Abstract

The aim of present investigation was undertaken with the objective of formulating buoyant tablet of Tolperisone HCl. Tolperisone HCl is a skeletal muscle relaxant. Drug is more stable in acidic medium (pH < 4.5), and in alkaline medium (pH 4 to 7) tolperisone breaks downinto4-MMPPO[2methyl-1-(4methylphenyl)-propanone] and piperidine. Thus, the patient is exposed to an uncontrollable quantity of genotoxic agent 4-MMPPO. 32 full factorial designs were used for optimization of formulation variable. The drug: polymer ratio (X1) and concentration of sodium bicarbonate (X2) were selected as independent variables, while time required for drug release 50% (t50), time required for drug release 90% (t90), drug release at 12hr (Q12), Floating lag time, release rate constant (k) and diffusion exponent (n) were selected as a dependent variable. Prepared tablets were evaluated for pre compression and post compression parameters. The release mechanisms were explored and explained by applying zero order, first order, and Higuchi and Korsmeyer equations. Regression analysis and analysis of variance were performed for dependent variables. Optimized formulation (B6) showed 99.27% drug release at the end of 24 hrs and maximum similarity factor (f2= 74.41) and minimum dissimilarity factor (f1= 4.24) with theoretical release profile of Tolperisone HCl. Optimized formulation followed by anomalous nonFickian release mechanism and found to be stable after 21 days at accelerated condition.

Keywords

Introduction

The  gastro  retentive  drug  delivery  system can be retained in the stomach and assist in improving the  oral  control  delivery of  drug that   have   an   absorption   window   in   a particular region of the gastrointestinal tract. This system helps in continuously releasing the       drug,       thus       ensuring       optimal bioavailability.  The  matrix  tablet  composed of  drug  and  the  release  retarding  material offers the simplest approach in designing of control   release   system.   Skeletal   muscle relaxants  are  drug  that  acts  peripherally  at neuromuscular   junction   or   muscle   fibre itself or centrally in the cerebrospinal axis to reduce   the   muscle   tone.   Centrally  acting muscle relaxants are used mainly for painful muscle    spasm    and    spastic    neurological condition     Tolperisone    HCl    causes muscle  relaxation  by  its  action  on  central nervous  system.  It  also  leads  to  membrane stabilizer  and  has  analgesic  activity. 

MATERIALS

Tolperisone. Xanthan,  Gum,  Guar  Gum  and Dibasic  calcium  phosphate  (DCP).Sodium bicarbonate, Magnesium stearate, Talc.

METHOD-

Preparation  of  Tolperisone  HCl  Buoyant Tablets

Direct Compression-

Direct     compression     was     followed     to manufacture   the   gas   generating   buoyant tablets    of    Tolperisone    HCl.    All    the ingredients   were   accurately   weighed   and

pass through sieve no. 60 before using into formulation.   Compressed   on   10   station rotary  tablet  machine  using  caplet  punch. The   tablets   were   compressed   to   obtain hardness in a range of 6-7 Kg/cm2.

Evaluation of Powder Blend and Tablets Drug-Excipients Compatibility study.

Fourier transform infrared spectroscopy has been    used    to    study    the    physical    and chemical  interaction  between  drug  and  the excipients  used.  Fourier  transform  infrared (FTIR) spectra of         Tolperisone hydrochloride, Xanthan Gum were recorded using KBr mixing method.

Loose Bulk Density

Weigh accurately 5 gm of powder blend, and transferred  in  100  ml  graduated   cylinder. Carefully  level  the  powder  blend  without tcompacting, and read the unsettled apparent volume  (V0).  Calculate  the  apparent  bulk density in gm/ml by the following formula: Bulk Density = Mass/ apparent volume Tapped

Bulk Density

Weigh accurately 5 gm of powder blend, and transferred  in  100  ml  graduated  cylinder. Then     mechanically     tap     the     cylinder containing the sample by raising the cylinder and allowing it to drop under its own weight using mechanically tapped density tester that provides  a  fixed  drop  of  14±2  mm  at  a nominal  rate  of  300  drops  per  minute.  Tap the   cylinder   for   500   times   initially   and measure   the   tapped   volume   (V1)   to   the nearest graduated units, repeat the tapping an additional 750 times and measure the tapped volume (V2) to the nearest graduated units, if the  difference  between  the  two  volumes  is less  than  2%  then  final  the  volume  (V2). Calculate  the  tapped  bulk  density  in  gm/ml by the following formula:

Tapped Density = Mass/ tapped volume

Carr’s Index

The  Compressibility  Index  of  the  powder blend      was      determined      by      Carr’s compressibility  index.  It  is  a  simple  test  to evaluate   the   Bulk   Density   and   Tapped Density  of  a  powder  blend  and  the  rate  at which   it   packed   down.   The   formula   for Carr’s Index is as below:

Carr’s    Index    =    Tapped    Density-Bulk

Density×100/ Tapped Density

Hausner’s Ratio

The   Hausner’s   ratio   is   a   number   that   is correlated  to  the  flowability  of  a  powder blend  material. 

Hausner’s  Ratio  =  Tapped Density/Bulk Density.

Angle of Repose

The angle of repose of powder blend powder was  determined  by  the  funnel  method.  The diameter   of   the   powder   blend   cone   was measured and angle of repose was calculated using  the  following  Equ.  Angle  of  Repose.

() = tan-1h/r

Where, h =Height of the powder blend cone r =Radius of the powder blend cone.

Weight Variation Test

The   20   tablets   were   selected   at   random, weighed    and    the    average    weight    was calculated.   Not   more   than   two   of   the individual  weights  should  deviate  from  the average weight by more than 10%

Fribility

For   each   formulation,   pre   weighed   tablet sample (10 tablets) were placed in the Roche friabilator  which  is  then  operated  for  100 revolutions.  The  tablets  were  deducted  and re-weighed. Conventional compressed tablets that  loose  <0>

Hardness

Hardness   of   tablet   was   determined   using Monsanto hardness tester. Content Uniformity The20tabletswerecrushedandthepowderequiv alentof100mg    of    drug    was    transferred to100ml  of  0.1N  HC1  in  volumetric  flask. The  solution  was  analyzed  at  261  nm  using double    beam    UV-Vis    spectrophotometer after  suitable  dilution.  The  content  of  drug was calculated from calibration curve.

In-vitro buoyancy study

The In-vitro buoyancy was characterized by floating  lag  time  (FLT)  and  total  floating time  (TFT).  The  test  was  performed  using USP24  type  II  paddle  apparatus  using  900 ml of 0.1 N HC1 at 50 rpm at 37±0.5°C. The time required for tablet  to rise to surface of dissolution medium and duration of time the tablet constantly float on dissolution medium were noted as FLT and TFT, respectively.

In vitro drug release study

The  In  vitro  drug  release  was  performed using  USP-24  type  II  paddle  apparatus  in

900 ml of 0.1N HC1 at 50 rpm at 37 ± 0.5°C. The    samples    were    withdrawn    at    pre- determined time intervals for period of 24 hr and  replaced  with  the  fresh  medium.  The samples    were    filtered    through    0.45µm membrane     filter     suitably     diluted     and analyzed at 261 nm using double beam UV- Vis  spectrophotometer.  The  content  of  drug was calculated using calibration curve. Kinetic model for release data The  drug  released  data  of  all  batches  were fitted  with  desired  kinetic  model  such  as Zero   order   kinetic,   First   order   kinetic, Higuchi   model   and   Korse   meyer   peppas model  to  ascertain  the  drug  release.  The Zero order and First order drug release. The Zero   order   and   First   order   drug   release explain  the  drug  release  depend  on  drug concentration   or   not.   The   Korse   meyer peppas model described the method of drug release  and  Higuchi  model  described  the diffusional drug release.

Zero order =   Q1 = Q0  + K0t

First order =   Qt = Q   -K1t

Higuchi model = m= (100-q) ×t1/2

Kinetic model for release data

The  drug  released  data  of  all  batches  were fitted  with  desired  kinetic  model  such  as Zero   order   kinetic,   First   order   kinetic, Higuchi   model   and   Korse   meyer   peppas model  to  ascertain  the  drug  release.  The Zero order and First order drug release. The Zero   order   and   First   order   drug   release explain  the  drug  release  depend  on  drug concentration   or   not.   The   Korse   meyer peppas model described the method of drug release  and  Higuchi  model  described  the diffusional drug release.

Zero order =   Q1 = Q0  + K0t

First order =   Qt = Q   -K1t

Higuchi model = m= (100-q) ×t1/2.

Dissimilarity factor

The  dissimilarity  factor  (f1)  calculates  the percent difference between the two curves at each time point and is a measurement of the relative  error  between  the  two  curves.  The values should lie between 0-15.For curves to be  considered  similar  f1   values  should  be close to 0.

RESULTS AND DISCUSSION

the drug and polymer were compatible with each   other.The   powder   mixture   used   for tablet  preparation  were  evaluated  for  pre- compression   parameter   like   bulk   density, tapped density, Hausner’s ratio,Carr’s index, andangle  of  repose. Tolperisone    HCl    floating    tablets    were prepared    and    evaluated    for    hardness, friability  and  drug  content  uniformity.   From  the dissolution profile it was observed that there was     significant     outcome     of     different polymers and polymer load on drug release. All  batches  exhibit  initial  burst  release  of drug  due  to  rapid  dissolution  of  drug  from tablet surfaceThe kinetics of the dissolution data were well fitted to zero order, Higuchi model   and   Korsmeyer-Peppas   model   as evident  from  regression  coefficients .

CONCLUSION

The   present   investigation   was   aimed   to formulate   and   evaluate   floating  tablet   of Tolperisone  HCl  were  prepared  by  direct compression    method    based    on    natural polymers   (e.g.   Xanthan   Gum   and   Guar Gum)   as   matrix   forming   material   and different       concentration       of       sodium bicarbonate  as  gas  generating  agents.FTIR spectroscopy   indicates   that   the   drug   is compatible     with     the     polymer.     The concentration  of  Xanthan  Gum  and  sodium bicarbonate were successfully optimized  by using   32    factorial   design.   From   the   32 factorial   design   and    different    graphical representation, it was finalized that batch B6 was  found  to  be  optimized  batch  having drug  release  up  to  24  hr.  More  ever,  the dissolution  profile  of  optimized  batch  B6 was found to be similar with theoretical drug release profile having similarity factor more than  50  (f2=74.41)  and  dissimilarity  factor less  than  15  (f1=4.24)  which  reflects  the feasibility  of  the  optimization  procedure  in successful  development  of  floating  matrix tablet  containing  Tolperisone  HCl  by using Xanthan    Gum.

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