1. INTRODUCTION:

The antiquity of drug use goes back many centuries. Drugs were used at the prophesy of the ancient world and also during commencement ceremonies. Beginning in the 19th century, the fresh wind of synthetic chemistry began to revolutionize the pharmaceutical products, for better consumption of tablets these are coated by sugar coating or film coating.

Whereas compressed mini tablets systems exist as a biphasic delivery system. The external layer that fills the void spaces amongst the mini tablets was formulated to release the drug in a very less time (fast release), while the mini tablets providing a prolonged release. For ease of use, they are frequently packed in a capsules, they can be compressed in bigger tablets or occupied into sachets after disintegration, discharge these subunits as various unit dosage forms. Mini tablets are moulded with multiple punches using peculiar or rotary tablet press machines. These are great alternatives for granules and pellets since they can be easily manufactured and converted into controlled drug delivery system (CDDS). So the progression of mini tablets for controlling drug release is an important focus point of investigation into oral controlled release solid dosage form. The main purpose in designing sustained or controlled drug delivery system is to decrease the frequency of the dosing and to increase the efficiency of the drug by localization at the specific site of action. The term controlled release includes both single unit dosage form and multiple unit dosage forms^1,2.

1.1. Mini Tablets:

Fig.1: Mini Tablets

Mini tablets are defined as, the solid dosage forms with a diameter ≤ 3 mm and separated into subunits of conventional tablets. Production techniques are similar to standard tablets, but only the change is the use of multiple punches. Mini tablets also offer a substitute for pellets because of their relative ease of manufacturing and dosage form of equal dimensions and weight with smooth steady surface are formed in a reproducible and continuous way. Mini tablets are appropriate for coating in order to sustain the drug release but the coating method is expensive, time consuming, and sometimes associated with reproducibility problem of release during storage. They can be easily divided and administered without loss of activity. Aged and paediatric patients who sometimes chew the tablets which releases drug all at once and may cause toxicity in case of regular tablets, but in case of mini tablets, they can be chewed as here each mini depot in the formulation act individually dose dumping may not occur. For local irritating drugs, mini tablet formulation reduces the irritation effect than that of single unit formulation^1,2.

1.2. Advantages:

1. They have excellent size uniformity, consistent shape and a plane surface, thereby acts as an excellent coating substrate.

2. Mini tablets can be manufactured relatively easily.

3. They offer flexibility at the time of formulation development.

4. Mini tablets have high medication stacking limit.

5. They have minimum risk of dose dumping.

6. They have a small amount inter and intra- subject variability.

7. Strength issues are diminished because of mini tablets did not involve any solvents for their generation.

8. Any drug or excipient which is problematic to coat with polymeric layer for modified drug release was adjusted as mini tablets.

9. They are a great substitute for pellets and granules, because of their relative ease of manufacturing and dosage forms of equal dimensions, weight with smooth regular surface can be produced in a reproducible and continuous way.

10. Technically demanding process like fluid bed granulation, extrusion or spheronization are required for the production of pellets. Whereas, mini tablets can be manufactured via simple tabletting procedures.

11. Unlike pellets, mini tablets does not require any solvents for its invention, as result problems with stability can be avoided.

12. They offer high drug loading, an extensive range of release rate patterns, and also fine tuning of these release rates.

13. They offer high degree of dispersion in the GI tract, thus reducing the risks of high local drug concentrations^3,4.

Fig.2: Mini-tablet size compared to capsule and tablet

1.3. Methods of Manufacturing Mini Tablets:

a) Direct compression,

b) Wet granulation,

c) Dry granulation and

d) Melt extrusion.

1.3.1. Direct compression:

Direct compression is the process by which tablets are compressed directly from powder blends comprising API as well as excipients directly compressed the powder blend into biconvex mini tablet. For getting the required hardness, excipients of direct compression grade are used here. Stability problems are fewer compared to that of tablets prepared by wet granulation.

1.3.2. Wet granulation:

In wet granulation method binder solution is used to form granules, which then compressed in compression machine to get mini tablets. PVP (Polyvinyl pyrrolidone) of different grades is generally used as a binding agent.

1.3.3. Dry granulation:

Dry granulation is rational technique of choice for the manufacture of tablets containing thermos labile and moisture sensitive drugs. This technique employs processing equipment known as roller compactor or chilsonator. This machine compress as premixed powders among two counter rotating rollers under extreme pressure. The resultant material is in the form of a brittle ribbon, sheet or piece depending on the configuration of the roller. The compressed material is reduced to the appropriate size to form granules that are mixed with other inactive excipients and finally compressed on a rotary compression machine.

1.3.4. Melt extrusion technique:

In this technique, the powder (API + excipients) were premixed this premixed powder is then transferred to melt extruder. In melt extruder parameters like screw speed, feed rate and temperature are set in the range of melting point range of material. After the process the extrudates are then milled and sieved. The obtained granules are then compressed to mini tablets using compression machine^5,6.

2. Formulation of Mini Tablets in Capsule System:

Fig. 3: Mini Tablets in Capsule System.

2.1. Steps involving in formulation:

· Formulation / production of mini tablets

· Coating with suitable coating polymer

· Filling of coated mini tablets into hard gelatine or HPMC capsules (Mini tablets in capsule systems).

2.2. Preparation of mini tablets and granules in capsule systems:

For the calculation of theoretical drug release profile, the coated mini tablet in capsule system pharmacokinetic parameters of drug were utilized. The immediate release part of drug was calculated using the following equation –

DL = C_maxV_d

Where,

C_max–Maximum plasma concentration,

V_d –Volume of distribution.

2.3. Preparation of immediate release component (Granules):

Calculated amount of immediate release dose drug and other suitable excipients [Microcrystalline cellulose (Avicel PH102)] were used because of its good compaction and disintegration properties. Any suitable superdisintegrants was used to obtain an immediate release of the drug. The granules were prepared by wet granulation method.

2.4. Preparation of immediate release coated mini tablets (IRCMT):

The IRCMT was prepared by using wet granulation method.

2.5. Preparation of sustained release coated mini tablet (SRCMT):

SRCMT was also prepared by wet granulation method. However, the SRCMT did not contain the any super disintegrates. 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 diminish friction between the surface of mini tablets, the mini tablets filling system and the HPMC capsules.

2.6. Preparation of coated mini tablets in capsule system:

For the preparation of CMTICS, two IRCMT and three SRCMT were placed in each HPMC capsule (size 1). Both similar and different ratios of SRCMT were placed in each HPMC capsule to achieve various sustained release profiles of the CMTICS^7,8,9.

3. Mini tablets can be administered by following methods:

3.1. Directly administered as single units.

3.2. Filled in hard gelatine capsules.

3.3. Use of automatic Dose dispensing device.

3.1. Directly administered as single units:

Mini tablets can be directly administered orally as it is. Required dose can be easily taken and these are packed in bottles. Sometime compressed mini tablets are again compressed to get tablets of normal size.

3.2. Filled in hard gelatine capsules:

Mini tablets are smaller in size as compared to normal tablets for this reason, these are difficult to handle so they are usually filled in hard gelatine capsules and then administered.

3.3. Automatic dose dispensing device:

Dose is decided on the basis of patient population average dose individualization is important as administration of right drug in wrong dose will result in adverse effects of decreased efficiency. Generally tablets are most commonly used but limited strengths available for administration. Dividing tablets for getting essential dose or combining different strengths will not give the desired therapeutic effect so an automatic dose dispensing device can used to dispense tablets of required dose^10-14.

4. Evaluation Test^15-18.

4.1. Disintegration test:

i. Hard gelatine capsules: Disintegration time shall not be more than 30 min.

ii. Soft gelatine capsules: Disintegration time shall not be more than 60 min.

iii. Enteric capsule:

In Acidic media; shall not disintegration 2 hrs and in alkaline medium capsules shall disintegrate within 30 min.

4.2. In-vitro drug release:

· Mini-tablets were subjected to in-vitro drug release studies in simulated gastric and intestinal fluids to assess their ability in providing the desired controlled drug delivery.

· By using USP dissolution test apparatus I drug release studies 3, 54, 55 were carried out at 100rpm, 37±0.5°C, and pH 1.2 buffer (900ml) (i.e. 0.1 N HCl) for 2 hours, since the average gastric emptying time is about 2 hours. The dissolution medium was replaced with pH 6.8 phosphate buffer (900ml) and experiment continued for another 10 hours. At different time intervals, 5ml of the samples were withdrawn and replaced with 5ml of drug-free dissolution medium.

· Through UV spectrophotometer by using multi component mode of analysis at required wave length, those samples withdrawn were analysed.

4.3. Preformulation Studies:

4.3.1. Angle of repose,

4.3.2. Bulk density,

4.3.3. Tapped density,

4.3.4. Compressibility index,

4.3.5. Hauser’s ratios.

4.1. Angle of repose:

Take weighed amount of powder (granules), allow passing through funnel to form pile on paper at lower end of the funnel. Draw the circle around this powder and calculate the diameter and radius(r). The height (h) of the pile and distance across the cone is to be noted. Angle of repose can be calculated by following formula-

ɵ=tanˉ¹h/r

Where,

h=height of pile,

r=radius of circle (pile).

4.2. Bulk density:

Bulk volume occupied by the sample (powder) is noted by using measuring cylinder.

Formula:

Bulk Density = Mass of the sample /Bulk volume of the sample

4.3. Tapped density:

Sample (powder) is filled in the graduated cylinder and tapped upto 100 times. Then it is calculated by using following formula –

Tapped Density =Mass of the sample/Tapped volume of the sample

4.4. Compressibility Index:

It indicates the flow properties of the blend. Compressibility are defined as the ability of powder to decrease in volume under pressure.

Formula-Compressibility index = (TD-BD)/TD × 100

Where, TD-Tapped density, BD-Bulk density

4.5. Hauser’s Ratio:

It is a number that is correlated to the flow ability of a powder or granular material.

Formula-

Hauser’s ratio=Tapped density/Bulk density

5. Other Evaluation Tests:

5.1. Content Uniformity Test,

5.2. Weight Variation Test,

5.3. Hardness,

5.4. Thickness,

5.5. Friability,

5.6. Disintegration,

5.7. Dissolution.

5.1. Content Uniformity Test:

This test is carried out by weighing 5 mini tablets and crushing in a mortar. Formed powder having weight equivalent to 10mg of drug, transferred in 100ml of dissolution medium to give a concentration of 100µg/ml. Take 15ml of this solution and diluted it up to 100ml with the same solution to give a concentration of 15µg/ml. And by using UV visible spectrophotometer absorbance is measured.

5.2. Weight Variation Test:

For this test take a 20 mini tablets were randomly choosen then weighed individually and calculate average weight. The percentage of weight variation can be calculated by using following formula-

Per wt. variation = (individual wt. of tablet-final wt. of tablet)/final wt. of tablet x100

5.3. Hardness:

It is defined as force required to break the tablets. The hardness of mini tablets is carried out by using ‘Monsanto hardness tester’ and which is expressed in kg/cm²

5.4. Thickness:

The thickness of arbitrarily choosen mini tablets is measured by using ‘screw gauge and digital calliper’ which is expressed in mm.

5.5. Friability:

Take randomly 20 tablets weighed it properly which is considered as initial weight (w₀), then deposited it in friabilator. The friabilator is rotated at 25rpm for 4 minutes after mini tablets were detached. Again tablets were weighed after friabilation which is considered as (w_f). The percentage of friability (F) is calculated by-

%F= (W₀-W_f)/W₀ X 100

Where,

%F- percentage of friability,

W₀- initial weight, W_f- final weight.

5.6. Disintegration test:

The breakdown of tab into small pieces is called disintegration. The disintegration test is measure the time required under a given set of condition of group of tablet to disintegrate into particles. The test is carried out in ‘disintegration tester’ which consist of basket rack holding 6 plastic tubes open at top and bottom, of the tube is covered by 10 mesh screen. The basket is immersed in a bath of suitable liquid held at 37˚C, preferably a beaker of 1L. Then at last note down the disintegration time of mini tablets.

5.7. Dissolution test:

The amount of drug substance that goes into a solution per unit time under standardised condition of liquid or solid interface, temp. And solvent composition is called dissolution. The dissolution test measure the amount of time required for a given percentage of a drug sub. In tablets to go into a solution under specified set of condition. This study is done by utilizing USP dissolution type I (basket) apparatus for mini tablets enclosing in capsules and type II (paddle) apparatus for mini tablets compacted as big tablet. The release rate of drug from mini tablets ﬁlled into capsules (‘‘0el’’size) was determined (n¼3) using USP Apparatus 2 (paddle method). The dissolution test was performed using 900 mL of 0.1 N HCl at 37±0.58˚C and 50rpm. A sample (5 mL) of the solution was withdrawn from the dissolution apparatus hourly for 10 h, and the samples were exchanged with fresh dissolution medium. The samples were ﬁltered through a 0.45-mm membrane ﬁlter and diluted to a suitable concentration with 0.1 N HCl. Absorbance of these solutions was measured at 274nm using a UV/Vis double-beam spectrophotometer (Elico, Hyderabad, India). By the equation obtained from a standard curve, cumulative percentage drug release was calculated.

6. CONCLUSIONS:

Pharmaceutical mini-tablets provide several benefits compared to conventional tablets, which make them as excellent alternatives for granules and pellets. They have low porosity and high mechanical strength. They can be formulated into tablets or filled in capsules. Mini-tablet can be used to deliver incompatible drugs for the effective treatment of different chronic disorders. It enhances the therapeutic efficacy and patient compliance. Mini-tablet can be promising tool for oral drug delivery. The controlled release of drug required in various conditions can be achieved by using either tablet in tablet or tablet in capsule technology also the delivery of drug in the form of mini-tablet may be helpful in chronotherapy as well as for separating the incompatible material for combined drug delivery.

7. ACKNOWLEDGEMENT:

The authors are highly thankful to the Sahyadri College of Pharmacy, Methwade, Sangola, Solapur, and Maharashtra, India for proving all the facilities to carry out the research work.

8. REFERENCES:

1. Hellebechgaard and gydahegermannnielsen. Controlled-release multiple-units and single-unit doses a literature review. Drug Development and Industrial Pharmacy, 1978; 4(1): 53-67.

2. Lennartz P., Mielck J. B. Mini tabletting: improving the compactability of paracetamol powder mixtures. International Journal of Pharmaceutics 1998; 173(1): 75-85.

3. Ghebre-Sellasie I, Multi particulate oral drug delivery, Marcel Dekker, Drugs and the Pharmaceutical Sciences, Taylor and Francis, New York. 1994; 65: 307-312.

4. Mohd Abdul Hadi, Raghavendra Rao NG, Novel Techniques in Formulations: An Overview. World Journal of Pharmaceutical Research. 2012; 1(3): 1-17.

5. Schmidt C, Kleinebudde P, Influence of the granulation step on pellets prepared by extrusion/spheronization, Chem. Pharm, Bull. 1999; 47(3): 405-412.

6. Gupta Swati, Singh Sushma, Multiple Unit System: An Approach towards Gastro retention. Journal of Biological and Scientific Opinion. 2014; 2(2): 188-195.

7. Lopes C. M., Lobo J. M. S., Pinto J. F., Costa P. Directly compressed mini matrix tablets containing ibuprofen: preparation and evaluation of sustained release. Drug Dev. Ind. Pharm. 2006; 32: 95-106.

8. Modi S. A., Gaikwad P. D., Bankar V. H., Pawar S. P. Sustained release drug delivery system: a review. International Journal of Pharma Research and Development. 2011; 11: 147-198. 10

9. Raghavendra Rao N. G., Mohd Abdul Hadi, Harsh Panchal. A Novel approach to sustained Montelukast sodium release: Differentially coated mini-tablets in HPMC capsules. International Journal of Pharmaceutical and Biomedical Sciences. 2011; 2(2): 90-97.

10. Karthikeyan D., Vijayalaxmi A., Santhosh Kumar C. Formulation and evaluation of biphasic Delivery system of Aceclofenac mini- tablets in hard gelatin capsules. International Journal of Novel Trends in Pharmaceutical Sciences. 2013; 3(2):39-45.

11. Solanki B., Patel R., Barot B., Parejiya P., Shelat P. Multiple Unit Dosage Forms: A Review, Pharmtechmedica. 2012; 1(1): 11-21

12. Mirelabodea, Ioantomuţă, Sorinleucuţa. Identification of Critical Formulation Variables for Obtaining Metoprolol Tartrate Mini-tablets. Farmacia. 2010; 58: 719-727.

13. Chauhan V., Kumar K., Teotia D. Fast dissolving tablets: a promising approach for drug delivery. Univ. J. Pharm. Res. 2017; 2(4): 58-64.

14. Garg D, Saini V., Gupta S., Kapoor D. N., Joshi L. Controlled-release multiple-units and single-unit doses a literature review. International Journal of Pharmaceutical Sciences. 2013; 4(2): 66-73.

15. Robert S. Rosenson Low high-density lipoprotein cholesterol and cardiovascular disease: Risk reduction with statin therapy. American Heart Journal. 2006; 151(3): 556-56.

16. Mali A. D., Bathe R. S. Design and optimization of gastro retentive floating matrix tablets of an antihypertensive drug Quinapril HCl. Int. J. Pharm. Technol. 2015; 7: 9212-9224.

17. Mali A. D., Bathe R. S. A review on gastro retentive floating drug delivery system. Ame. J. Pharm. Tech. Res. 2015; 5: 107-32.

18. A. D. Mali, R. S. Bathe. Development and evaluation of gastroretentive floating tablets of a Quinapril HCl by direct compression technique. Int. J. Pharm. Pharm. Sci. 2017; 9(8): 35-46.

Received on 15.11.2021 Modified on 07.04.2022

Asian J. Pharm. Tech. 2022; 12(3):266-271.

DOI: 10.52711/2231-5713.2022.00043