Download formulation and evaluation of effervescent granules of an anti

FORMULATION AND EVALUATION OF
EFFERVESCENT GRANULES OF AN ANTI-ALLERGIC
DRUG
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH
SCIENCES
KARNATAKA, BANGALORE
SUBMITTED BY
Ms. G. SWETHA
M.PHARM PART 1st YEAR
DEPARTMENT OF PHARMACEUTICS
UNDER THE GUIDENCE OF
Mrs. SAYANI BHATTACHARAYYA
THE OXFORD COLLEGE OF PHARMACY
BANGALORE -68.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE – II
Proforma for Registration of Subject for Dissertation
1.
Name of the candidate and address Ms .G.SWETHA
THE OXFORD COLLEGE OF PHARMACY,
No.6/9, 1ST CROSS, BEGUR ROAD,
HONGASANDRA, BENGALURU –560 068
KARNATAKA.
PERMANENT ADDRESS
HOUSE NO 1-1-.403/A/1,
FLAT
NO.G1,SAI
RAM
NARMADA HOSPITAL,
APTS,NEAR
GANDHI NAGAR,HYDERABAD
ANDHRA PRADESH-500080
2.
Name of the institution
THE OXFORD COLLEGE OF PHARMACY,
NO.6/9, 1st CROSS, BEGUR ROAD,
HONGASANDRA,BENGALURU-68
KARNATAKA
3.
Course of study and subject
Master of Pharmacy in Pharmaceutics
4.
Date of admission to course
18/10/ 2010
5.
Title of the topic
FORMULATION AND EVALUATION OF
EFFERVESCENT GRANULES OF AN ANTIALLERGIC DRUG
6.0 BRIEF RESUME OF THE INTENDED WORK:
6.1 Need for the study
 Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occurs
to normally harmless environmental substances known as allergens; these reactions
are acquired, predictable, and rapid. Strictly, allergy is one of four forms
of hypersensitivity and is called type I (or immediate) hypersensitivity. It is
characterized by excessive activation of certain white blood cells called mast
cells and basophils by a type of antibody
known as IgE , resulting in an
extreme inflammatory response1.
 Several antagonistic drugs are used to block the action of allergic mediators, or to
prevent
activation
of
cells
and
degranulation
processes.
These
include Antihistamines, Glucocorticoids,Epinephrine (Adrenaline), Theophylline and
Cromolyn
sodium.
Anti-leukotrienes,
such
as Montelukast (Singulair)
or Zafirlukast (Accolate), are FDA approved for treatment of allergic diseases. Anticholinergics, decongestants, mast cell stabilizers (Cromone therapy), and other
compounds thought to impair Eosinophil chemotaxis, are also commonly used. These
drugs help to alleviate the symptoms of allergy, and are imperative in the recovery of
acute anaphylaxis, but play little role in chronic treatment of allergic disorders2.
 Drugs that are difficult to digest or disruptive to the stomach, pH sensitive drugs,
drugs requiring a large dose can be formulated as effervescent granules.
 The use of conventional dosage form is associated with dose related adverse effects
and short duration of action. So effervescent granules are formulated to reduce this
effects which are intended to be dissolved or dispersed in water before use. This
dosage form includes a mixture which when incorporated in water, produces an
immediate rate of release of the therapeutic compound for instant release3.
 Combination of the effervescent granules with the other ingredients can provide
effective taste masking of particularly poor tasting compounds. These effervescent
granules contain acid substances and carbonates or bicarbonates, and that react rapidly
in the presence of water by releasing carbon dioxide3.
 Effervescent granules of anti-allergic drugs are an instant manner to relieve allergy
in emergency situations and improving patient compliance.
 Effervescent granules are convenient, attractive, and easy to use as premeasured
dosage forms. Effervescent tablets are more easily transported than liquid medication
because no water is added until it's ready to use.
6.2 Review of literature
Literature review for undertaking the study was done by referring to articles published
in various National and International Journals, official standard books and referring to
various websites on the internet.
1. This has proved utility of effervescent oral delivery system in the
pharmaceutical and dietary industries for decades. Effervescence is the
reaction (in water) of acids and bases producing carbon dioxide. Typical acids
used in this reaction are Citric, Malic, Tartaric, Adipic, and Fumaric. Citric
acid is the most commonly used, and it imparts a citrus-like taste to the
product. Malic acid can be used in effervescent formulas for a smoother
aftertaste. There are several categories of active ingredients: Those that are
difficult to digest or disruptive to the stomach. A classic example is Calcium
carbonate, the most widely used form of calcium. In a normal tablet or
powder, the Calcium carbonate dissolves in the stomach acid and is carried
into the digestive system for absorption, those that are pH-sensitive, such as
amino acids and antibiotics. The low pH in the stomach can cause active
ingredients to become denatured, lose activity, or cause them to remain
inactive; those requiring a large dose, those that are susceptible to light,
oxygen, or moisture. Many vitamins fall into this category. To satisfy these
criteria’s effervescent granules were formulated3.
2. The present invention concerns orodispersible tablets, which are able to
disintegrate in the buccal cavity upon contact with saliva by formation of an
easy-to-swallow suspension, in less than 60 seconds, preferably in less than 40
seconds, containing Fexofenadine in the form of coated granules, and a
mixture of excipients comprising at least one disintegrating agent, a soluble
diluent agent, a lubricant and optionally a swelling agent, a permeabilizing
agent, sweeteners, flavoring agents and colors; the process for obtaining such
orodispersible tablets and the coated granules incorporated therein and the use
of said orodispersible tablets in the treatment of seasonal allergic rhinitis4.
3. The formulation of effervescent tablet has been carried out. Effervescent tablet
is a tablet intended to be dissolved or dispersed in water before administration.
They show the special features like less irritation and greater tolerability,
swallowing can be prevented; more stability is achieved, improved therapeutic
effect. In this review formulation, manufacturing and applications of
effervescent tablets were covered. The people are very busy with their
schedules and have less time to care for health. Even in the treatment, they
were searching for quick relief and easily administrable formulations which
are effervescent granules5.
4. The formulation of the Niacin in the form of ET dosage form as an alternative
to the available marketed few conventional tablets. ET was made up of
effervescent granules (EG). EG are prepared by wet granulation method with
non-reactive liquids using PVP as a binder with concentration ratios of 1: 2: 4.
As the concentration of PVP is increased, the dissolution profile of niacin was
decreased. The formulation F8 containing citric acid, tartaric acid and sodium
bicarbonate in the ratio of 1:1:1 was considered to be the best formulation. All
the prepared EG and ET are evaluated for the official tests and found to be
within limits. In- vitro dissolution studies of formulation F8 shows good
release by about 95.2% in 3.30 hours. All prepared formulations are slightly
acidic (pH 4.0 to 4.2) to augment the taste of the solution. IR Spectra of
formulation F8 shows, there is no interaction between niacin and excipients
used. And the formulation F8 was most stable at temperature 25˚C to 40˚C. It
conclude that, niacin can prepared in the form of “pleasantly flavoured
effervescent drink” of ET by compressing EG, which is prepared by wet
granulation method with non-reactive liquids6.
5. This proposal includes the formulation of effervescent granules. Effervescent
granulation is an important step in the production of fizzy dosage forms that
most of the time cannot be avoided to achieve the desired characteristics of the
effervescent tablets .It is also very critical in maintaining the stability of the
final dosage form. Effervescent granules and tablets have become more and
more popular as a dosage form because they are readily soluble and easy to
consume just by drinking the glass of water where they are dissolved.
Disintegration usually within 2minutes or even less due to evolution of
Carbon-Dioxide. They have a pleasant taste due to carbonation which helps to
mask the bad taste of certain drugs7.
6. The formulation of granules using wet granulation method. Granules are by
definition agglomerates made of primary particles. e the wet granulation
methods where solvents or binder solutions are used to agglomerate powders.
Wet granulation methodologies are the fluid bed granulation, high shear
granulation or the spray drying processes. Nowadays granules are usually used
as intermediates for compression of tablets, the most often dosage form, or for
filling of capsules. Originally granules were administered in sachets as a
multiple unit dosage form. Granules offer several advantages in comparison to
pharmaceutical powders. In some cases they are as well necessary for the
production of a solid dosage form: a prerequisite for the tablet production are
good flowing properties which are improved with larger particle size. Thus
free-flowing granules assure a good dosing accuracy during a tablet
compression or capsule filling process. Another advantage is the increase in
bulk density after an agglomeration step which enables a better control of drug
content uniformity at low drug concentrations and avoids de-mixing or
segregation processes. Furthermore granulation leads also to a reduction in
dusting, an especially important fact for the production of high potent drugs8.
7. The formulation of effervescent granules using Hot-melt extrusion is one of
the most widely applied processing technologies in the plastic, rubber and
food industry. Today this technology has found its place in the array of
pharmaceutical manufacturing operations. Melt extrusion process are currently
applied in the pharmaceutical field for the manufacture of a variety of dosage
forms and formulations such as granules, pellets, tablets, suppositories,
implants, stents, Tran dermal systems and ophthalmic inserts. This review
article in detail describes the melt extrusion equipment and process. Industrial
application of this process along with specific areas on pharmaceutical
industry is illustrated. This article concludes with the overview of published
examples of melt extrusion process9.
8.
This proposal has given information that Effervescence can be defined as the
evolution of bubbles of gas in a liquid. Effervescent mixtures have been
known and used medicinally for many years. As discussed in this text, and as
commonly employed, an effervescent granule is dissolved in water to provide
a carbonated or sparkling liquid drink. In such a drink the effervescence helps
to mask the taste of medicaments. However, the use of effervescent granules
to prepare a beverage including medicament, is not convenient. It requires
preparatory steps before administration of the drug and also requires the
presence of a suitable mixing container10.
9.
The work disclosed a water soluble effervescent composition prepared by hotmelting (1) an active component and (2) an acid and a carbonate for
effervescent, with (3) a water soluble adjuvant whose melting point is not
lower than 40°C, for addition to drinking water. The effervescent composition
was prepared by mixing the active agent, the acid, the carbonate and the water
soluble adjuvant and then heating the entire mixture to melt the adjuvant and
subsequently cooling the mixture to room temperature while stirring to form
effervescent particles. Thus, there is no teaching or suggestion in the art of
preparing effervescent granules by hot-melt extrusion. Despite prior efforts
towards developments of suitable effervescent granules, there have been
unmet needs heretofore for improved effervescent granules having
controllable rates of effervescence and for methods for their preparation11.
10. This work presented the central composite study design was used to determine
the moisture scavenging effect of 0–2% w/w Potassium carbonate in an
effervescent dosage form containing 0.2–1.3% w/w total moisture. Total
moisture content of the tablets was calculated by adding the water contribution
of each ingredient based on loss on drying or Karl Fischer data. Tablets were
directly compressed on a rotary tablet press, packaged in cold form foil: foil
blisters, and then thermally stressed by exposure to 75°C for 3 h. In this study,
exposure of effervescence in such a manner has been shown to release water
of hydration from dextrose monohydrate, thus giving a convenient means of
adding water and then ‘activating’ it to perform rapid moisture stability
studies. After thermal stressing, tablets were given a rating from 0–7 (least to
most) as to the degree of tablet mottling due to effervescent base degradation.
Response surface regression of the data resulted in a quadratic equation with
an adjusted R2 of 0.92 and no evidence of lack of fit (P_0.85). Analysis of the
data showed the optimal level of potassium carbonate to be 1.3% w:w for the
formulations tested. This level of potassium carbonate will accommodate total
moisture levels up to 0.4% w:w and still prevent effervescent base
degradation12.
11. This work has been carried out on melt extrusion: from process to drug
delivery system starting from the plastic industry, today melt extrusion has
found its place in the array of pharmaceutical manufacturing operations. This
article reviews the process technology with regard to the set up and specific
elements of the extruder as well as its application. Melt extrusion processes
are currently applied in the pharmaceutical field for the manufacture of a
variety of dosage forms and formulations such as granules, pellets, tablets,
suppositories, implants, stents, transdermal systems and ophthalmic inserts. As
a specific area the manufacture of solid dispersions, in particular, solid
molecular dispersions using the melt extrusion process is reviewed. Melt
extrusion is considered to be an efficient technology in this field with
particular advantages over solvent processes like co-precipitation. Potential
drawbacks like the influence of heat stress and shear forces on the drug active
have been overcome in a number of examples with drugs of different chemical
structure. Examples of suitable excipients and recent findings like selfemulsifying preparations are presented. The article concludes with a number
of published examples of melt extrudates applying the principle of solid
molecular dispersions.
Improved bioavailability was achieved again
demonstrating the value of the technology as a drug delivery tool13.
12. The purpose of the present study was to develop and characterize mouth
dissolving tablets of Levocetrizine Hydrochloride by using direct compression
technique. Formulations were designed by factorial design technique. Sodium
starch glycolate, Crospovidone and Croscarmellose sodium were used as a
superdisintegrants while microcrystalline cellulose was used as diluents. The
powder blends were prepared and evaluated for the properties such as angle of
repose, loose bulk density, tapped bulk density, Carr’s compressibility index
and Hausner’s ratio. Tablets were evaluated for hardness, friability, drug
content, disintegration time, water absorption ratio, in vitro drug release in
0.1N HCl. Formulation containing Crospovidone and Croscarmellose sodium
in higher concentration showed a rapid disintegration, wetting and in vitro
drug release as compared to other formulations. Differential scanning
calorimetric studies indicated no possibility of interaction between
Levocetrizine Hydrochloride and superdisintegrants used in formulation. The
optimized formulation showed no change in physical appearance, drug
content, and disintegration time and dissolution pattern after storage at
40oC/75% RH for three months14.
13. This invention provides a novel and therapeutically advantageous solid,
rapidly disintegrating, effervescent, rapidly dissolving dosage form for oral
administration of Cetrizine. The dosage form contains organic edible acid,
alkali metal and an alkaline earth metal carbonate and bicarbonate and
optionally a pharmaceutically acceptable auxiliary ingredient along with the
drug. The formulation of this invention when dissolved in water yields a
solution having a pleasant taste with improvement in patient compliance. This
oblivates the need of tedious process of coating the individual crystal of
Cetrizine for masking the bitter taste. The patent describes the first ever
effervescent preparation of Cetrizine, which is very effective against allergic
disorders15.
6.3 Objectives of the study:
In the present work attempt will be made
1. To formulate Effervescent granules of anti-allergic drug against allergic attacks in
emergency situations and thereby improving patient compliance.
2. To evaluate dispersible effervescent granules containing an anti-allergic drug.
3. To conduct stability studies of the formulations.
Preparation:
The uncompressed effervescent granules can be prepared by any of the following
methods:
a) Dry fusion method
b) Wet granulation method
c) Hot melt-extrusion
Evaluation of the formulation:
This includes:
 Flow properties - Angle of repose.
 Bulk density.
 Physical characterization of the microspheres which includes.
a) Particle size analysis
b) Determination of Particle shape and
c) Surface morphology.
 Water content & Moisture Uptake Studies
 Uniformity of dispersion studies
 Stability studies on the selected formulations
7.0 Materials and Methods:
The suitable drug candidates for this proposal can be Cetrizine, Levo cetrizine, Zafirlukast,
Montirlukast, Fexofenadine etc, and anyone of the above mentioned drug will be selected for
the project work depending on the availability.
The materials will be chosen after the compatibility studies with the active ingredient.
Method
: Dry fusion method, Wet granulation method, Hot melt-extrusion
7.1 Source of data:
Data was obtained from drug invention today, Pub med, Science direct, Medline, US
patent office Website& other Internet facilities, Journals available at Jgate - Helinet of the
Rajiv Gandhi University Of Health Sciences Website , Literature search and Related
Articles from library of The Oxford College of Pharmacy.
7.2 Method of collection of data:
The data will be collected from,
1. Compatibility study by FTIR/IR.
2. Preparation of reproducible batches of formulations.
3. Evaluation of the product
a. Flow properties- Angle of repose.
b. Bulk density.
c. Water content & moisture uptake studies.
d. Uniformity of dispersion studies.
e. Stability studies on the selected formulations18.
7.3 Does the study require any investigation or interventions to be conducted on
patients or other humans or animals?
No.
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
NA
8. List of References:
1. Kay AB. Overview of allergy and allergic diseases with a view to the future 2000;
56 (4): 843–864.
2. Saha S, Siddiqui S, Bradding P. A synopsis on pharmacotherapy for Allergic
Diseases. World allergy organization 2007 April.
3. Lee RE. Effervescent tablets. The key facts about the unique effective dosage form. 14.
4. Ethypharm (Houdan, FR). Orodispersible tablets containing Fexofenadine. United
States Patent 6: 723,348.
5. Prabhakar C, Bala Krishna K. A review on effervescent tablets.International J.
Pharmacy &Technology 2011; 3: 704-712.
6. Mutahar RKM, Nagesh C, Ramesh R, Omer S. Formulation, development and in
vitro evaluation of effervescent tablets of Niacin for dyslipidemia. Biomedical and
Pharmacology J. 2008 June 1; 1.
7. Bertuzzi G. Effervescent granules. Hand book of pharmaceutical granulation
technology. 3rd ed. 365-384.
8. Von V, Djuric D, Lemgo A. Continuous granulation with twin screw extruder 2008
June: 1-2.
9. Chokshi R, Zia H. Hot melt extrusion method. Iranian J. Pharmaceutical Research
2004; 3: 3-16.
10. Dekker M, Lieberman A. In chapter 6 in Pharmaceutical Dosage Forms. 2nd ed. 1.
11. Kond et al., in U. S. Pat. No. 5: 223-246.
12. Wells ML, Wood DL, Sanftleben R, Shaw K, Hottovy J, Weber T et al., Potassium
carbonate as a desiccant in effervescent tablets. International J. Pharmaceutics 1997:
227–235.
13. Breitenbach J. Melt extrusion from process to drug delivery technology. European J.
Pharmaceutics and Bio pharmaceutics 2002: 107–117.
14. Aitha S,
Ayyappan T,
Shanmugam S,
Sundaramoorthy K, Vetrichelvan T.
Optimization, Formulation and In-Vitro Evaluation of Mouth Dissolving Tablets of
Levocetrizine Hydrochloride for the Treatment of Allergic Rhinitis. J. Of
Pharmaceutical Sciences and Research 2010; 2 (9): 555-561.
15. Asta Medica AG (DE). Solid, rapidly disintegrating formulation. Patent 6; 2001:
245,353.
16. European pharmacopoeia 5, Dosage forms 2005; 0499: 605-606.
17. Lindberg (Acta). Pharm. Suec 1988; 2: 239-246.
18. ICH Topic Q1A.Stability Testing Guidelines: Stability Testing Of New Drug
Substances and Products. http://www.eudra.org/emea.html.
9.
Signature of the Candidate
G.SWETHA
10.
Remarks of the Guide: The above information is true to the best of my knowledge
and the work will be done under my guidance.
11.
Name & Designation (in BLOCK LETTERS)
11.1 Guide
Mrs. SAYANI BHATTACHARYYA
ASSISTANT PROFESSOR,
DEPT. OF PHARMACEUTICS.
11.2 Signature of Guide
11.3 Name of the co-guide
-NA
11.4 Signature of the co-guide
-NA
11.5 Head of the Department
Dr. KALYANI PRAKASAM
11.6 Signature of HOD:
Dr. KALYANI PRAKASAM
12.
12.1 Remarks of the Principal: The above mentioned information is correct and I
recommend the same for approval. R
12.2 Signature of the Principal
Dr. PADMAA M. PAARAKH
The oxford college of pharmacy.