CA1108149A - D-glaucine phosphate salt - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The phosphate salt of d-glaucine is prepared by reacting d-glaucine base with excess phosphoric acid.
The glaucine salt has analgesic and antitussive properties, and improved flavor characteristics. Pharmaceutical compositions, and methods of using the same are also described.

27,804C-F

Description

~1~81~9 D-GLAUCINE PHOSPHATE SALT

~ extro-rotary glaucine or d-glaucine hydrobromide has been used as an antitussive agent.
D-glaucine can be isolated from the yellow poppy.
The racemate, d,l-glaucine can be synthesized from papaverine, following the procedure of Frank and Tietze, Angewandte Chemie (1967) pp 815-6, or Helm, Belgian Patent 866,079, and the racemate can be resolved with d-tartaric acid as disclosed by the above mentioned Helm Belgian patent. A variety of other preparative procedures are also known. Cham and Maitland, J. Org. Chem. J. Chem. Soc. (C) 1966, 753; and Cava, et al. J. Org. Chem. 35, 175 (1970).
Separation of the isomers has been carried out by conventional procedures, such as using d- or l-tartaric acid to form the d- or l-bitartrate salts and sep-arating the salts by fractional crystallization.

Glaucine has the structure O~CH3 27,804C-F

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and is thus structurally related to other plant alkaloids such as codeine and aporphine.
Antitussive agents are usually administered orally, most typically in the form of a liquid formulation such as an elixir, suspension or syrup, or in a solid lozenge or cough drop which is held in the mouth until it dissolves. In both cases the unpleasant bitter flavor of the alkaloid is known disadvantage of such agents.
Various formulations have been developed to mask the unpleasant taste and after taste of codeine, dihydrocodeine and dextro-methorphan, with varying degrees of success. None of these techniques have been completely successful. Glaucine, like codeine, has an unpleasant bitter taste.
According to the present invention, there is provided a process of preparing a d~glaucine phosphate salt by reacting d-glaucine with a molar excess of phosphoric acid.
The d-glaucine phosphate salts of the invention preferably are crystalline and have a melting point of 240 to 254C with decomposition, and a pH in water solution (0.5 grams/100 milli-liters) of 2.6 to 3Ø
D-glaucine phosphate has antitussive properties and has desirable solubility and unexpected flavor and palatability properties, and analgesic activity. `
Preferably, the novel phosphate salt of the invention is a crystalline solid which is prepared by reacting d-glaucine in the form of the base, with phosphoric acid under conditions adapted to the formation of phosphate salts of organic bases. The crystalline ., solid salt includes from 0.4 to 0.6 molar proportion of excess '.1 .
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phosphoric acid, e.g., typically one mole of glaucine base to 1.4 to 1.6 moles of phosphoric acid. The predominant crystalline phosphate salt, readily obtained using excess phosphoric -2a-:

acid, includes 1.~ to 1.6 and usually about 1.5 molecular proportions of phosphoric acid per molecular proportion of d-glaucine. The molecular proportions of glauclne and phosphoric acid in a particular preparation can be deter-mined by conventional procedures such as elemental analysis,or by X-ray crystallography and crystal density measurements.
This salt can be referred to as glaucine phosphate (2:3), or (glaucine)2 3H3PO4, or glaucine ll,~3PO4, for example.

The D-glaucine phosphate melts in the range from 240-254C and is soluble in water, and less soluble in organic solvents such as methylene chloride, acetone and diethyl ether. It is acidic in solution and generally has a pH in water solution (0.5 grams/100 ml) of 2.4 to

2.6. The exact melting point of particular preparations can vary depending on the preparative and purification procedures used, indicating that factors such as water of hydration or crystalline solvate formation with the reaction medium or with recrystallization solvents may be involved.

The compound can be readily prepared by re-acting the free glaucine base with phosphoric acid.
The reaction proceeds readily in the presence of an inert organic solvent, such as acetone, ethanol, chloro-form, methylene chloride, methanol, or diethyl ether, or ethyl acetate. The phosphate salt typically forms as a precipitate, which can be recovered by conventional techniques such as filtration or decantation and purified by conventional steps such as recrystallization and washing.

The reaction is typically carried out by dis-solving the free base glaucine in the inert organic sol-vent at a temperature from ambient temperature to the 27,804C-F -3-, 8~

boiling polnt of the mixture, and mixing the solution with an excess of phosphoric acid. Phosphoric acid is employed in from 0.5 to 1 to 2 to 3 fold molar excess or more. Use of equimolar amounts or excess glaucine reactant can result in production of a mixture of the glaucine phosphate (2:3) salt with impurities such as unreacted or partially reacted glaucine base. Such products can be reacted with additional phosphoric acid to convert the impurities to glaucine phosphate (2:3).

When using excess phosphoric acid, so as to obtain the glaucine phosphate (2:3) salt in relatively pure form or a solid phosphate associated with excess phosphoric acid, any excess phosphoric acid content can be reduced by partial neutralization followed by recrys-tallization, using amount of a alkali metal hydroxide sufficient to neutralize the excess phosphoric acid. The glaucine phosphate (2:3) salt can then be purified by conventional recrystallization, for example, with ethanol.
Partial neutralization is generally unnecessary to obtain a useful salt in crystalline form. Preferably, the product is digested by heating under reflux in ethanol for two to four hours, before recrystallization and drying.

The glaucine phosphate salt is an highly orally active antitussive agent and also has analgesic activity when administered orally, combined with surprising palata-bility and desirable solubility, and a useful freedom from undesired side effects. It can be administered at dosages of from 100 to 200 milligrams or more per kilo-grams (mg/kg) for antitussive effect, and at dosagescomparable to those used with d-glaucine hydrobromide for analgesic use, preferably by oral administration. It is also active parenterally as antitussives and analgesics, by intraperitioneal injection, for example.
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In practicing the method of the invention, an antitussive amount of the glaucine phosphate is administered internally to an anlmal, typically a mammal in need thereof. Administration can be carried out either by a parenteral route, such as by intravenous, intraperitoneal, or intramusuclar injection; or by introduction into the gastrointestinal tract via oral or rectal administration, for example, or by oral administration of a glaucine phosphate solution.

The antitussive amount of the compound, that is, the amount of the glaucine phosphate sufficient to inhibit or alleviate coughing depends on various factors such as the size, type and age of the animal to be treated, the route and frequency of administration, the severity of cough (if any) and the causative agent involved, and the time of administration. Similar considerations apply to selection of an analgesic dose for administration to animals. In antitussive evaluations in which codeine phosphate has an oral ED50 of 86.6 mg/kg, the oral ED50 obtained with (d-glaucine)2 3H3PO4 is 170.1 mg/kg. In particular cases, the dosage to be administered can be ascertained by conventional range finding techniques, for example, by observing the antitussive activity produced at different dosage rates.

It is generally desirable to administer indi-vidual dosages at the lowest amount which provides the desired cough suppression from consonant with a convenient dosing schedule. Oral administration is the route gener-ally preferred for administration of antitussive agents.
The glaucine phosphate of the invention thus combines high oral antitussive potency with palatability.

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~81~g Dosage units adaptable to oral administration such as tablets, capsules, lozenges, elixirs, syrups and the like are preferred and the active glaucine phosphate compound can be formulated in conventional timed release capsule or tablet formulations.

In using the compounds of the invention, the active d-glaucine phosphate ingredient is preferably incorporated in a composition comprising a pharmaceutical carrier and from 0.001 to 95 percent by weight of the glaucine phosphate salt compound or a pharmacologically--acceptable salt thereof. The term "pharmaceutical carrier" refers to known pharmaceutical excipients useful in formulating pharmacologically-active compounds for in-ternal administration to animals, and which are substan-tially non-toxic and non-sensitizing under conditions of use. The compositions can be prepared by known techniques for the preparation of tablets, capsules, cough drops, lozenges, troches, suppositories, solutions, elixirs, syrups, emulsions, dispersions, wettable and effervescent powders, sterile injectable compositions, and can contain suitable excipients known to be useful in the preparation of the particular type of composition desired. As with phosphates generally, liquid compositions should generally be substantially free of cations which form highly insoluble phosphate salts, to avoid undesired salt precipitation.

The compounds may be administered in conjunction with other active ingredients or other antitussive or anal-gesic agents. Other active ingredients can include, for example, antihistamines, decongestants, expectorants, muco-lytic agents, bronochodilators and antibacterial agents orlocal anesthetics. Combinations of this type are generally useful for treating coughing or pain in combination with other symptoms.

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Example 1 - Preparation of d-Glaucine Phosphate Three (3) grams (0.008 mole) of d,l-glaucine free base is dissolved in 50 milliliters of 95 percent ethanol (95 percent ethanol - 5 percent water) and heated to 50C.

The mixture is stirred while a warm solution (about 50C) of 1.27 grams (0.008 mole) d-tartaric acid in 20 milliliters of 95 percent ethanol is added. The solution is cooled to 10C and filtered to remove the resulting crystals of l-glaucine-d-tartrate. The filtrate is then evaporated to dryness under reduced pressure to obtain d-glaucine-d-tartrate. The resulting d-glaucine salt is dissolved in 50 milliliters of water and mixed with 5 milliliters of aqueous 10 percent sodium hydroxide.
The mixture is extracted twice with methylene chloride, using 50 milliliters methylene chloride for each extraction.
` The extracts are washed with water and dried over anhydrous sodium sulfate.
''' The combined methylene chloride extracts, now containing d-glaucine base, are mixed with a solution of 1.05 gram (0.01 mole) phosphoric acid in 20 milliliters of 95 percent ethanol, with stirring. ~nhydrous ether is added until the solution becomes slightly cloudy, and the mixture is cooled overnight in a refrigerator (5 to 10C). The resulting crystals are separated by filtration and digested for 16 hours in refluxing 95 percent ethanol (20 milliliters) with the addition of 0.2 milliliters of 85 percent phosphoric acid. The crystals are separated by filtration, then stirred in warm (about 40 to 50C) acetone for two hours. The mixture is filtered, and the white, plate crystalline d-glaucine phosphate product is , ,~

27,804C-F -7-1~8149 found to melt at 251C with decomposition. C, H, N (cal-culated) for C21H25NO4-1l-~3PO4: 50.2, 5.91, 2.79;
(found): 50.00, 6.09, 2.75.

The elemental analysis is thus consistent with the structure (d-glaucine)2 3H3PO4.

Example 2 Separate groups of guinea pigs were orally administered various doses of a test compound, or dis-tilled water for a control group. One hour after oral dosing, the guinea pigs were exposed to a 5 percent aerosol of citric acid for a 10 minute test period. The number of cough responses produced during the last five minutes of exposure to the citric acid aerosol was recorded and the dosage effect to suppress coughing in 50 percent of the guinea pigs (ED50) was calculated. An antitussive effect was recorded for a ~uinea pig when its total number of coughs during the S minute test period were at least two standard deviation units below the mean number of coughs per guinea pig in the control group. In these operations, codeine phosphate was found to have an oral ED50 of 86.6; and d-glaucine phosphate an ED50 of 170.1.

Example 3 D-glaucine hydrobromide and d-glaucine phos-phate were prepared as 0.2 percent (weight by volume) solutions in distilled water. The salt solutions were evaluated for palatability by touching a few drops to the tongue. In these operations the hydrobromide ex-hibited a bitter, sharp and metallic taste. D-glaucine phosphate (2:3) was found to have noticeable less sharp, metallic flavor and to be unobjectionable.

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Example 4 A. A flavored cough syrup formulation is prepared to contain the following:

Ingredient Amount 5 Sucrose (100% Invert Sugar~
-Dry ~asis) 26.4 Grams Sorbitol Syrup USP lO Milliliters (Ml) Glycerlne 5 Ml Alcohol USP 5.4 Ml 10 Piperonal 10.0 Milligrams (Mg) Vanillin 7.5 Mg Ethyl Vanillin 10.0 Mg Ethyl Maltol 7.5 Mg 1-Menthol 7.5 Mg d-Glaucine Phosphate (2:3) 600 Mg Purified Water USP g.s. to 100 Ml Total The syrup contains 0.6 percent (weight by volume) d-glaucine phosphate and a 5 ml dosage unit (1 teaspoon) contains 30 mg of active phosphate salt. The syrup can be sealed into 5 ml plastic lined foil pouches, or filled into conventional glass bottles. Dosage units of 15 mg and 20 mg per 5 ml dose can be made by using 300 or 400 mg of d-glaucine phosphate (2:3) in the above formula.

B. Capsules are prepared by blending 10 grams d-glaucine phosphate; 3 grams colloidal silica; 2 grams stearic acid and 285 grams lactose; and filling the blend into No. 2 gelatin capsules, 300 milligrams per capsule.
This provides 10 milligrams of glaucine phosphate per capsule. Larger unit dosages, such as 15, 20 or . 30 25 mg, can be prepared by using 15, 20 or 25 grams glaucine phosphate and lactose q.s. to 300 grams. Smaller dosages are similarly prepared.

27,804C-F -9-. .

-., ~ - , , 81~9 Example 5 In other operations, various dosages of d-glaucine phosphate (2:3) were administered to groups of mice by the oral route or by intraperitoneal injection, and the dosage which is lethal to 50 percent of the mice (LD50) was calculated from the mortality observations within 24 hours after administration. The LD50 for intraperitoneal injection was determined to be 180 mg/kg. The oral LD50 in these operations was determined to be 35,0 mg/kg.

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Claims (4)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process of preparing a d-glaucine phosphate salt by reacting d-glaucine with a molar excess of phosphoric acid.

2. D-glaucine phosphate whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

3. A process of preparing a d-glaucine phosphate salt by reacting d-glaucine in the form of the base with at least a 1.4 molar excess of phosphoric acid.

4. A crystalline d-glaucine phosphate (2:3) having a melting point of 240° to 254°C with decomposition, and a pH in water solution (0.5 grams/100 milliliters) of 2.6 to 3.0 whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.