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METHODOLOGY

METHODOLOGY
MATERIALS

Table no-1: List of materials and manufacturer/suppliers

RAW MATERIALS MANUFACTURER / SUPPLIERS

Loratidine Provided by Chandra labs-Hyderabad

Cross caramellose sodium Sisco research laboratories Pvt.Ltd Mumbai


Cross povidone Sisco research laboratories Pvt.Ltd Mumbai

Lactose mono hydrate ESSEL Fine Chem,Mumbai

Menthol Sisco research laboratories Pvt.Ltd Mumbai

Camphor Sisco research laboratories Pvt.Ltd Mumbai

Magnesium stearate ESSEL Fine Chem,Mumbai

Avicel pH 102
ESSEL Fine Chem,Mumbai
(Microcrystalline cellulose)

EQUIPMENTS
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METHODOLOGY

Table no-2: List of the equipments


MANUFACTURERS
EQUIPEMENTS MODEL

Digital balance AND GP-12K Electrolab

Bulk Density Apparatus Electrolab Model- ETD- 1020 Thermo lab

16 station Compression Cadmach


CM D3-16
machine
PHARMATEST
Tablet hardness tester PTB-311E

Disintegration test ED-2L THERMO LAB


apparatus

Tablet dissolution 2100C LAB INDIA


apparatus

Hot Air Oven KLT-1244 AC MOTORS

METHODOLOGY

a) PRE-FORMULATION STUDIES
Pre-formulation testing is an investigation of physical and chemical properties of a drug
substance alone and when combined with excipients.
Pre-formulation studies yield necessary knowledge to develop suitable formulation for
toxicological use. It gives information needed to define the nature of the drug substance and
provide a dosage form. Hence, the following pre-formulation studies were performed for the
obtained sample of drug.

Description and Solubility

Loratidine is a white to off white powder which is insoluble in water.

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METHODOLOGY

PRE-FORMULATION STUDIES
Pre-formulation testing is an investigation of physical and chemical properties of a drug
substance alone and when combined with excipients.
Pre-formulation studies yield necessary knowledge to develop suitable formulation for
toxicological use. It gives information needed to define the nature of the drug substance and
provide a dosage form. Hence, the following pre-formulation studies were performed for the
obtained sample of drug.

Melting point:
The melting points of loratidine were found out by capillary method using programmable

melting point apparatus.

PREPARATION OF CALIBRATION CURVE FOR LORATIDINE

A. STANDARD CURVE IN 6.8 PH PHOSPHATE BUFFER

1. Stock Sample Preparation

Accurately weighed 100 mg of drug was first dissolved in100 mL of 6.8 pH Phosphate buffer in
100 mL of volumetric flask to make a concentration of 1000 g/mL (primary stock solution). 5
mL of primary stock solution was pipetted out into 50 mL of volumetric flask and volume was
adjusted with 6.8 pH Phosphate buffer to make a concentration of 100g/mL (secondary stock
solution).

2. Sample Preparation

From the secondary stock solution pippetout 0.2,0.4,0.6,0.8 and 1ml in to 10ml of volumetric
flask and volume made up to with 6.8 pH Phosphate buffer Fto give various concentrations such
as 2,4,6,8,10g/mL were prepared for calibration curve. Standard curve was plotted by taking
absorbance of secondary stock solutions in UV double beam spectrophotometer at 245 nm.

Table No-3: . Standard graphs for loratadine

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METHODOLOGY

Absorbance at 245nm
SD, n=3
Concentration in mcg

0.0550.011
2

0.1050.012
4

0.1650.014
6

0.2120.012
8

0.2660.016
10

0.3

0.25 f(x) = 0.03x + 0


R = 1
0.2

0.15 Abs
Linear (Abs)
0.1

0.05

0
1 2 3 4 5 6 7 8 9 10 11

Figure No: 1. Standard graph of loratadine

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METHODOLOGY

DRUG - EXCIPIENT COMPATIBILITY STUDY

Fourier Transform infra-red (FTIR) spectroscopy

Infrared spectroscopy is a useful analytical technique utilized to check the chemical

interaction between the drug and excipients used in the formulation.1-2 mg of solid fine powder

of loratidine and 200-300 mg of dry powder of KBr (IR grade) were taken in a mortar and mixed

well with the help of a spatula. Spectrum measurement was carried out using KBr disk method in

the wavelength region of 4000-400cm-1 by FTIR spectrophotometer. The IR spectrum of the

physical mixture was compared with that of the pure drug to check any possible drug-excipient

interaction.

Bulk density
Bulk density of a compound varies substantially with the method of crystallization,
milling or formulation. Bulk density is determined by pouring pre sieved blend into a graduated
cylinder via a large funnel and measure the volume and weight.
Bulk density = weight of blend
Bulk volume of blend
Bulk density was expressed in g/cc.

Tapped density:
Tapped density is determined by placing a graduated cylinder containing a known mass
of blend and mechanical tapper apparatus, which is operated for a fixed number of taps until the
powder bed volume has reached a minimum volume. using the weight of the drug in the cylinder
and this minimum volume, the taped density may be computed.
Tapped density = weight of blend

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Tapped volume of blend

Carrs Index (CI):


Carrs index is measured using the values of bulk density and tapped density. The
following equation is used to find the Carrs index.
CI = (TD-BD) x100
TD
Where TD = Tapped density
BD = Bulk density
Table 4: Flow properties and corresponding Carrs Index values

Excellent <10

Good 11 15

Fair 16 20

Possible 21 25

Poor 26 31

Very poor 32 37

Very very poor >38

Hausners Ratio:

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METHODOLOGY

It indicates the flow properties of the powder and ratio of Tapped density to the Bulk
density of the powder or blend.
Hausners Ratio = Tapped density/Bulk density
Table-5 Flow Properties and Corresponding Hausners ratio

Excellent 1.00 1.11

Good 1.1 1.18

Fair 1.19 1.25

Possible 1.26 -1.34

Very poor 1.35 -1.45

Angle of repose:
The manner in which stresses are transmitted through a bead and the beads response to
applied stress are reflected in the various angles of friction and response. The method used to
find the angle of repose is to pour the powder ion a conical heat on a level, flat surface and
measure the included angle with the horizontal.
Tan = h/r
Where, h= height of the heap
r= Radius of the heap
Table-6 Flow Properties and Corresponding Angle of Repose

ANGLE OF REPOSE POWDER FLOW


< 25 Excellent
25 30 Good
30 40 Passable
> 40 Very poor
Procedure:

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METHODOLOGY

A series of sieves were arranged in the order of their decreasing pore diameter (increasing
sieve number) i.e. sieve number 20, 30, 60, 80, 100, collector. 30 grams of blend was weighed
accurately and transferred to sieve 20 which is kept on top. The sieves were shaken for about 5-
10 minutes. Then the drug retained on each sieve was taken, weighed separately and amount
retained was expressed in terms of cumulative percentage retained.

FORMULATION AND DEVELOPMENT OF LORATIDINE IMMEDIATE RELEASE


TABLETS

Formulation of Loratidine porous tablets by direct compression method

Porous tablets of Loratidine were prepared by direct compression method employing

camphor and menthol as sublimating agents. The concentrations of the above ingredients were

optimized as shown in below table on the basis of trial preparation of the tablets. All the

ingredients were weighed accurately. The drug was mixed with the release rate enhancing

disintegrants and other excipients, except magnesium stearate, in ascending order of their weight.

The powder mix was blended for 20 min to have uniform distribution of drug in the formulation.

Then, magnesium stearate was added and mixed for not more than 1 min (to ensure good

lubrication.) About 200 mg of the powder mix was weighed accurately and fed into the die of

single punch machinery and compressed using 8 mm flat- surface punches. The hardness of the

tablets was adjusted at 4-6 kg/cm2 using a Monsanto hardness tester.

Compression

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The lubricated blend was compressed using following parameters:


Compression parameters
Tooling: 8mm round punch.
Average weight: 200mg.

Table-7-: COMPOSITION OF FORMULATIONS

Ingredients F1 F2 F3 F4 F5 F6 F7 F8

Loratidine 10mg 10mg 10mg 10mg 10mg 10mg 10mg 10mg


Camphor 10 -- 20 -- 20 -- -- --
MCC 127 127 113 113 105 105 105 105
LM 42 42 42 42 42 42 42 42
Menthol -- 10 -- 20 -- 20 20 20
CCS 8mg 8mg 12mg 12mg 20mg 20mg -- --
CP -- -- -- -- -- -- 12mg 20mg
Mg.stearate 3mg 3mg 3mg 3mg 3mg 3mg 3mg 3mg
Total weight 200m 200m 200m 200m 200m 200m 200m 200m
g g g g g g g g
.
MCC- Micro crystalline cellulose, CCS- Cross caramellose sodium, CP- Cross
Povidone , LM- Lactose monohydrate

POST COMPRESSION EVALUATION OF TABLETS:


To design tablets and later monitor tablet production quality, quantitative evaluation and
assessment of tablet chemical, physical and bioavailability properties must be made. The
important parameters in the evaluation of tablets can be divided into physical and chemical
parameters.

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Physical appearance:
The general appearance of tablets, its visual identity and overall elegance is essential for
consumer acceptance. The control of general appearance of tablet involves measurement of
number of attributes such as tablet size, shape, colour, presence or absence of odour, taste,
surface texture and consistency of any identification marks.

Hardness test:
This is the force required to break a tablet in a diametric compression. Hardness of the
tablet is determined by Stocks Monsanto hardness tester which consists of a barrel with a
compressible spring. The pointer moves along the gauze in the barrel fracture.

Tablet size and Thickness:


Control of physical dimensions of the tablets such as size and thickness is essential for
consumer acceptance and tablet-tablet uniformity. The diameter size and punch size of tablets
depends on the die and punches selected for making the tablets. The thickness of tablet is
measured by Vernier Callipers scale. The thickness of the tablet related to the tablet hardness and
can be used an initial control parameter. Tablet thickness should be controlled within a 5%. In
addition thickness must be controlled to facilitate packaging.

Friability:
This test is performed to evaluate the ability of tablets to withstand abrasion in packing,
handling and transporting. Initial weight of 20 tablets is taken and these are placed in the
friabilator, rotating at 25rpm for 4min. The difference in the weight is noted and expressed as
percentage. It should be preferably between 0.5 to 1.0%.
%Friability = (W1-W2)/W1 X 100
Where, W1= weight o f tablets before test
W2 = weight of tablets after test

Weight variation of Tablets:

It is desirable that all the tablets of a particular batch should be uniform in weight. If any
weight variation is there, that should fall within the prescribed limits:

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Table -8: Acceptance criteria for tablet weight variation


Average weight of tablet(mg) Maximum % difference allowed
130 or Less than 10
130-324 7.5
More than 324 5
Twenty tablets were taken randomly and weighed accurately. The average weight was calculated
by,
Average weight = weight of 20 tablets
20

Disintegration test:
Disintegration time is considered to be one of the important criteria in selecting the best
formulation. To achieve correlation between disintegration time in-vitro and in-vivo, several
methods were proposed, developed and followed at their convenience. One tablet was placed
into each tube and the assembly was suspended into the 1000ml beaker containing water
maintained at 372oc and operated the apparatus for 15 minutes. The assembly was removed
from the liquid and the tablets were observed. If one or two tablets fail to disintegrate
completely, repeat the test on 12 additional tablets. The requirement is met if not less than 16 of
the total of 18 tablets tested are disintegrated.
Dissolution test:
Dissolution: It is the amount of the solid substance that goes into the solution per unit time under
standard conditions of the temperature and pressure

Types of dissolution apparatus:

Different types of dissolution apparatus are used. They are:-

1. Apparatus 1 or rotating basket type

2. Apparatus 2 or paddle assembly type

3. Apparatus 3 or reciprocating cylinder type

4. Apparatus 4 or flow through cell type

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5. Apparatus 5 or paddle over disk type

6. Apparatus 6 or cylinder type

7. Apparatus 7 or reciprocating holder type

Method: Dissolution media was taken as 6.8 pH Phosphate buffer, 500ml was placed in the
vessel and the USP apparatus 2 (paddle) was assembled. The medium was allowed to
equilibrate to temp of 37 + 0.5C. Tablet was placed in the basket and placed in the vessel, the
apparatus was operated for 15min at 50 rpm. At definite time intervals, 5 ml of the fluid was
withdrawn; filtered and again 5ml of the fluid was replaced. Suitable dilutions were done with
the dissolution fluid and the samples were analyzed using UV.

Dissolution parameters:

Medium: 6.8 pH Phosphate buffer, 500ml.

Apparatus: USP Type 2 (paddle).

Rotation speed: 50 RPM

Temperature: 375oC.

Time: 10, 15, 20, 30, 45 and 60 min.

Assay
The Assay for loratidine porous tablets was estimated by UV spectrophotometer at 245nm.

STABILITY STUDIES:

FDA and ICH specifies the guidelines for stability testing of new drug products, as a
technical requirement for the registration of pharmaceuticals for human life.The ICH tripartite
guidelines have established long term stability testing to be done at 25 0C/60%RH for 12 months.
Accelerated stability testing should be done at 40 0 C/75%RH for 6 months and stability testing at

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intermediate storage conditions should be done at 300C/65%RH. The following table shows
different storage conditions and period of stability testing.

Table 10: ICH Guidelines for stability study

Study Storage Condition Duration


Long term 252oC, RH 605% 12 months
Intermediate 302oC, RH 655% 6 months
Accelerated temperature 402oC, RH 755% 6 months

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