Method for preparing sertraline hydrochloride polymorphous formulation

FIELD: chemical technology, pharmacy.

SUBSTANCE: invention relates to an improved method for preparing sertraline hydrochloride form V that possesses the antidepressant effect. Method involves the following steps: (a) dissolving or suspending sertraline mandelate in a protonic solvent or a mixture of protonic solvents; (b) decreasing pH value of solution or suspension by addition of HCl aqueous solution of HCl solution in protonic solvent with addition of water to form a clear solution, and (c) isolation of the sertraline hydrochloride form V. At step (a) solvents from group comprising alcohol, water or their mixtures are chosen as solvents. For example, an alcoholic solvent used in step (a) can be chosen from group comprising methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, tert.-butyl alcohol and isobutyl alcohol or their mixtures but isopropyl alcohol is preferable. The dissolving or suspending step (a) is carried out at heating and/or stirring in solvent at temperature in the range 20-90oC usually. Decreasing the pH value in step (b) is carried out usually up to the range 1-3 preferably. Sertraline hydrochloride form V obtained at step (c) is isolated by cooling the mixture obtained at step (b). Cooling is carried out under natural conditions to room temperature or using mild cooling agents, such as cold water, water, alcohol or their mixtures wherein indicated alcohol is chosen from group comprising monohydric alcohol, dihydric alcohol or their mixtures. Also, invention relates to a method for preparing a pharmaceutical composition with immediate releasing the sertraline hydrochloride form V that involves mixing sertraline hydrochloride form V prepared by cl. 1 having particles size less 20 mcm and in the amount 90% of the total amount of particles, not less, with a pharmaceutically acceptable diluting agent, carrier or carrier. Proposed method provides simplifying the process for preparing the preparation based on decreasing the total amount of steps.

EFFECT: improved preparing method.

14 cl, 4 sch, 2 dwg, 1 tbl

 

The scope of the invention

The invention relates to a method for producing polymorphic form V hydrochloride (1S-CIS)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, i.e. hydrochloride sertraline. Hydrochloride sertraline is a means to treat depression, obsessive-compulsive disorders and panic States (WO 00/32551).

Description of the prior art

The need for medication devoid of harmful and limiting side effects from tricyclic antidepressants, stimulates the search for funds with high selectivity with respect to the specific mechanisms of action, which are believed to be essential for the antidepressant effectiveness. Researchers have made it their goal to find a selective competitive inhibitors re synaptosomal uptake of serotonin, and this search led to a series of 1-methylamine-4-killeralien, among which the most promising appeared to be similar to the 4-(3,4-dichlorophenyl). Test all possible stereoisomers showed that the required high selectivity for serotonin appears inCIS-1S,4S-isomer, i.e. hydrochloride (1S-CIS)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (I), known as sertraline hydrochloride

The literature describes various poly is ohnie forms of sertraline hydrochloride. In the light of modern needs of the pharmaceutical industry is very important polymorphic form V (WO 00/32551). Therefore, there is a need for large-scale production of polymorphic form V of sertraline hydrochloride with effective and affordable way.

"The way of sublimation-condensation to obtain a V shape proposed in U.S. patent No. 5248699. However, this "way of sublimation-condensation" is not suitable for use on an industrial scale, taking into account the needs of the V-shaped hydrochloride sertraline. This is due primarily to the fact that "the way of sublimation-condensation requires special equipment for sublimation of the source substances must at the same time enable high vacuum and temperature, and in order to collect the product of sublimation, requires special equipment and skill. Moreover, the complexity of the problem is aggravated by the fact that according to WO 0032551 "method of sublimation-condensation" turned out to be irreproducible.

WO 0032551 and WO 0172684 to get a V shape hydrochloride sertraline mostly use sertraline hydrochloride (scheme 1) or sertraline base (scheme 2).

Scheme 1

Sertraline mandelate → Sertraline base → Sertraline·HCl → Form V sertraline·HCl

Scheme 2

Sertraline mandelate → Sertraline base → Form V sertraline·HCl

Next WO0132601 discloses methods of obtaining the V-shaped sertraline· HCl of sertraline base. The form V sertraline·HCl, following WO 0132601 includes scheme 3 or scheme 4, as shown below:

Scheme 3

Sertraline mandelate → Sertraline base → Sertraline·HCl (Form CSC 2) → Form V sertraline·HCl

Scheme 4

Sertraline mandelate → Sertraline base → Sertraline·HCl → alcohol MES sertraline·HCl → form V sertraline·HCl

According to the techniques disclosed in U.S. patent 5248699, USA 4536518, WO 032551, sertraline base is obtained from the sertraline of mandelate in several stages, consuming equipment, workforce and to complete the production cycle time. Therefore, these methods are commercially expensive.

Therefore, there is a need for polymorphic form V of sertraline hydrochloride with a simple, effective and inexpensive method.

The purpose of the invention

The first object of the present invention to provide an efficient and inexpensive method of producing salts of sertraline.

The second object of the present invention to provide an efficient and inexpensive method of producing polymorphic form V of sertraline hydrochloride.

The third object of the present invention to provide a V shape hydrochloride cert is Alina, having a characteristic x-ray (XRPD).

The fourth object of the invention to provide a V shape hydrochloride sertraline with a characteristic IR spectrum (ICR).

The fifth object of the invention to provide pharmaceutical compositions with a V-shape sertraline hydrochloride as the active ingredient.

The invention

The present invention provides a method of obtaining salt of sertraline, which includes stages:

a) dissolution or suspension of sertraline mandelate in the solvent;

b) lowering the pH of the solution or suspension and

c) isolation of the salt of sertraline.

The present invention also provides a method of obtaining a V shape hydrochloride sertraline, which includes stages:

a) dissolution or suspension of sertraline mandelate in the solvent;

b) lowering the pH of the solution or suspension and

(C) the selection of the form V sertraline hydrochloride.

In addition, the present invention provides a method of obtaining a pharmaceutical composition with a V-shape sertraline hydrochloride as the active ingredient.

Detailed description of the invention

The sertraline hydrochloride of the formula (I) exist in different polymorphic forms, in particular, forms I-XVI, T1, CSC-1 and CSC-2 and in amorphous form. Crystallization of polymorphic forms is usually carried out by dissolving or melting connect the deposits, followed by gradual or fast cooling of the resulting solution or melt. In the solution of different polymorphic forms are identical, which follows from the data of NMR and IR spectral data in the solution). On the other hand, solid-phase methods such as x-ray diffraction or infrared spectroscopy (spectra in KBr), detect differences between polymorphic forms.

The present invention offers a new method of obtaining the V-shaped hydrochloride of sertraline sertraline of mandelate.

According to the present method, in contrast to methods of the prior art, there is no need to turn sertraline mandelate in the sertraline base and then in sertraline hydrochloride. Multistage methods of the prior art, including the intermediate stage of the transformation of sertraline mandelate in the sertraline base or sertraline hydrochloride other form (other than form V) sertraline hydrochloride, are excluded, because the present invention provides a direct conversion of sertraline mandelate in the form V of sertraline hydrochloride. Thus, the present invention provides a method of obtaining, which reduces the number of stages and, therefore, reduces the cost of equipment, labor and time needed to complete the production cycle. In the present invention offers a simple one-step method of the form V sertraline hydrochloride, which is an effective and inexpensive is.

The method of the present invention to obtain a salt of sertraline involves the following stages:

d) dissolution or suspension of sertraline mandelate in the solvent;

e) lowering the pH of the solution or suspension and

f) isolation of the salt of sertraline.

According to this invention polymorphic form V of sertraline hydrochloride get method, including

d) dissolution or suspension of sertraline mandelate in the solvent;

e) lowering the pH of the solution or suspension and

f) the selection of the form V sertraline hydrochloride.

The solvent used for dissolution or suspension of sertraline mandelate, selected from the group including proton solvents or mixtures thereof.

The solvent used for dissolution or suspension of sertraline mandelate, selected from the group consisting of alcohol, water and mixtures thereof. The alcohols can be selected from methanol, ethanol,n-propanol, isopropanol,nbutyl alcohol,tert-butyl alcohol, isobutyl alcohol, and mixtures thereof. The preferred solvent is isopropanol.

Dissolution or suspension is achieved by heating and/or stirring. Heating can be done up to 90°C. Preferably sertraline mandelate dissolve at 25-80°and more preferably at 25-30°under stirring.

The pH value can be is isiti by using organic or inorganic acids. Preferred to lower the pH are inorganic acids, such as HCl, H2SO4, HNO3.

HCl is used as a gas or dissolved in the solvent. The solvent may be water or an organic solvent or mixtures thereof. The organic solvent can be selected from alcohol solvents such as methanol, ethanol,n-propanol, isopropyl alcohol,n-butanol or mixtures thereof.

Preferably the pH is reduced with aqueous HCl.

After lowering the pH to 1-3, preferably 1-2, the reaction mixture can be in the form of a transparent solution or may be a suspension. A clear solution is not necessarily can be obtained by heating to 90°C.

Cooling is carried out either allowing the solution independently to reach room temperature, or by using a soft cooler containing cold water, water, alcohols or mixtures thereof. Alcohol is selected from the group consisting of monohydroxy alcohol, diatomic alcohol or their mixtures. Then the obtained solid substance can be identified with the acquisition of form V.

The method of the present invention can be represented by scheme 5.

Scheme 5

Sertraline mandelate → form V sertraline·HCl

According to a preferred embodiment of the method of the present invention sertraline mandelate treated with HCl in isopropyl alcohol. D. the lead pH to 1-2 and add water then heat the reaction mass until a clear solution is formed which, after cooling directly gives the form V sertraline hydrochloride.

The original connection is sertraline mandelate can be obtained by the method described in the patent EP 30081. It is preferable to obtain the sertraline of mandelate high purity, since it does not require much time and labor to re-kristallizatsii. According to the present invention is sertraline mandelate get method, which does not require purification by re-crystallization. Also, there is no need to get an additional batch of the substance as described in the patent EP 30081.

The pharmaceutical composition may be obtained using a therapeutically effective amount thus obtained form V of sertraline hydrochloride and a pharmaceutically acceptable carrier.

Brief description of drawings

Figure 1 shows the x-ray compounds obtained according to the present invention;

figure 2 shows the IR spectrum of the compound obtained according to the present invention. This is a characteristic infrared absorption spectrum of polymorphic form V of sertraline hydrochloride of the formula (I) in KBr.

Polymorphic form V of sertraline hydrochloride of the formula (I) characterized by the following data.

Form V hydrochlo the IDA sertraline is characterized by a powder x-ray (XRPD), below in table 1:

Table 1
Serial numberThe diffraction angle ±0,2°

(two theta degrees)
The lattice parameter (D)

(Angstroms)
15,217,119
210,98,122
314,16,259
416,35,433
517,15,181
619,04,671
719,74,506
820,94,256
922,04,046
1023,03,860
1123,53,776
12to 25.33,517
1325,93,437
1429,03,075

The sertraline hydrochloride obtained by the method of this invention can be characterized by its powder x-ray. Figure 1 shows a typical x-ray form V of sertraline hydrochloride. The main peaks are observed around: 5,2±0,2, 10,9±0,2, 14,1±0,2, 16,3±0,2, 17,1#x000B1; 0,2, 19,0±0,2, 19,7±0,2, 20,9±0,2, 22,0±0,2, 23,0±0,2, 23,5±0,2, 25,3±0,2, 25,9±0,2 and 29.0±0,2 °2 theta.

The IR spectrum of the form V sertraline hydrochloride obtained by the method according to the invention, is characterized by the following bands:

773 cm-1, 1011 cm-1, 1032 cm-1, 1054 cm-1, 1134 cm-1, 1330 cm-1, 1561 cm-1and 1591 cm-1as shown in figure 2.

The FTIR spectrum was recorded in the solid state as KBr dispersion on the spectrophotometer Shimadzu FT IR 8700.

The pharmaceutical composition of the form V sertraline hydrochloride can be obtained using the above-mentioned chemical compounds that meet the following tests:

Ser.

No.
TestsLimits
1.Related substances (%) (according to HPLC). The total number of known and unknown impuritiesNot more than 0,50
2.Sulfated ash (%)Not more than 0.2
3.Heavy metals (ppm)No more than 20
4.Analysis (%) (Titration)From 98,0 to 102.0;

anhydrous basis
5.Residual solvent (ppm)

(a) Isopropyl alcohol

(b) Methanol

(C) Acetone

(d) IU Lienhard
Not more than 2000

Not more than 100

Not more than 100

200
6.Polymorph according to x-rayValues of 2 theta (D):

5,2 (17,119), 10,9 (8,122), 14,1 (6,259), 16,3 (5,433), 17,1 (5,181), 19,0 (4,671), 19,7 (4,506), 20,9 (4,256), 22,0 (4,046), 23,0 (3,860), 23,5 (3,776), 25,3 (3,517), 25,9 (3,437) and 29.0 (3,075)
7.IR (cm-1)773, 1011, 1032, 1054, 1134, 1330, 1561 and 1591
8.Particle size (sitonomy analysis)

less than 20 microns
Not less than 90.0%
9.Content limits microbes

total aerobes (cfu/g)

(cfu/g is the number of colony forming units per gram)

Total fungi (cfu/g)

E.coli
No more than 1000

Not more than 100

Must be absent

The following section describes the preferred embodiment in the form of examples, which illustrate the method of the present invention. However, the examples in no way limit the scope of the present invention.

EXAMPLES RETRIEVE

Receiving sertraline of mandelate

from racemic hydrochloride sertraline

In liter round-bottom flask 250 ml of methylene chloride, 250 ml of water and 50 g of racemic sertraline hydrochloride at room temperature. Add 20% sodium hydroxide solution (10 g of sodium hydroxide solution in 50 ml of water) to establish a pH between the 9 and 10, as defined on paper pH indicator. Stirred for 45 minutes until a clear solution is formed. The methylene chloride layer is separated and the aqueous layer was extracted twice with methylene chloride (50 ml for each extraction). All methylenchloride layers are combined and washed with water to pH 7 to 8. All methylenchloride layers is collected and redistilled under vacuum at 60°and receive oil. To it add 200 ml of methanol and heated to 50-55°C. Add a solution of D(-)-almond acid (23 g in 50 ml of methanol) at 55-60°C. Increase the temperature to 60-65°and incubated for 10 minutes After 1 h, the mass is cooled to 30-35°and then to 20-25°C, the temperature is kept on this level, 30 minutes and get a solid substance. It is filtered off and washed 3 times with acetone (25 ml each time) and get 28,0 g of sertraline mandelate calculated on dry substance.

Getting a V shape hydrochloride of sertraline sertraline of mandelate

In a 1-liter chetyrehosnuju round-bottom flask equipped with a stirrer, a pocket for a thermometer and water fridge, placed 25 g of sertraline mandelate at room temperature. Then add 200 ml of isopropyl alcohol under stirring. Set the pH of the solution from 1 to 2 by adding concentrated HCl. Add 5 ml of water and heated under reflux until a clear solution is formed. Rast is the PR filtered over high-flow filter and cooled to room temperature and obtain 23 g of a white solid substance, that dried, yielding 13 g dry form V.

The pharmaceutical composition

The pharmaceutical compositions of the form V sertraline hydrochloride should preferably have a particle size less than 20 microns and a purity of at least 90%, when prepared in a mixture with a pharmaceutically acceptable diluent, carrier or excipient. The level of impurities in the hydrochloride sertraline in such compositions should preferably not exceed 0,50% when the content of sulfated ash not more than 0.2% heavy metals not more than 20 ppm, Preferably sertraline hydrochloride used in such a composition has a test indicator for the titration between 98,0 and 102% on the anhydrous basis.

Residual solvents in such compositions are preferably in the following ranges:

(a) isopropyl alcoholnot more than 2000 ppm
(b) methanolnot more than 100 ppm
(C) acetonenot more than 100 ppm
(d) methylene chloridenot more than 200 ppm

Limits on microbes in such compositions preferably the following:

total aerobes (cfu/g)no more than 1000
total fungi (cfu/g)not more than 100
E.colimust be absent

While the present invention has been described based on specific embodiments, the experts in this field will be obvious modifications and variants, which are also included in the scope of the present invention.

Obtaining the pharmaceutical composition is an immediate release form V of sertraline hydrochloride.
Ingredientsmg per tablet (mg)
1.Hydrochloride sertraline (form-V) equivalent to 100 g of sertraline112,00
2.Microcrystalline cellulose44,100
3.The glycolate, krahmalnaya, type a5,000
4.The calcium phosphate, dihydrate50,000
5.Hydroxypropylcellulose10,500
6.Polysorbate 807,500
7.Purified waterdost. number
8.Microcrystalline cellulose58,500
9.Glycolate krahmalnaya, type a10,000
10.theart magnesium 2,40
The mass of the core:300 mg
11.Gidromolot, 6 Santi-Poisson4,120
12.Propylene glycol0,630
13.Titanium dioxide1,250
14.Purified waterdost. number
The weight of the coated tablets:306 mg

Method of delivery:

1. Screening of sertraline hydrochloride (Form V), solvent, agent, causing the disintegration, a binder, and optionally other fillers through the appropriate sieve and thorough mixing.

2. Obtaining an aqueous solution of a surfactant and adding the resulting solution to the mixture obtained in stage 1; granulating the mixture in the appropriate granulator.

3. Drying the granules obtained in stage 2, and sizing the dried granules through an appropriate sieve.

4. Mixing the mixture obtained in stage 3, with the lubricant and optionally other fillers.

5. Compressing the mixture obtained in stage 4, the tablet is the right size.

6. The application shell on the pressed tablet.

1. The method of obtaining the V-shaped hydrochloride sertraline, including the tadji

a) dissolution or suspension of sertraline mandelate in proton solvent or in a mixture of proton solvents;

b) lowering the pH of the solution or suspension by addition of an aqueous solution of HCL or HCL in proton solvent with the addition of water with the formation of a clear solution; and

c) the selection of the form V sertraline hydrochloride.

2. The method according to claim 1, in which the proton of the solvent(s)used in stage (a)selected from the group comprising alcohol, water or mixtures thereof.

3. The method according to claim 2, wherein said alcoholic solvent used in stage (a)selected from the group comprising methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, tert-butyl alcohol and isobutyl alcohol or a mixture thereof.

4. The method according to claim 3, wherein said alcoholic solvent is izopropilovym alcohol.

5. The method according to claim 1, in which the specified stage (a) dissolution or suspension is carried out by heating and/or stirring.

6. The method according to claim 1, in which the specified stage (a) dissolution or suspension of sertraline mandelate in the solvent is carried out at a temperature in the range from 20 to 90°C.

7. The method according to claim 6, wherein said temperature range is from 25 to 80°C.

8. The method according to claim 7, wherein said temperature range is from 25 to 3° C.

9. The method according to claim 1, in which the pH at the stage (b) is reduced to the interval 1-3.

10. The method according to claim 9, in which the pH is reduced to the interval 1-2.

11. The method according to claim 1, in which the allocation of the V-shaped hydrochloride sertraline at the stage (C) is performed by cooling the contents of stage (b).

12. The method according to claim 11, in which the cooling is carried out, allowing the solution independently to reach room temperature or with soft coolers, including cold water, water, alcohol or mixtures thereof.

13. The method according to item 12, wherein said alcohol is selected from the group comprising monohydroxy alcohols, diatomic alcohols or mixtures thereof.

14. The method of obtaining the pharmaceutical composition is an immediate release form V of sertraline hydrochloride, comprising mixing a V shape sertraline hydrochloride obtained according to claim 1, with a particle size less than 20 microns, which constitutes at least 90% of particles with a pharmaceutically acceptable diluent, carrier or excipient.



 

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The invention relates to organic chemistry and petrochemistry, namely the synthesis of Penta[poly(ethylenoxy)carbonylmethyl] tricyclic derivatives of triphenols, which can be used as additives for improving the rheological properties of associated petroleum systems in the petroleum and petrochemical industries

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel derivatives of fullerenes comprising organic amines and hydrogen atoms bound to fullerene-C60 molecule by 6,6-double bonds of the general formula: C60Hn(R1R2N)n wherein R1 means -C6H5CH2; R2 means -C6H5CH2; n = 4 (tetra-(dibenzylaminohydro)[60]fullerene); R1 means -C5H9; R2 means hydrogen atom (H); n = 3 (tri-(cyclopentylaminohydro)[60]fullerene). Also, invention relates to using derivatives of fullerenes, in particular, (tetra-(benzylaminohydro)[60]fullerene, (tetra-(dibenzylaminohydro)[60]fullerene, tri-(cyclopentylaminohydro)[60]fullerene, 2-(azahomo[60]fullereno)-5-nitropyrimidine, 1,3-dipropyl-5-[5'-(azahomo[60]fullereno)pentyl]-1,3,5-triazin-2,4,6(1H,3H,5H)-trione, O,O-dibutyl-(azahomo[60]fullereno)phosphate as acceptors of electrons in composites polymer/fullerene designated for photovoltaic cells. Also, invention relates to photovoltaic device comprising mixture of poly-conjugated polymer and abovementioned fullerene derivative or their mixture as an active layer. Also, invention relates to a method for synthesis of derivatives of fullerenes comprising aromatic amines and hydrogen atoms bound to fullerene-C60 molecule by 6,6-double bonds. Method involves interaction of C60 with the corresponding organic amine in solution, and this reaction is carried out in aromatic solvent medium in amine excess at temperature 25-70°C for 2-5 days followed by evaporation of solution and precipitation of the end product by addition of alcohol.

EFFECT: improved method of synthesis.

6 cl, 1 tbl, 2 dwg, 6 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new substituted 1,2,3,4-tetrahydro-2-naphthalenamine formula I, where R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl; R3represents hydrogen, hydroxyl, C1-4alkoxyl, cyano, carbarnoyl; R4and R5independently represent hydrogen, C1-4alkyl, hydroxy2-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine; in the form of free bases or salts obtained by attaching acid

The invention relates to analogs of 2-aminoindane General formula I, where R1and R2independently represent hydrogen, C1-C8alkyl; X is CH2R3or NHSO2R4; Y represents hydrogen, NHSO2R4, SO2(Ph); R3is NHSO2R4,

SO2R4, CONR1R2; R4represents C1-C8alkyl, phenyl or phenyl, substituted by-CN or-CF3; and their pharmaceutically acceptable salts, active receptor Dopamine D3

The invention relates to new 8-carbonylation 2-aminotetraline, their enantiomers and salts, processes for their preparation, pharmaceutical preparations on their basis and use of such compounds in therapy

The invention relates to new derivatives of 1,2,3,4-tetrahydro-2-naphtylamine, as well as their pharmaceutically acceptable salts, having the properties to affect 5-HTIAmammals and humans, as well as subclass of dopamine D2receptors, and may find application in the pharmaceutical industry

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new chemical compound of general formula I , or salts, or hydrates thereof. In formula I R1 represents group of formula -G1-R1a (wherein G1 represents single bond, oxygen, sulfur; R1a represents C1-C10-alkyl optionally substituted with halogen or C3-C8-cycloalkyl); R2, R3 and R4 are independently hydrogen or -G20-R20 (wherein G20 represents single bond, oxygen, sulfur, sulfinyl or sulfonyl; R20 represents C1-C6-alkyl optionally substituted with 1-3 halogen atoms or C3-C8-cycloalkyl); R5 and R6 are independently -X5-X6-X7 group (meanings of X5, X6 and X7 are as defined in specification) or R3 and R4 may together form pyrrol ring optionally substituted with C1-C6-alkyl; Ar represents phenyl, 1,3-benzodioxolyl, naphthyl, pyridyl, optionally substituted with 1-3 substituents (as defined in specification) Compounds of formula I has antagonistic activity in relates to receptors of corticotrophin releasing factor (CRF). Also disclosed are compounds, characterized by preferable structures, pharmaceutical compositions, using such compounds, intermediates for production thereof and method for treatment of various diseases mediated by CRF.

EFFECT: new compounds as antagonists of CRF receptors.

33 cl, 1 tbl, 316 ex

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