation optimization and evaluation of Cefdinir nanosuspension using 23 Factorial design. Marmara Pharm J 2018; 22(4): 587-98. https://doi.org/10.12991/jrp.2018.101
Park J, et al. Preparation and pharmaceutical characterization of amorphous cefdinir using spray-drying and SAS-process. Int J Pharm 2010; 396: 239-45. https://doi.org/10.1016/j.ijpharm.2010.06.032
Morina D, Sessevmez M, Sinani G, Mülazımoğlu L, Cevher E. Oral tablet formulations containing cyclodextrin complexes of poorly water soluble cefdinir to enhance its bioavailability. J Drug Deliv Sci Technol 2020; 57: 101742.https://doi.org/10.1016/j.jddst.2020.101742
Chhayani RL, Chhayani RB, Patel D, Borkhataria CH. Development and characterization of self- microemulsifying drug delivery system for improvement of bioavailability of Cefdinir. JPMC 2016; 2(1): 57-83. https://doi.org/10.21088/jpmc.2395.6615.2116.7
Cho HJ, et al. Cefdinir solid dispersion composed of hydrophilic polymers with enhanced solubility, dissolution, and bioavailability in rats. Molecules 2017; 22, 280: 1-14. https://doi.org/10.3390/molecules22020280
Jain S, Jain S, Mishra A, Garg G, Modi RK. Formulation and characterization of fast disintegrating tablets containing Cefdinir solid dispersion. Int J Pharm Life Sci 2012; 3(12): 2190-99.
Maraie NK, Alhamadany AT, Radhi AA. Efficacy of combination solid dispersion technology on dissolution performance of nalidixic acid and cefdinir. Asian J Pharm Clin Res 2017; 10 (4): 394-01.https://doi.org/10.22159/ajpcr.2017.v10i4.16913
Prathibha B, Reddy DV, Reddy DS. Formulation and evaluation of once a day tablet of cefdinir. Int J Pharm Technol 2014; 5(4): 115-30.
Lakshmanarao P et al., Enhancement of solubility and dissolution rate of Cefdinir using solid dispersions. Indo Am j pharm res 2017; 4(3): 747-53.
Kumar P, Kumar S. Physicochemical characterization of solid dispersions of Cefdinir with PVP K-30 and PEG 4000. Int J Pharm Sci Nanotech 2010; 3(2). https://doi.org/10.37285/ijpsn.2010.3.2.8
Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today 2007; 12(23-24): 1068-75. https://doi.org/10.1016/j.drudis.2007.09.005
Heo MY, Piao ZZ, Kim TW, Cao QR, Kim A, Lee BJ. Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersion on enhanced dissolution and bioavailability of ketoconazole. Arch Pharm Res 2005; 28(5): 604-11. https://doi.org/10.1007/BF02977766
Paudel A, Worku ZA, Meeus J, Guns S, Van Den Mooter G. Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: Formulation and process considerations. Int J Pharm 2013; 453(1): 253-84. https://doi.org/10.1016/j.ijpharm.2012.07.015
Tran PHL, Tran HTT, Lee BJ. Modulation of microenvironmental pH and crystallinity of ionizable telmisartan using alkalizers in solid dispersions for controlled release. J Control Release 2008; 129(1): 59-65. https://doi.org/10.1016/j.jconrel.2008.04.001
Tran PHL, Tran TTD, Lee KH, Kim DJ, Lee BJ. Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility. Expert Opin Drug Deliv 2010; 7(5): 647-61. https://doi.org/10.1517/17425241003645910
Baka E, Comer JEA, Takács-Novák K. Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound. J Pharm Biomed Anal 2008; 46(2): 335-41. https://doi.org/10.1016/j.jpba.2007.10.030
Shah PB, Pundarikakshudu K. UV spectroscopic and colorimetric methods for the estimation of cefdinir in capsule dosage forms. Indian J Pharm Sci 2004; 66: 665-67.
Al-Badr AA, Alasseiri FA. Cefdinir. In: Profiles of Drug Substances, Excipients and Related Methodology Elsevier Inc. 2014; 39: 41-112. https://doi.org/10.1016/B978-0-12-800173-8.00002-7
Muqtader M, et al. Development of spray-dried amorphous solid dispersions of tadalafil using glycyrrhizin for enhanced dissolution and aphrodisiac activity in male rats. Saudi Pharm J 2020; 28(12): 1817-26. https://doi.org/10.1016/j.jsps.2020.11.007
de Waard H, Hinrichs WLJ, Visser MR, Bologna C, Frijlink HW. Unexpected differences in dissolution behavior of tablets prepared from solid dispersions with a surfactant physically mixed or incorporated. Int J Pharm 2008; 349(1-2): 66-73. https://doi.org/10.1016/j.ijpharm.2007.07.023
Khan KA. The concept of dissolution efficiency. J Pharm Pharmacol 1975; 27(1): 48-49. https://doi.org/10.1111/j.2042-7158.1975.tb09378.x
Ahuja N, Katare OP, Singh B. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers. Eur J Pharm Biopharm 2007; 65(1): 26-38. https://doi.org/10.1016/j.ejpb.2006.07.007
Higuchi T. Mechanism of sustained‐action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963; 52(12): 1145-49. https://doi.org/10.1002/jps.2600521210
Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 1983; 15(1): 25-35. https://doi.org/10.1016/0378-5173(83)90064-9
Ritschel WA. Biopharmaceutic and pharmacokinetic aspects in the design of controlled release peroral drug delivery systems. Drug Dev Ind Pharm 1989; 15: 1073-103. https://doi.org/10.3109/03639048909043666
Zhang Y, et al. DDSolver: An add-in program for modeling and comparison of drug dissolution profiles. AAPS J 2010; 12(3): 263-71. https://doi.org/10.1208/s12248-010-9185-1
Lepsy CS, Guttendorf RJ, Kugler AR, Smith DE. Effects of organic anion, organic cation, and dipeptide transport inhibitors on cefdinir in the isolated perfused rat kidney. Antimicrob Agents Chemother 2003; 47(2): 689-96. https://doi.org/10.1128/AAC.47.2.689-696.2003
Smeets A, Koekoekx R, Clasen C, Van Den Mooter G. Amorphous solid dispersions of darunavir: Comparison between spray drying and electrospraying. Eur J Pharm Biopharm 2018. https://doi.org/10.1016/j.ejpb.2018.06.021
Kwon J, Giri BR, Song ES, Bae J, Lee J, Kim DW. Spray-dried amorphous solid dispersions of atorvastatin calcium for improved supersaturation and oral bioavailability. Pharmaceutics 2019; 11(9). https://doi.org/10.3390/pharmaceutics11090461
Shinde Sunita S, Patil Manisha V, Amol Shete S, Disouza JI, Pranit A. Solid dispersions of poorly water soluble drug using spray drying technique. Int J Drug Deliv 2013; 5(3): 323-30.
El Maghraby G, Elsergany R. Fast disintegrating tablets of nisoldipine for intra-oral administration. Pharm Dev Technol 2014; 19(6): 641-50. https://doi.org/10.3109/10837450.2013.813543
Mohdavinia GR, Ettehadi S, Amini M, and Sabzi M. Synthesis and characterization of hydroxypropyl methylcellulose-g-poly(acrylamide)/LAPONITE® RD nanocomposites as novel magnetic- and pH sensitive carriers for controlled drug release. RSC Adv 2015; 5: 44516-23. https://doi.org/10.1039/C5RA03731J
Jena Pk, Singh S, Prajapati B, Nareshkumar G, Mehta T, Seshadri S. Impact of Targeted Specific Antibiotic Delivery for Gut Microbiota Modulation on High-Fructose-Fed Rats. Appl Biochem and Biotechnol 2014; 172(8): 3810-26. https://doi.org/10.1007/s12010-014-0772-y
Telang C, Mujumdar S, and Mathew M. Improved Physical Stability of Amorphous State through Acid Base Interactions. J Pharm Sci 2009; 98(6): 2149-59.https://doi.org/10.1002/jps.21584
Server NE, and Law D. WO2005100368A2. 2006.
Cabri W, et al. Cefdinir: A comparative study of anhydrous vs. monohydrate form. Microstructure and tabletting behaviour. Eur J Pharm Biopharm 2006; 64(2): 212-21. https://doi.org/10.1016/j.ejpb.2006.05.007
Chan S, Chung Y, Cheah X, Tan EY, Quah J. The characterization and dissolution performances of spray dried solid dispersion of Ketoprofen in hydrophilic carriers. Asian J Pharm Sci 2015; 10(5): 372-85. https://doi.org/10.1016/j.ajps.2015.04.003
Turner DT., Schartz A. The glass transition temperature of poly (n-vinyl pyrrolidone) by differential scanning calorimetry, Polymers 1985; 26: 757-62. https://doi.org/10.1016/0032-3861(85)90114-4
Al-mogherah AI, Abbas M, Abdelazeem M. Optimization and evaluation of venlafaxine hydrochloride fast dissolving oral films. Saudi Pharm J 2020; 28(11): 1374-82. https://doi.org/10.1016/j.jsps.2020.09.001
Ammar HO, Ghorab MM, Mahmoud AA, Noshi SH. Formulation of risperidone in floating microparticles to alleviate its extrapyramidal side effects. Futur J Pharm Sci 2016; 2(2): 43-59. https://doi.org/10.1016/j.fjps.2016.08.001
Amer MA, Essa EA, Donia AA, El Maghraby GM. Development and evaluation of liquid oral controlled release systems for Losartan potassium. J Appl Pharm Sci 2019; 9(8): 86-93. https://doi.org/10.7324/JAPS.2019.90812
Yang YY, Zhang M, Wang K, Yu DG. pH-sensitive polymer nanocoating on hydrophilic composites fabricated using modified coaxial electrospraying. Mater Lett 2018; 227: 93-96. https://doi.org/10.1016/j.matlet.2018.05.063
Jha DK, Shah DS, Amin PD. Thermodynamic aspects of the preparation of amorphous solid dispersions of Naringenin with enhanced dissolution rate. Int J Pharm 2020; 583, no. January, p. 119363. https://doi.org/10.1016/j.ijpharm.2020.119363
Fujimori M, Kadota K, Shimono K, Shirakawa Y, Sato H, Tozuka Y. Enhanced solubility of quercetin by forming composite particles with transglycosylated materials. J Food Eng 2015; 149: 248-54. https://doi.org/10.1016/j.jfoodeng.2014.10.010
Onoue S, et al. Improved dissolution and pharmacokinetic behavior of dipyridamole formulation with microenvironmental pH-modifier under hypochlorhydria. Int J Pharm 2012; 426(1-2): 61-66. https://doi.org/10.1016/j.ijpharm.2012.01.014
Ha NS, Tran TTD, Tran PHL, Park JB, Lee BJ. Dissolution-enhancing mechanism of alkalizers in poloxamer-based solid dispersions and physical mixtures containing poorly water-soluble valsartan. Chem Pharm Bull 2011; 59(7): 844-50. https://doi.org/10.1248/cpb.59.844
Xu WJ et al., Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers. Drug Deliv 2016; 23(1): 41-48. https://doi.org/10.3109/10717544.2014.903012
Rowe RC, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press. 2009 p.525- 33.
Liu X, Ma M, Kun E, Guo X, Yu Z, Zhang Z. Influence of lidocaine forms (salt vs. freebase) on properties of drug-eudragit® L100-55 extrudates prepared by reactive melt extrusion. Int J Pharm 2018; 547(1-2): 291-02. https://doi.org/10.1016/j.ijpharm.2018.06.009
Velasco MV, Ford JL, Rowe P, Rajabi-Siahboomi AR. Influence of drug:hydroxypropylmethylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets. J Control Release 1999; 57(1): 75-85. https://doi.org/10.1016/S0168-3659(98)00110-2
Fousteris E, Tarantili PA, KaravasE, Bikiaris D. Poly(vinyl pyrrolidone)-poloxamer-188 solid dispersions prepared by hot melt extrusion: Thermal properties and release behavior. J Therm Anal Calorim 2013; 113(3): 1037-47. https://doi.org/10.1007/s10973-012-2885-2
Yang M, et al. Microenvironmental pH-modified solid dispersions to enhance the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug: Preparation, characterization and evaluation in vivo. Int J Pharm 2014; 475(1-2): 97-109. https://doi.org/10.1016/j.ijpharm.2014.08.047
Marasini N, et al. Fabrication and evaluation of pH-modulated solid dispersion for telmisartan by spray-drying technique. Int J Pharm 2013; 441(1-2): 424-32. https://doi.org/10.1016/j.ijpharm.2012.11.012
Kayaert P, Van den Mooter G. An investigation of the adsorption of hydroxypropylmethyl cellulose 2910 5 mPa s and polyvinylpyrrolidone K90 around Naproxen nanocrystals. J Pharm Sci 2012; 101: 3916-23. https://doi.org/10.1002/jps.23267
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright (c) 2021 Raghad Al Nuss, Hind El-Zein