LV15016B - Polymorphyc forms of n-carbamoyl-4(r)-phenyl-2-pyrrolidinone - Google Patents

Abstract

The invention is related to N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidone crystalline polymorphic forms and their production methods, as well as to the use of said polymorphic forms for pharmaceutical compositions manufacturing.

Description

The present invention relates to crystalline polymorphic forms of the N-carbamoylmethyl-4 (7R) -phenyl-2-pyrrolidinone of the pharmaceutical industry and processes for their preparation. The invention also relates to the use of polymorphic forms in the preparation of a pharmaceutical composition.

Carfedone (Phenotropil, Phenylpyracetam, Noofen) is a well known and widely used psychometabolic stimulant [J. Med. Chem, 1984; Pharm. Chem. Journal, 14, 11, 776, 1980]. Recently, the α-isomer of Phenotropil has been shown to be the most pharmacologically active isomer in the racemic Phenotropil. [EP2013166, WO2007104780, US2010022784, etc.]

In the manufacture of pharmaceutical products it is essential to control the crystalline form of the active substance. Crystalline solids can exist in several crystalline forms. Crystals of various shapes are called polymorphs. Different polymorphs may have different chemical and physical properties, such as solubility, melting point, dissolution rate, stability, etc. These properties can directly affect the ability of the active substance and the drug product to be obtained, as well as the stability and bioavailability of the product. Thus, polymorphism can affect the quality, safety and efficacy of a drug product.

There are various methods that can be used to characterize active substance polymorphs. Polymorphism is demonstrated by the demonstration of non-equivalent structures using a single crystal X-ray analysis method. X-ray powder diffraction can be used to prove the existence of polymorphs. Other methods of analysis, including microscopy, thermal analysis (DSC, TGA), spectroscopy (infrared, Raman, solid state NMR), may also be used to characterize polymorphic forms.

The synthesis of N-carbamoylmethyl-4 (7R) -phenyl-2-pyrrolidinone was first described in WO2007104780, but the polymorphism of the resulting product was not described.

Investigations of different crystallization possibilities unexpectedly revealed that after crystallization different substances or different solvents were used to obtain non-identical substances. The IR spectra used to prove identity were also different in this case.

Recrystallization of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone yielded a stable crystalline form which was designated as polymorph I. Polymorph I can be characterized by one or more analytical results including X-ray powder diffraction (XRPD). ), differential scanning calorimetry (DSC) derivatograms and infrared spectroscopy (IS) spectra. The XRPD picture of Polymorph I is basically as shown

1 (Fig. 1). The location of the peaks in the polymorph I diffraction pattern and their relative intensities are detailed in Table 1.

Table 1.

Polymorph I Polymorph II 29th Relative intensity,% 2Θ Relative intensity,% 7,298 1.3 5,185 0.5 10,548 0.3 7,603 0.2 12,973 16.9 8,408 100.0 13,631 0.8 8,877 51.3 14,757 4.6 10,399 3.2 15.187 21.3 11,891 0.4 15,217 24.0 14,472 1.2 15,683 7.2 14,823 4.5 16,947 36.7 14,994 5.4 18,228 11.1 15,724 10.3 18,862 19.3 ,1 16,110 17.6 19,795 14.9 16,641 21.4 20,080 4.9 16,909 77.8 21,269 8.7 17,928 6.7 21,885 0.4 17,475 18.4 22,266 1.1 17,710 12.8 22,864 100.0 18,228 19.1 23.145 20.1 18,749 17.3 23,844 3.9 19,386 7.9 24,035 7.9 20.171 22.3 25,461 10.8 20,468 13.8 25,827 1.4 20,883 9.9 26,510 6.1 21,809 11.7 27,331 5.9 22.122 12.1 28,814 1.7 24,291 19.0 29,539 9.6 24,777 5.2 30,371 0.2 24,862 3.9 30,849 1.1 25,468 3.0 31,725 1.5 25,831 8.2 31,924 1.3 26,079 2.6 32,835 1.8 26,388 3.6 33,529 0.3 27,112 6.7 34,039 0.3 28,592 2.1 29,210 4.2 30,064 8.8 31,085 1.1 31,750 3.1 32,443 2.1 33,331 1.5 33,511 1.1 34,356 1.4

The 2Θ angles of peak placement may differ by approximately ± 0.2 °. The DSC curve for Polymorph I is shown in Figure 2 (Figure 2) with a characteristic peak at about 118 ° C or 117 ± 1 ° C. The IR spectrum of Polymorph I is depicted in Figure 3 (Figure 3).

Recrystallization of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone yields pure polymorph II from isopropanol. The XRPD pattern characterizing Polymorph II is basically as depicted in Figure 4 (Figure 4). The placement of the polymorph II peaks and their relative intensities are detailed in Table 1. The 2Θ angles of peak placement may vary by ± 0.2 °. The DSC curve for Polymorph II is shown in Figure 5 (Figure 5). The endothermic effect shown in the derivatogram with a maximum at 111 ° C characterizes the Form II melting, then recrystallization to Form I (high temperature), and the second endothermic effect with a maximum at 118 ° C characterizes the Form I melting. These peaks may shift by about 1 ° C. The IR spectrum of Polymorph II is depicted in Figure 6 (Figure 6).

Recrystallization of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone from a mixture of isopropanol-water at 60 ° C yields a mixture of two different polymorphs (I and II) and recrystallization from water at 60 ° C yields pure polymorph I. N -Carbamoylmethyl-4 (R) phenyl-2-pyrrolidinone polymorph II was recrystallized from a mixture of water, isopropanol and water isopropanol at 22 ° C, from isopropanol also at -4 ° C, and was suspended in these solvents and co-ground in the presence of these solvents. No changes in the diffraction pattern were observed.

If crystalline forms are obtained with impurities of other polymorphs, this can lead to instability and conversion to another polymorph. Therefore, it is very important to obtain crystalline forms of high polymorph purity to prevent these transformations. The object of the present invention was to develop methods for obtaining substantially pure polymorphs I and II. After obtaining pure polymorphs and studying their properties, better control of the production process is possible. Methods of obtaining pure polymorphs that are controllable and reproducible are suitable for use in industry, and pure polymorphs can be used to improve the properties of a pharmaceutical composition.

The method for obtaining pure polymorphs involves dissolving N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone in a suitable solvent followed by optional addition of the desired polymorph seed crystal, cooling and filtration. If necessary, the obtained crystals are washed with a suitable solvent. Depending on the solvent used and the crystallization temperature, pure polymorph I or II is obtained.

The dissolution dynamics of both polymorphs were also studied and compared (Fig. 7, Table 2).

Table 2.

Time, min V Dynamics of dissolution,% Polymorph II Polymorph I 0 0 0 1 67.2 24.7 3 69.7 33.1 5 70.9 45.0 7th 74.3 53.0 9th 77.4 62.2 11th 78.2 68.3 13th 80.1 75.3 15th 83.0 80.1 21st 86.3 86.6 29th 89.3 90.8 39 93.1 93.9 49 96.0 96.6 59 98.0 98.2 69 98.0 99.2 81 99.3 100.0

Polymorph II dissolution dynamics are better than polymorph I dissolution dynamics. This property positively influences the bioavailability of the active ingredient when the finished formulation is dissolved in the body. Polymorphs obtained by the process described in this invention are suitable for use in the preparation of pharmaceutical compositions. A pharmaceutical composition comprising the N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone polymorph and at least one pharmaceutically acceptable excipient is useful as a psychometabolic stimulant.

The invention is illustrated but not limited by the following examples.

Instrumental methods

X-ray powder diffraction (XRPD):

X-ray diffractograms were taken with the Bruker D8 Advance, LynxEye position-sensitive detector. Shooting mode: 3 - 35 ⁰ 2Θ, 0.2s / 0.02 ° speed. Samples were rubbed in an agate mortar before analysis.

Differential scanning calorimetry (DSC):

Differential scanning colorimetry curves were obtained using a differential scanning calorimeter Mettler ТА 4000 according to the experimental methodology appropriate for this equipment.

DSC curves were plotted over a temperature range of 50 ° C to 150 ° C with a heating rate of 5.0 ° C / min under nitrogen.

Infrared spectrum:

Infrared spectra were taken using a Nicolet IR200 infrared spectrophotometer, for a sample KBr tablet of the analyte. Spectra were recorded in an area of 4000 - 650 cm ⁴ .

Examples

Example 1. Preparation of N-carbamoylmethyl-4 (A) -phenyl-2-pyrrolidinone polymorph I g of N-carbamoylmethyl-4 (P) -phenyl-2-pyrrolidinone is dissolved in 560 mL of toluene at 90-95 ° C. The solution is then cooled slowly to 75 ° C and 0.5 g of seed crystal of R-phenotropil polymorph form I is added. Slowly cool the suspension to 1-5 ° C and hold for 5 h at the given temperature. It is then filtered, the filter cake is washed with 40 mL of toluene and dried at 45 ° C for 8 h. Yield: 36.7-37.6 g (92-94%).

Example 2. Preparation of Polymorph II of N-Carbamoylmethyl-4?

Dissolve 40.0 g of N-carbazoylmethyl-4 (R) -1H, 2'-pyrrolidone in 140.0 mL of boiling isopropyl alcohol. The solution is then cooled slowly to 50-55 ° C and 0.5 g of the crystalline form II seed of Rfenotropil polymorph is added. The suspension is slowly cooled to 45-49 ° C and allowed to stand at this temperature for 30 min. The suspension is then slowly cooled to 1-5 ° C and maintained at this temperature for 5 h and filtered. The filter cake was washed with 40.0 mL of isopropyl alcohol and dried at 45-50 ° C for 8 h. Yield: 35.9-37.5 g (90-94%).

Example 3. Investigation of dissolution dynamics

Weigh 5,0509 g of the test sample into a 0,5 L graduated flask and add the phosphate buffer solution (50 rpm) while stirring. Make up to the mark with phosphate buffer. Take 15 mL of the reaction mixture from time to time and measure the absorbance (258 nm) of the reaction against the reference sample (258 nm) (spectrophotometer - Agilent 8453 No. CN22805904). From these results plot the dissolution curve.

Claims (9)

Crystalline Form I of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone having one or more XRPD X-ray diffraction peaks selected from the group (2Θ): 13.0 ± 0.2; 15.2 ± 0.2; 16.9 ± 0.2; 18.2 ± 0.2; 18.9 ± 0.2; 19.8 ± 0.2; 21.3 ± 0.2; 22.9 ± 0.2; 24.0 ± 0.2; 25.5 ± 0.2; 26.5 ± 0.2; 29.5 ± 0.2. 2. Crystalline Form I of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone, characterized by an XRPD X-ray diffraction pattern as in FIG. 1. 3. Crystalline Form I of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone, characterized by a DSC curve as in FIG. 2. 4. Crystalline Form I of N-Carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone having an IR spectrum as shown in FIG. 3. Crystalline Form II of N-carbamoylmethyl-4 (N) -phenyl-2-pyrrolidinone having one or more XRPD X-ray diffraction peaks selected from (2as): 8.4 ± 0.2; 8.9 ± 0.2; 10.4 ± 0.2; 14.8 ± 0.2; 15.0 ± 0.2; 15.7 ± 0.2; 16.6 ± 0.2; 16.9 ± 0.2; 17.5 ± 0.2; 18.2 ± 0.2; 20.2 ± 0.2; 20.9 ± 0.2; 21.8 ± 0.2; 22.1 ± 0.2; 24.3 ± 0.2. 6. N-Carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone crystalline in shape П, to whom 7th a characteristic XRPD X-ray diffraction pattern as in FIG. 4. Crystalline from N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone in shape II, to whom 8th characteristic DSC curve as in Figs. 5. N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone crystalline in shape II, to whom characteristic IS spectrum as in Figs. 6th The crystalline form of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone according to any one of claims 1 to 4, containing not more than 10% of other crystalline N-carbamoylmethyl-4 (R) phenyl-2-pyrrolidinone forms. The crystalline form of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone according to any one of 5. A process according to any one of claims 5 to 8, containing up to 10% of other crystalline forms of N-carbamoylmethyl-4 (R) phenyl-2-pyrrolidinone. Use of a crystalline form of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone according to any one of claims 1 to 4 in the preparation of a pharmaceutical composition. Use of a crystalline form of N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidinone according to any one of claims 5 to 8 in the preparation of a pharmaceutical composition.