INTRODUCTION:

Solubilization of poorly soluble drugs is a frequently encountered challenge in screening studies of new chemical entities as well as in formulation design and development. A number of methodologies can be adapted to improve solubilization of poor water soluble drug and further to improve its bioavailability. ^{[1, 2,]} Orally administered drugs completely absorb only when they show fair solubility in gastric medium and such drugs show good bioavailability. Bioavailability depends on several factors, drug solubility in aqueous environment and drug permeability through lipophillic membranes being the important ones.

The techniques generally employed for solubilization of drug includes micronization, chemical modification, pH adjustment, solid dispersion, complexation, cosolvency, micellar solubilization, hydrotropy etc. ^{[3, 4]}

Only solubilized drug molecules can be absorbed by the cellular membranes to subsequently reach the site of drug action (vascular system for instance). Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption. ^{[5, 6]}as Solubility & permeability is the deciding factor for the in-vivo absorption of the drug, these can be altered or modified by enhancement techniques. These poorly water soluble drugs are allied with slow drug absorption leading to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. ^[7]

Solid Dispersion is a technique in which a poorly soluble drug is dispersed in a highly soluble solid hydrophilic matrix, which enhances the dissolution of the drug. Various strategies investigated to enhance solubility in solid dispersions are fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying ^[8] technology, use of surfactant, electro static spinning method and super critical fluid technology. ^[8,9]

Carvedilol is an antihypertensive drug of BCS class II drug. It exhibit poor bioavailability of about 25% which is attributed to its poor solubility. The present work aimed to overcome the limitations of poor solubility and poor bioavailability. ^{[10, 11]} The solubility enhancement technique used was spray drying using hydrophillic carriers (β-cyclodextrin and Plasdone K-30). Another purpose of this research work was to develop a press-coated pulsatile drug delivery using solid dispersion of Carvedilol. Various composition of ethylcellulose and L-HPC were used to prepare the barrier layer coating of the press-coated tablets. ^{[12, 13,
14, 15]} The effect on the lag time was studied. The intension was that the formulated tablet when administered at night at 10 p.m., will release the drug in the early morning at 5 a.m...(I.e. chronotherapy). ^{[16, 17, 18]}

MATERIALS AND METHODS:

Carvedilol was provided as a gift sample by Mylan Laboratories, Bangalore. β-Cyclodextrin, Plasdone K-30, croscarmellose sodium, microcrystalline cellulose, lactose, magnesium stearate, talc, ethylcellulose, L- hydroxypropyl cellulose and methanol were supplied by Research Lab Fine Chem. Industries, Mumbai. Sunset Yellow was supplied by Koel Colours Pvt. Ltd., Mumbai.

Method-:

6 batches of solid dispersion were prepared and evaluated for their drug release. The formulation table of these batches is shown in table no.1.

Table No.1. Formulation Table for preparing solid dispersion

Batch Code	Carvedilol (gm)	β-cyclodextrin (gm)	Plasdone K-30 (gm)
SD1	1	1	-
SD2	1	2	-
SD3	1	3	-
SD4	1	-	1
SD5	1	-	2
SD6	1	-	3

The batch SD6 was found to be the optimized batch for incorporating into press coated tablets. This was confirmed from the following tests: Fourier transform infrared spectroscopy, percentage practical yield, drug content, saturation solubility, In-vitro drug release study, DSC study and scanning electron microscopy.

Formulation of Immediate Release Press-Coated Tablets:

A} Formulation of immediate release core tablets using direct compression- ^[19,20]

The inner core tablets were prepared by using direct compression method. Carvedilol solid dispersion, microcrystalline cellulose, croscarmellose sodium, lactose and sunset yellow were weighed accurately, dry blended for 20 min, followed by addition of magnesium stearate. 100mg of resultant powder blend was manually compressed using KBr hydraulic press at a pressure of 1 ton, with a 10mm punch and die to obtain the core tablet. Table no.2 shows the formulation table for core tablet.

Table No.2: Formulation Table for core tablet

Ingredients	Batch Code
	L1 (mg)	L2 (mg)	L3 (mg)	L4 (mg)
Carvedilol Solid dispersion (Batch SD6)	Equivalent to 12.5mg Carvedilol
Croscarmellose sodium	20	20	10	-
Microcrystalline Cellulose	-	10	20	20
Lactose	q.s.	q.s.	q.s.	q.s.
Magnesium Stearate	0.25	0.25	0.25	0.25
Talc	1	1	1	1
Sunset Yellow	1	1	1	1

B} Formulation of mixed blend for barrier layer-:

As given in the Table no.3 the various barrier layer compositions containing ethylcellulose and L-HPC were prepared. These were weighed, dry blended for about 10 min. and used as press-coating material to prepare press-coated pulsatile tablets (PCT1-PCT5) by direct compression method using 13mm die and punch.

Table No.3: Compositions of barrier layer coating

Batch Code	Ethylcellulose(mg)	L-HPC (mg)
PCT1	100	0
PCT2	12.5	87.5
PCT3	87.5	12.5
PCT4	50	50
PCT5	0	100

C} Preparation of press-coated tablets-:

The core tablets were press-coated with 400mg of barrier coat as given in Table no.3. 200mg of barrier layer material was weighed and transferred into a 13mm die then the core tablet was placed manually at the center. The remaining 200mg of the barrier layer material was added into the die and compressed at a pressure of 5 tons for 3min using KBr hydraulic press.

Characterization of powder blend for core tablet and press coating material:

A} Precompression Evaluation of powder blend for core tablet and press coating Material- ^{[21,22,23,24]}

1) Angle of repose-:

Angle of repose is defined as the maximum angle possible between the surface of pile of powder and horizontal plane. Angle of repose has been used as indirect method of quantifying powder flow ability. Angle of repose for blend of each formulation was determined by fixed funnel method. The fixed funnel method employs a funnel that is secured with its tip at given height, h, which was kept 2 cm, above graph paper that was placed on a flat horizontal surface. With r, being the radius of base of conical pile, angle of repose can be determined using following equation-

tan θ =-------

Where; θ = Angle of repose

r = Radius of the base

h =Height from tip of funnel to the surface of graph paper.

Table No.4: Grading of powder flow property according to angle of repose

Angle of repose	Flow Property
<25	Excellent
25 -30	Good
30 -40	Passable
> 40	Very poor

2) Bulk density-:

It is the ratio of mass to bulk volume. It is required to decide the appropriate packing of dosage forms. An accurately weighed 20 gm powder was allowed to flow in a fine stream into a graduated cylinder and final volume was noted. The bulk density was obtained by dividing the weight of the sample in grams by final volume in cm³ and it was determined by equation given below-

Mass of powder

Bulk density = --------------------

Bulk volume

3) Tap density-:

An accurately weighed 20 gm powder was allowed to flow in a fine stream into a graduated cylinder of a mechanical tapping device. The measuring cylinder was tapped for 100 times and final tapped volume was noted. The tapped density was obtained by dividing the weight of the sample in grams by final tapped volume in cm³ and it was calculated by using equation given below-

Mass of powder

Top density = ---------------------

Tapped volume

4) Carr’s Compressibility index-:

It is also one of the simple methods to evaluate flow property of a powder by comparing the bulk density and tapped density. The percentage compressibility of a powder is a direct measure of the potential powder arch or bridge strength and stability. It is also known as Carr’s index. It can be calculated by following equation-

Tap density-bulk density

Carr' s compressibility index =--------------------------------- ×100

Tap density

Table No.5: Grading of compressibility of powder according to Carr’s index

Carr’s Index	Flow Property
5-15	Excellent
12-16	Good
18-21	Fair to passable
23-35	Poor
33-38	Very Poor
>40	Extremely Poor

5) Hausner’s ratio-:

Hausner found that the ratio of tapped density/bulk density was related to inter particle friction as such, and could be used to predict powder flow properties. He showed that the powder with low inter particle friction had ratio of approximately 1.2, whereas more cohesive less free flowing powders have ratio greater than 1.6. A Hausner’s ratio of less than 1.25 indicates good flow properties of the powder blends or granules.

Tapped density

Hausner' s ratio = ------------------------

Bulk density

6) Bulkiness-:

Specific bulk volume or reciprocal of bulk density is called as the bulkiness. Bulkiness increases with the decrease in particle size.

Bulkiness = --------------------

Bulk density

B} Postcompression Evaluation for core tablet and press coated tablets-:

1) Weight variation test-:

The USP weight variation test was run by weighing 20 tablets individually, calculating the average weight, and comparing the individual tablet weights to the average. The tablets meet the USP test if no more than 2 tablets are outside the percentage limit.

2) Friability-:

6 tablets were weighed and placed in the Roche friabilator test apparatus, the tablets were exposed to rolling and repeated shocks, resulting from free falls within the apparatus. After 100 revolutions the tablets were de-dusted and weighted again. The friability was determined as the percentage loss in weight of the tablets. The loss of less than 1% in weight is generally considered acceptable. Percent friablity was calculated as follows,

Initial weight-Final weight

% Friability = --------------------------------- ×100

Initial weight

3) Hardness-:

Hardness was measured using the Monsanto hardness tester. The tablet is compressed between the holding anvil and piston connected to a direct force reading gauge. The dial indicator remains at the reading where the tablet breaks and is returned to zero by depressing a reset button.

4) Thickness-:

The thickness and diameter of the tablets was determined using a Vernier caliper. Five tablets from each batch were used and average values were calculated.

5) In-vitro disintegration study-:

To test the disintegration time, one tablet was placed in the each tube of the USP disintegration apparatus and the basket rack was positioned in a one liter beaker of distilled water, at 37±2°C, such that the tablets remain 2.5cm below the surface of liquid on their upward movement and descend not closer than 2.5cm from the bottom of the beaker. Then motor driven device is used to move the basket assembly containing the tablets up and down through a distance of 5 to 6cm at a distance of 28 to 32 cycles per minute. To be in compliance with the USP standards, the tablets must disintegrate, and all particles must pass through the 10-meshscreen in the specified time. If any residue remains, it must have a soft mass with no palpably firm core. The disintegration time should be less and the disintegration rate of the tablets of batches (L1-L4) was also compared.

6) FTIR Spectra of physical mixture of tablet composition-:

The IR spectra of solid dispersion of carvedilol, croscarmellose sodium, microcrystalline cellulose and lactose was recorded in the range of 4000-400cm^-1.

7) In-vitro dissolution study of immediate release core tablets-:

Dissolution of the tablet of each batch was carried out using USP type II apparatus using paddles at 50rpm. 900ml of 6.8pH phosphate buffer was used as dissolution medium and the temperature of the medium was set at 37 ± 0.5⁰C. 5ml of sample was withdrawn at predetermined time interval of 5min, 10min, 15min, 20min and 30min and same volume of fresh medium was replaced to maintain sink condition. The withdrawn samples were analyzed by an UV-visible spectrophotometer at 241nm using 6.8pH phosphate buffer solution as blank solution.

8) In-vitro dissolution studies of press-coated tablets-

Dissolution of the tablet of each batch was carried out using USP type II paddle apparatus. Sequential pH change method was used. Initially the dissolution study was done using 900ml of 0.1 N HCl as dissolution medium for 2hours at 50rpm. The temperature was maintained at 37±0.5⁰C. Then pH 6.8 phosphate buffer was used for the remaining study. 5ml of sample was withdrawn at predetermined time interval. Sink condition was maintained. The withdrawn samples were analyzed by UV-visible spectrophotometer at 241nm and graph of cumulative percent drug release Vs time was plotted. The effect of the barrier layer composition on the lag time for drug release was also studied.

C} Precompression evaluation of immediate release core tablet blend-:

As per procedure noted in experimental part, the powder mixture was evaluated for angle of repose, bulk density, tapped density, bulkiness, Hausner’s ratio and Carr’s compressibility index. The observations are as shown in table no.6.

Fig. 1: Comparative graph of disintegration times of core tablets L1- L4

D} Postcompression evaluation of immediate release core tablet-:

The core tablets were evaluated for thickness, weight variation, crushing strength or hardness, friability, disintegration time and in- vitro drug release study.

The results of the tests were tabulated in Table no.7. Comparative graph of disintegration times of core tablets L1- L4 is shown in fig. 1.

All formulations show good compressibility. The formulated tablets were elegant and almost of uniform thickness in the range of 3.02 to 3.28mm. The weight variation of fast dissolving tablets of all batches was in the range of 98.1 mg to 99mg. The range of hardness was found to be 3.2±0.02 to 3.5±0.06 kg/cm²which shows good mechanical strength of the tablets. All the batches show less friability (<1%) which indicated that the tablets have good mechanical resistance and can withstand rigors of transportation and handling.

The objectives behind addition of disintegrants was to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet. Disintegrants expand and dissolve when wet causing the tablet to break apart, releasing the active ingredients for absorption. Their role is to rapidly break down the tablet into smaller fragments when it comes in contact with water, thereby facilitating dissolution.

Disintegration time of the formulated immediate release core tablets is in the range of 32 to 39 seconds which indicates that disintegration time of tablets is within 1minute. It is clear from the table no. 7 that disintegration time increased with increase in concentration of microcrystalline cellulose. Tablets rapidly disintegrate with increasing concentration of CCS. This indicates that increase in the level of MCC had a negative effect on tablet disintegration time. Hence, disintegrant power of cross-carmellose sodium is more than microcrystalline cellulose.

Crosslinking in croscarmellose sodium makes it an insoluble, hydrophilic, highly absorbent material, resulting in excellent swelling properties and its unique fibrous nature gives it excellent water wicking capabilities. CCS provides superior drug dissolution and disintegration characteristics, thus improving bioavailability of formulations. MCC acts by wicking action only also it has a tendency to develop static charges in the presence of excessive moisture content. With more concentration, it shows a tendency to stick due to rapid capillary absorption and faster dehydration of the tablet surface. Thus, the disintegration rate of crosscarmellose sodium is higher than that of MCC.

E} In-vitro drug release study of immediate release core tablets-

The drug release study of the core tablets was performed as mentioned in the experimental study and the results are shown in table no.8. Cumulative Drug Release data of immediate release core tablets is shown in fig. 2.

Table No.8: Cumulative Drug Release data of immediate release core tablets

Sr. No	Time (min)	% Cumulative drug release*
Sr. No	Time (min)	L1	L2	L3	L4
1	0	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00
1	5	25.21±0.12	23.63±0.13	29.73±0.13	25.35±0.13
2	10	43.44±0.15	42.19±0.15	43.57±0.12	48.49±0.12
3	15	79.56±0.14	77.61±0.12	67.50±0.12	75.27±0.15
4	20	86.81±0.12	85.96±0.13	78.48±0.13	81.61±0.13
5	25	95.67±0.12	88.49±0.12	89.18±0.14	87.69±0.13
6	30	98.58±0.13	92.34±0.12	95.73±0.15	90.88±0.12

*All values are expressed as mean ± SD (n=3)

Fig. 2: Cumulative % drug release profile of immediate release core tablets

Fig.3: Immediate Release Core Tablets of Carvedilol

Fig.4: Core tablet placed in the die along with the coating material

The maximum drug release was observed at 30min. Hence, these core tablets can be used as immediate release tablets in formulation of Press-coated tablets for treatment of hypertension. As the concentration of CCS was increased, the disintegration time decreased and dissolution rate of drug increased. From the observations, L1 was selected as best formulation since it showed maximum drug release in 30 minutes with greater disintegration rate. This batch was further used to formulate press-coated tablets. The images of core tablets are shown in fig. 3 and 4 respectively.

RESULTS AND DISCUSSION:

A} EVALUATION OF PRESS COATING MATERIAL USED FOR DIRECT COMPRESSION:

1] Precompression evaluation of coating material-:

All batches of press coating material were evaluated for angle of repose, loose bulk density, tapped bulk density, bulkiness and Carr’s index. The results are shown in table no. 9.

Angle of repose of batches PCT1 and PCT4 were observed to be 20.55⁰ and 21.79⁰ categorized as good flowing powder mixture while PCT2, PCT3 and PCT5 showed angle of repose 19.77⁰, 18.26⁰ and 19.34⁰ respectively, categorized as excellent flowing powder mixture.

Bulk density of press coating material of all batches was found to be in the range of 0.4089gm/cm³ to 0.4628 gm/cm³. Tapped density of press coating material of all batches was found to be in the range of 0.4347gm/cm³ to 0.4652gm/cm³.

The bulkiness of all the batches were in the range of 2.4003 to 2.50 cm³/gm. The batch PCT2 has lowest Carr’s index of 4.6657% whereas batch PCT3 has highest Carr’s index of 12.4973%. From all the above results we can conclude that batch PCT2 and PCT3 have excellent compressible characteristics.

2] Postcompression evaluation of press-coated tablets-:

Tablets of all batches were evaluate for thickness, average weight, hardness and friability and in vitro drug release study. The results are shown in table no. 10.

Table No.10: Postcompression Evaluation of press-coated tablets

Batch Code	Average weight(mg)	Thickness (mm)*	Hardness (kg/cm²)*	Friability (%)*
PCT1	499.16	0.403± 0.11	10.50±1.22	0.691±0.25
PCT2	495.67	0.402±0.10	10.64±1.31	0.644±0.14
PCT3	498.38	0.410±0.10	10.75±1.21	0.701±0.15
PCT4	499.30	0.401±0.10	10.45±1.25	0.645±0.24
PCT5	497.25	0.411±0.13	10.62±0.21	0.712±0.25

*All values are expressed as mean ± SD (n=3)

Thickness of press- coated tablets were in the range of 0.301 to 0.311cm. The weight variation of press- coated tablets of all batches was in the range of 495.67mg to 499.30mg. The range of hardness was found to be 10.45±1.21 to 10.75±1.25 kg/cm². All the batches show less friability. As per USP/NF loss of less than 1% in weight is generally considered acceptable.

3] FTIR Spectra of Physical mixture of tablet composition-:

The FTIR spectra of solid dispersion of Carvedilol, croscarmellose sodium, microcrystalline cellulose and lactose is shown in Fig.5.

There was no major deviation observed in the characteristic peaks of the pure drug Carvedilol. Hence, it can be concluded that the drug, superdisintegrants (CCS and MCC) and diluent (lactose) are compatible with each other and there was no evidence of any chemical reaction in between the drug and excipients.

4] In-vitro drug release study of Press- coated tablets-

The present study was aimed at developing press-coated pulsatile drug delivery system of appropriate lag time (7 hours) for the treatment of hypertension. As mentioned in the experimental part the in–vitro drug release study of the various batches (PCT1-PCT5) prepared by direct compression method was performed. The drug release profile of these batches is shown in fig. 6. From the various batches the formulation showing the predetermined lag time was selected as the optimized batch. The batch PCT3 shows the desired lag time. Hence it was selected as the optimized batch of press-coated tablets for the chronotherapeutic treatment of Hypertension. The comparative lag times of all batches is shown in Table no.12.

i. Batch PCT1:

Barrier Layer Composition- Ethylcellulose=100mg, L-HPC=0

This batch showed 3 hours lag time, after which the press coating material got completely eroded and the core tablet was exposed to the dissolution medium.Within 30 minutes the core tablet got completely disintegrated and released the drug.The highest percentage drug release observed at 4^th hour was found to be 86.91%.

ii. Batch PCT2:

Barrier Layer Composition- Ethylcellulose=12.5mg, L-HPC=87.5mg

This batch showed 5 hours lag time, after whichthe press coating material got completely eroded and the core tablet was exposed to the dissolution medium.Within 30 minutes the core tablet got completely disintegrated and released the drug.The highest percentage drug release observed at 6^th hour was found to be 83.60%.

iii. Batch PCT3:

Barrier Layer Composition- Ethylcellulose=87.5mg, L-HPC=12.5mg

This batch showed 7 hours lag time, after which the press coating material got completely eroded and the core tablet was exposedto the dissolution medium.Within 30 minutes the core tablet got completely disintegrated and released the drug. The highest percentage drug release observed at 8^th hour was found to be 90.48%.

iv. Batch PCT4:

Barrier Layer Composition- Ethylcellulose=50mg, L-HPC=50mg

This batch showed 8 hours lag time, after which the press coating material got completely eroded and the core tablet was exposedto the dissolution medium.Within 30 minutes the core tablet got completely disintegrated and released the drug.The highest percentage drug release observed at 9^th hour was found to be 83.86%.

v. Batch PCT5:

Barrier Layer Composition- Ethylcellulose=0, L-HPC=100mg

This batch showed 5 hours lag time, after which the press coating material got completely eroded and the core tablet was exposedto the dissolution medium. Within 30 minutes the core tablet got completely disintegrated and released the drug. The highest percentage drug release observed at 6^th hour was found to be 96.45%.

CONCLUSION:

The optimized batch of solid dispersion (SD6) was incorporated into immediate release core tablets for the formulation of press-coated tablets. The batches L1-L4 of core tablet prepared using different compositions of superdisintegrants, croscarmellose sodium and microcrystalline cellulose were evaluated. From the observations of disintegration time and in-vitro dissolution study the batch L1 showed the greater drug release with increase in disintegration rate. This is because of the superior disintegration power of CCS than that of MCC. Hence, batch L1 was further used to formulate press-coated tablets. Various compositions of the barrier layer coating were used for coating the tablets.

The barrier layer consisted of a blend of Ethylcellulose and Low substituted Hydroxypropyl cellulose (L-HPC). Ethylcellulose is a hydrophobic polymer and L-HPC is a disintegrant. As the drug release from the pulsatile drug delivery systems should occur after a predetermined lag time, the effects of the various coating material composition on the lag time were studied. From the in-vitro drug release data of the press-coated tablets the coating composition containing ethylcellulose (87.5mg) and L-HPC (12.5mg) showed the required lag time of 7 hours. It was observed that the lag time deccreased with increase in the concentration of L-HPC in the tablet coating. The drug release from the press- coated tablets of batch PCT3 were found to release the drug from core tablets after the lag time. Hence, it can be concluded that the prepared pulsatile drug delivery system of Carvedilol can be considered as a promising tool for chronotherapeutic management of Hypertension.

ACKNOWLEDGEMENT:

My heartiest thanks go to my beloved and respected guide Mr. M.A. Bhutkar, Associate professsor, Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon, for his excellent guidance, valuable suggestions, moral support and constant inspiration during this endaevour. Next with pride and elation I would like to give my humble thanks to my esteemed teacher respected Dr.C.S. Magdum, Principal, Dr. S.K. Mohite, Vice-Principal and Head of Department of Pharmaceutical Chemistry, and Dr. M. N. Nitalikar, Associate professor, Department of Pharmaceutics, Rajarambapu College of Pharmacy, Kasegaon, for providing the necessary infrastructure and all the facilities required to carry out my research work.

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Received on 15.05.2018 Accepted on 02.08.2018

Asian J. Pharm. Tech. 2018; 8 (3):123-131 .

DOI: 10.5958/2231-5713.2018.00020.X

Batch Code	*Bulk Density (g/cm³)**	Tapped Density* (g/cm³)	Angle of Repose* (°)	Bulkiness (cm³/gm)	Carr’s Compressibility Index(%)*	Hausner’s ratio*
L1	0.464±0.02	0.586±0.02	25.24±0.14	2.3407	22.4±0.03	1.23±0.01
L2	0.475±0.01	0.567±0.03	29.61±0.15	2.4281	20.5±0.01	1.24±0.01
L3	0.467±0.03	0.597±0.01	26.47±0.13	2.4304	21.6±0.02	1.26±0.03
L4	0.439±0.02	0.549±0.04	29.80±0.15	2.4972	21.7±0.02	1.24±0.05

Batch Code	Average Weight (mg)	Thickness (mm)*	Hardness (kg/cm²)*	Friability (%)*	Disintegration Time (sec)*
L1	99.0	0.302±0.04	3.2±0.02	0.197±0.003	32±0.078
L2	98.3	0.312±0.03	3.5±0.06	0.104±0.007	37±0.240
L3	99.5	0.328±0.03	2.8±0.02	0.132±0.001	34±0.015
L4	98.1	0.311±0.02	3.5±0.04	0.146±0.005	39±0.317

Batch Code	Bulk Density (g/cm³)*	Tapped Density (g/cm³)*	Angle of repose(°)*	Bulkiness (cm³/gm)	Compressibility index (%)*	Hausner’s ratio*
PCT1	0.4166±0.02	0.4545±0.01	20.55±0.12	2.4003	8.3388±0.02	1.24±0.02
PCT2	0.4166±0.03	0.4652±0.02	19.77±0.13	2.4065	5.3564±0.03	1.23±0.02
PCT3	0.4628±0.01	0.4545±0.01	18.26±0.12	2.4006	12.4973±0.02	1.25±0.03
PCT4	0.4089±0.02	0.4347±0.03	21.79±0.15	2.50	11.9912±0.03	1.24±0.02
PCT5	0.4166±0.03	0.4543±0.03	19.34±0.12	2.4003	4.6657±0.02	1.22±0.03

Sr. No.	Time (min)	% Cumulative drug release*
Sr. No.	Time (min)	PCT1	PCT2	PCT3	PCT4	PCT5
1	0	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00	0.00±0.00
2	60	4.95±0.14	2.37±0.26	1.04±0.12	1.06±0.16	3.57±0.24
3	120	6.28±0.25	4.61±0.36	2.24±0.15	3.20±0.14	9.20±0.16
4	180	78.27±0.12	7.54±0.14	6.31±0.14	6.73±0.13	11.45±0.12
5	240	86.91±0.12	9.06±0.16	10.99±0.12	8.25±0.15	13.67±0.13
6	300	-	61.49±0.19	11.97±0.25	10.26±0.24	15.81±0.24
7	360	-	95.60±0.13	13.85±0.15	11.84±p0.12	89.45±0.13
8	420	-	-	83.04±0.14	13.26±0.13	-
9	480	-	-	90.48±0.16	79.28±0.13	-
10	510	-	-	-	83.86±0.12	-

Sr. No.	Batch code	Lag Time(hours)
1	PCT1	3
2	PCT2	5
3	PCT3	7
4	PCT4	8
5	PCT5	5