Cocrystalline form of fenbufen

FIELD: chemistry.

SUBSTANCE: claimed is a cocrystalline form of fenbufen with pyrazinamide, where molar ratio of fenbufen with pyrazinamide constitutes 1:1, which has an endothermal peak from 148 to 152°C by the data of measurements by means of differential scanning calorimetry and peaks at 2θ(°) 7.38, 10.43, 11.04, 21.67 by the data of measurement of polycrystal X-ray radiation diffraction.

EFFECT: increased rate and level of solubility of the crystalline form of fenbufen and its suitability for application in the pharmaceutical industry.

2 ex, 7 dwg



The invention relates to pharmaceutical preparations, namely to the new cocrystal of fenbufen suitable for pharmaceutical preparations.

The level of technology

γ-oxo-(1,1'-biphenyl)-4-buchanania acid, also called fenbufen,

is a well-known nonsteroidal anti-inflammatory drug used for the treatment of inflammation in osteoarthritis, ankylosing spondylitis and tendonitis [Kerwar SS Pharmacologic properties of fenbufen // Am. J. Med. - 1983 - P.62-69].

Fenbufen is a derivative of propionic acid and differs from other drugs in this group. This drug is predecessor. By itself, it is inactive, the main active metabolite is 4-biphenyloxy acid [Dhaneshwar S.S., Sharma M. Preliminary studies on gastro-protective chimeric derivative of biphenyl acetic acid for rheumatoid arthritis // Int. J. Pharm. Pharm. Sci. - 2011 - 4(1) - P.162-168]. The compound has a long half-life that allows you to apply it once or 2 times a day.

Fenbufen well absorbed in the stomach. The maximum level of the drug in plasma is reached within 1 h, and the period of its half-life in plasma is 10 hours Maximum plasma levels of the main active metabolite of fenbufen - 4-biphenylacetic acid is achieved after 7 h; the half-life of this metabolite in the plasma which is also 10 o'clock

Fenbufen subjected to intensive metabolism, products of which are excreted mainly in the urine.

Most frequent side effects are gastro-intestinal tract [Brogden R.N., R.C. Heel, Speight T.M. Avery G.S. Fenbufen: a review of its pharmacological properties and therapeutic use in rheumatic disease and acute pain // Drugs - 1981 - 21(1) - P.1-22]. The rash appears more often than in the treatment of other anti-inflammatory drugs; it can be a reason for not using this drug. Symptoms of the digestive tract (abdominal pain, nausea, vomiting, diarrhea). Also observed increased activity of hepatic enzymes, particularly with long-term use of the drug. In some cases, were recorded anemia, leukopenia, thrombocytopenia, and eosinophilia, as well as allergic reactions. Only occasionally, but were fixed erythema multiforme syndrome, Layla requiring immediate termination of the use of drugs.

It was found that fenbufen effective in rheumatoid arthritis, osteoarthritis and other chronic rheumatic diseases. Most studies were conducted before the drug 2 times a day, although for maintenance treatment was enough for a single admission. On the effectiveness of fenbufen comparable with other anti-inflammatory drugs. It felt just as easy analg tiraumea means; single dose of 600 mg was comparable with the same dose of acetylsalicylic acid; the dose of 900 mg is significantly more effective.

Therapeutic use of fenbufen and some other non-steroidal anti-inflammatory drug compounds described in the literature [Champion G.D. Therapeutic usage of the non-steroidal anti-inflammatory drugs // Med. J. Australia. - 1988 - 149(4) - P.203-213]. But no less important criteria of effectiveness of the drug are pharmacokinetic parameters and physico-chemical properties of various structural modifications such as amorphous form, salt, cocrystal, polymorphic modifications. They have different physical and chemical properties that affect pharmaceutical API parameters such as storage stability, compressibility and others. Determinants of bioavailability are solubility and kinetic indicators of dissolution. The low solubility of pharmaceutical compounds in biological fluids leads to low efficiency of the drug. Therefore, the increase of the solubility and dissolution rate of the drug is an urgent technical problem.

The problem of increasing the solubility of doing for a long time, so at the moment there are a large number of methods that solve this problem:

- fine grinding to create a larger square is square in surface dissolved compounds [J. Chaumeil .Micronisation: a method of improving the Bioavailability of poorly soluble drugs // Methods Find. Exp.Clin. Pharmcol. - 1998 - 20(3) - P.211-215],

- use of salts of the studied objects with improved solubility [S. Agharkar, Lindenbaum, S., Higuchi T. Enhancement of solubility of drug salts by hydrophilic counter-ions: properties of organic salts of an anti-malarial drug // J. Pharm. Sci. - 1976-65(5) - P.747-749],

- dissolution in the complex [Amin K., Dannenfelser, R.-M., Zielinski J., Wang B. Lyophilization of polyethylene glycol mixtures // J. Pharm. Sci. - 2004 - 93(9) - P.2244-2249] and micellar solvents [Torchillin V.. Micellar nanocarriers: pharmaceutical perspectives // Pharm. Res. - 2007 - 24(1) - P.1-16],

- the formation of supramolecular complexes with cyclodextrins [R.A. Rajewski, Stella V.J. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery // J. Pharm. Sci. - 1996 - 85(11) - P.1142-1169],

- the use of phospholipid vesicles filled with a lipophilic compounds [Humberstone A.J., N. W. Charman Lipid-based vehicles for the oral delivery of poorly soluble drugs // Adv. Drug Deliv. Rev. - 1997 - 25(1) - P.103-128].

However, the known methods cannot be characterized as generic methods. So, despite the fact that the fine grinding of substances increases the dissolution rate of drugs, but it does not increase the equilibrium solubility of the substance. Because the increase in van der Waals interactions and electrostatic attraction between the particles lead to the reduction of effective surface area, dissolution and, thus, limit the limit of biological activity.

Increasing the solubility of the way of the receipt of unacceptable salts, as in the pharmaceutical industry are mainly used loosely of an ionisable and neutral molecules, and salt in this class of compounds not included.

The use of complex and micellar solvents suggests acceptable solubility and compatibility of molecules of medicinal compounds with the solvent, which is not always attainable.

The increase in solubility by the formation of complexes with cyclodextrins, as well as the use of phospholipid vesicles applicable only for drug compounds prolonged action, however, often require drugs fast action, for example, non-steroidal anti-inflammatory agents.

Despite the relatively high compared with other non-steroidal anti-inflammatory drug compounds solubility, fenbufen still rather poorly soluble [Chiarini, A., Tartarini, A., Fini A. pH-Solubility relationship and partitioning coefficients for some anti-inflammatory arylaliphatic acids // Arch. Pharm. - 1984 - 317 - P.268-273]. Currently work is underway, aimed at improving the solubility and/or reduction of side effects of fenbufen, such as:

- immobilization of fenbufen in nanoscale mesoporous silica [D. Carriazo, M. Del Arco, Femandez, A., Martin C., Rives V. Inclusion and release of fenbufen in mesoporous silica // J. Pharm. Sci. - 2010 - 99(8) - P.3372-3380],

- creation of complexes with cyclodextrins [I. Bratu, Gavira-Vallejo J.M., Hemanz A.1H-NMR Studyof the inclusion processes for α - and γ-cyclodextrin with fenbufen // Biopolymers - 2005 - 77 - P.361-367],

- obtaining complexes of fenbufen/poly(vinyl pyrrolidone) [Gashi Z., Censi R., Malaj L., R. Gobetto, Mozzicafreddo M., M. Angeletti, Masic, A., Di Martino P. Differences in the interaction between aryl propionic acid derivatives and poly(vinylpyrrolidone) K30: A multi-methodological approach // J. Pharm. Sci. - 2009 - 98(11) - P.4216-4228],

and other

The creation of fenbufen immobilized in nanoscale silicon oxide, although allows to increase the kinetic characteristics of NSPs, however, does not increase the overall level of solubility. Complexes with poly(vinyl pyrrolidone) insignificant increase the solubility of fenbufen, besides the use of this method is discouraged because polyvinylpyrrolidon is harmful food additive.

It is also known that to increase the solubility by education cocrystalline form API component contributing to the increase of dissolution. Secretary is supramolecular systems, where one component is poorly soluble API, i.e. the molecule drug connection, and the second component (conformera) is the molecule soluble compounds, which are better absorbed by the body and is involved in enzymatic processes [Lara-Ochoa F. and Espinosa-Pérez G. Cocrystals definitions // Supramolecular Chemistry. - 2007 - 19 (8) - P.553-557].

Societally used in the pharmaceutical industry, are attractive because they give the possibility of obtaining new crystalline forms API with the special is Linyi properties such as improved solubility, thermal stability, improved mechanical properties, etc. moreover, due to the possibility of selection of conformer for cocrystal, you can spend, so to say, "fine tuning" of the physical properties of cocrystal.

From literature is known only one case of obtaining cocrystal of fenbufen with PP [D.J. Berry, S. Seaton, W. Clegg, R.W. Harrington, S.J. Coles, P.N. Horton, M.B. Hursthouse, R. Storey, W. Jones, T. Friscic, N. Blagden Applying hot-stage microscopy to co-crystal screening: a study of nicotinamide with seven active pharmaceutical ingredients // Cryst. Growth Des. - 2008 - 8 (5) - P.1697-1712]. However, in the present paper we do not discuss the characteristics of dissolution.

The invention

The technical problem of the invention was to find cocrystalline form of fenbufen with a higher speed and level of solubility and is suitable for use in the pharmaceutical industry.

The invention consists in the following:

Cocrystalline form of fenbufen with pyrazinamide, where the molar ratio of fenbufen with pyrazinamide is 1:1, having an endothermic peak of from 148 to 152°C as measured using differential scanning calorimetry and peaks at 2θ(°) 7.38, 10.43, 11.04, 21.67 according to the measurement dipali x-ray radiation of the polycrystal.

The claimed invention allows to obtain the following advantage - increase is astronote in water is about 25 times as compared with the solubility of fenbufen in pure form. This is important because in the presence of inflammatory processes in the human body requires effective action of the medicinal product it is in the initial period of time that is provided cocrystalline form.

Further evaluation of the kinetics of dissolution of shows on any time interval solubility cocrystalline form of fenbufen higher than compounds in pure form. Increased equilibrium solubility of fenbufen in cocrystalline form allows you to increase efficiency as prolonged drug action, and in the initial period.

Data on solubility were obtained for an aqueous solution at room temperature for installation to measure the solubility of solid compounds by the method of isothermal saturation. Samples were taken at points approximately 0.12, 0.25, 0.35, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, and 24 hours and analyzed using a spectrophotometer VARIAN CARY 50 UV spectral range, the operating range of wavelengths λ=190÷400 nm.

Declared a new cocrystal - solid stable crystalline substance, not falling apart, not exposed to moisture and easy to prepare stable pharmaceutical preparations. Declared cocrystal of fenbufen can be used for the production of tools for the treatment of inflammation in osteoarthritis, ankylosing who eat spondylitis and tendonitis. In addition, due to the presence of pyrazinamide received cocrystal has the ability to prevent destructive tuberculosis, caseous lymphadenitis, tuberculoma and caseous-pneumonic processes.

The structure of the claimed cocrystal proved in two ways, in the aggregate, sufficient to assert that the formation of new connections:

diffraction of x-rays of the polycrystal

differential scanning calorimetry (DSC).

Figure 1 presents a typical profile XPRD of cocrystal fenbufen:pyrazinamide (1:1) in accordance with one variant of the invention.

Figure 2 presents a typical profile XPRD of fenbufen in its purest form.

Figure 3 presents a typical profile XPRD pyrazinamide in its purest form.

Figure 4 shows a typical DSC thermogram of cocrystal fenbufen:pyrazinamide (1:1) in accordance with one variant of the invention.

Figure 5 shows a typical DSC thermogram of fenbufen in its purest form.

Figure 6 shows a typical DSC thermogram of pyrazinamide in its purest form.

Figure 7 presents data on the solubility for cocrystal fenbufen:pyrazinamide (1:1) and fenbufen in its purest form.

Information verifying the playback inventions

To get the claimed cocrystal used the following substances.

- fenbufen - producing "Sigma", CAS 36330-85-5, purity ≥98%.

- pyrazinamide - producer firm Acros Organics", lot A CAS 98-96-4, purity 99%.

- ethanol - Alcohol brand "Luxury" GOST R-2000 2001-07-01 "ethyl Alcohol requireany from food raw material. TU".

New cocrystal of fenbufen substantially characterized by the results of x-ray analysis, shown in figures 1, 2, 3, and substantially describes the data of DSC thermograms presented in figure 4, 5, 6.

To obtain the claimed cocrystal can be in solid phase and in solution.

Example 1

A mixture of 51 mg (0.2 mmol) of fenbufen and 24.2 mg (0.2 mmol) of pyrazinamide placed in agate cells for grinding in the planetary micromelia. In the cell placed 10 agate beads with a diameter of 3 mm, the Process by grinding at a speed of 600 rpm continue twice for half an hour with a break of 5 minutes. The remaining powder is cocrystal fenbufen:pyrazinamide (1:1), which was confirmed by XPRD and DSC. The resulting profile XPRD final product substantially corresponds to that shown in figure 1. Received the DSC thermogram of the final product substantially corresponds to that shown in Figure 4.

Example 2

A mixture of 51 mg (0.2 mmol) of fenbufen and 24.2 mg (0.2 mmol) of pyrazinamide dissolved in 2 ml of ethanol to dissolve. The obtained clear solution is left in a fume hood until olego evaporation of the solvent. The remaining powder is cocrystal fenbufen:pyrazinamide (1:1), which is confirmed by the data of DSC thermogram of which coincides with the DSC thermogram of the final product obtained according to Example 1.

Cocrystalline form of fenbufen with pyrazinamide, where the molar ratio of fenbufen with pyrazinamide is 1:1, having an endothermic peak of from 148 to 152°C as measured using differential scanning calorimetry and peaks at 2θ(°) 7.38, 10.43, 11.04, 21.67 by measuring the diffraction of x-rays of the polycrystal.


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