Introduction
The O-demethylation of codeine to yield morphine has been reported using a variety of reagents, including sodium propylmercaptide in dimethylformamide and boron tribromide in chloroform. These methods require a considerable measure of chemical expertise and suitable laboratory equipment. The homebake laboratories have employed an elementary method based on the use of pyridine hydrochloride. This reagent was introduced to opiate chemistry by Rapoport and Bonner and applied to the conversion of codeine to morphine by Rapoport et al. Rapoport and Bonner carried out the reaction under nitrogen at a temperature of 220 °C. Morphine is prone to decomposition or oxidation reactions at elevated temperatures, and the nitrogen atmosphere prevents or reduces these. It also limits the access of moisture, which reduces the yield. In this topic, the procedure followed in homebake underground laboratories is fully described. Additional comments on the method, based on studies carried out in this laboratory on the reactions involved, are included in the discussion section.
Equipment and glassware:
- Buchner funnel and flask, 500 mL;
- Separating funnel 500 mL and 1 L;
- Beakers 1000 ml x2; 500 ml x2; 100 ml x2;
- Glass rod;
- Pyrex dish 1 L;
- Heating plate;
- Spirits burner;
- Boiling tube 10-20 mL x2;
- Boiling tube clamp;
- Rubber bung;
- Filter paper;
- pH indicator paper;
- Water-jet aspirator.
Reagents:
- 2 g of Codeine;
- ~2 L Distilled water;
- ~100 g Sodium hydroxide (NaOH);
- ~70 mL Chloroform (CHCl3);
- 20 mL Pyridine;
- ~100 ml Concentrated hydrochloric acid (HClaq);
Boiling Point: 462 °C at 760 mm Hg;
Melting Point: 280.0 °C;
Molecular Weight: 335.83 g/mole;
CAS Number: 1422-07-7.
Procedures
Step 1. Extraction of codeine
Several packets of tablets, sufficient to yield about 2 g of codeine, are crushed and mixed with water. The mixture is filtered using a filter pump, Buchner funnel and flask, to remove tablet binding agents, diluents and other excipients. The aqueous filtrate is poured into a separating funnel and sodium hydroxide solution added to make the solution strongly alkaline. This is then extracted with chloroform (about 50 ml). The chloroform layer is drained off and evaporated to dryness using gentle heating (often on a domestic stove) !without FLAME! The aqueous layer containing aspirin and paracetamol is discarded. The codeine base is recovered as a white crystalline solid for use in Step 3.
An alternative extraction method is described in the "Cold Water Extraction of codeine from over-the-counter analgesics" topic.
Step 2. Preparation of pyridine hydrochloride
In a 100 mL beaker, pyridine (20 ml) and concentrated hydrochloric acid (25 ml) are strongly heated (to about 190 °C) to drive off water. The product is cooled rapidly to form a waxy white solid, which is stored in a sealed container in a freezer to minimise exposure to moisture and avoid decomposition.Several packets of tablets, sufficient to yield about 2 g of codeine, are crushed and mixed with water. The mixture is filtered using a filter pump, Buchner funnel and flask, to remove tablet binding agents, diluents and other excipients. The aqueous filtrate is poured into a separating funnel and sodium hydroxide solution added to make the solution strongly alkaline. This is then extracted with chloroform (about 50 ml). The chloroform layer is drained off and evaporated to dryness using gentle heating (often on a domestic stove) !without FLAME! The aqueous layer containing aspirin and paracetamol is discarded. The codeine base is recovered as a white crystalline solid for use in Step 3.
An alternative extraction method is described in the "Cold Water Extraction of codeine from over-the-counter analgesics" topic.
Step 2. Preparation of pyridine hydrochloride
Codeine transformation to Morphine
Step 3. Reaction of codeine and pyridine hydrochloride
The reaction is carried out using a boiling tube which is flame-dried before use. Pyridine hydrochloride (3.5 g) as prepared in Step 2 is then heated in the tube until it melts, and any residual moisture is driven off. Any resulting condensation on the inside walls of the tube is wiped off. Codeine base (1.5 g) is added to the tube, which is then stoppered with a rubber bung covered with filter paper and heated until the mixture starts to fume. Heating is continued until a reddish-orange colour develops in the reaction melt, which becomes noticeably more viscous (6-12 min). The contents of the boiling tube are then poured into a 500 mL separating funnel and the volume made up to 100 mL with water. Sodium hydroxide solution (10%) is added until the contents of the separating funnel are strongly basic (pH 12). As the sodium hydroxide is added, the contents turn milky-brown before becoming clear brown again. Chloroform (20 mL) is added. After extraction, the greyish-brown chloroform layer is either discarded or put aside for later recovery of the codeine contained in it. The aqueous layer is poured into a 500 mL beaker and the pH is carefully adjusted to pH 9 using hydrochloric acid and narrow-range indicator paper. The solution is rapidly filtered under suction, using a Buchner funnel and 2 filter papers, to remove a fine, dark brown residue containing unwanted by-products. The filtered solution is then poured into a clean beaker and precipitation is induced by vigorously rubbing the side of the beaker with a 'seeding stick' (glass rod) as the pH is carefully lowered to 8.5 with additional hydrochloric acid. In homebake laboratories, a split wooden clothes peg is often used as the 'seeding stick'. The product is allowed to settle for at least 5 min before being filtered off under vacuum. The morphine product is recovered as a powder, ranging in colour from beige to dark brown.
The reaction is carried out using a boiling tube which is flame-dried before use. Pyridine hydrochloride (3.5 g) as prepared in Step 2 is then heated in the tube until it melts, and any residual moisture is driven off. Any resulting condensation on the inside walls of the tube is wiped off. Codeine base (1.5 g) is added to the tube, which is then stoppered with a rubber bung covered with filter paper and heated until the mixture starts to fume. Heating is continued until a reddish-orange colour develops in the reaction melt, which becomes noticeably more viscous (6-12 min). The contents of the boiling tube are then poured into a 500 mL separating funnel and the volume made up to 100 mL with water. Sodium hydroxide solution (10%) is added until the contents of the separating funnel are strongly basic (pH 12). As the sodium hydroxide is added, the contents turn milky-brown before becoming clear brown again. Chloroform (20 mL) is added. After extraction, the greyish-brown chloroform layer is either discarded or put aside for later recovery of the codeine contained in it. The aqueous layer is poured into a 500 mL beaker and the pH is carefully adjusted to pH 9 using hydrochloric acid and narrow-range indicator paper. The solution is rapidly filtered under suction, using a Buchner funnel and 2 filter papers, to remove a fine, dark brown residue containing unwanted by-products. The filtered solution is then poured into a clean beaker and precipitation is induced by vigorously rubbing the side of the beaker with a 'seeding stick' (glass rod) as the pH is carefully lowered to 8.5 with additional hydrochloric acid. In homebake laboratories, a split wooden clothes peg is often used as the 'seeding stick'. The product is allowed to settle for at least 5 min before being filtered off under vacuum. The morphine product is recovered as a powder, ranging in colour from beige to dark brown.
Results and discussion
Procedural detailsThe procedure outlined in the experimental section has been followed many times in laboratories. The glassware and other equipment required for the reaction are remarkably simple and readily available from scientific supply companies. Chloroform and pyridine are available from chemical supply companies. Recent awareness among supply companies of the significance of a request for small amounts of these chemicals has led to stricter monitoring of orders. In a number of laboratories, pyridine has been replaced by a crude mixture of picolines (methylpyridine isomers) and other substituted pyridines.
The most common source of heat found in laboratories has been small methylated spirits burners. These give a cooler flame than do laboratory Bunsen burners and enable better control of the reaction between codeine and pyridine hydrochloride. In a few laboratories, heating had been carried out using cooking oil on a domestic stove element. Under laboratory conditions, the reaction has been carried out using a heated sand bath. The use of a rubber hung in the boiling tube to produce a sealed reaction vessel is a simple solution to the problems of morphine oxidation and decomposition on heating and the need to minimise access of moisture to the reaction mixture.
Product yield
Homebake laboratory operators have claimed yields of morphine equivalent to <50% conversion from codeine, but the reaction also forms a complex mixture of by-products. Morphine having a purity of 92% calculated as the anhydrous free base and determined by HPLC has been prepared, although purities in the 80% region are more typical. Negligible codeine is present with the morphine, indicating that the chloroform extraction step is efficient in removing this. This high purity, with little or no codeine contamination, is characteristic of 'homebake' morphine.
The most common source of heat found in laboratories has been small methylated spirits burners. These give a cooler flame than do laboratory Bunsen burners and enable better control of the reaction between codeine and pyridine hydrochloride. In a few laboratories, heating had been carried out using cooking oil on a domestic stove element. Under laboratory conditions, the reaction has been carried out using a heated sand bath. The use of a rubber hung in the boiling tube to produce a sealed reaction vessel is a simple solution to the problems of morphine oxidation and decomposition on heating and the need to minimise access of moisture to the reaction mixture.
Product yield
Homebake laboratory operators have claimed yields of morphine equivalent to <50% conversion from codeine, but the reaction also forms a complex mixture of by-products. Morphine having a purity of 92% calculated as the anhydrous free base and determined by HPLC has been prepared, although purities in the 80% region are more typical. Negligible codeine is present with the morphine, indicating that the chloroform extraction step is efficient in removing this. This high purity, with little or no codeine contamination, is characteristic of 'homebake' morphine.
Conclusions
Countering these homebake laboratories has proved to be a frustrating exercise for police and for forensic scientists called on to provide scientific support. The entire procedure from extraction of the codeine tablets through to the preparation of usable morphine solution can be completed by a practiced operator in a few hours. The simplicity of the laboratory equipment allows easy portability. It has been known for operators to arrive at an address one afternoon and leave the next morning after having completed one or more syntheses. To support a charge of manufacturing morphine and/or heroin in court., the forensic scientist is asked by the prosecution to show that the required equipment and chemicals are present and, at least for key steps in the procedure, that they have been used. This frequently requires the determination of only trace amounts of products and by-products on the equipment seized. Laboratory operators have become aware of this and carefully clean and destroy vital evidence as they proceed. In some cases, the equipment for the laboratory has been divided and kept in two places to prevent an operator being caught in possession of the comprehensive set.
On the other hand, the problem is to some extent self-limiting. The laboratories are on a small scale, producing only enough product to satisfy the 'habit' of an individual addict and perhaps a few friends or clients. There are indications that the method does not lend itself to a large-scale operation, and the percentage yield drops significantly if attempts are made to increase the quantities involved. Although the original laboratory operators had chemical knowledge. Subsequent operators have had to be taught the method. The percentage yield in the codeine to morphine conversion step is unpredictable, and small variations in the experimental conditions at several crucial stages can make the difference between partial success and total failure. Experience is a big factor in judging the point of maximum yield in the reaction of codeine and pyridine hydrochloride, and also in manipulation of the pH to obtain maximum recovery of the morphine product.
On the other hand, the problem is to some extent self-limiting. The laboratories are on a small scale, producing only enough product to satisfy the 'habit' of an individual addict and perhaps a few friends or clients. There are indications that the method does not lend itself to a large-scale operation, and the percentage yield drops significantly if attempts are made to increase the quantities involved. Although the original laboratory operators had chemical knowledge. Subsequent operators have had to be taught the method. The percentage yield in the codeine to morphine conversion step is unpredictable, and small variations in the experimental conditions at several crucial stages can make the difference between partial success and total failure. Experience is a big factor in judging the point of maximum yield in the reaction of codeine and pyridine hydrochloride, and also in manipulation of the pH to obtain maximum recovery of the morphine product.
Last edited by a moderator:
