FORMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF PROCHLORPERAZINE MALEATE - RESULT AND DISCUSSION
results and
discussion
The
sample of promethazine theoclate was analyzed by various organoleptic,
physicochemical and spectrophotometric methods. The sample of promethazine
theoclate possessed similar color, odor, taste and texture as given in
officials. The melting point of the sample was analyzed by capillary fusion
method and found to be 2310. The FTIR spectrum of promethazine theoclate sample
was concordant with reference spectra as given in Clarke Analysis of Drug. The
FTIR spectra of reference and sample are shown in Fig respectively. The FTIR
spectra verified the authenticity of the procured sample as the characteristic
peaks of the promethazine theoclate was found at 749, 1160, 1220, 1259 cm-1 in
concordance to the reference spectra. The qualitative solubility of
promethazine theoclate was determined in various solvents.
The maximum solubility was found in chloroform and least in ether and acetone.
The result for solubility of promethazine theoclate in various solvents is
shown in Table 3.5. The absorption maxima of promethazine theoclate was
observed at 250 nm in Sorenson’s buffer (pH 6.8), which was concordant with the
value given in Clarke Analysis of Drug. The UV spectrum of promethazine
theoclate is shown in Table and Figure. The calibration curve of promethazine
theoclate was prepared in Sorenson’s buffer (pH 6.8). The plot of different
concentrations of promethazine theoclate versus absorbance was found linear in
the concentration range of 0 - 9 g/ml at 250 nm. The absorbances obtained at
different concentrations are shown in Table 3.7. The data of standard curve was
linearly regressed. The values of slope and correlation coefficient were found
to be 0.100 and 0.995 respectively. The intercept on Y-axis was found to be
0.049. The calibration curve is shown in Fig..
Promethazine theoclate polymer interaction study was
carried out for 4 weeks and samples were evaluated after every week for
physical changes, change in absorption maxima and by FTIR studies. Results are
shown in Table and Fig.. There was not any sign of physical change at the end
of study. The FTIR spectra of the various physical mixtures retained all the
peaks of the pure promethazine theoclate and there was no significant shift in
the peaks corresponding to the promethazine theoclate was observed on storage.
Both the promethazine theoclate and polymers were
found to be compatible with each other. As the promethazine theoclate and
polymer(s) were compatible and thus were found to be suitable for dosage form
design.
PREPARATION OF DRUG FREE TABLETS
Drug
free fast dissolving tablets were prepared by direct compression method because
of their several advantages.23-25
·
Easiest
way to manufacture tablets.
·
High
doses can be accommodated.
·
Use
of conventional equipment.
·
Use
of commonly available excipients.
·
Limited
number of processing steps.
The
tablets were prepared by using single punch tablet machine (Cadmach, Ahemdabad)
to produce flat faced tablets weighing 100 mg each with a diameter of 5
mm. A minimum of 50 tablets were prepared for each
batch. Before compression tablet blends were evaluated for mass-volume
relationship (bulk density, tapped density, Hausner’s ratio, compressibility
index) and flow properties (angle of repose). The formulations were developed
by using different techniques.
Technology Followed – Superdisintegrant Addition
The superdisintegrants (Ac-di-sol, sodium starch glycolate and crospovidone) in varying concentration (1-5% w/w) are used to develop the tablets. All the ingredients are shown in Table 3.9 were passed through sieve no. 60 and were co-grounded in a glass pestle motor.25-27
Technology Followed - Sublimation
Another technology employed for
developing fast dissolving tablets were incorporating subliming agents
(camphor, thymol and menthol) in varying concentration (5-20% w/w). Ingredients
shown in Table 5.2 were co-grounded in glass pestle glass mortar. The mixed blends
of excipients were compressed using a single punch machine to produce flat
faced tablets weighing 100 mg. Tablets were subjected for drying for 6 h under
vacuum (30 kpa) at 50o for sublimation to make tablets porous.28-30
Table 5.2: Formulation of drug free tablets with sublimating
agents
Technology Followed - Effervescent
Fast dissolving tablets were
prepared by using citric acid and sodium-bi-carbonate in combination in (1:2
ratio) with other excipients shown in Table 5.3 was co-grounded in glass pestle
glass mortar. These tablets contain (1-5% w/w) effervescent agent.31-33
Table 5.3: Formulation of drug free tablet
with effervescent technology
PRE-COMPRESSION CHARACTERIZATION
The quality of tablet, once formulated by rule, was generally dictated by the quality of physicochemical properties of blends. There were many formulations and process variables involved in mixing steps and all these can affect the characteristics of blend produced. The characterization parameters for evaluating the flow property of mixed blends includes bulk density, tapped density, Hausner’s ratio, compressibility index and angle of repose.
Bulk Density
Apparent bulk density (ρb) was determined by pouring the blend into a graduated cylinder. The bulk volume (Vb) and weight of powder (M) was determined.34-37 The bulk density was calculated using the formula
Tapped Density
The measuring cylinder containing a known mass of blend was tapped 100 times using density apparatus. The constant minimum volume (Vt) occupied in the cylinder after tappings and the weight (M) of the blend was measured.34-37 The tapped density (ρt) was calculated using the formula
Compressibility Index
The simplest way for measurement of flow of the powder was its compressibility, an indication of the ease with which a material can be induced to flow. 34-37 It is expressed as compressibility index (I) which can be calculated as follows
where, ρt = Tapped density; ρb = Bulk density
Table 5.4:
Compressibility index as an indication of powder flow properties
Hausner’s Ratio
Hausner’s ratio (HR) is an indirect index of ease of powder flow. It was calculated by the following formula
where, ρt is tapped density and ρb is bulk density.
Lower Hausner’s ratio (<1.25) indicates better flow properties than higher ones.34
Angle of Repose
Angle of Repose was determined using funnel method. The blend was poured through a funnel that can be raised vertically until a specified cone height (h) was obtained. Radius of the heap (r) was measured and angle of repose (θ) was calculated using the formula38-40
where,
θ is angle of repose; h is height of cone; r is radius of cone.
POST-COMPRESSION CHARACTERIZATION
After compression of powder blends, the prepared tablets were evaluated for organoleptic characteristics like color, odor, taste, diameter, thickness and physical characteristics like hardness, friability, disintegration time, wetting time, dispersion time. The results are shown in Table 5.8.
General Appearance
The general appearance of a tablet, its visual identification and over all ‘elegance’ is essential for consumer acceptance. This includes tablet’s size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws etc.41
Tablet Thickness
Ten tablets were taken and their thickness was recorded using micrometer (Mityato, Japan).
Weight Variation
The weight variation test would be satisfactory method of determining the drug content uniformity. As per USP42, twenty tablets were taken and weighted individually, calculating the average weight, and comparing the individual tablet weights to the average. The average weight of one tablet was calculated.
Hardness
Hardness
of tablet is defined as the force applied across the diameter of the tablet in
order to break the tablet. The resistance of the tablet to chipping, abrasion
or breakage under condition of storage transformation and handling before usage
depends on its hardness. Hardness of the tablet of each formulation was
determined using Pfizer Hardness Tester.41, 43
Wetting Time
Wetting time of the tablets was measured using a piece of tissue paper (12 cm x10.75 cm) folded twice, placed in a small petridish (ID = 6.5 cm) containing 6 ml of Sorenson’s buffer (pH 6.8). A tablet was put on the paper, and the time for the complete wetting was measured.35, 45-47
In Vitro Dispersion Time
In vitro dispersion time was measured by dropping a tablet in a glass cylinder containing 6 ml of Sorenson’s buffer (pH 6.8). Six tablets from each formulation were randomly selected and in vitro dispersion time was performed.46, 48, 49
Disintegration Test
DEVELOPMENT OF COMBINATIONAL DRUG FREE TABLETS
The fast dissolving tablets were prepared by the combination of two disintegrants to check their influence on the pre and post compression characteristics of the tablets. These tablets were prepared as methods described earlier. Only the least concentration of the disintegrants was used in tablets to evaluate their combined effect. The blends and tablets were characterized as described earlier. The formulation of the tablet is tabulated in Table 5.9.
From this study, it was clears that the combined effect of disintegrants with crospovidone shows the better results on the properties of the tablets.54, 55 The friability of the tablets was decreased by the incorporation of the crospovidone. The disintegration time of the prepared tablets was also decreased by the crospovidone.
In the batches, F33 and F34 fair to passable flow of blends were observed. The Hausner’s ratio was found greater than 1.25 and compressibility index was found more than 16%. The poor flow of the blends were also evidenced by the angle of repose, the values were higher than 30o. Hence it was clears, if a physical mixture of superdisintegrant was used in high speed tabletting; the problem of segregation of the disintegrants may be encountered. The attempt was made to overcome these problems by the coprocessing of superdisintegrants (Ac-di-sol with crospovidone and sodium starch glycolate with crospovidone).
DEVELOPMENT OF FDT BY COPROCESSED SUPERDISINTEGRANTS
Coprocessing is defined as combining two or more established excipients by an appropriate process. Coprocessing of excipients by could lead to formation of excipients with superior properties compared with simple physical mixture of their components or with individual components.55
Preparation of Coprocessed Disintegrant Blends
The coprocessed superdisintegrant
was prepared as follows. Blends of Ac-di-sol/SSG and crospovidone in different
ratios (1:1, 1:2, 1:3, 2:1, 2:3, 3:1, and 3:2) total weight of 10 g was added
to 50 ml of isopropyl alcohol. The content of beaker was stirred on a magnetic
stirrer at 50 rpm. The temperature was maintained between 65-700 and stirring
was continued till most of isopropyl alcohol evaporated. The wet coherent mass
was sieved through sieve number 100. The wet powder was dried in a tray drier at 600 for 20
min. The dried powder sifted on 120 mesh sieve and stored in airtight container
until further used. For the preliminary study and evaluation only coprocessed
superdisintegrant was prepared in 1:1 ratio. Rest of ratio was prepared for the
factorial design batch/optimization.
Evaluation of Coprocessed Disintegrant Blends
Particle size analysis
The microscopic technique was used to
test the particle size distribution of superdisintegrants and their blends. The
particle size of the disintegrants was evaluating to prepare the slides of
powder and observes under the microscope. To test the swelling of
superdisintegrant in water and Sorenson’s buffer (pH 6.8, saliva pH),
disintegrant powder were first dispersed in a small volume of liquid and the
ultrasonicated for 10 min. The suspension transferred with a pipette to a small
volume on the glass slide. The ratio of particle diameter in the dispersing
medium to the dry powders was used as an intrinsic swelling capacity of super
disintegrant in the test medium.
Scanning electron micrographs
Finally to
investigate the morphology of SSG, crospovidone and prepared coprocessed
superdisintegrant, scanning electron micrographs were taken using (JOEL,
JSM-35, CF) scanning electron microscope; where the samples were previously
sputter coated with gold.
Fig.
5.5: Scanning electron micrographs
A. Crospovidone; B. Ac-di-sol; C. Sodium starch glycolate; D. Coprocessed Ac-di-Sol + Crospovidone;
E. Coprocessed Sodium starch glycolate + Crospovidone
Preparation of FDT with Coprocessed Superdisintegrants
The fast dissolving tablets were
prepared with coprocessed superdisintegrants (Ac-di-sol with crospovidone and
sodium starch glycolate with crospovidone) and evaluated for pre and
post-compression properties. The evaluated parameters were compared with the
tablets prepared by physical mixture of superdisintegrants. The formulation and
evaluations are tabulated in Table 3.21
Table 5.13: Development of tablets with coprocessed superdisintegrants
Fig. 5.6: Comparison of tablets prepared by physical mixture and coprocessed
superdisintegrants
During preliminary studies, thirty two blind formulations were prepared by employing different concentrations of superdisintegrants (1-5% w/w), sublimating agents (5-20% w/w) and effervescent agents (1-5% w/w). The pre-compression characterizations of mixed blends were done for determination of mass volume relationship and flow properties. The evaluated parameters were bulk density, tapped density, Hausner’s ratio, compressibility index and angle of repose.
For drug free tablets prepared by using various disintegrating agents, the bulk density of blend varied between 0.371-0.658 gm/cc. The tapped density was found in the range of 0.395-0.749 gm/cc. The results indicated good packaging capacity of tablets. By using these two density data, Hausner’s ratio and compressibility index was calculated. If the bed particle was more compressible then the powder will be less flowable and vice versa. The value of compressibility index was found between 4.545-14.427%. The powder blends of all formulation had Hausner’s ratio less than 1.25 indicating good flow characteristics.34 The compressibility–flowability correlation data indicating a good flowability of the powder blend. The flowability of the powder was also evidenced by the angle of repose. The angle of repose below 30o range indicates good to excellent flow properties of powder.
Lower the friction occurring within the mass, better the flow rate.39 The angle of repose was found to be in range 23.29-29.62o. The results showed good flow property of the formulated mixed blends due to the addition of talc as lubricant and magnesium stearate as glidant in the 2% w/w and 2% w/w of the tablet weight respectively. The results for pre-compression characterization of blend are shown in Table 3.14.
After compression of powder blends, the tablets were evaluated for their post-compression properties like organoleptic, physical and quality control parameters (diameter, thickness, hardness, friability, disintegration time, wetting time and dispersion time). All the formulations are white in color, odorless, flat in shape with smooth surface. The prepared tablets were elegant and lot-to-lot tablet uniformity and also free from any surface texture problems.
The thickness of the tablets varied
between 2.343-2.521 mm. The average weight of the prepared tablets with
superdisintegrants and effervescent agents were found between 95.4-102.1 mg.
The average weight of the tablets prepared by vacuum drying technique was found 80.3-95.7 mg due to the
elimination of the sublimating agents from the tablets. So it was predicted
that all the tablets exhibited uniform weight with low standard deviation
values within the acceptable variation as per USP.42
The
friability of the formulations was less than 1.0%, showed the durability of the
tablets; resistance to loss of weight indicates the tablet’s ability to
withstand abrasion in handling, packaging and shipment.39 The friability of all
the formulations was found to be less than 1.0 % except those containing higher
concentrations of subliming agents (F19, F21, F27, F31 and F32). It was clear
from the study that as the concentration of sublimating agents was increasing the
percent friability was also increasing. The hardness of the prepared tablet
varied from 2.7-3.2 kg/cm2, which has satisfactory strength to withstand with
the applied mechanical shocks.
A
disintegrant was found in all the formulations to facilitate a breakup or
disintegration of the tablet when it contacts with water or saliva in mouth.
The disintegration process of the tablet was fully dependable on nature and
concentration of superdisintegrant used. Disintegrants drawing the water into
the tablet causes wicking, swelling and burst apart. The tablets with
crospovidone disintegrate faster than the tablets with the citric acid and
sodium-bi-carbonate, sodium starch glycolate and Ac-di-sol and camphor, menthol
and thymol. The tablets prepared with superdisintegrants disintegrate in 27-128
s. The tablets prepared with effervescent technology elaborates the
carbon-di-oxide gas when the tablet comes in contact with little amount of
saliva or water due to reaction between citric acid and sodium-bi-carbonate which
results in breakup of tablets. The tablets prepared with effervescent agents
disintegrate in 29-78 s. The porous structure of the tablets prepared with
sublimating agents was responsible for the for fast water uptake, which
facilitates the disintegration of tablets. The tablets prepared with
sublimating agents disintegrate in 29-102 s.
The in
vitro wetting time was also studied to know the time required for complete
wetting of tablets when placed on tong. The in vitro wetting time of all
the formulations were varied between 20-125 s. The swelling properties of the
tablets were depending upon their concentration and type of superdisintegrants.
The result shows that swelling time was reduced with increase in the
concentration of the superdisintegrant. The results are tabulated in Table
3.16.
The
tablets with crospovidone showed the best results on compare to others and
hence it was selected as one factor of the optimization of the fast dissolving
tablets.54 Thus, it was decided to carryout optimization studies with other
disintegrants in combination with the superdisintegrant crospovidone.
The
tablets prepared by combination of two disintegrants gave better results in
terms of disintegration time and friability than using single disintegrant. The
tablet may disintegrate by two properties. In the tablets, F35, F36 and F37 the
porous structure developed by sublimating agents (camphor, menthol and thymol)
was responsible for water uptake, hence it facilitates wicking action of
crospovidone in bringing faster disintegration.
By
the incorporation of crospovidone the friability of the tablets was also
decreased. In the tablets, batch F38 the capillary action of crospovidone
raises the medium, for the completion of reaction between sodium-bi-carbonate
and citric acid. The faster uptake of medium in the tablets faster the tablet
disintegrates. In tablet batch F33 and F34 pre-compression and post-compression
evaluations not found in limits, due to the great difference between shape,
size and compressibility properties of two superdisintegrants (Ac-di-sol/sodium
starch glycolate and crospovidone). The poor flow property and compressibility
properties of the physical mixture was observed (Table 3.18). Due to the less
compressibility the formed tablets were friable in nature. Thus, it was decided
to prepare coprocessed disintegrants (Ac-di-sol with crospovidone and sodium
starch glycolate with crospovidone). Coprocessing of excipients could lead to
formation of excipients with superior properties compared with the simple
physical mixture of their components or individual components.
In
preliminary investigation, water, ethyl alcohol, dichloromethane and isopropyl
alcohol were used for coprocessing of the superdisintegrant. Water was ruled
out for further experiment because gel formation occurs due to the presence of
starch in Ac-di-sol and sodium starch glycolate. Dichloromenthane was omitted
because of floating of crospovidone and sedimentation of Ac-di-sol and sodium
starch glycolate. Ac-di-sol and sodium starch glycolate was sparingly soluble
in ethyl alcohol. Isopropyl alcohol was selected considering the absence of gel
formation and phase separation.
The
diameters of superdisintegrants in different media was determined are given in
Fig.. A significant reduction in swelling capacity was also observed in
physical mixture as well as coprocessed superdisintegrants in Sorenson’s buffer
(pH 6.8). The sudden decrease in swelling capacity of chemically modified
starch may attribute to the converting of the carboxymethyl sodium moieties to
its free acid form in acidic medium. Since the acid medium form has less
hydration capacity than its salt form, the liquid holding capacity of the
disintegrant particle reduces after deionization in the slightly acidic
medium.26 Therefore, the total degree of substitution and the ratio of basic to
acidic substituent’s were potential factors determining the extent of influence
of medium pH on the swelling properties of disintegrants and blends particles.
Unlike
the other superdisintegrant, there was no apparent change in the swelling
capability of the nonionic polymer crospovidone in both media. The results
illustrated that the physical mixing and coprocessing give better swelling than
used alone.
The bulk
density, tapped density, compressibility index, Hausner’s ratio and angle of
repose studied all batches shown in Table 3.20. According to literature the
powder compressibility index between 5 to 16% was suitable for punching tablets
and those Hausner’s ratio below 1.25 exhibited good flowability.39 Only
coprocessed superdisintegrant batches were fallen in the limit/range. On the
evaluation of superdisintegrant angle of repose of the physical mixture and
coprocessed disintegrants (1:1) was found to be 37.83-39.360 and 22.42-24.160
respectively. According to literature, good flow (angle of repose between 200
and 350) was shown by coprocessed superdisintegrants. It was concluded that the
particle size distribution and shape of the excipients would be kept the same
to avoid the tabletting problem.
The
morphology and surface properties of Ac-di-sol, sodium starch glycolate,
crospovidone and coprocessed superdisintegrant were visualized using scanning
electron microscopy (SEM) shown in Fig. All powder batches were presented in
magnificence of X150. From these micrographs we observed clear difference
between the structure and size of superdisintegrants.
The
tablets were prepared by the coprocessed superdisintegrants showed better
results than the tablets prepared by using physical mixture or by using
individual components. The results clears that the disintegration time and
percent friability have a great difference in physical mixture and coprocessed
superdisintegrants. When, Ac-di-sol and sodium starch glycolate was used,
higher water uptake swelling and deformation of disintegrants take place, which
gives internal pressure to tablet to disintegrate. It was obvious that in the
presence of crospovidone, wicking was facilitated.57 The use of a physical mixture
superdisintegrant resulted in increased friability probably due to low
compressibility of excipients. By the coprocessing technology the friability of
tablets was also decreased.
By evaluating these
tablets, the levels for the optimization of the independent factors were to be
set. The three levels (-1, low; 0, medium; +1, high) of different
disintegrating agents were selected.
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