Controversial Role of Antipsychotics in Alzheimer's Disease Treatment

Volume 1 Issue 4 www.ijrpb.com July - August 2013
Indian Journal of Research in Pharmacy and Biotechnology
ISSN: 2320-3471 (Online)
ISSN: 2321-5674 (Print)
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ISSN: 2321-5674 (Print)
Volume 1 Issue 4 www.ijrpb.com July – August 2013
S.No. Contents Page No.
1. Controversial role of antipsychotics in the treatment of Alzheimer’s disease
Mahesh G, G Praveen Kumar
469-471
2. Formulation and evaluation of oro dispersible tablets of Amlodipine besylate
Shobha Krushnan G, Ravi M Britto, Perianayagam J, Rajendra Prasad R
472-477
3. Comparision of potency of anti bacterial activity and anti inflammatory activity of 10 years and
100 years old bark extracts of Azadirachta indica
Vijaya Kumar G, Srinivas N, P Sravanthi, Sravani B
478-483
4. Development and evaluation of carisoprodol tablets with improved dissolution efficiency using
solid dispersion technique
Mogili Daya Sagar, Mohammed Shahidullah, Shaik Rabbani Basha, Shaik Shahnaz, Harish.G
484-487
5. Transdermal drug delivery systems
R.sowjanya, Salman Khan, D.Bhowmik, Harish.G, S.Duraivel
488-495
6. Synthesis of new thiazolidine-2,4-dione derivatives and their antimicrobial and antitubercular
activity
Faiyazalam M Shaikh, Navin B Patel and Dhanji Rajani
496-503
7. Effects of permeability characteristics of different polymethacrylates on the pharmaceutical
characteristics of diltiazem hcl-loaded microspheres
V. Kamalakkannan, K.S.G.Arul Kumaran, C. Kannan, S.Bhama, R. Sambath Kumar
504-511
8. Importance of safety health environment in preventing occupational health hazards in indian
industries
Murty TN, Md Aasif Siddique Ahmed Khan, Abhinov T, Abhilash T
512-516
9. Optimization of Thiocolchicoside tablet with permeation enhancers using 32
factorial design
Devendra Singh, Pankaj Kumar Sharma, Udai Vir Singh Sara
517-524
10. Method development and validation for the simultaneous estimation of Desvenlafaxine and
Clonazepam in bulk & tablet formulation by RP-HPLC method
Regalagadda Mallikarjuna, Nanda Kishore Agarwal, Prem Kumar Bichala, Sukhen Som
525-532
11. Plant seeds used for anthelmintic activity: A review
Shambaditya Goswami, Sanjeev Nishad, Mayank Rai, Sarvesh Madhesiya, Ankita Malviya, Pawan
Pandey, Vikram Gautam, Sujeet Yadav
533-536
12. Development and validation of pemetrexed by RP-HPLC method in bulk drug and
pharmaceutical dosage forms
Suresh Kumar Agrawal, Devendra Singh Rathore
537-542
13. Stability indicating RP-HPLC method for the estimation of Ceftazidime pentahydrate and
Tazobactam sodium in bulk and dosage forms
S. Amareswari, Nandakishore Agarwal, Md Aasif Siddique Ahmed Khan
543-548
14. Effect of hydrotropic solute on in-vitro charecterization of Valsartan fast disintegrating tablets
Madhu Sudhan Reddy A, Kishore Babu G, Srinivasa Babu P, Bhardwaj G
549-553
15. A review on Gloriosa superba l as a medicinal plant
Kavithamani D, Umadevi M, Geetha S
554-557
16. Formulation and evaluation of floating drug delivery system of Clarithromycin tablets
Priyanka Shukla, Ajay Yadav
558-561
17. Antifungal activity of ethanolic extract of Eupatorium adenophorum leaves
Dharmendra Kumar Singh, Ranjeet Singh
562-564

ISSN: 2321-5674 (Print)
Volume 1 Issue 4 www.ijrpb.com July – August 2013
18. Formulation of mouth dissolving tablets of Naproxen
Rajesh Reddy K, Nagamahesh Nandru, Desam Asha Latha, Srinivasa Rao Chekuri
565-569
19. Preparation of immediate release Atorvastatin and sustained release matrix tablets of Gliclazide
using retardant hydroxypropyl methyl cellulose
Vinod Raghuvanshi, Jayakar B, Debjit Bhowmik, Harish G, Dureivel S
570-574
20. Phytochemical sreening and antidiabetic antioxidant effect of Ecbolium ligustrinum flowers
extracts
Ranjitsingh B Rathor, Rama Rao D, Prasad Rao
575-580

ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Mahesh and Praveen Indian Journal of Research in Pharmacy and Biotechnology
Volume 1(4) July-August 2013 Page 469
CONTROVERSIAL ROLE OF ANTIPSYCHOTICS IN THE TREATMENT
OF ALZHEIMER’S DISEASE
Mahesh G*1
, G Praveen kumar2
1. School of Pharmaceutical sciences, Vels University, Chennai.
2. C.L. Baid Metha College of Pharmacy, Chennai, Tamil Nadu.
*Corresponding author: Mail Id: udaynagamahesh@hotmail.com
ABSTRACT
Antipsychotics are the commonly prescribed drugs in the treatment of Alzheimer’s disease, which
is the most common form of dementia. Atypical antipsychotics are an effective short-term (6-12 weeks)
treatment in relieving the depression, psychotic symptoms (hallucinations and delusions) and behavioral
disturbances (physical and verbal aggression, motor hyperactivity, repetitive mannerisms and activities,
and combativeness). But several placebo studies & clinical based evidences which recorded the deaths of
the patients concluded that this medication nearly doubles the risk of death in patients over two to three
years by developing cerebrovascular adverse events, upper respiratory infections, oedema or extra
pyramidal symptoms. The use of selective serotonin reuptake inhibitors (SSRI’s), Nor- epinephrine
reuptake inhibitors (NERI’s) and Tricyclic antidepressants (TCA’S) may relieve depression but still they
are associated with serious adverse effects such as insomnia, agitation, confusion and GI adverse effects.
So there is a need for applying non-pharmacological treatment i.e. Psychotherapy rather than the
Pharmacotherapy in minimizing the symptoms & anticipates further research in developing the
appropriate medication, alternative to the antipsychotics which minimizes the suffering of the patient.
Typical antipsychotics were the first generation of the drugs aimed to treat psychosis by antagonizing D2
receptors. As a result, they reduce dopaminergic neurotransmission in the four dopamine pathways.
Typical Antipsychotics include Chlorpromazine, Chlorprothixene, and Haloperidol etc. Atypical
Antipsychotics are the drugs which not only block dopamine receptors but also serotonin
receptors.Risperidone, Olanzapine, Quetiapine, Aripiprazole, Clozapine, Ziprasidone include Atypical
Antipsychotics.
Key words: Antipsychotics, Alzheimer’s disease, Atypical Antipsychotics, Typical antipsychotics
INTRODUCTION
Atypical antipsychotics are not the FDA approved
drugs for the treatment of behavioral & psychotic
symptoms in dementia (BPSD). Placebo-controlled
trials revealed increased mortality rate in patients those
treated with Atypical Antipsychotics. The mostly
prescribed Antipsychotics include Risperidone,
olanzapine, quetiapine & Haloperidol (Typical
Antipsychotic). Alzheimer’s disease majorly affects
the Hippocampus & Cerebral cortex of the brain with
the formation of Neurofibrillary tangles & Neuritic
plaques which leads to the degeneration of cortex,
cholinergic & other neurons (Amresh Shrivastava,
1999).
15 out of 17 Placebos controlled trials showed
increased mortality in the drug treated group compared
to the Placebo treated patients (Monasterio E, 2011). It
involves Risperidone (7trials), Olanzapine (5trials),
Quetiapine (2 trials) & Aripiprazole (3 trials). 1.6-1.7
fold (i.e almost 2 times) increase in mortality is
observed in active treatment over placebo (Forbes DA,
2005).
Rate of death in drug treated patients was about
4.5%, compared to rate of about 2.6% in placebo group
(Ballard, 2009). Specific causes of these deaths are
cerebrovascular adverse events (heart failure with
sudden death) or infections (mostly pneumonia). In
2005, FDA approved the Black box warning that
“Atypical Antipsychotics increase the risk of death in
dementia patients” (Cummings JL, 2002).
The only FDA approved drugs for the treatment
of Alzheimer’s disease is for improving the cognition
i.e. for cognitive symptoms (memory loss,
disorientation, impaired executive functions such as
poor problem solving, planning, and attention,
thinking, remembering & reasoning).
Examples of drugs used for improving cognitive
symptoms are Donepezil, Rivastigmine, Galantamine
(Cholinesterase Inhibitors) and Memantine (N-methyl
D-aspartate receptor antagonist).

The U.S. Food and Drug Administration (FDA)
have approved only five medications till now to treat
the symptoms of Alzheimer's disease (Rayner AV,
2006).
Slow titration of drugs with continuous
monitoring of patient is essential to minimize the risk
of adverse effects. The common adverse effects of AD
medications include depression, insomnia, confusion,
decreased weight, and diarrhea. So the Cholinesterase
inhibitors, NMDA receptor antagonist & Atypical
antipsychotics which are used in treating cognitive &
non-cognitive symptoms (BPSD & depression) have
wide side effects & high risk of adverse effects
(Steffens, 2008)
CONCLUSION
The serious adverse effects due to the use of
Atypical Antipsychotics in treating Behavioral &
Psychotic symptoms in Dementia (BPSD) of
Alzheimer’s disease concludes the limitation for the
use of atypical-antipsychotics and their controversial
role in the current existing treatment. Despite the FDA
black box warning, antipsychotic use in dementia has
remained remarkably frequent; a recent study of
16,586 nursing home patients reported that 29%
receive at least one antipsychotic medication. As the
warnings initially slowed the rate of increase in new
prescriptions for atypical antipsychotics in patients
with dementia, but there is no decrease in the overall
prescription rate. (Devanand, 2011)
Non pharmacological interventions which include
Psychotherapy should be the primary intervention in
treatment.
The care giver should simplify the tasks to the
patient by providing 3 R’s-Repeat, Reassure &
Redirect. This improves the activities of daily living.
The current existing medication only slows down the
worsening of cognition & minimizes the BPSD but
cant arrest the progression of Alzheimer’s disease. So
there is an immediate need for developing new drugs
which curbs & reverses the neuro degeneration with a
cost effective treatment for Alzheimer’s disease
(Treloar, 2010).
Table.1.FDA approved medications for treating Alzheimer’s disease.
Drug name Approved For FDA Approved
Memantine Moderate to severe 2003
Galantamine Mild to moderate 2001
Rivastigmine Mild to moderate 2000
Donepezil All stages 1996
Tacrine Mild to moderate 1993
Figure 1: showing the presence of
neurofibrillary tangles & neuritic plaques
Figure 2: Comparison of Normal brain, early & late
Alzheimer brain by Positron emission tomography (PET
SCAN)

Figure 3: Risk Perception In Typical & Atypical Antipsychotics
Table 2: Cardiovascular risk factors associated with Atypical Antipsychotics
REFERENCES
Amresh Shrivastava, Megan Johnston, Kristen
Terpstra, Larry Stitt, and Nilesh Shah, Atypical
antipsychotics usage in long-term follow-up of
first episode schizophrenia, Indian J Psychiatry,
54(3), 2012, 248–252.
Ballard CG, Gauthier S, Cummings JL, Brodaty
H, Grossberg GT, Robert P, Cyketsos CG,
Management of agitation and aggression
associated with Alzheimer’s disease, Nature
Reviews, 5, 2009, 245-255.
Cummings JL, Frank JC, Cherry D, Guidelines for
managing Alzheimer's disease: part I. Assessment,
Am Fam Physician, 65, 2002, 2263-2272
Devanand D P, Susan M D, Schultz K,
Consequences of Antipsychotic Medications for
the Dementia Patient, Am J Psychiatry, 168, 2011,
767-769.
Forbes DA, Peacock S, Morgan D,
Nonpharmacological management of agitated
behaviors associated with dementia, Geriatrics
and Aging, 8, 2005, 26-30.
Monasterio E, McKean A, Off-label use of
atypical antipsychotic medications in Canterbury,
New Zealand, N Z Med J, 124, 2011, 1336.
Rayner AV, O'Brien JG, Schoenbachler B,
Behavior disorders of dementia: recognition and
treatment, Am Fam Physician, 73, 2006, 647-652.
Steinberg, M., Shao, H., Zandi, P., Lyketsos,
C.G., Welsh-Bohmer, K.A., Norton,
M.C.,Breitner, Steffens JC, Tschanz DC, Point
and 5-year period prevalence of neuropsychiatric
symptoms in dementia: the Cache County study,
International Journal of Geriatric Psychiatry,
23(2), 2008, 170-177.
Treloar A, Crugel M, Prasanna A, Solomons L,
Fox C, Paton C, Katona C, Ethical dilemmas:
should anti-psychotics ever be prescribed for
people with dementia? British Journal of
Psychiatry, 197(2), 2010, 88-90.

Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechnology
FORMULATION AND EVALUATION OF ORO DISPERSIBLE TABLETS OF
AMLODIPINE BESYLATE
Shobha Krushnan G*, Ravi M Britto, Perianayagam J, Rajendra Prasad R
Department of pharmaceutics, Aurobindo College of Pharmaceutical Sciences, Gangadevipally, Geesugonda,
Warangal, Andhra Pradesh, India
*Corresponding author: E.Mail: avinashjipz@gmail.com
ABSTRACT
Recent advances in technology have presented viable dosage forms alternative for patients who
may have difficulty in swallowing tablets or capsules. Oro-dispersible tablet is one such approach in which
the tablets were dispersed in the mouth rapidly. Amlodipine is a calcium channel blocker used in the
treatment of hypertension and angina pectoris, where ultra-rapid action is required. In the present study
Amlodipine Oro-dispersible tablets are formulated using sodium starch glycolate, croscarmellose sodium,
crospovidone superdisintegrants. The tablets were prepared by direct compression technique and were
evaluated for weight variation, friability, hardness, drug content, in-vitro disintegration time, wetting time,
in-vitro dissolution studies. All the formulations follow compendia specifications. Formulations containing
higher concentrations of sodium starch glycolate and cross povidone as superdisintegrant showed better
dissolution profile and disintegration time. The bioavailability of amlodipine was increased by formulating
amlodipine as ODT. Differential Scanning calorimetric study (DSC) and Fourier transform infrared
spectroscopy (FTIR) were conducted for drug excipient compatibility study.
Key words: Orodispersible tablets, Amlodipine, hypertension
INTRODUCTION
United States of America food and drug
administration (FDA) defines oral dispersible tablet
(ODT) as “A solid dosage form containing medicinal
substances (or) active ingredient which disintegrates
rapidly usually within a matter of seconds when placed
upon a tongue”. Oral route of drug administration have
widely accepted up to 50-60% of total dosage forms.
Solid dosage forms are popular because of ease of
administration, accurate dosage, self-medication, pain
avoidance and most importantly the patient
compliance. The most popular solid dosage forms are
tablets and capsules having the drawback of these
dosage forms for some patients, is the difficulty to
swallow. Drinking water plays an important role in the
swallowing of oral dosage forms. Often people
experience inconvenience in swallowing conventional
dosage forms such as tablet when water is not
available, in the case of the motion sickness and
sudden episodes of coughing during common cold,
allergic condition and bronchitis. For these reasons,
tablets that can rapidly dissolve or disintegrate in the
oral cavity have attracted a great deal of attention. Oro-
dispersible tablets are not only indicated for people
who have swallowing difficulties, but also are ideal for
active people (Valleri M, 2004).
Fast dissolving tablets are also called as
mouth-dissolving tablets, melt-in mouth tablets, oro-
dispersible tablets, rapimelts, porous tablets, quick
dissolving etc. Fast dissolving tablets are those when
put on tongue disintegrate instantaneously releasing the
drug, which dissolve or disperses in the saliva (Fu Y,
2004).The faster the drug into solution, quicker the
absorption and onset of clinical effect. Some drugs are
absorbed from the mouth, pharynx and esophagus as
the saliva passes down into the stomach. In such cases,
bio-availability of drug is significantly greater than
those observed from conventional tablets dosage form
(Ghosh TK, 2005, Deepak K, 2004). The basic
approach in development of ODT is the use of
superdisintegrants like cross linked carboxymethyl
cellulose (croscarmellose), sodium starch glycolate
(primogel, explotab), polyvinyl pyrollidone
(Crosspovidone) etc, which provide instantaneous
disintegration of tablet after placing on tongue, there
by release the drug in saliva.
The bioavailability of some drugs may be
increased due to absorption of drug in oral cavity and
also due to pre-gastric absorption of saliva containing
dispersed drugs that pass down into the stomach.
Moreover, the amount of drug that is subjected to first
pass metabolism is reduced as compared to
conventional tablet. The advantage of mouth dissolving
dosage forms are increasingly being recognized in
both, industry and academics. Their growing
importance was underlined recently when European
pharmacopoeia adopted the term “Oro-dispersible
tablet” as a tablet that to be placed in the mouth where
it disperses rapidly before swallowing. According to

European pharmacopoeia, the ODT should
disperse/disintegrate in less than three minutes.
MATERIALS AND METHODS
Amlodipine Besylate was received as gift
sample from Micro labs, Hosur, Tamilnadu, India.
Crospovidone(CP),Croscarmellosesodium(CCS),Sodiu
mstarchglycolate(SSG),Lactose, Magnesium stearate
and talc were used. And all other chemicals/solvents
used were of analytical grade.
Formulation of Amlodipine oro-dispersible tablets
by direct compression method: The drug and all
other excipients were accurately weighed and sifted
through #40 sieves and mixed thoroughly. The above
blend was lubricated with magnesium stearate. The
formulation development of Amlodipine ODT was
initially developed with different super-disintegrants,
SSG, CCS and CP in the concentration range of 5%,
7.5% and 10%. The tablets were prepared by direct
compression method. The tablets were compressed on
8 station rotary tablet punching machine (Rimek
manufacturers, Gujarat, India) using 6mm round punch
and the individual tablet weight was100mg. The
prepared tablets were evaluated for different
parameters like weight variation, friability, hardness,
thickness, disintegration time, wetting time, assay and
in vitro dissolution studies.
Weight variation: Twenty tablets were randomly
selected from each batch and individually weighed.
The average weight of these selected tablets was
calculated (Indian Pharmacopoeia, Vol ‐ I, 1996).
Tablet thickness: Tablet thickness is an important
characteristic in reproducing appearance and also in
counting by using filling equipment. Thickness was
recorded using vernier calliper.
Friability: Friability is a measure of mechanical
strength of the tablet. If a tablet has more friability it
may not remain intact during packaging,transport or
handling. Roche friabilator is used to determine the
friability by following procedure. Pre weighed tablets
are placed in the friabilator. Friabilator consist of a
plastic chamber that revolves at 25 rpm, dropping those
tablets at a distance of 6 inches with each revolution
(Lachman L, 1987). The tablets are rotated in the
friabilator for at least 4 minutes. At the end of test
tablets are dusted and reweighed; the loss in the weight
of tablet is the measure of friability.
Crushing strength: Tablet crushing strength, which is
the force required to break the tablet, was measured
with a Pfizer tablet hardness tester. The hardness
(crushing strength) of three tablets per batch was
determined and mean taken.
Drug content: Drug content was determined by taking
randomly ten tablets per batch. An amount equivalent
to 10 mg amlodipine was dissolved in methanol,
suitably diluted with PH
7.2 Phosphate buffer and
filtered (British pharmacopoeia commission 2007).
The absorbance of the solution was measured
spectrophotometrically against the blank (PH
7.2
Phosphate buffer) at 239 nm using a
U.V.spectrophotometer (Shimazdu-1800, Japan).
Wetting time: The wetting time of the tablet was
measured by placing five circular tissue papers (10 cm
in diameter) in a Petri dish of 10 cm diameter. Water
(10 ml) containing methylene blue (0.1% w/v) was
added to the Petri dish. A tablet was carefully placed
on the surface of the tissue paper and the time required
for the dye to reach the upper surface of the tablet was
recorded as wetting time (Radke RS et al, 2009). The
measurements were carried out in triplicate.
Disintegration time: One tablet each was placed in
each of the six tubes of the apparatus and time in
seconds taken for complete disintegration of the tablet
with no palatable mass remaining in the apparatus was
measured. The tablet was considered disintegrated
completely when all the particles passed through the
screen. The disintegration time of 6 individual tablets
were recorded and the average was reported. The
disintegration time set by U.S. Food and Drug
Administration (FDA) for all the ODT formulations
(60 s) were considered as a specification limit (Bi Y,
1999).
In-vitro drug release: In vitro drug release studies
were carried out using USP type II apparatus at 50
rpm. Phosphate buffer (500 ml) at 7.2 was used as the
dissolution medium. The temperature of the dissolution
medium was maintained at 37±0.50
C (Bhagwati ST,
2000). An aliqout (5 ml) of dissolution medium was
withdrawn at specific time intervals, filtered and
suitably diluted prior to spectrophotometric analysis.
Sink condition were maintained by replenishing the
medium with an equal amount (5 ml) of dissolution
fluid. Absorption of the solution was measured by UV
spectroscopy (Shimadzu-1800, Japan) at 239 nm.
Drug-Excipient Compatibility Study: Drug-excipient
compatibility was performed by FTIR and DSC
studies,

a) Fourier Transform Infrared Spectroscopy (FT-
IR): The FT-IR spectrums of pure drug and physical
mixtures of drug with SSG, CCS and CP. FT-IR
(Thermo Nicolet 670 spectrometer) was used for the
analysis in the frequency range between 4000 and 400
cm-1
resolution. A quantity equivalent to 2 mg of pure
drug was used for the study.
b) Differential scanning calorimetric study (DSC
study): Thermal properties of pure drug and physical
mixtures of drug with SSG and CP were evaluated by
Differential scanning calorimetry (DSC) using a
Diamond DSC (Mettler Star SW 8.10). The analysis
was performed at a rate 50
C min-1 from 500
C to 2000
C
temperature range under nitrogen flow of 25 ml min-1.
RESULTS AND DISCUSSION
Weight variation and Thickness: The weight
variation of all the formulations was within the range
and the Thickness of the tablets found to be 2.7mm to
2.92mm.
Hardness and Friability: The hardness was
constantly maintained between 3-3.5 kg / cm2
during
compression and Friability for all the formulation
shown less than 1% which is in the acceptable limits
which indicates formulations have good mechanical
strength.
Drug content and Wetting time: The drug content of
Amlodipine from all the formulations was found in the
range of 98% to 99% and Wetting time in above
formulations found to be between 41-56 seconds
Disintegration time: Disintegration time of
formulations containing 5% SSG (F1),5% CCS
(F2),5% CP (F3), found to be between 36-39 seconds.
Disintegration time of formulations containing
7.5%SSG (F4), 7.5%CCS (F5), 7.5% CP (F6), found to
18-28 seconds. And disintegration time of formulations
containing 10% SSG (F7), 10% CCS (F8), 10% CP
(F9) found to be 9-13 seconds. Based on the above
results it was clearly observed that the above
formulations improved the disintegration with
increased concentration of superdisintegrants.
In-vitro dissolution: In this work the table No 5 shows
dissolution profile of different formulation in which F7
and F9shows maximum % released and increases
bioavailability hypothetically.As per USFDA
guidelines ODT tablets, the tablets should disintegrate
in less than 60 seconds, it should directly reflect on the
mouth disintegration. Based on these considerations it
was decided to increase the concentration of super-
disintegrants in the further study.
Fourier Transform Infrared Spectroscopy (FT-IR):
The FTIR spectrum peak points of pure drug
Amlodipine at 561.52, 613.36, 667.66, 753.76, 996.54,
1031.94, 1090.98, 1202.19, 1263.25, 1300.93, 1364.91,
1432.65, 1468.64, 1614.45, 1672.20, 1696.53, 2979.01
and 3154.55. Similar spectrum peak points were
observed in all the formulations. This clearly indicates
that there is no drug excipient interaction. Table 2
shows the spectrum peak points of the pure drug and
the formulations of Amlodipine.
Differential scanning calorimetric study (DSC):
DSC study was conducted on the selected
formulations. The DSC results shows sharp
endothermic peak for pure Amlodipine at 209.98 °C.
Similar sharp endothermic peaks were observed in the
formulations at almost similar temperatures. This
clearly indicates that there is no drug excipient
interaction.
CONCLUSION
This present research work demonstrates that
orodispersible tablet with higher percentage of
superdisintegrant by direct compression technique
yields a good pharmaceutically accepted dosage forms
and show increased dissolution profiles which reflects
enhanced bioavailability.
ACKNOWLEDGEMENT
The authors are thankful to Micro labs, Hour,
Tamilnadu, India for providing gift sample of
Amlodipine besylate and thankful to Principal of
Aurobindo college of Pharmaceutical sciences,
Gangadevipally, Warangal, Andhra Pradesh.

Table 1: Formulation of Amlodipine Oro-dispersible tablet
Ingredients (mg) F1 F2 F3 F4 F5 F6 F7 F8 F9
AMLODIPINE 10 10 10 10 10 10 10 10 10
SSG 5 - 7.5 - 10 -
CCS - 5 - - 7.5 - - 10 -
CP - - 5 - - 7.5 - - 10
LACTOSE 81 81 81 78.5 78.5 78.5 76 76 76
TALC 3 3 3 3 3 3 3 3 3
MG. STEARATE 1 1 1 1 1 1 1 1 1
Total Weight 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg
Table 2: FTIR spectrum peak points of pure drug and the formulation of Amlodipine
Table 3: DSC melting points of the selected formulations
Formulations DSC melting point in °C
PURE AMLODIPINE 209.98
AMD -SSG 208.19
AMD -CP 206.12
Pure AMD WITH SSG WITH CCS WITH CP
561.52 561.09 561.58 559.55
613.36 613.38 613.20 609.53
667.66 666.54 667.22 665.63
727.94 727.22 726.36 726.37
753.76 753.48 752.92 752.59
996.54 998.12 997.24 997.02
1031.94 1032.81 1029.36 1029.22
1090.98 1089.94 1089.86 1089.70
1202.19 1202.44 1201.99 1202.13
1263.25 1263.89 1262.43 1262.77
1300.93 1301.42 1301.39 1299.89
1364.91 1365.00 1365.27 1365.22
1432.65 1431.33 1431.76 1431.61
1468.64 1470.12 1469.56 1469.56
1614.45 1613.36 1613.28 1613.12
1672.20 1672.98 1672.99 1672.18
1696.53 1695.30 1695.39 1694.80
2979.01 2980.52 2980.96 2980.34
3154.55 3155.03 3155.64 3155.42

Table 4: Physicochemical Parameters of Amlodipine ODT
Parameter
F1 F2 F3 F4 F5 F6 F7 F8 F9
Weight Variation 100.1 101 102 100.3 102 102 100.2 100 101
Friability (%) 0.47 0.58 0.78 0.56 0.64 0.87 0.68 0.72 0.92
Hardness(Kg/Cm2
) 3.0 3.1 3.0 3.0 3.5 3.0 3.5 3.2 3.5
Thickness (mm) 2.78 2.84 2.81 2.78 2.81 2.92 2.8 2.8 2.7
Disintegration
time(Sec)
37.6 39.49 36.04 25.9 28.5 18.81 9.3 12.57 9.26
Wetting time(sec) 52 56 50 41 46 43 42 45 42
Drug content (%) 99 98 99 99 98 99 99 99 99
Table 5: In-vitro dissolution data Amlodipine ODT
Time
(min)
F1 F2 F3 F4 F5 F6 F7 F8 F9
5 66.70 64.90 65.15 75.26 72.67 74.63 83.24 80.28 82.56
10 76.51 75.15 75.00 81.82 79.82 80.68 89.90 87.57 88.98
15 81.90 79.40 80.20 88.81 85.85 87.94 93.3 92.79 93.1
20 87.65 85.28 86.1 93.96 90.78 92.96 95.4 94.5 95.1
30 96.90 93.67 95.98 97.96 96.72 97.86 98.82 96.5 98.9
Fig 1: FTIR of pure Amlodipine Fig 2: FTIR of AMD + SSG
Fig 3: FTIR of AMD +CCS Fig 4: FTIR of AMD + CP

Fig 7: DSC of AMD + CP
REFERENCES
Bhagwati ST, Hiremath SN, Sreenivas SA,
Comparative evaluation of disintegrants by
formulating cefixime dispersible tablets, Indian J.
Pharm.Edu.Res, 39, 2000, 194‐197.
Bi Y, Evaluation of rapidly disintegrating tablets
prepared by direct compression method, Drug Dev
Ind Pharm, 25(5), 1999, 571‐581.
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Capsule 7, 2004, 30-35.
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fast disintegrating tablets: Developments,
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Ghosh TK, Pfister WR, Quickdissolving oral dosage
forms: Scientific and regulatory considerations from
a clinical pharmacology and biopharmaceuticals
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Molecules to market. New York, CRC Press, 2005,
337-356.
Indian Pharmacopoeia, Vol ‐ I, 4th ed. Controller of
publication, Govt. of India, New Delhi, 1996, 736.
Lachman L, Liberman H, Kanig J, The theory and
practice of industrial pharmacy, Varghese Publishing
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Radke RS., Jadhav JK., Chajeed MR. Formulation
and evaluation of orodispersible tablets of baclofen.
International Journal of Chemtech Research, 1,
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Valleri M, Mura P, Maestrelli F, Cirri M, Ballerini
R, Development and evaluation of glyburide fast
dissolving tablets using solid dispersion technique,
Drug Dev Ind Pharm, 30(5), 2004, 525-534.
Fig 5: DSC of Pure Amlodipine Fig 6: DSC of AMD + SSG

Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology
COMPARISION OF POTENCY OF ANTI BACTERIAL ACTIVITY AND ANTI
INFLAMMATORY ACTIVITY OF 10 YEARS AND 100 YEARS OLD BARK EXTRACTS OF
AZADIRACHTA INDICA
Vijaya Kumar G, Srinivas N*, P Sravanthi, Sravani B
Department of Pharmacology, A.K.R.G College of Pharmacy, Nallajerla, W.G. Dist, A.P, India.
*Corresponding author: Email: srnvs_87@rediffmail.com, 8019189741
ABSTRACT
Azadirachta indica (Meliaceae) commonly known as neem contains many biologically active
compounds including alkaloids, flavonoids, triterpenoids, phenolic compounds, Carotenoids, steroids and
ketones, azadirachtin. Oil from the leaves, seeds and bark possesses a wide spectrum of antibacterial
action against Gram-negative and Gram-positive microorganisms, including M. tuberculosis and
streptomycin resistant strains. The present study was undertaken to evaluate the comparision of potency
of anti bacterial and anti-inflammatory activities of 10 and 100 years old bark extract of Azadirachta
indica. The antibacterial activity was performed by using both gram positive and gram negative
organisms viz., Bacillus Subtilis, E. coli and Staphylococcus Aureus. The anti-inflammatory activity was
evaluated by using carrageenan induced paw edema method in rats. From the results of anti bacterial
activity and anti-inflammatory activity, it has been concluded that 100 years old neem bark extract
showed greater activities than the 10 years old neem bark extract.
Key words: Azadirachta indica, Anti bacterial activity, Anti-inflammatory activity, 10 years and 100
years old plants.
1. INTRODUCTION
Azadirachta indica (Meliaceae) commonly
known as neem is native of India and naturalized in
most of tropical and subtropical countries is of great
medicinal value and distributed widespread in the
world. The Chemical constituents contain many
biologically active compounds that can be extracted
from neem, including alkaloids, flavonoids,
triterpenoids, phenolic compounds, Carotenoids,
steroids and ketones, Azadirachtin is actually a mixture
of seven isomeric compounds labeled as azadirachtin
A-G and azadirachtin E is more effective (P Sudhir
Kumar, 2010). Other compounds that have a biological
activity are salannin, volatile oils, meliantriol and
nimbin. Oil from the leaves, seeds and bark possesses a
wide spectrum of antibacterial action against Gram-
negative and Gram-positive microorganisms, including
M. tuberculosis and streptomycin resistant strains. In
vitro, it inhibits Vibrio cholerae, Klebsiella
pneumoniae, M. tuberculosis and M. pyogenes.
Antimicrobial effects of neem extract have been
demonstrated against Streptococcus mutans and S.
faecalis. NIM-76, a new vaginal contraceptive from
neem oil showed inhibitory effect on the growth of
various pathogens, including bacteria, fungi and virus.
Recently, the antibacterial activity of neem seed oil was
assessed in vitro against 14 strains of pathogenic
bacteria. (Baswa M, 2001)
The present study was undertaken to evaluate
the comparision of potency of anti bacterial activity of
10 and 100 years old acetonic bark extract of azadiracta
indica by using agar disc diffusion method on Bacillus
subtilis, Escherichia coli, Staphylococus aureus and
also to evaluate the comparision of potency of anti-
inflammatory activity of 10 and 100 years old aqueous
bark extract of azadiracta indica on carrageenan
induced paw edema in rats.
2. MATERIALS
Both the 10 years old and 100 years old neem
plants were collected from Bapatla, Guntur district,
Andhra Pradesh. Gentamycin (Nicholas piramil ltd,
Mumbai), Penicillin (Alembic labs, Ahmedabad) and
Diclofenac sodium (Novartis pharma ltd, Ahmedabad)
were purchased from local medical stores, Nallajerla.
Carrageenan was procured from Ozone internation,
Mumbai.
2.1. Animals: Albino Wistar rats weighing 180–200g
of either sex were obtained from the animal house of
A.K.R.G. College of Pharmacy, Nallajerla, Andhra
Pradesh, were used for this study. The animals were
housed in separate groups (six rats in each cage) in
clean sanitized polypropylene cages containing sterile
paddy husk as bedding. The bedding material of the
cages was changed every day. They had free accessed
to standard pellet diet and water ad libitum. The
animals were maintained under day and night 12:12 h
cycles and with maintenance of room temperature 25 ±

2◦
C. All procedures were performed in accordance with
the Institutional Animal Ethics Committee (IAEC)
constituted as per the direction of the Committee for the
Purpose of Control and Supervision of Experiments on
Animals (CPCSEA), under ministry of Animal Welfare
Division, government of India, New Delhi IAEC
approved the experimental protocol
(AKRGCP/IAEC/03/2011-12) dated 11/02/2012.
3. METHODS
3.1. Preparation of neem bark extracts (NBEs): The
stem bark of neem plants was peeled with sharp knife
and chopped into pieces which was sun dried and
ground into powder using a blender. The resulting
powder stored at room temperature in clean, air tight
and wide mouth container.
3.2. Preparation of acetonic neem bark extract:
Twenty grams of neem bark was mixed with 200ml of
acetone in a conical flask. The mixture was then
magnetically stirred for 24hrs at room temperature. The
homogenate was vacuum filtered through filter paper.
The clarified filtrate was evaporated using at about
35o
C and the residue was collected.
3.3. Preparation of aqueoes neem bark extract:
Twenty grams of neem bark was mixed with 200ml of
distilled water in a conical flask. The mixture was then
magnetically stirred for 60hrs at room temperature. The
homogenate was vacuum filtered through filter paper.
The clarified filtrate was evaporated using at about
350
C and the residue was collected.
3.4. Antimicrobial Studies (A Kottai Muthu, 2010)
3.4.1. Test solution: Test solution of each extract was
prepared by dissolving 100mg of each extract
separately in 1ml of sterile dimethyl formamide (DMF)
in a specific gravity bottle and stored in refrigerator.
The solution was removed from the refrigerator one
hour prior to each use and allow warming at room
temperature.
3.4.2. Standard solution: The standard drugs
Gentamycin (200µg/ml) and Pencillin (750µg/ml) was
prepared in sterile water for injection. These were used
as standard drugs for Antimicrobial studies.
3.4.3. Preparation of medium: Nutrient broth was
used for preparation of inoculum of bacteria. Nutrient
agar was used for preparation of medium for
Antimicrobial screening. The composition of nutrient
agar medium was as follows.
Peptone - 5.0g
Beef extract - 1.5g
Yeast extract - 1.5g
Agar - 1.5g
Distilled water - 1000 ml
pH adjusted -7.2
3.4.4. Preparation of inoculums: Inoculum was
prepared by transferring a loopful of stock culture to a
150ml of Erlenmeyer containing 80ml of nutrient broth.
The composition of inoculum broth was same as that of
stock culture with exception of agar. The inoculum
flasks were incubated at 370
C for 24 hrs and used for
experiments.
3.4.5. Inoculation: The nutrient agar medium was
sterilized by autoclaving at 121o
C for 15 min. The
petridishes and pipette were sterilized in an oven at
150o
C for one hour. About 25ml melted nutrient agar
medium (40o
-50o
C) was poured in each sterilized
petridishes and 0.5ml of inoculum broth of bacteria was
added to the respective petridishes. The content
petridishes were thoroughly maintained at rotary
motion. The medium containing inoculum was allowed
to solidify at room temperature. After solidification of
the medium, fine whattman filter paper disc were made
it equal distance. The whattman filter paper discs were
dipped in test and standard solution and kept in the
petridish and the petridish undisturbed for one hour at
room temperature. The petridish were incubated at
37o
C for 24 hours and the zone of inhibition was
recorded in mm. The experiment was performed in
triplicate and the average readings are recorded.
3.5. Anti inflammatory activity (A M Mujumdar,
2000)
3.5.1. Experimental design: Male Wistar rats
weighing 180-200 g were divided into four groups of
six animals each. The treatment groups are designated
as follows
Group Treatment
Group I Control (Solvent)
Group II 100 yrs old NBE (200mg/kg)
Group III 10 yrs old NBE (200mg/kg)
Group IV Standard (Diclofenac
100mg/kg)
3.5.2. Experimental procedure: Male Wistar rats
weighing 200 g are starved for 48 h. having access to
drinking water ad libitum. The test compounds and
standard drugs are administered by oral route. Thirty
min later the rat are challenged by a sub-contentious
injection of 0.05ml of 1% solution of carrageenan on
the plantar surface of the left hind paw. The paw is

marked with ink at the level of lateral malleolus and
immersed in the mercury column of a plethysmometer
for measuring the paw volume after carrageenin
injection and then at 0.5, 1, 2, 3 and 4 hrs.
The increase in paw volume at each time
interval is calculated as percentage compared with the
volume measured immediately after the injection of
carrageenan for each animal.
The percentage edema inhibition was
calculated by sing the following formula
Table 1: Percentage yield data of 100 yrs and 10 yrs old plants with different solvents
Solvent Percentage Yield
100 Yrs 10yrs
Acetone 1.5 1.9
Water 1.2 1.6
Figure 1: Percentage yield profile of 100 yrs and 10 yrs old plants with different solvents
Table 2: Comparison of inhibition zones of acetonic neem bark extracts of 100 yrs and 10 yrs old plants
against different standard organisms
Organism Zone of inhibition (mm)
100 Yrs 10yrs Penicillin Gentamicin DMF
Bacillus subtilis 31 14 25 22 -
E. coli 35 15 19 30 -
Staphylococcus aureus 27 10 21 18 -
(-) No zone of inhibition DMF – dimethyl Formamide
Figure 2: Comparison of inhibition zones of acetonic neem bark extracts of 100 yrs and 10 yrs old plants
against different standard organisms
0
0.5
1
1.5
2
Acetone Water
PecentageYieldof
NeemBarkExtract
100 Yrs
10yrs
0
10
20
30
40
100 Yrs 10yrs Gentamicin Penicillin
Zoneofinhibition
(mm)
Bacillus Subtilis
E. coli

Table 3: Paw volume data of test and standard drugs on carrageenan induced rat paw edema
Group Treatment Change in paw volume (ml) measured by mercury displacement at
different time intervals (hrs) (mean±S.D)
0 0.5 1 2 3 4
Group I Control 0 0.13±0.001 0.3±0.002 0.4±0.001 0.5±0.002 0.5±0.001
Group II 100 yrs old NBE 0 0.11±0.002 0.2±0.001 0.2±0.001 0.11±0.002 0.1±0.001
Group III 10 yrs old NBE 0 0.11±0.001 0.23±0.002 0.3±0.001 0.27±0.001 0.2±0.002
Group IV Standard 0 0.1±0.001 0.2±0.001 0.19±0.002 0.1±0.001 0.1±0.001
Figure 3: Paw volume profiles of test and standard drugs on carrageenin induced rat paw edema
Table 4: Percentage oedema inhibition of test and standard drugs on carrageenan induced rat paw edema
Group Treatment
Percentage of edema inhibition measured by mercury
displacement at different time intervals (hrs)
0 0.5 1 2 3 4
Group I Control 0 0 0 0 0 0
Group II 100 yrs old NBE 0 15.38 33.3 50 78 80
Group III 10 yrs old NBE 0 15.38 23.33 25 46 60
Group IV Standard 0 23 33.33 52.5 80 80
Figure 4: Percentage oedema inhibition of test and standard drugs on carrageenin induced rat paw edema
0
0.1
0.2
0.3
0.4
0.5
0.6
0 1 2 3 4 5
changeinpawvolume
(ml)
Time (hrs)
Control
100 yrs
10 yrs
Standard
0
20
40
60
80
100
0 1 2 3 4 5
Percentageinhibition
ofoedema
Time (hrs)
100 yrs
10 yrs
Standard

4. DISCUSSION
The present study has been undertaken to compare
the potency of anti microbial and anti-inflammatory
activities of 100 years and 10 years old neem bark
extracts. In this study acetone, and aqueous extracts were
used for anti microbial and anti-inflammatory activities
respectively. The percentage yield of different extracts
were calculated and tabulated in table 1.
The inhibition zones of acetonic neem bark
extracts of 100 years and 10 years old plants against
different standard organisms (Bacillus subtilis, E. coli and
Staphylococcus aureus) were measured. Similarly the
inhibition zones of standard drugs that are Gentamicin and
Penicillin against the same organisms were also measured
and data shown in table 2. The data was treated
statistically and the statistical interaction implies that the
difference in zone of inhibition was statistically significant
between 100 years and 10 years old neem plants. It is clear
that the both test drugs (100 years and 10 years old) are
showed anti microbial activity against gram positive micro
organisms (Bacillus Subtilis and Staphylococcus Aureus)
and gram negative micro organisms (E. coli). The solvent
(DMF) used as vehicle did not showed anti microbial
activity and confirmed there is no solvent action on the
micro organisms.
Anti inflammatory activity was evaluated by using
carrageenan induced rat paw oedema method. A single
subcutaneous injection of 0.1 ml of 2% formalin in rats
produced inflammation significantly (p<0.001). Paw
volume was measured by mercury displacement at
different time intervals and right leg considered as control
for left leg which is received carrageenan on plantar
region. The change in paw volume (L-R) was measured
and data shown in table 3. From this data percentage
oedema inhibition of test and standard drugs was
calculated and tabulated in table 4. The data was treated
statistically and the statistical interaction implies that the
difference in paw volume was statistically significant
between 100 years and 10 years old neem plants. At the
time of 3 hours the percentages of oedema inhibition were
0, 78, 46 and 80 for control, 100 years old plant extract, 10
years old plant extract and standard drugs respectively.
5. CONCLUSION
The bark extracts were extracted by
different solvents. All these activities are evaluated and
observed that the age of plant is influenced the index of
activity. It is may be due to the age of plant influence the
chemical cinstients or their potency. The young plant (10
years age neem plant) showed high percentage yield when
compared with old plant (100 years age neem plant). The
crude extracts are sparingly soluble in water; hence DMF
(dimethyl formamide) used as solvent for the test dose
preparations. From the results of anti microbial activity, it
has been concluded that 100 years old neem bark acetonic
extract showed greater anti microbial activity than the 10
years old neem bark acetonic extract and both the drugs
showed broad spectrum anti bacterial activity. From the
results of anti inflammatory activity, it has been concluded
that 100 years old neem bark aqueous extract showed
greater anti inflammatory activity than the 10 years old
neem bark aqueous extract and the results met the
standard NSAID drug that is diclofenac sodium. From this
investigation it was concluded that the selection of age of
plant is important to their significant pharmacological
action.
6. AKNOWLEDGEMENTS
The authors are thankful to Management,
A.K.R.G College of Pharmacy, Nallajerla, Andhra
Pradesh, India for permitting and providing necessary
facilities for carrying out to do the project work.
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A Kottai Muthu, Penugonda Sravanthi, D Sathesh Kumar,
A Anton Smith and R Manavalan, International Journal of
Pharma Sciences and Research, 1(2), 2010, 127-130.
A M Mujumdar, D G Naik, C N Dandge, H M
Puntambekar, Anti inflammatory activity of curcuma
amada Roxb in albino rats. Indian Journal of
Pharmacology, 32, 2000, 375-377.
Ara I, Siddiqui B S, Faizi S, Siddiqui S, Diterpenoids from
stem bark of Azadirachta indica, Phytochemistry, 28,
1989, 1177-1180.
Baswa M, Rath CC, Dash SK, Mishra RK, Antibacterial
activity of Karanj (Pngamia pinnata) and neem
(Azadirachta indica) seed oil: a preliminary report,
Microbios, 105, 2001, 183-189.
Biswas, Kausik, Ishita Chattopadhyay, Ranajit K,
Banerjee and Uday Bandyopadhyay, Biological activities
and medicinal properties of Neem (Azadirachta indica),
Current Science, 82(11), 2002, 1336-1345.
Naqvi S N H, Pharmacological importance of neem
Azadiracta indica A Juss (Meliacae), J. Baqai Med. Uni,
1(2), 1998, 39-50.

P Sudhir Kumar Debasis Mishra, Goutam Ghosh and
Chandra S Panda, Biological action and medicinal
properties of various constituent of Azadirachta indica
(Meliaceae) an Overview, Annals of Biological Research,
1 (3), 2010, 24-34.
Siddiqui S, Siddiqui B S, Faizi S, Mahmood T, Isolation
of a tetranortriepenoid from Azadirachta indica.
Phytochemistry, 23, 1984, 2899-2901.
Thaker A M and Anjaria JV, Antimicrobial and infected
wound healing response of some traditional drugs, Indian
Journal of Pharmacology, 18, 1986, 171-174.

Harish et.al Indian Journal of Research in Pharmacy and Biotechnology
DEVELOPMENT AND EVALUATION OF CARISOPRODOL TABLETS WITH
IMPROVED DISSOLUTION EFFICIENCY USING SOLID DISPERSION
TECHNIQUE
Mogili Daya Sagar, Mohammed Shahidullah, Shaik Rabbani Basha, Shaik Shahnaz, Harish.G*
Department of Pharmaceutics, Nimra college of Pharmacy, Vijayawada, AP, India
*Corresponding author: E.Mail: harishgopinath4u@gmail.com
ABSTRACT
Carisoprodol is indicated in patients with acute muscular pain. Carisoprodol is typically
prescribed as 350 mg tablets. The aim of the present study is to design and development Carisoprodol
tablets with improved dissolution efficiency using solid dispersion technique. The present work is
planned to prepare solid dispersion system consisting of Carisoprodol with hydrophilic carriers by
employing different methods, to study the physicochemical properties of Carisoprodol solid
dispersions, develop fast dissolving tablets of Carisoprodol solid dispersions by using super-
disintegrant such as starch, Croscarmelose sodium, sodium starch glycolate and to study the effect of
the preparation methods of solid dispersions on dissolution characteristics.
Key words: Carisoprodol, Solid dispersion, super-disintegrant.
INTRODUCTION
The potential drug candidates are
characterized by a low oral bioavailability. Often
poor drug dissolution/solubility rather than limited
permeation through the epithelia of the
gastrointestinal tract are responsible for low oral
bioavailability (Vasconcelos TF, 2007). Thus
aqueous solubility of any therapeutically active
substance is a key property as it governs dissolution,
absorption and thus the in-vivo efficacy (Vemula VR,
2010). Drugs with low aqueous solubility have low
dissolution rates and hence suffer from oral
bioavailability problems. The rate and extent of
dissolution of the active ingredient from any dosage
form often determines the rate of extent of absorption
of the drug. When an active agent is given orally, it
must first dissolve in gastric acid and/or intestinal
fluids before it can then permeate the membranes of
the GI tract to reach systemic circulation. Therefore,
a drug with poor aqueous solubility will typically
exhibit dissolution rate limited absorption, and a drug
with poor membrane permeability will typically
exhibit permeation rate limited absorption. Hence,
two areas focus on improving the oral bioavailability
of active agents include:
 Enhancing solubility and dissolution
rate of poorly water-soluble drugs
 Enhancing permeability of poorly
permeable drugs
There are various techniques available to
improve the solubility of poorly soluble drugs, such
Micronization, Nanosuspension, Modification of the
crystal habits, Eutectic mixtures, Solid dispersions,
Microemulsions, Self micro emulsifying drug
delivery systems, cyclodextrin inclusion and lipid
based delivery systems etc (Sharma D, 2010).
Solid dispersion is one of the most promising
approaches for solubility enhancement. In the
biopharmaceutical classification system (BCS) drugs
with low aqueous solubility and high membrane
permeability are categorized as Class II drugs.
Therefore, solid dispersion technologies are
particularly promising for improving the oral
absorption and bioavailability of BCS Class II drugs.
In case of solid dispersion drug disperse in the matrix
generally a hydrophilic matrix and a hydrophobic
drug, thereby forming a solid dispersion. When the
solid dispersion is exposed to aqueous media, the
carrier dissolves and the drug releases as fine
colloidal particles. The resulting enhanced surface
area produces higher dissolution rate and
bioavailability of poorly water-soluble drugs.
Solid dispersion: Solid dispersion technology is the
science of dispersing one or more active ingredients
in an inert matrix in the solid stage in order to
achieve increased dissolution rate, sustained release
of drugs, altered solid state properties, and enhanced
release of drugs from ointment and suppository
bases, and improved solubility and stability
(Mohanachandran PS, 2010).
MATERIALS AND METHODS
Materials: Carisoprodol was obtained as gift sample
from SYNED LABS LIMITED, Medak, AP, Starch,
SSG, Cross carmelose sodium, Crospovidone, MCC,
Lactose was obtained as a gift sample from
ICPAHealthcare, Ankaleshwar. PVP, Talc and
Magnesium Stearate were obtained from Signet
Mumbai. All other chemicals and Solvents used in
this study are of analytical grade.

Pre-formulation Studies: Pre-formulation study
relates to pharmaceutical and analytical investigation
carried out proceeding and supporting formulation
development effort of the dosage forms of the drug
substance. Pre-formulation studies yield basic
knowledge necessary to develop suitable
formulation. It gives information needed to define the
nature of the drug substance and provide frame work
for the drug combination with pharmaceutical
excipients in the dosage forms. Hence the following
pre-formulation studies were performed on the
obtained sample of drug such as Solubility, bulk
density, tapped density, Percentage compressibility,
Identification of drug sample, Drug excipient
compatibility studies (Patidar Kalpana, 2010).
Formulation of Carisoprodol Solid dispersion:
The accurately weighed quantity of the drug and
polymer in various ratios has been formulated by
melting the polymer and dispersing the drug in it.
The formulated SD has been dried and grounded by
passing through mesh #22.
Formulation of Carisoprodol Tablet:
Preparation of the Fast dissolving tablet of
Carisoprodol: Fast dissolving tablets of
Carisoprodol had been formulated by direct
Compression method using Super-disintegrants such
as SSG, CP, Starch, CCS etc. in various ratios. These
ingredients were weighed and mixed
stoichometrically to obtain the final formulation. The
weight of the tablet in all formulations was kept
constant to 130mg. All the batches were prepared by
direct compression method using the 16-station
rotary punch tablet compression machine using 7 mm
biconvex plain on both side die-punches set. The
variables maintained in the formulation were the
different types of super-disintegrant and their
concentration (in mg) in the formulation. Completely
dried complex used for the preparation of fast
dissolving tablet. Tablets were prepared from blends
by direct compression method. All the ingredients
including drug were passed through mesh no. 60
excepting lubricants. Lubricants were passed through
mesh no.80. Lubricants were added at the time of
compression. Blend is mixed uniformly by manually
for 30 minutes. Tablets of convex faced weighing
130mg each with 3.3mm thickness and 7mm in
diameter.
Evaluation of Post-Compression Characteristics:
The formulated Carisoprodol SD has been
compressed in to tablet and the following evaluation
has been performed as per BP pharmacopoeia. The
following evaluation of tablets was performed such
as Drug content, Weight variation, Hardness,
Friability, Content uniformity, Thickness, In-Vitro
Dissolution.
Table.1. Formulation of Carisoprodol solid dispersion
Drug:Polymer (Urea) Drug:Polymer (Mannitol)
1:1 1:1
1:2 1:2
1:3 1:3
Table.2. Formulation of Fast dissolving tablet of Carisoprodol SD
INGREDIENTS F1 F2 F3 X4 X5 X6 Z7 Z8 Z9 C10 C11
Carisoprodol SD (mg) 10 10 10 10 10 10 10 10 10 10 10
Starch 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5
SSG 2 4 6 - - - - - - - -
CCS - - - 2 4 6 - - - -
CP - - - - - - 2 4 6 - -
MCC - - - - - - - - - - 41
PVP 16 16 16 16 16 16 16 16 16 16 16
Lactose 11.5 10.5 8.5 12.5 10.5 8.5 12.5 10.5 8.5 14.5 36
Talc 10 10 10 10 10 10 10 10 10 10 10
Magnesium Stearate 18 17 17 17 17 17 17 17 17 17 17
Total Weight 130 130 130 130 130 130 130 130 130 130 130

RESULTS AND DISCUSSION
Evaluation of Blend:
Table.3. Pre-compression parameters of Carisoprodol SD
Formulation
Series
Bulk
Density(gm/ml)
Tapped
Density(gm/ml)
Compressibility
Index
Hausner’s
Ratio
Angle of
Repose
F1 0.510 0.598 15.81 1.17 26o
28’
F2 0.512 0.597 15.38 1.18 26 o
85’
F3 0.512 0.60 14.87 1.17 27 o
14’
X4 0.505 0.591 14.64 1.17 27 o
75’
X5 0.507 0.595 14.72 1.17 28 o
07’
X6 0.507 0.597 14.97 1.17 28 o
07’
Z7 0.512 0.595 13.84 1.16 29 o
39’
Z8 0.515 0.598 13.91 1.16 29 o
74’
Z9 0.515 0.602 14.43 1.16 29 o
02’
C10 0.510 0.641 20.40 1.22 32 o
82’
C11 0.534 0.714 25.13 1.33 34 o
59’
Table.4. Evaluation of Formulation Series
Batch
no.
Weight
variation
Hardnes
kg/cm2
Thickness
(mm)
Friability
(%)
Disintegration
time (sec)
Wetting
time (sec)
Water
absorption
ratio
Drug
Content
(%)
F-1 Passes 3.1 2.1 0.41 42 63 75 99.78
F-2 Passes 3.2 2.1 o.37 31 55 88.72 99.62
F-3 Passes 3.1 2.1 0.37 25 49 96.29 100.8
X-4 Passes 2.9 2.1 0.38 48 69 67.40 100.2
X-5 Passes 3.1 2.1 0.4 35 59 85.82 100.4
X-6 Passes 3 2.1 0.41 29 50 94.77 100.3
Z-7 Passes 2.8 2.1 0.41 55 71 64.70 99.9
Z-8 Passes 2.9 2.1 0.41 41 65 82.82 99.7
Z-9 Passes 2.9 2.1 0.43 34 56 93.28 100.1
C-10 Passes 3.5 2.1 0.41 74 79 58.33 99.6
C-11 Passes 4.1 2.1 0.32 161 93 42.69 99.5
M-1 - 5.3 - - 257 429 68.33 101.1
M-2 - 5.6 - - 291 486 63.01 99.7
M1:- Marketed Tablet of Carisoprodol; M2:- Marketed Tablet of Carisoprodol
Fig.1.Percentage Drug release profile of Carisoprodol formulations
CONCLUSION
The Mannitol and Urea is used as polymer
for the enhancement of the solubility of Carisoprodol
solid dispersion and improve the rate of dissolution
by fast dissolving tablet using various super
disintegrates which shows rapid onset of action and
faster rate of drug delivery. The formulation F3 and
X6 showed faster disintegration time a faster rate of
in-vitro dissolution above 99% at the end of 8min.
hence formulation of Carisoprodol SD using the SSG
(6%) and CCS (6%) showed a rapid onset of drug
release. Hence, formulation of the poorly soluble
drug with improved solubility using solid dispersion

and faster rate of action can be developed by following the method discussed so far in this study.
REFERENCES
Aggarwal S, Gupta GD and Chaudhary S, Solid
dispersion as an eminent strategic approach in
solubility enhancement of poorly soluble drugs.
International Journal of Pharmaceutical Sciences
and Research, 1, 2010, 1-13.
Batra V, Shirolkar VS, Mahaparale PR, Kasture
PV, Deshpande AD, Solubility and Dissolution
Enhancement of Glipizide by Solid Dispersion
Technique, Indian J Pharm Educ Res, 42(4), 2008,
373-378.
Chaulang G, Patil K, Ghodke D, Khan S, Yeole P,
Preparation and Characterization of Solid
Dispersion Tablet of Furosemidewith
Crospovidone, Research J Pharm andTech, 1(4),
2008, 386-389.
Kumar DS, Solubility improvement using solid
dispersion; strategy, mechanism and characteristics:
responsiveness and prospect way outs. International
Research Journal of Pharmacy, 2, 2011, 55-60.
Mohanachandran PS, Sindhumo PG and Kiran TS,
Enhancement of solubility anddissolution rate: an
overview, International Journal of Comprehensive
Pharmacy, 4, 2010, 1-10.
Patidar Kalpana, Solid Dispersion: Approaches,
Technology involved, Unmet need & Challenges in
Drug Invention Today, 2(7), 2010, 349-357.
Sharma D, Soni M, Kumar S and Gupta GD,
Solubility Enhancement –Eminent Role in Poorly
Soluble Drugs. Research Journal of Pharmacy and
Technology, 2, 2009, 220-224.
Vanshiv SD, Rao MRP, Sonar GS, Gogad VK,
Borate SG, Physicochemical Characterization and
In Vitro Dissolution of Domperidone by Solid
Dispersion Technique, Indian J Pharm Educ Res,
43 (1), 2009, 86-90.
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enhancement techniques, International Journal of
Pharmaceutical Sciences Review and Research, 5,
2010, 41-51.

Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
TRANSDERMAL DRUG DELIVERY SYSTEMS
R.Sowjanya*, Salman Khan, D.Bhowmik, Harish.G, S.Duraivel
Department of pharmaceutics, Nimra college of pharmacy, Nimranagar,
Ibhrahimpatnam, Vijayawada, Andhra Pradesh.
*Coreesponding author: E. Mail id:debjit_cr@yahoo.com
ABSTRACT
Transdermal therapeutic systems have been designed to provide controlled continuous delivery of
drugs via the skin to the systemic circulation. The relative impermeability of skin is well known, and this is
associated with its functions as a dual protective barrier against invasion by microorganism and the
prevention of the loss of physiologically essential substances such as water. Elucidation of factors that
contribute to this impermeability has made the use of skin as a route for controlled systemic drug delivery
possible. The market for Transdermal devices is currently estimated at US$ 1.2 billion, approximately 10%
of the entire US $ 28 billion drug delivery market. In addition, Transdermal drug delivery market is
currently based on only 10 drugs. Hence, Pharmaceutical scientists are striving to add new deliverables to
the short list of approved Transdermal products.
Keywords Therapeutic activity, Bioavailability, First pass metabolism, Ionophoresis.
1. INTRODUCTION
For many decades, medication of an
acute disease or a chronic illness has been
accomplished by delivering drugs to the patients via
various pharmaceutical dosage forms like tablets,
capsules, pills, creams, ointments, liquid aerosols,
injectable and suppositories, as carriers. Recently,
several technical advancements have been made. They
have resulted in the development of new techniques of
drug delivery. These techniques are capable of
controlling the rate of drug delivery, sustaining the
duration of therapeutic activity, and/or targeting the
delivery of drug to a tissue. In responses to these
advances, several transdermal drug delivery systems
have recently been developed, aiming to achieve the
objective of systemic medication through topical
application on the intact skin surface. The principal of
transdermal drug delivery systems is that they could
provide sustained drug delivery (and hence constant
drug concentrations in plasma) over a prolonged period
of time. For these attributes, it is often extrapolated that
sustained therapeutic activity will also be obtained with
transdermal drug delivery systems. Thus, it is
anticipated that transdermal drug delivery systems can
be designed to input drugs at appropriate rates to
maintain suitable plasma-drug levels for therapeutic
efficacy, without the periodic sojourns into plasma
concentrations that would accompany toxicity or lack
of efficacy. Today, four drugs have been successfully
incorporated into transdermal drug delivery systems
for clinical use (Scopolamine, Nitroglycerine,
Clonidine and Estradiol), which establishes the dermal
route for systemic drug delivery. Ultimately, the
success of all transdermal systems depends on the
ability of the drug to permeate skin in sufficient
quantities to achieve its desired therapeutic effect.
(Roberts MS, 1997)
1.1. Advantages of TDDS:
1. Avoids the risk and inconveniences of
intravenous therapy
2. Bypass the variation in the absorption and
metabolism associated with oral
administration
3. Permit continuous drug administration and the
use of drugs with a short biological half-life.
4. Increase the bioavailability and efficacy of
drugs and bypass of hepatic first pass
metabolism.
5. Treatment can be continued or discontinued
according to the desire of the physician.
6. Greater patient compliance due to the
elimination of multiple dosing schedules.
1.2. Selection of drug candidate for transdermal
delivery: The transdermal route of administration
cannot be employed for a large number of drugs.
Judicious choice of the drug substance is the most
important decision in the successful development of a
transdermal system. The drug candidate should have
following ideas characteristics:
1.2.1. Adequate skin permeability:
 Drugs with low molecular weight
 Drugs with low melting point
 Drugs with moderate oil and water solubility
1.2.2. Adequate skin acceptability:

 Non-irritating drugs
 Non-irritating drugs
 Non-metabolizing drugs
1.2.3. Adequate clinical need:
 Need to prolong administration
 Need to reduce side effects on target tissues
 Need to increase patient compliance
1.3. Factors affecting transdermal permeation: The
principle transport mechanism across mammalian skin
is by passive diffusion through primarily the
transepidermal route at steady state or through trans-
appendageal route ay initial non-steady state. The
factors controlling transdermal permeability can be
broadly placed in the following cases
1.3.1. Physico-chemical properties of the penetrant
molecules: Partition co-efficient: Drugs possessing
both lipid and water solubility are favorably absorbed
through the skin. Transdermal permeability co-efficient
shows a linear dependency on partition co-efficient. A
lipid/water partition co-efficient of one or greater is
generally required.
1.3.2. pH conditions: The pH value of very high or
very low can be destructive to the skin. With moderate
pH values, the flux of ionisable drugs can be affected
by changes in pH that alter the ratio of charged and
uncharged species and their transdermal permeability.
1.3.3. Penetrant concentration: Increasing
concentration of dissolved drug causes a proportional
increase in flux. At higher concentrations, excess solid
drug functions as a reservoir and prolonged period of
time.
1.3.4. Physico-chemical properties of drug molecule:
Release characteristics: solubility of the drug in the
vehicle determines the release rate. The mechanism of
drug release depends on the following factors. Whether
the drug molecules are dissolved or suspended in the
delivery system.
1.3.5. Enhancement of transdermal permeation:
Majority of drugs will not penetrate the skin at the
rates sufficiently high for therapeutic efficacy; the
permeation can be improved by the addition of
permeation enhancer like dimethyl sulfoxide, dimethyl
formamide, propylene glycol, etc into the system
1.4. Physiological and pathological conditions of
skin:
1.4.1. Reservoir effect of horny layer: The horny
layer is deeper layer, can sometimes act as depot and
modify the transdermal permeation of drugs. The
reservoir effect is due to irreversible binding of a part
of the applied drug with the skin.
1.4.2. Lipid film: The lipid film on the skin surface
acts as a protective layer to prevent the removal of
moisture from the skin and helps in maintaining the
barrier function of stratum corneum.
1.4.3. Skin hydration: Hydration of stratum corneum
can enhance permeability. Skin hydration can be
achieved simply by covering or occluding the skin with
plastic sheeting, leading to accumulation of sweat.
Increased hydration appears to open up the dense,
closely packed cells of the skin and increase its
porosity.
1.4.3. Skin temperature: Raising the skin temperature
results in an increase in the rate of skin permeation;
this may be due to availability of energy required for
diffusivity.
1.4.4. Regional variation: Differences in nature and
thickness of the barrier of skin causes variation in
permeability.
1.4.5. Pathological injuries to the skin: Injuries that
disrupt the continuity of the stratum corneum,
increases permeability due to increased vasodilatation
caused by removal of the barrier layer.
1.4.6. Cutaneous self-metabolism: catabolic enzymes
present in the epidermis may render the drug inactive
by metabolism and thus the topical bioavailability of
the drug.
1.4.7. Penetration enhancers and their use in
transdermal therapeutic system: The transdermal
route for drug administration is limited by the barrier
properties of the skin. Only the most potent drugs with
low daily dose and appropriate physicochemical
characteristics are candidates for transdermal delivery.
To circumvent the low permeability nature of human
skin, pharmaceutical scientists are searching for safe
and effective skin penetration enhancers. Development
of penetration enhancer is important to improve the
low permeability of drug across the skin. Although
many penetration enhancers are known, their mode of
action is still not fully understood. The penetration
enhancers are agents that increase the permeability of
the skin or substances that reduce the impermeability
of the skin. According to Chien et.al., penetration
enhancers or promoters or promoters are agents that

have no therapeutic properties of their own but can
transport the sorption of drugs from drug delivery
systems onto the skin and/or their subsequent
transdermal permeation through skin. The accelerant
causes the keratin to swell and leaches out essential
structural material from the stratum corneum, thus
reducing the diffusional resistance and increasing the
permeability of drugs through skin.
1.5. Mechanisms of transdermal permeation: For a
systemically active drug to reach a target tissue, it has
to possess some physicochemical properties which
facilitate the sorption of the drug through the skin and
enter the microcirculation. The rate of permeation,
dq/dt, across various layers of skin tissues can be
expressed as:
dq/dt = Ps (Cd—Cr) .......... (1)
Where Cd and Cr are respectively, the
concentrations of a skin penetrant in the donor phase
(stratum corneum) and in the receptor phase (systemic
circulation), and Ps is the overall permeability
coefficient of the skin and is defined by
Ps = Ks Dss/ hs ...........(2)
Where, Ks = partition coefficient of the penetrant.
Dss = apparent diffusivity of penetrant,
hs = thickness of skin
Thus, permeability coefficient (Ps) may be a
constant, if Ks, Dss and hs terms in equation (2) are
constant under a given set of conditions. A constant
rate of drug permeation is achieved if Cd >> Cr, then
the equation (1) may be reduced to
dq / dt = Ps Cd
Molecular penetration through the various
regions of the skin is limited by the diffusional
resistances encountered. The total diffusional
resistance (Rskin) to permeation through the skin has
been described by Chien as:
R skin = Rsc + Re + Rpd .............. (4)
Where R is the diffusional resistance and
subscripts sc, e , pd refer to stratum corneum,
epidermis and papillary layer of the dermis
respectively. Of these layers, the greatest resistance is
put up by the stratum corneum and tends to be the rate
–limiting step in percutaneous absorption. When more
than one phase of the membrane is capable of
supporting separate diffusional currents through each
transdermal patch, then the pathways are configured in
parallel to one another and the total fluxes of matter
across the membrane is the sum of the fluxes of each
route and is expressed by:
J = A (f1 p1 + f2 p2 + ..........+ fn pn) C
Where J = diffusional flux and the term f1p1 +
f2p2 + ..........fnpn, defines the overall permeability
coefficient, C being the concentration drop.
1.6. Components of transdermal devices:
Transdermal drug delivery devices have come of age.
It is 24 years since the first US patents were issued to
these systems; today more than 100 patents describing
transdermal devices have been issued. Transdermal
devices are of 3 types, they are adhesive device,
monolithic matrix device and the reservoir system.
These devices basically contain:
1. Backing layer
2. Drug reservoir
3. Release control layer (polymer matrix)
4. Adhesive and peel strip
5. Enhancers and excipients.
The backing layer/membrane is flexible and
they provide a good bond to the drug reservoir, prevent
drug from leaving the dosage form through the top, and
accept printing. It is impermeable substance that
protects the product during use on the skin. Eg.,
metallic plastic laminate, plastic backing with
absorbent pad and Occlusive base plate (aluminium
foil), adhesive foam pad (flexible polyurethane) with
occlusive base plate (aluminium foil disc) etc.
The drug reservoir is generally made up
of adhesives and allow for the transport of drug at a
desired rate. The drug should be selected depending
upon clinical need and its physicochemical properties.
The following are some of the desirable properties of a
drug for transdermal delivery.
1.7. Physicochemical properties:
1. The drug should have a molecular weight
less than approximately 1000 daltons.
2. The drug should have affinity for both
lipophilic and hydrophilic phases.
3. The drug should have a low melting point.
1.8. Biological properties:
1. The drug should be potent with a daily
dose of the order of a few mg/day.
2. The half life (t1/2) of the drug should be
short.
3. The drug must not induce a cutaneous
irritant or allergic response.

4. Drugs which degrade in the GI tract or/are
inactivated by hepatic first-pass effect are
suitable candidates for transdermal
delivery.
5. Tolerance to the drug must not develop
under the near zero-order release profile of
transdermal delivery.
6. Drugs which have to administer for a long
period of time or which cause adverse
effects to non-target tissues can also be
formulated for transdermal delivery.
1.9. Polymer Matrix: The polymer controls the
release of the drug from the device. The following
criteria should be satisfied for a polymer to be used in a
transdermal system.
1. Molecular weight, glass transition
temperature and chemical functionality of
the polymer should be such that the
specific drug diffuses properly and gets
released through it.
2. The polymer should be stable, non-reactive
with the drug, easily manufactured and
fabricated into the desired product; and
inexpensive.
3. The polymer and its degradation products
must be non-toxic or non-antagonistic to
the host.
4. The mechanical properties of the polymer
should not deteriorate excessively when
large amounts of active agent are
incorporated into it.
1.10. Possible useful polymers for Transdermal
devices are:
1.10.1. Natural Polymers: Cellulose derivatives, Zein,
Gelatin, Shellac, Waxes, Proteins, Gums and their
derivatives, Natural rubber, Starch etc.
1.10.2. Synthetic elastomers: Polybutadiene, Hydrin
rubber, Polysiloxane, Silicone rubber, Nitrile,
Acrylonitrile, Butyl rubber, Neoprene etc.
1.10.3. Synthetic Polymers: Polyvinyl alcohol,
Polyvinyl chloride, Polyethylene, Polypropylene,
Polyacrylate, Polyamide, Polyurea,
Polyvinylpyrrolidine, Polymethylmethacrylate, Epoxy
etc.
1.10.4. Adhesives: The fastening of all transdermal
devices to the skin has so far been done by using a
pressure sensitive adhesive. The pressure sensitive
adhesive can be positioned on the face of the device or
in the back of the device and extending peripherally.
Both adhesive systems should fulfil the following
criteria. Should not irritate or sensitize the skin or
cause an imbalance in the normal skin flora during its
contact time with the skin. It should adhere to the skin
aggressively during the dosing interval without its
position being disturbed by activities such as bathing,
exercise etc. It should be removed easily from the
skin. It should not leave a un washable residue on the
skin. It should have excellent (intimate) contact with
the skin at macroscopic and microscopic level.
1.10.4.1. The face adhesive system should also fulfill
the following criteria:
1. Physical and chemical compatibility with the
drug, excipients and enhancers of the device of
which it is a part.
2. Permeation of drug should not be affected.
3. The delivery of simple or blended permeation
enhancers should not be affected.
4. Some widely used pressure sensitive adhesives
include polyisobutylenes, acrylics and
silicones.
1.11. Permeation Enhancers: These are compounds
which promote skin permeability by altering the skin
as a barrier to the flux of a desired penetrant.
Permeation enhancers are hypothesized to affect one or
more of these layers to achieve skin penetration
enhancement. A large number of compounds have
been investigated for their ability to enhance stratum
corneum permeability. These may be conveniently be
classified under the following main headings
1.11.1. Solvents: These compounds increase
penetration possibly by swelling the polar pathway
and/or by fluidizing lipids. Eg.,water alcohols-
methanol and ethanol ; alkyl methyl sulfoxides-
dimethyl sulfoxide, dimethyl acetamide and dimethyl
formamide, miscellaneous solvents-propylene glycol,
glycerol, isopropyl palmitate.
1.11.2. Surfactants: These compounds are proposed to
enhance polar pathway transport, especially of
hydrophilic drugs. Anionic surfactants can penetrate
and interact strongly with the skin. Cationic surfactants
are reportedly more irritant than the anionic surfactants
and they have not been widely studied as skin
permeation enhancers. Of the 3 major classes of
surfactants, the nonionics have long been recognised as
those with the least potential for irritation and have
been widely studied. Egs., of commonly used
surfactants are :

1.11.3. Anionic surfactants: Dioctyl sulphosuccinate,
Sodium lauryl sulphate, Decodecylmethyl sulphoxide
etc.
1.11.4. Nonionic surfactants: Pluronic F127, Pluronic
F68, etc.
1.11.5. Bile salts: Sodium taurocholate, Sodium
deoxycholate, Sodium tauroglycocholate.
Binary systems systems apparently open up the
heterogeneous multilaminate pathway as well as the
continuous pathways. Eg. Propylene glycol-oleic acid
and 1,4-butane diol-linoleic acid.
1.11.6. Miscellaneous chemicals: Urea, N,N-
dimethyl-m-toluamide, Calcium thioglycolate,
1.11.7. Anticholinergic agents: The enhancers used
should be pharmacologically inert, non-toxic, non-
allergenic and non-irritating. They should show a quick
onset of action, reduction of barrier function of the skin
only in one direction. On removal from skin, the
tissues should quickly and fully recover normal barrier
function. It should be compatible with all the
formulation components and should be an excellent
solvent for drugs.
2. TECHNOLOGIES OF DIFFERENT TYPES OF
TRANSDERMAL DRUG DELIVERY SYSTEM
Several technologies have been successfully
developed to provide a rate-control over the release
and skin permeation of drugs. These technologies can
be classified into the following approaches.
2.1. Membrane permeation controlled TDDS: In this
system, the drug reservoir is sandwiched between a
backing membrane and a rate-controlling membrane,
through which the drug is released. In the drug
reservoir, drugs are either dispersed uniformly in the
solid adhesive matrix (polyisobutylene) or suspended
in a viscous, leachable liquid (silicone fluid) or
dissolved in a releasable solvent (alkyl alcohol). The
rate controlling membrane can be either microporous
or non-porous membrane (Ethylene vinyl acetate
copolymers)
2.2. Adhesive type TDDS: In this system, the drug
resrvoir is formulated by directly dispersing the drug in
an adhesive polymer (polyisobutylene or
polyacrylate), then spreading the medicated adhesive
by solvent casting or hot melt, onto a backing support
to form a single layer or multiple layers of drug
reservoir
2.3. Matrix type TDDS: The drug reservoir here is
formed by homogeneously dispersing the drug in a
hydrophilic or lipophilic polymer matrix and the
medicated polymer formed is then moulded into
medicated discs with a defined surface area and
controlled thickness. This is then mounted onto a
backing membrane and the adhesive is applied outside
the disc along the circumference to form a strip of
adhesive rim.
2.4. Microreservoir TDDS: This type of drug delivery
system is formed by first suspending the drug in the
aqueous solution of a water-soluble polymer (eg.PEG)
and then dispersing homogeneously, the drug
suspension in a lipophilic polymer, by high shear
force, to form unleachable microscopic drug
reservoirs. These are also known as ‘Microsealed
Delivery Devices.
2.5. Poroplastic or Moleculon Type Devices: These
systems, developed at Moleculon, (Cambridge,
Massachusetts) utilise poroplastic films. The film is
made utilizing the concept of water coagulation of
cellulose triacetate solution in organic acids at low
temperature. The coagulation is performed under
controlled conditions and the extent of water content
may be varied to a great condition and degree.
2.6. Penetration enhancement: The permeation of
drugs across the skin is enhanced by physical means
like pulsed DC iotophorosis or effect of ultrasounds
may have synergistic effect depending upon the current
density of pulse current applied and ultrasound
intensity time (Chien YW, 1992).
2.6.1. Iontophoresis: It is a process that utilizes
bipolar electric fields to propel ionic drug molecules
across the intact skin into the underlying tissues.
Positively charged drug ions in solution are transferred
from a positive polarity chamber and vice versa.
Delivery of positively charged compounds is easier
than negatively charged compounds as the skin itself
possesses a net negative charge. Iontophoresis can
enhance transport across skin by a number of ways
including an electrophoretic driving force and an
electro-osmotic driving force and thus transiently
increasing skin permeability. The transdermal transport
can be increased by orders of magnitude relative to
passive diffusion-based methods and can be modulated
by controlling electrical parameters.
Food and Drug Adminstration (FDA) has
approved a number of products based on this technique
like pilocarpine and lidocaine patches. The delivery of

proteins and peptides and other small macromolecules
has been demonstrated in various articles. An
iontophoretic electrode, Trans-Q has been developed
such that the charge is delivered to a hydrogel pad
loaded with the drug solution. Most of the work is
going on to develop novel bioadhesive drug containing
electrodes for use in iontophoretic drug delivery.
Iontopatch SP transdermal drug delivery system is a
self-constrained ultra-thin technology that eliminates
the need of wires or batteries. It has an active area of
15.5 cm2
containing 40 mcg of the medicament.
Mostly this technology has been introduced as an
alternative to traditional treatment with injections.
Non-steroidal anti-inflammatory drugs and
corticosteroids are delivered by this mechanism. Alza
Corporation Ltd., has developed electro transport
system (E-Trans) for delivering fentanyl to treat acute
and post operative pain. The patient has to push the
button on the device which causes current to flow
between two electrodes and a predetermined amount of
drug is released through the skin. Also, a disposable
kind of iontophoretic patch called Power Patch for
delivering calcitonin to treat osteoporosis is under
clinical trial.
2.6.2. Sonophoresis: It involves the introduction of
substance into the body by ultrasound energy.
Ultrasound energy vibrates molecules and creates tiny
holes in the skin surface through ultrasound
technology. The pores remain open for 12 hrs
only.SonoPrep transdermal system from Sontra
Medical uses low frequency ultrasound for skin
permeation of lidocaine. It involves exposing the skin
to a coat of lipids and then applying ultrasound at a
frequency of 55,000 cycles per second causing creation
of tiny bubbles which expands both in the liquid layer
applied and the lipids of the skin. Thus, the skin of
that area becomes leaky and remains as such.
However, the pores get changed once the sound is
turned off. Similarly, ImaRx Therapeutics has
developed ultrasound assisted transdermal system
utilizing ultrasound transducers to activate a drug and
to open the skin pores for enhanced transdermal
delivery. This technique has been employed for large
molecular weight drugs such as peptides or proteins
having molecular weight between 6000 to 48000
Daltons.
2.6.3. Electroporation: It is known that the
mammalian skin is having intercellular lipids arranged
in bilayers, which do not allow the transport of the
drug transdermally. Electroporation is the technique by
which aqueous pores are created by electric pulse of
milliseconds causing transient permeability in the outer
membrane which facilitates transport of drug. Flux
increase upto four orders of magnitude was observed
with human skin in vitro for three polar molecules
having charges between –1 and –4 and molecular
weights up to slightly more than 1000 daltons. Similar
increase in flux was observed in- vivo with animal
skin. The commercial product MedPulser (Genetronics
Biomedical) is used on electroporation therapy system
for use in delivering pharmaceuticals and genes. This
electroporation system takes about 30 minutes and uses
very small dose of the drug. The flux values of the
model drugs increases exponentially and reaches the
steady state flux. The examples are heparin and
leutinizing hormone releasing hormone (LHRH),
which show increased transdermal absorption with this
technique.
2.6.4. Heat and Microneedles: Heat is also now
expected to enhance the transdermal delivery of
various drugs by increasing skin permeability, body
circulation, blood vessel wall permeability, rate
limiting membrane permeability and drug
solubility.Heating prior to or during topical application
of a drug will dilate penetration pathways in the skin,
increase kinetic energy and the movement of particles
in the treated area and facilitate drug absorption.
Heating the skin after topical application of a drug will
increase the drug absorption into vascular network,
enhancing the systemic delivery but decreasing the
local delivery as drug molecule is carried away from
local site. Tempera
are necessary to cause measurable changes in cell
permeability. Recently, some researchers have reported
the use of pressure driven jets for the intradermal
delivery of a variety of drugs. The pressure and
velocity of the jet were measured using calibrated
pressure transducers and high-speed photography and
showed the dependence on the drug delivery. Another
innovation in this field is controlled heat aided drug
delivery system (CHADD), which uses a thin heating
device, attached to the top of the transdermal patch.
The heat and temperature are controlled to deliver the
drug either as bolus or to match circadian rhythms. S-
Caine, a pediatric formulation of lidocaine and
tetracaine uses CHADD technology for attaining a
dense anesthetic effect in 15 to 20 minutes. Another
product-Titragesia, uses the same technology to deliver
fentanyl for treating pain.

3. CONCLUSION
The novel drug delivery system has brought
renaissance into the pharmaceutical industry for
controlled drug delivery. The novel drug delivery
systems include transdermal drug delivery system,
mucoadhesive drug delivery system, nasal drug
delivery system etc. The transdermal route of drug
delivery is gaining accolade with the demonstration of
percutaneous absorption of a large number of drugs.
This type of drug delivery with the intention of
maintaining constant plasma levels, zero order drug
input and serves as a constant I.V. infusion. Several
transdermal drug delivery systems (TDDS) have
recently been developed aiming to achieve the
objective of systemic medication through application
to the intact skin. The intensity of interest in the
pontential bio-medical application of transdermal
controlled drug administration is demonstrated in the
increasing research activities in a number of health
care institutions in the development of various types of
transdermal therapeutic systems(TTS) for long term
continuous infusion of therapeutic agents including
antihypertensives, antianginal, anti-histamine, anti-
inflammatory , analgesic drugs etc.
REFERNCES
Brahmankar DM, Jaiswal SB, Biopharmaceutics and
pharmacokinetics A Teatise, Vallabh Prakashan, Delhi,
1995, 335-371.
Chien YW, Novel drug delivery systems, Drugs and
the Pharmaceutical Sciences,
Vol.50, Marcel Dekker, New York, 1992, 797.
Roberts MS, Targeted drug delivery to the skin and
deeper tissues: role of physiology, solute structure and
disease, Clin Exp Pharmacol Physiol, 24(11), 1997,
874-9.
Amgaokar MY, Chikhale RV, Lade UB, Biyani DM,
Umekar MJ, Design formulation and evaluation of
transdermal drug delivery system of budesonide, Dig J
Nanomater and Biostruct, 6(2), 2011, 475-97.
Patel MP, Patel KN, Patel DR, Patel UL, Formulation
and evaluation of transdermal patches of
glibenclamide, Int J Pharm Res, 1(2), 2009, 34-42
Jamakandi VG, Mulla JS, Vinay BL, Shivakumar HN,
Formulation, characterization and evaluation of matrix-
type transdermal patches of a model antihypertensive
drug, Asian J Pharm, 3(1), 2009, 59-65.
Irfani G, Raj R S, Tondare A, Noola, Design and
Evaluation of transdermal drug delivery system of
valsartan using glycerine as plasticizer, IJPRD, 3(2),
2011, 185-92
Shivaraj A, Selvam RP, Mani TT, T Sivakumar,
Design and evaluation of transdermal drug delivery of
ketotifen fumarate Int J Pharm Biomed Res, 1(2),
2010, 42-47
Ashok KJ, Pullakanda N, Prabu SL, V Gopal,
Transdermal drug delivery system an overview,
IJPSRR, 3(2), 2010, 49-54

Navin et.al Indian Journal of Research in Pharmacy and Biotechnology
SYNTHESIS OF NEW THIAZOLIDINE-2,4-DIONE DERIVATIVES AND
THEIR ANTIMICROBIAL AND ANTITUBERCULAR ACTIVITY
Faiyazalam M Shaikh1
, Navin B. Patel1*
and Dhanji Rajani2
1. Veer Narmad South Gujarat University, Udhana-Magdalla Road, Surat-395 007, Gujarat, India.
2. Microcare Laboratory and Tuberculosis diagnosis & Research Centre, Surat.
* Corresponding author: E-mail: faiyaz_online007@yahoo.co.in; drnavin@satyam.net.in, Mobile:
+919825350484
ABSTRACT
New 1,3-thiazolidine-2,4-dione (TZD) derivatives 16-29 have been prepared by Knoevenagel
condensation reaction between TZD and aromatic aldehydes followed by condensation with 3,4-
dichloro benzoyl chloride. The structures of the newly synthesized compounds were assigned on the
basis of elemental analysis, IR, 1
H NMR and 13
C NMR spectral data. All the synthesized compounds
were tested for antibacterial activity against Gram-positive cocci and Gram-negative rods, antifungal
activity and antitubercular activity. Moderate to good activity results were found for the newly
synthesized compounds.
Key Words: 1,3-thiazolidine-2,4-dione, Knoevenagel condensation, antibacterial, antifungal,
antitubercular activity
1. INTRODUCTION
One of the main objectives of organic and
medicinal chemistry is to design, synthesize and
produce molecules possessing value as human
therapeutic agents. Compounds containing
heterocyclic ring systems are of great importance
receiving special attention as they belong to a class
of compounds with proven utility in medicinal
chemistry. Thiazolidine-2,4-dione (TZD) is a
heterocyclic ring system with multiple applications.
Thiazolidine-2,4-dione inhibits corrosion of mild
steels in acidic solution. These are also used in
analytical chemistry as highly sensitive reagents for
heavy metals and as a brighter in electroplating
industry. In 1982 a number of TZDs were intensively
studied for their anti-hyperglycaemic property. The
ﬁrst representative of this class was ciglitazone,
whereas other derivatives like englitazone,
pioglitazone and troglitazone followed soon. The
thiazolidine-2,4-dione nucleus has been reported for
being responsible for majority of their
pharmacological actions. Henceforth, thiazolidine-
2,4-dione derivatives have been studied extensively
and found to have diverse chemical reactivities and
broad spectrum of biological activities (Jain, 2013).
Thiazolidinediones (TZD) are biologically
active compounds having five membered rings, with
two heteroatoms. Thiazolidinediones displayed a
broad spectrum of biological activities including
antimicrobial (Gouveia, 2009; Tuncbilek and
Altanlar, 2006), antidiabetic (Murugan, 2009; Pattan,
2005), antiobesity (Bhattarai, 2009), anti-
inflammatory (Youssef, 2010), antioxidant (Bozdag-
Dundar, 2009), antiproliferative (Patil, 2010),
antitumor (Shimazaki, 2008), etc.
Currently, the antibiotic era is threatened by
the convergence of three adverse circumstances: high
levels of antibiotic resistance among important
pathogens, an uneven supply of novel classes of
antibiotics, and a dramatic reduction in the number of
pharmaceutical companies engaged in the discovery
and development of anti-infective agents (Wenzel,
2004). As a result, multidrug-resistant, and therefore
difficult-to-treat, infections continue to occur and are
clearly increasing in some areas. New antibiotics can
help stave off the catastrophe. But since 1987, no
major antibiotic has been discovered. In this regard,
it is important to develop new and safe nuclei to
combat with multidrug-resistant bacterial and fungal
infections. Substantial investment and research in the
field of anti-infectives are now desperately needed if
a public health crisis is to be averted. Looking
towards this turmoil of situation in the field of
antibiotics, we are reporting herewith synthesis and
antibacterial, antifungal and antitubercular activity of
new thiazolidinediones.
2. MATERIALS AND METHODS
2.1. General: Laboratory Chemicals were supplied
by Rankem India Ltd. and Ficher Scientific Ltd.
Melting points were determined by the open tube
capillary method and are uncorrected. The purity of
the compounds was determined by thin layer
chromatography (TLC) plates (silica gel G) in the
solvent system n-hexane: ethyl acetate (7.5:2.5). The
spots were observed by exposure to iodine vapors or
by UV light. The IR spectra were obtained on
Thermo Scientific Nicolet iS10 FT-IR spectrometer
(using KBr pellets). The 1
H-NMR & 13
C-NMR
spectra were recorded on a Varian Gemini 200
spectrometer using TMS as an internal standard in
DMSO-d6. Elemental analyses of the newly

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