INTRODUCTION:

Suitably, for the improvement of absorption in delayed release tablets, easy dissolvable polymers are used, in order to improve the hardness and the compatibility of the tablet (1). Pharmaceutical particle technology is used to improve the solid state parameters of the tablet in order to improve the bio- availability of the drug as well as drug absorption in the Gastro Retentive Drug delivery system in order to improve the drug from delayed release to immediate action at the site of administration (2). It was brought into notice that extrusion of HPC Nisso –Has itself challenging and becomes difficult in order to bring its objective as a sustained release in combination with a crystalline drug.

Furthermore, the research work deals with further development of the formulators that are added along with the drug with their acquired quantities and effective usage and ratio quantity of binders, surfactants, glidant, sugar agents or sweetening agents, super dis- integrating agents, polymers and other polymers with suitable chemical constituents that are necessary (3). The different strategies and instruments used for the formulation in the of tablet fast dissolving are the disintegration tester, dissolution apparatus, friability test, hardness tester, compressors, RMG, other miscellaneous apparatus used are impellers, propellers, turbines (4).

The use of formulators have improved the technology for tablet preparation. Some common formulators are; Hydroxy propyl methylcellulose (HPMC), MC (methyl cellulose), Povidone, Cross povidone from the functional group of cellulose and ethers, the cellulose derived polymers are water soluble and are used as vital binding agents. HPMC polymers are best suitable due to their versatility and high grade of its binding properties, hence they are suitable for binding of both soluble and insoluble drugs in single and multiple doses (5).

Multiple dosing of the drug gains more advantage than that of single dose of drug due to limited dose dumping, improved reduction the gastric irritation, improved bioavailability of the drug disposition (6).

MECHANISM OF ACTION FOR TABLET DISINTEGRATING METHOD:

Disintegration is usually referred to the mechanical breakdown of drug molecules into smaller granule particles easier for particle compaction and compression. It has favouring capabilities in the particle disintegration and produces changes in the physical appearance of the tablet: i) Particle arrangement analysis, ii) Elasticity deformation parameters, iii) Plastic deformation mechanism, and iv) Breakdown of particles, as well as v) Inter- particulate matter segregation (6).

Use Studies:

Stability parameter is a critical parameter for maintain the dosage form of the drug, since it is primarily based on temperature, light sensitivity, heat resistant and pressure under systemized conditions as a result it promotes sustained release with maximum absorption of drug. Whereas, the stability of implantable devices and other such controlled release formulations are dependent upon the required dose of use, with relative mimic of heat, enzymatic condition, moisture content and relative humidity should be maintained under the physiological conditions.

QUALITY BY DESIGN AND SCALE-UP:

IV bolus route of administration under which certain drugs are classified, they are subjected to IV infusion which is initially a slow process. Subsequently, studies of potentially available IV saline solution, is mandatory than these chemicals should be checked for its relative stability of the compound. They have certain critical parameters that are to be followed in certain formulation by the method of dilution. A major drawback could also be the change in the environment due to the impact of Hydration of the compound and the choice of diluent that could alter the confirmation of the drug product with its different degradation parameters. Other critical factors responsible are ph, mixing capacity at the IV site, adsorption of the compound and also the increased rate of oxidative degradation (7).

FORMULATION ASSESSMENT:

· Colour

· Particle size and morphology

· Thermo-analytical profile

· Hygroscopic

· Solubility based on pH

· Apparent volume pH

· ^{p K}a ^{value in ionizing groups}

· Amino acid sequence

· Secondary and tertiary structural characteristics

· Stability parameters

· pH

· Temperature

· Humid, temperature and light

· Mechanical stress action

· O2 sensitivity

· Impurities quantity

· Expression system impurities

· Potent level

· ^{Animal (PK/PD)
and T}max ^{profiles (8)}

Scale - Up and Process Changes:

The FDA concluded from the result of process validation according to the established document shows high degree of quality assurance parameters that is specific for a predetermined quality condition (9). However, validation is performed at the full scale technique either in laboratory or industrial down technique. The latter, pre and post characterization studies is crucial for product manufacturing process variables for a successful process validation for both the API and drug product. (10). However, it is important in order to meet the desired rate of quality with a critical time management parameter, characterization studies and control parameters for each specific unit variable operations which should be monitored at regular intervals of time (11).

Usually, scale up is a difficult challenge for generation of small molecules. Problems such as homogenous mixing, handle and management of bulk transfer and sterile filtration could be compounded as a result of stress and increased scale (12). This study is only applicable if the experimental design have been utilized to study the process variables are used to identify the special design for the production of molecule. Hence, it is also suitable for producing phase diagrams for development (13). The method of QBD, produces a good result of quality attributes in the product hence the rate limiting factors should be maintained in order for each degrees of correlation are met as a result a good final product is obtained. (14).

In order to meet the needs for a successful QBD level, the prior step is to identify those process levels which are necessary for product quality and perform well- validated analytical methods to check and maintain these certain parameters. (15). Usually, monitoring of process variables are performed in order to reduce the time required for production, to recognize the potentiality during the development process and also to facilitate flexibility in drug product development with its specific process characterisation. It is a site-specific process that has the potential to introduce variability into the system hence it is necessary for a specific process, personnel training, processing technology transfer, validation stability in order to ensure good quality of product by the survey of each batch process (16).

By form and function, QBD is desired method to produce a degree of process knowledge for controlled parameters without any alteration of the final product (17). For immediate - and controlled - release solid dosage forms, SUPAC guidelines should be followed in order to meet the defined product specifications (18). Stability plays an important role in the drug- product bio- activity that are to be added on metrics for biopharmaceuticals (19). Hence, any change in the process variables could have a relative impact on the efficacy and its safety on the final drug product (20).

Some common designs Factorial designs:

Such designs are useful to evaluate the key parameters with their study of interactions (21). However, through study it authors found that it was very complex to interpret the conditions for more than 3 factorial designs and noted in data collection in a coherent fashion and was difficult to vale such designs which have high level of interaction with the statistical significant variables. One of the necessary reasons for the usage factorial design is for easy interpretation of the interactions in each unit operation along with its critical parameters (22). Hence, for instance, a 3×2 factorial count is basically presented in the form of a representative data in tables of 6 columns with either the first or second factor is listed within each other, when the first factor in enlisted with-in the second factor or in the other way round. It is obvious that the main effect must not be considered into the secondary effect, since all the readers only calculate the main effect rather than the secondary effect, but is not possible to calculate individual factors, there’s a separate column to calculate the S.E. (23).

Latin squares:

Latin square designs allow constant assessing of the response or result of each variable in the specific factorial design that can be used for the application of the treatment (24). In general, single stage of 2×2 Latin squares consisting of two experimental units ,they are not sufficient enough to detect the respective statistical analysis, repetitive count of 2×2, Latin square design could overcome this problem (25). Subsequently, 3×3 Latin squares have problems similar to 2×2 squares, but they have to undergo a problem that is not possible for each treatment to complete every treatment, hence a risk is formed creating an unequal risk to carry in every unit operation (26). Among all the Latin square designs used in animals or else experimental units per cell, 4×4 designs are the most powerful as they have the potential to ensure that all the treatments are related to one other and the each treatment follows the repetition of the previous treatments in order to make the treatment carryover in equilibrium for its upcoming carryover treatment effects. However, Latin square method of design must not be used if substantial carryover effects are likely to be different from each other (27). Latin squares also have the disadvantage which is not possible to evaluate treatment interactions that are likely to be similar to each other and do not have positive interaction in each level of the factorial design. (28). As a result, it leads to the issue of accurate period of length, as the rate of period interacting with the treatment itself reduces due to decline in the treatment levels. Usually, shorter length periods do not allow full expression to perform its treatment. Hence, the length of the treatment level should not exceed the anticipated time for the result expression to be evaluated (29).

A. IMPROVEMENT IN THE DISSOLUTION RATE AND TABLET PROPERTIES:

Class 2 drugs of the BCS classification system are usually divided based on solubility and permeability of the drug and also high or slow dissolution rate due to low aqueous solubility and high dose of drug (30). The rate and extent of absorption in the GIT is mainly dependent upon the solubility and the rate of dissolution of the drug (31). Several methods have been used for the enhancement of solubility and dissolution rate of poorly water- soluble drugs, such as (a) by reducing the particle size in order to increase the surface area; (b) usage of soluble enhancers in surfactant surface systems; (c) the formation of water soluble complexation forms of drug; (d) usage of prodrug usually have higher dissolution rates; (e) lyophilization (f) manipulating of the solid state of the drug substance in order to improve the dissolution of the drugs (32).

B. PARAMETERS FOR THE USE OF SUPER DISINTEGRANTS:

Effect of drug particle size on content uniformity:

Certain tablets that were prepared that differed only in particle size of the drug which were used to make blends with different chemical constituents of varied ratio. The average of the mean particle size diameters for two batches of the drug particles were 18 and 6μm. Some portion of the blending mixture should be equivalent to the unit dosage form of Samples of 11μg per 90mg of blend were analysed for its potent nature. For blending of larger particle size, for the mixture blend that contains smaller particle size of drug. A qualitative Analysis was performed in order to simulate the recorded potent nature of the standard drug particles using the method of particle size method of distribution and for accurate ideal mixing. Hence, the result observation was to prevent the blend of drug sample from poor content uniformity and improve its stability (34).

Enhanced Drug Content Uniformity:

Films prepared by conventional casters on the trays like Teflon-coated per –specs trays (TCPTs) that may produce a defect of poor drug content uniformity. Hence, it is appropriate to use a prepared silicone – mouldable tray that consists of individual wells for film casting that improves the drug stability and also enhances the drug content uniformity. The techniques incorporated for the preparation of the films were by solvent evaporation and emulsification technique followed by solidification in order to cast on TCPT’S and SMT. The films that were prepared by the SMT method was superior in order to meet the drug content uniformity maintenance. It also had the potential to the variance in the Muco-adhesive reaction, drug release and film thickness (33).

C. PROPERTIES OF BINDERS FOR DRUG FORMULATION:

According to the proposed Strategic Highway Research Program (SHRP), it’s proved that the effective use of binder showed an active component for the initiating of the binding property. However, its shown that certain the fatigue parameter, G* sin delta measure have proven that the measures calculated varied when compared to the theoretical data that is both these data don’t co-relate with each other. This fatigue parameter illustrated that, only the specific binder usage could prove the success in the stability of the drug product. It was hence proved that this parameter does not have any relation to the life of the tablet. Hence, this study was performed to make it useful for the usage of certain kinds of binders that produce fatigue life mix containing various binders like those which have "extreme" properties, due to which there are some documented performance data that exists.

D. LUBRICATION PROPERTIES:

Suitable mechanisms were illustrated for solid–lubrication using certain transition metals like di- chalcogenides and like other polymers such as, HPMC, MC, MCC, MC cross-povidone and povidone. These are applied either on the solid surface or as fillers. There is wear and tear process with the specific solid lubricant coating in order to transfer into a thin layer from which transfer of tri -layered film is formed on the surface of the coating. The wear and tear at the specific regions can produce different chemical properties, small structure and different crystal graphic texture from bulk coating due to the presence of chemical reactions acting on the surface. Hence, as a result certain solid lubricants that give long duration on wear and tear and low friction fail in a different environment. Most of the lubricant should exhibit Non- Newton forces in order to improve the stability of the product and increase the contact stress. By the help of interfacial forces it can erode this problem and improve the submission of worn coating and transfer film. This method is responsible for low friction followed by interfacial sliding between the worn coating and the transfer of films (34).

E. USE OF SURFACTANTS:

Colloidal particles act as surface acting agents in different ways, such as surfactant molecules, mainly follows fluid interface. Similarly as water in oil linkage tendency for a surfactant to get quantised of HLB hydrophilic – lipophilic balance. In order to produce a spherical particle based on its wettability resulting in its contact angle variance. In various ways like surfactant molecules, mainly if adsorbed to a fluid interface. Some crucial differences that are produced are due to the formation of different surface acting agents that exist, however, there are 2 different types of surface active material depending open the different forces that act in between the particles due to their strong forces of interfacial attraction between the particles. Hence, they type, texture, quality and quantity of the surfactants play a crucial role in the formulation of any tablet in order to produce a good and a stabilised product (35).

F. SOLUBLIZERS:

For large scale preparation, Sodium Silicate gels are very suitable candidates for a successful conformance treatment. For a successful treatment, most common ingredient used is gel that delays the interaction of silicate solution within the drug mixture reservoir, in order to minimize rock/fluid interactions during solubility and ensure the increase in the stability of the gel .The choice of the sample ingredient plays a crucial role due to the presence of moisture content in it hence it should increase the rate of solubility that helps in the formation of gels. From the result of long term stability studies, it was found that to notice that silicates tend to contract and form into strong hard gels, expelling water. This method is called as synargesic effect clearly explains the long term effectiveness of silicate treatment .Possible reasons maybe: 1) gel formation is not well performed 2) retardation of gel is not effective and controlled 3) penetration of silicate is positive based on the formation of limited by the buffering capacity of the rock 4) blockade did not last long hence made the tablet easily breakable (36).

G. BINDERS:

· Taste masking compatibility.

· Portability with taste masking.

· Pleasant mouth feel.

· Residues in mouth should be absent after oral administration

· Low stability to environmental conditions as humidity and temperature.

· Tablet manufacturing allowance using conventional processing and packaging techniques and minimal usage of equipment cost (37).

H. SWEETENING AGENTS:

Sweeteners are certain necessary factors intended for disintegration in order to make dissolved easy in the oral cavity. Certain compounds like Sorbitol, Mannitol Isomalt are additional agents used in order to provide good feel in the mouth and also cooling sensation for providing good mouth feel and cooling sensation. Hence, choice of artificial sweeteners have gained more importance than that of natural sugars and in also in pharmaceutical preparation. First generation of artificial sweeteners; Saccharin followed by the second generation artificial ace –sulfame -K, sucralose which fall under the second generation artificial sweeteners (38).

Formulation factor:

1. Pellet core:

The features for a successful tabletting process in the nature and type pellet core which is also essential for coated pellets. Core of tablets having good elastic parameters and rigidity, should meet the necessities for deformation ongoing in tabletting procedures. It should also have the capability to recover the coating films and ensure that the films are intact with each other. Prominent factors of tensile strength that consists the composition of core, porosity of the particle size and other toxic factors. Cores that are coated with nice tensile strength property should maintain pressure during the tabletting and compression process and to stabilize the intactness of the coating film (39).

2. Core composition:

Certain pellets formed by themselves usually produce good tensile strength properties and so should sustain drug release of tablet beads during tabletting. Pellet composition if the main factor during tabletting mechanism. The composition of pellets play a crucial role in the quality of the tablet. Constituents of pellets are diluents, adhesives, like lactose, starch, MCC, hydroxyl-methyl cellulose, PVP, and HPMC (40). Pellets having high level of porous nature had high level of deformation parameters and densification factors, but its release behaviour of drug had hardly any impact, which showed no rate of destruction on coating film of the tablet. This could be considered for the increase in space during coating of the surface film (41).

3. Particle size:

Compression of the tablet with different diameters of tablet-pellet cores have a direct relation with the tablet compression of tablet- excipients interactions and have some desired effects on compression performance and drug release. According to the study of Johansson et al. (1998) developed 2 MCC-containing pellets by using respective varied diameters for the 2 pellets by spheronizer extrusion technique(42). Main factors such as porous nature and tensile of tablets were to be determined in order to show the mechanism of compression of pellets with deformation and densification. The accurate size of the tablet has no affect on the porosity of the tablets but the degree of deformation and densification has an increase in the size of the particle. The rate of drug release from coated pellets slowed small increase in the size of core and level of coating (43).

4. Coating:

Polymeric coating is usually useful for the meeting the needs in pharmaceutical industry in order to improve the drug release control parameters in oral dosage and hence the stable nature of its chemical nature by forming a barrier to prevent high level of toxic barrier to prevent from the interaction of other environmental and external environment. Gradually due to the increase in temperature, the motion of polymer increases and hence as a results a chain like formation between the polymer and the particles (44) (45).

5. Core drying:

Pellet cores upon different drying methods can effect porosity and hence subsequently has influence on compression performance of pellets. There have been used four different techniques for drying such as, freeze-drying method, fluid-bed drying mechanism, hot air oven drying strategy and desiccation using silica- gel were compared with each other and summarized (46). The result obtained were dependent upon the drying methods, and also be altered from ow to high i.e. freeze-drying, fluid-bed drying, hot air oven drying and desiccation with silica-gel (47).

6. Coating polymer:

Polymers that are used for prominent purposes are classified into cellulosic and acylic polymer. Cellulosic polymers such as ethyl- cellulose is mainly used as extended release, whereas Acrylic polymers such as Eudragit –L is used for control drug release and in the property of taste masking capacities. These polymers are used for the formulations of aqueous colloidal preparation as well as organic solutions (48).

Due to the effect of puncturing at reduced rate and reduced elongation with poor mechanical properties lose the property of sustained release of the drug. By the addition of plasticizer and also pseudo –latex –cast ethyl cellulose films. According to the study he tried a different layer of tabletting excipients such as MCC, on the EC coated pellets, a layer was produced in order to produce integrity of EC coating process during compression (49). However, as the result produced was not sufficient to maintain the integrity of film coating. Certain glidants incorporated are, magnesium stearate into or in between the layer and the EC coating, as a result the compression effect on release of drug could be reduced (50).

Eudragit NE 30 D is a neutral polymer that produces flexible and accurate matrix structure since it has high rate of elasticity and elongation break period it is not necessarily 500%, of Eudragit NE30D is combined with plasticizers (51). Eudragit L 30D55 is the aqueous dispersed solution of positively charged polymers with meta- crylic acid as a functional group. Due to strong chain of hydrogen bonding caused by the impacts of carboxyl groups, Eudragit L 30D55 was found to be weak and brittle (52).

7. Plasticizer:

They work by attaching each other between the polymeric chains and then space them apart and hence are responsible in lowering the glass transition temperature. Concentration of plasticizer in the solution of coating depends on several factors which are like polymeric properties usage of other additives (53).

Special factors are needed for the coating films of tablet formed pellets during compression, types and amount of plasticizer that is used must be calculated well. The frequently used plasticizers are (TEC), (PPG) and (PEG). These concluded for different drug properties, hydrophilic or hydrophobic plasticizers (54).

In addition, the extent of moisture content is also essential for a successful tablet and pellet compression. Coated tabletted pellets are to be stored with different humidity at room temperature for 1 month, including ^{50%, 85%, 80%, 95% and 101% RH. Tg of
coating film were lowered in order to produce lowered and}reduced degree of temperature with increasing RH. (55).

8. Coating film thickness:

Coating weight has the direct impact on the thickness of the film and hence influences the release of drug. Coated tablet pellets having thick films have strong rigidity but drug release could be delayed. Several tests were performed which showed that different coating weights could meet different needs of drug release without any destruction on the coating films. If isolation of the different layers in the tablets are employed, thickness of the layer can be determined based on ability of these isolation of layers and drug release character (56).

9. Tabletting excipient:

The optimized excipient selection is essential for tabletting process:

1. Can be used as space fillers between the tablet or pellet formation and also reduce pressure during the compression mechanism.

2. It can prevent direct contact between pellets and mutual integration of polymeric films in order to maintain the film integrity.

3. To improve compressibility.

4. Improve the uniformity and decrease the of tablets weight differentiation of the drugs (57).

Excipient are usually powder form or in the form of granules. By the study of Habib et al. (2002) prepared tablets by spheronizer technique was then followed by freeze drying mechanism in order to avoid any formation of agglomerates and certain content uniformity effects. Other factors are like includes type, dosage and quantity of drug, and physical and mechanical strength, such as elasticity, plasticity, and porosity (58).

10. Technological factors:

In addition to composition factors, technology is of great importance to compression of pellets likewise. The compaction process of coated pellets can be summarized in four stages:

1. Re-position of pellets as a result in volume reduction of beads.

2. surface deformation of pellets resulting in volume reduction of the pellet bed further.

3. Bulk structure deformation of pellets resulting identification.

4. Low inter- and intra-granular porosity to stop volume reduction (59).

11. Coating parameters:

The most common instrument used for the coating of pellets is FBD coating technology. This technique utilize spray gun technology .It follows the below mechanism of bottom spray technique.

Figure 2: Schematic diagram 1 is Inlet filter; 2 is heater; 3 is Spray gun in the bottom; 4 is Fluidized bed; 5 is Guide cylinder; 6 is Settling chamber; 7 –is Strainer; 8 is Bartizan; 9 is Induced draft fan (60)

The capacity and the rate of feeding decides the fluidized nature of the pellets. Reproducibility and its coating quality gets reduced with too much or too little fluidized capacity. Feeding capacity is based on feeding capacity and will reduce reproducibility. The quality of the fluidized bed is based on the low supply of air rate, with loss of material and enhances yield. Atomic pressure and rate of spraying system decides the affect of coating solvent system. There is force of adhesion between the pellets and the outcome of uneven distribution of coating with too low atomizing power not only the cracked or broken pellets, but also causes lack in the quantity of coating solution. The rate of spraying process is based on different coating solutions in dispersed phase systems. Due to low volatile nature and high efficiency of drying, the driers should be controlled at lower speed and are performed to protect the outer coat of the film layer (61).

12. Tabletting parameters:

The rate of compression affects the hardness of the tablet, friability and the time for disintegration of tablets. Disintegration time and the hardness of the tablet increases with the enhancement of forces on compressibility. The property of friability on the tablet depends upon the tabletting force exerted on the tablet. The optimisation of compression force is usually based on the pellet formation property and its composition(62).

COCLUSION:

From the study, we study the basic requirements, process and dependent and non- dependent parameters that are required for the general preparation of tablets and other solid dosage forms. The critical parameters are also to be mattered parallel in order to maintain the stability of the tablet and the protocol of the quality and quantity of the chemical contents that are added are also to be maintained. The parameters are also used for various strategies in equipment handling. The different techniques for equipment protocol should be analysed and the movement parts should be validated at regular intervals of time. The quality and quantity of the drug is mainly dependent upon the primary and secondary factors. The dependent and the independent factors are mainly related to the primary and secondary factors for the stability of the final product. Hence based upon the above study, it proves the qualitative and quantitative requirements for a good stabilized and quality product.

ACKNOWLEDGEMENT:

The Author is very grateful towards the college JSS College of Pharmacy, Mysuru for providing the facilities.

CONFLICT OF INTEREST:

The Authors declare no conflict of Interest.

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Received on 16.09.2019 Modified on 13.11.2019

Research J. Pharm. and Tech. 2020; 13(10):4973-4980.

DOI: 10.5958/0974-360X.2020.00872.0