A New Method for Obtaining Fine Powders of Paracetamol for ...

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Paracetamol (N (p hydroxyphenyl)acetamide) is a widely used non narcotic analgesic having also anti inflammatory and antipyretic action. Several crystal.
ISSN 00125016, Doklady Physical Chemistry, 2011, Vol. 437, Part 2, pp. 78–81. © Pleiades Publishing, Ltd., 2011. Original Russian Text © A.G. Ogienko, E.V. Boldyreva, A.Yu. Manakov, V.V. Boldyrev, M.A. Mikhailenko, A.S. Yunoshev, A.A. Ogienko, A.I. Ancharov, A.F. Achkasov, A.V. Ildyakov, A.A. Burdin, N.A. Tumanov, A. S. Stoporev, and N. V. Kutaev, 2011, published in Doklady Akademii Nauk, 2011, Vol. 437, No. 6, pp. 785–788.

PHYSICAL CHEMISTRY

A New Method for Obtaining Fine Powders of Paracetamol for Compression without Excipients A. G. Ogienkoa, b, E. V. Boldyrevaa, c, A. Yu. Manakova, b, Academician V. V. Boldyreva, c, M. A. Mikhailenkoa, c, A. S. Yunosheva, d, A. A. Ogienkoa, e, A. I. Ancharova, c, A. F. Achkasova, A. V. Ildyakovb, A. A. Burdinb, N. A. Tumanova, A. S. Stoporeva, b, and N. V. Kutaeva, b Received December 3, 2010

DOI: 10.1134/S0012501611040063

An attempt to prepare pure monoclinic paraceta mol suitable for direct compression has been under taken [8]. To this end, paracetamol was recrystallized from a solution or suspension in 1,4 dioxane to give a paracetamol solvate with dioxane (1 : 1/2) and then the solvating dioxane was removed. This gave highly porous paracetamol particles. It was noted [8] that a considerable disadvantage of this method for the prep aration of paracetamol for tablet manufacture is the high thermal stability of the solvate and also rather low product yield in the case where saturated solutions are used (~21 g of paracetamol from 1000 mL of a solution saturated at 50°С). Meanwhile, the use of higher tem perature (80–90°С) with the same solvent increased the product yield (200–300 g per 1000 mL of the solu tion). However, at higher temperature, paracetamol may be partly oxidized. In the case of a suspension, the yield was even higher (at 50°С, this was ~164 g from 1000 mL of a suspension containing 200 g of paraceta mol). Although the authors demonstrated some improvement of the compressibility and dissolution rate of the paracetamol samples they obtained as com pared with the starting reagent, the subsequent testing was carried out with the standard excipients used to prepare paracetamol tablets. Instrumental methods for the preparation of fine powders of pharmaceutical products based on spray or freeze drying have been reported [9]. The use of high cooling rates to give amorphous phases followed by the removal of solvents by sublimation makes it possible to avoid enlargement of the formed crystallites due to the absence of contact with the liquid phase. By the beginning of our studies, it was known that a considerable increase in the paracetamol solubility is attained when a binary mixture comprising a volatile liquid (dioxane, ethanol, acetone) and water is used as the solvent [10]. One more reason for using systems with dioxane and acetone is the formation of clathrate hydrates with cubic structure II at low temperatures (CS II, the volatile liquid to water ratio is 1 : 17) [11]. Hence, only solid phases coexist over broad concen tration and temperature ranges. A favorable condition

Paracetamol (N(phydroxyphenyl)acetamide) is a widely used nonnarcotic analgesic having also anti inflammatory and antipyretic action. Several crystal line polymorphs of paracetamol are known. One of these (monoclinic form I) is thermodynamically stable and is readily prepared but cannot be compressed to tablets without excipients (fillers). Another poly morph (orthorhombic form II) can be readily com pressed to tablets without excipients [1, 2] and is better soluble but its formation as a pure phase is not repro ducible, and, what is worse, it is metastable and is spontaneously converted to the monoclinic form on storage [1]. The idea of obtaining compressible forms of paracetamol that would be stable on storage attracts considerable attention of the scientific community and pharmaceutical companies. For solving this prob lem, it has been proposed to use, instead of pure paracetamol, its mixtures with polyvinylpyrrolidone [3], carbohydrates [4], chitosan and sodium alginate [5] or mixed crystals based on oxalic acid, naphthalene and other compounds [6] or the inclusion compounds with hydroxypropylβcyclodextrin [7].

a

Molecular Design and Environmentally Safe Technologies Science and Educational Center, Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090 Russia b Nikolaev Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of Sciences, pr. Akademika Lavrent’eva 3, Novosibirsk, 630090 Russia c Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch, Russian Academy of Sciences, ul. Kutateladze 18, Novosibirsk, 630128 Russia d Lavrent’ev Institute of Hydrodynamics, Siberian Branch, Russian Academy of Sciences, pr. Akademika Lavrent’eva 15, Novosibirsk, 630090 Russia e Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, pr. Akademika Lavrent’eva 10, Novosibirsk, 630090 Russia 78

A NEW METHOD FOR OBTAINING FINE POWDERS OF PARACETAMOL

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1400

10 µm

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20 µm Breaking force, N

500 µm

10 µm

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Fig. 1. Photomicrographs of various finely powdered paracetamol samples obtained in this work at different magnifications. The images were obtained by a scanning electron microscope (Pt sputtering).

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Piston displacement, mm

is the fact that the dioxane melting point allows removal of the solvent by sublimation at a temperature limited by the rate of removal of ice, which is the less volatile component in this system in the solid state. However, this solvent system was rejected because we detected the formation of a stable paracetamol solvate. We proposed a new method for the preparation of monoclinic paracetamol based on freeze drying of the frozen solutions of paracetamol in acetone–water mixtures. This method produced pure paracetamol samples as fine powders of the thermodynamically sta ble form I. These were easily compressed to tablets without excipients and had better dissolution kinetics than monoclinic paracetamol (commercial chemical). A monoclinic paracetamol powder (Merck), chro matographic grade acetone, and distilled water were used. An acetone–water mixture (water content of 15–30 wt %) was used as the solvent; the paracetamol concentration in the solutions was not more than 95% of the equilibrium concentrations at 25°С [10]. The solution was sprayed into a liquid nitrogen vessel. The mixture of solid phases formed after cooling was trans ferred onto a massive holder cooled to liquid nitrogen temperature, which was placed into a vacuum cham ber at the same temperature. The chamber was closed and pressure was reduced to P < 5 × 10–2 mm Hg. The drying was performed in the temperature ranges cho sen on the basis of powder Xray diffraction data (a Bruker D8 Advance powder diffractometer equipped with a TTK 450 Anton Paar lowtempera ture attachment and a cell for investigations under vacuum down to 10–3 mm Hg) and experimental selection of the optimal modes in such a way that only solid phases were present in the system in each stage. It was shown by powder Xray diffraction that all of the obtained samples represented pure form I. DOKLADY PHYSICAL CHEMISTRY

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Fig. 2. Determination of the breaking force for paraceta mol tablets (the force is applied along the cylinder axis). The tablets were prepared from: (1) and (1') commercial sample (Merck); (2) and (2') samples obtained in this work.

According to scanning electron microscopy (a Hitachi TM1000 tabletop scanning electron microscope), the obtained samples comprised flat par ticles with linear dimensions of 1–10 µm and thick ness of 60–150 nm assembled into 30–200 µm associ ates (depending on the spraying gas pressure and deliv ery capillary diameter), Fig. 1. The paracetamol fine powders we obtained demon strated much better compressibility (Zwick/Roell Z010 electromechanical testing machine, piston diameter 6.0 mm, sample weight ~150 mg) than usual commercial polycrystalline form I samples. Upon compression of paracetamol samples obtained in this work, the tablet was readily separated from the piston. Note that polycrystalline commercial samples stick to the piston during compression. To avoid sticking, var ious lubricating additives (e.g., magnesium stearate) are used in industry. However, it was shown that form II is not formed during the tablet production. The compressibility is apparently improved due to the high surface energy of paracetamol particles [12] caused by large surface area and the particle shape that promotes aggregation. The porosity of the produced tablets (6.0% at 345 MPa) proved to be comparable with the porosity of tables obtained by compression of pure form II (5.2% at 335 MPa) [2]. Experiments on determination of the tablet breaking force (with the force directed a) along the cylinder axis or b) along the cylinder diame ter) showed much higher strength of the tablets manu 2011

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Fig. 3. Appearance of the tablets after the breaking experiment (with breaking force applied along the cylinder axis). The tablet on the left was obtained from the commercial sample. The two tablets on the right were obtained from the sample prepared in this work.

factured from the paracetamol samples obtained in this work (a: 1118 ± 148 N, b: 45.5 ± 5 N) compared with the tablets prepared from the commercial mono clinic paracetamol sample (a: 184 ± 18 N, b: 8 ± 1 N) (Fig. 2). The breaking force of our tablets obtained by com pressing paracetamol samples determined by method (b), which is used in the pharmaceutical industry, (1.27 ± 0.27 MPa) proved somewhat greater than the breaking force of the tablets obtained by compressing pure form II (~0.95 MPa for the tablets obtained at compression force of 335 MPa) [2]. The force deter mined by method (b) is much higher than the force required to break the tablets obtained by compressing monoclinic paracetamol (commercial sample) deter mined both in this work (0.225 ± 0.03 MPa) and by other researchers (~0.2 MPa (polycrystalline sample) [2]; 0.38 MPa (spraydried sample) [4]). This force is somewhat lower or is at the level of the breaking force for the tablets produced by compressing mixed crystals

Paracetamol concentration, mg/mL

24 1 22 2

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Fig. 4. Dissolution of paracetamol. Samples: (1) obtained in this work; (2) commercial monoclinic paracetamol sample (Merck).

(1.15–2.79 MPa) [6] or spraydried mixtures with car bohydrates (0.45–2.39 MPa) [4]. Unlike the tablets obtained from the commercial product, the tablet that we obtained did not crumble after the collapse experi ment, but comprised a set of fragments that retained the hardness of the initial tablet (Fig. 3). The paracetamol samples obtained by our proce dure are readily soluble in water. The dissolution was performed using a 705 DS (Varian) solubility tester. At certain intervals, samples were taken and filtered into vials maintained at a constant temperature. The paracetamol concentration was determined by pho tometry (a Cary 50 spectrophotometer (Varian), l = 10 mm, λ = 243 nm) after the appropriate dilution of the filtrate. Comparison of the dissolution dynamics of the paracetamol samples (a 705 DS (Varian) solubility tester) obtained by the procedure we propose and by the traditional technique showed that for several days the paracetamol concentration in the solution remains above the equilibrium concentration [13]. The presence of concentrations (Fig. 4) above the equilibrium value in the initial stages of dissolution is typical of pharmaceutical agents with a high degree of amorphization, nanodispersed samples or metastable crystalline modifications, for example, samples obtained by mechanical activation [14]. However, usually a multiple excess over the equilibrium concen tration is observed and is retained over considerably shorter time periods than it is observed in this work for the finely dispersed paracetamol still retaining the crystallinity. This difference might be caused by the morphology of samples obtained by freeze drying of frozen solutions. The electronmicroscopic examination of the insoluble precipitates of paracetamol showed that despite the vigorous stirring of the solution, the associ ates of microcrystallites are not destroyed with time. The particle size slowly increases and faceting more typical of paracetamol samples obtained from aqueous solutions appears, i.e., on longterm contact of finely powdered paracetamol samples with a saturated aque ous solution, recrystallization of the sample occurs

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gradually. This process is apparently retarded due to the diffusion restrictions caused by the intricate sur face relief of the associates and the developed internal surface. Thus, the method we proposed made it possible to solve for the first time the problem of preparing the stable form of paracetamol suitable for direct com pression to tablets without excipients. This form com bines the stability on storage, high mechanical strength, and high dissolution rate to give supersatu rated solutions stable for long time periods, which is important for sample bioavailability. In our opinion, this method based on the freeze drying of frozen solu tions prepared from mixed water–organic solvents may prove suitable for obtaining new forms of other pharmaceutical agents with enhanced characteristics. ACKNOWLEDGMENTS This work was supported by the BRHE (grants Y5 C0801, Y5C0808, Y5C0809, RUX0008NO 06), the Ministry of Education and Science of the Rus sian Federation (the program “Fundamental Science for Medicine,” State contract no. 02.740.11.5102), Presidium of the RAS (program “Nanomaterials,” grant 27.44), and the Siberian Branch of the RAS (Integration Project nos. 13 and no. 109). REFERENCES 1. Di Martino, P., GuyotHermann, A.M., Conflant, P., et al., Int. J. Pharm., 1996, vol. 128, pp. 1–8.

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