Solid dispersion of glimepiride for the production of antidiabetic drugs.

Description

1 / 13 Solid dispersion of glimepiride for the production of antidiabetic drugs. Field of invention

[01] The present invention relates to a coamorphous solid dispersion obtained from the intermolecular interaction between the drug glimepiride (GLP) and the coformer tromethamine (TRIS) in a molar ratio of 1:1. GLP, chemically known as 1-[[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolino-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea, hereinafter referred to as Compound I in this application, has the molecular formula C24H34N4O5S. TRIS, chemically known as 2-amino-2-(hydroxymethyl)propane-1,3-diol, hereinafter referred to as Compound II in this application, has the molecular formula C4HHNO3. Compound I Compound II ch2oh c—nh2ch2oh

[02] The present invention falls within the field of invention relating to the specific therapeutic activity of chemical compounds or medicinal preparations for the production of antidiabetic drugs. Fundamentals of the Invention

[03] Compound I (490.62 g / mol) is a second-generation sulfonylurea used in the treatment of Diabetes Mellitus Petition 870240110054, dated 12 / 26 / 2024, p. 7 / 25 2 / 13 Type 2. This pathology occurs when there is not enough insulin or the body cannot properly use the insulin produced. This medication increases the number of glucose transporter molecules in the plasma membrane of adipose and muscle tissue, thus improving glucose uptake. (IWATA, M. et al. Glimepiride. Acta Crystallographica Section C: Crystal Structure Communications, v. 53, n. 3, p. 329-331, 1997. DOI: https: / / doi.org / 10.1107 / S0108270196002363; HYDRIE, M. et al. Glimepiride study on type-2 diabetic subjects. Pakistan Journal of Medical Sciences, vol. 22, no. 2, p. 132, 2006.)

[04] Compound I is practically insoluble in water and exhibits high membrane permeability, belonging to Class II of the Biopharmaceutical Classification System (BCS). It is chemically known as 1-[[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolino-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea. It appears as a white or almost white powder, being soluble in dimethylformamide, slightly soluble in methylene chloride and very slightly soluble in methanol, in addition, it has a pKa of 6.3. (PHARMACOPOEIA, E. EUROPEAN PHARMACOPOEIA. 10. ed. Strasbourg: Council of Europe, 2019; SEEDHER, N.; KANOJIA, M. Mechanism of interaction of hypoglycemic agents glimepiride and glipizide with human serum albumin. Central European Journal of Chemistry, v. 7, n. 1, p. 96-104, 2009. DOI: https: / / doi.org / 10.2478 / s11532-008-0080-x.) Petition 870240110054, dated 12 / 26 / 2024, p. 8 / 25 3 / 13

[05] Compound II (121.14 g.mol⁻¹) is used as a coformer in the production of solid dispersions by improving the physicochemical properties of drugs, such as dissolution rate, bioavailability of poorly soluble drugs, and stability. Furthermore, it has important applications in the study of restoring the pH of body fluids and alterations in acid-base balance. (ABDELKADER, H.; ABDALLAH, OY; SALEM, HS Comparison of the effect of tromethamine and polyvinylpyrrolidone on dissolution properties and analgesic effect of nimesulide. Pharmaceutical Science. Drug Discovery Today, v. 13, n.

[06] Compound II exhibits high aqueous solubility (5.50 x 10 mg.L⁻¹) and high membrane permeability, belonging to Class I of the SCB. It is chemically known as tris(hydroxymethyl)aminomethane. Furthermore, it is presented as a white crystalline powder or colorless crystals, with pKa = 8.1. (BATES, RG; ROBINSON, RA Tris(hydroxymethyl)aminomethane. Useful secondary pH standard. Analytical Chemistry, v. 45, n. 2, p. 420-420, 1973. DOI: https: / / doi.org / 10.1021 / ac60324a021.)

[07] The therapeutic efficacy of drugs depends on their physicochemical properties, morphological characteristics, Petition 870240110054, dated 12 / 26 / 2024, page 9 / 25 4 / 13 Particle size and shape presented. Furthermore, water solubility is extremely important for drugs administered orally, because aqueous solubility regulates the pharmacological and biopharmaceutical profiles of absorption, metabolism, elimination, and distribution of these substances in the body. (CID, AG et al. Solid dispersion technology as a strategy to improve the bioavailability of poorly soluble drugs. Therapeutic delivery, v. 10, n. 6, p. 363-382, 2019. DOI: https: / / doi.org / 10.4155 / tde-2019-0007.)

[08] Due to low aqueous solubility and low membrane permeability, drugs administered orally may have their therapeutic efficacy affected. Therefore, to achieve the desired therapeutic effect, higher doses of the drug may be prescribed. However, with the ingestion of high doses of the drug, adverse effects may occur and increase the rates of drug treatment abandonment. (O'HARA, T. et al. A review of methods used to compare dissolution profile data. Pharmaceutical Science & Technology Today, v. 1, n. 5, p. 214-223, 1998. DOI: https: / / doi.org / 10.1016 / S1461-5347(98)00053-4.)

[09] Amorphous forms tend to exhibit high levels of supersaturation in aqueous media compared to crystals, thus demonstrating greater solubility in water. However, amorphous materials generally exhibit thermodynamic instability, generating concern regarding their tendency to recrystallize during storage, limiting Petition 870240110054, dated 12 / 26 / 2024, page 10 / 25 5 / 13 Thus, its pharmaceutical application. Therefore, as a way to stabilize the amorphous form, coamorphous solid drug dispersions (SDPs) emerge as an alternative to overcome this instability, in which the active pharmaceutical ingredient (API) interacts with one or more coformers, generating a homogeneous amorphous system. (NEWMAN, A. et al. Assessing the performance of amorphous solid dispersions. Journal of Pharmaceutical sciences. n. 11, v. 97, p. 1355-77, 2012. DOI: https: / / doi.org / 10.1002 / jps.23031; KARAGIANNI, A.; KACHRIMANIS, K.; NIKOLAKAKIS, I.; Co-Amorphous Solid Dispersions for Solubility and Absorption Improvement of Drugs: Composition, Preparation, Characterization and Formulations for Oral Delivery. Pharmaceutics. n. 3, vol. 10, p. 2-26, 2018.DOI: https: / / doi.org / 10.3390 / pharmaceutics10030098; PAJULA, K. et al. Phase separation in coamorphous systems: in silico prediction and the experimental challenge of detection. Molecular Pharmaceutics, vol. 11, no. 7, p. 2271-2279, 2014. DOI: https: / / doi.org / 10.1021 / mp400712m.)

[010] Coamorphs lack long-range structural order, hence the absence of crystallographic peaks in X-ray diffractograms and the presence of halos. They exhibit short-range molecular organization, lacking periodicity, which is related to the short hydrogen bonds between their functional groups and weak intermolecular bonds between the components of the system. Petition 870240110054, dated 12 / 26 / 2024, page 11 / 25 6 / 13 (CHAVAN, RB et al. Co amorphous systems: A product development perspective. International journal of pharmaceutics, v. 515, n. 1-2, p. 403-415, 2016. DOI: https: / / doi.Org / 10.1016 / j.ijpharm.2016.10.043) [Oil] Through different types of methods, DSFs can be obtained, such as mechanochemical milling, melting, lyophilization, spray-drying, and slow solvent evaporation. The solvent evaporation (SE) method consists of dispersing or dissolving a coformer or active pharmaceutical ingredient (API) in a solvent, after which the solvent is evaporated. (PAUDWAL, G. et al. Recent advances in solid dispersion technology for efficient delivery of poorly water soluble drugs. Current pharmaceutical design, v. 25, n. 13, p. 1524-1535, 2019. DOI: https: / / doi.org / 10.2174 / 1381612825666190618121553; CHAVAN, RB SHASTRI, NR Overview of Multicomponent Solid Forms. Journal of Nanotoxicology and Nanomedicine (JNN), v. 3, n. 1, p. 23-48, 2018. DOI: 10.4018 / JNN.2018010102; Pharmaceutics: X, v.2, p. 100052, 2020. DOI: https: / / doi.Org / 10.1016 / j.ijpx.2020.100052.).

[012] In this context, a coamorphous solid dispersion of glimepiride using tromethamine as Petition 870240110054, dated 12 / 26 / 2024, p. 12 / 25 The 7 / 13 coformer should be able to improve the aqueous solubility and dissolution rate of this drug. Brief description of the drawings

[013] Figure 1 presents the methodological scheme used to obtain the GLP-TRIS coamorph in a 1:1 molar ratio by the solvent evaporation method (dimethylformamide - DMF).

[014] Figure 2 shows: (a) the diffraction profiles of the starting compounds recrystallized by ES (GLPREC and TRISREC), the GLP-TRIS (1:1) coamorph and the physical mixture of GLP-TRIS (1:1)MF; (b), (c) and (d) the diffractograms of GLPREC, TRISREC and GLP-TRIS (1:1)MF subjected to refinement by the Rietveld method.

[015] Figure 3 shows: the DSC curves of the recrystallized starting compounds (GLPREC and TRISREC), the GLP-TRIS (1:1) coamorph and the GLP-TRIS (1:1)MF physical mixture. Description of the invention

[016] The present invention relates to a coamorphous type solid dispersion obtained from the intermolecular interaction of the drug glimepiride (GLP) with tromethamine (TRIS), in a molar ratio of 1:1.

[017] Dimethylformamide (DMF) was used to solubilize the starting compounds, and it was evaporated during the coamorph production process. Figure 1 shows the methodological scheme for obtaining the GLP-TRIS coamorph at a 1:1 molar ratio. Petition 870240110054, dated 12 / 26 / 2024, p. 13 / 25 8 / 13 Method of obtaining

[018] The invention was obtained by means of the solvent evaporation (SE) technique. For this purpose, masses containing the equivalent of the starting compounds of LPG (80.88 mg) and TRIS (20.00 mg) were weighed so that the binary mixture was in a molar ratio of 1:1. Then, these masses were transferred to a 250.0 mL beaker and completely solubilized in 30.0 mL of DMF. Subsequently, the solution was placed in an incubator at 50.0±1.0 °C, under agitation at 150 rpm for 4 h. The resulting material was then dried in a forced-air circulation oven at 50.0±1.0 °C for 2 h, collected and stored in a desiccator for characterization. The starting compounds (GLP and TRIS) are also subjected to ES recrystallization, being named GLPREC and TRISREC, to verify the possible occurrence of polymorphism in these compounds.In order to verify the occurrence of interaction between the starting compounds through simple physical contact, a physical mixture (PM) was obtained between GLP and TRIS in a molar ratio of 1:1.

[019] Compounds I and II, the GLP-TRIS (1:1) coamorphous compound and the GLP-TRIS (1:1) physical mixture were characterized by powder X-ray diffractometry (PXRD). For this purpose, a Bragg-Brentano (2Θ) reflection geometry diffractometer with Cu Κα radiation (λ = 1.5418 Â) was used, operating at a voltage of 40 kV and a current of 30 mA. The analyses were performed with a step of 0.02°, a time per step of 2 seconds and Petition 870240110054, dated 12 / 26 / 2024, page 14 / 25 9 / 13 angular scan (2θ) from 5° to 45°. The diffractograms of GLPReC, TRISrEC and CLP-TRIS (1:1)MF were subjected to the crystal structure refinement method called the Rietveld Method. Thus, the diffraction patterns provided by the crystallographic database for the starting compounds were used for statistical comparison with the experimental results from an appropriate program.

[020] DSC curves for compounds I and II, the coamorph, and the LPG-TRIS (1:1) physical mixture were obtained using a thermal analyzer. For this purpose, single heating cycles were performed within the temperature range suitable for the thermal stability of each compound, under a nitrogen atmosphere, with a flow rate of 50 mL.min-1 and a heating rate of 10°C.min-1. The thermal analyzer was previously calibrated for temperature and energy using the enthalpy of fusion of metallic indium as a standard (Tonset = 156.4°C; ΔH^5 = 28.5 J g-1), with a purity of 99.99%. Correction factors were calculated according to the manufacturer's procedure and specifications. All measurements were performed under atmospheric pressure, using sample masses of approximately 2.00 mg. Examples of how the invention can be implemented

[021] Figure 2 shows: (a) the diffraction profiles of the ES-recrystallized starting compounds (GLPReCe TRISReC), the GLP-TRIS (1:1) coamorph, and the GLP-TRIS (1:1)MF physical mixture; (b), (c), and (d) the diffractograms of GLPReC, TRISReCe Petition 870240110054, dated 12 / 26 / 2024, p. 15 / 25 10 / 13 of GLP-TRIS (1:1)MF subjected to refinement by the Rietveld Method.

[022] Figure 2 (a) shows the diffractograms of the samples analyzed in this work and Figures 2 (b), (c) and (d) show the diffraction patterns subjected to refinement by the Rietveld Method.

[023] Compound I exhibits a phase mixture between Form I and Form II; it is arranged in Form I with lattice parameters: a = 15.279 A, ​​b = 9.812 A and c = 18.178 A and V = 2527 A3, space group P21 / ne monoclinic system and in Form II with lattice parameters: a = 12.570 (3) A, b = 9.110 (4) A and c = 43, 970 (9) A and V = 5107,225 A3e space group Pbca. The results for the convergence factors (Figure 2 (b)) are satisfactory, where Rwp = 15.73%, Rp = 12.10% and S = 3.07. Compound II is in its polymorphic phase named α-form, its most thermodynamically stable form, with lattice parameters: a = 8.807 A, b = 8.872 A, ec = 7.709 A, and V = 602 A3, exhibiting a crystal structure belonging to the orthorhombic system and space group Pna21. The results for the convergence factors (Figure 2 (c)) are satisfactory, where Rwp = 11.50%, Rp = 9.01%, and S = 1.15. (IWATA, M. et al. Glimepiride. Acta Crystallographica Section C: Crystal Structure Communications, v. 53, n. 3, p. 329-331, 1997. https: / / doi.org / 10.1107 / S0108270196002363; ENDO, T. et al. Polymorphism of glimepiride: Crystallographic study, thermal transitions behavior and dissolution study. STP Petition 870240110054, dated 12 / 26 / 2024, page 16 / 25 11 / 13 pharmaceutical sciences, v. 13, n. 4, p. 281-286, 2003; KENDI, Engineer. Molecular and crystal structure of tris(hydroxymethyl)aminomethane. Zeitschrift für Kristallographie, vol. 160, no. 12, pp. 139–143, 1982. DOI: https: / / doi.org / 10.1524 / zkri.1982.160.1-2.139.).

[024] The diffractogram of GLP-TRIS at a molar ratio of 1:1 (Figure 2(a)) is typical of the diffraction profile of an amorphous material, due to the absence of crystallographic peaks and diffraction halo appearance, indicating the occurrence of intermolecular interactions between the starting compounds, resulting in the formation of a coamorphous DSF. The diffractogram of the GLP-TRIS (1:1)MF physical mixture consists of the sum of the diffraction peaks of the starting compounds, as confirmed by the refinement of this diffraction pattern (Figure 2(d)), suggesting that no intermolecular interactions occur between the starting compounds by simple physical contact. The refinement results for the convergence factors are satisfactory, where Rwp = 11.4%, Rp = 7.0% and S = 2.1.

[025] Figure 3 shows: (a) the DSC curves of the recrystallized starting compounds (GLPREC and TRISREC), the GLP-TRIS (1:1) coamorph and the GLP-TRIS (1:1)MF. The curve of GLPREC DSC showed two endothermic events. The first event occurred at 153.1 °C (Tonset) and refers to the solid-solid phase transition from Form II to Form I. The second event was observed at 204.3 °C (Tonset) and is related to... Petition 870240110054, dated 12 / 26 / 2024, page 17 / 25 12 / 13 the fusion of this drug. The DSC curve of TRISrec also showed two endothermic events. The first occurred in 133.9 °C (Tonset) and refers to the solid-solid phase transition from the α-orthorhombic form to the body-centered γ-cubic form. The second event presented at 168.3 °C (Tonset) refers to the melting of this compound. (ENDO, T. et al. Polymorphism of glimepiride: Crystallographic study, thermal transitions behavior and dissolution study. STP pharma sciences, v. 13, n. 4, p. 281-286, 2003; BONFILIO, R. et al. A discriminating dissolution method for glimepiride polymorphs. Journal of pharmaceutical sciences, v. 101, n. 2, p. 794-804, 2012. DOI: https: / / doi.org / 10.1002 / jps.22799; EILERMAN, D. RUDMAN, R. Polymorphism of crystalline poly (hydroxymethyl) compounds. Ill. The structures of crystalline and plastic tris (hydroxymethyl) aminomethane. The Journal of Chemical Physics, vol. 72, no. 10, p. 5656-5666, 1980. DOI: (https: / / doi.org / 10.1063n.438982.)

[026] The DSC curve of the GLP-TRIS coamorph in a 1:1 ratio shows two endothermic events. These events were observed at 155.8 °C and 176.7 °C (Tonset) and are related to the decomposition of this material. The absence of an event in this curve confirms the amorphous nature of this material. The DSC curve of GLP-TRISmf(1:1) showed three thermal events. The first event occurred at 135.5 °C (Tonset) due to the aforementioned solid-solid phase transition of TRIS. The second event observed at 174.2 °C (Tonset) was attributed to the melting of this compound. The Petition 870240110054, dated 12 / 26 / 2024, page 18 / 25 13 / 13 third event, presented at 212.9 °C (Tonset), was related to the fusion of GLP (EILERMAN, D. RUDMAN, R. Polymorphism of crystalline poly (hydroxymethyl) compounds. III. The structures of crystalline and plastic tris (hydroxymethyl) aminomethane. The Journal of Chemical Physics, v. 72, n. 10, p. 5656-5666, 1980. DOI: https: / / doi.org / 10.1063 / 1.438982.)

[027] In view of this, this invention is a solid dispersion of the coamorphous type of GLP-TRIS in a molar ratio of 1:1 obtained by slow evaporation of the solvent. Considering that amorphous materials tend to be more water-soluble compared to their respective crystalline forms, this invention is very attractive for increasing the aqueous solubility of GLP and, consequently, increasing its dissolution rate, bioavailability, and therapeutic efficacy. Thus, the GLP-TRIS coamorphous (1:1) could be used as an input for the production of more effective medications in the treatment of Type 2 Diabetes Mellitus. Petition 870240110054, dated 12 / 26 / 2024, p. 19 / 25

Claims

1 / 1 CLAIMS 1. SOLID DISPERSION, obtained by the solvent evaporation method (ES), characterized by comprising Compound I (1[[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolino-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl) urea) and Compound II ((tris(hydroxymethyl) in a molar ratio of 1:1 (Compound I:Compound II).

2. SOLID DISPERSION, according to claim 1, characterized by using dimethylformamide (solvent) as a solubilizing medium for compounds I and II.

3. SOLID DISPERSION, according to claims 1 and 2, characterized by being an amorphous material.

4. SOLID DISPERSION, according to claims 1 to 3, characterized by being a coamorphous type solid dispersion in a 1:1 molar ratio, whose diffraction profile showed an absence of crystallographic peaks and a diffraction halo appearance.

5. SOLID DISPERSION, as defined in claims 1 to 5, characterized as an input for the production of medicines intended for the treatment of Type 2 Diabetes Mellitus. Petition 870240110054, dated 12 / 26 / 2024, pp. 20 / 25

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