A Comparative Assessment of Capsule Formulations Based on Amorphous Solid Dispersion and Salt Formation of Indomethacin
DOI:
https://doi.org/10.32947/ajps.v25i5.1305Keywords:
Indomethacin, solid dispersion, Indomethacin sodium, hard gelatin capsules, flowabilityAbstract
Background: Indomethacin (IND) is a nonsteroidal anti-inflammatory drug (NSAID) that belongs to the BCS class II and exhibits poor dissolution in the GIT fluids. Solid dispersion (SD) and salt formation (SF) are two acceptable and widely used approaches for dissolution enhancement.
Objective: The aim of the present study is to formulate and in vitro evaluate capsules from IND-Soluplus® SD and IND sodium SF, and compare the dissolution profile of the formulated capsules with pure IND.
Methods: Both IND SD and SF were prepared by the solvent evaporation method and characterized for their production yield, drug content, in vitro release, solid state characterization, and stability studies. Capsules were prepared by manual filling into hard gelatin capsules with IND SD and IND SF used as a source for the active ingredient, lactose or mannitol as diluent, and three types of super disintegrants: croscarmellose sodium, crospovidone, and sodium starch glycolate. The prepared capsules were tested for flow properties, weight variation, content uniformity, disintegration time, and in vitro dissolution test.
Results: The solvent evaporation method successfully produced IND SD and SF with high production yield and drug content, which were above 95%. Solid state characterization revealed complete amorphization of IND in the SD without any incompatibility, while it was in its crystalline state in SF. Both IND SD and SF were stable during the storage period with minor changes in drug content and drug release. The results showed proper flow properties with acceptable results for the weight variation test (all around 500 mg since it is a size 0 capsule), capsule content uniformity (98-99 %), and disintegration time (4-9 min). The disintegration of hard gelatin capsules is impacted by the type of disintegrant used, with superior performance of crospovidone (4 min) and croscarmellose sodium (5.3 min) compared to sodium starch glycolate (7.1-7.4 min). IND solid dispersion showed an enhanced dissolution (100% within 45 min) compared to the pure IND capsules (less than 50% within 45 min) and IND SF (100% within 45 min). Also, the dissolution of IND SD capsules containing crospovidone was superior to those containing croscarmellose sodium and sodium starch glycolate.
Conclusions: Indomethacin SD proved its efficacy in enhancing the dissolution of IND compared to pure IND capsules and IND SF.
References
1- Schrieber R. Gelatine handbook: Theory and industrial practice: John Wiley & Sons; 2007.
2- Lachman L, Lieberman HA, Kanig JL. The theory and practice of industrial pharmacy: Lea & Febiger Philadelphia; 1976.
3- Zilhadia Z, Harahap Y, Jaswir I, Anwar E. Evaluation and characterization of hard-shell capsules formulated by using goatskin gelatin. Polymers. 2022;14(20):4416.
4- Dandić A, Rajkovača K, Jozanović M, Pukleš I, Széchenyi A, Budetić M, et al. Review of characteristics and analytical methods for determination of indomethacin. Reviews in analytical chemistry. 2022;41(1):34-62.
5- O'Brien M, McCauley J, Cohen E. Indomethacin. In: Florey K, editor. Analytical Profiles of Drug Substances. 13: Academic Press; 1984. p. 211-38.
6- Bittner B, Mountfield RJ. Intravenous administration of poorly soluble new drug entities in early drug discovery: the potential impact of formulation on pharmacokinetic parameters. Current opinion in drug discovery & development. 2002;5(1):59-71.
7- Chaudhary A, Nagaich U, Gulati N, Sharma V, Khosa R. Enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: A recent review. Journal of Advanced Pharmacy Education and Research. 2012;2(1-2012):32-67.
8- Pandi P, Bulusu R, Kommineni N, Khan W, Singh M. Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products. International journal of pharmaceutics. 2020;586:119560.
9- Hatem AQ, Ali WK. Preparation and characterization of carvedilol solid dispersion by kneading method. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2023;23(4):367-77.
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- Ali WK, Sabar MH, Habeeb AD, Mahdi ZH. Enhancing Dissolution of Ibuprofen via Solid Dispersion Using Hydrophilic Carrier and Fast Dissolving Sugars. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2014;14(1):52-61.
13- Serajuddin AT. Salt formation to improve drug solubility. Advanced drug delivery reviews. 2007;59(7):603-16.
14- Bani-Jaber A, Hamdan I, Al-Khalidi B. Sodium mefenamate as a solution for the formulation and dissolution problems of mefenamic acid. Chemical and Pharmaceutical Bulletin. 2007;55(8):1136-40.
15- Zhang W, Zhang C-n, He Y, Duan B-y, Yang G-y, Ma W-d, et al. Factors affecting the dissolution of indomethacin solid dispersions. Aaps Pharmscitech. 2017;18:3258-73.
16- Manosroi J, Chankhampan C, Foe K, Apriyani M, Manosroi W, Manosroi A. Inclusion Complexation of Indomethacin with Hydroxypropyl-beta-cyclodextrin. Chiang Mai J Sci. 2016;43(3):631-42.
17- Xu L, Li Y, Jing P, Xu G, Zhou Q, Cai Y, et al. Terahertz spectroscopic characterizations and DFT calculations of indomethacin cocrystals with nicotinamide and saccharin. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2021;249:119309.
18- Fael H, Demirel AL. Indomethacin co-amorphous drug-drug systems with improved solubility, supersaturation, dissolution rate and physical stability. International Journal of Pharmaceutics. 2021;600:120448.
19- Trasi NS, Bhujbal SV, Zemlyanov DY, Zhou QT, Taylor LS. Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach. International Journal of Pharmaceutics: X. 2020;2:100052.
20- Chinthala SP, Thummaluru RR. Formulation and In Vivo Evaluation of Trilayer Matrix Tablets of Rosuvastatin Solid Dispersions by Geomatrix Technology. International Journal of Pharmaceutical Sciences and Drug Research. 2021;13(3):334-42.
21- Ali MH, Ahmed KK. Preparation and Evaluation of Solid Dispersion-Based Bilastine Effervescent Granules. Al-Rafidain Journal of Medical Sciences (ISSN 2789-3219). 2024;6(2):116-23.
22- Trivedi MK, Panda P, Sethi KK, Gangwar M, Mondal SC, Jana S. Solid and liquid state characterization of tetrahydrocurcumin using XRPD, FT-IR, DSC, TGA, LC-MS, GC-MS, and NMR and its biological activities. Journal of pharmaceutical analysis. 2020;10(4):334-45.
23- Anwer MK, Ahmed MM, Alshetaili A, Almutairy BK, Alalaiwe A, Fatima F, et al. Preparation of spray dried amorphous solid dispersion of diosmin in soluplus with improved hepato-renoprotective activity: In vitro anti-oxidant and in-vivo safety studies. Journal of drug delivery science and technology. 2020;60:102101.
24- Wang F, Xiao X, Yuan Y, Liu J, Liu Y, Yi X. Solubilization of phloretin via steviol glycoside-based solid dispersion and micelles. Food chemistry. 2020;308:125569.
25- Ghobashy MM, Alshangiti DM, Alkhursani SA, Al-Gahtany SA, Shokr FS, Madani M. Improvement of in vitro dissolution of the poor water-soluble amlodipine drug by solid dispersion with irradiated polyvinylpyrrolidone. ACS omega. 2020;5(34):21476-87.
26- Tong M, Wu X, Zhang S, Hua D, Li S, Yu X, et al. Application of TPGS as an efflux inhibitor and a plasticizer in baicalein solid dispersion. European Journal of Pharmaceutical Sciences. 2022;168:106071.
27- S’ari M, Blade H, Cosgrove S, Drummond-Brydson R, Hondow N, Hughes LP, et al. Characterization of amorphous solid dispersions and identification of low levels of crystallinity by transmission electron microscopy. Molecular Pharmaceutics. 2021;18(5):1905-19.
28- KUMAR UA, SURESH G. Preparation and in vivo evaluation of candesartan cilexetil solid dispersions. Asian J Pharm Clin Res. 2021;14(8):129-33.
29- 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.
30- 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.
31- 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.
32- Chavan H, Chhabra G, Gujarathi N, Jadhav A. Comparative study of In-process and finished products quality control test for tablet and capsules according to pharmacopoeias. Asian Journal of Pharmaceutical Research and Development. 2018;6(3):60-8.
33- 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.
34- 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).
35- Brown W, Marques MR. 14 The United States Pharmacopeia/National Formulary. Generic Drug Product Development: Solid Oral Dosage Forms. 2013:319.
36- Lin H-L, Zhang G-C, Lin S-Y. Real-time co-crystal screening and formation between indomethacin and saccharin via DSC analytical technique or DSC–FTIR microspectroscopy. Journal of Thermal Analysis and Calorimetry. 2015;120:679-87.
37- Lavra ZMM, Pereira de Santana D, Ré MI. Solubility and dissolution performances of spray-dried solid dispersion of Efavirenz in Soluplus. Drug development and industrial pharmacy. 2017;43(1):42-54.
38- Valizadeh H, Nokhodchi A, Qarakhani N, Zakeri‐Milani P, Azarmi S, Hassanzadeh D, et al. Physicochemical characterization of solid dispersions of indomethacin with PEG 6000, Myrj 52, lactose, sorbitol, dextrin, and Eudragit® E100. Drug development and industrial pharmacy. 2004;30(3):303-17.
39- 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.
40- Sutthapitaksakul L, Thanawuth K, Sriamornsak P. Salt Formation, Stability Study and Tablet Formulation of Mefenamic Acid with Improved Drug Dissolution. Indian Journal of Pharmaceutical Sciences. 2022;84(6):1488-97.
41- Tran PH-L, Tran TT-D, Park JB, Lee B-J. Controlled release systems containing solid dispersions: strategies and mechanisms. Pharmaceutical research. 2011;28:2353-78.
42- Nyamba I, Sombie CB, Yabre M, Zime-Diawara H, Yameogo J, Ouedraogo S, et al. Pharmaceutical approaches for enhancing solubility and oral bioavailability of poorly soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics. 2024:114513.
43- Wang H, Li R, Rao Y, Liu S, Hu C, Zhang Y, et al. Enhancement of the bioavailability and anti-inflammatory activity of glycyrrhetinic acid via novel Soluplus®—a glycyrrhetinic acid solid dispersion. Pharmaceutics. 2022;14(9):1797.
44- Obaidat R, Alnaief M, Jaeger P. Significant solubility of carbon dioxide in Soluplus® facilitates impregnation of ibuprofen using supercritical fluid technology. Pharmaceutical development and technology. 2018;23(7):697-705.
45- Shamma RN, Basha M. Soluplus®: a novel polymeric solubilizer for optimization of carvedilol solid dispersions: formulation design and effect of method of preparation. Powder technology. 2013;237:406-14.
46- Liu Q, Li X, Liu B, Kong J, Wang Q, Gao Z. Using Polymers as Crystal Inhibitors to Prevent the Crystallization of the Rotigotine Patch. Pharmaceutics. 2024;16(5):630.
47- Butkevičiūtė A, Liaudanskas M, Ramanauskienė K, Janulis V. Biopharmaceutical Evaluation of Capsules with Lyophilized Apple Powder. Molecules. 2021;26(4):1095.
48- Hameed GS, Mohamed MBM, Sahib MN. Binary or ternary mixture of solid dispersion: Meloxicam case. Pharmacia. 2022;69:801-8.
49- 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).
50- Tekade AR, Yadav JN. A Review on Solid Dispersion and Carriers Used Therein for Solubility Enhancement of Poorly Water Soluble Drugs. Adv Pharm Bull. 2020;10(3):359-69.
51- Mukesh S, Joshi P, Bansal AK, Kashyap MC, Mandal SK, Sathe V, et al. Amorphous salts solid dispersions of celecoxib: enhanced biopharmaceutical performance and physical stability. Molecular Pharmaceutics. 2021;18(6):2334-48.
52- Dhaval M, Dudhat K, Gadoya A, Shah S, Pethani T, Jambukiya N, et al. Pharmaceutical Salts: Comprehensive Insights From Fundamental Chemistry to FDA Approvals (2019–2023). AAPS PharmSciTech. 2025;26(1):36.
53- Sutthapitaksakul L, Thanawuth K, Huanbutta K, Sriamornsak P. Effect of a superdisintegrant on disintegration of orally disintegrating tablets determined by simulated wetting test and in vitrodisintegration test. Die Pharmazie-An International Journal of Pharmaceutical Sciences. 2022;77(10):287-90.
54- Almiahi A, Fareed NY, Sattar M, Alshawi MA, Mousa MN. Effect of disintegrants on spironolactone tablet stability. International Journal of drug delivery technology. 2021;11(3):756-61.
55- Wankhede D, Mundhare D, Deshmukh L, Sawarkar S, Tohid S, Hakeem S, et al. A REVIEW ON SUPERDISINTEGRATING AGENT USED IN PHARMACEUTICAL FORMULATION. Volume. 2023;11:2320-882.
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