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                         United States Patent 6,054,584
            Process for Extracting and Purifying Morphine from Opium
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        ABSTRACT

        A process for extracting morphine from opium is described. In the
        process, opium is extracted with a basic alcoholic solution. The
        basic alcoholic solution is filtered and the alcohol removed from
        the filtrate to leave a residue. The residue is then extracted
        with a basic aqueous solution having a pH of at least 11. The
        basic aqueous solution may be filtered to remove any solid matter
        remaining after the aqueous extraction step, and then be stirred
        with a sufficient amount of a salt to avoid emulsion formation.
        The basic aqueous solution or filtrate is then extracted with
        benzene or toluene. Next, adjusting the pH of the basic aqueous
        filtrate to pH 8.5 to 9.5 allows The morphine to precipitate and
        be recovered.


FIELD OF THE INVENTION

This invention relates to an improved process for the 10 extraction and 
purification of morphine from opium. The object of this invention is to provide
a more economical method of preparing morphine that utilizes less
environmentally toxic solvents.


BACKGROUND

Morphine is useful as an analgesic drug. It is also used as the starting 
material for the preparation of codeine, which is another analgesic and
antitussive drug. Morphine Occurs naturally in opium to the extent of 9 to 17%
by weight, depending upon the opium source. There are many alternative methods
of extracting and purifying morphine from opium. However, these methods suffer
from several disadvantages, such as prolonged extraction times, low efficiencies
and the involvement of hazardous chemicals such as chloroform and sulfur
dioxide. What is needed is a cost-effective prowls which does not require large
amounts of potentially toxic or hazardous solvents. When viewed from this
perspective, none of the current methods are entirely satisfactory.

Generally, current methods extract the alkaloids present in opium with either
water or an acidic (e.g. oxalic acid) solution. Due to the limited solubility of
the alkaloids in aqueous solutions, the extract is very dilute. This results in
a large amount of [he aqueous extract. Recovery of the alkaloids from the
aqueous extract also requires large amount of organic solvents. The process is
also lengthy and labor intensive. One batch of opium generally needs to he
extracted four times over a period of four days for complete recovery of the
alkaloids. Separation and purification of morphine from the other alkaloids in
the aqueous extract is also lime consuming and relatively complicated due to the
physical properties of the extract and the nature of the substances present.


SUMMARY OF THE INVENTION

The present invention relates to a process for extracting morphine from opium.
The process of the invention answers the deficiencies of prior art processes. In
the process, opium is extracted with a basic alcoholic solution. The basic
alcoholic solution is filtered and the alcohol removed from the filtrate to 
leave a residue.The residue is then extracted with a basic aqueous solution
having a pH of al least 11. The basic aqueous solution may be filtered to remove
any solid matter remaining after the aqueous extraction step, and may then he
stirred with a sufficient amount of a salt to avoid emulsion formation. The
basic aqueous solution is then extracted with a substantially water-immiscible
solvent such as benzene or toluene. Next, adjusting the pH of the basic aqueous
solution to pH 8.5 to 9.5 allows the morphine to precipitate and be recovered.


DESCRIPTION OF THE INVENTION

According to the invention described herein, morphine is extracted from opium by
stirring and/or heating, or preferably refluxing, opium in a basic solution of
an alcohol, preferably methanol at about pH 9. The pH may be adjusted by the
addition of an inorganic base (alkali hydroxide, or carbonate), ammonia, and the
like. Preferred inorganic bases include, but are not limited to, sodium
hydroxide and potassium hydroxide. After the extraction is complete, the alcohol
extract is filtered to remove the undissolved particulate matter. The alcohol
itself is then removed from the extracted alkaloids, preferably by evaporation
under reduced pressure. The resulting residue, which contains the alkaloids, is
mixed or extracted with an basic aqueous solution having a pH of at least II,
preferably an aqueous solution of an alkali hydroxide. This converts the
morphine free base present into its anionic (morphinate) form which is soluble
in basic solutions of pH values of 11 or above. Other opium alkaloids arc
relatively insoluble and, in general, al least partially precipitate out of the
basic aqueous solution. After removing any precipitate, preferably by
filtration, the remaining alkaloids are separated from the morphinecontaining
basic aqueous solution by extraction with a substantially water-immiscible
solvent, such as toluene or benzene. Finally, the morphine free base is
precipitated out of the resulting aqueous solution by adjusting the pH of the
aqueous filtrate to pH 8.5 to 9.5. Preferably, the pH to precipitate the
morphine ranges from about 9 to 9.3, and most preferably is about 9.1. This is
accomplished by adding either an organic acid or a mineral acid. The yield and
purity of morphine produced by this procedure are economically satisfactory. The
morphine obtained from this process may then be further purified by known
methods or utilized directly in a further process to convert it into codeine. As
discussed above, the extraction of morphine from opium may be accomplished by
stirring and/or heating, preferably refluxing, opium with a basic solution of an
alcohol capable dissolving morphine in its neutral, cationic, and/or anionic
form. Preferably, the alcohol is a C,-C, alcohol. Particularly preferred
alcohols include methanol, ethanol, and isopropanol. Mixtures of alcohols may
also be used. Methanol, the preferred solvent for the invention, is a excellent
solvent foe extracting alkaloids from opium. Almost all of the alkaloids,
especially morphine, are highly soluble in methanol. Advantageously, the
alkaloids are soluble in methanol in their neutral, cationic, or anionic forms.
The addition of an alkali, alkaline earth, or other suitable base to adjust the
pH of the alcohol, to about 9, so snakes the extraction process more efficient.
This results in more alkaloids and less impurities being extracted into the
alcohol. Refluxing opium in a basic solution of the alcohol, preferably methanol
at about pH 9, for approximately one to two hours extracts more than 90% of the
morphine present.

In a preferred embodiment, 5 g of opium, cut into small pieces, may be extracted
by reflux with 0.2 to 0.6 g, preferably 0.4 g, of sodium hydroxide in 25 ml of
methanol for 1 to 2 hours. An additional extraction of the opium with a basic
alcohol, such as methanol at pH 9, can recover essentially all of the alkaloids
from opium. The second extract can either be combined with the first extract or
can be used to extract another batch Of opium. Separation of the alcohol extract
from the undissolved residue by filtration or other similar means is generally
easy and fast. Unlike an aqueous extraction process, the assistance of filter
aid at this step is generally unnecessary.

The removal of alcohol by distillation, under reduced pressure, at elevated 
temperatures, or by other known techniques is much easier and more rapid than
the concentration of aqueous extracts or organic solutions (e.g. toluene)
usually required in prior art methods. A small amount of filter aid may be added
to the alcohol extract before distillation to prevent the alcohol extract from
foaming and bumping. As another advantage, the recovered alcohol, particularly
methanol, can be recycled and used for another extraction without further
purification.

In the prior art extraction methods, morphine is usually kept as an acid salt
due to concerns regarding the stability of morphine in basic solutions. To test
the stability of morphinate in basic aqueous solutions, morphinate was analyzed
by High Performance Liquid Chromatography (HPLC) and then allowed to stay 
ovemight at room temperature. The morphinatc was then reanalyzed by HPLC. No
loss of morphine was found.

According to the invention, the residue remaining after removing the alcohol is
then extracted with a basic aqueous solution having a pH of at least 11.
Preferably, the basic aqueous solution is a solution of an alkali hydroxide such
as sodium hydroxide or potassium hydroxide. Solutions of other bases may also be
used. Maintaining the pH of the aqueous extract al this pH and preferably within
a relatively -5 narrow preferred range allows high quality morphine to be
obtained with good recovery. At lower pH values, greater amounts of morphine may
be lost in the initial precipitate. At higher pH values, less impurities may be
extracted into toluene. Maintaining the pH in the range of 11.5 to 11.9 is,
therefore, preferred.

The basic aqueous solution may optionally be filtered to remove any solid 
material remaining after the aqueous extraction step. Filtering the basic
aqueous solution at this point removes insoluble non-morphine alkaloids. Any
precipitate may be washed with an additional quantity of the basic aqueous 
solution to ensure increased recovery of the morphine.

The basic aqueous solution or filtrate, if filtered, is then extracted with a
substantially water-immiscible organic solvent to remove the remaining alkaloids
from the basic aqueous filtrate. Suitable solvents include, but are not limited
to, benzene, toluene, xylene, diethyl ether, and chloroform. Separation of the
resulting aqueous and organic phases, may be accomplished by techniques known in
the art.

Theoretically, non-morphine alkaloids are supposed to precipitate out of 
concentrated aqueous solutions at pH values around 11-12. However, the presence
of concentrated morphinate ions may increase the solubility of the other
alkaloids. Thus, substantial amounts of non-morphine alkaloids may remain in
solution. Direct extraction of the basic aqueous solution or filtrate, if
filtered, with a substantially water-irnrniscible solvent can remove those
alkaloids, but may result in formation of an emulsion To avoid emulsion
formation, the aqueous solution/filtrate may, before extraction with the
substantially water-immiscible solvent, first be treated with a sufficient
amount of an alkali metal salt or alkaline earth metal salt, for example 0.5 to
5 grams salt for each 5 grams of opium. Preferred salts are, for example,
lithium chloride, lithium bromide, lithium acetate, sodium chloride, sodium
bromide, sodium acetate, potassium chloride, potassium bromide, or potassium
acetate. A preferred amount of the salt is 0.5 to 2 grams per 5 grams of opium.
Sodium chloride and sodium acetate are preferred salts with sodium acetate being
particularly preferred. The extract may then preferably filtered again to get
rid of any gummy or other precipitate prior to extracting with a substantially
water-immiscible solvent, such as benzene or toluene. The sequence of the
morphine purification procedure may, however, affect the recovery of morphine.
For example, if, to avoid emulsion formation upon extraction, a salt is added to
the basic aqueous solution before it is filtered after the aqueous extraction
step, as much as about 20% of the morphine may precipitate out along with the
other alkaloids.

Accordingly, the recovery of morphine will he  substantially lower. When
extracting the aqueous solution/filtrate with a substantially water-immiscible
solvent, such as toluene or benzene, a small amount, generally about 8%, of the
morphine may be extracted into the solvent. This may be recovered by back
extraction with additional basic solution, for instance, a sodium hydroxide
solution. Any loss of morphine in the aqueous mother liquor, about 2%, may be
recovered by additional extraction with the solvent. For health reasons, the use
of toluene is preferred, particularly over benzene, in the process of the
invention.

Any alkaloids precipitated on a filter aid or paper in the process may be 
recovered by extraction with an alcohol, preferably methanol. The filter aid can
be used again without further purification. The other opiate alkaloids that were
extracted into the substantially water-immiscible solvent may be combined with
the alkaloids which precipitated from the aqueous extract at pH 11.5 to 11.9 and
further purified by other known methods.

After extraction with the substantially water-immiscible solvent, the pH of the
basic aqueous solution/filtrate is adjusted to about 8.5 to 9.5 to precipitate
the morphine. Preferably, the pH is adjusted to 9 to 9.3 and more preferably to
9.1. The pH may be adjusted using an acid such as, for example, sulfuric acid,
hydrochloric acid or acetic acid.

Preferably, a 50% acetic acid in water solution is used. The precipitated
morphine may then be recovered using techniques known in the art such as
filtration or decantation. The recovered morphine is preferably washed with
water before drying. The foregoing procedure provides a cost-effective process
fox isolating morphine from opium. This procedure provides good recovery and a
high quality product FIG. 1 depicts a preferred process of the invention. The
whole process, from extraction of opium to precipitation of purified morphine,
can generally be completed in one day. This is much more efficient than other
existing commercial purification methods 50 The following specific example
illustrates the invention, but is not intended to limit the scope of the
invention.


EXAMPLE

5 g of opium were cut into small pieces and extracted by reflux with 0.4 g of
sodium hydroxide in 25 ml of methanol for 1 to 2 hrs. The methanol extract was
then filtered to remove particulate materials. After addition of 1 g of filter
aid to the methanol extract, which contained 465 to 485 mg of morphine, the
methanol was removed under reduced pressure. The residue was then mixed with 5.5
ml of 1.0 N sodium hydroxide solution at 35°C. for 10 min. and the pH adjusted
to about 11.5 to 11.9 with 50% acetic acid in water. This aqueous extract was
then filtered and the precipitate washed with 5.5 ml of 0.01 N sodium hydroxide
solution. The combined aqueous filtrate was stirred with 0.5 g of sodium acetate
for 10 minutes and filtered again. The filtrate was then extracted twice with 5
ml of toluene and the pH of the aqueous filtrate was then adjusted to pH 9.1,
with 50% acetic acid in water. The mixture was allowed to remain for a period of
6-10 hrs at room temperature for complete precipitation and was then filtered.
This precipitate was washed with water and dried at room temperature. This final
precipitate contained 400-426 mg of morphine, which represented a recovery of
86-88% based upon the amount of morphine in the initial methanol extract. The
purity of morphine following this procedure was 84% to 86% by weight.

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