Annals of Phytomedicine 1(2): 39-44, 2012
Formulation of solid dosage forms using natural ingredients and
novel method development for estimation of drug content
Syed Mohammed Kazim * and Mohammed Ibrahim *, **
* Nizam Institute of Pharmacy and Research Center, Deshmukhi, Pochampally, Near Ramoji Film City, Nalgonda-508284, AP, India
**Asian Institute of Advance Scientific and Pharmaceutical Research, Hyderabad-500058, A.P, India.
Received for publication September 7, 2012; accepted November 10, 2012
The study is based upon the formulation of solid dosage forms, using naturalingredients and a novel method development for the estimation of individualingredients in various combination units. Tablets of analgesic drug mafenemicacid in combination with dicyclomine, a smooth muscle relaxant was prepared. Ahepatoprotective agent DL-methionine was also incorporated in the formulation.
Enhancement of bioavailability of analgesic tablets by introducing the seeds ofLallemantia royleana
(commonly known as Balanga) was achieved,accompanied with the estimation of the amount of methionine, incorporated in theformulation. The mathematical tool of orthogonal polynomials was implementedfor the above estimation of percentage purity of a particular ingredient in theabove complex formulation.The novel formulation is evaluated in terms of itsbioavailability by comparing the parameters like disintegration time and dissolutiontime, with that of the standard formulations. The above assessment was carriedout to establish the role of the natural disintegrant used. There are many methodsto enhance bioavailability; one of the methods is the reduction of disintegrationtime. Balanga seeds are used for the above purpose as the seeds are known tocontain plenty of mucilage within its chemical constituents. The mucilage absorbswater by imbibition and helps in tablet disintegration.
Balanga seeds, Bioavailability, Disintegration time, Orthogonal
(i) Effect of water absorption
It can be defined as the process by which
The water absorbed by the tablet initiate disintegration, but
the tablet breaks down or loses cohesion. It is the time required
this depends on the solubility of the drug and other ingredients
for the tablet to break down into aggregates. Several
mechanisms of tablet disintegration have been proposed.
Eventhough these concepts are listed separately.
Interrelationships probably occur in almost all tablet
The grains of the disintegrant, particularly of starches, swell
in the presence of water and exert pressure on the granulesto force them apart. Shangraw et al.
(1980) reported thattablets of water insoluble drugs disintegrated faster withstarches than those of water soluble drugs due to thediminished water absorption capacity of the starches in the
Author for correspondence:
Professor Syed Mohammed Kazim
Nizam institute of Pharmacy and Research Centre, Deshmukhi,
Imbibition is defined as the displacement of one fluid by
Pochampalli, Near Ramoji Film City, Nalgonda-508284, A.P., India
another immiscible fluid. This process is controlled and
affected by a variety of factors. The capillary number (Ca)
and the mobility ratio (M) have the greatest importance. It isalso defined as the phenomenon by which the living or deadplant cells absorb water by surface attraction.
Porosity of tablets:
It has been shown that penetration of
water into a tablet is proportional to its mean pore diameter or
porosity. The porosity and permeability of tablets decrease as
the tabletting pressure is increased, and as the porosity
decreases, the disintegration time increases. Though, no
quantitative relationships have been reported between
disintegration and penetration times, generally short
disintegration times are associated with rapid fluid penetrationand drug absorption. Thus, the above parameter is related
Dicyclomine hydrochloride occurs as a fine, white, crystalline,
directly to the absolute bioavailability of drugs (
practically odorless powder with a bitter taste. It is soluble in
water, freely soluble in alcohol and chloroform, and veryslightly soluble in ether (Chananont and Hamor,1981).
Lallemantia royleana Benth (Commonly known as Balanga)
10.8% of fixed oil is present.
Verbenone (16.4%) and trans-carveol (9.8%) were the major
components of the oil (Braj Kishore Malavya and
Shikibhushan Dutt.,1941). The exact chemical constituents
responsible for the specific therapeutic activity are not
known. When moistened with water, the seeds become
voluminous and form translucent mucilage.
Chemical structure for DL-METHIONINE
Methionine may be one of the earliest organic substances,formed in evolution. In man, it is essential as a donor of thecritical methyl (CH ) group (Banesh,1978) and as a sulphur
donor. The CH group comes from its activated form, SAM
(S-adenosyl N-methionine), and goes into the formation ofimportant compounds like choline (in bile acids,phospholipids), creatine (in muscles), epinephrine (a neuro-transmitter), and carnitine (essential for oxidation of fat).
Methionine is also a component of enkephalin and variousendorphins (the painrelieving brain peptides), coenzyme A,
heparin, biotin, and the tripeptide glutathione, an all-important
Systematic (IUPAC) name 2-(2,3-dimethylphenyl) amino
antioxidant and detoxifying agent. Vitamin B , B and folate,
and probably magnesium are involved in methionine
Mefenamic acid binds the prostaglandin synthetase receptors
metabolism; and selenium, an essential trace element, needsmethionine for absorption, transportation and bioavailability
COX-1 and COX-2, inhibiting the action of prostaglandinsynthetase. As these receptors have a role as a major mediator
(Chaitow,1985). With low methionine levels, folate is trapped
of inflammation and/or a role for prostanoid signalling in
in the liver causing temporary folic acid deficiency
activity-dependent plasticity, the symptoms of pain are
(Anonymous,2008). Methionine is metabolised to
temporarily reduced ( Cryer and Feldman,1998).
homocysteine, excess of which is believed to causeatherosclerosis by its oxidant effect (Murphy et al
is an antispasmodic and
This hazard is less with adequate Vitamin B which helps
anticholinergic (antimuscarinic) agent available in various
reconversion of homocysteine to the antioxidant
(cystathione). Methionine hastens histamine breakdown and
Chemically, BENTYL (dicyclomine hydrochloride) is
reputedly lowers serum calcium in animals.
[bicyclohexyl]-1-carboxylic acid, 2-(diethylamino) ethyl ester,
Methionine has been used to acidify urine, to antagonize
hydrochloride with the following chemical structure:
radiation effects and to treat paracetamol poisoning
(Meredith et al
.,1978) through its conversion into cysteine
top and bottom is held against a 10 no. screen. Tablet is
and glutathione. The average methionine dose is 1-2 g/day
placed in each tube and the basket rack is positioned in a 1
liter beaker of water at 37 0C such that the tablet remains 2-5cm below the surface of liquid on their upward movement
and descend not closer than 2-5 cm from the bottom of the
Extraction of balanga mucilage
beaker. A standard motor device is used to move the basketassembly ontaining the basket up and down through distance
Crushed seeds were extracted by hot benzene in a large
of 5-6 cm at a frequency of 28-32 cycles/min. limit specified is
extraction flask, and after removal of the solvent by distillation;
the crude fixed oil was left behind as a bottle green andsomewhat opalescent liquid. It was treated with animal
Estimation of methionine in the pharmaceutical dosage forms
charcoal and Fuller’s earth and was ultimately obtained as
by applying orthogonal polynomials
transparent light green oil(Mohammad Amini and Razavi,
A novel method for the estimation of DL-Methionine in
Three different formulations were prepared which are as
various pharmaceutical dosage forms like tablets and syrups
follows: Formulation-I was prepared according to the standardprocedure without the incorporation of balanga mucilage.
was developed. The absorbance of the solution was
measured at 570 nm. Beer-Lambert’s law was observed to
mucilage. Formulation-III was prepared by adding 4 g of
obey in the range of 10-100 µg. In the estimation of methionine
balanga mucilage. These three formulations were compared
in pharmaceutical dosage forms, the quadratic polynomial
by conducting the evaluation tests for tablet dosage forms
coefficient was computed by measuring the fluorescence of
such as weight variation, hardness, friability, disintegration
the drug in 0.01N hydrochloric acid and six points equally
spaced at 5nm levels on the emission spectrum from 550 to575 nm were plotted. The quadratic polynomial coefficient
was found to be linear (directly proportional) to the
The conventional tablets were prepared with wet granulation
concentration in the range 0.5 to 2.0µg.
technique. The active ingredients were mixed with the diluents
Method - A
for about 4-5 min.Granulating agent was prepared withsoluble starch in the form of a paste. Granulation was done
For quantitative analysis, mafenemic acid, dicyclomine,
by mixing the mass powders to form a dough. Disintegrating
methionine suspension (20 mg) was transferred to 100 ml.
agent as per the formula was dried starch and balanga
calibrated flask and made up to the mark with water. In the
mucilage. The mucilage was mixed along with the wet dough.
case of tablets accurately weighed powder equivalent to
The dough was made to pass through a sieve of number10.
20 mg of methionine was transferred to 100 ml of calibrated
The above obtained granules were dried in the hot air oven
flask and made up to the mark with water. Weigh accurately
for about 30 minutes at a temperature of 45 degrees. The
20 mg of the reference standards and transferred into a 250 ml
above dried granules after removing the fines were lubricated
calibrated flask and make up to the mark with water. Filter the
with talc and aerosol. The above granules were punched into
test reference standard solution, and pipette 5 ml of the test
tablets using 10mm punch of concave surface (Table 1).
and reference standard into 25 ml calibrated flasks. The flasks
Evaluation tests as per I.P.
are kept for 20 minutes in the boiling water along with the
blank. The violet blue coloured chromogen having a maximumabsorbance was recorded at 570 nm. The flasks were allowed
Monsanto hardness tester is used. The hardness of uncoated
to cool to room temperature before being made up to mark with
tablets should be between 3-7 kg/cm2 (Table 2).
water and the absorbance of the test and reference standard
solutions were read against blank at 570 nm. (Table 5).
Roche friabilator is used. 20 tablets are selected at random
Method - B
and weighed. They are placed in a friabilator and operated
The fluorescence readings of the standard methionine solution
for 100 revolutions at 25 rpm. The tablets are dropped at a
was scanned from 550 nm to 575 nm at 5 nm intervals, using
distance of 6 inches with each revolution. The tablets are
0.01N hydrochloric acid as blank. The excitation wavelength
then dusted and reweighed. The acceptable limit is 0.5 to 1%
to measure the fluorescence reading was set at 570 nm as the
excitation maxima occurred at this wavelength. The quadratic
polynomial coefficient was calculated for six points of 5 nm
The standard pharmacoepial disintegration apparatus is used.
intervals for every segment from 550 nm to 575 nm.
It consists of 6 glass tubes that are 3 inches long, open at the
P2f=(5) F -(1) F - (4) F – (4) F (-1) F + (5) F
sec,7.0 min, 3 min 50 sec,4min 50 sec.and 1 min 10 sec ,2 min
18 sec, respectively. The subsequent reduction in the
Where F is the value of fluorescence and the subscript
disintegrating time is attributed again to the increase in the
denotes the wavelength at which it is measured and the figures
content of balanga. The disintegrant, particularly of
in the brackets taken from standard texts on numerical
mucilage’s, swell in the presence of water and exert pressure
analysis. The quadratic polynomial coefficient (P2f) was more
on the granules to force them apart quickly.
for the segment 550 to 575 nm and, hence, was chosen for themethod (George,1968 and Rao,1966). The amount of drug
Both isomers of methionine D and L forms, gave Rf values
content in the dosage form was calculated from equation 2.
0.32 and 0.40, respectively. The test sample showed thepresence of both the isomers. The violet blue chromogen
Vt / Vs x Ws/ Wt x A.W/D x 100 = % of the label claim. …Eq. 2
gave linear responses on the concentration range 10-100
Where Ws and Wt are the weights of the standard drug and
mcg. The recovery experiments gave 98 to 99% recovery
the sample preparation.A.W is the average weight of the
with 99 to 100% reproducibility by method A as shown in
tablet and D the labeled drug content, all the weight being
expressed in the mg. Vt and Vs are the values of quadratic
Also the formulation was put on trial for the estimation of
polynomial coefficient, calculated for the test and standard,
percentage purity of methionine by applying orthogonal
respectively, using Eq….active ingredients like asprin,
polynomials to all the three formulations. The formulation 1
Ibuprofen and excipients like mannitol, parabens, sugar.
was considered as the standard and the other two formulations
Essence and coloring agents did not interfere with proposed
were compared with that of the standard one. The quantitative
method as indicated by the quantitative recovery. The
analysis for methionine in the test formulations 2 and 3
proposed method can be used for quantitative analysis of
showed that the foreign absorbance’s were ignored by the
application of the polynomial coefficients. The analysis was
Results and Discussion
done by the application of quadratic polynomials with taking6 points into consideration.
Chemical tests of Lallemantia royleana Benth
Balanga powder was subjected to ruthenium red test, gavereddish pink colour, indicating the presence of mucilage in
It is ascertained that natural disintegrants are far more superior
the seeds. The above powder was also subjected to molisch
to the synthetic ones. The disintegrant (balanga mucilage) is
test formation of reddish pink ring indicates the presence of
found to be absorbing water instantly, followed by its
imbibition. This results in the easy break down of the tablets
Evaluation of physical properties of tablets
in turn resulting in the deaggregation of all the granules.
Furthmore, mucilage of balanga seeds also helps in the
The hardness of tablets of all the three groups of formulations
dissolution of the drug. The high water absorption tendency
1, 2, and 3. was measured and was found to be within the
of balanga mucilage which encircles each drug particle retains
range of 5.0-6.2, 4.5-5.5,3.0-4.0, respectively. The addition of
water within the vicinity and promotes the drug solvation.
balanga mucilage appears to have reduced the bulk density
Balanga mucilage is found to be superior to other suitable
of the powder blend and subsequently granules. However,
disintegrants like aerosil (silica) in terms of action, availability
the reduction in hardness for formulation 3 was found to be
. Aerosil has been found to be less preferable as a
disintegrating agent because it has carcinogenic properties,
The three formulation categories were subjected to
it is highly expensive and furthermore it has very low density
comparative studies, taking their friability into account. The
which creates difficulty in granulating tablets.The mucilage
friabilities of three formulations were found to be in the range
of balanga is, furthermore known to have various other
of 0.48-0.88%,0.46-1.0%, and 0.97-1.2%, respectively. The
properties like healing, laxative, etc
. The mucilage is found to
increase in friability is attributed the proportionate increase
be stable and does not interact with other drugs or excipients.
in the content of balanga from formulations 1-3. However,
The above study needs to be conducted in much more
the friability of formulation 3 is still within the acceptable
elaborated way and has a lot of scope and potential in
limits. The three formulations were again subjected to
upgrading the formulations in drug industry. Also the method
disintegration test. The disintegrating times of the three
of estimating drug content by using orthogonal polynomials
formulations were found to be within the ranges of 5 min 50
is much more feasible and reliable and is also precise.
Fromulation of tablets with natural ingredients
Formulation-II (a) for
Formulation-II (b) for
(Qty in g)
(Qty in g)
(Qty in g)
Hardness tests as per I.P
Friability tests as per I.P
Friability= (W1-W2)/W1X 100
Disintegration tests as per I.P
(time in min)
(a) (time in min)
(b) (time in min)
Assay of methionine by the proposed method% amount found
Chananont, P. and Hamor, T. A. (1981). Stereochemistry ofanticholinergic agents. XV. Structure of 2-(diethylamino)ethyl 1-
I sincerely thank to my guide, Dr. Mohammed Ibrahim,
cyclohexylcyclohexanecarboxylate hydrochloride (dicyclomine
hydrochloride) Acta Cryst, 37
Principal, Nizam Institute of Pharmacy and Research Centre,for rendering his suggestions and helping me at each and
Shangraw, R.F.; Mitrevej, A. and Shah, M. (1980). A new era of tablet
every step of completion of this research work successfully.
disintegrants. Pharm Technol., 4
Shargel, L. and Yu, A.B. (1999). Applied biopharmaceutics and
pharmacokinetics (4th ed.). New York: McGraw-Hill.
Mohammad Amini, A. and Razavi, S. (2012). Dilute solution properties
of Balangu (Lallemantia royleana
) seed gum: Effect of temperature,
salt, and sugar. International Journal of Biological Macromolecules,
Benesh, F.C. and Carl, G.F. (1978). Methyl Biogenesis, Bio Psychiat,13
Braj Kishore Malavya and Shikibhushan Dutt ( 1941). Chemicalexamination of the fixed oil derived from the seeds of Lallemantiaroyleana
Benth. Ph.D. Thesis, Department of Chemistry, Universityof Allahabad, Allahabad, U.P. India.
Chaitow L. (1985). Amino acids in therapy. Northamptonshire, UK:Thorsons Publishers Ltd.
Cryer, B. and Feldman, M. (1998). Cyclooxygenase-1 and
cyclooxygenase-2 selectivity of widely used nonsteroidal anti-
inflammatory drugs. Am. J. Med. May, 104
George, W.S and William, G.C. (1968). Statistical Methods, Oxfordand IBH. (6th edition, Indian). IBH Publishing Co. Calcutta.
Meredith, T.J. (1978). Paracetamol poisoning in children. BMJ: 2
Murphy, D.R.; Wexman, M.P. and Grieco, A.J.(1985). Methionine
intolerance, a possible risk factor for coronary heart disease. JACC,6
Oluwatoyin A. Odeku, (2008), Theories of disintegration.
Research Fate of Estrogens in a Municipal concentrations for fish ( 5 - 9 ). Ozonation, UV-radiation,membrane filtration, and activated carbon adsorption are Sewage Treatment Plant potential treatments that might improve the effectiveness ofestrogen removal in a STP ( 4 , 5 , 10 - 15 ). However, imple-mentation of these techniques would increase the cost ofwastewater treatment. Alterna
The World Journal of Biological Psychiatry , 2010; Early Online, 1–8 ORIGINAL INVESTIGATION H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study EIRAN VADIM HAREL 1 , ABRAHAM ZANGEN 3 , YIFTACH ROTH 3 , IRVING RETI 4 , YORAM BRAW 1,5 & YECHIEL LEVKOVITZ 1,2 1 The Emotion-Cognition Research Cente