Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and Purification kilomentor | 20 August, 2008 15:48 Pamoates are one of the pharmaceutically acceptable salts; however, they should only be considered for testing in an extended release formulation since the salts are almost always poorly soluble in water or stomach acid. The salts are prepared for retarding the dissolution of basic drugs. Stahl and Wermuth in Handbook of Pharmaceutical Salts Properties, Selection, and Use mention the pamoate salts of amitriptiline, benzphetamine, chlorpromazine, cyclguanyl, difenidol, dothiepin, imipramine, levomepromazine, metformine, noscapine, pamaquine, phendimetrazine, promazine, pyrantel, pyrvinium, and rhodoquine as being used in this way. The acid was first described by Hosaeus in 1892 and a use was suggested for it in a patent to I.G. Farbenindustrie A.G. in 1992 where it was claimed as a method for manufacturing sparingly soluble, tasteless salts of nitrogenous basic compounds in particular salts of alkaloids such as strychnine and of bases of the ‘plasmochin’ type. Kilomentor proposes that if one is faced with the problem of isolating an organic nitrogenous base by precipitation from any mixture, a reaction mixture say, the pamoate is probably the best first choice. A good second choice would be 2,2’-dihydroxy1,1’-dinaphthyl-3,3’-dicarboxylic acid, which is the compound similar to embonic acid but with the single difference that the methylene connecting the two naphthalene rings is gone. Both these compounds are either commercially available or easily synthesized. Syntheses are provided below from the paper by Barber and Gaimster, J. Appl. Chem., 2 October, 1952p. 565. Embonic Acid Method I- 2-hydroxy-3-naphthoic acid (750 g.) was suspended in glacial acetic acid (7.5 L.) and stirred at 5-100 C until dissolved. A mixture of glacial acetic acid (750 g.), 40% formaldehyde solution (450 g.) and concentrated sulfuric acid (71 g.) was added over20 minutes, the reaction being sufficiently exothermic to maintain the temperature between 95 and 100 C The suspension of embonic acid was stirred at 95-100 Cfor 30 minutes, allowed to cool to 70, filtered and washed first with ht glacial acetic acid (4.5 l.) and then distilled water until the washings were no longer ed to Congo red. The material was dried at 100 C to give embonic acid (700 g,) Method II- 2-Hydroxy-3-naphthoic acid (500 g.) and 10% NaOH(1500 ml) were heated to 90 C with stirring; about 2/3of the solid dissolved. 40% formaldehyde solution (63 g.) was added, the temperature rising to 92 C, then a further 83 g. of 40% formaldehyde solution which caused a further rise in temperature to 95 C. No solid remained at this stage. After heating at 95 for a further 5 minutes, the solution crystallized spontaneously. The mixture was maintained at 95 C for 1 hour, cooled to 20 C and the sodium embonate filtered and washed with saturated brine (125 ml.) The damp sodium embonate (about 1.2 kg.) could be used as such or converted to the acid by dissolving in a mixture of water (3 l.) ad acetone (700 ml.), by heating to 50 C and adding glacial acetic acid (225 ml.)and then concentrated hydrochloric acid (bout 200 ml.) until the mixture was acid to Congo red. The precipitated embonic acid (480 g.) was filtered, washed with hot water until free of chloride, and dried at 100 C. 2,2’-Dihydroxy1,1’-dinaphthyl-3,3’-dicarboxylic acid 2,-Hydroxy-3-naphthoic acid (18.8 g.) was dissolved in a solution of sodium hydroxide (8.0 g.) in water (580 ml) and the solution was refluxed while a solution of ferric chloride (23 g.) of the hexahydrate) and conc. Hydrochloride acid (26 ml.) in water (29 ml.) was added drop-wise with stirring during a 20 minute period./the dark coloured reaction mixture was stirred at the boil for a further 30 minutes, then cooled, filtered and the filtrate rejected. After washing with a little water, the residue was dissolved in a slight excess of N-sodium hydroxide solution (200 ml.) The solution was treated with charcoal, filtered, acidified with concentrated hydrochloric acid and filtered. The yellow residue, after washing with water, was recrystallized from aqueous ethanol to give 2,2’-dihydroxy-1,1’-dinaphtrhyl-3,3’dicarboxylic acid (2.8 g.) as a pale-yellow hemi-hydrate m.p. 330-333 C. US2397903 describes the poorly soluble salts with thiamine and dipyridoxine. US2641610 claims the use of the insoluble embonate salts of bis quartenary ammonium substances as a means of purifying and making the double salts with other anions by exchange. Experimental details for making embonates either from relatively free bases or from mixtures of natural products are provided below for inspiration with your own problems. WO9425460A1 Risperidone Example I A solution of 3- [2- [4-(6-fluoro- 1,2-benzisoxazol-3-yl)- I-piperidinyl) ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-Pyrido[1,2-ajpyrimidin-4-one,19.70 g (0. 048mol) in ethanol (600ml) was added to a solution 18.64 g of pamoic acid (0. 048mol) in N,N-dimethylformamide (400ml). (1g/22 ml ) The mixture was stirred for 3 hours. The resulting precipitate was filtered off by suction, washed with ethanol and dried, yielding 3 1 g (8.1 %) of 3-[2-[4-(6-fluoro- 1,2benzisoxazol-3-yl)- I -piperidinyl)ethyl) -6,7,8,9-tetrahydro-2-methyl-4H-pyfido[ 1, 2ajpyrimidin-4-one 4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylate) (1: 1); mp. 269.2'C. This is a very poor yield of salt; just 8.1%. Pamoic acid apparently is soluble in dimethyl formamide. This is useful information. The risperidone was dissolved in the usual ethanol. Perhaps the experimentalist did not wait long enough for the solid to all precipitate. They filtered after 3 hours. WO05016261A2 Example 1: The pamoate salt of haloperidol can be prepared by treatment of haloperidol with pamoic acid or pamoate salt in solvent. Haloperidol pamoate can be prepared by adding a solution of haloperidol in an appropriate solvent, ea. ethanol with acetic acid, to a solution of disodium pamoate, pamoic acid or other pamoate salt and leaving undisturbed for 1-3 or more days until precipitation. Alternatively, other methods such as evaporation, slow or fast cooling or stirring solutions can also be used to precipitate salt. Specifically, 2.5 ml of a O.1M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 2.5 ml of a O.1M solution of disodium pamoate (2.5ml) in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 240mg of 1:1 haloperidol pamoate salt. Example 2: 2.5 ml of a 0.25M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 12.5 ml of a 0.05M solution of disodium pamoate in ethanol/water (75/25). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 206mg of 2:1 haloperidol pamoate salt. Example 3: 2.5 ml of a 0.25M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 6.25 ml of a O.1M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 264mg of 2:1 haloperidol pamoate salt. - 1 1 Example 4: ml of a 0.05M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 1 ml of a 0.25M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 107 mg of 1:1 haloperidol pamoate salt. Example 5: 5.ml of a 0.05M solution of haloperidol in an acidified ethanol (5% acetic acid) was added to 2.5 ml of a O.1M solution of disodium pamoate in ethanol/water (50/50). The mixture was allowed to sit at room temperature for 1-3 days. The resulting precipitate was filtered off by suction, washed with ethanol and dried in a vacuum oven at 60°C, yielding 119 mg of 1:1 haloperidol pamoate salt. Example 6: A (0.05 - 0.5M) solution of aripiprazole in an acidified ethanol is added to a (0.05 - 0.5M) disodium pamoate solution in a mixture of water/ethanol (100/0 0/100). The mixture is allowed to sit at room temperature for 1-3 days. The resulting precipitate is filtered off by suction, washed with solvent and dried in a vacuum oven at 60°C. These methods teach the method of adding the base acidifuied with 5% acetic acid in ethanol to the disodium pamoate in ethanol/water. The disodium salt is more soluble and so this method depends upon the acidification of sodium pamoate with acetic acid to create the pamoic acid in situ where it can interact with the amine in the presence of acetic acid. The more insoluble amine pamoate crystallizes. These examples illustrate the fact that pamoates often must be allowed to change form from a gel like form to crystalline over some time. Heating sometimes accelerates this change. WO04017970A1 (C) Preparation of 3-(3-methoxyphenyl)-3-(3- dimethylaminopropyl]-4,4-dimethyl-piperidine-2,6-dione pamoate salt (anhydrous) A solution of AGN-2979 bisulphate salt obtained in Step B (1 mmole, 430 mg) in 10 ml of water was mixed with methylene chloride (20 ml) and basified with aqueous ammonium hydroxide (29% w/w). After separation of the layers, the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml) and mixed with a hot solution of pamoic acid (embonic acid, 390 mg,1 mmole) in hot ethanol (30 ml) and the mixture was heated to reflux. After cooling, the pamoate salt crystallised and the salt was recrystallised in hot ethanol to give a pale yellow powder (melting point = 146°-150°C. The procedure separates free base, evaporates to an oil and dissolves it in ethanol. It is mixed with a hot solution of pamoic acid dissolved in hot ethanol. The embonate came out in crystalline form on cooling. WO05075454A2 FORMS OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-n-[4-METHYL-3-(4-PYRIDIN-3-YL)PYRIMIDIN-2-YLAMINO)PHENYL]-BENZAMIDE - IMATINIB Example 10 4.l(4-Methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[ [4-(3-pyridinyl)-2- pyrimidinyl]amino]phenyl]- benzamide, pamoate A mixture of 4-[(4-methyl-1- piperazinyl) methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino] phenyl]-benzamide (4.94 g, 10 mmol) and 4,4'-methylenebis[3-hydroxy-2- naphthoic acid (Fluke, Buchs, Switzerland; 3.88 g, 10 mmol) in ethanol (50 mL) is heated. Water (25 mL) is then added. Upon cooling, the product crystallizes and is filtered-off and dried to afford 4-[(4-methyl-1- piperazinyl)methyl]-N- [4-methyl-3-[[4-(3-pyridinyl)- 2- pyrimidinyl]amino]phenyl]-benzemide, pamoate as a pale- yellow solid, having the following analytical properties: Analysis found: C, 69.12; H. 5.62; N. 10.88%; H2O, 2.50%. Calculated for C52H47N7O7- 1.26 H2O: C, 69.04; H. 5.52; N. 10.84%; H2O, 2. 51%. Heating pamoic acid in ethanol will create some solubility. The solids must have dissolved since the addition of water is usually done to the point of turbidity and then the crystals allowed to come out as the solution cools. WO05012233A1 MELDONIUM SALTS, METHOD OF THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION ON THEIR BASIS EXAMPLE 10 Meldonium pamoate (1:1; x H20). Meldonium (5.46 g, 30 mmol) and pamoic acid (5.82 g, 15 mmol) are mixed with water and acetone (15 ml), the formed suspension is evaporated, 30-40 ml toluene is added to the residual viscous mass, it is grated, and evaporation is repeated. If the residue is insufficiently dry, treatment with toluene is repeated. Mp. 128-133°C (decomp.). H NMR spectrum (DMSO-d6), 6, ppm: 2.41 (2H, t, CH2COO-); 3.14 (2H, t, CH2N); 3.25 (9H, s, Me3N+); 4.75 (2H, s, -CH=(pam)) , 7.12 (2H, t, Harom); 7.26 (2H, td, Harom); 7.77 (2H, d, Harom); 8.18 (2H, d, Harom); 8.35 (2H, s, Harom). Found, %: C 62,90; H 5,83; N 4,98. Calculated, %: C 63,07; H S,84; N 5,07. Initially H:O content in the sample was 1.71%; after 24 hours maintenance at 100% humidity sample mass increased by 9% due to absorbed water. Pamoic acid is not particularly soluble in either water or acetone. Evaporation would readily remove the acetone. The water would only be grudgingly removed as an azeotrope with toluene. WO0008016A1 PAROXETINE SALTS Example 32 : Preparation of paroxetine pamoate 1: 1 salt. A solution of paroxetine base in toluene (5 ml, 2. 10 g) was added to a solution of pamoic acid (2.48 g) in pyridine (40 ml), and the mixture was stirred at ambient temperature for 30 minutes. The solvent was then removed by distillation at reduced pressure, the residual oil diluted with toluene (30 ml) and the solvent again removed by distillation at reduced pressure. This procedure was repeated two more times. The solid product was washed with hot diethyl ether (c. 100 ml x 3) , and filtered under nitrogen to give a pale yellow solid. The product was washed twice more with diethyl ether (2 x 100 n- A), and then with methanol (30 ml), and finally dried under vacuum. Yield = 3.27 g, IR nujol mull: Bands at 1636, 1558, 1508, 1459, 1377, 1183, 1036, 830, 722 CM-1. Example 33 : Preparation of paroxetine pamoate 2:1 salt. A solution of paroxetine base in toluene (10 ml, 4.2 g) was added to a solution of pamoic acid (2.48 g) in pyridine (40 ml). The mixture was stirred at ambient temperature for 30 minutes. The solvent was then removed by distillation at reduced pressure, the residual oil diluted with toluene (30 ml) and the solvent again removed by distillation at reduced pressure. This procedure was repeated two more times. The solid product was washed with diethyl ether (c. 50 ml), and filtered under nitrogen to give a white solid. This solid was washed twice more with diethyl ether (2 x 10 ml), and then dried under vacuum. Yield 6.7 g. IR nujol mull: Bands at 1641, 1461, 13 77, 1181, 1035, 829, 757 cm- 1. Pamoic acid is soluble in pyridine presumably as a pyridinium salt. It can be recrystallized from dilute aqueous pyridine. It is also soluble in nitrobenzene. Molecules 2007, 12 1313 Extraction and precipitation of alkaloid-embonates Homogenous dried leaves of a registered Finnish variety of C. roseus (1.0 g) were extracted for 30 minutes with 0.1 M hydrochloric acid solution (100 mL) in an ultrasonic bath (USF Finnsonic W 181,Ultra Sonic Finland). The mixture was then centrifuged at 2000 rpm for 10 min and the sediment was re-extracted with additional HCl (100 mL) for another 30 minutes. The combined supernatant from two repeated extractions was filtered and extracted with petroleum ether (200 mL) to eliminate chlorophyll and other lipophilic compounds. The acidic fraction was separated and an alkaline solution(pH 10.5) of 10 % embonic acid was slowly added for the precipitation of alkaloids as their embonate complexes. The pH of the resultant solution was increased to 5.0. The precipitate was separated simply by decantation and it was used as starting material for the semi-synthesis. ---------------------------------