Resumen
Introducción. La solubilidad y la velocidad de disolución son dos factores fisicoquímicos clave en la eficacia terapéutica de un fármaco administrado por vía oral, ya que estos parámetros determinan la cantidad de fármaco disponible para su absorción. En este contexto, el desarrollo de co-amorfos farmacéuticos es una estrategia prometedora para mejorar la solubilidad y la velocidad de disolución de compuestos poco solubles en medios fisiológicos. En este sentido, la sulfasalazina se caracteriza por una elevada permeabilidad intestinal pero una baja solubilidad que resulta en una biodisponibilidad menor al 15%. Con base en lo anterior, la obtención de sistemas co-amorfos de sulfasalazina que posean mayor solubilidad y velocidad de disolución, incrementaría la cantidad de fármaco disponible para su absorción, mejorando su biodisponibilidad y su eficacia terapéutica. Objetivo: Obtener y caracterizar química y biofarmacéuticamente un co-amorfo de sulfasalazina:L-Arginina con propiedades mejoradas de solubilidad y velocidad de disolución. Metodología el co-amorfo se obtuvo mediante las técnicas de slurry y de molienda mecanoquímica en proporción 1:1 de sulfasalazina y L-Arginina. Su caracterización incluyó la difracción de rayos X para determinar su naturaleza cristalina o amorfa, espectroscopía FT-IR y microscopía Raman para analizar interacciones intermoleculares y homogeneidad. La estabilidad térmica y la presencia de solvatos o hidratos fueron evaluadas con calorimetría diferencial y termogravimetría. Además, se analizaron su estabilidad en medios fisiológicos, solubilidad y la velocidad de disolución. Resultados: Se obtuvo un co-amorfo puro con estequiometría sulfasalazina: L-Arginina:agua de 1:1:2, estable hasta 50 °C sin humedad y hasta 40 °C con 75 % de humedad relativa. Este mostró estabilidad en medios con pH 1.2, 4.5 y 6.8, y triplicó la solubilidad y la velocidad de disolución en comparación con la sulfasalazina libre. Conclusión: La obtención de un co-amorfo estable y con mejor solubilidad sugiere un potencial aumento en la biodisponibilidad de la sulfasalazina, favoreciendo su aplicación en formulaciones más eficaces.
Co-amorphous of sulfasalazine:arginine with improved solubility and dissolution
rate properties for enhanced bioavailability and therapeutic efficacy
Introduction: Solubility and dissolution rate are two key physicochemical factors in the therapeutic efficacy of an orally administered drug, as these parameters determine the amount of drug available for absorption. In this context, the development of pharmaceutical co-amorphoses is a promising strategy to improve both solubility and dissolution rate of poorly soluble compounds in physiological media. Sulfasalazine is characterised by high intestinal permeability but low solubility, resulting in a bioavailability of less than 15%. Based on the above, obtaining co-amorphous of sulfasalazine with higher solubility and dissolution rate would increase the amount of drug available for absorption, thereby improving its bioavailability. Objective: To obtain and characterize chemically and biopharmaceutically a sulfasalazine: L-arginine co-amorphous with improved solubility and dissolution rate properties. Methods The co-amorphous is obtained by slurry and/or mechanochemical milling in a 1:1 ratio of sulfasalazine and L- rginine. Its characterization included X-ray diffraction to determine its crystalline or amorphous nature, FT-IR spectroscopy and Raman microscopy to analyze intermolecular interactions and homogeneity. Thermal stability and the presence of solvates or hydrates were evaluated by differential calorimetry and thermogravimetry. In addition, their stability in physiological media, solubility and dissolution rate were analyzed. Results: A pure co-amorphous was obtained with a sulfasalazine:L-arginine:water stoichiometry of 1:1:2, which was stable up to 50°C without humidity and up to 40°C with 75% relative humidity. It showed stability in media with pH 1.2, 4.5 and 6.8 and tripled the solubility and dissolution rate compared to free sulfasalazine. Conclusion: Obtaining a stable co-amorph with better solubility suggests a potential increase in the bioavailability of sulfasalazine, favoring its application in more effective formulations.
Citas
Byrn SR et al. Solid-State Properties of Pharmaceutical Materials, 1st edn. New Delhi: John Wiley & Sons, 2017. b) Hilfiker R, Blatter F. Relevance of Sol-id-state Properties for Pharmaceutical Products, Chap 1. In Hilfiker R, ed. Poly-morphism: in the Pharmaceutical Industry. Weinheim: Wiley-VCH GmbH & Co, 2006:1-19.
Aaltonen J, Rades T. Towards Physico-Relevant Dissolution Testing: The Im-portance of Solid-State Analysis in Dissolution. Dissol Tech 2009; 16: 47-54.
Hancock B C, Zografi G J. Characteristics and significance of the amorphous state in pharmaceutical systems. Pharm. Sci. 1997, 86(1), 1-12.
Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv. Drug Delivery Rev. 2001; 48(1): 27-42.
Löbmann K, Laitinen R, Grohganz H, Gordon K C, Strachan C, Rades T. Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen. Mol. Pharmaceutics. 2011; 8(5): 1919-1928.
Laitinena R, Löbmanna K, Strachana C J, Grohganzb H, Rades T. Emerging trends in the stabilization of amorphous drugs. Int. J. Pharm. 2013; 453(1): 65-79.
Dengele S J, Grohganz H, Rades T, Löbmann K. Recent Advances in Co-amor-phous Drug Formulations. Adv. Drug Deliv. Rev. 2016; 100: 116-125.
Choi J, Patel P, Fenando A. Sulfasalazine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025. Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK557809/
The United States Pharmacopeia. National Formulary 36. Vol. 1. Rockville (MD: United State Pharmacopeial Convention; 2018. Test Solutions; p. 5676.
Wood J H, Syarto J E, Letterman H. Improved Holder for Intrinsic Dissolution Rate Studies. J. Pharm. Sci. 1965; 54(7): 1068-1068.
Safa A N, Sheibani A, Baei M T, Sayyed-Alangi S Z, Tazikeh Lemeski E. Theo-retical and experimental studies on sulfasalazine interactions with poly (lactic acid): Impact of hydrogen bonding and charge transfer interactions on mo-lecular structure, electronic and optical properties. Heliyon. 2023 16; 10(1): e23813.
Roda A, Santos F, Chua Y Z, Kumar A, Do H T, Paiva A, Duarte A R C, Held C. Unravelling the nature of citric acid:l-arginine:water mixtures: the bifunctional role of water. Phys. Chem. Chem. Phys. 2021; 23: 1706-1717.
Bunaciu A A, UdriŞtioiu E G, Aboul-Enein H Y. X-Ray diffraction: Instrumen-tation and Applications. Crit. Rev. Anal. Chem. 2015; 45: 289-299.
Thakral S, Terban M W, Thakral N K, Suryanarayanan R. Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry. Adv. Drug Deliv. Rev. 2016; 100: 183-193.
Kaushal A M, Chakraborti A K, Bansal K. FTIR Studies on Differential In-termolecular Associationin Crystalline and Amorphous States of Structural-lyRelated Non-Steroidal Anti-Inflammatory Drugs. Mol. Pharmaceutics. 2008; 5(6): 937-945.
Han Y, Pan Y, Lv J, Guo W, Wang J. Powder Grinding preparation of co-amor-phous β-azelnidipine and maleic acid combination: Molecular interactions and physicochemical properties. Powder Technol. 2016; 291: 110-120.
Widjaja E, Sampanthar J T, Ding Han X, Goh E. Use of Raman microscopy and band-target entropy minimization technique to differentiate physical mixture from chemical mixture in mixed metal oxides. Catal. Today. 2008; 131(1-4):21-27.
Kilpeläinena T, Pajulaa K, Ervasti T, Uurasjärvi E, Koistinen A, Korhonen O. Raman imaging of amorphous-amorphous phase separation in small mol-ecule co-amorphous systems. Eur. J. Pharm. Biopharm. 2020; 155:49-54
Suresh K, Chaitanya Mannava M K, Nangia, A. A novel curcumin–artemis-inin coamorphous solid: physical properties and pharmacokinetic profile. RSC Adv. 2014; 4: 58357-58361.
Chiou W L, Riegelman S. A Pharmaceutical applications of solid disper-sion systems. J. Pharm. Sci. 1971; 60(9): 1281–1302.
Kaushal A M, Chakraborti A K, Bansal A K. FTIR Studies on Differential Intermolecular Association in Crystalline and Amorphous States of Struc-turally Related Non-Steroidal Anti-Inflammatory Drugs. Mol. Pharmaceutics. 2008; 5(6): 937-945. b) Kaushal A M; Bansal A K. Thermodynamic behavior of glassy state of structurally related compounds. Eur. J. Pharm. Biopharm. 2008, 69,1067-1076.
Babu N J, Nangia, A. Solubility Advantage of Amorphous Drugs and Phar-maceutical Cocrystals. Cryst. Growth Des. 2011; 11(7): 2662-2679.
Bavishi D D, Borkhataria C H. Spring and parachute: How cocrystals en-hance solubility. 2016; 62(3): 1-8. b) Fujita.
Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial 4.0.