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Tramadol as a racemic mixture.svg
R-tramadol3Dan2.gif S-tramadol3Dan2.gif

2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol

Tramadol (marketed as Ultram, and as generics) is an opioid pain medication used to treat moderate to moderately severepain.[1] When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.[5]It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin andnorepinephrine.[6][7]

Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Common side effects include: constipation, itchiness and nausea, among others. A change in dosage may be recommended in those with kidney or liver problems. Its use is not recommended in women who are breastfeeding or those who are at risk of suicide.[1]

Tramadol is marketed as a racemic mixture of both R– and Sstereoisomers.[2] This is because the two isomers complement each other’s analgesic activity.[2] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.[2] Tramadol is metabolised to O-desmethyltramadol, which is a more potent opioid.[8] It is of the benzenoid class.

Tramadol was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 inWest Germany, and 20 years later it was launched in countries such as the UK, U.S., and Australia.[7]

Developed (from 1962) by the German company Grünenthal, and is marketed through much of the world under various trade names, including Acugersic (Malaysia), Mabron (some Eastern European countries as well as parts of the Middle and Far East), Ultram (USA), Zaldiar (France and much of Europe, as well as Russia) and Zydol (UK and Ireland).

CONFUSION ON CIS TRANS

There is some confusion within the literature as to what should be called cis and what should be called trans. For purposes of this disclosure, what is referred to herein as the trans form of Tramadol includes the R,R and S,S isomers as shown by the following two structures:

Figure US06399829-20020604-C00001

The cis form of Tramadol, as that phrase is used herein, includes the S,R and the R,S isomers which are shown by the following two structures:

Figure US06399829-20020604-C00002

 

Tramadol is marketed as a racemic mixture of both R and S stereoisomers. It is a μ-opioid receptor agonist, like morphine, but much less active. It inhibits reuptake of the neurotransmitters serotonin and norepinephrine, suggesting that it lifts mood and thereby may dull the brain’s perception of pain.

1R2R-tramadol 1S2S-tramadol

1R,2R-Tramadol

1S,2S-Tramadol

In the body, tramadol undergoes demethylation to several metabolites by a Cytochrome P450 enzyme (CYP2D6) in the liver, the most important of these products being O-desmethyltramadol. O-desmethyltramadol has a much stronger (200x) affinity for the μ-opioid receptor than tramadol, so in effect tramadol is a prodrug.

1R2R-odsmt 1S2S-odsmt

1R,2RO-desmethyltramadol

1S,2SO-desmethyltramadol

Not everyone’s liver works identically. Around 6% of the Caucasian population has a reduced CYP2D6 activity (hence reducing metabolism), so there is a reduced analgesic effect with Tramadol. These people require a dose increase of 30% to get the same pain relief as the norm. A case has been reported of a patient where, following an overdose, their ultrarapid tramadol metabolism led to excessive norepinephrine levels, with near-fatal consequences.

However, it has recently been discovered at relatively high concentrations in the roots of the African peach or pin cushion tree (Nauclea latifolia), which has a long tradition as a folk remedy. As usual, Nature got there first.

The African pin-cushion tree -from:http://upload.wikimedia.org/wikipedia/commons/4/49/Nauclea_latifolia_.jpg
The African pin-cushion tree (Nauclea latifolia)

In the area of “legal highs”, a disturbing development is a drug blend known as “Krypton”. This isn’t the noble gas, but a mixture of O-desmethyltramadol withKratom (Mitragyna speciosa, a medicinal plant that originates in SE Asia, seemingly the local equivalent of khat), which contains an alkaloid mitragynine which is also a μ-receptor agonist. Several fatalities have been linked with its use, notably in Sweden.

SYNTHESIS

(1R,2R)-Tramadol   (1S,2S)-Tramadol
(1R,2R)-Tramadol     (1S,2S)-Tramadol
(1R,2S)-Tramadol   (1S,2R)-Tramadol
(1R,2S)-Tramadol     (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.[35] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at thecyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

  • (1R,2R)-isomer
  • (1S,2S)-isomer
  • (1R,2S)-isomer
  • (1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described[36] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects[37] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[38] and in humans.[39]

Synthesised by chemists at the German company Grünenthal and brought to the market in 1977. It can readily be made by nucleophilic attack of a Grignard or RLi species upon a carbonyl group.

Synthesis of tramadol

ALSO

Paper

http://www.jmcs.org.mx/PDFS/V49/N4/04-Alvarado.pdf

Tramadol hydrochloride (1). To a solution of 3-bromoanisol 13 (0.823 g, 4.4 mmol) in dry THF (10 mL), 1.75 M n-BuLi (2.5 mL, 4.4 mmol) was added dropwise at -78°C under argon atmosphere. The mixture was stirred at the same temperature during 45 minutes and a solution of 2-dimethylaminomethylcyclohexanone 6a (0.62 g, 4mmol) in dry THF was added dropwise. The resulting mixture was stirred at -78°C for 2 h. and the solvent was removed in vacuo. Water (30 mL) was added and the product was extracted with ethyl ether (3X30 mL). The extracts were dried over sodium sulfate, filtered and evaporated in vacuum. The residue was treated with 5mL of ethyl ether saturated with hydrogen chloride; the ethyl ether was evaporated in vacuo and the resulting solid was purified by crystallization from acetone. Tramadol hydrochloride 1 was obtained as white crystals (0.94 g, 78.6%),

MP 168- 175°C.

IR (KBr): 3410, 3185, 2935, 2826, 2782, 1601, 1249, 702 cm-1;

1H NMR (CDCl3, 300 MHz) δ 1.2-1.9 (10H, m), 2.15 (6H, s), 2.45 (1H, dd, J = 15.1, 4.4 Hz), 3.82 (3H, s), 6.76 (1H, dd, J = 8, 2.4 Hz), 7.04 (1H, d, 7.6 Hz), 7.14 (1H, s), 7.26 (1H, t, 3.9 Hz), 11.4 (1H, bs);

MS (EI): m/z 263 M+ (28), 58 (100).

PATENT

http://www.google.com.ar/patents/WO1999003820A1?cl=en

Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-l-(3- methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic

Tramadol means the racemic mixture of cis-Tramadol as shown by the following chemical structures:

Figure imgf000004_0001

(1 R, 2R) (1S. 2S) cis-Tramadol

Step l Formation of Dimethylaminomethyl Cyclohexanone Hydrochloride

Figure imgf000008_0001

Dimethylaminomethyl Cyclohexanone Hydrochloride

Step 2 Formation of Tramadol Mannich Base

NaOH, Water

Toluene, TBME

Figure imgf000008_0002
Figure imgf000008_0003

Tramadol Mannich Base

Step 3 Formation of Tramadol Base Hydrate

Figure imgf000008_0004

Tramadol Base Hydrate (crude) Step 4 Purification of Tramadol Base Hydrate

Figure imgf000009_0001

Tramadol Base Hydrate (pure)

Step 5 Formation of Tramadol Hydrochloride

Figure imgf000009_0002

Tramadol Hydrochloride

Example 1

To produce the Tramadol base hydrate, a reaction vessel is charged successively with 69 Kg of Magnesium, 400 1 of dry Tetrahydrofuran (THF) and 15 1 of 3- bromoanisole.

With careful heating, the reactor temperature is brought up to ca. 30°C. The Grignard initiates at this point and exotherms to approximately 50°C. A further 5 1 of bromoanisole are added which maintains reflux. 400 1 of THF are then added before the remainder of the bromoanisole. This addition of the remainder of the bromoanisole is carried out slowly so as to sustain a gentle reflux. The reaction is refluxed after complete addition of 3-bromoanisole. The vessel is cooled and Mannich base is added. When addition is complete, the vessel is reheated to reflux for 30 minutes to ensure complete reaction. After cooling to ca. 10°C, 2,300 1 of water are added to quench the reaction. When complete, part of the solvents are distilled under vacuum. Approximately 260 1 of concentrated HC1 is added at a low temperature until a pH of 0 – 1 is reached. This aqueous phase is extracted with toluene. The toluene phases are discarded and ethyl acetate is added to the aqueous phase. 30% Ammonia solution is then charged to reach pH 9 – 10 and the phases are separated. The aqueous phases are extracted again with ethyl acetate and finally all ethyl acetate layers are combined and washed twice with water. Ethyl acetate is then distilled from the reaction solution at atmospheric pressure. Process water is added and the solution cooled to 20°C and seeded. After crystallisation, the vessel is cooled to -5 to 0°C and stirred for one hour.

The product is centrifuged at this temperature and washed with cold ethyl acetate 5 x 50 1. Approximately 310 – 360 Kg of moist cis-Tramadol base hydrate are obtained.

Purification

A reactor vessel is charged successively with cis-Tramadol base hydrate (crude) 200 Kg and ethyl acetate 300 1 and the contents of the vessel heated to 50°C until all solids are in solution. The vessel is then cooled to -5 to 0°C and the product crystallises. Stirring is continued for two hours and the product is then centrifuged and washed with cold ethyl acetate, 2 x 25 1. Approximately 165 – 175 Kg (moist) of cis(+/-) Tramadol base hydrate are obtained from this procedure.

The overall process produced high yields of cis-Tramadol with a trans isomer content of less than 0.03%. Analytical data of the base hydrate of cis-Tramadol

Melting point: 79 – 80°C (in comparison cis-Tramadol base anhydrous is an oil). Water content (KF) : 6.52% (= monohydrate) IR-spectrum of the base hydrate of cis-Tramadol (see Fig. 1).

IR-spectrum (=cis-Tramadol base anhydrous, see Fig. 2).

The invention provides a unique process in which a base hydrate of cis-Tramadol is selectively crystallised without impurities. The base hydrate is processed to readily form cis-Tramadol hydrochloride. The process is substantially simpler than known processes and does not require the use of potentially toxic solvents. Thus the process is environmentally friendly.

The base hydrate of cis-Tramadol prepared may also be used in various formulations.

The base hydrate of cis-Tramadol may be formulated in the form of a solid with a slow release profile. For example, slow release pellets may be prepared by coating a suitable core material with a coating, for example, of ethylcellulose/schellack solution (4:1) and suitable pharmaceutical excipients. The pellets have typical average diameter of 0.6 to 1.6 mm. The pellets may be readily converted into gelatine capsules or pressed into tablet form using well-known techniques.

Alternatively the base hydrate of cis-Tramadol may be formulated into effervescent tablets by forming granules of the base hydrate with acidity/taste modifiers and a suitable effervescent base such as sodium hydrogen carbonate /anhydrous sodium carbonate (12:1). The ingredients are typically blended in a mixer /granulator and heated until granulation occurs. The resulting granules may be pressed into tablet form, on cooling. Of particular interest is the use of the base hydrate of cis-Tramadol in a form for parenteral use/injectables. The base hydrate is typically dissolved in water together with suitable excipients (as necessary). The solution is filtered through a membrane to remove solid fibres or particles. The filtered solution may then be filled into ampoules, typically containing 10.0 mg of the active compound. Usually the formulation is prepared for intramuscular injection.

PATENT

http://www.google.com/patents/EP1346978A1?cl=en

  • Various processes for the synthesis of tramadol hydrochloride have been described in the prior art. For example, US 3 652 589 and British patent specification no. 992 399 describe the preparation of tramadol hydrochloride. In this method, Grignard reaction of 2-dimethylaminomethyl cyclohexanone (Mannich base) with metabromo-anisole gives an oily mixture of tramadol and the corresponding cis isomer, along with Grignard impurities. This oily reaction mixture is subjected to high vacuum distillation at high temperature to give both the geometric isomers of the product base as an oil. This oil, on acidification with hydrogen chloride gas, furnishes insufficiently pure tramadol hydrochloride as a solid. This must then be purified, by using a halogenated solvent and 1,4-dioxane, to give sufficiently pure tramadol hydrochloride. The main drawback of this process is the use of large quantities of 1,4-dioxane and the need for multiple crystallizations to get sufficiently pure trans isomer hydrochloride (Scheme – 1).
  • [0004]

    The use of dioxane for the separation of tramadol hydrochloride from the corresponding cis isomer has many disadvantages, such as safety hazards by potentially forming explosive peroxides, and it is also a category 1 carcinogen (Kirk and Othmer, 3rd edition, 17, 48). Toxicological studies of dioxane show side effects such as CNS depression, and necrosis of the liver and kidneys. Furthermore, the content of dioxane in the final tramadol hydrochloride has been strictly limited; for example, the German Drug Codex (Deutscher Arzneimittel Codex, DAC (1991)) restricts the level of dioxane in tramadol hydrochloride to 0.5 parts per million (ppm).

    Figure 00020001
  • In another process, disclosed in US patent specification no. 5 414 129, the purification and separation of tramadol hydrochloride is undertaken from a reaction mixture containing the trans and cis isomers, and Grignard reaction side products, in which the reaction mixture is diluted in isopropyl alcohol and acidified with gaseous hydrogen chloride to yield (trans) tramadol hydrochloride (97.8%) and its cis isomer (2.2%), which is itself crystallized twice with isopropyl alcohol to give pure (trans) tramadol hydrochloride (Scheme – 2). This process relies on the use of multiple solvents to separate the isomers (ie butylacetate, 1-butanol, 1-pentanol, primary amyl alcohol mixture, 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol and anisole). The main drawback of this process is therefore in using high boiling solvents; furthermore, the yields of tramadol hydrochloride are still relatively low and the yield of the corresponding cis hydrochloride is relatively high in most cases.

    Figure 00030001
  • PCT patent specification no. WO 99/03820 describes a method of preparation of tramadol (base) monohydrate, which involves the reaction of Mannich base with metabromo-anisole (Grignard reaction) to furnish a mixture of tramadol base with its corresponding cis isomer and Grignard impurities. This, on treatment with an equimolar quantity of water and cooling to 0 to -5°C, gives a mixture of tramadol (base) monohydrate with the corresponding cis isomer (crude). It is further purified with ethyl acetate to furnish pure (trans) tramadol (base) monohydrate, which is again treated with hydrochloric acid in the presence of a suitable solvent to give its hydrochloride salt (Scheme – 2). The drawback of this method is that, to get pure (trans) tramadol hydrochloride, first is prepared pure (trans) tramadol (base) monohydrate, involving a two-step process, and this is then converted to its hydrochloride salt. The overall yield is low because of the multiple steps and tedious process involved.

    Figure 00040001
  • More recently, a process for the separation of tramadol hydrochloride from a mixture with its cis isomer, using an electrophilic reagent, has been described in US patent specification no. 5 874 620. The mixture of tramadol hydrochloride with the corresponding cis isomer is reacted with an electrophilic reagent, such as acetic anhydride, thionyl chloride or sodium azide, using an appropriate solvent (dimethylformamide or chlorobenzene) to furnish a mixture of tramadol hydrochloride (93.3 to 98.6%) with the corresponding cis isomer (1.4 to 6.66%), (Scheme – 3). The product thus obtained is further purified in isopropyl alcohol to give pure (trans) tramadol hydrochloride. However, the drawback of this process is that a mixture of tramadol base with its cis isomer is first converted into the hydrochloride salts, and this is further reacted with toxic, hazardous and expensive electrophilic reagents to get semi-pure (trans) tramadol hydrochloride. The content of the cis isomer is sufficiently high to require further purification, and this therefore results in a lower overall yield.
  • Therefore, all the known methods require potentially toxic solvents and/or reagents, and multiple steps to produce the desired quality and quantity of tramadol hydrochloride. By contrast, the present invention requires a single step process (or only two steps when tramadol hydrochloride is made via the tramadol (base) monohydrate route) using a natural solvent (ie water) in the absence of carcinogenic solvents (such as the category 1 carcinogen, 1,4-dioxane) to produce pure tramadol hydrochloride, so it is ‘ecofriendly’ and easily commercialized to plant scale without any difficulties.

PATENT

http://www.google.co.in/patents/US6399829

EXAMPLE 8 Hydrochloride Formed without Improvement of the Trans:Cis Ratio

Whether a recrystallization step improves the trans:cis ratio of Tramadol depends upon the solvent composition from which the recrystallization is performed. When the hydrochloride form of Tramadol is produced and then crystallized in the presence of a solvent with a high toluene concentration, the ratio of trans:cis remains essentially unchanged. This is in contrast to the recrystallization from a solvent which has a high acetonitrile concentration as was the case in Examples 5-7.

A 21 mL solution of 1.8 g of HCl gas (bubbled at 5° C.) in acetonitrile (yielding a 2.0 M solution), was added to 10.2 g of Grignard product C (90/10 of trans/cis) in 30 mL of toluene and stirred mechanically for 3 hours. The mixture was filtered and washed with toluene. Drying in vacuo yielded 11.2 g (96% recovery). The resulting hydrochloride had a trans/cis ratio of 92:8, essentially the same trans:cis ratio as did the 10.2 g of Grignard product C.

Recrystallization from 90 mL of acetonitrile yielded 8.83 g, which was 96.6/3.4 of trans/cis by HPLC. Of this, 8.6 g was recrystallized from 75 mL of acetonitrile to give 7.44 g, trans/cis ratio of 99.6/0.4.

This example shows that the formation of the hydrochloride in the presence of a relatively large amount of toluene (here about 60%) and crystallization from toluene-acetonitrile does not improve the trans:cis ratio. As the percentage of toluene present in the mixture of toluene and acetonitrile in a crystallization step is decreased, the trans:cis ratio of the recovered product will increase. Steps in which the hydrochloride is recrystallized from acetonitrile do yield an improved trans:cis ratio.

 

PATENT

https://www.google.com/patents/EP0831082A1

The synthesis of Tramadol is described in U.S. Patent No. 3,652,589 and in British Patent No. 992,399. The synthesis of Tramadol consists of a Grignard reaction between 2-dimethylaminomethylcyclohexanone and 3-methoxyphenyl magnesium bromide (Equation 1). From the reaction scheme, it is clear that both isomers (RR,SS) (Structure 1) and (RS, SR) (Structure 2) are obtained in variable ratios, depending on the reaction conditions.

The original patents assigned to Gruenenthal GmbH describe the isolation of the (RR,SS) isomer, as follows:

The complex mixture of products containing both isomers of Tramadol obtained from the Grignard reaction is distilled under reduced pressure. The isomers are distilled together at 138-140°C (0.6 mm Hg). The distillate is dissolved in ether and is reacted with gaseous HCl. The resulting mixture of both isomers of Tramadol is precipitated as hydrochlorides and filtered. The resulting mixture contains about 20% of the (RS,SR) isomer. The isomer mixture is then refluxed twice with five volumes of moist dioxane, and filtered. The cake obtained consists of pure (RR,SS) isomer. The residual solution consists of “a mixture of about 20-30% of the cis (i.e. RS,SR), which cannot be further separated by boiling dioxane” [U.S. Patent 3,652,589, Example 2].

Dioxane, used in large quantities in this process, possesses many undesirable properties. It has recently been listed as a Category I carcinogen by OSHA [Kirk & Othmer, 3rd Ed., Vol. 9, p. 386], and it is known to cause CNS depression and liver necrosis [ibid., Vol. 13, p. 267]; in addition, it tends to form hazardous peroxides [ibid., Vol 17, p. 48]. As a result, the concentration of dioxane in the final product has been strictly limited to several ppb’s, and the DAC (1991) restricted the level of dioxane in Tramadol to 0.5 ppm.

A different separation method, described in Israeli Specification No. 103096, takes advantage of the fact that the precipitation of the (RR,SS) isomer of Tramadol from its solution in medium chained alcohols (C4-C8) occurs faster than the precipitation of the (RS,SR) isomer, which tends to separate later. The main disadvantage of this method is, that the time interval between the end of separation of the (RR,SS) isomer and the beginning of the (RS,SR) isomer separation is variable, and seems to depend sharply on the composition of the crude mixture. Therefore, variations in the yield and the quality of the product often occur. Furthermore, about 40% of the (RR,SS) isomer does not separate and remains in solution, along with the (RS,SR) isomer. This remaining mixture cannot be further purified by this method.

Another method, described in Israeli Specification No. 116281, relies on the fact that the (RS,SR) isomer of Tramadol undergoes dehydration much faster then the (RR,SS) isomer, when treated with 4-toluenesulfonic acid, or sulfuric acid; furthermore, when the reaction is carried out in an aqueous medium, a certain amount (up to 50%) of the (RS,SR) isomer is converted to the (RR,SS) isomer. This may, of course increase the efficiency of the process.

The unreacted (RR, SS) isomer is then separated from the dehydrated products and from other impurities by simple crystallization.

While further examining the results of the latter process, it was surprisingly found that the hydroxyl group of the (RS,SR) isomer of Tramadol reacts faster than the same group of the (RR,SS) with various reagents. A plausible explanation for this observation can be supplied by comparing the structures of both isomers, and their ability to form hydrogen bonds.

Looking closely at Fig. 1 [(RR,SS) Tramadol hydrochloride] and at Fig. 2 [(RS,SR) Tramadol hydrochloride], one can provide a plausible explanation for the difference in the OH group’s activity, as follows: The proton attached to the nitrogen atom of the protonated (RR,SS) isomer of Tramadol is capable of forming a stable hydrogen bonding with the oxygen atom of the hydroxyl group (see Fig. 1). Thus, any reaction involving protonation of the hydroxyl group (such as dehydration), or any reaction in which the hydroxyl group reacts as a nucleophile (such as a nucleophilic substitution or esterification process) is less favored to occur.

In the (RS,SR) isomer, on the other hand, there is no possible way of forming a stable intramolecular hydrogen bond, and therefore, any of the above-mentioned types of reactions can easily occur, considering the fact that this particular hydroxyl group is tertiary and benzyllic.

The general purification procedure of the present invention consists of reacting a mixture of both geometrical isomers of Tramadol hydrochloride with a potential electrophile under such conditions that the (RS,SR) isomer reacts almost exclusively, while the (RR,SS) isomer remains practically intact. The resulting mixture is evaporated and the resulting solid substance is then recrystallized from isopropanol or any other suitable solvent.

Example 1

11.1 g of a mixture consisting of 77% (RR,SS) Tramadol hydrochloride and 23% of the corresponding (RS,SR) isomer were dissolved in 30 ml DMF. 1.3 g acetic anhydride were added and the reaction mixture was stirred at room temperature for 12 hours. The solvent was partly evaporated under reduced pressure and 15 ml toluene were added. The suspension obtained was filtered and washed with 5 ml toluene. 5.8 g of crystals were obtained, in which the (RR,SS):(RS,SR) isomer ratio was 70:1. The product obtained was crystallized from 12 ml isopropanol and 4 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 2

19.5 g of a mixture consisting of 60.5% (RR,SS) Tramadol hydrochloride and 40.5% of the corresponding (RS,SR) isomer were suspended in 55 ml chlorobenzene. A solution of 4 ml thionyl chloride in 15 ml chlorobenzene was added dropwise for two hours. The suspension was partly evaporated, the residue was filtered and rinsed with toluene, and 8.1 g of crystals were obtained, in which the (RR,SS):(RS, SR) isomer ratio was 14:1. The product obtained was recrystallized from isopropanol, and 6.7 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 3

33.4 g of a mixture consisting of 45% (RR,SS) Tramadol hydrochloride and 55% of the corresponding (RS,SR) isomer was immersed in 50 ml trifluoroacetic acid, 5.2 g of sodium azide was added, and the reaction mixture was stirred for 24 hours. The reaction mixture was then evaporated under reduced pressure, 50 ml water was added, and the solution was brought to pH 12 with solid potassium carbonate. The suspension was extracted with 50 ml toluene, the solvent was evaporated and 25 ml hydrogen chloride solution in isopropanol were added. The solution was cooled and filtered. 9.5 g of crude (RR,SS) Tramadol were obtained, and the crude product was purified by recrystallization from isopropanol.

 

The hitherto unknown (RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride was isolated from the reaction mixture, recrystallized from isopropanol and characterized as follows:

 

(RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride

  • ms : 288 m+
  • IR : 2050 cm-1 (N3)

 

  • 1H-NMR (DMSO): 10.42 ppm: (acidic proton); 1H; 7.40-6.90 ppm: (aromatic protons) 4H; 3.79 ppm; (OCH3 ), 3H; 2.78, 2.42 ppm: NCH2 ; 2H; 2.58, 2.37 ppm: [N(CH3 )2], 6H; 2.30-1.40 ppm: cyclohexane ring protons, 9H.

 

  • 13C-NMR (DMSO): 159.74 ppm: C1; 144.12 ppm: C5; 130.08 ppm: C3; 117.36 ppm: C4; 112.97, 111.35 ppm: C2, C6; 69.61 ppm: C8; 59.29 ppm: C14; 55.21 ppm: C7; 44.6 ppm: C15; 40.12 ppm: C13; 35.94, 27.02, 23.56, 21.63 ppm: cyclohexane ring carbon nucleii.

AZIDE COMPD

Bibliography

Synthesis of Tramadol

http://www.nioch.nsc.ru/icnpas98/pdf/posters1/156.pdf

    • http://www.opioids.com/tramadol/synthesis/index.html
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Action

    • R. B. Raffa, E. Friderichs, W. Reimann, R. P. Shank, E. E. Codd and J. L. Vaught, J. Pharmacol. Exp. Ther., 260 (1992) 275-285 (means of action)
    • P. Dayer, L. Collart and J. Desmeules, Drugs (Suppl. 1), (1994) 3-7.
    • T. A. Bamigbade, C. Davidson, R. M. Langford and J. A. Stamford, Br. J. Anaesthes., 79 (1997) 352-356. (action of enantiomers)
    • P. W. Keeley, G. Foster and L. Whitelaw, BMJ, 321 (2000) 1608 (auditory hallucinations with tramadol)
    • U. M. Stamer, F. Musshoff, M. Kobilay, B. Madea, A. Hoeft and F. Stuber, Clin. Pharmacol. Ther., 82 (2007) 41-47 (different CYP2D6 Genotypes and metabolism)
    • W. Leppert, Pharmacology, 87 (2011)274–285 (metabolism of tramadol to O-desmethyltramadol by CYP2D6)
    • A. Elkalioubie, D. Allorge, L. Robriquet, J.-F. Wiart, A. Garat, F. Broly and F. Fourrier, Eur. J. Clin. Pharmacol., 67 (2011) 855–858 (ultrarapid metabolism of tramadol)
    • C. F. Samer, K. I. Lorenzini, V. Rollason, Y. Daali and J. A. Desmeules, Molecular Diagnosis & Therapy, 17 (2013), 165–84 (variations in tramadol response)

Tramadol abuse

    • M. K. Wedge, Can. Pharm. J., 142 (2009) 71-73. (tramadol and antidepressants)
    • ACMD advice on O-desmethyltramadol
    • Y. Progler, J. Res. Med. Sci., 15 (2010) 185-188 (Tramadol abuse and smuggling into Gaza)
    • M. M. Fawzi, Egypt. J. Forensic Sci., 1 (2011) 99–102 (Tramadol abuse in Egypt)
    • I. Giraudon, K. Lowitz, P. I. Dargan, D. M. Wood and R. C. Dart, Br. J. Clin. Pharmacol., 76, (2013) 823–824 (prescription opioid abuse in the UK)
    • C. Stannard, BMJ, 347 (2013) f5108 (tramadol problem)
    • N. Hawkes, BMJ, 347 (2013) f5336 (deaths from tramadol and legal highs)
    • A. Winstock, J. Bell and R. Borschmann, BMJ 347 (2013) f5599 (monitoring Tramadol abuse)
    • S. H. Park, R. C. Wackernah and G. L. Stimmel, J. Pharm. Pract., 27 (2014) 71-78.
    • Unemployment in Gaza and Tramadol addiction.

Tramadol in “highs”

    • T. Arndt, U. Claussen, B. Güssregen, S. Schröfel, B. Stürzer, A. Werle and G. Wolf, For. Sci. Int., 208 (2011) 47-52. (Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer)
    • R. Kronstrand, M. Roman, G. Thelander and A. Eriksson, J. Anal. Toxicol., 35 (2011) 242–247. (fatalities from mitragynine and O-desmethyltramadol combinations in Krypton herbal mixture)
    • C. D. Rosenbaum, S. P. Carreiro and K. M. Babu, J. Med. Toxicol., 8 (2012) 15-32 (review of herbal marijuana alternatives, including Kratom)

Tramadol in cycling

 

EP0778262A2 * 19 Nov 1996 11 Jun 1997 Chemagis Ltd. Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts
EP0787715A1 * 21 Dec 1996 6 Aug 1997 Grünenthal GmbH Process for the optical resolution of tramadol
EP0831082A1 * 19 Aug 1997 25 Mar 1998 Chemagis Ltd. Process for the purification of (RR-SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride
US5414129 * 8 Sep 1993 9 May 1995 Chemagis, Ltd. Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts
Reference
1 * CHEMICAL ABSTRACTS, vol. 126, no. 26, 30 June 1997 Columbus, Ohio, US; abstract no. 343383v, page 597; column 1; XP002079824 & IL 103 096 A (CHEMAGIS LTD) 5 December 1996
2 * CHEMICAL ABSTRACTS, vol. 127, no. 20, 17 November 1997 Columbus, Ohio, US; abstract no. 278028n, QIAO, BEN-ZHI ET AL.: “Synthesis and structure of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl )cyclohexanol.” page 683; column 2; XP002079825 & GAODENG XUEXIAO HUAXUE XUEBAO , vol. 18, no. 6, 1997, pages 902-905,
Citing Patent Filing date Publication date Applicant Title
WO1999036389A1 * 14 Jan 1999 22 Jul 1999 Nicholas Archer Purification of tramadol
WO2000078705A1 * 22 Jun 1999 28 Dec 2000 Bernhard Akteries Method for separating the diastereomer bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol
WO2003078380A2 * 20 Mar 2003 25 Sep 2003 Shahid Akhtar Ansari Process for preparing tramadol hydrochloride and/or tramadol momohydrate
WO2004020390A1 * 7 Aug 2003 11 Mar 2004 Bernhard Akteries Method for the production of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
EP1346978A1 * 21 Mar 2002 24 Sep 2003 Jubilant Organosys Limited Process for preparing tramadol hydrochloride and/or tramadol monohydrate
US6521792 * 21 Dec 2001 18 Feb 2003 Gruenenthal Gmbh Process for separating the diastereomeric bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cylohexanol
US6649783 3 Oct 2001 18 Nov 2003 Euro-Celtique, S.A. Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US6784319 15 Sep 2003 31 Aug 2004 Euro-Celtique, S.A. Synthesis of (±)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US7030276 9 Feb 2005 18 Apr 2006 Gruenenthal Gmbh Process for preparing 2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol
US8221792 7 Jul 2006 17 Jul 2012 Farnam Companies, Inc. Sustained release pharmaceutical compositions for highly water soluble drugs
EP0940385A1 * Mar 3, 1999 Sep 8, 1999 Dinamite Dipharma S.p.A. Process for the separation of the (RR,SS)-2-(dimethylamino)methyl-1-(3-methoxyphenyl)-cyclohexanol isomer from the (RS,SR) isomer by selective precipitation
WO1999003820A1 * Jun 26, 1998 Jan 28, 1999 Nikolopoulos Angelo Tramadol, salts thereof and process for their preparation
WO1999036390A1 * Jan 14, 1999 Jul 22, 1999 Nicholas Archer Purification of tramadol
WO2000078705A1 * Jun 22, 1999 Dec 28, 2000 Bernhard Akteries Method for separating the diastereomer bases of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol
Citing Patent Filing date Publication date Applicant Title
US7470816 Nov 13, 2006 Dec 30, 2008 Ipac Laboratories Limited Tramadol recovery process
US3652589 * 27 Jul 1967 28 Mar 1972 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US5414129 * 8 Sep 1993 9 May 1995 Chemagis, Ltd. Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts
EP0778262A2 * 19 Nov 1996 11 Jun 1997 Chemagis Ltd. Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts
Citing Patent Filing date Publication date Applicant Title
US6828345 * 31 Mar 2003 7 Dec 2004 Gruenenthal Gmbh O-substituted 6-methyltramadol derivatives
US7030276 9 Feb 2005 18 Apr 2006 Gruenenthal Gmbh Process for preparing 2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol
US7470816 13 Nov 2006 30 Dec 2008 Ipac Laboratories Limited Tramadol recovery process
US20050215821 * 9 Feb 2005 29 Sep 2005 Gruenenthal Gmbh Process for preparing 2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol
US20070112074 * 13 Nov 2006 17 May 2007 Ashok Kumar Tramadol recovery process
EP0778262A2 * Nov 19, 1996 Jun 11, 1997 Chemagis Ltd. Process for the purification of (RR-SS)-2-dimethyl-aminomethyl-1-(3-methoxyphenyl)cyclohexanol and its salts
US3652589 * Jul 27, 1967 Mar 28, 1972 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US5414129 * Sep 8, 1993 May 9, 1995 Chemagis, Ltd. Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts

 

Referenced by
Citing Patent Filing date Publication date Applicant Title
EP0940385A1 * Mar 3, 1999 Sep 8, 1999 Dinamite Dipharma S.p.A. Process for the separation of the (RR,SS)-2-(dimethylamino)methyl-1-(3-methoxyphenyl)-cyclohexanol isomer from the (RS,SR) isomer by selective precipitation
DE10218862A1 * Apr 26, 2002 Nov 6, 2003 Gruenenthal Gmbh Verfahren zur Chlorierung tertiärer Alkohole
US6169205 Mar 4, 1999 Jan 2, 2001 Dipharma S.P.A. Process for the purification of (RR,SS)-2-(dimethylamino) methyl-1-(3-methoxyphenyl)-cyclohexanol from (RS,SR)-2-(dimethylamino)methyl-1-(3-methoxyphenyl) cyclohexanol
US6469213 Jan 14, 2000 Oct 22, 2002 Russinsky Limited Tramadol, salts thereof and process for their preparation
US6649783 Oct 3, 2001 Nov 18, 2003 Euro-Celtique, S.A. Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US6784319 Sep 15, 2003 Aug 31, 2004 Euro-Celtique, S.A. Synthesis of (±)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US7235693 Oct 26, 2004 Jun 26, 2007 Gruenenthal Gmbh Process for chlorinating tertiary alcohols
US7470816 Nov 13, 2006 Dec 30, 2008 Ipac Laboratories Limited Tramadol recovery process
WO1999003820A1 * Jun 26, 1998 Jan 28, 1999 Nikolopoulos Angelo Tramadol, salts thereof and process for their preparation
Systematic (IUPAC) name
2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Clinical data
Trade names Ryzolt, Tramal, Ultram
AHFS/Drugs.com monograph
MedlinePlus a695011
Licence data US FDA:link
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
Dependence
liability
Present[1]
Routes of
administration
Oral, IV, IM, rectal
Pharmacokinetic data
Bioavailability 70–75% (oral), 77% (rectal), 100% (IM)[2]
Protein binding 20%[3]
Metabolism Liver-mediated demethylation andglucuronidation via CYP2D6 &CYP3A4[2][3]
Biological half-life 6.3 ± 1.4 hr[3]
Excretion Urine (95%)[4]
Identifiers
CAS Registry Number 27203-92-5 Yes
ATC code N02AX02
PubChem CID: 33741
DrugBank DB00193 Yes
ChemSpider 31105 Yes
UNII 39J1LGJ30J Yes
KEGG D08623 Yes
ChEBI CHEBI:9648 
ChEMBL CHEMBL1066 Yes
Chemical data
Formula C16H25NO2
Molecular mass 263.4 g/mol

DMF

 

23121 A II 9 / 21 / 2009 RAKSHIT DRUGS PVT LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH INDIA Status: P = Pending A = Active I
24285 A II 10 / 29 / 2010 AUROBINDO PHARMA LTD TRAMADOL HYDROCHLORIDE USP (NON STERILE DRUG SUBSTANCE) AS MANUFACTURED IN ANDHRA PRADESH INDIA Status: P
24954 A II 5 / 6 / 2011 PIRAMAL HEALTHCARE LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH, INDIA Status: P = Pending A = Active I
Holder Subject 27159 A II 5 / 21 / 2013 RAKS PHARMA PVT LTD TRAMADOL HYDROCHLORIDE USP API (PROCESS-2) (ESUB) AS MANUFACTURED IN ANDHRA PRADESH,
22687 A II 3 / 31 / 2009 CADILA HEALTHCARE LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA Status: P = Pending A = Active I = Inactive
22687 A II 3 / 31 / 2009 CADILA HEALTHCARE LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA Status: P = Pending A = Active I = Inactive
21249 A II 12 / 6 / 2007 ZHEJIANG HISOAR PHARMACEUTICAL CO LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN ZHEJIANG, CHINA Status: P = Pending A = Active
21915 A II 8 / 27 / 2008 KAMUD DRUGS PVT LTD TRAMADOL HYDROCHLORIDE BP AS MANUFACTURED IN MAHARASHTRA, INDIA Status: P = Pending A = Active
21805 A II 7 / 15 / 2008 HEBEI ZHONGSHENG PHARMACEUTICAL CO LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN HEBEI, CHINA Status: P = Pending A = Active
22531 A II 2 / 11 / 2009 SEQUEL PHARMACHEM PRIVATE LTD TRAMADOL HYDROCHLORID EP AS MANUFACTURED IN MAHARASHTRA, INDIA Status: P = Pending A = Active
20204 A II 23-Jan-2007 TONIRA PHARMA LTD TRAMADOL HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA Status: P = Pending A = Active I = Inactive A | B |
ASSIGNED NUMBER 27159 A II 5 / 21 / 2013 RAKS PHARMA PVT LTD TRAMADOL HYDROCHLORIDE USP API (PROCESS-2) (ESUB) AS MANUFACTURED IN ANDHRA PRADESH,
ASSIGNED NUMBER 27159 A II 5 / 21 / 2013 RAKS PHARMA PVT LTD TRAMADOL HYDROCHLORIDE USP API (PROCESS-2) (ESUB) AS MANUFACTURED IN ANDHRA PRADESH,

Tramadol hydrochloride..CEP

Product Name Country Manufacture Chemical formula CAS # CEP DMF
Tramadol hydrochloride India IPCA Laboratories Ltd C16H26ClNO2 22204-88-2   R0-CEP 2008-189-Rev 00 – – –
Tramadol hydrochloride India Dishman Pharmaceuticals and Chemicals Ltd. C16H26ClNO2 22204-88-2   R0-CEP 2003-148-Rev 01 – – –
Tramadol hydrochloride India Sun Pharmaceutical Industries Ltd. C16H26ClNO2 22204-88-2   R1-CEP 2002-232-Rev 02 – – –
Tramadol hydrochloride China CSPC OUYI PHARMACEUTICAL CO., LTD. C16H26ClNO2 22204-88-2   R0-CEP 2005-227-Rev 02 – – –
Tramadol hydrochloride India JUBILANT LIFE SCIENCES LIMITED C16H26ClNO2 22204-88-2   R1-CEP 2002-199-Rev 03 – – –
Tramadol hydrochloride India Cadila Pharmaceuticals Ltd. C16H26ClNO2 22204-88-2   R1-CEP 2004-098-Rev 01 – – –
Tramadol hydrochloride Germany AREVIPHARMA GMBH C16H26ClNO2 22204-88-2   R0-CEP 2005-020-Rev 02 – – –
Tramadol hydrochloride New process India Inogent Laboratories Private Limited C16H26ClNO2 22204-88-2   R0-CEP 2007-129-Rev 00 – – –
Tramadol hydrochloride India SPIC Limited, Pharmaceuticals Division C16H26ClNO2 22204-88-2   R0-CEP 2004-245-Rev 00 – – –
Tramadol hydrochloride Switzerland Cilag AG CH C16H26ClNO2 22204-88-2   R0-CEP 2006-262-Rev 00 – – –
Tramadol hydrochloride Italy Dipharma Francis S.r.l. C16H26ClNO2 22204-88-2   R0-CEP 2002-105-Rev 01 – – –
Tramadol hydrochloride Israel Chemagis Ltd C16H26ClNO2 22204-88-2   R1-CEP 2003-146-Rev 00 – – –
Tramadol hydrochloride India Wanbury LTD C16H26ClNO2 22204-88-2   R0-CEP 2005-151-Rev 01 – – –
Tramadol hydrochloride Germany Excella GmbH C16H26ClNO2 22204-88-2   R0-CEP 2003-137-Rev 02 – – –
Tramadol hydrochloride Switzerland Proto Chemicals AG C16H26ClNO2 22204-88-2   R1-CEP 2002-204-Rev 01 – – –
Tramadol hydrochloride Czech Republic ZENTIVA K.S. C16H26ClNO2 22204-88-2   R0-CEP 2009-214-Rev 00 – – –
Tramadol hydrochloride United States Noramco, Inc. C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride Germany GRUNENTHAL GMBH C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride Ireland IROTEC LABORATORIES C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride Switzerland HELSINN CHEMICALS SA C16H26ClNO2 22204-88-2 US – –
TRAMADOL HYDROCHLORIDE Israel Chemagis Ltd US – –
Tramadol hydrochloride Slovakia “ZENTIVA, A.S.” C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride United States WYCKOFF CHEMICAL CO INC C16H26ClNO2 22204-88-2 US – –
TRAMADOL HYDROCHLORIDE Germany Excella GmbH US – –
Tramadol hydrochloride USP (BULK) China SHIJIAZHUANG PHARMACEUTICAL GROUP CO LTD C16H26ClNO2 22204-88-2 US – –
TRAMADOL HYDROCHLORIDE Germany EVONIK DEGUSSA GMBH US – –
Tramadol hydrochloride Italy RECORDATI S.p.A. C16H26ClNO2 22204-88-2 US – –
TRAMADOL HYDROCHLORIDE India Dishman Pharmaceuticals and Chemicals Ltd. US – –
TRAMADOL HYDROCHLORIDE India Sun Pharmaceutical Industries Ltd. US – –
TRAMADOL HYDROCHLORIDE India Cadila Pharmaceuticals Ltd. C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride Switzerland PROTO CHEMICALS AG C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride EP India DAI ICHI KARKARIA LTD C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride India PEARL ORGANICS LTD C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride EP China SHIJIAZHUANG PHARMACEUTICAL GROUP HUASHENG PHARMA CO LTD C16H26ClNO2 22204-88-2 US – –
TRAMADOL HYDROCHLORIDE India JUBILANT LIFE SCIENCES LIMITED US – –
TRAMADOL HYDROCHLORIDE Germany AREVIPHARMA GMBH US – –
Tramadol hydrochloride India TONIRA PHARMA LTD C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride India INOGENT LABORATORIES PRIVATE LIMITED C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride China ZHEJIANG HISOAR PHARMACEUTICAL CO LTD C16H26ClNO2 22204-88-2 US – –
TRAMADOL HYDROCHLORIDE India IPCA Laboratories Ltd US – –
Tramadol hydrochloride China HEBEI ZHONGSHENG PHARMACEUTICAL CO LTD C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride BP India KAMUD DRUGS PVT LTD C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride India Raks Pharma Pvt Ltd. C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride USP n/sterile India Aurobindo Pharma Ltd. C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride (YT3 PROCESS) India IPCA Laboratories Ltd C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride India PIRAMAL HEALTHCARE LTD C16H26ClNO2 22204-88-2 US – –
Tramadol hydrochloride India Asence Pharma Private Ltd C16H26ClNO2 22204-88-2 – – –

 

SYNOPSIS FOR M. PHARM DISSERTATION

K RAMARAO – rguhs.ac.in
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION. 9. Shaikh AC et al.,
Formulated and Optimized Hydrodynamically balanced Oral Controlled release Bioadhesive
Tablets of Tramadol Hydrochloride using different polymers like Carbopol 971P (CP) and

 

////////TRAMADOL,


1 Comment

  1. larryhbern says:

    Reblogged this on Leaders in Pharmaceutical Business Intelligence and commented:
    Tramadol (marketed as Ultram, and as generics) is an opioid pain medication used to treat moderate to moderately severepain.[1] When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.[5]It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin andnorepinephrine.[6][7]

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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