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SPECTROPHOTOMETRIC  DETERMINATION OF  PARACETAMOL USING ZIRCONIUM (IV)  OXIDE  AND AMMONIUM  TRIOXOVANADATE (V)

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ABSTRACT

A simple and sensitive spectrophotometric  method for  the determination of paracetamol was explored, using zirconium(IV)  and vanadium(V)  oxides. The method was based on the oxidation of paracetamol by zirconium(IV) and vanadium(V)   m     alkaline  and  acidic  media  respectively.  The   stoichiometric studies indicated  a mole-ratio of  1: 1   for  the reactions of paracetamol  with both zirconium(IV)  and vanadium(V).  Effects  of other variables like  pH,  temperature and  time   were  determined  and  showed that  the  optimum  conditions  for  the oxidation of paracetamol  by  zr(IV)  were  pH  of 9.0,    temperature of 50C  and at

20  min  yielding  red-   brown p-benzoquinone which absorbed  at a  Amax  of 420nm.  Similarly,  optimum  conditions  for  the  oxidation  of  paracetamol  by  V(V) were pH  of 1.0, temperature of 70C at 8 min, and V(V) reduced to bluish-violet vanadium(II)  ions  which absorbed at a Amax  of 600  nm.  The  Beer-Lambert’s law was obeyed at a  concentration  range of 5.0-40.0 µg/cm3   for  paracetamol  with both  Zr(IV)   and  V(V)   respectively;   and  the  correlation  coefficients   for  both oxidants   were   0.997   and   0.999   respectively.    The    mean   %   recovery   of paracetamol in  dosage form with Zr(IV) was 99.06 %, while  V(V) gave  100.17 %. Hence,  the recovery studies had proved the method to be  accurate,  simple and precise.

CHAPTER ONE

1.0     INTRODUCTION

Spectroscopy involves the  study  of the absorption  and emission of light and   other   radiations   as    related   to   wavelength   of   the   radiation.   Hence, spectroscopy  is  the  branch  of  science  dealing with  the  study  of  interaction between  electromagnetic  radiation  and  matter.  It   is  the  most  powerful  tool available for the study of atomic and molecular structures,  and is  used in  the analysis of wide  range of samples.  Optical spectroscopy includes  the region on

electromagnetic spectrum  between  100  A and 400   m.   Hence,   the  regions of

electromagnetic spectrum  are thus  –  far (or vacuum)  ultraviolet  (10-200 nm), near ultraviolet (200-400  nm),   visible  (400  —  750  nm),   near infrared   (0.75  •

2.2   m), mid  infrared  (2.5 – 50   m),  and far  infra red  (50 – 1000   m)  region.2. 3

1.1      Ultraviolet – visible spectrophotometry (UV-visible  spectrophotometry).

UV – visible spectrophotometry is  one  of  the  most frequently  employed techniques in pharmaceutical analysis. It involves measuring the amount of ultraviolet   or   visible   radiations    absorbed   by    a    substance   in    solution. 4

Instruments  which measure  the ratio,  or function  of ratio,  of the intensity  of two  beams  of light in  the  UV-visible region are  called ultraviolet-visible spectrophotometers. 4

A spectrophotometer consists  of two  instruments,  a  spectrometer and a photometer,  both housed in  one cabinet.  The  spectrometer is  used to  split or resolve  light  in  bands  of  wavelength  before  it  is  fed   to  the  photometer.  To achieve the  designed  resolution,   a  spectrometer  is  specially  equipped  with  a

high   resolution  wavelength  selector known  as  monochromator.  This monochromator can isolate  an  extremely narrow bandwidth  almost comparable to a single  wavelength. 5

In qualitative analysis, organic compounds can be  identified by the use of spectrophotometer; if any  recorded data is available; and quantitative spectrophotometric  analysis  is  used  to   ascertain  the  quantity  of  molecular species absorbing the radiation. 4

Spectrophotometric technique  is  simple,  rapid,  moderately  specific and applicable   to   small  quantities   of   compounds.   The   fundamental   law   that governs the quantitative  spectophotometric analysis  is the Beer-Lambert’s law.

Beers   Law:    it   states   that   the   intensity    of   a    beam   of   parallel

monochromatic   radiation    decreases    exponentially   with   the   number    of absorbing   molecules.   In   other   words,   absorbance   is   proportional   to   the concentration.

Lamberts   law:   It   states   that   the  intensity   of   a   beam   of   parallel

monochromatic  radiation   decreases   exponentially  as    it  passes   through  a medium of homogeneous thickness. A combination of these two  laws yields the Beer – Lambert law.4

Beer  Lamberts   Law:   When  a   beam  of  light  is   passed  through  a

transparent cell  containing a  solution of an  absorbing substance,  reduction of the  intensity  of  light  may  occur.  Mathematically,   Beer  -Lambert’s  law  is expressed as  –

A=3

Where,  A=  absorbance  or optical density

= absorptivity or extinction coefficient

b = path length  of radiation through sample (cm)

c = concentration of solute in  solution (mol/dm3).

Both    b   and       are  constants,    so        is   directly  proportional    to   the concentration,  C.  When C is  in  gm/ 100ml,  then the constant is  called A (1  %,

lcm).  i. .e.,  A=     %           4

Quantification  of  medicinal  substance  using  spectrophotometer  may be carried  out  by  preparing  solution  in  transparent   solvent and  measuring  its absorbance   at   suitable  wavelength.   The  wavelength   normally   selected   is wavelength of maximum absorption  ( (           ) .

The  assay of single   component sample,  which contains  other absorbing substances is  then calculated from  the measured absorbance by  using  one of the three principal  procedures.  However,  these three principal  procedures are • use  of  standard  absorptivity  value,  calibration  graph;  and  single   or  double point   standardization.   In   standard   absorptive  value  method,   the  use   of standard  A(l  %,   1    cm)  is  used  in   order  to  determine  its  absorptivity.  It  is advantageous in  situations where it is  difficult  or expensive to  obtain a  sample of the reference substance.

In  calibration  graph  method,  the absorbances  of a  number of  standard solutions   of   the  reference  substance   at  concentrations   encompassing  the sample  concentrations  are measured  and   a  calibration  graph  is  constructed.

The  concentration  of the analyte in  the sample solution is  read from  the graph as  the concentration corresponding to the absorbance of the solution.

The  single   point standardization  procedure involves the measurement  of the absorbance of a sample solution and of a standard solution of the reference substance.  The   concentration  of  the  substances  in  the  sample  is  calculated from  the proportional relationship that exists between absorbance and concentration.

C          =  (A      x C     ) /Astd

Where   Ces   and  Cst   are  the  concentrations   in   the   sample  and standard  solutions respectively;  and Atest  and Asta  are the absorbances  of the sample and standard solutions respectively4•

For  assay  of  substances  m   multi  component  samples  by spectrophotometer;   the  following    methods  are  being  used  routinely,   which include    –   simultaneous   equation   method,    derivative    spectrophotometric method,  absorbance  ratio method (Q  – Absorbance method),  difference spectrophotometry and solvent extraction method6.

1.2    Paracetamol

Paracetamol has the following   genenc  names -acetaminophen7, paracetamol   or  acetophenum8•    However,   chemical   names  by   which   it   is identified  are:  4-hydroxyacetanilide,  p-hydroxy acetanilide,  p-acetaminophenol, p-acetylaminophenol  or  N-acetyl-p-   aminophenol7.   It   is   a   white,   odorless, crystalline  powder with a  bitter taste.  It  has a  molecular formula  of CsHoNO and a molecular weight of 151. 1 7.  Hence,  its  molar mass is  151. 1 7 g/ mol.

Paracetamol    or   acetaminophen    is    a    widely     used    analgesic   and antipyretic. An antipyretic analgesic is a remedial agent or drug that lowers the temperature   of   the   body    in    pyrexia,    i.e.,   in    situation   when   the   body temperature has been raised above  normal,  (i.e. 37°C).  Hence, paracetamol has been  found  to  be  significantly  effective  in  reducing  fever to  normal  levels   in human 9,

However,  the onset of analgesia is approximately 11 to 29.5 minutes after oral administration  of paracetamol  and its  half-life is  1  —  4 hours\.  Although,  it is  used  to  treat  inflammatory  pain,  it  is  not  generally  classified  as   a  non• steroidal  anti-inflammatory  drug  (NSAID)  because  it  exhibits  only weak  anti• inflammatory  activity.   Paracetamol  is  part  of  the  class  of  drugs  known  as “aniline  analgesics”,  and  it is  the only such  drug  still  in  use today!I.  This   is because the other aniline derivatives -acetanilide and phenacetin (acetophenatidin),  commonly used  as  antipyretic  agents  have been withdrawn completely  from   being  used  due  to   their  numerous  toxic   and  undesirable effects,  such as  skin   manifestations, jaundice,  cardiac irregularities,  hemolytic anemia,  kidney and  liver cancer9•

1.3    The  structure of paracetamol.

Scheme 1.3: 4-hydroxyacetanilide  (paracetamol)

The   mam  mechanism   proposed  is   the  inhibition   of   cyclooxygenase

(COX),  and  recent findings  suggest that it is highly selective for cyclooxygenase-

2  (COX-2)13.  Because  of  its  selectivity  for  COX  -2,  it  does   not  significantly inhibit   the   production   of   the   pro-clotting   thromboxanes13.   While    it   has analgesic  and  antipyretic  properties  comparable  to  those  of  aspirin  or other

non-steroidal  anti-inflammatory drugs,  its peripheral  anti-inflammatory activity is usually limited by  several factors,  one of which is  the high  level  of peroxides present   in    inflammatory   lesion.    However,    in    some     circumstances,    even peripheral  anti-inflammatory  activity comparable to NSAIDS  can be  observed.

However,   Anderson   et  al14   had  reported  the  analgesic  mechanism  of

acetaminophen  (paracetamol),  being that  the  metabolites  of  acetaminophen, e.g.,    N-acetyl-p-benzo-quinone   imine   (NAPQI)    act   on    (transient   receptor potential  sub  family   A,  member  I)   TRPAI  —   receptors  in   the  spinal  cord  to suppress  the signal transduction  from  the  superficial  layers of the dorsal horn, to alleviate pain.

The    COX   family    of   enzymes   is   responsible   for   the   metabolism   of arachidonic  acid   to  prostaglandin  H,  an   unstable  molecule that  is,  in  turn, converted to numerous other pro-inflammatory compounds. Classical anti• inflammatories  such as  the NSAIDs  block this   step.  Only when  appropriately oxidized  is  the  cyclooxygenase,  (COX)  enzyme  highly  active15.  16.  Paracetamol reduces  the  oxidized form of  the  cyclooxygenase (COX)   enzyme preventing  it from forming pro-inflammatory  chemicals!7.18,  This  leads to  a  reduced amount

of  prostaglandin   E in  the  central   nervous  system  (CNS),   thus  lowering the hypothalamic set point in the thermoregulatory center.

Also,  there is  another possibility that paracetamol  blocks cyclooxygenase (as in  aspirin), but in  an  inflammatory environment where the concentration of peroxides is  high,  the high   oxidation state of paracetamol prevents its  actions. Therefore,  paracetamol  has no  direct effect at the site of inflammation,  rather it acts  in   the  central   nervous  system  (CNS)   where  the  environment   is   not

oxidative;  to reduce temperature19.

However,  it should  be  noted that cyclooxygenase (COX),  officially known as    prostaglandin-endoperoxide   synthase    (PTGS)    is    an     enzyme  that    is responsible   for    the   formation   of    important    biological    mediators   called prostanoids, including prostaglandin, prostacyclin and thromboxanes?20. Pharmacological inhibition of cyclooxygenase  (COX)  can provide relief  from  the symptoms of inflammation  and pain20.  At present,  the three COX  iso enzymes are  COX-1,   COX-2,   and COX-3;   and in  humans,   it has  been  discovered  that

acetaminophen   works  by   inhibiting   COX-221.    There   is   much   less  gastric

irritation   associated  with  COX-2   inhibiters,   with  a  decreased  risk  of  peptic ulceration.   However,   the  selectivity  of  COX-2   does   not  seem  to negate  other

side-effects of NSAIDS,  notably an  increased  risk of renal  failure21.

1.5     Metabolism

Paracetamol   is    metabolized   primarily   in    the   liver,    into    non-toxic products. There are three metabolic pathways involved and  they include glucuronidation  which  is  believed  to  account  for  40  %  to  two-thirds  of  the metabolism of paracetamol22;  sulfation (sulfate  conjugation)  which may account for   20-40   %    22;      and   thirdly,    N-hydroxylation   and   rearrangement,    then glutathione  sulfhydryl  (GSH)  conjugation which accounts  for  less than  15  %. The  hepatic  cytochrome P450  enzyme system metabolizes paracetamol,  forming a   minor  yet  significant  alkylating  metabolite  known  as   NAPQI   (N-acetyl-p• benzo-quinone imine) 23.  N-acetyl-p-benzo-quinone imine is then irreversibly conjugated with the sulfhydryl  groups of glutathione23.   All the three pathways yield  final products that are inactive,  non-toxic and eventually excreted by  the kidneys.  In  the third pathway,  however,  the intermediate  product -NAPQI,  is toxic.  N-acetyl-p-benzo-quinone  imine  (NAPQI)  is  primarily responsible for the toxic  effects  of paracetamol.



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