Formulation of Cefdinir Ternary Solid Dispersion and Stability Study under Harsh Conditions
DOI:
https://doi.org/10.32947/ajps.v25i1.1106Keywords:
Cefdinir, Ternary solid dispersion, Polyvinylpyrrolidone k30, Stability, CapsuleAbstract
Cefdinir (CEF) is classified as a third-generation cephalosporin within class IV of the Biopharmaceutical Classification System (BCS). Cefdinir has low solubility and permeability, which may reduce oral bioavailability.
The aim of this research was the preparation of cefdinir ternary solid dispersion in order to enhance its solubility. Then, after evaluating this ternary SD, investigate its stability under harsh conditions. In addition, formulation and evaluation of CEF ternary SD as capsule dosage form. The ternary SD is prepared by the solvent evaporation method using CEF, curcumin, and polyvinylpyrrolidone k30 in a weight ratio of 1:1:1. The ternary SD is subject to evaluation using Differential Scanning Calorimetry (DSC), Powder X-ray Diffractometry (PXRD), and Fourier Transform Infrared Spectroscopy (FTIR), saturated solubility, release, antibacterial activity, and a two months stability study under conditions of 40 ºC and 75% relative humidity. Then, six different capsule formulas were prepared using different excipients; each formula contained 300 mg of CEF. The capsule formulas were subjected to pre-formulation and capsule evaluation tests, which included weight variation, drug content, disintegration time, and In-vitro dissolution tests. The selected optimum capsule formula was subjected to further antibacterial activity test. Evaluation of ternary SD showed that, the system is totally amorphous with enhanced dissolution, saturated solubility, and antibacterial activity compared to pure CEF. Stability studies showed that, ternary SD remains amorphous after two months. Compared to commercial capsules (Sefarin® 300 mg) and other formulas, the F6 formula released 90% of CEF in 30 min. Antibacterial activity test results showed that the F6 formula was active against Staphylococcus aureus and Proteus vulgaris bacterial isolate. This research concludes that CEF solubility, antibacterial activity enhancement, and stability insurance could be obtained by preparing CEF ternary SD. All the ternary SD prepared capsule formulas showed enhancements in release compared to commercial capsules.
References
1- Hameed GS. Controlling phase transformation during milling in the pre-formulation of Active pharmaceutical Ingredients. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2019;19(2):37-46.
2- Baghel S, Cathcart H, O'Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. Journal of pharmaceutical sciences. 2016;105(9):2527-44.
3- Jermain SV, Brough C, Williams III RO. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery–an update. International journal of pharmaceutics. 2018;535(1-2):379-92.
4- Wani SUD, Kakkar V, Gautam SP, Gangadharappa H, Ali M, Masoodi MH, et al. Enhancing therapeutic potential of poor aqueous soluble herbal drugs through solid dispersion-An overview. Phytomedicine Plus. 2021;1(4):100069.
5- Hashim GM, Hameed GS, Hanna DB. The possible techniques that used to improve the bioavailablity, pharmacological activity, solubility and permeability of anti-viral drugs: Insight for COVID-19 antiviral drugs. AJPS. 2023:231.
6- Bhujbal SV, Mitra B, Jain U, Gong Y, Agrawal A, Karki S, et al. Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies. Acta Pharmaceutica Sinica B. 2021;11(8):2505-36.
7- Schittny A, Huwyler J, Puchkov M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Delivery. 2020;27(1):110-27.
8- Liu X, Feng X, Williams RO, Zhang F. Characterization of amorphous solid dispersions. Journal of Pharmaceutical Investigation. 2018;48:19-41.
9- ISMAEL QA, HAMEED GS, AZIZ FM. Effect of Introduction of Polymers on the Antibacterial Activity of Crystalline Antibiotics. International Journal of Pharmaceutical Research (09752366). 2020;12(3).
10- Akram A, Irfan M, Abualsunun WA, Bukhary DM, Alissa M. How to Improve Solubility and Dissolution of Irbesartan by Fabricating Ternary Solid Dispersions: Optimization and In-Vitro Characterization. Pharmaceutics. 2022;14(11):2264.
11- Kyeremateng SO, Voges K, Dohrn S, Sobich E, Lander U, Weber S, et al. A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development. Pharmaceutics. 2022;14(5):1044.
12- Sarpal K, Munson EJ. Amorphous solid dispersions of felodipine and nifedipine with Soluplus®: drug-polymer miscibility and intermolecular interactions. Journal of Pharmaceutical Sciences. 2021;110(4):1457-69.
13- Saberi A, Kouhjani M, Yari D, Jahani A, Asare-Addo K, Kamali H, et al. Development, recent advances, and updates in binary, ternary co-amorphous systems, and ternary solid dispersions. Journal of Drug Delivery Science and Technology. 2023:104746.
14- Borde S, Paul SK, Chauhan H. Ternary solid dispersions: Classification and formulation considerations. Drug Development and Industrial Pharmacy. 2021;47(7):1011-28.
15- Tian B, Ju X, Yang D, Kong Y, Tang X. Effect of the third component on the aging and crystallization of cinnarizine-soluplus® binary solid dispersion. International Journal of Pharmaceutics. 2020;580:119240.
16- Shi X, Xu T, Huang W, Fan B, Sheng X. Stability and bioavailability enhancement of telmisartan ternary solid dispersions: the synergistic effect of polymers and drug-polymer (s) interactions. AAPS PharmSciTech. 2019;20:1-13.
17- Tai K, Rappolt M, Mao L, Gao Y, Li X, Yuan F. The stabilization and release performances of curcumin-loaded liposomes coated by high and low molecular weight chitosan. Food Hydrocolloids. 2020;99:105355.
18- Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G. Curcumin—from molecule to biological function. Angewandte Chemie International Edition. 2012;51(22):5308-32.
19- Mun S-H, Kim S-B, Kong R, Choi J-G, Kim Y-C, Shin D-W, et al. Curcumin reverse methicillin resistance in Staphylococcus aureus. Molecules. 2014;19(11):18283-95.
20- El-Shereafy S, Gomaa E, Yousif A, Abou El-Yazed A. Electrochemical and thermodynamic estimations of the interaction parameters for bulk and nano-silver nitrate (NSN) with cefdinir drug using a glassy carbon electrode. Iranian Journal of Materials Science & Engineering. 2017;14(4):48-57.
21- Dinç E, Dermiş S, Can Akcasoy S, Ceren Ertekin Z. A New Chemometric strategy in electrochemical method optimization for the quantification of cefdinir in tablets, effervescent tablets and suspension samples. Electroanalysis. 2020;32(3):613-9.
22- Abou‐Taleb NH, El‐Wasseef DR, El‐Sherbiny DT, El‐Ashry SM. Optimizing the spectrofluorimetric determination of cefdinir through a Taguchi experimental design approach. Luminescence. 2016;31(3):856-64.
23- 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. Journal of Drug Delivery Science and Technology. 2020;57:101742.
24- 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 development and industrial pharmacy. 2016;42(5):758-68.
25- Al Okla S, Prashanth GP, Kurbet S, Al Attraqchi Y, Asaad A. Emergent “Bloody Diarrhea” Associated with the Use of Oral Cefdinir in Young Children: A Brief Report and Review of Literature. The Journal of Emergency Medicine. 2023.
26- Al Nuss R. pH-Modified Solid Dispersions of Cefdinir for Dissolution Rate Enhancement: Formulation and Characterization. J Pharm Nutr Sci. 2021;11:101-15.
27- Al-Badr AA, Alasseiri FA. Cefdinir. Profiles of Drug Substances, Excipients and Related Methodology. 2014;39:41-112.
28- Kim YC, Kim I-B, Noh C-K, Quach HP, Yoon I-S, Chow EC, et al. Effects of 1α, 25-dihydroxyvitamin D3, the natural vitamin D receptor ligand, on the pharmacokinetics of cefdinir and cefadroxil, organic anion transporter substrates, in rat. Journal of Pharmaceutical Sciences. 2014;103(11):3793-805.
29- Jung D-H, Song JG, Han H-K. Development and evaluation of a sustained release solid dispersion of cefdinir using a hydrophobic polymeric carrier and aminoclay. Journal of Drug Delivery Science and Technology. 2023;84:104503.
30- Guay DR. Cefdinir: an advanced-generation, broad-spectrum oral cephalosporin. Clinical therapeutics. 2002;24(4):473-89.
31- 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.
32- Al Nuss R, El Zein H. Cefdinir Inclusion in Mesoporous Silica as Effective Dissolution Enhancer with Improved Physical Stability. J Pharm Nutr Sci. 2021;11:73-86.
33- 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. Journal of pharmaceutical and biomedical analysis. 2008;47(3):535-40.
34- Bansal S, Aggarwal G, Chandel P, Harikumar S. Design and development of cefdinir niosomes for oral delivery. Journal of pharmacy & bioallied sciences. 2013;5(4):318.
35- Park J, Park HJ, Cho W, Cha K-H, Kang Y-S, Hwang S-J. Preparation and pharmaceutical characterization of amorphous cefdinir using spray-drying and SAS-process. International journal of pharmaceutics. 2010;396(1-2):239-45.
36- Jain S, Jain S, Mishra A, Garg G, Modi RK. Formulation and characterization of fast disintegrating tablets containing Cefdinir solid dispersion. International Journal of Pharmacy & Life Sciences. 2012;3(12).
37- Cho H-J, Jee J-P, Kang J-Y, Shin D-Y, Choi H-G, Maeng H-J, et al. Cefdinir solid dispersion composed of hydrophilic polymers with enhanced solubility, dissolution, and bioavailability in rats. Molecules. 2017;22(2):280.
38- Bali DE, Arafa MF, Gamaleldin NM, El Maghraby GM. Nanographene oxide for enhanced dissolution rate and antibacterial activity of cefdinir. Journal of Drug Delivery Science and Technology. 2021;62:102411.
39- Arora S, Sharma P, Irchhaiya R, Khatkar A, Singh N, Gagoria J. Development, characterization and solubility study of solid dispersions of cefuroxime axetil by the solvent evaporation method. Journal of Advanced Pharmaceutical Technology & Research. 2010;1(3):326.
40- Douroumis D, Bouropoulos N, Fahr A. Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method. Journal of pharmacy and pharmacology. 2007;59(5):645-53.
41- abbakhian M, Hasanzadeh F, Tavakoli N, Jamshidian Z. Dissolution enhancement of glibenclamide by solid dispersion: solvent evaporation versus a supercritical fluid-based solvent-antisolvent technique. Research in pharmaceutical sciences. 2014;9(5):337.
42- Nagaraj K, Narendar D, Kishan V. Development of olmesartan medoxomil optimized nanosuspension using the Box–Behnken design to improve oral bioavailability. Drug development and industrial pharmacy. 2017;43(7):1186-96.
43- Garrepally P, Gonugunta CSR. Studies on development and characterization of gastroretentive drug delivery system for antibiotics: Cefdinir. Journal of pharmacy research. 2013;6(8):836-44.
44- Obaidat RM, Khanfar M, Ghanma R. A comparative solubility enhancement study of cefixime trihydrate using different dispersion techniques. AAPS PharmSciTech. 2019;20:1-13.
45- Kim K-I, Han C-H, Choe Y-A, Ju K-S, Ri D-H, Ri S-B, et al. Influence of temperature and humidity on the detection of benzene vapor by a piezoelectric crystal sensor. Instrumentation Science & Technology. 2019;47(4):436-47.
46- Müller D, Fimbinger E, Brand C. Algorithm for the determination of the angle of repose in bulk material analysis. Powder Technology. 2021;383:598-605.
47- Aulton ME, Taylor K. Aulton's pharmaceutics: the design and manufacture of medicines: Elsevier Health Sciences; 2013.
48- Mudrić J, Arsenijević J, Maksimović Z, Ibrić S, Gopčević K, Đuriš J. Tablet and capsule formulations incorporating high doses of a dry optimized herbal extract: The case of Satureja kitaibelii. Journal of Drug Delivery Science and Technology. 2021;66:102776.
49- Gaisford S, Saunders M. Essentials of pharmaceutical preformulation: John Wiley & Sons; 2012.
50- Hoag S. Capsules dosage form: formulation and manufacturing considerations. Developing solid oral dosage forms: Elsevier; 2017. p. 723-47.
51- Sager M, Grimm M, Jedamzik P, Merdivan S, Kromrey M-L, Hasan M, et al. Combined application of MRI and the salivary tracer technique to determine the in vivo disintegration time of immediate release formulation administered to healthy, fasted subjects. Molecular Pharmaceutics. 2019;16(4):1782-6.
52- Stegemann S, Bornem C. Hard gelatin capsules today-and tomorrow: Capsugel Library; 1999.
53- Khar R, Vyas S, Ahmed F. Jain Gk. Lachman/liebermans: the theory and practice of industrial pharmacy. Novel drug delivery systems 4th ed New Delhi: CBS Publishers and Distributor. 2015:883-5.
54- Gusev PA, Andrews KW, Savarala S, Tey P-T, Han F, Oh L, et al. Disintegration and dissolution testing of green tea dietary supplements: Application and evaluation of United States Pharmacopeial standards. Journal of Pharmaceutical Sciences. 2020;109(6):1933-42.
55- HAMEED GS, MOHAMED M, BASIM M, MOHAMMED YA. Effect of storage condition on the physicochemical properties of ibuprofen. International Journal of Pharmaceutical Research (09752366). 2020;12(2).
56- Brown W, Marques MR. 14 The United States Pharmacopeia/National Formulary. Generic Drug Product Development: Solid Oral Dosage Forms. 2013:319.
57- Alhasan DA. In Vitro Antimicrobial Activity of Curcumin-Copper Complex. University of Thi-Qar Journal. 2021;16(1):73-97.
58- Albadarin AB, Potter CB, Davis MT, Iqbal J, Korde S, Pagire S, et al. Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion. International journal of pharmaceutics. 2017;532(1):603-11.
59- Al-Japairai KA, Alkhalidi HM, Mahmood S, Almurisi SH, Doolaanea AA, Al-Sindi TA, et al. Lyophilized amorphous dispersion of telmisartan in a combined carrier–alkalizer system: Formulation development and in vivo study. ACS omega. 2020;5(50):32466-80.
60- Tang J, Bao J, Shi X, Sheng X, Su W. Preparation, optimisation, and in vitro–in vivo evaluation of febuxostat ternary solid dispersion. Journal of microencapsulation. 2018;35(5):454-66.
61- Convention USP, Convention USP. < 1174> Powder flow. US Pharmacopoeia Rockville, MD, USA; 2012.
62- Zaid AN, Rowa’J A-R, Ghoush AA, Qaddumi A, Zaaror YA. Weight and content uniformity of lorazepam half-tablets: A study of correlation of a low drug content product. Saudi Pharmaceutical Journal. 2013;21(1):71-5.
63- Khar RK. Lachman/liebermans: the theory and practice of industrial pharmacy: Cbs Publishers & Distribu; 2013.
64- Revision USPCCo, editor The United States Pharmacopeia1985: United States Pharmacopeial Convention, Incorporated.
65- Garbacz G, Cadé D, Benameur H, Weitschies W. Bio-relevant dissolution testing of hard capsules prepared from different shell materials using the dynamic open flow through test apparatus. European Journal of Pharmaceutical Sciences. 2014;57:264-72.
66- Berardi A, Bisharat L, Blaibleh A, Pavoni L, Cespi M. A simple and inexpensive image analysis technique to study the effect of disintegrants concentration and diluents type on disintegration. Journal of Pharmaceutical Sciences. 2018;107(10):2643-52.
67- Berkenkemper S, Keizer HL, Lindenberg M, Szepes A, Kleinebudde P. Functionality of disintegrants with different mechanisms after roll compaction. International Journal of Pharmaceutics. 2020;584:119434.
68- Balata GF, Zidan AS, Abourehab MA, Essa EA. Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene–polypropylene block copolymer for maximized disintegration and dissolution. Drug Design, Development and Therapy. 2016:3211-23.
69- Chaerunisaa AY, Sriwidodo S, Abdassah M. Microcrystalline cellulose as pharmaceutical excipient. Pharmaceutical formulation design-recent practices: IntechOpen; 2019.
70- Mendes C, Valentini G, Chamorro Rengifo AF, Pinto JM, Silva MA, Parize AL. Supersaturating drug delivery system of fixed drug combination: sulfamethoxazole and trimethoprim. Expert review of anti-infective therapy. 2019;17(10):841-50.
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