Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 298-46-4 | MDL No. : | |
Formula : | C15H12N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FFGPTBGBLSHEPO-UHFFFAOYSA-N |
M.W : | 236.27 | Pubchem ID : | 2554 |
Synonyms : |
CBZ;NSC 169864;Carbamazepine, Tegretol, Epitol
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 76.05 |
TPSA : | 46.33 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.0 cm/s |
Log Po/w (iLOGP) : | 2.1 |
Log Po/w (XLOGP3) : | 2.45 |
Log Po/w (WLOGP) : | 2.79 |
Log Po/w (MLOGP) : | 2.99 |
Log Po/w (SILICOS-IT) : | 1.65 |
Consensus Log Po/w : | 2.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.28 |
Solubility : | 0.125 mg/ml ; 0.00053 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.07 |
Solubility : | 0.203 mg/ml ; 0.000858 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.93 |
Solubility : | 0.0278 mg/ml ; 0.000117 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.93 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P260-P270-P264-P314-P301+P312+P330 | UN#: | N/A |
Hazard Statements: | H302-H373 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With peracetic acid; potassium permanganate supported on alumina; sodium carbonate In dichloromethane; acetic acid at 20℃; for 1.66667 h; Heating / reflux | Example 1: lla,10b-Dihydro-6H-dibenz/b.f/oxireno[d1 azepine- 6-carboxamide (5); [44] To a stirred suspension of carbamazepine (3) (20Og, 847.5mmol) and sodium carbonate (287.4g, 271 lmmol) in dichloromethane (1000ml) were added tablets of potassium permanganate supported on alumina (3.5percent w/w, 3.46g, 0.77mmol). Thereafter, peroxyacetic acid (39percent solution in acetic acid, 432ml, 2538mmol) was added dropwise over one hour, causing a gradual rise in temperature until gentle reflux of the solvent. The mixture was stirred for twenty minutes and then allowed to stand for twenty minutes. The sodium carbonate and supported catalyst were then removed by filtration and washed by dichloromethane (200ml); the alumina beads were separated from sodium carbonate by screening through a sieve. The combined filtrate was then stirred with an aqueous solution of sodium sulphite (2Og) and sodium bicarbonate (2Og) in water (250ml) for one hour. The phases were then separated and the aqueous phase extracted by dichloromethane (50ml). The combined organic layers were washed by water (100ml), saturated aqueous sodium bicarbonate (100ml), water again (100ml) and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent (rotary evaporator, water aspirator pressure, 4O0C) gave the crude epoxide (5) as a beige solid which was crystallised from ethyl acetate (100ml) to give the product as an off-white solid, 194.2g, (91percent yield). |
91% | With peroxyacetic acid; potassium permanganate on alumina; sodium carbonate; acetic acid In dichloromethane for 1.66667 h; Reflux | Step-1 : Synthesis of compound 2: 2 00101) To a stirred suspension of compound 1 (200 g, 847.5 mmol) and sodium carbonate (287.4 g, 271 1 mmol) in dichorometbane (1000 ml) were added tablets of potassium permanganate supported on alumina (3.5percent w/w, 3.46 g, 0.77 mmol). Thereafter, peroxyacetic acid (39percent solution in acetic acid, 432 ml, 2538 mmol) was added dropwise over one hour, causing a gradual rise in temperature until gentle reflux of the solvent. The mixture was stirred for twenty minutes and then allowed to stand for twenty .minutes. The sodium carbonate and supported catalys were then removed by filtration and washed by dichloromethane (200 ml); the alumina beads were separated from sodium carbonate by screening through a sieve. The combined filtrate was then stirred with an aqueous solution of sodium sulphite (20 g) and sodium bicarbonate (20 g) in water (250 ml) for one hour. The phases were then separated and the aqueous phase extracted by dichloromethane (50 ml). The combined organic layers were washed by water (100 ml), saturated aqueous sodium bicarbonate (100 mi), water again (100 ml) and brine, then dried over anhydrous sodium sulphate and fil tered. Evaporation of the solvent (rotary evaporator, water aspirator pressure, 40° C.) gave the crude epoxide 2 as a beige solid which was crystallised from ethyl acetate (100 ml) to give the product as an off-white solid, 194.2 g, (91percent yield). |
91% | With perpropionic acid; sodium carbonate; acetic acid In dichloromethane at 20℃; for 2 h; Reflux | To a stirred suspension of compound 1 (200 g, 847.5 mmol) and sodium carbonate (287.4 g, 2711 mmol) in dichloromethane (1000 ml) were added tablets of potassium permanganate supported on alumina (3.5percent w/w, 3.46 g, 0.77 mmol). Thereafter, peroxyacetic acid (39percent solution in acetic acid, 432 ml, 2538 mmol) was added dropwise over one hour, causing a gradual rise in temperature until gentle reflux of the solvent. The mixture was stirred for twenty minutes and then allowed to stand for twenty minutes. The sodium carbonate and supported catalyst were then removed by filtration and washed by dichloromethane (200 ml); the alumina beads were separated from sodium carbonate by screening through a sieve. The combined filtrate was then stirred with an aqueous solution of sodium sulphite (20 g) and sodium bicarbonate (20 g) in water (250 ml) for one hour. The phases were then separated and the aqueous phase extracted by dichloromethane (50 ml). The combined organic layers were washed by water (100 ml), saturated aqueous sodium bicarbonate (100 ml), water again (100 ml) and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent (rotary evaporator, water aspirator pressure, 40° C.) gave the crude epoxide 2 as a beige solid which was crystallised from ethyl acetate (100 ml) to give the product as an off-white solid, 194.2 g, (91percent yield). |
66% | With peracetic acid; aluminum oxide; potassium permanganate; sodium carbonate In dichloromethane at 20℃; for 2 h; | Peroxyacetic acid (2 mL) was added dropwise to the suspension of carbamazepine (954 mg, 4 mmol), Na2CO3 (1.4 g, 13 mmol) and KMnO4/Al2O3 (0.6 mg/18 mg) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 h. After neutralization with aqueous solution of NaHCO3 (5 g) and NaHSO3 (5g), the mixture was extracted with dichloromethane (2 × 100 mL). The combined organic phase was washed with brine (200 mL) and dried with MgSO4. After evaporation of the solvent, the product was purified by recrystallization from EtOAc as pale yellow powders (662 mg, 66percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; acetic acid; In ice-water; | EXAMPLE 10 2.0 g of 5-cyano-5H-dibenz[b,f]azepine are introduced portionwise at room temperature into a mixture of 16 ml of acetic acid and 4 ml of concentrated sulfuric acid, and a complete solution is obtained after one hour's stirring. It is poured into 200 ml of ice-water, and the formed white suspension is stirred for 10 minutes; filtration is then performed and the precipitate is washed neutral with water. The yield is 2.0 g (95.2% of theory) of 5H-dibenz[b,f]azepine-5-carboxamide, which according to DC and IR analysis is identical to authentic material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | [0161] 10 mg (0.0423 mmol) <strong>[298-46-4]carbamazepin</strong>e was dissolved in a mixture of approximately 1 mL formamide/1 mL THF or 1 mL formamide/1 mL methanol. Slow evaporation of the solvent mixture produced an average yield of clear needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/formamide co-crystal, as shown in FIG. 21B. [0162] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C16H15N3O2, M=281.31, triclinic P-1; a-5.1077(11), b=16.057(3), c=17.752(4) , alpha=73.711(3), beta=89.350(3), gamma=88.636(3), V=1397.1(5) 3, T=100 K, Z=4, mu(MO-Kalpha)=0.091 mm-1, Dc=1.337 Mg/m3, lambda=0.71073 3, F(000)592, 2thetamax=28.33. 11132 reflections measured, 6272 unique (Rint=0.1916). Final residuals for 379 parameters were R1=0.0766 and wR2=0.1633 for I>2?(I). [0163] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxamide homodimers between two <strong>[298-46-4]carbamazepin</strong>e moieties and carboxylic acid homodimers between two formamide moieties. Infinite chains are formed by the homodimers linked side by side, with every other set of CBZ molecules attached on the sides of the chain but not bonded to form a dimer. [0164] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3392 cm-1, (N-H stretch, 11 amine, CBZ); 2875 cm-1, (C-H stretch, alkene); 1653 cm-1, (CO); 1590 cm-1, (CC). [0165] Melting Point: 142-144 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., formamide m.p.=-94 C.). [0166] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 27% weight loss starting at 1380, a 67% weight loss starting at 195 followed by complete decomposition. | |
In methanol; | [0161] 10 mg (0.0423 mmol) <strong>[298-46-4]carbamazepin</strong>e was dissolved in a mixture of approximately 1 mL formamide/1 mL THF or 1 mL formamide/1 mL methanol. Slow evaporation of the solvent mixture produced an average yield of clear needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/formamide co-crystal, as shown in FIG. 21B. [0162] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C16H15N3O2, M=281.31, triclinic P-1; a-5.1077(11), b=16.057(3), c=17.752(4) , alpha=73.711(3), beta=89.350(3), gamma=88.636(3), V=1397.1(5) 3, T=100 K, Z=4, mu(MO-Kalpha)=0.091 mm-1, Dc=1.337 Mg/m3, lambda=0.71073 3, F(000)592, 2thetamax=28.33. 11132 reflections measured, 6272 unique (Rint=0.1916). Final residuals for 379 parameters were R1=0.0766 and wR2=0.1633 for I>2?(I). [0163] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxamide homodimers between two <strong>[298-46-4]carbamazepin</strong>e moieties and carboxylic acid homodimers between two formamide moieties. Infinite chains are formed by the homodimers linked side by side, with every other set of CBZ molecules attached on the sides of the chain but not bonded to form a dimer. [0164] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3392 cm-1, (N-H stretch, 11 amine, CBZ); 2875 cm-1, (C-H stretch, alkene); 1653 cm-1, (CO); 1590 cm-1, (CC). [0165] Melting Point: 142-144 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., formamide m.p.=-94 C.). [0166] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 27% weight loss starting at 1380, a 67% weight loss starting at 195 followed by complete decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | Carbamazepine:4-aminobenzoic acid Co-crystal [00189] 40 mg (0.1693 mmol) of <strong>[298-46-4]carbamazepin</strong>e and 30 mg (0.1421 mmol) of 4- aminobenzoic acid were dissolved in approximately 3 mL methanol. Slow evaporation of the solvent yielded clear plates of carbamazepme:4-aminobenzoic acid (2:1) co- crystal. The co-crystal was analyzed via IR spectroscopy and single-crystal x-ray diffraction. [00190] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3460 cm 1, (N-H stretch, 1 amine, <strong>[298-46-4]carbamazepin</strong>e); 3162 cm"1, (C-H stretch, alkene); 1673 cm'1, (C=O); 1603 cm"1, (C=C). [00191] A MEL-TEMP was used to determine the melting point of the <strong>[298-46-4]carbamazepin</strong>e:4-aminobenzoic acid co-crystal. The melting point was determined to be 185-187 degrees C. [00192] Single crystal x-ray data (Bruker SMART-APEX CCD): (C15H12N2O)2:C7H7NO2, M = 609.67, monoclinic C2/c, a = 31.013(3) angstroms, b = 12.1319(9) angstroms, c = 13.599(1) angstroms, alpha = 90 degrees, beta = 99.173(1) degrees, gamma = 90 degrees, V = 6028.4(8) cubic angstroms, T = 100 K, Z = 8, D0 = 1.343 g/cm , lambda = 0.71073 angstroms. Final residuals for 415 parameters were R1 [I>2sigma(I)] = 0.0416 and wR2 = 0.106. [00193] The <strong>[298-46-4]carbamazepin</strong>e:4-aminobenzoic acid co-crystal contains both an acid-amide 2-point supramolecular heterosynthon and a primary amide dimer. Two acid-amide supramolecular heterosynthons form a tetrameric motif, which is bonded to the primary amide dimers on each side through the amino N-H...0 hydrogen bonds. This tetrameric motif is found in 13 percent of the structures in the CSD that contain acid-amide supramolecular heterosynthons. The OH... O and N-H... O hydrogen bond interaction distances for the acid-amide supramolecular heterosynthon are 2.540 and 2.982 angstroms, which compare to the mean values of 2.56 and 2.96 angstroms, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 48h;Heating / reflux; | Carbamazepme:4-aminobenzoic acid: Water Co-crystal [00194] Yellow crystals of <strong>[298-46-4]carbamazepin</strong>e:4-aminobenzoic acid:water (2:1:1) co- crystal were obtained via slow evaporation of a solution containing <strong>[298-46-4]carbamazepin</strong>e (0.030 g, 0.127 mmol) and 4-aminobenzoic acid (0.0087 g, 0.063 mmol) dissolved in 1 ml of heated ethanol after 2 days. The co-crystal was analyzed via TGA and single- crystal x-ray diffraction. [00195] A MEL-TEMP was used to determine the melting point of the <strong>[298-46-4]carbamazepin</strong>e:4-aminobenzoic acid:water co-crystal. The melting point was determined to be about 143 degrees C. [00196] TGA analysis of the <strong>[298-46-4]carbamazepin</strong>e:4-aminobenzoic acid: water co- crystal showed a 3 percent weight loss at 135 degrees C, a 68 percent weight loss at 174 degrees C, and a 12 percent weight loss at 306 degrees C. [00197] Single crystal x-ray data (Bruker SMART-APEX CCD): (C15H12N2O)2:C7H7NO2:H2Q, M = 627.68, monoclinic P21/n, a = 13.760(1) angstroms, b = 17.457(1) angstroms, c = 14.624(1) angstroms, alpha = 90 degrees, beta = 115.876(1) degrees, gamma = 90 degrees, V = 3160.8(4) cubic angstroms, T = 100 K, Z = 4, D0 = 1.319 g/cm3, lambda = 0.71073 angstroms. Final residuals for 424 parameters were R1 [I>2sigma(I)] = 0.0431 and wR2 = 0.1112. [00198] Co-crystallizing the same components as Example 1 but from ethanol produced a 2:1:1 co-crystal of <strong>[298-46-4]carbamazepin</strong>e:4-aminobenzoic acid: water. The crystal packing is markedly different from the crystal structure of the <strong>[298-46-4]carbamazepin</strong>e:4- aminobenzoic acid co-crystal. It forms an eight molecule discrete unit through O- H...0 and N-H...0 hydrogen bonds that contain four <strong>[298-46-4]carbamazepin</strong>e molecules, two 4- aminobenzoic acid molecules, and two water molecules. The water molecules insert between the primary amide carbonyl and the acid OH, thereby sustaining 1 -point N- H... O acid-amide supramolecular heterosynthons. The (amide) N-H... O (acid) interaction distance is 2.878 angstroms, versus a mean of 2.96 angstroms. Notably, the amide anti-oriented NH's are not involved in hydrogen bonding. Table XXI- Geometrical parameters of H-bond interactions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 70℃; for 0.0833333h; | Carbamazepine: Cinnamic acid Co-crystal [00224] To <strong>[298-46-4]carbamazepin</strong>e (12 mg, 0.05 mol) was added cinnamic acid (8 mg, 0.05 mol). To the solid mixture was added ethyl acetate (1 mL) and the solution was heated at 70 degrees C for 5 minutes. The homogeneous solution was then cooled to room temperature (about 22 degrees C) and the solvent was slowly evaporated. After 24 hours at room temperature, a precipitate was observed, collected, and dried to give a 1:1 <strong>[298-46-4]carbamazepin</strong>e: cinnamic acid co-crystal as large colorless rods. The crystals were characterized using DSC, MEL-TEMP, PXRD, IR and single-crystal x-ray analysis. [00225] DSC thermogram shows an endothermic transition at about 144 degrees C (Figure 10). The <strong>[298-46-4]carbamazepin</strong>e:cinnamic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the IR peaks in Figure 11 including, but not limited to, 1703, 1658, 1633, 1574, 1489, 1449, 1434, 1276, 1173, 978, 872, 769, 706, and 673 cm'1. A MEL-TEMP was used to determine the melting point of the carbarnazepine:cinnamic acid co-crystal. The melting point was determined to be about 142 -143 degrees C. The <strong>[298-46-4]carbamazepin</strong>e xinnamic acid co- crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the PXRJD peaks in Figure 12 including, but not limited to, 5.78, 9.91, 16.70, 21.82, and 27.24 degrees 2-theta. [00226] Single crystal x-ray data (Bruker SMART-APEX CCD): monoclinic P2(l)/c, a = 15.2187(15) angstroms, b = 5.4243(5) angstroms, c = 23.435(2) angstroms, alpha = 90 degrees, beta = 95.346(2) degrees, gamma = 90 degrees, V = 1926.1(3) cubic angstroms, T = 100 K, Z = 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 70℃; for 0.0833333h; | Carbamazepine:Acetylsalicylic acid Co-crystal [00227] To <strong>[298-46-4]carbamazepin</strong>e (18 mg, 0-08 mol) was added acetylsalicylic acid (14 mg, 0.08 mol). To the solid mixture was added ethyl acetate (1 mL) and the solution was heated at 70 degrees C for 5 minutes. The homogeneous solution was then cooled to room temperature (about 22 degrees C) and the solvent was slowly evaporated. After 24 hours at room temperature, a precipitate was observed, collected, and dried to give a 1:1 <strong>[298-46-4]carbamazepin</strong>e: acetylsalicylic acid co-crystal as small colorless plates. The crystals were characterized using DSC, MEL-TEMP, PXRD, IR, and single-crystal x-ray analysis. [00228] DSC thermogram shows an endothermic transition at about 128 degrees C (Figure 13). The <strong>[298-46-4]carbamazepin</strong>e: acetylsalicylic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the IR peaks in Figure 14 including, but not limited to, 1750, 1691, 1640, 1607, 1555, 1493, 1416, 1364, 1302, 1280, 1258, 1203, 1085, 986, 927, 806, and 773 cm'1. A MEL-TEMP was used to determine the melting point of the <strong>[298-46-4]carbamazepin</strong>e: acetylsalicylic acid co- crystal. The melting point was determined to be about 125 -126 degrees C. The <strong>[298-46-4]carbamazepin</strong>e: acetylsalicylic acid co-crystal can be characterized by any one, any two, any three, any four, any five, or any six or more of the PXRD peaks in Figure 15 including, but not limited to, 12.7, 15.1, 17.68, 20.72, 24.84, 25.86, and 33.08 degrees 2-theta. [00229] Single crystal x-ray data (Bruker SMART- APEX CCD) : triclinic P- 1 , a = 9.0317(18) angstroms, b = 11.364(2) angstroms, c = 11.424(2) angstroms, alpha = 60.350(4) degrees, beta = 85.599(4) degrees, gamma = 84.724(4) degrees, V = 1014.0(3) cubic angstroms, T = 100(2) K, Z = 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichloroacetic acid; In water; toluene; | EXAMPLE 1 723 g of trichloroacetic acid are dissolved in 600 ml of toluene and, in the course of 11/2 hours, this solution is added to a suspension of 407 g of iminostilbene and 290 g of sodium cyanate in 600 ml of toluene, the temperature being maintained at 25 C. by cooling. The whole is then allowed to react for 1/2 hour at 25 C. and for 1 hour at 50 C. and 1300 ml of water are subsequently added slowly. The mixture is then cooled to 20 C. and the product is filtered off, washed with toluene and water and drived at 85-90 C. in vacuo. Yield: 475 g of carbamazepine. | |
With sulfuric acid; In acetic acid; | EXAMPLE 2 25 g of iminostilbene are suspended in 180 ml of acetic acid and 14 g of 96 % sulphuric acid are slowly added. 13.5 g of sodium cyanate are added in portions at 30 C. while stirring well. The whole is stirred for 3 hours at 30 C., and the product is filtered off and washed with acetic acid and then with water. 29.5 g of carbamazepine are obtained after drying at 80 C. in vacuo. | |
With phosphoric acid; urea; In acetic acid; | EXAMPLE 2 Preparation of Carbamazepine-Phosphoric Acid Catalyst To a suspension of urea (80 g, 1.333 mols) in acetic acid (100 ml), phosphoric acid (8 ml) was added, followed by iminostilbene (20 g, 0.103 mols), under stirring at 25-30 C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; dichloromethane; | [0173] 36 mg (0.1524 mmol) <strong>[298-46-4]carbamazepin</strong>e and 31 mg (0.1475 mmol) trimesic acid were dissolved in a solvent mixture of approximately 2 mL methanol and 2 mL dichloromethane. Slow evaporation of the solvent mixture yielded white starbursts of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/trimesic acid co-crystal, as shown in FIG. 23B. [0174] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C24H18N2O7, M=446.26, monoclinic C2/c; a=32.5312(50), b=5.2697(8), c=24.1594(37) , alpha=90, beta=98.191(3), gamma=900, V=4099.39(37) 3, T=-173 K, Z=8, mu(MO-Kalpha)=0.110 mm-1, Dc=1.439 Mg/m3, k=0.71073 3, F(000)1968, 2thetamax=26.43. 11581 reflections measured, 4459 unique (Rint=0.0611). Final residuals for 2777 parameters were R1=0.1563, wR2=0.1887 for I>2((I), and R1=0.1441, wR2=0.1204 for all 3601 data. [0175] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxylic acid homodimers between <strong>[298-46-4]carbamazepin</strong>e and trimesic acid moieties and hydrogen bonded carboxylic acid-amine heterodimers between two trimesic acid moieties arranged in a stacked ladder formation. [0176] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3486 cm-1 (N-H stretch, 1 amine, CBZ); 1688 cm-1 (CO, 1 amide stretch, CBZ); 1602 cm-1 (CC, CBZ). [0177] Differential Scanning Calorimetry: (TA Instruments 2920 DSC). 273 C. (endotherm). m.p.=NA, decomposes at 278 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191192 C., trimesic acid m.p.=380 C.) [0178] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 62.83% weight loss starting at 2530 and a 30.20% weight loss starting at 2780 followed by complete decomposition. [0179] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using CuKalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2 in continuous scan mode using a step size of 0.022 and a scan speed of 2.0/min. XRPD analysis experimental: 10.736, 12.087, 16.857, 24.857, 27.857. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | [0096] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 7 mg (0.0521 mmol) p-phthalaldehyde were dissolved in approximately 3 mL methanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/p-phthalaldehyde co-crystal, as shown in FIG. 10B. [0097] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C38H30N4O4, M=606.66, monoclinic C2/c; a=29.191(16), b=4.962(3), c=20.316(11) , beta=92.105(8), U=2941(3) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm, Dc=1.370 Mg/m3, lambda=0.71073 3, F(OOO)=1272, 2thetamax=43.660, 3831 reflections measured, 1559 unique (Rint=0.0510). Final residuals for 268 parameters were R1=0.0332, wR2=0.0801 for I>2?(I), and R1=0.0403, wR2=0.0831 for all 1559 data. [0098] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers that crystallize in the space group C2/c. The 10 amines of the homodimer are bifurcated to the carbonyl of the p-phthalaldehyde forming a chain with an adjacent homodimer. The chains pack in a crinkled tape motif sustained by ?-? interactions between phenyl rings of the CBZ. [0099] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). The 10 amine unsymmetrical and symmetrical stretching was shifted down to 3418 cm-1; aliphatic aldehyde and 10 amide CO stretching was shifted up to 1690 cm-1; N-H in-plane bending at 1669 cm-1; C-H aldehyde stretching at 2861 cm-1 and H-CO bending at 1391 cm-1. [0100] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 128.460 C (endotherm), m.p.=121-124 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.20 C, p-phthalaldehyde m.p.=116 C.). [0101] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 17.66% weight loss starting at 30.330 C then a 17.57% weight loss starting at 100.14 C. followed by complete decomposition. [0102] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Ka (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 30 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD derived from the single crystal data, experimental (calculated): 8.5 (8.7); 10.6 (10.8); 11.9 (12.1); 14.4 (14.7) 15.1 (15.2); 18.0 (18.1); 18.5 (18.2); 19.8 (18.7); 23.7 (24.0); 24.2 (24.2); 26.4 (26.7); 27.6 (27.9); 27.8 (28.2); 28.7 (29.1); 29.3 (29.6); 29.4 (29.8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0167] 40 mg (0.1693 mmol) <strong>[298-46-4]carbamazepin</strong>e was dissolved in approximately 2 mL formic acid. Slow evaporation of the solvent yielded off-white starbursts of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/formic acid co-crystal, as shown in FIG. 22B. [0168] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C16H14N2O3, M=282.29, monoclinic P2I/c; a=5.2031(9), b=14.741(2), c=17.882(3) , alpha=90, beta=98.132(3), gamma=900, V=1357.7(4)3, T=100 K, Z=4, mu(MO-Kalpha)=0.097 mm1, Dc=1.381 Mg/m3, k=0.71073 3, F(000)592, 2thetamax=28.3. 9402 reflections measured, 3191 unique (Rint=0.111). Final residuals for 190 parameters were R1=0.0533 and wR2=0.1268 for I>2?(I). [0169] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxylic acid-amineheterodimers arranged in centrosymmetric tetramers. [0170] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3439 cm-1, (1 amine stretch,CBZ); 3026 cm-1 (C-H stretch, CBZ); 1692 cm-1, (1 amide, CO stretch). [0171] Melting Point: 187 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., formic acid m.p.=8.4 C.). [0172] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 14.60% weight loss starting at 123 and a 68.91% weight loss starting at 1960 followed by complete decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0155] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e was dissolved in approximately 1.5 mL DMSO. Slow evaporation of the solvent yielded colorless plates of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/DMSO co-crystal, as shown in FIG. 20B. [0156] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C34H36N4O4S2, M=628.79, triclinic P-1; a-7.3254(19), b=8.889(2), c=12.208(3) , alpha94.840(5), beta=94.926(5), gamma=100.048(5), V=775.8(3)3, T=200(2) K, Z=2, mu(MO-Kalpha)=0.216 mm-1, Dc=1.320 Mg/m3, k=0.71073 3, F(000)320, 2thetamax=28.3. 4648 reflections measured, 3390 unique (Rint=0.0459). Final residuals for 209 parameters were R1=0.0929, wR2=0.3043 for I>2?(I). [0157] Crystal packing: The co-crystals are sustained by the hydrogen bonded carboxamide homosynthon. The 1 amines are hydrogen bonded to the sulfoxide of the DMSO on each side of the homosynthon. The crystal is stabilized by ?-? interactions from the tricyclic azepine ring system groups of the CBZ. [0158] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3369 cm-1 (N-H stretch, 1 amine, CBZ); 1665 cm-1 (CO stretching); 1481 cm-1 (CC). [0159] Differential Scanning Calorimetry: (TA Instruments 2920 DSC). 100 C., 193 C. (endotherms). m.p.=189 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., DMSO m.p.=18.45 C.) [0160] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 26% weight loss starting at 1020, a 64% weight loss starting at 2120 followed by complete decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; | [0103] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were dissolved in 4 mL of DMSO, methanol or ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide co-crystal, as shown in FIG. 11. [0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4). | |
[0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4). | ||
In ethanol; | [0103] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were dissolved in 4 mL of DMSO, methanol or ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide co-crystal, as shown in FIG. 11. [0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4). |
In methanol; | [0103] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were dissolved in 4 mL of DMSO, methanol or ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide co-crystal, as shown in FIG. 11. [0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4). | |
11.1 g | In methanol; cyclohexane; at 17 - 22℃; under 724.572 - 782.178 Torr; for 3h; | An anti-solvent (33.4g/97.5 wt % of anhydrous cyclohexane) and a solvent (0.75g/2.5 wt % of anhydrous methanol) were poured into the flow mixer to form a liquid medium for cocrystallisation of the precursor components of the active cocrystalline material. The motion generator was operated to provide an oscillatory motion to the liquid medium (stroke amplitude = 10mm; frequency 1.5Hz) and an active precursor component and a cocrystal coformer precursor component (8.3 lg <strong>[298-46-4]carbamazepin</strong>e and 4.3g nicotinamide (stoichiometric ratio 1:1), respectively) were then introduced into the flow mixer. The reaction took place at ambient temperature and pressure as described in Example 1. After 3 hours, the motion generator was stopped and the slurry of the liquid medium, active cocrystalline material and residual precursor components were removed from the flow mixer and were subjected to a filtration process. Any remaining solvent was allowed to evaporate from the residue. The residue (11. lg) was analysed using powder x-ray diffraction spectroscopy and confirmed to contain 1:1 <strong>[298-46-4]carbamazepin</strong>e:niotinamide cocrystal. |
at 175℃; | Example 3 of the present invention consists in a mixture of <strong>[298-46-4]carbamazepin</strong>e (CARB anhydrous from TCI Development Co., Ltd.) and nicotinamide (NIC, from Sigma-Aldrich Company,Ltd), in a molar proportion 1:1 (total mass of -30 grams). Further processing of the physical mixture was identical to the procedure applied in EXAMPLE 1 and 2. Total melting of the physical mixture was observed at 175C. Spray congealing was conducted in the same equipment and in the same conditions as in EXAMPLE 1 and 2 (i.e. open-cycle mode, extended set-up, jacketed two fluid nozzle with 1.20 mm tip). The atomization flow rate was set to 11.8 L/min, while the congealing gas flow rate was maintained to 0.35 m3/min. The inlet and outlet temperatures (i.e. T_in and T_out, respectively) of the congealing gas after stabilization were 50C and 36C. At the end of the process, the resultant powders were characterized by the same analytical techniques and respective experimental methods as in EXAMPLE 1 and 2 (i.e. mDSC, XRPD and SEM) for characterization. The pure API, coformer and respective physical mixture were also analyzed through mDSC and XRPD for comparison.FIG.7 shows the mDSC heat flow curves correspondent to the thermal analysis of pure CARB, pure NIC, 1:1 CARB:NIC AC physical mixture and 1:1 CARB:NIC powder obtained using spray congealing.Similarly to the DSC profile of pure CAF, pure CARB first underwent a polymorphic transformation at 150C and second the melting of the new phase formed at 186C (J. Pharm. Sd. 2003, 92(11), 2260-71). The thermogram of pure NIC presented a single endothermic peak at 126C attributed to the thermodynamic melting of the material. The thermogram of the 1:1 CARB:NIC physical mixture showed two sharp endothermic peaks at 122C and 157C, which corresponded to the eutectic and cocrystal melting, respectively. Another endothermic peak was observed at a temperature of 103C with a much smaller associated enthalpy as compared with aforementioned endothermic peaks, which may correspond to a phase transformation. The thermogram observed for the powder produced using spray congealing was in agreement with the thermogram of the respective physical mixture and was indicative that cocrystals were formed. Similarly to EXAMPLE 2, the endotherm correspondent to the eutectic disappeared while the peak correspondent to the melting of the cocrystal was still observed at 154C. These results were in agreement with the literature, where 1:1 CARB:NIC cocrystals were produced using different manufacturing approaches (Cryst. Growth Des. 2009, 9(5). 2377-86; Pharm, Res, 2012, 29, 806-17). | |
In water; at 80℃; for 5h;Heating; Green chemistry; | For the slurry conversion synthesis, 2 mmol of <strong>[298-46-4]carbamazepin</strong>e (472.5 mg) was weighed in a beaker. In a different recipient, 2 mmol of nicotinamide (244.3mg) and 1.5 mL of ultrapure water were placed. This solution was added to the <strong>[298-46-4]carbamazepin</strong>e powder and the reaction was monitored by Raman spectroscopy. The reaction was heated using an IKA heating plate, model C-MAG HS 7, equipped with electronic thermometer and magnetic stirrer. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | [0118] 36 mg (0.1524 mmol) <strong>[298-46-4]carbamazepin</strong>e and 26 mg (0.1556 mmol) 2,6-pyridinedicarboxylic acid were dissolved in approximately 2 mL ethanol. Slow evaporation of the solvent yielded clear needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/2,6-pyridinedicarboxylic acid cocrystal, as shown in FIG. 14B. [0119] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C22H17N3O5, M=403.39, orthorhombic P2(1)2(1)2(1); a=7.2122, b=14.6491, c=17.5864 , alpha=90, beta=90, gamma=90, V=1858.0(2) 3, T=100 K, Z=4, mu(MO-Kalpha)=0.104 mm, Dc=1.442 Mg/m3, lambda=0.71073 3, F(000)840, 2thetamax=28.3.116641 reflections measured, 4466 unique (Rint=0.093). Final residuals for 271 parameters were R1=0.0425 and wR2=0.0944 for I>2?(I). [0120] Crystal packing: Each hydrogen on the CBZ 1 amine is hydrogen bonded to a carbonyl group of a different 2,6-pyridinedicarboxylic acid moiety. The carbonyl of the CBZ carboxamide is hydrogen bonded to two hydroxide groups of one 2,6-pyridinedicarboxylic acid moitey. [0121] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3439 cm-1, (N-H stretch, 1 amine, CBZ); 1734 cm-1, (CO); 1649 cm-1, (CC). [0122] Melting Point: 214-216 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., 2,6-pyridinedicarboxylic acid m.p.=248-250 C.). [0123] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 69% weight loss starting at 215 C. and a 17% weight loss starting at 392 followed by complete decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.8% | In water; acetic acid; at 15 - 60℃; for 4h;Product distribution / selectivity; | 3 kg iminostilbene are stirred in a mixture of 28.5 l acetic acid and 1.5 l water, and heated to 60 C. Within about 2 hours 1.66 kg 98% sodium cyanate is added, the the mixture is cooled to 15 C. and held for a further 2 hours between 15 C. to 20 C., then the crystals are sucked off, washed with 2 l acetic acid and dried, yielding 3.39 kg (92.5% of theoretical) of the end product, having a melting point of 190 C. to 192 C.Next 22 l acetic acid was distilled off, 10 l water was added to the residue, briefly stirred, sucked off and washed with 5 l water and dried and a further 0.28 kg of the product was obtained which was recrystallized from toluene to 0.23 kg (6.3% of theoretical) having a melting point of 191 C. to 194 C. This resulted in a total yield of 98.8% of theoretical). |
95.9% | In acetic acid; at 18 - 60℃; for 5h;Product distribution / selectivity; | A stirred suspension of 100 g iminostilbene in 1000 ml acetic acid is heated to 60 C. Next, within 160 minutes 54 g 90% sodium cyanate is added in 11 installments. During the reaction the iminostilbene goes almost completely into solution before carbamazepine begins to crystalize out. After the addition of the sodium cyanate is completed the reaction mixture is continued to be stirred for another 20 minutes at 60 C. Then it is cooled to 18 C.-20 C. and stirred at that temperature for two more hours. The precipitated carbamazepine is collected by filtration, washed with 60 ml water free acetic acid, and is dried. A yield of 107.8 g (87.9% of theoretical) of carbamazepine is obtained having a melting point of 193 C. to 194 C.The acetic acid is distilled off from the mother liquor under vacuum produced by a water jet aspirator. The sodium acetate is dissolved from the residue with water, the carbamazepine is collected, dried, and recrystallized from toluene. A further 9.8 g (8.0% of theoretical) carbamazepine is obtained having a melting point of 191 C. to 193 C. Thus, the gross yield is 95.9% of theoretical. |
93.7% | In ethanol; acetic acid; at 60 - 80℃; for 1.5h;Product distribution / selectivity; | 30 g iminostilbene are heated to 60 C. in 360 ml acetic acid and 50 ml ethanol, and 20 g 98% sodium cyanate is added within 1.5 hours at this temperature. After a short heating to 80 C., the mixture is further stirred at 60 C., and then cooled to 15 C., sucked off, washed with 20 l acetic acid and dried to yield 29.4 g (80.3% of theoretical) of carbamazepine, having a melting point of 189 C. to 192 C.After adding 1 g sodium cyanate to the mother liquor, distilling it, adding water to the residue and recrystallization of the dried product from toluene a further 4.9 g (13.4% of theoretical) carbamazepine is obtained with a melting point of 190 C. to 193 C. to result in a total yield of 93.7%. |
93.9 - 94% | In water; acetic acid; at 18 - 80℃; for 3.75 - 4.25h;Product distribution / selectivity; | A suspension of 100 g iminostilbene in a mixture of 900 ml water-free acetic acid and 100 ml water is heated to 60 C. during stirring, then within 2.75 hours 58.3 g of 90% sodium cyanate is added in 16 installments. After a two hour reaction time the mass is heated briefly to 80 C. to bring small amounts of undissolved iminostilbene into solution.After the adding of the sodium cyanate is completed, the reaction mixture is cooled to 18 C. to 20 C. and stirred for half and hour at this temperature. The precipitated carbamazepine is sucked off, washed with 70 ml of a mixture of 63 ml acetic acid and 9 ml water, and is then dried. 110.1 g of the end product is obtained (89.8% of theoretical), having a melting point of 191 C. to 195 C.The solvent is distilled off from the mother liquor and the sodium acetate is dissolved from the residue, carbamazepine is sucked off, dried, and recrystallized from toluene to produce a further 5 g (4.1%) carbamazepine, having a melting point of 188 C. to 190 C., resulting in a total yield of 93.9%.A suspension of 30 g iminostilbene in admixture with 225 ml acetic acid and 45 ml water is heated to 60 C. while stirring. Then within 2.75 hours, 17.5 g 90% sodium cyanate is added in 16 installments. After 1.5 hours reaction time the mixture is briefly heated to 80 C. to dissolve any undissolved iminostilbene. After the addition of the sodium cyanate the reaction mixture is rested for further ten minutes at 60 C. and then cooled to 18 C. to 20 C. and stirred for a further hour at this temperature. The precipitated carbamazepine is sucked off and washed in 20 ml acetic acid water mixture (6:1) and then dried. 32.9 g (89.2% of theoretical) of the end product is obtained, having a melting point of 189 C. to 191 C.The entire solvent is distilled off from the mother liquor and the sodium acetate is dissolved from the residue with water, carbamazepine is sucked off, dried and recrystallized from toluene. Thus a further 1.8 g (4.8%) carbamazepine is obtained having a melting point of 191 C. to 193 C., producing a total yield of 94%. |
70% | Pyridinium bromide (14.35 g, 0.090 mol) was added to 3 ml water in a 250 ml three necked flask, equipped with mechanical stirrer and thermometer. The mixture was stirred at room temperature [(22 C)] for about 10 minutes, and then 50 ml toluene was added, followed by [5H-DIBENZ [BFLAZEPINE] (10 g, 0.052 mol) and sodium isocyanate (9 g, 0.138 mol). The reaction was stirred at room temperature for about 3-5 hours. 50 ml water was added, and the mixture stirred for 15 minutes. The solid material was filtered, washed with about 50 ml of water, and dried, providing 8.6 g (70%) of [5H-] dibenz [[B FLAZOPINE-5-CARBOXAMIDE (CARBAMAZEPINE).] The product may be recrystallized from [95%] ethanol. | |
With MANDELIC ACID; In toluene; for 10h;Reflux; | EXAMPLE-5: Preparation of carbamazepine from iminostilbene; A suspension of 1Og of iminostilbene in 100 ml toluene was treated with 20.2g of sodium cyanate and 27.5g of mandelic acid and was heated to reflux for about 10 hrs. The reaction mixture was cooled to room temperature and charged with sodium hydroxide solution and maintained for 8 hrs. The resulting suspension was filtered, washed with water and dried to give H g of carbamazepine. | |
With MANDELIC ACID; In toluene;Reflux; | EXAMPLE-5 Preparation of carbamazepine from iminostilbene A suspension of 10 g of iminostilbene in 100 ml toluene was treated with 20.2 g of sodium cyanate and 27.5 g of mandelic acid and was heated to reflux for about 10 hrs. The reaction mixture was cooled to room temperature and charged with sodium hydroxide solution and maintained for 8 hrs. The resulting suspension was filtered, washed with water and dried to give 11 g of carbamazepine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0149] 10 mg (0.0423 mmol) <strong>[298-46-4]carbamazepin</strong>e was dissolved in approximately 1 mL butyric acid. Slow evaporation of the solvent mixture produced an average yield of yellow/brown crystals of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/butyric acid co-crystal, as shown in FIG. 19B. [0150] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C19H2ON2O3, M=324.37, triclinic P-1; a=9.1567, b=10.1745, c=10.5116 , alpha=72.850, beta=70.288, gamma=67.2690, V=832.17 3, T=100 K, Z=2, mu(MO-Kalpha)0.088 mm-1, Dc=1.290 Mg/m3, lambda=0.71073 3 F(000)344, 2thetamax=28.28. 5315 reflections measured, 3686 unique (Rint=0.0552). Final residuals for 217 parameters were R1=0.0499, wR2=0.1137 for I>2?(1), and R1=0.0678, wR2=0.1213 for all 3686 data. [0151] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxamide-carboxylic heterodimers between the <strong>[298-46-4]carbamazepin</strong>e moieties and the butyric acid moieties. The second 1 amine hydrogen from each CBZ joins 2 heterodimers side by side forming a tetramer. [0152] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3486 cm-1, (N-H stretch, 1 amine, CBZ); 3307 cm-1, (C-H stretch, alkene); 1684 cm-1, (CO); 1540 cm-1, (CC). [0153] Melting Point: 63-64 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., butyric acid m.p.=-94 C.). [0154] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA).16% weight loss starting at 540, a 16% weight loss starting at 134 and a 49% weight loss starting at 1740 followed by complete decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | [0143] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 11 mg (0.1018 mmol) benzoquinone was dissolved in 2 mL methanol or THF. Slow evaporation of the solvent produced an average yield of yellow crystals of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/benzoquinone co-crystal, as shown in FIG. 18B. [0144] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C21H16N2O3, M=344.36, monoclinic P2(1)/c; a=10.3335(18), b=27.611(5), c=4.9960(9) , beta=102.275(3), T=100(2) K, Z=3, Dc=1.232 Mg/m3, mu(MO-Kalpha)=0.084 mm-1, lambda=0.71073 3, F(000)540, 2thetamax=28.24. 8392 reflections measured, 3223 unique (Rint=0.1136). Final residuals for 199 parameters were R1=0.0545 and wR2=0.1358 for I>2?(I), and R1=0.0659 and all 3223 data. [0145] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. Each 1 amine on the CBZ is bifurcated to a carbonyl group of a benzoquinone moiety. The dimers form infinite chains. [0146] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3420 cm-1, (N-H stretch, 1 amine, CBZ); 2750 cm-1, (aldehyde stretch); 1672 cm-1, (CO); 1637 cm-1, (CC, CBZ). [0147] Melting Point: 170 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., benzoquinone m.p.=115.7 C.). [0148] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 20.62% weight loss starting at 1680 and a 78% weight loss starting at 223 followed by complete decompositon. | |
In tetrahydrofuran; | [0143] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 11 mg (0.1018 mmol) benzoquinone was dissolved in 2 mL methanol or THF. Slow evaporation of the solvent produced an average yield of yellow crystals of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/benzoquinone co-crystal, as shown in FIG. 18B. [0144] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C21H16N2O3, M=344.36, monoclinic P2(1)/c; a=10.3335(18), b=27.611(5), c=4.9960(9) , beta=102.275(3), T=100(2) K, Z=3, Dc=1.232 Mg/m3, mu(MO-Kalpha)=0.084 mm-1, lambda=0.71073 3, F(000)540, 2thetamax=28.24. 8392 reflections measured, 3223 unique (Rint=0.1136). Final residuals for 199 parameters were R1=0.0545 and wR2=0.1358 for I>2?(I), and R1=0.0659 and all 3223 data. [0145] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. Each 1 amine on the CBZ is bifurcated to a carbonyl group of a benzoquinone moiety. The dimers form infinite chains. [0146] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3420 cm-1, (N-H stretch, 1 amine, CBZ); 2750 cm-1, (aldehyde stretch); 1672 cm-1, (CO); 1637 cm-1, (CC, CBZ). [0147] Melting Point: 170 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., benzoquinone m.p.=115.7 C.). [0148] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 20.62% weight loss starting at 1680 and a 78% weight loss starting at 223 followed by complete decompositon. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0131] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e was dissolved in approximately 2 mL acetic acid. Slow evaporation of the solvent yielded yellow needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/acetic acid co-crystal, as shown in FIG. 16B. [0132] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C17H16N2O3, M=296.32, monoclinic P2(1)/c; a=5.1206(4), b=15.7136(13), c=18.4986(15) , alpha=90, beta=96.5460(10), gamma=900, V1478.8(2)3, T=100(2) K, Z=4, mu(MO-Kalpha)=0.093 mm-1, Dc=1.331 Mg/m3, lambda=0.71073 3, F(000)624, 2thetamax=28.4. 12951 reflections measured, 3529 unique (Rint=0.076). Final residuals for 203 parameters were R1=0.0492, wR2=0.1335 for I>2?(I). [0133] Crystal packing: The co-crystal is sustained by hydrogen bonded carboxamidecarboxylic heterodimers. The second 1 amine hydrogen from each CBZ joins 2 heterodimers side by side forming a tetramer. [0134] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3462 cm-1, (N-H stretch, 1 amine, CBZ); 1699 cm-1, (CO); 1629 cm-1, (CC, CBZ); 1419 cm-1, (COOH, acetic acid). [0135] Melting Point: 187 C. (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., acetic acid m.p.=16.6 C.). [0136] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 20.62% weight loss starting at 104 and a 77.05% weight loss starting at 2000 followed by complete decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; | [0111] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 19 mg (0.1037 mmol) saccharin were dissolved in approximately 4 mL ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/saccharin cocrystal, as shown in FIG. 12. Solubility measurements indicate that this multiple-component crystal of <strong>[298-46-4]carbamazepin</strong>e has improved solubility over previously known forms of <strong>[298-46-4]carbamazepin</strong>e (e.g., increased molar solubility and in aqueous solutions). [0112] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C22H17N3O4S1, M=419.45, triclinic P-1; a=7.5140(11), b=10.4538(15), c=12.6826(18) , a=83.642(2), beta=85.697(2), gamma=75.411(2) , U=957.0(2) 3, T=200(2) K, Z=2, mu(Mo-Kalpha)=0.206 mm-1, Dc=1.456 Mg/m3, k=0.71073 3, F(000)=436, 2thetamax=56.200; 8426 reflections measured, 4372 unique (R1.t 0.0305). Final residuals for 283 parameters were R1=0.0458, wR2=0.1142 for I>2?(I), and R1=0.0562, wR2=0.1204 for all 4372 data. [0113] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 2 amines of the saccharin are hydrogen bonded to the carbonyl of the CBZ on each side forming a tetramer. The crystal has a space group of P-i with n-g interactions between the phenyl groups of the CBZ and the saccharin phenyl groups. [0114] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts up to 3495 cm1 accounting for 10 amines; CO aliphatic stretching was shifted up to 1726 cm-1; N-H in-plane bending at 1649 cm; CC stretching shifted down to 1561 cm-1; (OSO) sulfonyl peak at 1330 cm-1 C-N aliphatic stretching 1175 cm-1. [0115] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 75.310 C (endotherm) and 177.32 C. (endotherm), m.p.=148-155 C. (MEL-TEMP); (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.20 C, saccharin m.p.=228.8 C.). [0116] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 3.342% weight loss starting at 67.03 C. and a 55.09% weight loss starting at 118.71 C. followed by complete decomposition. [0117] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD derived from the single crystal data, experimental (calculated): 6.9 (7.0); 12.2 (12.2); 13.6 (13.8); 14.0 (14.1); 14.1 (14.4); 15.3 (15.6); 15.9 (15.9); 18.1 (18.2); 18.7 (18.8); 20.2 (20.3); 21.3 (21.5); 23.7 (23.9); 26.3 (26.4); 28.3 (28.3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | [0137] 15 mg (0.1524 mmol) <strong>[298-46-4]carbamazepin</strong>e and 20 mg (0.1556 mmol) 1,3,5,7-adamantanetetracarboxylic acid were dissolved in approximately 1 mL methanol or 1 mL ethanol. Slow evaporation of the solvent yields clear plates of a 2:1 <strong>[298-46-4]carbamazepin</strong>e/1,3,5,7-adamantanetetracarboxylic acid co-crystal, as shown in FIG. 17B. [0138] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C44H40N2O10, M=784.80, monoclinicC2/c; a=18.388(4), b=12.682(3), c=16.429(3) , beta=100.491(6), V=3767.1(14) 3, T=100(2) K, Z=4, mu(MO-Kalpha)=0.099 mm-1, Dc=1.384 Mg/m3, lambda=0.71073 3, F(000)1648, 2thetamax=28.20. 16499 reflections measured, 4481 unique (Rint=0.052). Final residuals for 263 parameters were R1=0.0433 and wR2=0.0913 for I>2?(I). [0139] Crystal packing: The co-crystals form a single 3D network of four tetrahedron, linked by square planes similar to the PtS topology. The crystals are sustained by hydrogen bonding. [0140] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3431 cm, (N-H stretch, 1I amine, CBZ); 3123 cm-1, (C-H stretch, alkene); 1723 cm-1, (CO); 1649 cm, (CC). [0141] Melting Point: (MEL-TEMP). 258-260 C. (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., adamantanetetracarboxylic acid m.p.=>390 C.). [0142] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 9% weight loss starting at 189 C., a 52% weight loss starting at 251 C. and a 31% weight loss starting at 374 C. followed by complete decomposition. | |
In ethanol; | [0137] 15 mg (0.1524 mmol) <strong>[298-46-4]carbamazepin</strong>e and 20 mg (0.1556 mmol) 1,3,5,7-adamantanetetracarboxylic acid were dissolved in approximately 1 mL methanol or 1 mL ethanol. Slow evaporation of the solvent yields clear plates of a 2:1 <strong>[298-46-4]carbamazepin</strong>e/1,3,5,7-adamantanetetracarboxylic acid co-crystal, as shown in FIG. 17B. [0138] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C44H40N2O10, M=784.80, monoclinicC2/c; a=18.388(4), b=12.682(3), c=16.429(3) , beta=100.491(6), V=3767.1(14) 3, T=100(2) K, Z=4, mu(MO-Kalpha)=0.099 mm-1, Dc=1.384 Mg/m3, lambda=0.71073 3, F(000)1648, 2thetamax=28.20. 16499 reflections measured, 4481 unique (Rint=0.052). Final residuals for 263 parameters were R1=0.0433 and wR2=0.0913 for I>2?(I). [0139] Crystal packing: The co-crystals form a single 3D network of four tetrahedron, linked by square planes similar to the PtS topology. The crystals are sustained by hydrogen bonding. [0140] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3431 cm, (N-H stretch, 1I amine, CBZ); 3123 cm-1, (C-H stretch, alkene); 1723 cm-1, (CO); 1649 cm, (CC). [0141] Melting Point: (MEL-TEMP). 258-260 C. (<strong>[298-46-4]carbamazepin</strong>e m.p.=191-192 C., adamantanetetracarboxylic acid m.p.=>390 C.). [0142] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 9% weight loss starting at 189 C., a 52% weight loss starting at 251 C. and a 31% weight loss starting at 374 C. followed by complete decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | [0124] 40 mg (0.1693 mmol) <strong>[298-46-4]carbamazepin</strong>e and 30 mg (0.1421 mmol) 5-nitroisophthalic acid were dissolved in approximately 3 mL methanol or ethanol. Slow evaporation of the solvent yielded yellow needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/5-nitroisophthalic acid co-crystal, as shown in FIG. 15B. [0125] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C47H40N6O16, M=944.85, monoclinic C2/c; a=34.355(8), b=5.3795(13), c-23.654(6) , alpha=90, beta=93.952(6), gamma=900, V=4361.2(18)3, T=200(2) K, Z=4, mu(MO-Kalpha)=0.110 mm-1, Dc=1.439 Mg/m3, lambda=0.71073 3, F(000)1968, 2thetamax=26.43. 11581 reflections measured, 4459 unique (Rint=0.0611). Final residuals for 311 parameters were R1=0.0725, wR2=0.1801 for I>2?(I), and R1=0.1441, wR2=0.1204 for all 4459 data. [0126] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxylic acid homodimers between the two 5-nitroisophthalic acid moieties and hydrogen bonded carboxy-amide heterodimers between the <strong>[298-46-4]carbamazepin</strong>e and 5-nitroisophthalic acid moiety. There is solvent hydrogen bonded to an additional N-H donor from the <strong>[298-46-4]carbamazepin</strong>e moiety. [0127] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3470 cm-1, (N-H stretch, 10 amine, CBZ); 3178 cm-1, (C-H stretch, alkene); 1688 cm-1, (CO); 1602 cm-1, (CC). [0128] Differential Scanning Calorimetry: (TA Instruments 2920 DSC). 190.51 C. (endotherm). m.p.=NA (decomposes at 197-200 C.) (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191192 C., 5-nitroisophthalic acid m.p.=260-261 C.). [0129] Thennogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 32.02% weight loss starting at 2020, a 12.12% weight loss starting at 224 and a 17.94% weight loss starting at 285 followed by complete decomposition. [0130] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using CuKa (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2 in continuous scan mode using a step size of 0.022 and a scan speed of 2.0/min. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 10.138 (10.283), 15.291 (15.607), 17.438 (17.791), 21.166 (21.685), 31.407 (31.738), 32.650 (32.729). | |
In ethanol; | [0124] 40 mg (0.1693 mmol) <strong>[298-46-4]carbamazepin</strong>e and 30 mg (0.1421 mmol) 5-nitroisophthalic acid were dissolved in approximately 3 mL methanol or ethanol. Slow evaporation of the solvent yielded yellow needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/5-nitroisophthalic acid co-crystal, as shown in FIG. 15B. [0125] Crystal data: (Bruker SMART-APEX CCD Diffractometer). C47H40N6O16, M=944.85, monoclinic C2/c; a=34.355(8), b=5.3795(13), c-23.654(6) , alpha=90, beta=93.952(6), gamma=900, V=4361.2(18)3, T=200(2) K, Z=4, mu(MO-Kalpha)=0.110 mm-1, Dc=1.439 Mg/m3, lambda=0.71073 3, F(000)1968, 2thetamax=26.43. 11581 reflections measured, 4459 unique (Rint=0.0611). Final residuals for 311 parameters were R1=0.0725, wR2=0.1801 for I>2?(I), and R1=0.1441, wR2=0.1204 for all 4459 data. [0126] Crystal packing: The co-crystals are sustained by hydrogen bonded carboxylic acid homodimers between the two 5-nitroisophthalic acid moieties and hydrogen bonded carboxy-amide heterodimers between the <strong>[298-46-4]carbamazepin</strong>e and 5-nitroisophthalic acid moiety. There is solvent hydrogen bonded to an additional N-H donor from the <strong>[298-46-4]carbamazepin</strong>e moiety. [0127] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR). 3470 cm-1, (N-H stretch, 10 amine, CBZ); 3178 cm-1, (C-H stretch, alkene); 1688 cm-1, (CO); 1602 cm-1, (CC). [0128] Differential Scanning Calorimetry: (TA Instruments 2920 DSC). 190.51 C. (endotherm). m.p.=NA (decomposes at 197-200 C.) (MEL-TEMP). (<strong>[298-46-4]carbamazepin</strong>e m.p.=191192 C., 5-nitroisophthalic acid m.p.=260-261 C.). [0129] Thennogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA). 32.02% weight loss starting at 2020, a 12.12% weight loss starting at 224 and a 17.94% weight loss starting at 285 followed by complete decomposition. [0130] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using CuKa (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2 in continuous scan mode using a step size of 0.022 and a scan speed of 2.0/min. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 10.138 (10.283), 15.291 (15.607), 17.438 (17.791), 21.166 (21.685), 31.407 (31.738), 32.650 (32.729). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.2 - 97% | In water; acetic acid; at 20 - 80℃; for 2 - 5.5h;Product distribution / selectivity; | A suspension of 60 g iminostilbene in 600 ml acetic acid is heated during stirring to 60 C. Next a solution of 40 g 98% potassium cyanate in 66 ml water is added dropwise for 2 hours, while the reaction mixture is briefly heated to 80 C. to bring all of the iminostilbene into solution. After the addition of the potassium cyanate, the reaction mixture is cooled to room temperature and the precipitating carbamazepine is sucked off and dried. 33 g (89.9% of theoretical), having a melting point of 190-193 C. are obtained.The mother liquor is further processed as described in Example 3, to yield a further 3.3 g of the end product, resulting in a total yield of 93.2% of the theoretical. A stirred suspension of 100 g iminostilbene in a mixture of 1000 ml acetic acid and 150 ml water is heated to 60 C. Then within 5 hours 60.8 g 98% potassium cyanate is added in 13 installments. After the potassium cyanate addition is complete the reaction mixture is stirred for a further 30 minutes and cooled to 18 C. to 20 C. The precipitated crystals are sucked off, washed with a mixture of 60 ml acetic acid and 400 ml water, and then dried, yielding 11.2 g end product (90.9% of theoretical), having a melting point of 191 C. to 193 C.The solvent is distilled off from the mother liquor and potassium acetate is dissolved from the residue. The carbamazepine is sucked off, washed with water, recrystallized from toluene, to yield a further 7.5 g (6.1% of theoretical) carbamazepine, having a melting point of 190 C. to 192 C. The total yield is 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate; In methanol; water; | EXAMPLE 9 2.0 g of 5-cyano-5H-dibenz[b,f]azepine are suspended in 40 ml of methanol, and 10 ml of 30% H2 O2 are added at room temperature. The mixture is stirred for 30 minutes, and 10 g of sodium hydrogen carbonate are then added portionwise. After being stirred overnight at room temperature, the mixture is diluted with 50 ml of water; the formed precipitate is subsequently filtered off, and washed several times with water. The yield after drying is 3.0 g (95.2% of theory) of 5H-dibenz[b,f]azepine-5-carboxamide, which is shown by means of DC and IR analysis to be identical to authentic material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In nitrogen; ethyl acetate; | EXAMPLE 8 19.3 g of iminostilbene are suspended in 200 ml of ethyl acetate and 1.0 ml of sulphuric acid (98 %) is added. At 25 C., 6.5 g of monomeric cyanic acid (in a stream of nitrogen) are introduced. The whole is left to stand overnight, then concentrated to dryness by evaporation in vacuo, and the residue is taken up with toluene. After filtration, washing with toluene and water and drying at 80 C. in vacuo, 19.7 g of carbamazepine are obtained. | |
With acetic acid; In nitrogen; | EXAMPLE 9 19.3 g of iminostilbene are heated to 45 C. with 100 ml of acetic acid. In the course of 11/2 hours, 6.5 g of monomeric cyanic acid (in a stream of nitrogen) are introduced and the whole is left to react for 12 hours at 40 C. After cooling to 15 C., filtration is carried out followd by washing cold with acetic acid and drying in vacuo at 60 C. The resulting crude product is recrystallized from methanol/water (7:3) and yields 19.1 g of carbamazepine. | |
In nitrogen; water; acetic acid; | EXAMPLE 10 29.0 g of iminostilbene are heated to 45 C. in 150 ml of acetic acid. In the course of 11/2 hours, 9.7 g of monomeric cyanic acid (in a stream of nitrogen) are introduced and the whole is then allowed to react for 2 hours at 40 C. and for 12 hours at 20 C. After the addition of 15 ml of water, the whole is cooled to 0 C. and, after 1 hour, the product is filtered off and washed twice with 15 ml of acetic acid and water to give a crude product which, after recrystallisation from methanol/water (7:3), yields 29.1 g of carbamazepine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In nitrogen; toluene; | EXAMPLE 4 17.4 g of iminostilbene and 2.3 g of iminostilbene hydrochloride are suspended in 250 ml of toluene. The suspension is heated to 80 C. and, in the course of 11/2 hours, 6.5 g of monomeric cyanic acid are introduced in a stream of nitrogen and the whole is then heated for a further 1/2 hour at 100 C. After cooling to 5 C., the product is filtered off, washed four times with cold toluene and dried in vacuo at 60 C. b 18.5 g of carbamazepine are obtained. | |
In 5,5-dimethyl-1,3-cyclohexadiene; nitrogen; | EXAMPLE 5 17.4 g of iminostilbene and 2.3 g of iminostilbene hydrochloride are suspended in 250 ml of xylene (isomeric mixture). At 20 C., 6.5 g of monomeric cyanic acid are introduced in a stream of nitrogen and the whole is then allowed to react for 4 hours at 30 C. Subsequently, the whole is cooled to 0 C., and the product is filtered off, washed with xylene and dried in vacuo at 80 C. to yield 22.1 g of carbamazepine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In nitrogen; ethyl acetate; | p EXAMPLE 7 29.0 g of iminostilbene are suspended in 150 ml of ethyl acetate at 20 C. First of all 0.6 g of hydrogen chloride and then 9.7 g of cyanic acid in gaseous form (in a stream of nitrogen) are introduced. After stirring for 15 hours at 20 C., the product is filtered off, washed with ethyl acetate and then dried in vacuo at 60 C. 32.0 g of carbamazepine are obtained. An analogous test at 50 C. reaction temperature yielded 29.4 g of carbamazepine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; In chloroform; | a. 11.8 g (0.05 mole) of <strong>[298-46-4]5H-dibenz[b,f]azepine-5-carboxamide</strong> are dissolved at app. 25 C in 80 ml of chloroform. With gentle cooling, 8.2 g of bromine (0.1025 mole) in 40 ml of chloroform are added dropwise with stirring at 15-25 C in the course of 40 minutes. After about one third of this amount has been added, a precipitate forms which becomes more dense as the dropwise addition continues. The batch is subsequently stirred for a further 2 hours and the reaction product is then filtered off with suction. The filter cake is washed with a small amount of chloroform and then dried for 8 hours in a high vacuum at 70-80 C to yield the crude 10,11-dibromo-10,11-dihydro-<strong>[298-46-4]5H-dibenz[b,f]azepine-5-carboxamide</strong> which melts at 144.5 C with decomposition. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetic acid; | EXAMPLE 4: Preparation of Carbamazepine using Urea.HCl To a suspension of urea hydrochloride (100g, 1.036 mols) in acetic acid (125ml), iminostilbene (25g, 0.129 mols) was added under stirring at 25-30C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1. | |
In acetic acid; | EXAMPLE 4 Preparation of Carbamazepine using Urea.HCl To a suspension of urea hydrochloride (100 g, 1.036 mols) in acetic acid (125 ml), iminostilbene (25 g, 0.129 mols) was added under stirring at 25-30 C. The resulting reaction mixture was worked up according to the method of Example 1 to produce carbamazepine, which was identical to the product of Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 20℃; for 0.166667h;pH 1.1 - 6.3; | Example 1: CBZ-SAC (<strong>[298-46-4]carbamazepin</strong>e-saccharin) cocrystallization by lowering pH[0077] 0.2g (0.97mmol) sodium saccharin is dissolved in 3 mL unbuffered water, resulting in a pH of 6.3. 0.16g (0.69mmol) <strong>[298-46-4]carbamazepin</strong>e anhydrous (form III) is added to the sodium saccharin solution. The pH is lowered by addition of HCl, to a pH of 1.1. This process is carried out at room temperature. Cocrystal formation is monitored on-line by Raman spectroscopy and confirmed by comparing spectra to a reference cocrystal spectrum. Cocrystal is formed within 10 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20 - 60℃;Product distribution / selectivity; | Crystallization of <strong>[298-46-4]carbamazepin</strong>e:glycolamide co-crystal on milliliter scale .Prom acetonitrile: <n="19"/>A small quantity, about 60 mg of the starting material was placed in a HPLC vial. The solvent acetonitrile was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 1000 microliter and a concentration of about 60 mg/ml . The vial was shaken and the qualitative solubility was assessed visually. The solution was heated and maintained at 60 0C for 16 hours minutes. Subsequently, the solution was cooled at a rate of 0.1 C/ min. Crystalline material started to form at 32 C. The resulting solid was analysed by X-ray powder diffraction, DSC and identified as a <strong>[298-46-4]carbamazepin</strong>e :glycolamide co-crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20 - 60℃;Product distribution / selectivity; | From ethylacetate :A small quantity, about 60 mg of the starting material was placed in a HPLC vial . The solvent ethylacetate was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 1000 microliter and a concentration of about 60 mg/ml. The vial was shaken and the qualitative solubility was assessed visually. The solution was heated and maintained at 60 C for 16 hours minutes. Subsequently, the solution was cooled at a rate of 0.1 0C/ min. Crystalline material started to form at 32 0C. The resulting solid form was analysed by X-ray powder diffraction, DSC and identified as <strong>[298-46-4]carbamazepin</strong>e :glycolamide co-crystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20 - 60℃; | Crystallization of <strong>[298-46-4]carbamazepin</strong>e : lactamide co-crystal on milliliter scale.From acetonitrile:A small quantity, about 60 mg of the starting material was placed in a HPLC vial. The solvent acetonitrile was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 1000 microliter and a concentration of about 60 mg/ml. The vial was shaken and the qualitative solubility was assessed visually. The solution was heated and maintained at 60 C for 16 hours minutes. Subsequently, the solution was cooled at a rate of 0.1 0C/ min. Crystalline material started to form at 32 0C. The resulting solid was analysed by X-ray powder diffraction, DSC and identified as a <strong>[298-46-4]carbamazepin</strong>e: lactamide co-crystal. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :