International Journal of Pharmacy Research and Technology

2012, Volume 2, Issue 4, 19-22

ISSN 2250 – 0944 (Online)
ISSN 2250 – 1150 (Print)
Research Article

Formulation and Evaluation of Pulsatile Drug Delivery System of Venlafaxine HCL

Hyma P.*, Tejaswi, Priyanka, Sai Krishna, Abbulu K.

Mallareddy Institute of Pharmaceutical Sciences, Dhulapally, Secunderabad-16, India
*Corresponding author Email: rk_hyma@yahoo.com
Received: 16/10/2012, Revised: 10/11/2012 Accepted: 21/11/2012
ABSTRACT
Pulsatile drug delivery system of Venlafaxine Hydrochloride has been successfully prepared for oral delivery of drug. This is
a type of controlled drug delivery system which shows sustained therapeutic action; with lag time where there is no release
of the drug during initial lag phase of drug administration. Venlafaxine Pulsatile formulations were prepared using sodium
alginate, pectin AS104, and sodium bicarbonate for obtaining required lag time. The prepared beads were examined for
morphology using scanning electron microscopy, tested for entrapment efficiency and later filled into formaldehyde treated
hard gelatin capsules. Drug release studies on the capsules filled with drug loaded beads showed a lag phase of 3hrs, 5hrs
and 6 hrs respectively based on concentration of gelling agent used. Thus time delayed capsule device of Venlafaxine Hcl, a
highly water soluble drug was prepared to avoid dose dumping and achieve time controlled release for chronotherapeutic
delivery of drug.

Key words: Venlafaxine HCL, sodium alginate, Pectin AS104, Entrapment efficiency, Lag time; in vitro drug release.

INTRODUCTION methyl]-p-methoxybenzyl] cyclohexanol hydrochloride. It

Controlled drug delivery systems (CDDS) have
acquired a major role in drug development and
research. The oral CDDS release the drug over
prolonged period of time which maintain drug
concentration in therapeutic window for longer
duration.[1] However there are certain conditions where
controlled release pattern does not suit the drug releas
hence demand the release of drug after a lag time
during which the drug should not be released and the
release pattern is known as pulsatile release.[2] Thus
following lag time; there should be rapid and complete
release of the drug such systems are called pulsatile
drug delivery systems, time controlled systems or
sigmoidal release system.
These types of Novel drug delivery systems have been
developed for chrono pharmacotherapy of diseases that
show circadian rhythm in their pathophysiology; and
targeting drugs to specific sites. Pulsatile devices can be
fabricated either in form of tablets, capsules beads [3].
Floating pulsatile beads are prepared by simple process of
acid-base reaction and crosslinking of polymers which in
turn decides the lag time of the system [4,5]. The lag time is
decided based on length of plug, insertion distance for
osmotic systems and for water insoluble drugs rapid release
is achieved by inclusion of effervescent agents.
The hydrogel formulations [6] are governed by nature
of polymer used. In the present study the lag time was
achieved by using formaldehyde as crosslinking agent on
hard gelatine capsules and the prepared drug beads were
filled into these capsules.
Pulsatile delivery systems have various advantages
over conventional delivery with reduced dosage frequency,
extended daytime or night time activity, drug targeting and
drug adaption to suit circadian rhythms of body functions
or diseases. [7]
Venlafaxine hydrochloride (VX) is chemically (R/S)-
1-[2-(dimethylamino)-1-(4-ethoxyphenyl) ethyl]
cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino)
is a serotonin noradrenaline reuptake inhibitor active orally,
used in treatment of various major depressive disorders.[8,9]
Its bioavailability is 10 – 45 % with high water solubility of
572mg/ml (adjusted to ionic strength of 0.2M with NaCl).
It is used to treat depression and suicidal tendencies
associated with it. Formulating as pulsatile delivery can
overcome the circardian tendencies of disease, circardian
rhythm is any biological process that displays an
endogenous entrainable oscillation of about 24 hrs and
depressive suicidal tendencies are more prevalent during
early morning hours of the day, hence preferred lag time
is selected to achieve desired therapeutic effect.[10]
In this study alginate drug loaded beads of VX were
developed to prevent the drug release in initial lag time and
later rapid release of drug after lag time lapses. For
improved lag time calcium pectinate beads were prepared
and these beads were filled in hard gelatine capsules treated
with formaldehyde vapours. Different formulation
parameter like particle size of beads, entrapment efficiency
and in vitro drug release were investigated for selecting the
optimised formulation of VX pulsatile drug delivery
systems.
MATERIALS AND METHODS
Materials
Venlafaxine Hcl was a gift sample from Dr. Reddys
laboratory, Hyderabad. Pectin AS 104 was procured from
Krishna pectins pvt ltd, Jalgaon, India. Sodium alginate was
procured from SD Fine Chemical Ltd, Mumbai, India. All
other chemicals and reagents used were either of analytical
or pharmaceutical grades.
Methods
Preparation of VX beads: [11]
The hollow porous beads were prepared by dissolving
2gms of alginate and 75 mg of venlaflaxine Hcl (from
formulations F1 – F6) in 10 ml of deionised water and
various amounts of sodium bicarbonate uniformly mixed,

IJPRT | October – December | 19

 Hyma et al / International Journal of Pharmacy Research & Technology 2012 2(4) 19-22

as shown in formulation table 1. The dispersion was
sonicated for 30 min to remove any air bubbles. The
resultant dispersion was dropped via 23 guage syringe
needle into 100ml of 1% calcium chloride solution. The
content was stirred at 100 rpm using magnetic stirrer for 15
minutes. The beads were filtered and washed 3 times with
distilled water and oven dried at 50° C for 4 hrs.
(Formulations F1 –F4)
Calcium pectinate beads were prepared similarly
replacing with low methoxy pectin 300 mg with various
amounts of sodium bi carbonate in 80 ml of 2% w/v
calcium chloride solution containing 10% of acetic acid
(F5-F8). Low methoxy Pectin is used to prolong the lag
phase and crosslinking agent concentration is increased for
effective hardening of the beads, pectinate beads are
stabilised only in presence of acetic acid. [11]
Preparation of cross linked Gelatin capsules
Hard gelatin capsules about 500 mg were taken and
their body was separated from their cap, then the body was
placed on a wire mesh. 25 ml of 37% V/V of formaldehyde
solution was taken in a in a empty dessicator and a pinch of
potassium permanganate was added to it to develop vapors.
The wire mesh containing the body of the caps was kept in
the dessicator.

Table 1 Composition of Venlafaxine HCL [ratios]

Ingredients F1 F2 F3 F4 F5 F6 F7 F8
Venlafaxine Hcl(mg) 75 75 75 75 75 75 75 75
Sodium alginate (gm) 2 2 2 2 - - - -
Pectin AS 104(mg) - - - - 300 300 300 300
Sodium
75 100 125 150 0.065 0.22 0.30 0.35
Bicarbonate(mg)
Calcium chloride(gm) 1 1 1 1 2 2 2 2

They are treated with formaldehyde for 24 hrs later steel blade and sputtered with gold to thickness of about
they are removed and kept in a filter paper for 48 hrs so 30nm under vaccum and microscopy was performed in
there is complete reaction between formaldehyde and scanning mode with magnification ranging from 50X -
gelatin. Then the capsules were kept in an open atmosphere 500X and a spatial resolution of 50nm-100nm. It was
for some time so that the residual formaldehyde gets viewed for the presence of polymer layer.
evaporated. Then these capsules were fitted with caps
and stored in a polythene bag. RESULTS AND DISCUSSIONS
The capsules were filled with alginate beads and Entrapment efficiency
further evaluated for various tests. Result shows on Table 2 that the entrapment
efficiency was in range of 95-92. %; the formulation
EVALUATION TESTS containing pectin AS and comparable increments of sodium
Drug entrapment efficiency [12] bicarbonate showed high entrapment of 95.6% whereas it
100 mg of beads from each batch was placed in 100 ml was 93.2% and 92.1 %for formulation F4 (VX with sodium
conical flask containing 100 ml pH 7.2 phosphate buffer. alginate as polymer and sodium bicarbonate as effervescent
Beads were agitated in a mechanical shaker for 24 hrs, to regulator for drug release). The entrapment efficiency
promote swelling and breakup of the cross linked structure. values are high for formulations with increase amount of
The solution was filtered and the drug was quantified at gas forming agent due to formation of thick peripheral
225nm sphectrophotometrically after appropriate dilution boundaries by gas molecules, which prevents the leaching
with buffer. The encapsulation efficiency was determined of drug.
by using the following empirical relationship. Each
determination was performed in triplicate manner. Table 2 Entrapment efficiency of bead
Actual % Entrapment efficiency
% Entrepment ef iciency = × 100 Formulation code
theoritical Sodium alginate
F1 75.7
In Vitro drug release [13] F2 79.4
In Vitro drug release rate of Venlafaxine HCL beads of F3 81.2
different formulations were determined using USP F4 88
dissolution test apparatus (basket type). Sample of drug Pectin AS104
equivalent to 75mg were kept in the basket placed into F9 77
900ml of preheated dissolution medium at 37 C consisted F10 79.8
of pH 1.2 HCL buffer for first 2 hrs, then the medium is F11 81.5
replaced with pH 7.2 phosphate buffer. Aliquots of 5ml F12 90.9
were withdrawn at regular intervals of time (for every half
an hour and the same is replaced with fresh dissolution In vitro drug release
medium each time. The samples were measured for Results of dissolution studies of VX loaded alginate
absorbance at 225nm. beads, pectinate beads and alginate beads filled in capsules
are shown in Figure 1, 2 & 3, the formulations containing
Morphology of beads (Scanning electron microscope) [14] sodium bicarbonate and sodium alginate showed lag time of
Morphological examination of the surface and internal 2-3hrs; with % of drug release as 72.1, 89.4, 91.4 and 97.2
structure of dried beads was carried out using a scanning %for F1, F2, F3 and F4 formulations at the end of 12 hrs
electron microscope. Each of CaPG and sodium alginate respectively. Next four formulations containing low
beads of selected formulation were transversely cut with a

20 | IJPRT | October – December

 Hyma et al / International Journal of Pharmacy Research & Technology 2012 2(4)
methoxy grade pectin with sodium bicarbonate showed lag
time of 5 hrs with % drug release of 84.1, 88.9, 97.2, 99.7
% for formulations F5, F6, F7 and F8 at the end of 12 hrs
respectively and final four formulations developed by
filling drug loaded alginate beads in formaldehyde treated
capsules showed prolonged lag time of 6 hrs with % drug
release of 89.1, 94.6, 96.1, 99.8 % at the end of 12 hrs. The
release rate was found to increase steadily after lag phase
and 99 % release was achieved later. The above results
were compared to conventional tablets of VX and the
release rate clearly indicates the lag phase of release where
there was almost zero release of drug and subsequent rapid
release of drug later. Whereas marketedeted sustained release
tablets of VX released drug steadily with 94.2 % release at
the end of 12 hrs with no lag time in release profile.
Figure 1 Rate of drug release of different formulations of
alginate beads.
Figure 2 Rate of drug release of different
erent formulations of
alginate beads filled in capsules
Figure 3 Rate of drug release of different formulations of
calcium pectinate beads filled in capsules
Scanning electron microscopy
The SEM photomicrographs of beads show a
characteristic surface area increment which favours
effective surface area increment which favours effective
dissolution of the drug. Efficient polymerization of drug
and polymer is observed: which is clearly depicted
depict by
2( 19-22
SEM. The pectin ate beads SEM Figure 5 is observed to
have more increase in surface area compared to alginate
beads in Figure 4,, with satisfactory regular spherical shape
and well separated particles with no agglomeration.
Figure 4 SEM of alginate beads of Venlafaxine.
Figure 5 SEM of pectinate beads of Venlafaxine
CONCLUSION
Venlafaxine Hcl is anti depressant drug and highly
water soluble,(534mg/ml
534mg/ml in water, to avoid dose dumping
and achieve time controlled release timed delayed capsule
device for chronotherapeutic delivery of drug was
successfully developed. F12 formulation is recommended
as the better formulation. The lag time achieved where
whe
almost the release of drug was negligible was due to
combined effect of sodium alginate; sodium bicarbonate,
pectin and formaldehyde in varying proportions.
Formulations F4, F8 and F12 burst release after lag hrs
time 3, 5, 6 which is applicable pulsatile
pulsat drug delivery of
Venlafaxine for anti suicidal and anti depressant actions.
The lag time criterion of 5hrs was satisfied by formulation
12. The dosage form can be taken at bed time and will
release the contents in the early morning hours when
depressantt attacks are more potent.
REFERENCES
1. Krogel I, Bodmeier R. “ Pulsatile drug release from
an insoluble capsule body controlled by an erodible
plug”, Pharm Res. 5,474-478 (1998)
( .
2. Krogel I, Bodmeier R. “Evaluation of an enzyme
containing capsular shaped pulsatile drug delivery
system” Pharm Res. 16,1424-2929 (1999).
3. Krögel I, Roland B, “Floating or pulsatile drug delivery
systems based on coated effervescent cores”, Int. J.
Pharm, 187, 175-184 (1999).
4. Kataoka K, Harada A, Harada A, Nagasaki Y, “Block
copolymer micelles for drug delivery: design,
characterization and biological significance”, Adv.
Drug Del. Rev. 47, 113-131 (2001
2001).
IJPRT | October – December | 21
 Hyma et al / International Journal of Pharmacy Research & Technology 2012 2(4) 19-22
5. A. Kikuchi, T. Okano, “Pulsatile drug release control
using linear region of the current versus drug release
curve hydrogels”, Adv. Drug Deliv. Rev. 54, 53–77
(2002).
6. Nitin S, Satarkar, Zach Hilt S. “Magnetic hydrogel
nanocomposite for remote controlled pulsatile drug
release”. J Cont Release .130, 246-251 (2008).
7. Veena S Belgamwar, Madhavi V. Gaikwad, Ganesh B
Patil , Sanjay Surana. “Pulsatile Drug Delivery System”
Asian J. Pharmaceutics. 2(3), 141-145 (2008).
8. Dollery Collin, Therapeutic Drugs. Churchill
livingstone, Edinburg, 2, V16-V20 (1996).
9. Thomson, Physicians’ Desk Reference, Thomson PDR,
Motvale, NJ. 58, 3413-3424 (2004).
10. Shan-Yang Lin, Yoshiaki Kawashima, “Current trends
and approaches to developing press coated
chronodelivery drug systems”, J. Control. Rel. 157
(3): 331-353 (2012).
22 | IJPRT | October – December
11. Somani V G, Shahi S R, Udavant Y K, Atram S C,
Satpute R, Shinde N M, “A floating pulsatile drug
delivery system based on hollow calcium pectinate
beads” , Asian J. Pharmaceutics. 2 (3), 120-124 (2009).
12. Shraddha S. Badve, Praveen Sher, Aruna Korde,
Atmaram P. Pawar, “Development of hollow / porous
calcium pectinate beads for floating pulsatile drug
delivery; European. J. Pharm & Biopharm. 65 (1), 85-
93 (2007).
13. Maryam Maghsoodi, Elham Hemati, Bahram
Qadermazi, Zahra Yari, “Hollow microspheres for
gastroretentive floating- pulsatile drug delivery:
preparation and in vitro evaluation”, Advanced
pharmaceutical Bulletin. 1 (2), 55-61 (2011).
14. Sameer Sharma, Atmaram Pawar, “Low density
multiparticulate system for pulsatile release of
meloxicam” , Int. J. Pharm. 313(1-2); 150-158 (2006).