FORMULATION AND EVALUATION OF DICYCLOMINE
HYDRO CHLORIDE SUSTAINED RELEASE TABLETS
M. Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore– 560 041
By
Mr. SAINI UDAY BHANU, B.Pharm
Under the Guidance of
Mr. SHIVANAND KALYANAPPA, M.Pharm
Asst. Professor
Department of Pharmaceutics
Acharya & B. M. Reddy College of Pharmacy
Soldevanahalli, Chikkabanavara (Post),
Hesaraghatta Main Road, Bangalore – 560 090
2009-2010
1
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1
NAME OF THE CANDIDATE
Mr. SAINI UDAY BHANU
AND ADDRESS
H.no:1-2, village: Karnamamidi,
Mandal: Mancherial, Dist: Adilabad,
Andhra Pradesh, 504207.
2
NAME OF THE
ACHARYA & B.M. REDDY COLLEGE OF
INSTITUTION
PHARMACY,
Chikkabanavara post
Hesaraghatta Main Road
Soldevanahalli
Bangalore - 560 090
3
COURSE OF THE STUDY
M. Pharm
AND SUBJECT
(Pharmaceutics)
11th June 2010
4 DATE OF ADMISSION
5 TITLE OF THE PROJECT:FORMULATION AND EVALUATION OF DICYCLOMINE HYDRO CHLORIDE
SUSTAINED RELEASE TABLETS
2
6
BRIEF RESUME OF INTENDED WORK :-
6.1 NEED OF THE STUDY :Gastrointestinal tract spasms are convulsive pain attacks projected to the abdomen. They
are generated by stimulation of mechanoreceptors in the enteric nervous system with successive
maximal increase of gastrointestinal mobility.
Irritable bowel syndrome (IBS or spastic colon) is a diagnosis of exclusion. It is
a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and
alteration
of
bowel
habits. In
some
cases,
the
symptoms
are
relieved
by bowel
movements. Diarrhea or constipation may predominate, or they may alternate. IBS may begin
after an infection, a stressful life event, or onset of maturity without any other medical
indicators.
IBS can be classified as either diarrhea-predominant (IBS-D), constipation-predominant
(IBS-C) or IBS with alternating stool pattern (IBS-A) or pain-predominant In some individuals,
IBS may have an acute onset and develop after an infectious illness characterized by two or
more of the following: fever, vomiting, diarrhea, or positive stool culture. This post-infective
syndrome has consequently been termed "post-infectious IBS" (IBS-PI).
Most people can control their symptoms with diet, stress management, and prescribed
medications. For some people, however, IBS can be disabling. They may be unable to work,
attend social events, or even travel short distance.
As many as 20 percent of the adult population, or one in five Americans, have symptoms
of IBS, making it one of the most common disorders diagnosed by doctors. It occurs more often
in women than in men, and it begins before the age of 35 in about 50 percent of people.
Acute enter colitis is one of the disease categories used for intestinal inflammation caused
by external factors such as viruses, bacteria and pharmaceutical agents.
References:
www.En.wikipedia.org/wiki/Irritable bowel syndrome.
www.Digestive.niddk.nih.gov/ddiseases/pubs/ibs
3
Dicyclomine Hydrochloride is an antispasmodic, anticholinergic drug, a medication that reduces
the effect of acetylcholine, a chemical released from nerves that stimulates muscles, by blocking
the receptors for acetylcholine on smooth muscle (a type of muscle). It also has a direct relaxing
effect on smooth muscle.
Dicyclomine Hydrochloride is used to treat or prevent spasm in the muscles of the
gastrointestinal tract in the irritable bowel syndrome. In addition, Dicyclomine Hydrochloride
inhibits gastrointestinal propulsive motility and decreases gastric acid secretion and controls
excessive pharyngeal, tracheal and bronchial secretions. In controlled clinical trials involving
over 100 patients who received drug, 82% of patients treated for functional bowel/irritable
bowel syndrome with Dicyclomine hydrochloride at initial doses of 160 mg daily demonstrated
a favorable clinical response compared with 55% treated with placebo (p<.05). In these trials,
most of the side effects were typically anticholinergic in nature and were reported by 61% of
the patients.
References: www.drugs.com/monograph/dicyclomine-hydrochloride.
www.flexyx.com/D/Dicycloverine%20Hydrochloride.
4
6.2
REVIEW OF LITERATURE : Ibrahim H et al., developed three coated wire electrodes (CWEs) for the antispasmodic
drugs; dicyclomine , mebeverine and drotaverine hydrochlorides based on ion-associate
of a heteropoly anion with the drug cation incorporated in membrane sensor modified
with graphite and deposited on silver internal solid contact. They compared the
characteristics of the new electrodes with characteristics of previously reported
traditional liquid inner contact electrodes of the same drugs. They demonstrated the
practical utility of each electrode has been d by using potentiometric determination of its
respective drug in pharmaceutical preparations both in batch and flow injection
conditions.1
 Ibrahim H et al., Used five plastic membrane electrodes for the determination of
dicyclomine hydrochloride (DcCl).The membranes of these electrodes consist of
dicyclominium-silicotungstate (Dc-ST), silicomolybdate (Dc-SM), phosphotungstate
(Dc-PT), phosphomolybdate (Dc-PM) or tetraphenylborate (Dc-TPB) ion-associations
dispersed in PVC matrix with dibutyl phthalate plasticizer. The electrodes exhibit good
selectivity for DcCl with respect to a large number of inorganic cations, organic cations,
sugars and amino acids2
 Claudio A L et al., investigated the influence of pellet core properties and different
coating parameters on in vitro theophylline release. They showed that pellet size and
pellet surface have a distinct effect on the release behaviour, with the surface
morphology also playing a They compared organic solvent-based and two aqueous
dispersion-based polymer systems for sustained-release diffusion membranes were with
respect to the influence of coating process parameters. They demonstrated product bed
temperature, an important process parameter, proved to be noncritical for the organic
solvent-based system within a product bed temperature range of 30-45”C, by well
reproducible release values. Release values showed a distinctly higher relative standard
deviation at the lower spray rate, probably due to spray losses, the spray rate has to be
carefully optimised. They demonstrated compared with organic solvent-based lacquer
5
systems, aqueous latex systems involve higher development and production costs, by
the influence of the product bed temperature and the subsequent curing3.
 Hoffman A et al., demonstrated features of sustained release (SR) mode of drug
administration impact on the magnitude of the pharmacologic response: (a) it minimizes
fluctuation in blood drug concentrations (i.e. between peak and trough). Due to the
pronounced non-linear relationship between drug concentration and pharmacologic
effect (i.e. pharmacodynamics) the impact of this property differs considerably as a
function of the shape of the pharmacodynamics profile and the position of the specific
range of concentrations on the curve of this profile; (b) it produces a slow input rate
which tends to minimize the body’s counteraction to the drug’s intervening effect on
regulated physiological processes; and(c) it provides a continuous mode of drug
administration. This important pharmaco dynamic characteristic may produce, in certain
cases, an opposite clinical effect than that attained by an intermittent (pulsatile) mode of
administration of the same drug.4
 Reitz C et al., focused on the structural characterization of sustained-release lipid
matrices prepared by solid lipid extrusion. They analysed drug-containing lipid
extrudates in order to identify differences between the chemical and structural
composition of surface and core elements. Independent of the lipid the dissolution from
the outer extrudate surfaces was slower compared with dissolution from surfaces
prepared by cutting the extrudate. The burst effect was higher for the cross-sections
indicating more drug was exposed on these surfaces. The release from glycerol
trimyristate (Dynasan 114®) extrudates was slower compared with glycerol
palmitostearate (Precirol ATO 5®) extrudates. By solid-state analysis using DSC, ATRFTIR and SEM measurements the differences between surface material and core material
could be attributed mainly to morphological differences. Chemical differences between
the core and the outer surface were not relevant. The differences between the surfaces
might be explained by the friction induced temperature increase during extrusion in the
die plate. Results obtained and a proposed scheme were used to explain the influence of
different formulation/processing parameters, such as drug particle size and milling on the
6
drug dissolution behaviour. Small drug particles and intact extrudates are a means of
minimizing the burst release5.
 Ishida M et al., developed and optimised a novel oral controlled delivery system for
propranolol hydrochloride (PPL). They determined in vitro dissolution profiles of
sustained-release matrix tablets of racemic PPL and compared with the United States
Pharmacopeia (USP) tolerance specifications for propranolol hydrochloride extendedrelease capsules. They investigated the influence of matrix forming agents (native
dextran, hydroxypropyl methylcellulose (HPMC), and cetyl alcohol) and binary mixtures
of them on PPL release in vitro. They applied a central composite design to the optimize
the sustained-release tablet formulation. They obtained sustained-release matrix tablets
with good physical, mechanical and technological properties with a matrix excipient:PPL
ratio of 60:40 (w/w), with a dextran:HPMC ratio of 4:1 (w/w) and with a cetyl alcohol
amount of 15% (w/w). Established a comparative kinetic study of the present matrix
tablets and commercial SUMIAL RETARD capsules (Spain) .The value for the
similarity factor (f2 = 69.6) suggested that the dissolution profile of the present two
sustained-release oral dosage forms are similar6.
 Ishida M et al., developed and optimized a novel pseudoephedrine hydrochloride (PSE)
sustained-release dosage form. The system comprises immediate-release mini-tablets (IRMT)
and sustained-release mini-tablets (SRMT) contained in a hydroxypropyl methylcellulose
(HPMC) capsule. The IRMT contained PSE, excipients and low-substituted hydroxypropyl
cellulose (a disintegrate), and the tablets were coated with HPMC, a water-soluble polymer.
IRMT prepared with varying amounts of low-substituted hydroxypropyl cellulose all dissolved
completely within the first 60 min, so low-substituted hydroxypropyl cellulose content does not
greatly influence PSE release. The SRMT contained only PSE and excipients, and were coated
with a mixture of HPMC and the water-insoluble polymer ethylcellulose. They released PSE
release profile for the SRMT could be controlled by varying the thickness of the coat, and the lag
time could be controlled by varying the amount of ethylcellulose present in the polymer coat.
PSE immediately from our encapsulated mini-tablet system and release was sustained over an
extended period of time: the PSE in the IRMT dissolved within 60 min, whereas the PSE in the
7
SRMT was released over 8–10 h. This system can be modified to yield various extended drugrelease profiles, thereby harnessing the benefits of both SRMT and IRMT7.

Goudanavar
P S et al., Prepared sustained release Microcapsules of Salbutamol
Sulphate using cellulose acetate phthalate, cellulose acetate and glyceryl monostearate
polymers in different drug polymer ratio and evaluated for drug content, particle size
determination and in vitro release behavior as per United states Pharmacopoeia in
simulated gastric fluid (pH 1.2 ± 0.1) up to 0-2 hrs and in simulated intestinal fluid (pH
7.5 ± 0.1) up to 2-12 hrs. They prepared three formulations of 1:1, 1:2 and 1:3 in drug
polymer ratio for cellulose acetate phthalate and cellulose acetate by solvent evaporation
technique and three formulations of glyceryl monostearate by melt dispersion technique.
All the formulations shown uniformity in drug content, sieve analysis results indicated
that major fraction of microcapsules lies in the range of 425 to 600μm in all formulations
and in vitro dissolution studies pointed that only CAP 1 and GMS 1 formulations failed
to sustain the drug release up to 12 hrs. They prepared drug release mechanism from
microcapsules and found to be diffusion controlled and they followed first order release
kinetics. Finally it was concluded that Solbutamol sulphate can be effectively
microencapsulated using Cellulose acetate phthalate (CAP) and cellulose acetate by
solvent evaporation technique and glyceryl monostearate by melt dispersion technique.8
 Abhijit N M et al., formulated and evaluated a matrix system for sustained and
simultaneous delivery of anti-asthmatic drug Salbutamol sulphate which is often
indicated for the management of asthma, their frequent dosing may reduce compliance,
thus making prolonged release formulation necessary. The matrix tablets prepared by
wet granulation method using Ion exchange resins. The granules showed satisfactory
flow properties and compressibility. All the five tablet formulations showed acceptable
pharmaco technical properties and complied with the in-house specifications for tested
parameters. They evaluated for angle of repose, friability, hardness, disintegration and
dissolution.9
8
 Fei W et al .,maintained polymer-based sustained-release delivery systems therapeutic
concentration of protein drugs for extended periods of time, there has not been a single
product in this category successfully commercialized to date despite clinical and market
demands. To achieve successful systems, technical difficulties ranging from protein
denaturing during formulation process and the course of prolonged in vivo release, burst
release, and incomplete release, to low encapsulation efficiency and formulation
complexity have to be simultaneously resolved. Reported based on this updated
understanding,
formulation
strategies
attempting
to
address
these
aspects
comprehensively 10
 Raghuram
Reddy K et al., developed once-daily sustained-release matrix tablets of
nicorandil, a novel potassium channel opener used in cardiovascular diseases. They
prepared tablets by the wet granulation method. Etha-nolic solutions of ethylcellulose
(EC), Eudragit RL-100, Eudragit RS-100, and polyvinyl pyrrolidone used as granulating
agents along with hydrophilic matrix materials like hydroxypropyl methylcellulose
(HPMC), sodium carboxymethylcellulose, and sodium alginate. They evaluated granules
for angle of repose, bulk density, compressibility index, total porosity, and drug content.
The tablets were subjected to thickness, diameter, weight variation test, drug content,
hardness, friability, and in vitro release studies. The granules showed satisfactory flow
properties, compressibility, and drug content. All the tablet formulations showed
acceptable pharmacotechnical properties and com-plied with in-house specifications for
tested parameters. Ac-cording to the theoretical release profile calculation, a once-daily
sustained-release formulation should release 5.92 mg of nicorandil in 1 hour, like
conventional tablets, and 3.21 mg per hour up to 24 hours. The results of dissolution
studies indicated that formulation F-I (drug-to-HPMC, 1:4; ethanol as granulating agent)
could extend the drug release up to 24 hours. In the further formulation development
process, F-IX (drug-to-HPMC, 1:4; EC 4% wt/vol as granulating agent), the most
9
successful formulation of the study, exhibited satisfactory drug release in the initial
hours, and the total release pattern was very close to the theoretical re-lease profile. All
the formulations (except F-IX) exhibited diffusion-dominated drug release. The
mechanism of drug release from F-IX was diffusion coupled with erosion.11
10
6.3 OBJECTIVE OF THE STUDY :The objectives of the present study is highlighted as given below:
1. To carry out pre-formulation studies such as angle of repose, bulk density, Carr’s index
whichever are required.
2. To design and develop SR tablet by wet granulation method, dry granulation or direct
compression whichever is suitable.
3. To carry out in-vitro release studies using suitable testing apparatus.
4. To carry out stability studies on the most satisfactory formulation as per ICH guidelines
at 30 ± 2°C (65 ± 5 %RH) and 40 ± 2°C (75 ± 5 %RH).
11
7
MATERIALS AND METHOD :-
7.1 SOURCE OF DATA:1) The review of literature of the following study has been obtained from the following journals
as mentioned below:
a) Journals such as
i) European Journal of Pharmaceutical Sciences
ii) International Journal of Pharmaceutics
iii) Indian Journal of Pharmaceutical Sciences
iv) Asian Journal of Pharmaceutics
2) The review for the forthcoming studies will be taken from the following:
a) World Wide Web.
b) J-Gate @ Helinet.
12
7.2 METHOD OF COLLECTION OF DATA :1. To carry out preformulation study
a) Drug polymer interaction by FTIR.
b) Micrometrics studies
 Angle of repose
 Bulk density
 Percentage Compressibility.
2. To develop and formulate SR tablets by direct compression/wet granulation methods
using various polymers.
3. Evaluation of the various properties of the formulated floating tablets.
a) Physico-chemical properties: Diameter and thickness
 Hardness and friability
 Uniformity of weight and content
b) In vitro dissolution studies will be carried out in a USP Type-II dissolution
apparatus containing simulated gastric fluid (pH-1.2, without enzyme) for 12 h.
4. To carry out short term stability studies on the most satisfactory formulation as per
ICH guidelines at 30 ± 2ºC (65 ± 5% RH) and 40 ± 2ºC (75 ± 5%RH).
13
7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INVESTIGATION TO BE
CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?
“NO”
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN
CASE OF 7.3?
“NOT APPLICABLE”
14
8 REFERENCES :1.
Ibrahim H , Issa Y M , Hazem M A. Improving the detection limits of antispasmodic
drugs electrodes by using modified membrane sensors with inner solid contact . J Pharm
Biomed Anal 2007;44:8- 15.
2. Ibrahim H, Issa Y M , Hazem M A. Potentiometric flow injection analysis of
dicyclomine hydrochloride in serum, urine and milk. Analytica Chimica Act
2005;532:79-88.
3. Claudio A L , Grunenberg P C , Junger H , Laicher A. Influence of process parameters
on sustained – release theophylline pellets coated with aqueous polymer dispersions and
organic solvent – based polymer solutions. Eur J Pharm Bio pharm 1997; 43:149 –57.
4. Hoffman A. Pharmacodynamic aspects of sustained release preparations. Adv Drug
Deliv Rev1998; 33: 185 – 99.
5. Reitz C, Strachan C, Kleinebudde P. Solid lipid extrudates as sustained – release
matrices: The effect of surface structure on drug release properties. Eur J Pharm sci
2008; 35:335 – 343.
6. Castellanios E, Iraizoz C A , Bataille B, Pedraz J L , Fernand R, Heinamaki J.
Development and optimization of a novel sustained – release dextran tablet formulation
for propranolol hydrochloride. Int J Pharm. 2006; 317(1):32-9.
7. Ishida M, Abe K, Hashizume M, Kawamura M. A novel approach to sustained
pseudophedrine release: Differentially coated mini-tablets in HPMC capsules.
Int J Pharm2008;359:46-52
8. Goudanavar P S, Patil S M, Manavi F V. Design and characterisation of Sustained
Release Microcapsules of Salbutamol Sulphate. Int J PharmTech
Research2010;2(2):1144-1149.
9. Abhijit N M, Rahul K G, Smita K P, Bhanudas S K, Prakash N K, Prasad P T, Nachiket
S D. Formulation and in vitro – in vivo evaluation of Salbutamol Sulphate sustained
release tablets. Der Pharmacia Lettre2010;2(1):546-552.
10. Fei W , Tuo J. Polymer – Based Sustained – Release Dosage Forms for Protein Drugs,
Challenges and Recent Advances AAPS PharmSciTech,2008;9(4).
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11. Raghuram Reddy K , Srinivas M, Srinivas Reddy. Once – Daily Sustained – Release
Matrix Tablets of Nicorandil :Formulation and In – Vitro Evaluation. AAPS
PharmaSciTech.2003;4(4):61.
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Signature of the candidate:
10
Remarks of the Guide:
11
Name and Designation of:
12
11.1
Institutional Guide:
11.2
Signature:
11.3
Co-Guide:
11.4
Signature:
11.5
Head of the Department:
11.6
Signature
12.1
Remarks of the Principal
12.2
Signature
Dr. Goli Divakar
PRINCIPAL
Dr. Kalyani Prakasam
Professor & HOD
Dr. Goli Divakar
Principal
Acharya & B. M. Reddy
College of Pharmacy,
soldevanahalli,
hesaraghatta main road,
Bangalore-90.
17
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