HANOI UNIVERSITY OF SCIENCE AND TECHNOLOGY

School of Chemistry and Life Sciences

Department of Chemical Engineering

Group of Pharmaceutical, Cosmetic and Pesticide Chemistry Technology

Pharmaceutical Chemistry I Essay

Lecturer: Dr. Nguyen Thi Thuy My

Group 5:

Trinh Minh Duc (Group Leader) 20221787

Doan Huong Giang 20221792
Vu Tuan Bao 20221781
Linh Quang Hieu 20211596
Nguyen Tien Dat 20221785

Active Pharmaceutical Ingredient Research: Tramadol

Hanoi 2024
TABLE OF CONTENTS
 ABSTRACT
Tramadol is a synthetic opioid analgesic widely used for the treatment of moderate to
severe pain. Its pharmacological action includes binding mu-opioid receptors and
inhibiting the reuptake of serotonin and norepinephrine, which contributes to its analgesic
effects. Unlike typical opioids, tramadol has a lower potential for abuse, making it a
common choice for managing both acute and chronic pain conditions.

The synthesis of tramadol typically involves the Grignard reaction. Subsequent steps
include reduction and methylation to achieve the final structure of racemic tramadol,
consisting of two enantiomers with slightly different pharmacological effects. The
synthesis is relatively straightforward and can be optimized for large-scale production.
While tramadol is effective, it carries risks such as dependency, serotonin syndrome, and
other opioid-related side effects, requiring careful clinical oversight in its use.

For all the above reasons, our group choose tramadol as the object of this Pharmaceutical
Chemistry I Essay research to investigate further about its properties both theoretically
and clinically, and to investigate about its methods of its synthesis on the industrial scale.

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 PART I: OVERVIEW OF TRAMADOL
I. Name

 IUPAC Name: (1RS, 2RS)-2- [(dimethyl amino) methyl]-1-(3-methoxyphenyl)

cyclohexanol hydrochloride (1:1)

 Common Name: Tramadol Hydrochloride

 Other Names:

o Tramal (international)

o Ultram (brand name)

 Molecular Formula:

o Tramadol Hydrochloride: C16H26ClNO2

o Tramadol (base): C16H25NO2

OCH3

Cl-
OH H
CH3
N+

CH3

 CAS Number: 27203-92-5 (hydrochloride salt), 36282-47-0 (base form)

 Drug Class:

o Narcotic analgesic

o Opioid agonist for moderate to severe pain (Tramadol-hydrochloride-…)

(Tramadol-hydrochloride-…).

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II. Physical properties

 Molecular Weight:

o Tramadol Hydrochloride: 299.84 g/mol

o Tramadol (base): 263.4 g/mol (Tramadol-hydrochloride-…).

 Melting Point: 180–181°C (Tramadol Hydrochloride)(Tramadol-hydrochloride-

…).

 Appearance: White to off-white, crystalline powder.

 Odor: Odorless.

 Hygroscopicity: Tramadol hydrochloride is hygroscopic—it absorbs moisture from

the air.

 pH: When dissolved in water, tramadol hydrochloride has a pH of around 5.0–6.5.

 Solubility:

o Water soluble: Highly soluble in water (Tramadol-hydrochloride-…)

(Tramadol-hydrochloride-…).

o Also soluble in methanol, slightly soluble in ethanol.

 UV-Vis Absorbance: Maximum absorbance at 271 nm (Tramadol-hydrochloride-

…).

 Appearance: White or off-white crystalline powder (Tramadol-hydrochloride-…).

 Density: Approx. 1.2 g/cm³(Tramadol-hydrochloride-…).

III. Chemical properties

 pKa: 9.41(Tramadol-hydrochloride-…).

 Chemical Structure:

3
 o Tramadol contains a cyclohexanol ring with a methoxyphenyl group
attached to the ring, as well as a dimethyl amino methyl group.

o Salt form: The hydrochloride salt form enhances its water solubility, making
it suitable for oral administration (Tramadol-hydrochloride-…)(Tramadol-
hydrochloride-…).

 Stability:

o Stable under normal storage conditions but sensitive to light and moisture.

 Reactivity:

o Reacts with strong oxidizing agents.

o Involved in cation-exchange reactions when used in drug delivery systems

like montmorillonite composites (Tramadol-hydrochloride-…).

 Toxicity:

o LD50 (oral, rats): 300 mg/kg

o Overdose Effects: Can lead to serotonin syndrome, seizures, respiratory

depression, and opioid overdose symptoms (Tramadol-hydrochloride-…).

 Salt Formation:

o The hydrochloride salt improves tramadol’s bioavailability when taken

orally by making it readily dissolvable in water.

 Chemical Synthesis:

o Tramadol is synthesized from the condensation of 3-methoxyphenylacetone

and dimethylamine, followed by a cyclization reaction to form the
cyclohexanol core.

IV. Pharmacological effects

 Indication:
- Tramadol is approved for the management of moderate to severe pain in adults.
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 - Tramadol is also used off-label in the treatment of premature ejaculation.
1. Pharmacodynamics: (lực)

Tramadol is a synthetic opioid analgesic that has a centrally acting analgesic effect and
can be addictive like morphine. The drug and its metabolite O-desmethyltramadol
(M1) bind to the µ receptor of neurons and reduce the reuptake of norepinephrine and
serotonin into cells, thus having an analgesic effect. The metabolite M1 has a 200-fold
higher affinity for the µ receptor and is 6 times more analgesic than tramadol.

The analgesic effect appears 1 hour after taking the drug and reaches its maximum
effect after 2 - 3 hours. Unlike morphine, tramadol does not cause histamine release,
does not affect heart rate and left ventricular function, and at therapeutic doses
tramadol is less depressive of respiration than morphine

2. Pharmacokinetics: (động)
2.1. Absorption and bioavailability:

After oral administration, tramadol is rapidly and almost completely absorbed. The
plasma concentrations are detectable within approximately 0.5 h . Times to reach peak
plasma concentration (Tmax) are within 1.2 h after oral administration of drops and within
2 h after oral administration of solid dose. Peak plasma concentrations (Cmax) and area
under the curve (AUC) increase linearly over the dose range of 50–400 mg. The extent of
oral absorption of tramadol is almost 100%. Due to the first-pass metabolism, the absolute
bioavailability is 70%.

Following multiple oral administration of tramadol 100 mg four times daily, Cmax and
AUC are 16% and 36% higher, respectively, than after a single 100-mg dose. The
increased bioavailability is likely due to the saturated first-pass metabolism.

Oral administration of tramadol 100 mg following a high-fat food results in a 17% higher
Cmax and a 10% higher AUC than the corresponding values in fasted subjects. This
increase of the bioavailability by food is not considered clinically relevant.

5
The absorption of tramadol after rectal administration of 100 mg suppositories began
within a few minutes. Cmax was reached within 3.3 h. The absolute bioavailability is
slightly higher than that after oral administration, probably due to a reduced first-pass
metabolism after rectal administration.

2.2. Distribution:

Tramadol is rapidly distributed in the body after intravenous administration, with a

distribution half-life in the initial phase of 6 min, followed by a slower distribution phase
with a half-life of 1.7 h. Volumes of distribution following oral and intravenous
administration to young healthy subjects were 306 and 203 L, respectively, indicating that
tramadol has a high tissue affinity. Plasma protein binding is low (20%).

Tramadol passes placental barrier with umbilical venous plasma concentrations being
80% of maternal concentration. Very small amount of tramadol and its active metabolite
are excreted in breast milk.

2.3. Metabolism:

Tramadol is extensively metabolized in the liver by cytochrome P450 2D6 (CYP2D6) .

Tramadol undergoes biotransformation to form the N and O-demethylated compounds
(phase 1 reactions) displayed in Figure below. The O-demethylated metabolites (M1, M4,
and M5) are further conjugated to glucuronides and sulfates (phase 2 reactions). The main
metabolites are O-demethyl tramadol (M1) and its conjugates, di-N,O-demethyl tramadol
(M5) and its conjugates and N-demethyl tramadol (M2). N,N-Didemethyl tramadol (M3)
and O-demethyl-N,N didemethyl tramodal (M4) and its conjugates are only formed in
minor quantities. Among them, M1 is pharmacologically active and is mainly responsible
for the analgesic efficacy of tramadol.

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 2.4. Elimination:

Tramadol is mainly excreted via the kidneys. Following oral administration of 14C-
labeled tramadol to humans, approximately 90% is excreted in urines and 10% in feces.
25–32% of an oral dose is excreted as unchanged tramadol. The mean elimination half-
life is about 5–6 h. The mean total clearance of tramadol was 467 and 742 mL/min
following intravenous and oral administration.

2.5. Pharmacokinetics in special population:

The metabolism and analgesic effect of tramadol was higher in “extensive metabolizers”
of CYP2D6 than in “poor metabolisers.” M1 production in microsomes prepared from the
liver of a poor metabolizer was markedly reduced.Biotransformation of tramadol appears
to be significantly reduced in African subjects. In 10 Nigerian volunteers, about 96% of
tramadol was excreted unchanged in the urine after oral administration. The terminal
elimination half-life of tramadol is prolonged in patients with impaired renal and hepatic
function. Doses and intervals may be adjusted.

3. Toxicity:

In long-term treatment, if the drug is suddenly stopped, it can cause withdrawal

syndrome, symptoms include: panic, sweating, insomnia, nausea, tremors, diarrhea, and
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hair growth. In some cases, hallucinations and paranoia may occur. Therefore, in
treatment, the lowest effective dose of tramadol should be used. The drug should not be
used regularly or for a long time, and the dose should not be stopped suddenly but should
be gradually reduced.

At therapeutic doses, the drug can cause seizures, so extreme caution should be exercised
in people with a history of epilepsy or people with certain diseases that are at high risk of
causing seizures or when combined with MAO inhibitors, tricyclic antidepressants, and
neuroleptics.

Although the drug does not cause histamine release, in some cases when using the drug
for the first time, it can cause severe anaphylactic shock, but death is rare. People with a
history of anaphylactic shock to codeine or other opioids when using tramadol are at risk
of anaphylactic shock.

People with a history of opioid dependence, if using tramadol will cause drug dependence
again, so do not use the drug for people with a history of opioid dependence.

In cases where it is necessary to combine with central nervous system depressants, the
dose of tramadol must be reduced.

Although tramadol causes respiratory depression less than morphine, when used in high
doses or combined with anesthetics, alcohol will increase the risk of respiratory
depression.

Patients with signs of increased intracranial pressure or head injury when using tramadol
need to monitor their mental status carefully.

People with reduced liver and kidney function need to reduce the dose of tramadol.

Tramadol reduces alertness, so do not use the drug when driving, operating machinery, or
working at heights.

8
Be careful when using tramadol because the drug has the potential to cause morphine-like
addiction. Patients crave the drug, seek the drug, and increase the dose due to drug
tolerance. Avoid prolonged use of the drug, especially for people with a history of opioid
addiction.

4. Dosage

The dose and frequency of tramadol administration depend on the response of each
patient and whether the pain is acute or chronic.

*Acute pain

Oral or rectal, intramuscular, or slow intravenous injection (over 2-3 minutes) or

intravenous infusion. The usual oral dose is 50-100 mg, taken every 4-6 hours. For slow-
release tablets, take 1-2 times a day. The total daily dose should not exceed 400 mg.

*Rectal:

100 mg each time, up to 4 times a day.

For postoperative pain relief, the initial dose is 100 mg, followed by 50 mg every 10-20
minutes, if necessary, up to a maximum total dose of 250 mg (including the initial dose)
in the first hour, then 50-100 mg every 4-6 hours. The total daily dose should not exceed
600 mg.

*Chronic Pain:

In the treatment of chronic pain, long-term medication is often required and does not
necessarily provide rapid pain relief. Therefore, it is necessary to conduct a trial
treatment, starting with a low dose and then gradually increasing it to select the
appropriate dose for the patient. Initially, use a dose of 25 mg/day. Then, increase the
dose by 25 mg every 3 days, up to 4 times/day, reaching a dose of 100 mg/day. If the
patient's pain relief requirements are still not met, increase by 50 mg every 3 days, until

9
the total dose is 200 mg/day or more. After selecting the appropriate dose, the patient can
be given a dose of 50 - 100 mg/time, each time 4 - 6 hours apart. The total dose should
not exceed 400 mg/day.

In patients with reduced liver or kidney function, the dose should be reduced and the
interval between doses should be extended. People with reduced kidney function
(creatinine clearance < 30 ml/min) the interval between 2 doses is 12 hours and the total
dose does not exceed 200 mg/day. If the kidney failure is more severe (creatinine
clearance < 10 ml/min), tramadol should not be used. Patients with severe liver failure
should take a single dose of 50 mg, taken every 12 hours.

People on hemodialysis should still take a regular dose on the day of hemodialysis
because only 7% of the oral dose is removed by dialysis. People from 65 to 75 years old:
Do not take more than 300 mg/day, divided into several times.

5. Side effects:

The most frequent adverse events of tramadol are nausea, dizziness, drowsiness, fatigue,
sweating, vomiting, and dry mouth. Tramadol has less respiratory depressant potential
than other opioids, such as morphine and oxycodone. Tramadol also has a low abuse
potential and does not precipitate withdrawal syndrome. Overdose of tramadol is
associated with neurological toxicity. Cardiovascular toxicity has not been reported. The
most common symptoms of tramadol overdose are lethargy, nausea, tachycardia,
agitation, seizures, coma, hypertension, and respiratory depression.

V. Pharmacopoeia standards: Based on British Pharmacopeia

1. Definition
- (lRS,2RS)-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol
hydrochloride.
2. Content
- 99.0 per cent to 101.0 per cent (anhydrous substance).
3. Characters
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- Appearance: White or almost white, crystalline powder.
- Solubility: Freely soluble in water and in methanol, very slightly soluble in
acetone.
4. Identification
- First identification: B, D.
- Second identification: A, C, D.
 A. Melting point (2.2.14): 180°C to 184 °C.
 B. Infrared absorption spectrophotometry (2.2.24).
Comparison tramadol hydrochloride CRS.
 C. Chromatograms obtained in the test for impurity E.
Results The principal spot in the chromatogram obtained with test solution (b) is
similar in position and size to the principal spot in the chromatogram obtained with
reference solution (a).
 D. It gives reaction (a) of chlorides (2.3.1).
5. Tests
- Solution S: Dissolve 1.0 g in water R and dilute to 20 mL with the same solvent.
- Appearance of solution: Solution S is clear (2.2.1) and colourless (2.2.2, Method
II).
- Acidity: To 10 mL of solution S, add 0.2 mL of methyl redsolution R and 0.2 mL
of 0.01 M hydrochloric acid. The solution is red. Not more than 0.4 mL of 0.01 M
sodium hydroxide is required to change the colour of the -indicator to yellow.
- Optical rotation (2.2.7): -0.100 to + 0.10 0 , determined on solution S.
6. Storage
- Protected from light.
VI. Applications
- Tramadol is a centrally acting synthetic opioid analgesic and SNRI
(serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine
and morphine. Due to its good tolerability profile and multimodal mechanism of
action, tramadol is generally considered a lower-risk opioid option for the
treatment of moderate to severe pain in adults.
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- Tramadol has also been shown to affect a number of other pain modulators within
the central nervous system as well as non-neuronal inflammatory markers and
immune mediators. Due to the broad spectrum of targets involved in pain and
inflammation, it's not surprising that the evidence has shown that tramadol is
effective for a number of pain types including neuropathic pain, post-operative
pain, lower back pain, as well as pain associated with labour, osteoarthritis,
fibromyalgia, and cancer. Due to its SNRI activity, tramadol also has anxiolytic,
antidepressant, and anti-shivering effects which are all frequently found as
comorbidities with pain.
VII. Spectrum types
1. UV–vis spectroscopy
- The UV spectrum of tramadol hydrochloride was obtained on a Perkin-Elmer
Lambda 2 UV/vis spectrometer. The drug substance was dissolved in methanol at a
concentration of 10.58 mg/L and scanned from 200 to 400 nm. The UV spectrum
(Figure below) shows absorption maxima at 217 nm (ε=7.2x103 ) and 272 nm
(ε=2.0x103 ).

2. Vibrational spectroscopy

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- The FT-IR spectrum of tramadol hydrochloride was obtained using a Perkin-Elmer
Paragon 16PC FT-IR spectrometer. The spectrum was recorded for a potassium
bromide pellet containing 1.7 mg of the drug substance and 178 mg of KBr.
- The resulting spectrum is displayed in Figure 11.6. A summary of the functional
group assignments for the characteristic absorption bands that were observed is
provided in Table 11.2.

3. Nuclear magnetic resonance spectroscopy

13
- Both the 1 H NMR (including a D2O exchange experiment) and 13C NMR spectra
of tramadol hydrochloride were obtained in a Bruker AV-400 spectrometer,
operating at 400.133 MHz ( 1H NMR) or at 100.623 MHz (13C NMR). Spectra
were recorded for a solution of tramadol hydrochloride in DMSO-d6. Chemical
shifts are reported in ppm relative to TMS.
1
3.1. H NMR spectrum:
- The 1H NMR spectra of tramadol hydrochloride are shown in Figures 11.7 and 11.8
(D2O exchange spectrum), and the resonance signal assignments are provided in
Table 11.3.

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15
 13
3.2. C NMR spectrum
- The 13C NMR and DEPT-135 13C NMR spectra of Tramadol hydrochloride are
shown in Figures 11.9 and 11.10, respectively. The resonance signal assignments
are provided in Table 11.4.

16
17
3.3. Mass spectrometry
- An electrospray ionization mass spectrometry study of tramadol hydrochloride was
carried out on a Perkin-Elmer/Sciex API-300 triple quadrupole mass spectrometer.
The sample was dissolved in methanol and injected into a 5-µL sample loop of the
mass spectrometer and carried into the ionization source by the mobile phase (1:1
mixture of methanol and 0.1% aqueous acetic acid) at a flow rate of 100 µL/min.
The electrospray ionization mass spectrum of tramadol hydrochloride is shown in
Figure 11.11. The spectrum displays the protonated tramadol molecular ion peak
[M+H]+ at m/z 264. The MS/MS spectrum of this ion is shown in Figure 11.12.
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One major fragment ion having an m/z of 58 is observed and is proposed to
originate from the protonated molecular ion of tramadol as shown in Scheme 11.1.

19
 VIII. Price/Commercial product

No PRODUCT QUANTI IMAGE PRICE MANUFACT DOSAGE

NAME TATIVE URER FORM;
ROUTE

$398.23
100mg (30
capsule)

$518.94
200mg (30
1 ConZip capsule)
Vertical Capsule;
Pharmaceutic Oral
$714.16 als Inc
300mg (30
capsule)

20
 Ortho-
$32.05 McNeil- Tablet;
2 ULTRAM 50mg (30 Janssen Oral
tablets) Pharmaceutic
als, Inc.

$131.38 Ortho McNeil

3 ULTRAM 100mg (30 Pharmaceutic Tablet;
ER tablets) al Oral

4 Ryzolt 100mg $131.38 Purdue Tablet;

(30 Pharma LP Oral
tablets)

Athena Solution;
5 QDOLO 5mg/ml $622.35 Bioscience, Oral
(473ml) LLC

21
 1. ConZip:

Generic name: tramadol

Drug class: Opioids (narcotic analgesics)

AU TGA pregnancy category: C

CSA Schedule: Schedule 4

WADA Class: S7 - Narcotics

ConZip is used to treat moderate to severe pain.

The extended-release form of tramadol is for around-the-clock treatment of severe pain

and follows a daily dosing schedule. This form of tramadol is not for use on an as-needed
basis.

Common side effects of ConZip may include:

 Itching, constipation, nausea, vomiting, stomach pain; or

 Dizziness, drowsiness, tiredness, headache.

2. ULTRAM:

Generic name: tramadol

Drug class: Opioids (narcotic analgesics)

AU TGA pregnancy category: C

CSA Schedule: Schedule 4

WADA Class: S7 - Narcotics

Ultram is a pain medicine similar to an opioid. It acts in the central nervous system (CNS)
to relieve pain.

Ultram is used to treat moderate to severe pain in adults.

22
The extended-release form of tramadol (Ultram ER) is for around-the-clock treatment of
pain. Ultram ER is not for use on an as-needed basis for pain.

Common Ultram side effects may include:

 Constipation, nausea, vomiting, stomach pain;

 Dizziness, drowsiness, tiredness;

 headache; or

 Itching.

3. ULTRAM ER

Generic name: tramadol

Drug class: Opioids (narcotic analgesics)

AU TGA pregnancy category: C

CSA Schedule: Schedule 4

WADA Class: S7 - Narcotics

Ultram ER is used to treat moderate to severe pain.

The extended-release form of tramadol is for around-the-clock treatment of severe pain

and follows a daily dosing schedule. This form of tramadol is not for use on an as-needed
basis.

Common side effects of Ultram ER may include:

 Itching, constipation, nausea, vomiting, stomach pain; or

 Dizziness, drowsiness, tiredness, headache.

4. RYZOLT

Generic name: tramadol

Drug class: Opioids (narcotic analgesics)

23
AU TGA pregnancy category: C

CSA Schedule: Schedule 4

WADA Class: S7 - Narcotics

Ryzolt is a narcotic-like pain reliever.

Ryzolt extended-release tablets are used to treat moderate to severe chronic pain when
treatment is needed around the clock.

Common Ryzolt side effects may include:

 Headache, dizziness, drowsiness, tired feeling;

 Constipation, diarrhea, nausea, vomiting, stomach pain; or

 Feeling nervous or anxious.

 Itching, sweating, flushing (warmth, redness, or tingly feeling).

5. QDOLO

Generic name: tramadol hydrochloride

Drug class: Opioids (narcotic analgesics)

AU TGA pregnancy category: C

CSA Schedule: Schedule 4

WADA Class: S7 - Narcotics

Qdolo is:

 A strong prescription pain medicine that contains an opioid (narcotic) that is used
for the management of pain in adults, when other pain treatments such as non-
opioid pain medicines do not treat your pain well enough or you cannot tolerate
them.

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  An opioid pain medicine that can put you at risk for overdose and death. Even if
you take your dose correctly as prescribed you are at risk for opioid addiction,
abuse, and misuse that can lead to death.

The possible side effects of Qdolo include: constipation, nausea, sleepiness, vomiting,
tiredness, headache, dizziness, abdominal pain.

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PART II: SYNTHETIC METHODS OF TRAMADOL
*Explanation: Complexing HCl (hydrochloric acid) with tramadol often involves
creating a stable form of the drug that can enhance its solubility or absorption. Tramadol
is an analgesic used to treat moderate to severe pain, and its efficacy can be affected by
how well it dissolves in the gastrointestinal tract.

I. Preparation of Tramadol Base racemic mixture for Method 1 and 2

1. Reactions

O
O
CH3
CH3
O 1) Mg, THF
2) m-bromoanisole
CH3 OH
3) Vacuum distillation OH +
N CH3 CH3
N N

CH3 CH3
CH3

Trans Tramadol Base Cis Tramadol Base

- 1: 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.
- 2: 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.
2. Procedure

English Vietnamese

Step 1: 5 g. of magnesium turnings are Bước 1: Thêm 5 g magiê dạng bột vào
added to the Mannich base, while stirring, dung dịch Mannich, khuấy đều, vào hỗn
to a mixture of 37.4 g. of m-bromo anisol hợp gồm 37,4 g m-bromo anisol và 160 ml
and 160 ml of absolute tetrahydrofuran at tetrahydrofuran tuyệt đối với tốc độ sao
such a rate that the reaction mixture boils cho hỗn hợp phản ứng sôi nhẹ do nhiệt
gently due to the heat produced by the sinh ra từ phản ứng bắt đầu ngay lập tức.
immediately starting reaction.

26
Step 2: Thereafter, the reaction mixture is Bước 2: Sau đó, hỗn hợp phản ứng được
refluxed, while being stirred, until the đun sôi trở lại, trong khi khuấy, cho đến
magnesium is completely dissolved. The khi magiê tan hoàn toàn. Hỗn hợp phản
reaction mixture is cooled to between 0° ứng được làm lạnh đến nhiệt độ từ 0° C
C. and -10 C.and a mixture of 23.25 g of đến -10° C và thêm hỗn hợp gồm 23,25 g
2-dimethylamino methyl cyclohexanone 2-dimethylamino methyl cyclohexanone
and 45 ml. of absolute tetrahydrofuran is và 45 ml tetrahydrofuran tuyệt đối từng
added dropwise thereto. giọt vào đó.

Step 3: The mixture is stirred at room Bước 3: Khuấy hỗn hợp ở nhiệt độ phòng
temperature for about 4 hours and is then trong khoảng 4 giờ và sau đó từ từ đổ vào
poured slowly, while stirring, into a hỗn hợp gồm 25 g amoni clorua, 50 ml
mixture of 25 g. of ammonium chloride, nước và 50 g đá trong khi khuấy. Các lớp
50 ml. of water, and 50 g. of ice. The được hình thành do đó được tách ra và lớp
layers formed thereby are separated and nước được chiết xuất hai lần với 50 ml ete
the aqueous layer is extracted twice with mỗi lớp. Các lớp dung môi hữu cơ được
50 ml. of ether each. The organic solvent kết hợp, sấy khô trên natri sulfat và các
layers are combined, dried over sodium dung môi được làm bay hơi. Cặn được
sulfate, and the solvents are evaporated. chưng cất, nhờ đó thu được 1 - (m-
The residue is distilled, whereby 1 - (m- methoxy phenyl) - 2 - dimethyl amino
methoxy phenyl) - 2 - dimethyl amino methyl cyclohexanol-(1) với năng suất
methyl cyclohexanol-(1) is obtained in a bằng 78,6% so với lí thuyết.
yield of 78.6% of the theoretical yield.

II. Method 1 (Start with the racemic mixture)

 Procedure

27
 O O
O
CH3 CH3 1. Solvent CH3
2. Concentrated HCl
3. Water Cl-
OH OH OH H
+
CH3 CH3 CH3
N N N+

CH3 CH3 CH3

Trans Tramadol Base Cis Tramadol Base

English Vietnamese

Step 1: An oily mixture of cis and trans Bước 1: Hỗn hợp dầu của bazơ tramadol
tramadol base (100g; trans 82.0%, cis = cis và trans (100g; trans 82,0%, cis =
17.0%) was acidified with concentrated 17,0%) được axit hóa bằng axit clohydric
hydrochloric acid (33g) at room đậm đặc (33g) ở nhiệt độ phòng trong khi
temperature under stirring to pH 3 to 5. khuấy đến độ pH từ 3 đến 5.

Step 2: The water content of the reaction Bước 2: Hàm lượng nước trong hỗn hợp
mixture was adjusted to 3-5%; if less were phản ứng được điều chỉnh đến 3-5%; nếu
present, a catalytic amount of water was hàm lượng nước thấp hơn, thêm một
added into the reaction mixture to achieve lượng nước xúc tác vào hỗn hợp phản ứng
the required moisture content (specified in để đạt được hàm lượng ẩm cần thiết (được
Table - 1). nêu trong Bảng - 1).

Step 3: The thick reaction mass was stirred Bước 3: Khuấy khối phản ứng đặc ở nhiệt
at 40-50°C for 30 min. and water distilled độ 40-50°C trong 30 phút và chưng cất
out under vacuum to produce solid cis and nước trong điều kiện chân không để tạo ra
trans tramadol hydrochloride. tramadol hydrochloride dạng rắn cis và
trans.

Step 4: Solid cis and trans tramadol Bước 4: Hydrochloride cis và trans
hydrochloride was dissolved in 200mL or tramadol rắn được hòa tan trong 200mL
300mL of solvent (as specified in Table - hoặc 300mL dung môi (như được chỉ định
1) at 40-50°C. The reaction mixture was trong Bảng - 1) ở 40-50°C. Hỗn hợp phản
maintained at room temperature for 6 ứng được duy trì ở nhiệt độ phòng trong 6
28
hours and then cooled at 0-5°C for 3 hours giờ và sau đó làm lạnh ở 0-5°C trong 3 giờ

Step 5: The resulting white solid material Bước 5: Vật liệu rắn màu trắng thu được
was filtered and dried to constant weight được lọc và sấy khô đến khối lượng không
at 50-55°C under vacuum to produce trans đổi ở 50-55°C trong điều kiện chân không
tramadol hydrochloride (specified in Table để tạo ra trans tramadol hydrochloride
- 1 under "yield"). The purity was (được chỉ định trong Bảng - 1 ở mục
determined by HPLC as specified in Table "Hiệu suất"). Độ tinh khiết được xác định
- 1, below. bằng HPLC như được chỉ định trong Bảng
- 1 bên dưới.

Ex Solvent used Qty. of Water HPLC Analysis

No. solvent Content
used (ml) (%) Trans (%) Cis (%) Total
other
impurity
1 Ethylacohol 200 4.20 99.73 0.20 0.07
2 Isopropylacohol 200 3.15 99.47 0.41 0.12
(IPA)
3 n-Butanol 200 3.38 99.91 0.08 0.01
4 Methoxyelthanol 200 3.00 99.00 0.90 0.10
5 Acetone 200 5.00 98.71 0.75 0.54
6 Methylethylketone 200 3.12 99.26 0.18 0.56
(MEK)
7 Acetonitrile 200 3.20 98.20 1.34 0.46
8 Tetrahydrofuran 200 3.70 99.58 0.40 0.02
9 Toluene: IPA 300 3.12 99.63 0.22 0.15
10 Toluene: MEK 200 4.12 98.83 0.77 0.40
III. Method 2 (Transfer through Tramadol Monohydrate)
 Procedure
29
 O O O O
CH3 CH3 CH3 CH3
1) Solvent
Water 2) Conc. HCl
pH = 7.5-8.5 3) Water Cl-
OH + OH .H2O OH H
OH
CH3 CH3 CH3
N N N
CH3 N+
CH3 CH3 CH3 CH3

Cis Tramadol Base Trans Tramadol Monohydrate

Trans Tramadol Base Trans Tramadol HCl

English Vietnamese

Step 1: 100g of an isomeric mixture of cis Bước 1: Pha loãng 100g hỗn hợp đồng
and trans tramadol base was diluted with phân của tramadol dạng cis và trans với
1000mL demineralized water at room 1000mL nước khử khoáng ở nhiệt độ
temperature. phòng.

Step 2: The mixture was stirred for 5 min. Bước 2: Khuấy hỗn hợp trong 5 phút và
and 1% diluted acid (Hydrochloric Acid) thêm rất chậm 1% axit loãng (axit
added very slowly, dropwise, to pH 7.5 to clohydric) từng giọt đến khi pH đạt 7,5
8.5. The reaction mixture was cooled and đến 8,5. Hỗn hợp phản ứng được làm
maintained for 3 hours at ambient nguội và duy trì trong 3 giờ ở nhiệt độ
temperature. phòng.

Step 3: The white solid was filtered and Bước 3: Chất rắn màu trắng được lọc và
dried to constant weight at room sấy khô đến khối lượng không đổi ở nhiệt
temperature under vacuum to produce độ phòng trong điều kiện chân không để
trans tramadol base monohydrate. tạo ra trans tramadol monohydrat.

Step 4: The purity of the trans tramadol Bước 4: Độ tinh khiết của trans tramadol
base monohydrate was determined by base monohydrate được xác định bằng
HPLC (98.66%) HPLC (98,66%)

IV. Method 3 (Tramadol Hydrochloride Lab Synthesis)

30
 O
O O CH3
O H O

Cl-
N OH H
Br 1. HCl / Solvent
N OH CH3
N+
CH3
N 2. Crystallize
HO(CH2O)nH THF / Mg CH3
EtOH / HCl CH3
Trans Tramadol HCl

 Procedure
- The preparation of Tramadol Hydrochloride in lab experiences through three main
steps: Mannich reaction, Grignard reaction and crystallization with HCl/ Solvent
1. Mannich reaction

English Vietnamese

Step 1: To a clean and dry 100 mL round- Bước 1: Cho 50 mmol cyclohexanone, 25
bottom flask, add 50 mmol mmol paraformaldehyde và 25 mmol amin
cyclohexanone, 25 mmol đã chọn vào bình tròn đáy tròn dung tích
paraformaldehyde, and 25 mmol of your 100 mL sạch và khô.
chosen amine.

Step 2: Use acetic acid (conc.) as solvent Bước 2: Sử dụng axit axetic (conc.) làm
and drop a stir bar in before refluxing for dung môi và thả thanh khuấy vào trước
~2-3 hours. Follow the reaction by TLC. khi đun sôi lại trong khoảng 2-3 giờ. Theo
Allow the reaction to stir at room dõi phản ứng bằng TLC. Để phản ứng
temperature overnight in the hood. After khuấy ở nhiệt độ phòng qua đêm trong tủ
taking a TLC of the crude reaction hút. Sau khi lấy TLC của hỗn hợp phản
mixture, move the RBF from the reflux ứng thô, chuyển RBF từ thiết lập đun sôi
setup to a distillation setup, and distill the lại sang thiết lập chưng cất và chưng cất
acetic acid. axit axetic.

Step 3: Use acetone and hydrochloric acid Bước 3: Sử dụng acetone và axit clohydric
to produce the HCl salt of your compound. để tạo ra muối HCl của hợp chất của bạn.
If recrystallization does not occur, a two- Nếu không xảy ra quá trình kết tinh lại, có
solvent system such as methanol/diethyl thể cần đến hệ thống hai dung môi như
ether may be necessary. Filter the white to methanol/diethyl ether. Lọc các tinh thể
31
off-white crystals. màu trắng đến trắng ngà.

2. Grignard Reaction (Create Racemic Mixture)

English Vietnamese

Step 1: Before performing the reaction Bước 1: Trước khi thực hiện phản ứng,
itself, you will need to generate the bạn sẽ cần tạo ra thuốc thử organometallic
organometallic reagent to be used in the để sử dụng trong phản ứng. Thêm THF
reaction. Add freshly distilled THF to the mới chưng cất vào khối lượng magiê theo
stoichiometric mass of magnesium needed tỷ lệ thành phần cần thiết cho phản ứng (tỷ
for the reaction (stoichiometric ratio = 3 lệ thành phần = 3 phần Mg : 1 phần bazơ
parts Mg : 1 part Mannich base) in an Mannich) trong bình ngưng tụ RBF sấy
oven-dried RBF and reflux condenser khô trong lò và bình ngưng tụ hồi lưu
(sealed with a rubber septum.) (được bịt kín bằng vách ngăn cao su).

Step 2: Reflux the THF/Mg mixture under Bước 2: Đun sôi hỗn hợp THF/Mg dưới
a nitrogen atmosphere until the bầu khí nitơ cho đến khi magie tan hết, sau
magnesium dissolves, then add the organic đó thêm thành phần hữu cơ của hợp chất
component of your organometallic (also in organometallic (cũng theo tỷ lệ thành phần
a 3:1 stoichiometric ratio with the hóa học 3:1 với chất nền Mannich) từ từ
Mannich base) slowly over the course of
32
20-30 minutes. trong khoảng 20-30 phút.

Step 3: While refluxing your Grignard Bước 3: Trong khi đun sôi phản ứng
reaction, you will prepare your Mannich Grignard, bạn sẽ chuẩn bị sản phẩm
product for addition. Add toluene and Mannich để thêm vào. Thêm toluene và
potassium hydroxide to your Mannich kali hydroxit vào sản phẩm Mannich và
product and extract the organic layer three chiết xuất lớp hữu cơ ba lần bằng KOH
times with KOH in a separatory funnel. trong phễu chiết.

Step 4: Dry the organic layer over sodium Bước 4: Làm khô lớp hữu cơ trên natri
or magnesium sulfate, filter the drying hoặc magie sunfat, lọc chất làm khô và thu
agent, and collect the remaining organic thập lớp hữu cơ còn lại trong bình. Sau khi
layer in a flask. After the magnesium has magie đã hòa tan trong bình phản ứng của
dissolved in your reaction flask, put the bạn, hãy đặt phản ứng trên đá, hút lớp hữu
reaction on ice, draw the organic layer cơ bằng bazơ tự do Mannich của bạn vào
with your Mannich free base into a một ống tiêm và từ từ thêm vào bình phản
syringe, and add it slowly to the reaction ứng theo từng lượng nhỏ.
vessel in small increments.

Step 5: Once all of your Mannich base has Bước 5: Sau khi đã thêm toàn bộ bazơ
been added, stir the reaction for an Mannich, khuấy phản ứng trong XX giờ
additional XX hours. Quench the reaction nữa. Làm nguội phản ứng bằng dung dịch
with a saturated solution of aqueous amoni clorua bão hòa, loại bỏ lớp nước
ammonium chloride, remove the aqueous trong phễu tách và chưng cất lớp hữu cơ
layer in a separatory funnel, and distill the để loại bỏ dung môi. Kết tinh sản phẩm
organic layer to remove solvent. của bạn theo cùng cách như trong phản
Crystallize your product in the same ứng Mannich.
manner as in the Mannich reaction.

3. Purification of Tramadol by Recrystallization of the Hydrochloride from

Acetonitrile

English Vietnamese
33
Step 1: A 21 mL solution of 1.8 g of HCl Bước 1: Thêm 21 mL dung dịch gồm 1,8 g
gas (bubbled at 5° C.) in acetonitrile khí HCl (sục ở 5° C) trong acetonitril (thu
(yielding a 2.0 M solution), was added to được dung dịch 2,0 M) vào 10,2 g sản
10.2g of Grignard product (90/10 of phẩm Grignard (90/10 trans/cis) trong 30
trans/cis) in 30 mL of toluene and stirred mL toluen và khuấy cơ học trong 3 giờ.
mechanically for 3 hours.

Step 2: The mixture was filtered and Bước 2: Hỗn hợp được lọc và rửa bằng
washed with toluene. Drying in vacuo toluen. Sấy khô trong chân không thu
yielded 11.2 g (96% recovery). The được 11,2 g (tỷ lệ thu hồi 96%).
resulting hydrochloride had a trans/cis Hydrochloride thu được có tỷ lệ trans/cis
ratio of 92:8, essentially the same trans:cis là 92:8, về cơ bản là tỷ lệ trans:cis giống
ratio as did the 10.2 g of Grignard product như 10,2 g sản phẩm Grignard

Step 3: Recrystallization from 90 mL of Bước 3: Kết tinh lại từ 90 mL acetonitril

acetonitrile yielded 8.83g, which was thu được 8,83g, tương ứng với 96,6/3,4
96.6/3.4 of trans/cis by HPLC. Of this, 8.6 trans/cis bằng HPLC. Trong đó, 8,6 g
g was recrystallized from 75 mL of được kết tinh lại từ 75 mL acetonitril để
acetonitrile to give 7.44 g, trans/cis ratio of thu được 7,44 g, tỷ lệ trans/cis là 99,6/0,4.
99.6/0.4.

34
 PART III: TECHNOLOGICAL SCHEME OF
TRAMADOL
I. Block diagram
II. Pipe & Instrument Diagram (P&ID)
III. P&ID explanation
35
 IV. Properties of the main materials used in P&ID

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40
 CONCLUSION
From this essay, our group not only gains knowledge in the specialized field of medicinal
chemistry and technological scheme, but we also gain new knowledge about tramadol –
an essential active pharmaceutical ingredient in our life. After finishing the essay, we have
developed our logical reasoning in analyzing and reflecting on various problems to be
able to develop more intensively in the future. In acknowledgement, our group would like
to thank Dr. Nguyen Thi Thuy My for the incredible learning opportunities she had made

41
possible for us in the limit of only one semester with her class General Pharmaceutical
Chemistry CH4510E.

42