INTERNATIONAL JOURNAL OF PHARMACEUTICAL … 1033.pdf · FORMULATION AND EVALUATION OF PULSATILE TABLET OF NEBIVOLOL ... The inner core tablet was prepared by direct compression …

Research Article CODEN: IJPRNK ISSN: 2277-8713 Mehul Nayak, IJPRBS, 2015; Volume 4(2): 388-401 IJPRBS

Available Online at www.ijprbs.com 388

FORMULATION AND EVALUATION OF PULSATILE TABLET OF NEBIVOLOL

FOR CHRONOPHARMACOTHERAPY OF HYPERTENSION

MEHUL NAYAK, DR. UPENDRA PATEL, MR. BHAVIN BHIMANI, MR. GHANSHYAM PATEL

DR. SUNITA CHAUDHRY Arihant School of Pharmacy and Bio-Research Institute, Adalaj.

Accepted Date: 15/04/2015; Published Date: 27/04/2015

Abstract: In Hypertension raise in blood pressure shows circadian rhythm dependency, where blood pressure raise in early morning and fall as day progresses and reaches to its lowest level at night. So for effective treatment such type of drug delivery system required which provide minimum amount of drug release at night highest at morning. Through pulsatile delivery system this type of release can be provide. The aim of present work is formulate and evaluate a press coated pulsatile release tablets of Nebivolol HCl using an admixture of hydrophilic polymer i.e. low substituted hydroxy propyl cellulose (L-HPC) and hydrophobic polymer i.e. ethyl cellulose (Ethocel 10 cps) in order to achieve a predetermined lag time for chronopharmacotherapy of Hypertension. Experimental work: The core tablet is prepared by using superdisintegrants like MCC, Croscarmellose Na. The press coated pulsatile tablets containing Nebivolol HCl in the inner core were prepared by compression coating with L-HPC and Ethocel 10 cps as the outer layer in different ratios. The effect of polymer ratio and weight gain of the outer layer on lag time of drug release and T90% was investigated using 3

2 full factorial design. The parameters

determined were tablet hardness, friability, drug content, lag time, T90%, in vitro dissolution. Results: The release profile of the press coated tablet exhibited a distinct lag time before burst release of Nebivolol HCl. Lag time and T90% was dependent on the ratio of L-HPC/Ethocel 10 cps and weight gain in outer shell. The lag time was from 1 to 10 hr and could be modulated as it decreased as the amount of L-HPC in the outer layer increased. A surface plots are also presented to graphically represent the effect of independent variables on the lag time and T90%. Conclusion: Formulation PCPT7 with L-HPC/Ethocel 10 cps(10:90) and weight gain 300 mg showing predetermined lag time of 5.25 hr prior to burst release of the drug from the press coated tablet was taken as the optimized formulation.

Keywords: Hypertension, Pulsatile, Lag time, Nebivolol HCl, Chronopharmacotherapy, Superdisintegrants

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Mehul Nayak, IJPRBS, 2015; Volume 4(2): 388-401



INTRODUCTION

For the treatment of various diseases oral route is the most preferred route and conventional

dosage forms are widely used for treatment. In conventional therapy drug is released

immediately after medication. So, the drug concentration in the plasma is raised and

sometimes it is more than the toxic level. Another problem associated with conventional

formulation is multiple dose administration which leads to poor patient compliance. The target

of drug discovery is to obtain maximum drug efficacy and minimum side effect with better

patient compliance. Although various controlled release systems has been developed, biological

systems are not so responsive to these release systems. Several controlled release preparation

present numerous problems such as resistance and drug tolerance, dose dumping and

activation of the physiological system due to long term constant drug concentrations in the

blood and tissues. [1-3] However certain diseases which follows circadian rhythm demands

particular type of drug release system which provide maximum amount of drug release at its

greatest need when pathological expression of diseases is higher( Once in 24 hour). Pulsatile

drug delivery system is most suitable to achieve such a kind drug release profile. A pulsatile

drug delivery system is characterized by a lag time that is an interval of no drug release

followed by rapid drug release. [4, 5]

Various diseases like asthma, hypertension and arthritis show circadian variation, that demand

time scheduled drug release for effective drug action. In Hypertension blood pressure (BP)

exhibits a diurnal variation with increase in the morning (morning BP surge) and decreases as

day progress and reaches to its lowest level at night. So for cardiovascular diseases specific type

of delivery system required which deliver the antihypertensive drug in higher amounts in early

morning hours (i.e.at time of greatest need)and lower amounts at night(i.e.at the middle of

sleep cycle when the need of drug is less). Pulsatile drug delivery system is ideal to provide such

a kind of drug delivery. Pulsatile drug delivery system are characterized by two release phases,

first phase with no drug released (at night) followed by a second phase, during which the drug

is released completely within a short period of time (at early morning) after the lag time,

providing maximum drug concentration at time of its greatest need. [6, 7]

Nebivolol is a highly cardio selective β1-receptor blocker with nitric oxide potentiating

vasodilatory effect and widely used in for the treatment of the hypertension. Because of its

selective β1-receptor blocking activity it minimizes the side effect associated with β2- receptor

blockers (e.g.bronchoconstriction). [8] The aim of this work is to formulate and evaluate a press

coated pulsatile release tablets of Nebivolol HCl using an admixture of hydrophilic polymer i.e.

low substituted hydroxy propyl cellulose (L-HPC) and hydrophobic polymer i.e. ethyl cellulose

(Ethocel 10 cps) in order to achieve a predetermined lag time for chronopharmacotherapy of

Hypertension.



MATERIALS

Nebivolol HCl was obtain from torrent pharmaceuticals ltd Bhat, India. Low

Hydroxypropylcellulose was obtain as gift sample from Arihant inochem, Mumbai. Ethocel

10cps and pregelatinized starch was obtain as gift sample from Cololrcon Asia Private Limited,

Goa, India. Microcrystalline cellulose and crosscarmellose sodium was obtained through

S.D.Fine chemicals, Baroda.

METHODS

Preparation of core tablet

The inner core tablet was prepared by direct compression method as per the composition given

in Table 1. All the ingredients were passed through standard sieve # 40 separately, weighed and

mixed in geometrical order. Then lubricant and glidant (standard sieve # 60) were added and

mixed for further 5 minute. The resulting powder mixtures were then compressed into tablets

using a rotary tablet machine equipped with 6 mm flat faced punch. Core tablet formulations

were coded as A1 to A6.

Preparation of press coated pulsatile release tablets [9]

I: Prefilling the half amounts of outer coating materials into the die.

II: Putting the inner core tablet on the powder bed of outer coating materials.

III. Centering.

IV: Filling the residual half amounts of outer coating materials.

V. Compression

VI. Ejection of press-coated tablet from the die.

Optimization Using Factorial Design:

A full factorial 32 design was used for formulation optimization procedure. ). The studied factors

(independent variables) were percentage weight ratios of ethyl cellulose to hydroxypropyl

cellulose (X1) and coating weight (X2). Preliminary studies provided a setting of the levels for

each formulation variable. The response (dependent variables) studied was lag time (Y1) and

T90%. The response (dependent variables) studied was lag time (Y1) and T90%. Table 2.

summarizes the independent and dependent variables along with their levels. The resulted

formulations (testing runs) are listed in Table 3. The factorial formulations were coded as PCPT1

to PCPT9. Thus X1, X2 and X11 has significant effect on dependent variable (Y2) T90% while



other term X12 and X22 were rendered insignificant having P value greater than 0.05. For both

response Lag time & T90% independent variable X1, X2 and X11 has significant effect while other

term X12 and X22 were rendered insignificant having P value greater than 0.05.

Table 4. Composition of factorial formulations for press coated pulsatile release formulation

EVALUATIONS

Pre Compression Parameters [10, 11]

The pre compression parameters evaluated include bulk density, tapped density, hausner’s

ratio, carr’s index and angle of repose.

Post Compression Parameters [10, 11]

Post compression parameters evaluated are thickness, hardness, friability, weight variation of

the tablets. Further the tablets are subjected to the following evaluation parameters.

Disintegration test for core tablet [12]

The in vitro disintegration time was determining using disintegration test apparatus. A tablet

was place in each of the six tubes of the apparatus with lid on upper side and the time

(seconds) taken for complete disintegration of the tablet in phosphate buffer pH 6.8 (since

dosage form is designed to release drug after the lag time) at 37±0.5 °C with no palatable mass

remaining in the apparatus is measured.

Drug content determination for core tablet [17]

Drug content was determined by taking twenty tablets and amount of drug present in each

tablet was determined. Randomly selected 20 tablets were weighed and powdered in a glass

mortar pestle. The weight equivalent to 10 mg nebivolol was weighed and dissolved in 10 ml of

methanol in volumetric flask, the volume was adjusted to 100 ml with phosphate buffer (pH

6.8) and the solution was filtered. An aliquot of 1.0 ml of solution were diluted to 10 ml

phosphate buffer (pH 6.8) in separate volumetric flask. The content in was determined

spectrophotometrically at 280 nm.

In vitro dissolution study of core tablet [13]

Dissolution test was performed using a USP apparatus type-II (paddle type) at 37 ֯C ± 0.5 ֯C in

900 ml of phosphate buffer pH 6.8 at speed of 50 rpm. At specific time intervals 5 ml of aliquot

of sample was withdraw and replace with fresh phosphate buffer pH 6.8 solution. The aliquot

was analyzed for drug content using UV-visible spectrophotometer after appropriate dilution

against reference using phosphate buffer pH 6.8.



Rupture test (Lag time determination) [14]

The lag time of the tablets is defined as the time required for the outer coat to rupture. It was

determined visually using 900 ml of phosphate buffer pH 6.8, at 37 ± 0.5 ºC, and at 50 rpm in

the USP type II dissolution apparatus.

In vitro drug release study of press coated tablet [15]

The prepared press coated tablets were subjected to in vitro drug release sequentially in two

different suitable dissolution media to assess their ability to provide the desired lag time before

drug release. USP type II dissolution apparatus was used. The dissolution medium for the first 2

hr was 900 ml of 0.1 N HCl (pH 1.2) and continued in phosphate buffer pH 6.8) for the next 10

hr. The temperature of dissolution medium was maintained at 37 ± 0.5 °C and the paddle was

rotated at 50 rpm. An aliquot of 5 ml was withdrawn at predetermined time intervals and

replaced with an equal volume of the fresh dissolution medium to maintain sink conditions. The

samples were filtered through a 0.45 µm cellulose acetate filter and analyzed at 279 nm, for the

percentage drug release using an UV-Visible double beam spectrophotometer. One tablet was

used for each determination and the experiment was performed in triplicates.

Stability study of optimized formulation [16]

The optimized formulation was monitored up to 1 month at short term stability conditions of

temperature and relative humidity (40 ± 2 0C /75% ± 5%RH). The tablets were sealed in

aluminum foil and kept in humidity chamber. Samples were withdrawn after one month and

characterized for thickness, hardness, drug content and in vitro drug release.

RESULTS AND DISCUSSION

Precompression parameters (Core tablet)

The results of precompression parameters of core tablets powder blend are given in Table 5.

The results of angle of repose, bulk density, tapped density, carr’s index and hausner’s ratio

indicates that powder blend has good flow property with good compressibility and suitable for

direct compression method.

Postcompression parameters (Core tablet)

The results of postcompression parameters of core tablet are given in Table 6. and 7. Tablets

prepared by direct compression technique showed uniform thickness, diameter and acceptable

weight variations limit as per pharmacopoeial specifications.



Hardness was found in the range of 3-6 kg/cm2 for all the formulations of the core tablet and

the friability for all formulations was found to be less than 1% indicating sufficient mechanical

integrity and strength of the prepared tablets.

The disintegration time of formulation A1 was 42 seconds and it was found to decrease as the

concentration of crosscarmellose sodium increased. Formulation A2 showed disintegration

time of 16 seconds which was the lowest and attributed to the highest concentration of

croscarmellose sodium .Formulation A3 and A4 was contain sodium starch glycolate alone and

in combination with CCS and their disintegration time found to be 24 and 46 seconds

respectively. The disintegration time of formulation A5 and A6 was 42 and 48 seconds

respectively

Precompression parameters (Press coated tablet)

Results of pre compression parameters of coating powder blend for factorial formulations are

mentioned in Table 8.

From result it was found that the powder blend prepared for press coating of core tablets have

Angle of repose (25.08 ± 0.80 to 28.56 ± 1.32), Hausner’s ratio (1.13 ± 0.01 to 1.18 ± 0.16) and

Carr’s index (11.62 ± 0.65 to 16.66 ± 0.12), which shows good flow property and

compressibility of powder blend for press coating.

Post compression parameters (Press coated tablet)

Results of post compression parameters of factorial formulations of pulsatile tablet are listed in

Table 9.

Tablets prepared by press coat technique were passed the weight variation test. Hardness was

found in the range of 7.8 to 10.4 kg/cm2 for and Friability found in the range of 0.52 %-0.89 %

for all the formulations of press coated tablets.

In vitro drug release study of Core tablet formulations (A1-A6)

It can be seen from the figure 2. that the cumulative % drug release from formulation A6

provides more than 75% drug release within 5 minutes and 100% drug release within 60

minutes. So, formulation A6 was selected for the further study as a core tablet.

Determination of lag time by rupture test

Results of rupture test of factorial formulations are mentioned in Table 10. It shows variation in

the lag time and T90% as the ratio of polymer and coating weight changes. Lag time and T90%

was decreased as the amount of hydrophilic polymer increases and coating weight decreases.



In vitro drug release study of factorial formulations

All the factorial formulations were subjected to in vitro drug release study. The results of in

vitro release of Nebivolol HCl from different factorial formulations (PCPT1 to PCPT4) are shown

in Figure 3.

All press coated tablet showed pulsatile release behavior with distinct lag time. Figure 3 and 4

shows the dissolution profile of press coated tablets.

It can be seen from the Figure 3. that the cumulative % drug release from formulation PCPT1

and PCPT4 was found to be 100 % after 4.5 hr and 5 hr respectively. Cumulative % drug release

from formulation PCPT2 and PCPT3 was found to be 100 % after 6 hr and 7.5 hr respectively.

It can be seen from the Figure 4. that the cumulative % drug release from formulation PCPT5

and PCPT7 was found to be 100 % after 6.5 hr and 7 hr respectively. Cumulative % drug release

from formulation PCPT6 and PCPT8 was found to be 100 % after 8 hr and 9 hr respectively.

While formulation PCPT9 showed 100 % drug release after 10.5 hr.

Coating level also affect the lag time of press coated tablets as the coating level increases lag

time increases. The result indicates that coating weight proportional to the lag time. The larger

amount of coating material produces tablets with higher thickness and longer path for buffer

media to penetrate into the core.

Formulation PCPT7 (polymer ratio 90:10 & coating weight 300 mg) provides a desired lag time

of 5.25 hr hence it was selected as a optimized formulation.

Stability study of optimized formulation (PCPT 7)

Short term stability studies were performed at temp of 40±20C / 75±5% RH over a period of

one month (30 days) on the promising press coated tablets of Nebivolol HCl (formulation PCPT

7). Sufficient number of tablets (15) were packed in rubber stopper vials & kept in stability

chamber maintained at 40±20C / 75±5% RH.

Samples were taken at one month interval. At the end of one month period, dissolution test

was performed to determine the drug release profile. Results are given in Figure 5.

The lag time and T90% before and after storage were found to be similar. Dissolution profiles

before and after storage are nearly overlapable. The change in the drug release pattern i.e.

dissolution profile was not significantly different from the one month previous tablet

dissolution profile. The developed dosage form passes stability study carried out for 30 days at

40±20C / 75±5% RH.



Table 1. Composition of core formulation

Ingredients (mg) A1 A2 A3 A4 A5 A6

Nebivolol HCl 10 10 10 10 10 10 MCC 25 25 25 25 25 25 Crosscarmellose sodium 2.5 5 - - 2.5 Pregelatinised starch - - - 10 12 12 Lactose 62.8 60.3 57.8 52.8 50.8 48.3 Sodium lauryl sulfate 0.2 0.2 0.2 0.2 0.2 0.2 Magnesium stearate 1 1 1 1 1 1 Talc 1 1 1 1 1 1 Total weight (mg) 100 100 100 100 100 100

Table 2. Coding of variable

Coded values Actual values Responses

Y1 Y2 X1= polymer ratio X2= weight gain(mg) Lag time T90%

-1 80:20 300 0 85:15 350 +1 90:10 400

Table 3 Formulation layout for factorial formulations

Formulation code Coded values True values

X1 X2 X1 X2(mg)

PCPT1 -1 -1 80:20 300

PCPT2 -1 0 80:20 350

PCPT3 -1 +1 80:20 400

PCPT4 0 -1 85:15 300

PCPT5 0 0 85:15 350

PCPT6 0 +1 85:15 400

PCPT7 +1 -1 90:10 300

PCPT8 +1 0 90:10 350

PCPT9 +1 +1 90:10 400



Table 4. Composition of factorial formulations for press coated pulsatile release formulation

Ingredients(mg) Formulation

PCPT 1

PCPT 2

PCPT 3

PCPT 4

PCPT 5

PCPT 6

PCPT 7

PCPT 8

PCPT 9

Nebivolol HCl 10 10 10 10 10 10 10 10 10 MCC 25 25 25 25 25 25 25 25 25 CCS 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Pregelatinised starch 1500

12 12 12 12 12 12 12 12 12

Lactose 48.3 48.3 48.3 48.3 48.3 48.3 48.3 48.3 48.3 SLS 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Mg. stearate 1 1 1 1 1 1 1 1 1 Talc 1 1 1 1 1 1 1 1 1 Subtotal (mg) 100 100 100 100 100 100 100 100 100 Coating layer Ethocel 10cp 240 280 320 255 297.5 340 270 315 360 L-HPC 60 70 80 45 52.5 60 30 35 40 Total (mg) 400 450 500 400 450 500 400 450 500

Table 5. Precompression parameters of core tablet powder blend

Formulation Code

Bulk density* (gm/ml)

Tapped density* (gm/ml)

Carr’s index* (%)

Hausner’s ratio*

Angle of repose*

A1 0.48±0.02 0.56±0.02 14.28±0.34 1.16±0.02 26.43±0.82 A2 0.43±0.05 0.49±0.05 12.24±0.48 1.13±0.05 26.65±0.78 A3 0.48±0.04 0.54±0.04 11.11±0.62 1.12±0.04 28.12±1.24 A4 0.49±0.02 0.57±0.03 15.78±0.72 1.16±0.12 28.09±1.18 A5 0.43±0.01 0.50±0.02 14.00±0.58 1.16±0.16 27.82±1.16 A6 0.45±0.04 0.51±0.02 11.76±0.52 1.13±0.40 28.15±0.67

* Values are mean ± SD, (n=3)

Table 6. Post compression parameters core tablet (A1-A3)

Parameters A1 A2 A3

Thickness*(mm) 2.04 ±0.04 2.09 ±0.04 2.01 ±0.02 Diameter*(mm) 6.04 ±0.25 6.06 ±0.38 6.03 ±0.28 Hardness*(kg/cm2) 3.0 ±0.5 3.3 ±0.25 3.2 ±0.42 Friability*(%) 0.78 ±0.025 0.62 ±0.030 0.68 ±0.042 Disintegration time*(sec) 75 ±1.2 52 ±2.8 46 ±1.6 Weight variation* 100.25 ±0.38 100.58 ±0.56 100.47 ±0.25



Drug Content (%)* 99.45 ±0.18 101.46 ±0.22 98.86 ±0.45


Table 7. Postcompression parameters core tablet (A4-A6)

Parameters A4 A5 A6

Thickness*(mm) 2.10 ±0.02 2.05±0.05 2.11 ±0.04 Diameter*(mm) 6.04 ±0.42 6.05±0.58 6.04 ±0.34 Hardness*(kg/cm2) 3.8 ±0.40 4.1±0.82 4.3±0.25 Friability*(%) 0.57 ±0.02 0.55±0.06 0.52 ±0.03 Disintegration time*(sec) 46 ±1.2 48±0.9 42±1.4 Weight variation* 99.82 ±0.35 100.15 ±0.40 101.08 ±0.25 Drug Content (%)* 100.18 ±0.72 101.02 ±0.30 102.58 ±0.42


Table 8. Precompression parameters of powder blend for press coating

Formulation Bulk density* (gm/ml)

Tapped density* (gm/ml)

Carr’s index% Hausner’s ratio*

Angle of repose*

PCPT1 0.36 ±0.02 0.41±0.01 12.19 ±0.54 1.13 ±0.01 26.38±0.5 PCPT2 0.38±0.04 0.45±0.03 15.55 ±0.62 1.18 ±0.05 25.14±1.02 PCPT3 0.35±0.01 0.42±0.01 16.66 ±0.12 1.20 ±0.02 26.32±0.60 PCPT4 0.37±0.05 0.44±0.01 15.90 ±0.45 1.18 ±0.12 25.08±0.80 PCPT5 0.32±0.01 0.38±0.02 15.78 ±0.49 1.18 ±0.16 27.54±1.05 PCPT6 0.38±0.02 0.43±0.03 11.62 ±0.65 1.13 ±0.12 28.24±1.12 PCPT7 0.36±0.04 0.42±0.04 14.28 ±0.11 1.16 ±0.02 24.56±1.16 PCPT8 0.39±0.02 0.45±0.01 13.33 ±0.11 1.15 ±0.08 25.74±0.22 PCPT9 0.35±0.01 0.40±0.02 12.50 ±0.45 1.14 ±0.02 28.56±1.32

Table 9. Post compression parameters of press coated tablets

Formulation code

Weight variation*

Thickness (mm)*

Diameter (mm)*

Hardness (kg/cm 2)*

%Friability

PCPT1 400±1.00 5.08±0.01 8.95±0.01 7.8±0.40 0.89±0.05 PCPT2 454±0.82 5.52±0.03 8.92±0.26 8.8±0.25 0.76±0.09 PCPT3 508±1.36 6.34±0.01 9.00±0.15 9.2±0.16 0.68±0.08 PCPT4 405±0.25 5.06±0.01 8.98±0.02 8.4±0.48 0.86±0.12 PCPT5 450±1.25 5.65±0.01 8.95±0.04 9.6±0.40 0.72±0.16 PCPT6 500±2.18 6.42±0.04 8.96±0.25 9.9±0.35 0.60±0.14 PCPT7 400±1.52 5.12±0.02 8.95±0.05 8.8±0.52 0.64±0.08 PCPT8 450±0.54 5.72±0.01 9.00±0.08 10.2±0.42 0.52±0.12 PCPT9 500±1.36 6.32±0.02 9.00±0.12 10.4±0.34 0.48±0.06



Table 10. Lag time and T90% study of factorial formulations

Formulation code Lag time* (hour) T90%

(hour)

PCPT1 1.5±0.24 3.62 PCPT2 2.86±0.18 4.5 PCPT3 4.58±0.12 5.95 PCPT4 2.25±0.28 4.06 PCPT5 4±0.16 5.5 PCPT6 5.96±0.14 7.2 PCPT7 5.25±0.26 6.3 PCPT8 6.75±0.38 7.73 PCPT9 8.53±0.32 9

Figure1. Manufacturing processes of press coating. Preparation of press coated pulsatile

release tablets

.

(I) (II) (III) (IV) (V) (VI)

Figure 2. In vitro release profile of Nebivolol HCl from core tablets

0

20

40

60

80

100

120

0 20 40 60 80 % c

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A3

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100

120

0 20 40 60 80 % C

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A6



Figure 3. In vitro dissolution profile of press coated pulsatile release tablets of formulation

(PCPT1 to PCPT4)

Figure 4. In vitro dissolution profile of press coated pulsatile release tablets of formulation

(PCPT5 to PCPT9)

Figure 5. Comparison of in vitro dissolution profile of formulation- PCPT7 tablets before and

after (30th day) stability study stored at 40oC

0

20

40

60

80

100

120

0 2 4 6 8

% C

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BEFORE 30 DAYS

AFTER 30 DAYS



Figure 6. Response surface 3D plot showing the influence of coating weight and polymer ratio

on lag time

Figure 7. Contour plot showing relationship between polymer ratio and coating weight on lag

time

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Design-Expert® SoftwareFactor Coding: Actuallag time

Design points above predicted valueDesign points below predicted value8.53

1.5

X1 = A: Coating ratioX2 = B: Coating weight

-1

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0

0.5

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-1

-0.5

0

0.5

1

0

2

4

6

8

10

lag

tim

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A: Coating ratio (mg)B: Coating weight (mg)

Design-Expert® SoftwareFactor Coding: Actuallag time

Design Points8.53

1.5

lag time = 5.25Std # 1 Run # 7

X1 = A: Coating ratio = 1X2 = B: Coating weight = -1

-1 -0.5 0 0.5 1

-1

-0.5

0

0.5

1

lag time

A: Coating ratio (mg)

B:

Co

ati

ng

we

igh

t (m

g)

2

4

6

8

Prediction 5.16222



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INTERNATIONAL JOURNAL OF PHARMACEUTICAL … 1033.pdf · FORMULATION AND EVALUATION OF PULSATILE TABLET OF NEBIVOLOL ... The inner core tablet was prepared by direct compression …