Alkaloids introduction

For B.PHARM, 5th Semester

4. HISTORY
most notorious poisons in the history
of civilization.
used by humanity for thousands of
years.
The first civilizations to use them
were probably the ancientSumerians
and Egyptians
it was called a vegetable alkali.

5. •Thename“alkaloid”comesfromtheArabicword
forash“al-qali”.
•TermalkaloidwascoinedbyMeissner,aGerman
pharmacist(1819).
•Derosne(Frenchchemist)isolatedNarcotine
(1803).
•Serturner(1803)isolatedmorphinefromopium

6. ???????
NO DEFINITE DEFINITION

7. “Naturallyoccurring
nitrogenoussubstance
whichisisolatedfrom
plantsandreactslike
bases”

8. Konigs(1880):-“Naturally occurring organic bases which contains a Pyridine
ring”.

9. Albert Ladenburg“Alkaloid are natural plant compound that have basic
character and contains at least one nitrogen atom in heterocyclic ring”.

10. MUSCOPYRIDINE

11. “Basicnitrogenouscompound,
containsoneormorenitrogen
inheterocyclicringsystem
havingmarkedphysiological
actiononhumanandanimals
whenuseinsmallquantities”.

12. MORPHINE

13. DEVIATION FROM
ABOVE MOST ACCEPTED
DEFINITION:

14. COLCHICINE RICININE

15. Ephedrine

17. CAFFIENE

18. DEFINATION
Thesearethesynthesizedornaturally
occurringacidicorBasic(alkali)
nitrogenouscompoundscontainingone
ormorenitrogeninheterocyclicring
system&sometimeobtained/not
obtainedfromaminoacidasa
precursorhavingmarkedphysiological
actiononhumanandanimalswhenuse
insmallquantities.

19. Some facts
1806–PharmacyassistantFriedrichWilhelm
Serturnerisolatedmorphinefrompoppyseeds
Socratesdiedwhenhewasforcedtodrinkextract
ofhemlockcontainingconiine.
Nicotine(tobacco)isusedasverypotent
insecticideforfumigatinggreenhouses.
Cleopatrausedextractscontainingatropineto
dilateherpupilinordertoappearmore
attractive;atropineinlowdosesdilatespupilsof
theeye.

20. a)Ranunculaceae : Aconitine (aconite).
b)Leguminoceae :physostigmine (physostigma)
.
c)Loganiaceae: strychnine and Brucine (Nux-
vomica).
d)Papavaraceae :Morphine, Codiene, Thebaine
(Opium).
e)Solanaceae : Belladona.

21. f)Berberidaceae ; Berberine (Berberis).
g)Rubiaceae: Quinine and Quinidine (Cinchona).
h)Apocyanaceae : Reserpine (Rauwolfia) ,
Vincristine and Vinblastine (Vinca).
i)Liliaceae : Veriterine (Veratrum).
j)Clavicipitaceae : Ergotamine and Ergometrine (Ergot).

22. GENERAL
PROPERTIES OF
ALKALOIDS

23. a) Most alkaloids are crystalline solid, but
some are liquide.g.
Volatile; --Nicotine,Coniine & Spartine.

24. Non-Volatile:-Pilocarpine , Hyoscine

25. b) Majority of alkaloids are colorless but
some are colored, e.g
Colchicine and Berberine are Yellow.
Canadineis Orange.

26. C) SOLUBILITY :-Difference in solubility used as a
base for their isolation and purification from non-
alkaloidal bases.
The following can be mentioned :-
a) Both alkaloidal base and their salts are soluble in
alcohol.
b) Generally bases are soluble in organic solvents
and alkaloidal salts are soluble in water.

27. EXCEPTION :
A) Bases soluble in water:-Caffeine, Codeine, Ephedrine.
B) Bases in-soluble or sparingly soluble in certain organic solvent :-
Morphine in ether(1:5000),
C) Salt insoluble in water :---Quinine sulphate
quinine sulphate is only soluble in water to the extent of 1:1000 ,
although quinine hydrochloride is soluble 1 in less than l part of water
D) Salts soluble in organic solvents :-Lobelline and Apoatropine
HCl are soluble in chloroform.

28. 1) Salt formation:--Due to their basic character alkaloid reacts
with acid to form salt
--strong bases form salt with very weak acid.
--weak bases forms salt with strong acid
--very weak bases form unstable salts, e.g
caffeine , Narcotine , piperine.

29. 2) Amphoteric Alkaloids :-Can form salts with both
acid and alkali.
e. g. phenolic group :--Morphine, Psychotrine,
Cephaline.

30. Carboxylic group:--Narciene(a narcotic alkaloid that
occurs in opium).

31. 3).Effect of heat:
Alkaloids are decomposed by heat, except Strychnine
and caffeine(Sublimable).
4). Effect of light and Oxygen :
Decomposed whenallowed to stand at a temperature
above 70°C for long time.
Light Sensitivity varies in degree with different alkaloids.
Decomposition occur rapidly and easily when an alkaloid is
in solution than when it is in dry form.
Most tertiary amine alkaloids are easily transformed to the
N-oxides.

32. 5) Reaction with acids:
•Salt formation.
•Dil. acids hydrolyze Ester Alkaloids e.g.
Atropine
•Conc. acids may cause :
Dehydration: Atropine → Apoatropine
Morphine → Apomorphine
Demethoxylation: e.g. Codeine

33. 6.Effect of alkalis.
•Weak alkalis liberate most alkaloids from their salts
e.g. NH3
•Strong alkalis: such as aqueous NaOHand KOHform
salts with phenolic alkaloids.
•Hot alkalis: results hydrolysis of ester alkaloids e.g.
atropine, cocaine and physostigmine and cleavage of
lactone ring, if present, to produce the corresponding
acid, e.g. pilocarpine is transformed to pilocarpic acid.

34. 7).BASICITY OF ALKALOIDS :--The basicity of alkaloid
is due to presence of a lone pair of electron on
nitrogen atom.
--the basicity increasedif the adjacent group is
electron releasing like alkali .
--the basicity decreases if the adjacent group is
electron withdrawing like carbonyl and amide
group.
R2-NH > R-NH2 > R3-N

35. According to basicity Alkaloids are
classified into:
a). Weak bases e.g. Caffeine
b). Strong bases e.g. Atropine
c). Amphoteric *Phenolic Alkaloids e.g. Morphine
*Alkaloids with Carboxylic groups e.g. Narceine
d). Neutral alkaloids e.g. Colchicine

36. Differenttypesofamines
presentinAlkaloids

37. •Primary amines (R-NH2 ) e.g. Norephedrine

38. •Secondary amines (R2-NH) e.g. Ephedrine

39. •Tertiary amines (R3-N), e.g. Atropine

40. •Quaternary ammonium salts (R4-N ), e.g.
d-Tubocurarine
Note :--Unsaturation decreases the basicity e.g. piperidine is more
basic than pyridine alkaloid.

41. BIOSYNTHESIS OF ALKALOIDS :
It is well established that alkaloids are derived
from Amino acid.
Alkaloids-12000 structures known.
The most common ones are:phenylalanine,
tyrosine, lysine, tryptophan, ornithine,
histidineand anthranilic acid.

43. Biosynthesis of Atropine from Ornithine(Atropabelladonna)

44. Biosynthesis of nicotine from Ornithine(Nicotianatabacum)

45. Biosynthesis of Cocaine from Ornithine(Papaversomniferum)

46. EXTRACTION OF
ALKALOIDS

47. Any method will be a good technique, if it
will accelerate:
1.Wetting of the surface of the herb particles.
2. Permeability of cell walls.
3. Rate of dissolution of cell contents in the
solvent.
4. Outward diffusion of the solution.

48. 1. It should be non-toxic and selective.
2. It should not cause the extract to complex or dissociate.
3. It should be preservative in action.
4. It should promote rapid physiologic absorption of the
extract.
5. It should be easily evaporated at low heat.
NOTE:-Alcohol (Methanol, Ethanol) will meet all above criteria.

49. 1.Organic water-immiscible solvent:-Chloroform, Benzene, Ether, Ethylene
chloride.
Use:-They are use to extract most of alkaloid except
quarternary bases .
2.Organic water-miscible solvent:--Ethyl and Methyl alcohol.
Use:-extractbothalkaloidandtheirsalts.
3.Aqueousacid:--Cheapbutnotusedbecauseitalsoextractimpuritieslike
sugar,mucilage,tannins,coloringmatter.
Ex:HCl(Aq.),hydrosulfuricacid(H2S),

50. The technique involve the distribution of alkaloidal bases between acid or
aqueous solution and immiscible organic solvent.
Amethodof extraction of alkaloids from plants and animal bodies: the
substance is digested in alcohol and tartaric acid, the fatty and resinous matters
are precipitated with water, the fluid is made alkaline, and the alkaloids are
extracted with ether or chloroform
Jean-Servais, Belgian chemist, 1813-1891.

51. A). stage1:-Powdered material is moistened with water and
mixed with alkali like sodium & potassium carbonate ,
ammonia, lime. Make a paste with water ,dry, repowder.
Concept :-Lime (calcium hydroxide),combines with acid ,
tannins, and other phenolicsubstances and sets free
alkaloids.

52. B).Stage2:--Extract the free alkaloids by hot
continous percolation with chloroform or any other
organic solvents.
Concept :-The free alkaloids dissolve together with other
substances soluble in solvent.
C).Stage3:--Agitate the chloroform soln. with successive portion
of dil.sulphuric acid separating the aqueous layer before adding
the next portion of acid.
Concept :-The alkaloids are converted into alkaloidal sulphates,
which being soluble in water, pass into aqueous layer.

53. D).Stage4:--Makethemixedaqueousliquidalkalinewith
ammonia,collecttheprecipitatethatforms,washwithwater
anddry.
Concept:-Ammoniadecomposesthealkaloidalsulphates
formingammoniumsulphates,solubleinwater,andthefree
alkaloidwhichbeingpracticallyinsolubleinwateris
precipitated.

54. Powdered drug
Containing alkaloidal salts
Free alkaloids
Total extracts
Aq. Acid sol
n
Residual organic fraction
(Alkaloidal salts) (pigments, fats & weak bases or
chloroform soluble alkaloids sulphates)
Residual aq. Fractionorganic sol
n
(alkaloidal bases)
crude alkaloidal mixture
Moisten lime, NH
3& render alkaline
with Na
2CO
3,
Defatted if necessary
Exhaust with org. solvent like CHCl
3,
ether
Conc. & shake with acid like dil. H
2SO
4
Make alkaline extract with
immisiciblesolvent
Remove solvent
Method 1

55. Thepowderisextractedwithwatersolubleorganic
solventssuchasMeOHorEtOHwhicharegood
solventsforbothsaltsandfreebases.Andtheresultant
extractissubmittedtosameprocessasthatofmethod1.
ADVANTAGE :--Thismethodrequiresnoalkali,gives
goodpenetrationofdrug,thereforeonly4extractionmay
beneeded,whereasmethod1requires10-12extraction,
i.e.Economical.

57. The powdered material is extracted with water or aqueous alcohol
containing dilute acid.
Disadvatage:--Cheap but not used because it also extract impurities like
sugar, mucilage, tannins, coloring matter.

59. 1. DIRECT CRYSTALLISATION FROM SOLVENT.
2. STEAM DISTILLATION.
3.CHROMATOGRAPHY TECHNIQUES.
4. GRADIENT pH TECHNIQUES.

60. Thoughalkaloidsarebasicinnature,therearevariationsinthe
extentinthebasicityofvariousalkaloidsofthesameplant.
Dependingonthischaracter,thecrudealkaloidalmixtureis
dissolvedin2%tartaricacidsolutionandextractedwith
benzenesothatthefirstfractioncontainsnaturaland/orvery
weaklybasicalkaloids.
pHoftheaqueoussolutionisincreasedgraduallyby0.5
incrementuptopH9,andextractioniscarriedoutateachpH
levelwithorganicsolvent,bythiswayalkaloidswithdifferent
basicityareextracted.
Strongly basic alkaloids are extracted at the end.

62. PRECIPITATION REACTION :
1-Mayer's or Valser's reagent ( Potassium mercuric
iodide)
-giveswhiteoryellowcolormostlyamorphous
precipitateswithalkaloids,exceptthepurinebases,
ephedrine,Colchicineandricinine.
Mercuric chloride -1.36g
Potassium iodide -5.00 g
Water to make-100 ml.

63. 2.Wagner'sreagent(Iodine-potassiumiodide):-It
producesbrownorreddish-brownprecipitateswithallalkaloids.
Iodine -1.3 g
Potassium iodide -2.0 g
Water to make -100 ml
3.Dragendorff's or Kraut’s reagent ( potassium iodide+
bismuth nitrate):-It produces orange-red precipitate which is usually
amorphous.
Bismuth nitrate 8.0 g
Nitric acid 20.5 g
Potassium iodide 27.2 g
Water to 100 ml
4. Hager's reagent (picric acid):-Gives yellow crystalline
precipitate.

64. 5.Tannicacidsolution:(5%w/v).:--givesbuffcolored
ppt.whichissolubleindil.acidorammonia.
6.Ammoniumreineckatesolution:2%solution,
producesprecipitateswithheterocyclicnitrogen
alkaloids,withquaternaryandsometertiaryamines.

65. A). Van-Urkstest:(Para-dimethyl-amino-benzaldehyde +
sulphuricacid)--(for Ergot alkaloids).-gives Bluecolour.
B). Vitali-Morin test:--test for solanceous alkaloids givesviolet
colour when treated with conc. nitric acid and alcoholic KOH.
Mechanism :--These color tests usually depend upondehydration or
oxidation of the alkaloid with a resultant characteristic color.
Merits:--a).very sensitive
b). the intensity of the colour so formed is in linear proportion
to the concentration of the alkaloid

66. U.V. Spectroscopy
IR Spectroscopy
Nuclear Magnetic Resonance Spectroscopy
Mass Spectroscopy
Optical RotatoryDispersion & Circular Dichroism.
Conformational Analysis
X-Ray Diffraction

67. 1.As reservoir of nitrogen.
2. As reservoir for protein synthesis
3.Afford plant safety from herbivorous and insects.
4. Might have possible role as growth regulatory factor.
5. Acting as carrier within plants for transportation of acids.

68. 1. The pharmacological action (biological activity).
2. The chemical structure (heterocyclic or non-heterocyclic type of ring
structure).
3. The biochemical origin (biosynthetic pathway of production in the plant).
4. The taxonomical origin (plant families rich in alkaloids).

69. 1. Analgesics and narcotics: morphine and codeine.
2. CNS stimulants : caffeine and strychnine.
3. Anticancer: vincristine, vinblastine and taxol.
4. Mydriatics: atropine.
5. Anti-asthmatics : ephedrine.
6. Anti-tussives: codeine, vasaka.
7. Expectorants: lobeline.
8. Anti-hypertensive: reserpine.
9. Smooth muscle relaxants: atropine and papaverine
10. Skeletal muscle relaxants: d-tubocurarine.
11. Anthelmintics: pelletierine and arecoline.
12. Antiparasitics/antimalarials: quinine and emetine.

70. Hegnauer's classification
1)."TRUE-alkaloids", which contain nitrogenin the heterocyclic ring
and originate from amino acids
.
examples are atropine, nicotine,
morphine, and Quinine.
All the heterocyclic alkaloids are true alkaloids.
The true alkaloids should have following characters:
a) It should be sufficiently toxic.
b) Should have marked physiological activity.
c) should be basic in nature.
d) Nitrogen should be present in a heterocyclic ring.
e) Should be derived from amino acids.
f) Should occur in plant as salt of organic acids.

71. 2. PROTO-Alkaloids:-These are alkaloids which are derived from
amino acid but do not have nitrogen in a heterocyclic ring. They are
also called as “Biological amine”.
Examples include:-mescaline, adrenalineand ephedrine.
3. PSEUDO-Alkaloids:--They do not derived from amino acid but
having nitrogen in heterocyclic ring .
They do not show many of the typical characters of alkaloids , but
give standard qualitative test for alkaloids.
e.g. steroidal alkaloids:-Conessine
Purine bases :--Caffeiene

72. CHEMICALCLASSIFICATION:--Accordingtochemical
structure,twobroaddivisionmayberecognized:
•Non-heterocyclicalkaloidsthataresometimescalled
''protoalkaloids'orbiologicalamines.
•Heterocyclicalkaloidsthataresub-classifiedinto
differentgroupsaccordingtotheirringstructure.

74. PYRROLE and
PYRROLIDINE
Hygrine , Stachydrine,
Coca species
PYRROLIZIDINE Echimidine,Senecionine,
Seneciphylline,
Symphitine

75. PYRIDINE and
PIPERIDINE
Nicotine , Coniine ,
Arecoline,Lobeline,
Pelletierine
TROPANE Cocaine , atropine ,
Hyoscyamine , Hyoscine

76. QUINOLINE Quinine , quinidine,
Cinchonine,
Cinchonidinecupreine
ISO-QUINOLINE Morphine , Codeine ,
Berberine, Emetine
,Tubocurarine , Papverine,
Narcotine,Narceine,
Emitine, Cephaeline

77. APORPHINE (reduced
Iso-quinoline and
naphthalene)
Boldine
NORLUPINANE Lupanine , sparteine,
Cytisine, Laburnine

78. INDOLE or BENZO-
PYRROLE.
Ergotamine , ergometrine,
Physostigmine,
Reserpine, Strychnine ,
Brucine,Vinblastine
strychnine, Vincristine
IMIDAZOLE Pilocarpine,Isopilocarpine,
Pilosine

79. PURINE
(Pyrimidine+imidazole)
Caffeine , Theobromine,
Theophylline
STEROIDAL (cyclo
pentanoperhydrophenan-
threne)
Conessine , Solanidine,
Protoveratrine, Funtumine

80. NON-HETEROCYCLIC :--
1.Ephedrine
2. Colchicine
3.Erythromycin
4.Mescaline
5. Taxol

81. Quantitative Determination
of Alkaloids

82. 1.Volumetric methods:
Thesearebasedonreactionofalkaloidalbaseswithacids(Acid-
Basetitration).Theyinclude:
a).Aqueoustitration:Thisiscarriedbyeither:
•Directtitrationofthealcoholicsolutionofthealkaloidalresidue
withstandardacid,or
•Backtitrationbydissolvingtheresidueinaknownamountof
standardacidandbacktitrationofresidualacidagainststandard
alkali.
b).Non-aqueoustitration:Thismethodissuitablefor
determinationofweakbasese.g.Caffeine

83. 2. Gravimetric methods:
These methods are recommended for determination of:
i-Veryweakbaseswhichcannotbedeterminedbyvolumetric
methodse.g.caffeineandColchicine.
ii-Mixturesofalkaloidsthatareobtainedfromthesameplantbut
differgreatlyintheirmolecularweighte.g.CinchonaandRauwolfia
alkaloids.
They can be performed by either:
-Direct Weighing of the alkaloidal mixtures
-Precipitation of the total alkaloids and determination of the
weight of the precipitate obtained.

84. The major drawbacksof the gravimetric methods
are:
1-They are insensitive to micro-amounts of alkaloids.
2-They could not be applied in case of thermolabile
and volatile alkaloids.
3-Lipophilic impurities in the residue are calculated
as alkaloids.

85. SOME IMPORTANT CRUDE DRUGS
1. Belladonna
2. Opium
3. Cinchona
4. Ergot
5. Datura