INTRODUCTION:

An important goal of drug delivery systems is to achieve well controlled drug release rates, while offering the versatility to be used in various drug release strategies¹. For example, an optimal drug delivery technology would be capable of zero order drug release profiles² or pulsatile administration of vaccines for enhancing immune response.³ Mini-tablets are tablets with a diameter equal to or smaller than 2-3 mm⁴ which can be filled into HPMC capsules for the production of a sustained release multiple unit dosage form and have specific advantages over single unit dosage forms.

These advantages include a lower risk of dose dumping, less inter and intra subject variability, a high degree of dispersion in the gastrointestinal tract thus minimizing the risks of high local drug concentrations^5,6. Mini-tablets offer an alternative for microparticles and beads because of their relative ease of manufacturing and because dosage forms of equal dimensions and weight with smooth regular surfaces are produced in a reproducible and continuous way. Mini-tablets are very suitable for coating in order to sustain the drug release but the coating process may be expensive, time consuming and sometimes associated with poor reproducibility of drug release.⁷The oral route is the route of administration by which the majority of pharmaceuticals are administered and tablets of various different types are the most common oral dosage forms. The small intestine is the major site of drug absorption in the gastrointestinal tract. Therefore, the time a drug is present in this part of the gastrointestinal tract is extremely significant in the drug absorption process. If sustained or controlled release drug delivery systems are being designed, it is important to consider factors that affect their drug release behaviour and, in particular, their transit times through certain regions of the gastrointestinal tract.⁸

Oral controlled release drug delivery systems can be classified in two broad groups: single unit dosage forms (SUDFs), such as tablets or capsules, and multiple unit dosage forms (MUDFs) such as granules, pellets or mini-tablets.⁹

Single unit systems⁸:

This is essentially a tablet formulation, but with differences from conventional dosage forms. Modified release tablet cores do not disintegrate, but dissolve slowly over an extended period of time. A formulation is required that allows water to penetrate and the drug to dissolve so that diffusion of the drug out of the tablet can occur. Because single unit cores are most often compressed tablets, a satisfactory lubricant will also be required.

Multiple unit systems⁸:

The concept of MUDFs was initially introduced in the early 1950s. The production of MUDFs is a common strategy to control the release of a drug, as shown by the reproducibility of the release profiles when compared to the ones obtained with SUDFs. This type of dosage form comprises more than one discrete unit. Typically, such systems consist of coated spheroids filled into a hard gelatin capsule shell, or less commonly, compressed into a tablet. The mini-tablet in capsule system is also considered to be a multiple unit dosage form. The development of mini-tablet is a promising area in pharmaceutical research concerned with a high control over the release rate of the drug combined with a high flexibility on the adjustment of both the dose and the release of a drug or drugs and has attracted some attention in the 1990s.The concept of MUDFs is characterised by the fact that the dose is administered as a number of subunits, each one containing the drug. The dose is then the sum of the quantity of the drug in each subunit and the functionality of the entire dose is directly correlated to the functionality of the individual subunits.⁹

Osmotic pump systems⁸:

Osmotic pump systems are another form of membrane-controlled release drug delivery systems. A drug is included in a tablet core, which is water soluble, and which will solubilise (or suspend) the drug in the presence of water. The tablet core is coated with a semi permeable membrane, which allows water to pass through into the core that subsequently dissolves. As the core dissolves, hydrostatic (osmotic) pressure builds up and forces (pumps) drug solution (or suspension) through a hole drilled in the coating. The rate at which water is able to pass in through the membrane and how quickly the drug solution (or suspension) can pass out of the hole, govern the rate of drug release. The rate at which the drug solution/suspension is forced out through the orifice can be modified by changes in the viscosity of the solution formed inside the system. The essential difference between an osmotic pump system and a classic membrane-controlled system is that for osmotic pump only diffusion process through the membrane is required. As mentioned above, in the conventional membrane-controlled system, two processes are involved namely: water in and drug out.

Materials and Methods:

Terbutaline sulphate was received as a gift sample from Watson Pharma Limited, Mumbai. Croscarmellose sodium, Sodium starch glycolate, HPMC (5cps and 15cps), Ethyl cellulose (18-22cps) was gifted by Colorcon Asia Pvt. Limited, Verna, India. HPMC empty capsules and all other chemicals were of analytical grade.

Preformulation study:

The drug-polymer and polymer-polymer interaction was studied by FTIR spectrometer (Shimadzu 8400-S, Japan). Two percent (w/w) of the sample with respect to a potassium bromide disc was mixed with dry KBr. The mixture was ground into a fine powder using an agate mortar and then compressed into a KBr discs in a hydraulic press at a pressure of 10000 psi. Each KBr disc was scanned 16 times at 2 mm/sec at a resolution of 4 cm^–1 using cosine apodization. The characteristic peaks were recorded.

Preparation of immediate release mini-tablet (IRMT)¹⁰:

The IRMT was prepared using the wet granulation method. The ingredients consisting of terbutaline sulphate, D-mannitol, anhydrous dibasic calcium phosphate, HPC, CCS and SSG in proportions varying according to the experimental design were passed through sieve no. 80 (250um) separately and dry mixed. The dry mixing was carried at a slow speed for 10 min and the blend was granulated with 10 % ethanol. The resulting wet mass was immediately passed through a 16 mesh screen (1000μm). The granules obtained were dried for 24 h in a thermostatic hot air oven maintained at 30-35⁰C to moisture content of 2 to 3 %. The dried granules were passed through the same sieve (1000μm) to break the lumps and blended with extra granular portion of CCS, aerozil and magnesium stearate. The lubricated granules were compressed into mini-tablets weighing 50mg using 6 mm round convex punches in a rotary tablet press.

Preparation of sustained release mini-tablet (SRMT)¹⁰:

A coating suspension was prepared from HPMC (5cps/15cps), ethyl cellulose, magnesium stearate, ethyl alcohol and water. Magnesium stearate was used in the coating preparation to minimize friction between the surfaces of mini-tablets, the mini-tablets filled system and the HPMC capsules. HPMC, ethyl cellulose and magnesium stearate were dispersed in an ethanol/water mixture. Aqueous ethanol solutions of HPMC and ethyl cellulose were mixed at the desired ratios (75:25, 80:20, and 85:15) based on the experimental design. The mini-tablets were coated using an aqueous ethanolic solution of HPMC and ethyl cellulose to yield 5 % increase in weight. A coating load of 5 % was used to test the effect of the various ratios of HPMC and ethyl cellulose.

Dip coating method for sustain release mini-tablet (SRMT)^11,12:

Mini- tablets are prepared by using wet granulation method and then further coating of that mini tablets was done by using ethyl cellulose and HPMC. Different concentration (75:25, 80:20, and 85:15) of coating solution of ethyl cellulose and HPMC was prepared in mixture of ethanol:water (15:85) system. The coating of mini-tablet was performed by immersion in the coating solution followed by dip coating technique.

Preparation of mini-tablet-in-capsule system ¹⁰:

To prepare the MTICS, two IRMT and three SRMT were placed in each HPMC capsule (size 4). Both similar/different ratios of SRMT were placed in each HPMC capsule to achieve various sustained release profiles of the MTICS. The qualitative and quantitative composition of the different formulations of the MTICS can be seen in Table.no.3

Evaluation of mini –tablets:

Hardness test^13,14:-

Tablets require a certain amount of strength, or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging and shipping. The hardness of the tablets was determined using hardness tester. It is expressed in Kg/cm². Three mini-tablets were randomly picked from each formulation and the mean and standard deviation values were calculated.

Friability test^13,14:

It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when subjected to mechanical shock or attrition. The friability of tablets was determined by using friabilator. It is expressed in percentage (%). Twenty tablets were initially weighed (W_inital) and transferred into friabilator. The friabilator was operated at 25 rpm for 4 min or run up to 100 revolutions. The tablets were weighed again (W_final).

Weight variation test^13,14:

The mini-tablets were selected randomly from each formulation and weighed individually to check for weight variation. The I.P allows a little variation in the weight of a tablet

Uniformity of thickness^13,14:

The crown thickness of individual mini-tablet may be measured with a micrometer, which permits accurate measurements and provides information on the variation between tablets. Other technique employed in production control involves placing 5 or 10 tablets in a holding tray, where their total crown thickness may be measured with a sliding caliper scale. The tablet thickness was measured using screw gauge.

Drug content uniformity¹⁵:

Five mini-tablets weighted and crushed in a mortar then weighed powder contained equivalent to 100 mg of drug transferred in 100 ml of phosphate buffer pH 6.8 solution to give a concentration of 1000 µg/ml. Take 15 ml of this solution and diluted it up to 100 ml with phosphate buffer pH 6.8 solution to give a concentration of 150 µg/ml. Absorbance measured at 281 nm using UV-Visible spectrophotometer.

In vitro disintegration time¹⁵:

The In vitro disintegration of the immediate-release core mini-tablets were determined using disintegration test apparatus as per I.P specifications. Place one tablet in each of the six tubes of the basket. Add the disc to each tube and run the apparatus using 900 ml of phosphate buffer pH 6.8 solution as the immersion liquid. The assembly should be raised and lowered between 30 cycles per minute in distilled water maintained at 37 ±0.5 ⁰c .The time in seconds for complete disintegration of the mini-tablets with no palable mass remaining in the apparatus was measured and recorded.

Table No.1 Composition of tablet of IRMT and SRMT:

Ingredients	Tablet Code (Quantity mg/tablet)
Ingredients	IRMT-A	IRMT-B	IRMT-C	IRMT-D	SRMT
Terbutaline sulphate	0.75	0.75	0.75	0.75	2
Sodium starch glycolate	1.8	3.6	-	-	-
Croscarmellose sodium	-	-	1.8	3.6	-
Hydroxy propyl cellulose	1.6	1.6	1.6	1.6	1.6
Anhydrous dibasic calcium phosphate	5	5	5	5	16
D-mannitol	39.65	37.65	39.65	37.65	29.2
Aerozil	0.6	0.6	0.6	0.6	0.6
Magnesium stearate	0.6	0.6	0.6	0.6	0.6
Total weight	50	50	50	50	50

Table No. 2 Composition of coating solution for sustained-release mini-tablets (SRMT):

Ingredients	SRMT- A	SRMT-B	SRMT-C	SRMT-D	SRMT-E	SRMT- F
Ethyl cellulose (18-22CPS)	75	80	85	75	80	85
HPMC (5cps)	25	20	15	-	-	-
HPMC (15cps)	-	-	-	25	20	15
Magnesium stearate	1.52	1.52	1.52	1.52	1.52	1.52
% Coating load	5	5	5	5	5	5

Table No. 3 Composition of mini-tablet-in-capsule system formulations (MTICS):

Formulation Code	Composition
MTICS -1	IRMT-A : IRMT-B : SRMT-A : SRMT-B : SRMT-C
MTICS -2	IRMT-B : IRMT-C : SRMT-D : SRMT-E : SRMT-F
MTICS -3	IRMT-C : IRMT-D : SRMT-B : SRMT-C : SRMT-D
MTICS -4	IRMT-A : IRMT-C : SRMT-E : SRMT-F : SRMT-A
MTICS -5	IRMT-A : IRMT-D : SRMT-C : SRMT-D : SRMT-E
MTICS -6	IRMT-B : IRMT-D : SRMT-F : SRMT-A : SRMT-B
MTICS -7	IRMT-A : IRMT-A : SRMT-A : SRMT-E : SRMT-B
MTICS -8	IRMT-B : IRMT-B : SRMT-F : SRMT-C : SRMT-D
MTICS -9	IRMT-C : IRMT-C : SRMT-B : SRMT-D : SRMT-C
MTICS -10	IRMT-D : IRMT-D : SRMT-E : SRMT-F : SRMT-A
MTICS -11	IRMT-A : IRMT-B : SRMT-A : SRMT-A : SRMT-B
MTICS -12	IRMT-B : IRMT-C : SRMT-B : SRMT-C : SRMT-C
MTICS -13	IRMT-C : IRMT-D : SRMT-F : SRMT-E : SRMT-E
MTICS -14	IRMT-D : IRMT-A : SRMT-D : SRMT-D : SRMT-C
MTICS -15	IRMT-B : IRMT-B : SRMT-F : SRMT-F : SRMT-A

In vitro dissolution studies¹⁵:

Dissolution rate of Terbutaline sulphate from all formulations were performed using dissolution test apparatus i.e. USP model II. The dissolution fluid was phosphate buffer pH 6.8 at a speed of 50 rpm and a temperature of 37 ±0.5 ⁰c were used in each test. Samples of dissolution medium (5ml) were withdrawn through a filler of 0.5μm at different time intervals, suitably diluted and assayed for Terbutaline sulphate by measuring absorbance at 281nm. The dissolution experiments were conducted in triplicate. For all tests 5ml samples of the test medium were collected at set intervals (1, 2, 4, 6, 8, 10, 11, 12, 13, 14, 16, 18, 20, 22 and 24 h.) and were replaced with equal volume of phosphate buffer pH 6.8.

Fig: 1 In vitro drug release profiles of IRMT-A, B, C, D

RESULT:-

Table No. 4 Pre-compressional parameters of the prepared granules:-

Tablet code	IRMT-A	IRMT-B	IRMT-C	IRMT-D	SRMT
Angle of repose (degree)	23.04⁰ ±0.3	23.77⁰±0.4	23.53⁰±0.5	23.37⁰±0.4	22.16⁰±0.2
Bulk density (gm/cc)	0.54±0.01	0.55±0.01	0.55±0.02	0.53±0.03	0.48±0.02
Tapped density (gm/cc)	0.57±0.01	0.59±0.02	0.61±0.03	0.58±0.04	0.55±0.01
Carr’s index (%)	5.26±2.0	6.78±2.0	9.84±2.0	8.62±2.2	12.14±4.9
Hausner’s ratio	1.06±0.02	1.07±0.03	1.11±0.03	1.09±0.03	0.65±0.23

(n = 3, Mean ± SD)

Table No. 5 Post-compressional parameters of the prepared mini-tablets:

Tablet code	IRMT-A	IRMT-B	IRMT-C	IRMT-D	SRMT
Thickness (mm)	1.9±0.065	2±0.051	1.95±0.09	1.85±0.05	2.9±0.097
Diameter (mm)	4.00±0.00	4.00±0.00	4.00±0.0	4.00±0.0	4.02±0.03
Hardness (kg/cm²)	2.5±0.025	2.45±0.08	2.5±0.015	2.5±0.020	2.53±0.07
Friability (%)	0.25±0.08	0.26±0.05	0.25±0.01	0.24±0.06	0.20±0.08
Average weight (mg)	50.5±1.08	49.00±1.1	51.00±1.4	51.5±1.02	50.07±0.6
% Drug content	95.2±1.65	97.81±1.1	95.57±1.1	98.56±1.1	93.25±1.8
Disintegration time (min)	10.3±0.46	10.45±0.4	11.1±0.31	10.00±.29	-

(n = 3, Mean ±SD)

Dissolution Study:-

Table No – 6 In vitro release study of Immediate-release mini-tablet (IRMT-A, B, C, D)

Time (Min)	Percent Drug Release
Time (Min)	IRMT-A	IRMT-B	IRMT-C	IRMT-D
10	22.89	18.12	19.03	21.91
20	33.39	29.09	30.12	34.12
30	40.07	41.02	41.67	39.77
40	66.78	61.77	60.82	64.43
50	80.14	75.13	74.01	78.70
60	90.36	90.03	89.23	95.01

Table No – 7 In vitro release study of sustained release mini-tablets (SRMT-A,B,C):

Time (h)	Percent Drug Release
Time (h)	SRMT-A	SRMT-B	SRMT-C
1	22.65	19.55	6.43
2	46.27	32.43	14.21
4	61.06	50.32	22.89
6	71.79	68.21	34.34
8	83.00	77.99	42.21
10	85.86	81.57	50.32
12	87.29	85.15	58.43
16	89.68	88.48	69.64
20	91.82	91.82	82.76
24	94.21	93.73	93.02

Table No. 8 In vitro release study of sustained-release mini-tablets (SRMT-D, E, F):

Time (h)	Percent Drug Release
Time (h)	SRMT-D	SRMT-E	SRMT-F
1	3.10	3.57	8.34
2	9.54	12.16	21.22
4	11.41	23.37	37.44
6	21.22	28.14	43.88
8	32.43	35.53	51.99
10	36.49	41.02	57.72
12	39.59	46.03	65.83
16	47.70	52.47	76.80
20	55.30	60.34	89.20
24	62.01	67.73	97.31

Fig: 2 In vitro drug release profiles of SRMT- A,B,C

Table No - 9: In vitro release study of mini-tablet in capsule system (MTICS) formulation:-

FC	% Amt drug released in 6 h	% Amt drug released in 12 h	% Amt drug released in 18h	% Amt drug released in 24h
MTICS -1	54.85	66.78	74.65	82.52
MTICS -2	64.63	76.56	84.07	91.59
MTICS -3	50.80	65.79	73.70	81.81
MTICS -4	65.59	78.71	86.34	93.97
MTICS -5	68.21	77.04	85.98	94.92
MTICS -6	62.25	77.99	87.53	97.03
MTICS -7	56.28	69.64	80.37	91.11
MTICS -8	53.42	69.16	80.25	91.35
MTICS -9	58.91	69.88	80.13	90.39
MTICS -10	66.30	74.89	84.19	93.49
MTICS -11	58.91	70.60	78.11	85.65
MTICS -12	54.85	66.78	76.20	85.62
MTICS -13	44.60	55.09	65.70	76.32
MTICS -14	41.02	48.89	59.26	69.64
MTICS -15	66.54	79.42	86.81	94.21

_{Table
No. 10 Curve fitting
analysis for different formulations:-}

FC	Zero order ( r )	First order ( r )	Higuchi’s ( r )	Peppas
FC	Zero order ( r )	First order ( r )	Higuchi’s ( r )	( r )	( n )
MTICS-1	0.7745	0.9434	0.9519	0.9351	0.42
MTICS-2	0.7429	0.9682	0.9385	0.9567	0.35
MTICS-3	0.8065	0.9554	0.9618	0.9395	0.44
MTICS-4	0.7534	0.9786	0.9434	0.9547	0.37
MTICS-5	0.7113	0.9671	0.9134	0.9115	0.33
MTICS-6	0.8496	0.9837	0.9838	0.9808	0.40
MTICS-7	0.8238	0.9813	0.9743	0.9748	0.34
MTICS-8	0.7981	0.9744	0.9653	0.9739	0.38
MTICS-9	0.7800	0.9624	0.9522	0.9413	0.39
MTICS-10	0.7328	0.9650	0.9226	0.9226	0.35
MTICS-11	0.7560	0.9458	0.9429	0.9359	0.38
MTICS-12	0.7919	0.9594	0.9618	0.9527	0.42
MTICS-13	0.8356	0.9549	0.9695	0.9316	0.41
MTICS-14	0.8156	0.9289	0.9528	0.9164	0.36
MTICS-15	0.7505	0.9813	0.9442	0.9743	0.36

Fig: 3 In vitro drug release profiles of SRMT- D, E, F

DISCUSSION:

In the present study, the hardness of both core mini-tablets of IRMT-A to IRMT-D ranges from 2.45 to 2.50 kg/cm² and SRMT were found to be 2.53 kg/cm² indicating that they possessed sufficient mechanical strength to withstand physical and mechanical stress conditions while handling. In the present study, percent friability of both the batches was below 1 % limit as shown in the Indian pharmacopoeia, indicating that the friability is within the standard limit. The average percentage deviation for both the core mini-tablets of IRMT-A to IRMT-D ranges from 49 to 51.5 mg and SRMT were found to be 50.50 mg and it was found to be within the pharmacopoeial limits according to Indian pharmacopoeia. The percentage drug content of terbutaline sulphate for both the core mini-tablets of IRMT-A to IRMT-D ranges from 95.20 to 98.56 % and SRMT 93.25 % indicating good content uniformity in both the batches. That indicates drug was uniformly distributed throughout the core mini-tablets. The immediate-release core mini tablets passed the disintegration test for uncoated tablets as they were ranges from 10 to 11.10 min. The quick disintegrating time of the core mini-tablets can be attributed to the presence of the super disintegrant CCS and SSG in optimum concentration. It was also found that when the viscosity of the pore former (HPMC) was increased (i.e. from 5cps to 15cps) as a result a decreased release of terbutaline sulphate was observed. It has been postulated that relaxation and swelling of EC films increased as the amount of HPMC in the film increased. HPMC is believed to hydrate and subsequently produce water logged regions (pores) within the film. Some HPMC migrates into the dissolution medium thereby creating regions with higher film permeability to the drug. Further, the In vitro drug release study was carried out for these MTICS formulations. The results revealed that the formulations MTICS-1, MTICS-3, MTICS-11, MTICS-12, MTICS-13 and MTICS-14 shown decrease in terbutaline sulphate release. It is due to the reason that these formulations contain the SRMT which has been coated with increased viscosity grade (15cps) of pore former in higher concentration which results in decreased terbutaline sulphate release at the end of 24 h. The formulations MTICS-6 were found to release the terbutaline sulphate in both immediate (95.09 % in an h) and sustained manner and also shown better release at the end of 24 h (98.60 %) and hence were considered as the best formulations. MTICS-6 contains IRMT-A, IRMT-D, SRMT-A, SRMT-B and SRMT-F.

The In vitro release profile of this MTICS coincided with the profile expected from the combination of two IRMT and three SRMT. The MTICS undergoes four processes as follows: (a) the HPMC capsule dissolves rapidly, and has no influence on the release rate of terbutaline sulphate from the MTICS; (b) once dissolved, the HPMC capsule releases the IRMT and SRMT subunits; (c) terbutaline sulphate is released rapidly from the IRMT; and (d) terbutaline sulphate is released from the SRMT over a period of 24 h.

When the data were plotted according to zero-order equation, the formulations showed correlation coefficient values between 0.7113 to 0.8496 but when the data were plotted according to the first order equation, the formulations showed significantly higher correlation coefficient vales than the zero-order plots 0.9289 to 0.9837. Hence, the results revealed that all the MTICS formulations release the drug by first-order kinetics.

To ascertain, the drug release mechanism the In vitro release data were also subjected to Higuchi’s diffusion plots and Peppas plots and the correlation coefficient values were in the range of 0.9134 to 0.9838 and 0.9164 to 0.9808 respectively. So it confirms that, the calculated r values for Higuchi plot and Peppas plots were nearer to one in all the cases suggesting that drug released by diffusion mechanism.

The value of n indicates the drug release mechanism related to the geometrical shape of the delivery system, if the exponent n = 0.5, then the drug release mechanism is Fickanian diffusion. If n < 0.45 the mechanism is quasi-Fickanian diffusion, and 0.45 < n < 0.89, then it is non-Fickanian or anamolous diffusion and when n = 0.89 mechanism is non-Fickanian case ІІ diffusion, n > 0.89 mechanism is non-Fickanian super case ІІ. In the present study the mean diffusional exponent values (n) ranged from 0.33 to 0.44 indicating that all these formulations presented a dissolution behaviour controlled by quasi-Fickanian (When 0.45 < n < 0.).

ACKNOWLEDGEMENT:

Authors are thankful to the Watson Pharma Limited, Mumbai for providing gift sample of terbutaline sulphate and Colorcon Asia Pvt. Limited, Verna for providing gift sample of croscarmellose sodium, sodium starch glycolate, HPMC (5cps and 15cps), ethyl cellulose (18-22cps).

REFERENCES:

1. Berkland C, Pollauf E, Packa D, Kim K. Uniform double walled polymer microspheres of controllable shell thickness. J Cont Rel. 2004; 96: P.101-111.

2. Wise D, Debra j, Rachel T, Marino, Kitchell J. Opportunities and challenges in the design of implantable biodegradable polymeric systems for the delivery of antimicrobial agents and vaccines. Adv Drug Deliv Rev. 1984 ; 1 (1) : P.19- 40.

3. Cleland J, Lim A, Barron L, Duenas E, Powell M. Development of a single-shot subunit vaccine for HIV-1: Part 4 optimizing microencapsulation and pulsatile release of MN rgp120 from biodegradable microspheres. J Cont Rel. 1997 ; 47 : P. 135 - 150.

4. Lennartz P, Mielck J. Mini-tabletting: improving the compactability of paracetamol powder mixtures. Int J Pharm. 1998 ; 173 :P.75 – 85.

5. Bechgaard H., Nielsen G. Controlled-release multiple-units and single-unit doses. Drug Deve and Ind Pharm.1978; 4(1): P.53-67.

6. Follonier N, Doelck, E. Biopharmaceutical comparison of oral multiple–unit and single–unit doses sustained–release dosage forms. S.T.P. Pharm Sci. 1992 ; 2:P.141-158.

7. Brabander C, Vervaet C, Fiermans L, Remon J. Matrix mini-tablets based on starch: microcrystalline wax mixtures. Int J Pharm. 2000 ; 199 : P.195 -203.

8. Aulton M, The design and manufacture of medicine. 3^rd edition reprint Churchill livingstone Elsevier; 2008: Chapter no.1, 8, 12. 4-14, 275, P. 442-498.

9. Lopes C, Loboa J, Pinto J, Costa P. Compressed mini-tablets as a biphasic delivery system. Int J Pharm. 2006; 323:P. 93-100

10. Ishida M, Abe K, Hashizume M, Kawamura M. A novel approach to sustained pseudoephedrine release : differentially coated mini-tablets in HPMC capsules. Int J Pharm. 2008; 359: P. 46-52.

11. Wilson B., Babubhai P, Sajeev M, Jenita J, Priyadarshini S. Sustained release enteric coated tablets of pentaprazole : formulation, In vitro and in vivoevalution. Acta pharm. 2013; 63 ( 1) :P. 131-140.

12. Mehta R, Chawla A, Sharma P, Pawar P. Formulation andIn vitro evaluation of eudragit s-100, coated naproxen matrix tablets for colon targeted drug delivery system. J. Adv. pharm Tech. 2013; 4 (1) :P. 31-41.

13. Lachman L, Lieberman H., KanigJ.. The theory and practice of industrial pharmacy. 3rd ed. Varghese Publishing House; 1991: Chapter No. 13, 14. P.293-345, 374-429.

14. Bhupendra P, Patel K. Design and In vitro evaluation of nicorandil sustained release matrix tablets based on combination of hydrophilic and hydrophobic matrix system. Int. J. Pharm. Sci. 2010; 1:P. 33-38.

15. Janugade B, Patil S, Patil S, Lade P. Formulation and evaluation of press-coated montelukast sodium tablets for pulsatile drug delivery system. Int J Chem Tech Res. 2009 ; 1(3):P. 690-91

Received on 24.09.2013 Modified on 20.10.2013

Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1350-1356