Development of the Formulation and Assessment of Colon Targeted Drug Delivery or Oral Administered Prednisolone

1.1. Drug Delivery Systems

Dosage forms are also known as “Drug Delivery Systems” or “Finished Drug Products. A drug delivery system (DDS) is a formulation or a device that allows the administration of a therapeutic substance to achieve a therapeutic effect in humans or animals. It also increases the therapeutic effect and safety of a drug by regulating the release of drugs in the body and controlling the rate, time, and/or site of release [1]. It must limit the interaction of the drug substance with other receptors of the patient in order to avoid undesirable effects. This encompasses the use of the therapeutic product, the subsequent release of active components by the product, and then the transport of active ingredients via biological membranes to the site of action. Oral drug delivery is the most sought after and widely used method for the delivery of therapeutic agents to the body systems to obtain a systemic effect because of its patient acceptance, ease in administration, and cost-effective manufacturing process [2].  Conventional immediate-release formulations provide clinically effective therapy for many drug substances, maintaining the necessary balance of pharmacokinetic and pharmacodynamic characteristics for an optimal therapeutic outcome with clinically acceptable safety. Therapeutic agents for conventional drug therapy need to be administered as periodic doses. These agents are designed to provide optimal stability, activity, and bioavailability [3].  For most drugs, standard methods of administration are suitable; however, some drugs are reactive or hazardous and have a limited therapeutic window. Besides that, these conventional dosage forms also have a lot of side effects, and in some cases, the initial dose of the drug may not be sufficient to get into the therapeutic range to provide a pharmacological response [2]. In those scenarios, a continual dose of a therapy agent is needed in such a way that the fixed plasma levels are sustained in Figure 1. On the other hand, the conventional drug administration at the fixed intervals can lead to extreme side effects. The controlled drug delivery system has solved these problems of conventional dosage forms. Controlled drug delivery systems pack several advantages over previous formulations, including enhanced efficacy, lower toxicity, and better patient compliance. Controlled drug delivery systems are mainly determined to enhance drug therapy efficacies [3]. Profiles of drug levels attained with conventional (a) and controlled release (b) drug delivery systems, with conventional delivery methods, the drug levels fluctuate around the therapeutic range. Controlled release systems, however, may cause the drug level to remain therapeutic for an extensive time [4].  The United States Pharmacopoeia To define the Modified Release (MR) dosage form as “the one that the drug release characteristics where time course and/or position are selected to meet therapeutic or convenience objectives not provided by conventional dosage forms such as remedies, ointments, or instantly dissolving dosage forms.”

Figure 1: Comparison of Conventional and Controlled Drug Delivery Systems

0. 1. 1. Classification of Modified Release dosage forms
1. Delayed release
2. Extended release

1. Sustained release

2. Controlled release

3. Site-specific and receptor targeting.

Therapeutic drug levels maintained for 8-12 h after a single dose administration are achieved from special technology of preparation of dosage forms, which are referred to as extended release (ER) formulations [5]. The extended-release products are formulated to release the drug at a predetermined rate, duration, and location to maintain optimum therapeutic blood levels of the drug. When presented as such a conventional dosage form (a solution or a prompt drug-releasing dosage form), it permits at least a 2-fold reduction in the dosing frequency and a substantial improvement in patient compliance or therapeutic performance [6].  Despite the decreased active ingredient release in sustained release (SR) dosage forms as compared to conventional formulations, it still remains greatly influenced by external environments of release. Controlled release (CR) systems are designed to liberate an amount of drug sufficient to sustain the therapeutic concentration of the drug over a prolonged duration of time, and the release profiles are generally governed primarily by the special technological construction and design of the system itself. The release of the active agent is ideally independent of external variables [7].

1. 2. DELAYED RELEASE DOSAGE FORMS

Delayed release (DR) systems are designed for the drug to be released sometime (after a predetermined period of time) (in a predetermined location), i.e., they will not release the drug immediately after ingestion. Significance of Dosage Form in Pharmacotherapy E.g., Enteric-Coated† Tablets and Pulsatile Release Capsules.

Delayed action dosage form is not releasing the drug immediately after they are given, but the drug is released only after the tablet has travelled from one segment of the GIT to another. The release of drug from an oral dosage form may be deliberately retarded until the dosage form reaches the intestine in order to:

1) Prevents the drug from being affected by gastric fluids

2) Alleviate gastric irritation from drugs that are especially irritating to the stomach.

3) To promote GIT Peyote for medications that are better absorbed from the intestine, in addition to the drugs, these are damaged in the belly or by the digestive enzymes and meant to exert area impact at a particular GIT website [8]. In the formulation of delayed-release dosage forms, hydrophobic excipients having weak acidic groups are preferable due to their less solubility in water at lower pH and their solubility in neutral and alkaline regions as a result of the ionization of acidic groups. Highly pH dependent, it would cause increased drug release from the stomach to the higher pH environment of the upper small intestine for delayed release dosage form [9].

1.2.1. CLASSIFICATION OF DELAYED RELEASE SOLID ORAL DOSAGE FORMS

There are two types of delayed release solid oral dosage forms: single-unit (non-divided formulations, such as tablets or capsules) and multi-unit (divided formulations, such as pellets or mini-tablets) [10].

1. 1. 1. 1. Single unit Dosage Forms

Single unit dosage forms normally implies to diffusion controlled systems which may be monolithic systems, where the diffusion of a drug through the matrix is the rate- controlling step, reservoir or multi layered matrix systems, where the diffusion of the drug through the polymer coating layer of the system is the rate- limiting factor. However, in most cases drug release may happen in through combination two mechanisms.

1.2.1.2 Multiple unit dosage forms

Types of multiple unit dosage forms compare

1. Pellets
2. Granules
3. Mini-tablets and mini-depots (which are disseminated throughout the gastrointestinal system when the tablet or capsule breaks down.)
4. Nanoparticles and microparticles (also known as microspheres or microcapsules) 
5. Multiple unit tablets (which, because the subunit functions as a self-contained depot, can be split upon injection without losing the depot action)

The standard example of a modified release dosage form is an enteric coated tablet. Delayed release dosage forms are all enteric coated tablets (maintain integrity in the stomach but release quickly in the upper intestine). All delayed release dosage forms are neither enteric coated nor enteric effect intended [11].

Common pharmaceutical delayed release solid oral dosage forms in use today include tablets, capsules, granules and pellets.

Figure 2: Relationship of pharmaceutical Delayed Release solid oral dosage forms

1.2.2 Types of Delayed release systems:

Can be of the following two types depend up on the site of the drug release: 

1. Intestinal release system
2. Colonic release system

1.2.2.1 Intestinal release system

It is often that a given drug may be coated with enteric polymers for intestinal release; this can be for multiple known factors including the avoidance of gastric irritation, avoidance destabilization in gastric pH and the like [12].

1.2.2.2 Colonic release system

Drugs have limited absorption through the colon, but may be targeted to such a site for the following two reasons:

a) Local mechanism of action in ulcerative colitis

b) Permeation of protein and peptide drugs into circulation

The system has benefit of using pH sensitive bio-erodible polymers like polymethacrylates which releases the medicament only at alkaline pH of colon or divinylbenzene cross linked polymer in which the drug can only cleaved by the enzyme, azo-reductase of colonic bacteria and drug can be released for local action or systemic absorption [13].

1. 3. Tablet

Tablet may be defined as the solid unit dosage form of medicament medicament with or without suitable diluents and prepared either by moulding or by compression [14].

Tablet is normally a compressed form containing:

1. 5-10% of the drug (active substance)
2. 80% of fillers, lubricants, glidants and binders
3. 10% of disintegrants and other compounds which ensure easy disintegration, disaggregation and dissolution of the tablet in the stomach or the intestine

The time of disintegration can be regulated to be fast-acting or long-acting. Special coatings can render the tablet resistant to stomach acids so that it will only disintegrate in the duodenum when acted upon by enzymes or alkaline pH.

1.3.1 Advantages of Tablets

i. They are a single dosage forms, and they provide advanced functionality than some of the other oral dosage forms for the maximum medicate precision and least content redundancy.

ii. They are the least expensive of all oral dosage forms.

iii. They are the lightest and smallest of any oral dosage form.

iv. They are overall the simplest and least expensive of all oral dosage forms to package and ship.

v. Tablet formulations can give the greatest ease of swallowing and the least propensity for “hang up” of tablets above the stomach if they are coated, provided that disintegration of the tablet on entering the gastrointestinal tract is not too rapid.

vi. They have the best combination of chemical, mechanical and microbiologic stability of all the oral forms.

vii. Drug can be released in a sustained manner [15].

1.3.2 Disadvantages of Tablets

i. Some drugs are resistant to compaction into dense petard strains due to their naturally flocculent, low density amorphous form.

ii. It may be difficult or impossible to formulate and produce a tablet for compounds exhibiting poor wetting/slow dissolution properties, intermediate to large dosage and/or optimum absorption high in the GIT or both.

iii. Bitter or unpalatable drugs, drugs with objectionable odor or drugs sensitive to oxygen or moisture of atmosphere may need encapsulation or entrapment before compression or post compression tablets may need coating [16].

1.3.3 IDEAL REQUIREMENTS

i. They must be accurate and of equal weight.

ii. The drugs must be uniformly distributed into the tablets.

iii. It should be able to be given by mouth, and the quantity and form should be reasonable.

iv. The tablets are not too hard that it will not break in stomach.

v. Must not have any incompatibility.

vi. Their chemical and physical stability should endure shelf storage.

vii. They must not fall to pieces en route or in the hands of the patient.

viii. They must be attractive to look at.

ix. It should not possess any manufacturing defects and you should not have either cracking, chipping or discoloration.

x. It should then dissolve easily after it's been administered.

xi. They need to be simple and inexpensive to produce [17].

1.3.4 Various types of tablets

1.3.4.1. Oral tablets for ingestion

Except for chewable tablet, the tablets are supposed to be consumed whole with enough of drinking water. More than 90% of the tablets produced today are swallowed. Thus, it indicates that, this class of formulation as dominating worldwide and the maximum focus of the researchers is in this direction [18].

1. Standard compressed tablets
2. Multiple compressed tablets

1. Compression coated tablets
2. Layered tablets
3. Inlay tablets

3. Modified Release tablets
4. Delayed Release tablets
5. Targeted tablets

1. Floating tablets
2. Colon targeting tablets

6. Chewable tablets
7. Dispersible tablets

1.3.4.2. Tablets used in the oral cavity

Tablets in this category are intended for delivery of drug to the oral cavity, provides local action at this site while avoiding of first pass metabolism, destruction in stomach environment, nauseatic impulses and provides rapid onset of action. In this region, properly formulated oral cavity–specific tablets go into this region [19].

1. Lozenges and troches
2. Sublingual tablets
3. Buccal tablets
4. Dental cones
5. Mouth dissolving tablets

1.3.4.3. Tablets administered by other routes

These are the tablets given by routes other than GIT and the drugs avoids passing through GIT. Other formulations may be inserted into other body part holes or applied directly under the skin, absorbing into the body from the localized area of application [20].

1. Vaginal tablets
2. Implants

1.3.4.4. Tablets used to prepare solution

Tablets classified under this category are to be dissolved first in water or some other forms of solvents prior to administration or application. It can be intended for ingestion, or parenteral application, or may be a topical application based on its route of administration [21].

1. Effervescent tablets
2. Hypodermic tablets

1.3.5. Various steps involved in the manufacturing of tablets

The manufacture of oral solid dosage forms like tablets is a complex multi-stage process wherein the starting materials undergo repeated changes in their physical properties before the final dosage form is achieved. Tablets are usually prepared by granulation which provides two important properties to the formulation: Compatibility and fluidity. In wet granulation and dry granulation (slugging and roll compaction). Regardless of whether tablets are produced via direct compression or via granulation route, the initial step of milling and mixing is equivalent, however the following processes differ [22].

Following are the various unit processes which are involved in making tablets:

1. Dispensing
2. Sizing
3. Powder blending
4. Granulation
5. Drying
6. Tablet compression
7. Packaging

Figure 3: Various Unit Operation Sequences in Tablet Manufacturing

1.3.6. Granulation

Granulation is the process of adhering primary powder particles to form larger, multiparticle entities known as granules. Granulation can be described as a process of size enlargement which converts small particles into physically stronger agglomerates and granules. The size of pharmaceutical granules is normally between 0.2- and 4.0-mm. Granulation aims to enhance the flowability and handling of powders, reducing dustiness and avoiding product segregation [24].

There are two fundamental techniques to produce granules of powder for the compression into a tablet: wet granulation and dry granulation. Direct compression (DC) powders; are powders that mix well should not be granulated, and can be compressed into tablets via direct compression.

1.3.6.1 Direct Compression

The name “direct compression” means that tablets are compressed directly from powder mixture of API and proper excipients. The powder blend does not require pre-treatment by way of a wet or dry granulation process.

Direct formation takes relatively few steps:

a. Grinding of the drug as well as excipients

b. Mixing the drug and excipients

c. Tablet compression

Diluents, binders and disintegrants are the main types of direct compression excipients. Typically, these are common substances that have been transformed during the polymer manufacturing process to enhance the compressibility and flowability of the material. In direct compression tableting, the physicochemical properties of the ingredients like particle size, flowability etc. are crucial. Direct compression formulation can lead to high product yields, but success depends on excipients functional behaviour.

1.3.6.2 Wet Granulation

Wet granulation Exposed amounting process using water binder or either an adhesive to the power mixture. The correct amount of moisture can be controlled and an excess will make the granules too brittle, while an insufficient amount will cause the granules to be soft and crumbly. Procedure: Aqueous solutions are safer to handle than solvents.

Procedure

Step 1: Weighing and Blending - the active ingredient, filler, disintegration agents, are weighed and mixed.

Step 2: Make the Granulating fluid: Add liquid binder/adhesive to make the step wet granulate. Examples of binders/adhesives can include aqueous preparations of natural gums such as acacia, cellulose derivatives such as HPC, gelatins and povidone. A granulator receives ingredients that help provide composition density.

Step 3: Wet Screening: The moist lump is screened into adhesive pellets or granules.

Step 4: Drying the granules.

Step 5: Dry screening: Dry granules are then screened through a smaller screen than the wet mass screen to obtain a uniform size of granules for even fill in the diecavity.

Step 6: Lubrication: Dust and add a dry lubricant, antiadherent and glidant either over the spread granules or blend with the granules. This decreases the resistance between the tablet and the walls of the die cavity. Antiadherent minimizes adhesion of the tablet with the die and the punch.

Step 7: Tableting: The tablet is fed into the die cavity and then compressed between a lower and an upper punch.

While we might use water as a liquid binder, often many actives do not dislike water. Water added to the powder forms bonds between its particles, bonds strong enough to hold them in together. However, when the water is gone, the powders might disintegrate and thus may not be sufficient to form and maintain a bond. HPC is one of the most widely used pharmaceutical binders. During the processing, HPC and a solvent are combined with the powders to bond them together and the solvent evaporates. After the solvent is evaporated and the powders have compacted into a stoutly bonded mass, the granulation is milled, producing granules. In current formulation wet granulation method given by Rapid Mixer Granulator (RMG) [24].

1.3.6.2.1 RAPID MIXER GRANULATOR (RMG)

This refers to a total blending unit that is used to mix as well as granulate raw materials. It has a dual speed adjustable speed multi-bladed impeller fitted near the bottom of the mixing bowl having the chopper is mounted in a wall of the mixing bowl. The dual speed options enable the chopper and the impeller use towards distributing granulating solution and for the charge's fluidization and vortex creation by vertical and horizontal components of the material that is mixed [25].

Figure 4: Rapid Mixer Granulator                     Figure 5: Parts of Rapid Mixer Granulator

1.3.6.3 Dry Granulation

The process of dry granulation is when the product must be granulated and may be effected by moisture and heat. Dry granulations can be performed on a press using slugging tooling, and also on a roller compactor–otherwise known as a chilsonator. The use of a wide range of pressures and types of rolls is applied to achieve correct densification for wet/poorly flowing formulations during dry granulation process. In practice, reaching the proper granule and point of the process may involve multiple rounds of compaction. The cost becomes lower because process times are usually shorter and equipment needs are more simplified. On the other hand, dry granulation, generally, produces finer/fines/non compacted products, such that it may alter the quality or generate yield problems for the tablet. It needs either cohesive drugs or excipients [27].

Procedure for Dry Granulation

Step1: Milling of drugs and excipients.

Step2: Mixing of milled powders.

Step3: Compression into large, hard tablets to make slug.

Step4: Screening of slugs.

Step5: Mixing with lubricant and disintegrating agent.

Step6: Tablet compression.

Some granular chemicals (free flowing) are ok for direct compression powders E.g., potassium chloride Direct compression of various drugs is possible with the use of suitable tableting excipients that possess desirable flow properties and compressibility.

1.4 ENTERIC COATED TABLET

An enteric coated tablet is a type of formulated tablet that is coated with a compound that resists low pH of the stomach and allows it to dissociative fully in the small intestine. After dissolving the enteric coating, the tablet can disintegrate and the active ingredient is absorbed into the patient. Enteric coated tablets and capsules that are specially coated so that they do not dissolve in the stomach and instead release their contents in the intestines. Post contact with intestinal fluids, the coatings swell irrespective of pH and release the active ingredients by a diffusion-controlled mechanism [28].

Delayed release is meant to protect a drug that is destroyed by acid pH especially those which are acid-labile drugs like Aspirin, Pantoprazole etc or those which are absorbed completely in the stomach causes gastric distress such as Naproxen. Enteric coatings are also used to protect medications from being damaged by the stomach.

Film Coating:

Film coating is a complicated process during which a polymer-based coating is applied to the substrate as follows:

• Each type of fluid that is used to coat follows a very specific method on how it gets laid down and how quickly it dries.
• Coating material is uniformly distributed on the substrate surface.
• This way, the quality and functionality of the applied coating are maximized and reproducible.
• The typical thickness of such coating is in the range of 20-100µm.

Figure 6: Process of Film-Coating

1.4.1 Enteric Coating

An enteric coating is an effective film coating that controls the location where a given oral medication is absorbed in the digestive system. The word enteric means to do with the small intestine, so enteric coatings stop medication from being released until it gets to the small intestine [29].

Most enteric coatings function by having a surface that is stable at the very low pH of the stomach, but dissolves quickly at a higher (more basic) pH

In fact, they will not dissolve in the acidic juices of the stomach (pH∼3), but they do so in the more neutral (pH>5.5) environment, usually found in the small intestine.

Rationale for Use of Enteric Coatings

• NSAIDs induce gastric mucosal injury leading to clinical manifestations from GERD-like symptomatology to erosions, ulceration, upper gastrointestinal (GI) tract bleeding and death – collectively known as ‘NSAID gastropathy’.
• Prevention of the drug from being destroyed by gastric enzymes or by the acidity of gastric fluid.
• Prevention of drug-induced nausea and vomiting due to gastric mucosal irritation.
• Delivering the drug to its point of local action, in the intestine.
• Adding a throttled release action.
• The release of a molecule that is primarily absorbed in the intestine, at high concentrations, to that site.

In clinical routine, the strategies have been followed to prevent NSAID-induced gastropathy (i) CIA-assisted with gastro protective drug (ii) Through selective COX-2 inhibitors (iii)Helicobacter pylori eradication and (iv)Enteric Coating of Drugs.

1.4.2 ENTERIC COATING POLYMERS

Enteric coatings are customarily made from synthetic polymers having ionizable functional groups, usually the free carboxylic acid from a phthaloyl moiety, which render the polymer water soluble at a given pH. During conditions of high temperature and humidity, because many of these enteric polymers are esters (and thus susceptible to degradation as a result of hydrolysis), such hydrolysis can lead to marked alteration of enteric properties. Enteric coating polymers work through a variable pH solubility profile where the polymer co polymer will remain intact at low pH without dissolution but at a higher pH will dissolve to allow for the release of the contents of the dosage form [30].

Gastrointestinal pH and Polymer Performance

All enteric polymers currently in-use contain ionizable acid groups, typically through a free carboxylic acid from a phthalyl moiety. The pH of the medium and the pKa of the polymer will define the equilibrium between unionide insoluble polymer and ionized soluble polymer [31]. Using these two parameters, one can predict the ratio of ionized to unionized polymer using the Henderson-Hasselbach equation.

To be effective, therefore, an enteric form must prevent substantial release of drug in the stomach, but rapid dissolution of the polymer and total release of active material must occur in the environment of intestine. But it is true that all of the enteric-coating polymers, when hydrated, in the stomach will be more or less permeable to a particular active substance. There will be an important role to play for formulation measures, like variation of the type and concentration of additions to the film, to maintain this permeability within acceptable limits. The modulation of performance by adjustment of the amount of the applied enteric coating agent has an important role to play in this regard. The variation of this parameter has such a dominating effect that it can be tempting to almost exclusively rely on it in the design of an enteric-coated formulation. Rather than field on maximizing the effective quantity of enteric-coating agent in the bio adherent product, the need should be given to factors related to formula processes in establishing the minimum effective level of said agent.

1.4.3 Ideal Enteric Coatings

An enteric coating should have the general characteristics of a non-functional film coating, with appropriate changes to the pH solubility requirements [32]. The ideal qualities of a good enteric coating are as follows:

i. pKa to permit theshold pH of solubility to be pH 5 7, preferably 5 6

ii. Less variation in dissolution with ionic media and ionic strength of dissolution fluid.

iii. Dissolution very fast in non-gastric mediums.

iv. Low permeability.

v. Can accept commonly used plasticizers, pigments and other additives without excessive loss of properties.

vi. response of good between quantity applied and power to withstand gastric juice

vii. Able to be processed from aqueous media.

viii. The material in solution/suspension should have low viscosity (liquid), not easily coagulated, non-tack at application conditions, and aesthetically pleasing in its final coating form. Cleaning equipment should be no unnecessarily complicated.

ix. The matrix of the enteric-coating material should remain stable on storage. These changes in performance on storage should be unrelated for tablets or granules which are completely coated with film.

x. Adhesion between film and substrate should be strong.

Desirable entering coating: In the range of pH 5 to 6. This is based on the premises that the pH of the stomach itself, even when in the fed state, will rarely achieve this level but will surpass in the duodenum, where release of bicarbonate serves to neutralize the acidic chyme exiting the stomach. And, there cannot be a single polymer that should be used for enteric coating of all the drug molecules. The type of core materials (i.e acidity, basicity or permeability through various enteric polymer films) might restrict selection of the polymer.

If the film gets cracked either at the time of application or on storage, the enteric properties will be lost. Hence, the mechanical properties of the film applied must be taken into consideration. Plasticization is an effective means of overcoming cracking problems. Plasticizer, on the other hand, it was used to lower the permeability of the polymer films to water vapor. We limit suitable plasticizer to non-water-soluble materials, as these will probably work best.

Using 1:10 plasticizer to polymer is a general guideline to follow. The viscosity of the plasticizer, its effect on the final coating solution, permeability of the film, tack, flexibility, solubility, taste, toxicity, compatibility in the coating solution and stability of the film and final product are also factors to be considered. The majority of enteric coatings will not dissolve in solutions with a pH of less than 5.5 [33].

Enteric coating polymers are essentially those that are used most frequently by the industry.

• CAP– Cellulose Acetate Phthalate
• PVAP (polyvinyl acetate phthalate)
• HPMC-P (Hydroxypropyl methyl cellulose phthalate)
• Methacrylic acid (Copolymer Type A, B & C)
• Acrylate polymers
• Shellac

Cellulose Acetate Phthalate (CAP)

CAP is produced by the phthalic anhydride treatment of a partially acetate esterified cellulose. About half of the free hydroxyl groups provided by each glucose unit of the cellulose chain in the formed polymer is acrylated and 1/4 is esterified with one of the two carboxylic acid groups of the moiety phthalate. The sound carboxylic acid group tends to be unsealed and can form salts, thus forming the basis for its enteric character [34].

It is a proven enteric coating that is soluble above pH 6. Compared to other enteric polymers, it is permeable to moisture and simulated gastric fluid. On storage, it is prone to hydrolytic decomposition.

Poly Vinyl Acetate Phthalate (PVAP)

The PVAP is prepared by the esterification reaction between partially hydrolyzed polyvinyl acetate and phthalic anhydride. It is less permeable to water and synthetic gastric juice. "It is more stable to hydrolysis on storage. PVAP is used as a coating agent for enteric dosage forms and disintegrates at pH 5 [35].

Hydroxypropyl Methylcellulose Phthalate (HPMCP) 

Hydroxypropyl methylcellulose phthalate (HPMCP) is produced through the reaction of Hydroxypropyl methylcellulose and phthalic acid. The polymer properties are governed by the degree of substitution of the the possible substituents, most notably the pH of dissolution [36].

Plasticized to diethyl phthalate, acetylated monoglyceride or triacetin HPMCP. It is a more flexible polymer mechanically and will require less plasticizer than CAP on a weight basis.

It is available in two grades

a) HP 50 and

b) HP 55

HP 55 is more viscous than HP 50. HP 50 HP 50 pH 5 HP 55 HP 55 pH 5.5 It has similar stability characteristics to PVAP and dissolves within the same pH range. The major benefit is that it doesn't need plasticizer.

Methacrylic acid Copolymers

These polymers are used as enteric coating materials because they include free carboxylic acid groups, produce salts with alkalis, and are soluble at pH values higher than 5.5.  The two versions that are sold commercially are Eudragit L and Eudragit S.  Intestinal fluid may dissolve Eudragit L and Eudragit S at pH 6 and 7, respectively [37]. 

Eudragit S-100 dissolves at a higher pH than Eudragit L100 because it has a lower degree of carboxyl group substitution than the other of the two organic solvent-soluble polymers.  When combined, these substances can produce films with a desirable pH range where solubility will take place.

It is advised to utilize plasticizers in conjunction with all of these polymers. Since they neutralize the sticky properties of the polymers, pigments and opacifiers are beneficial additives. Polyethylene glycols are commonly used because they give the finished product a certain sheen.

1. 1. 4.  Other Additives

Plasticizers

A plasticizer is a low molecular weight compound that adds flexibility, resilience, and ease of handling to another material, generally a polymer.  Esters like citrates and phthalates make up the majority of the synthetic organic compounds used as plasticizers nowadays.  Plasticizers are liquids or solids with a low molecular weight.  They can be volatile at room temperature and usually have low melting points (less than 100 °C) [38]. 

Plasticizers work by enhancing the macromolecules that make up polymeric materials' intramolecular and intermolecular mobility.  Low concentrations, usually less than 5% w/w, are where the most effective plasticizers work.  In order to increase the workability and mechanical toughness of film coatings, plasticizers are frequently applied. 

For instance, polyhydric alcohols such as propylene glycol, glycerol, and acetate esters such as castor oil, ethyl citrate, diethyl phthalate esters, and acetylated monoglycerides.

Solvents

Dissolving or dispersing the polymers and other additives and transporting them to the substrate surface is the main purpose of a solvent system.

The following qualities are suitable for a solvent system: 

a) It ought to distribute additional coating solution ingredients into the solvent system with ease.

b) Processing issues should not arise from a highly viscous solution system (>300 CPS) caused by small polymer concentrations (2–10%).

c) It should dry quickly—that is, it should be able to coat a 300 kg weight in 3 to 5 hours.

Water, ethanol, methanol, isopropanol, chloroform, acetone, and methylene chloride are the most often used solvents, either separately or in combination.

Colorants 

Colorants are employed to give a dose form a unique colour and style.  The use of fine-powdered colorants (<10 µ) is necessary to obtain the correct distribution of suspended colorants in the coating solution.  Certified Food, Drug, and Cosmetic (FD&C) or Drug and Cosmetic (D&C) colorants are the most widely used colorants.  For instance, riboflavin, caramine, titanium dioxide, alura red, and tartrazine [39].

Opaquant – Extenders

These extremely fine inorganic powders are added to coating solution compositions to boost film coverage and provide more pastel hues.  These opaquants might cover the tablet core's color or give it a white covering.  Compared to these inorganic compounds, colorants are far more costly, and using opaquants actually requires less colorant.  Titanium dioxide is the most often utilized substance for this purpose.  Silicates, carbonates, sulfates, and the oxides and hydroxides of some metals are examples of additional materials [40].

1. 5. COATING EQUIPMENTS

Coating Processes and Equipment

Perforated closed system pans are used for most tablet film coating operations.  These offer the required regulated temperature and airflow conditions that make it possible to apply functional and aesthetic coatings in a repeatable and effective manner.  They also reduce operator exposure [41].

The following considerations should be made when selecting a film coating system:

1) A sufficient amount of process air for the pan's capacity.

2) The capacity to keep the temperature within a specific range, usually between 30 and 70 degrees Celsius.

3) The capacity to keep the dew point within a specific range, usually between 10 and 20 degrees Celsius.

4) A pan and spray system that is simple to clean and sterilize.

5) Since many coating formulations are dispersions or suspensions, the fluid path of the spray system should have as few dead spaces as possible.

6) Fan air and spray system atomization are readily regulated, ideally from the pan's outside. 

7) The ability to bypass air flow (particularly if the pan is going to be used for sugar coating).

 8) If flammable solvents are to be utilized, construction that prevents explosions should be employed.

 9) Inlet and exhaust air treatment in accordance with GMP and environmental standards.

The general equipment types that are most frequently utilized are as follows:

1) Regular Coating Pan

2) A Coating Pan with Perforations

3) Bed Coater with Fluidization

1.5.1. Standard Coating Pan

Another name for it is the Conventional Pan System. The typical coating pan system is a circular metal pan that is positioned slightly angularly on a stand. A motor rotates the pan on its horizontal axis, directing hot air into the pan and onto the bed surface. Ducts are placed through the front of the pan to exhaust the hot air. Applying coating solutions involves misting the bed surface with the substance. Within a perforated rotating drum, tablet coating occurs in a controlled environment. The tablet bed is mixed by air movement inside the drum and angled baffles installed therein. In order to expose every tablet surface to an equal quantity of deposited or sprayed coating, the tablets are raised and rotated from the sides into the centre of the drum [42].

Figure 7: Standard coating pan

Figure 8: Process Parameters of Standard coating pan

After that, warm air from an intake fan is pumped through the tablet bed to dry the liquid spray coating onto the tablets. In order to offer the operator with a totally isolated process environment, the drum pressure is kept slightly negative in relation to the room while the air flow is adjusted for temperature and volume to give controlled drying and extraction rates.

1.5.2. COATING DEFECTS

1. Picking and Sticking: The tablet surface sticks to the coating pan as a result of the tablets not being thoroughly dried. Picking is a type of sticking when a tiny piece of tablet adheres to the coating pan and expands as the pan rotates, creating a hollow on the tablet face.

Causes include: Excessive or insufficient tablet wetting, as well as low-quality tablets.

Solutions: Lowering the pace at which liquid is applied and raising the drying air's temperature or volume.

2. Bridging: This happens when the tablet's writing or logo is filled in by the coating.

Causes include: Inadequate atomization pressure, excessive coating viscosity, high percentage of particles in the solution, poor tablet embrossing design, and inappropriate solution application.

Solutions: Changing the plasticizer or adding more plasticizer.

3. Capping: The term "capping" refers to the partial or whole separation of a tablet's top or bottom crowns from the tablet's main body.27, 28 

Reasons:  The pills become brittle due to improper compression and over-drying during the pre-heating phase. 

Solutions: Shorten the tablet's drying period.

4. Erosion: This can be caused by soft tablets, a surface that is too moist, inadequate drying, or a weak tablet surface.

5. Peeling and Frosting: This flaw occurs when a tablet sheet's covering peels off the tablet surface.

Causes: The coating solution, excessive wetting, and a high level of moisture in the tablet core.

6. Chipping: Tablets that have parts broken out or chipped, generally around the edges, are referred to as chipping.

Causes: A friable tablet core, a high pan speed, or a coating solution deficient in a suitable plasticizer.

7. Mottled Colour: A tablet with bright or dark patches that stand out on a uniform surface is said to have mottled colour. 

Causes: cold tablet cores, incorrectly prepared coating solution, a spray rate that is different from the intended spray rate, and an unsatisfactory drying rate.

Remedy: Using a dye lake.

8. Orange peel effect: A coating texture that mimics an orange's surface.

Causes: Excessively high spray rates combined with excessive atomization pressure.

Solution thinning with more solvent is the remedy.

9. Twinning: Two tablets that adhere to one another are referred to as twinning.

Remedy: The solution is to balance the spray rate (lower) and pan speed (raise).

1.5.3. OPTIMIZATION PARAMETERS FOR COATING

Process Parameters

1. Inlet Temperature
2. Product Temperature
3. Exhaust Temperature
4. Drive speed
5. Spray pump speed
6. Air flow
7. Operating air
8. Actual weight
9. Spray rate.

1.5.3.1. Process controls:   Pan variables

1.5.3.1.1. Rotating speed of pan:

Tablet breakage, edge wear, and surface erosion may all be significantly impacted by tablet motion, which is mostly determined by pan speed.  Higher pan speeds are beneficial in this sense because of the uniformity of the coating's application.  It is commonly known that improving the pan's rotational speed enhances tablet mixing.  The amount of time spent in the spraying zone and, consequently, the uniform dispersion of the coating solution throughout the surface of every tablet in the batch are both influenced by the pan speed.  Raising the pan speed improves coating consistency and reduces thickness variance.  The tablet will shatter and experience needless attrition if the pan rotates too quickly [43].

1.5.3.1.2. Pan Loading:

Rather than weight, volume fill is used to characterize it. As a result, the ideal pan load by weight will differ for each product based on its apparent density.

The following factors contribute to the difficulty:

1. Making sure a pan is loaded correctly is not difficult at all on the laboratory scale. This issue can be resolved by combining active pills with placebos to provide a complete charge, even in cases when there is a very limited quantity of product available.
2. The coating pan's side walls or even baffles are more exposed to the spray when it is underloaded, which leads to a build-up of coating liquid on the exposed metal surfaces. This frequently causes tablets to adhere to the surfaces.

The following methods can help reduce this:

1. Modifying the gun-bed separations.

2. The distance between guns

3. The issue can be reduced by the quantity of firearms utilized.

1.5.3.2. Spray variables:

1.5.3.2.1. Gun-to-tablet- bed distance

It is up to the operator to set up the gun position using simple positioning aids like a ruler.  Gun placement must be optimized in order to:

 1. Verify that the ideal and consistent bed covering is attained.

 2. Allow for maximum surface drying time while facilitating wide coverage.

 3. As the spray droplets reach the tablet surface, get repeatable spray droplet properties.

1.5.3.3. SPRAY-GUN VARIABLES

The following qualities of film coating tablets are linked to spray gun performance:

1. Appearance

a. Coating gloss

b. Coating roughness

c. Existence of defects (picking etc)

d. Colour uniformity

2. Functional: 

a. Uniformity of distribution of coating

b. Coating uniformity

c. Solvent penetration into the tablet cores, and hence product stability.

1.5.3.3.1. Spray rate

The spray rate is an important factor since it affects the moisture content of the coating that forms and, in turn, the film's quality and consistency. Because of inadequate wetting, a low coating liquid spray rate results in partial polymer coalescence, which may lead to brittle coatings. The tablet surface may get too moist due to a high coating liquid spray rate, which might lead to issues like sticking and picking. Rapid drying frequently results in fractures in the films, and films are not created during the spraying phase but rather during the post-drying phase if the tablet surface temperature is low and the spray rate is high.

1.5.3.4. Atomizing air pressure

Increasing the spraying air pressure generally results in denser and thinner films and reduces the surface roughness of coated tablets. Excessive air pressure when spraying causes significant spray loss, very small droplets that may spray-dry before reaching the tablet bed, and insufficient droplet coalescence and spreading.32, 33 The film thickness and thickness variation increase with insufficient spraying air pressure, presumably as a result of altered film density and reduced spray loss. Furthermore, large droplets might locally moisten the tablet surface due to low spraying air pressure, which would make the tablets adhere to one another [44].

1.5.3.5. Inlet air temperature 

The uniformity of coatings and the drying efficiency (i.e., water evaporation) of the coating pan are impacted by the incoming air temperature. Reduced water penetration into the tablet core lowers the coated tablets' core porosity, tensile strength, and residual moisture content, while high inlet air temperature improves the drying efficiency of the aqueous film coating process. An excessively high air temperature causes the spray to dry up too soon during application, which lowers coating efficiency. By controlling the ideal conditions during the coating process, measuring the pan air temperature makes it possible to anticipate potential drying or over-wetting issues that could degrade the film's appearance or negatively impact the moisture and heat-sensitive tablet cores.

1.5.3.6. DRYING-AIR VOLUME

The volume of drying air is chosen based on:

a. The advice given by the equipment seller

b. In accordance with ideal circumstances created for the fitted air handling system.

Depending on the equipment being utilized, the supply and exhaust air fan speeds should be adjusted to match the typically advised negative pressure pan values. Following the establishment of the proper drying air volume, this parameter starts to influence other crucial processing parameters, such spray rate [45].

1.6. INTRODUCTION TO COLON

Many studies are being conducted on the colon as a potential medication delivery location. The oral colon-specific drug delivery system (CDDS), which was created by combining one or more controlled release mechanisms, releases the medication quickly in the colon after oral administration but barely at all in the upper gastrointestinal (GI) tract. Additionally, CDDS specifically delivers medication to the colon rather than the upper gastrointestinal system, making it useful for treating localized colonic disorders including ulcerative colitis, Crohn's disease, and constipation, among others [46]. Because of its comparatively low proteolytic enzyme activity and lengthy transit time, the colon is known as the best location for protein and polypeptide absorption following oral administration. For the treatment of conditions including nocturnal asthma, angina, and rheumatoid arthritis that have circadian cycles and peak symptoms in the early morning, CDDS might be helpful when a delay in absorption is desired from a therapeutic standpoint. Pectin, amylose, guar gum, chitosan, inulin, cyclodextrins, chondroitin sulphate, dextrans, dextrin, and locust bean gum are just a few of the many polysaccharides that have been studied for use in colon-targeted drug delivery systems. One new NSAID with a multifaceted mode of action is aceclofenac. Aceclofenac was created to offer a very efficient pain-relieving medication with a lower profile of adverse effects, particularly colon events, which are common with NSAID therapy. According to the current study's findings, tablets that target the colon with Aceclofenac show promise in coordinating the successful treatment of rheumatoid arthritis [47].

1.6.1. FACTORS TO BE CONSIDERED IN THE DESIGN OF COLON SPECIFIC DRUG DELIVERY SYSTEM

Structure and functions of colon

The colon runs from the ileocecal junction to the anus and makes up the lowest portion of the G I T.  The bottom six inches of the large intestine are called the rectum, while the top five feet are called the colon.  For the most part, the rectum is a pelvic organ, whereas the colon is predominantly located in the belly. The lumen is a passageway that is around 2 to 3 inches in diameter and is bordered with the mucosa, a moist, soft point lining those lines the colon.

Figure 9. Anatomy of Colon

Consolidating intestinal material into feces through water and electrolyte absorption and storing the feces until expulsion are the colon's primary functions. More than 90% of the 2000 ml of fluid that enters the colon through the ileocecal valve each day is absorbed, demonstrating the high absorptive capacity. Normally, sodium and chloride ions are released in a healthy human colon. It has been calculated that the colon typically contains about 220 grams of wet material, which is equal to just 35 grams of dry stuff. This dry substance is mostly made up of bacteria.  Movements in the colon can be classified as either segmenting or propulsive. Circular muscle segmenting motions, which provide the appearance of a sac-like haustra, are predominant and induce the luminal substance to mix. Defecation-related significant propulsive activity influenced by longitudinal muscle is less frequent and typically happens three or four times per day [48].

1.6.2. pH IN THE COLON

There is variance in the GIT's pH between and between subjects. An overview of the GIT's pH is provided in the table.

Table 1: average pH of the GIT

The pH of the gastrointestinal tract in healthy human volunteers has been measured using radio telemetry.  The terminal ileum has the greatest pH level (7.5 ± 0.5).  The pH falls to 6.4 ± 0.6 when it enters the colon.  The midcolon's pH is 6.6 ± 0.8, whereas the left colon's is 7.0 ± 0.7.  It has been demonstrated that illness lowers the pH of the colon.  Five patients undergoing therapy had a mean pH of 5.5 ± 0.4, while seven patients with untreated ulcerative colitis had a mean pH of 4.7 ± 0.7. 

1.6.3. GASTRO INTESTINAL TRANSIT

The subject's feeding or fasting status, as well as the size and density of the dosage form, all affect how quickly the stomach empties the form.  The arrival of an oral dose form at the colon depends on the small intestine time and the pace of stomach emptying.  Table 2 shows the transit time for tiny dose forms in the GIT. Food usually lengthens the duration of residence, and in certain situations involving frequent eating, dose forms have been known to stay in the stomach for longer than 12 hours. At three to four hours, small intestinal transit is very consistent and seems to be unaffected by the dose form or whether the patient is fasting or fed. As a result, after oral administration, a dose form may take as little as four hours or more than twelve hours to reach the colon [49].

Table 2: transit time of dosage form in GIT

Dosage forms like capsules and tablets travel through the colon in around 20 to 30 hours in healthy young adults, while transit times might range from a few hours to more than two days. Drug distribution is significantly impacted by diseases that influence colonic transit; constipation reduces colonic transit, while diarrhoea enhances it. However, transit time seems to be rather consistent in the majority of illness situations. Drugs that impact transit time include codeine, diphenoxylate, loperamide, sulfasalazine, mesalazine, bisacodyl, sucralfate, and docusates (Doss). 

1.6.4. COLONIC FLORA:

All throughout the length of the human GIT, there are several aerobic and anaerobic microorganisms. There are very few bacteria in the upper part of the GIT, and they are mostly gram-positive facultative bacteria. Staphylococci, lactobacilli, streptococci, and several fungi are the most frequently isolated species. The colon's bacterial flora is made up of about 400 strains and is primarily anaerobic. Bacteroides, Bifidobacterium, Eubacterium, Peptococcus, Peptostreptococcus, Reminococus, Propionibacterium, and Clostridium are the most significant anaerobic bacteria.  Lactobacillus and Escherichia coli are two significant facultative bacteria in the large intestine.

1.6.5. Bacterial action in the colon 

The absorbing colon naturally contains a variety of bacteria, particularly colon bacilli.  These have the ability to break down a tiny quantity of cellulose, giving the body a few calories of nourishment every day.  Additional compounds produced by bacterial activity include thiamin, riboflavin, vitamin K, vitamin B12, and many gasses that cause flatus in the colon, including CO2, hydrogen gas, and methane [50].

Composition of the feces:

The feces typically consist of one-fourth solid matter and three-fourth water, with roughly 30% dead bacteria, 10%–20% fat, 10%–20% inorganic matter, 2%–3% protein, and 30% undigested food roughage and dried digestive juice components like bile pigment and sloughed epithelial cells. The significant quantity of fat was mostly obtained from bacterial and sloughed epithelial cell fat [51].

1.6.6. ABSORPTION OF DRUGS FROM THE COLON:

Despite its enormous width, the colon may not be the optimum place for medication absorption since the mucosa of the colon lacks the well-defined villi that are present in the small intestine, which significantly lowers the absorptive surface area. Furthermore, a drug's ability to permeate from the colon is further complicated by the high viscosity of the colonic contents, particularly after the hepatic plexure when plasma is converted to feces [52]. Several obstacles restrict the amount of medication that may be absorbed from the gut, including

• The duration of colonic residency as determined by GI tract motility 
• breakdown by bacterial by products and enzymes 
• Both selective and nonselective medication binding to dietary or intestinal bacterial metabolites
• the drug's local physiological impact and 
• The condition of the illness

Drugs are absorbed passively through transcellular or paracellular pathways. The majority of lipophilic medications are absorbed by transcellular absorption, which includes passing the drug through cells; most hydrophilic drugs are absorbed through paracellular absorption, which involves passing the drug through the tight junctions between cells. Rat studies have shown that whereas transcellular absorption seems to be limited to the small intestine and has very little colonic absorption through this pathway, paracellular absorption is consistent throughout the small intestine. The tight epithelial cell connections in the colon cause poor paracellular absorption of several medications. The most common method of absorbing lipid-soluble compounds is passive diffusion. Generally speaking, lipid-soluble undissociated forms of organic acids, bases, and medications are the ones that are absorbed the fastest. Comparing the colon to the jejunum (8A?) and ileum (4A?), the corresponding pore size is calculated to be 2.3 A?.

The colon is a more selective location for drug absorption than the small intestine due to the limited degree of paracellular transport. Glibenclamide, diclofenac, theophylline, ibuprofen, metoprolol, and oxprenolol are among the medications that have been demonstrated to have good absorption. Furosemide, piretanide, buflomedil, atenolol, cimetidine, hydrochlorothiazide, lithium, and ciprofloxacin are among the medications that have been demonstrated to have reduced absorption. The following factors decrease the oral absorption of most peptide and protein medications:

• degradation in the stomach's acidic environment. 
• breakdown by enzymes in the large and small intestine. 
• poor permeability of the mucosa. 
• quick transit of the small intestine. 
• large liver and absorption membrane first pass metabolism

1.6.7. DRUG CANDIDATES FOR COLON DRUG DELIVERY:

For the treatment of big bowel disorders and for the systemic absorption of protein and peptide medications, oral drug delivery that targets the colon specifically is growing in popularity. Selective local medicine delivery to the colon is necessary for inflammatory bowel disorders (IBD), including Crohn's disease and ulcerative colitis. The most often recommended drug for these conditions is sulfasalazine. Steroids including hydrocortisone, dexamethazone, and prednisolone are also used to treat IBD.  Compared to oral or intravenous administration, these steroids have fewer and milder adverse effects when given particularly to the colon. The potential therapeutic benefit of nicotine in the management of ulcerative colitis is now being studied. A medication called pinaverium bromide is used to treat irritable syndrome locally. If left untreated, advanced ulcerative colitis can result in colon cancer. Anti-cancer medications such as 5-fluorouracil, doxorubicin, and nimustine must be administered precisely to the colon in these situations in order to provide a safe and successful course of treatment [54].  

Metronidazole, for example, would be particularly helpful in treating infectious disorders like amoebiasis by lowering the likelihood of recurrence and limiting the negative effects of the medications' systemic absorption. Numerous protein and peptide medications, including insulin, calcitonin, interleukins, interferon, erythropoietin, and growth hormone, are being researched for systemic absorption by colon-specific administration [54].

In addition to peptides and protein medications, the colon is an excellent location for the absorption of medications that are broken down by small intestine enzymes or that are unstable in the stomach's acidic environment and cause gastric distress, such as aspirin and iron supplements. Anti-inflammatory medications are among the several medicine types that are offered in this manner. These medications' intended usage in the treatment of their respective illnesses through sustained release or timed-release formulations will be dubious unless they have adequate colonic absorption characteristics. This is because the majority of these formulations are designed to distribute their pharmacological content gradually over a 12-hour or occasionally 24-hour timeframe.

The formulation will spend little more than five to six hours in the stomach and small intestine. The medication will be removed in the feces in their natural form if it lacks the colon's natural absorption capabilities. Theophyllin, glibenclamide, oxprenolol, diclofenac, ibuprofen, brompheniramine, nifedipine, nisoldipine, isosorbide, metoprolol, and other medications with high absorption qualities from the colon can be studied for improved bioavailability by colon-specific drug administration. Nonetheless, the colon has poor absorption of furosemide, piretanide, buflomedil, atenolol, cimetidine, and hydrochlorothiazide [55].

1.6.8. APPROACHES TO COLON SPECIFIC DRUG DELIVERY:

The targeting of orally administered drug to the colon is accomplished by

i. Coating with pH dependent polymers

ii. Timed release dosage forms 

iii. Delivery systems based on the metabolic activity of colonic bacteria. 

I. Coating with pH dependent polymers

In these systems, medications are made into solid dosage forms including pellets, pills, and capsules and covered with polymers that are sensitive to pH.  Methacrylic resins (Eudragits), which come in water-soluble and water-insoluble varieties, are often utilized polymers for this purpose.  Methacrylic acid and methyl methacrylate copolymerize to form eudragit L and S.  Eudragit L is utilized as an enteric coating polymer and is soluble at pH 6 or above.  Eudragit S is used to transport medications to the end of the small and large intestines since it dissolves at pH 7 or above. The prototype core tablet was coated with three layers of pH-sensitive polymer, in that order: HPMC 2910 (barrier coating), Eudragit L-100 (enteric coating), and Eudragit E-100 (acid soluble coating).  Laboratory Development Coating System (LDCS) vectors were employed.  The weight gain of the coating was around 8%, 2%, and 6%, in that order.  This technique's drawback is that the polymer doesn't always dissolve at the intended location.

II. Timed release dosage forms:

The transit time through the small intestine is mostly unaffected by the type of formulation that is used. According to studies, the formulation reaches the ileocaecal junction around three to four hours after administration. A capsule that is half enteric coated and the other half non-disintegrating makes up this delivery method. The degree of cross-linking determines how quickly the enteric coat expands after dissolving upon entering the small intestine and a hydro plug, which stops the non-disintegrating portion [55]. After a set amount of time (for example, five hours), the hydrogel plug expands to the point where it is expelled from the capsule's non-dissolving bottom half, releasing the medication. It should be mentioned that the hydrogel plug's swelling occurs independently of pH.  Additional findings on the application of pH-dependent timed-release systems for site-specific medication release in the colon can also be found in the literature.

Water-insoluble ethyl cellulose and swellable polymer (hydroxypropyl cellulose) have also been used to create time-controlled formulations. A core, medication, swelling agent, and water-insoluble membrane made up each formulation. As the core swells, the ethylcellulose covering breaks down and the swelling agent absorbs fluids. A human bioavailability investigation revealed that this formulation had a lag time of 4±0.5 hours for absorption, which was unaffected by eating [56]. However, because to significant variance in stomach emptying durations and transit across the ileo-caecal junction, the site-specificity of timed-release dosage forms is deemed inadequate.

III. Delivery based on the metabolic activity of colonic bacteria.

Numerous metabolic reactions and hydrolysis are carried out by the intestinal bacteria. Depending on the behaviour, several tactics were employed to direct medications to the colon. These systems' site-specificity is its primary characteristic [57].

Below is a description of these tactics.

A. Coating with biodegradable azo-polymers

Because of the gut microflora's high metabolic ability, it seems that colonic bacteria generally react when azo linkages are reduced. To coat insulin and vasopressin oral dosage forms, a copolymer of styrene and 2-hydroxymethyl methacrylate was cross-linked with divinyl azobenzene and N, N1 bis (β-styrene sulphonyl)-4, 41-diaminoazobenzene. Bacterial azoreductases broke down the coat when it entered the gut, releasing the medication.

An in vivo assessment of theophylline capsules coated with azopolymers based on methacrylic acid, methyl methacrylate, and 2 hydroxyethyl methacrylate was conducted. Male rats' caecum and the proximal portion of their small intestine were used in the experiments. When the capsules were swallowed in the caecum rather than the small intestine, the drug's plasma concentration was shown to be greater [58]. It was discovered that the drug was released by both drug diffusion and bacterial azoreductases breaking down the coatings. The described colonic drug delivery system, however, was thought to be inadequate for the administration of drugs with a narrow therapeutic index for systemic effect, however it could be helpful for drugs intended for local action in the colon.

B. Prodrug 

Sulfasalazine, a well-known colonic prodrug, is used to treat Crohn's disease and ulcerative colitis. Sulfasalazine is chemically 5-aminosalicylic acid (5-ASA) bonded via azo bonding to sulfapyridine. Colonic azo reductases break down the azo bond into 5-ASA and sulphapyridine once it reaches the colon. 5-ASA is the active component, whereas sulphapyridine only serves as a carrier to transport 5-ASA to the colon undamaged [59]. The majority of sulfasalazine adverse effects are brought on by the colon's systemic absorption of sulphspyridine. Olsalazine was created to transport 5-ASA to the colon without the usage of sulphapyridine. It is made up of two 5-ASA molecules connected by an azo bond. One well-known class of enzymes that the gut microbiota produces are glycosidases. β-D-xylo-pyranosidase, α-Larabinofuranosidases, β-D-galactosidases, and β-D-glucosidase are the main glycosidases that are present in human feces. Since they are bigger and hydrophilic, prodrugs of prednisolone, dexamethasone, hydrocortisone, and fludrocortisone containing β-D-glucosides are not absorbed from the small intestine. With poly-L-aspartic acid acting as a carrier, prodrugs of steroids with a hydroxyl group at the C21 position are made. In vitro drug release investigations in rat GIT homogenates revealed that the ester prodrug of dexamethasone with poly-L-aspartic acid released dexamethasone due to bacterial enzymes cleaving the ester link [60].  

Prodrugs have some limitations 

• For dextrans, they require a carboxyl group in the drug, and for esterification with poly-L-aspartic acid, they require a hydroxyl group at position 21. 
• The majority of prodrugs can only hold 20% of their weight, hence they might not be appropriate for high-dosage medications. 
• Prodrugs are thought to be costly. 

C. Hydrogels: 

Enzymatically degradable azo aromatic cross-links and acidic co-monomers are present in the hydrogels. The gels' modest degree of swelling in the stomach's acidic pH shields the medication from being broken down by digestive enzymes. The gel swells more as it moves through the gastrointestinal tract and enters the colon, reaching a point where the cross-links are accessible to mediators (electron carriers) or enzymes (azoreductase) [61]. Following the breakdown of the cross-links, the medication is liberated from the broken gels. In vitro degradation tests in rat caecal content medium and in vivo degradation research by implanting in male rats' stomach and caecum have been used to assess the effectiveness of the hydrogels for colon-specific medication delivery.

D. Polysaccharides as carrier:

Bacteria in the colon break down natural polysaccharides like pectin and xylon, which are not broken down in the human stomach or small intestine. Numerous polysaccharides found in food can be broken down by bacterial enzymes. The colon's pH drops as a result of the bacteria's fermentation of polysaccharides into gases including hydrogen, CO2, and methane as well as short-chain fatty acids. Thus, these dietary polysaccharides may serve as non-toxic delivery systems for drugs targeted to the colon. Below is a list of many polysaccharides that are being researched for colon-specific medication delivery [62]. The endosperms of Cyamopsis tetragonolobus seeds, which belong to the leguminosae family, are ground and then partially hydrolyzed to produce guar gum, a naturally occurring polymer. In vitro techniques have been used to study a new tablet formulation for oral administration that uses guar gum as the carrier and Indomethacin as the model drug for colon-specific drug delivery. Guar gum prevents the medicine from being fully released in the physiological milieu of the stomach and small intestine, according to research on drug release conducted under conditions that replicate the mouth to colon transit [63]. Studies using rat feces in pH 6.8 PBS have shown that guar gum is susceptible to the action of colonic bacterial enzymes, which results in the release of drugs. Enzymes that particularly act on guar gum were induced by giving rats 1 milliliter of a 2% w/v aqueous dispersion of guar gum orally for three days, which increased drug release. Rat caecal contents collected seven days after treatments showed a further increase in drug release. Biphasic drug release curves were seen in the presence of 4% w/v caecal content acquired after 3 and 7 days of enzyme induction. The findings demonstrate guar gum's potential use as a colon-specific medication delivery vehicle. The study also shows that the ideal conditions for evaluating guar gum in vitro were established by using 4% w/v of rat caecal content in PBS, which was produced after 7 days of enzyme induction [64].

Pectin is a refined carbohydrate that is made from apple pomace or the inner part of the rind's diluted acid extract. The majority of the polygalacturonic acids it contains are partly methoxylated. High methoxy pectin, when used as a compression coat, shields the core tablet from breakdown and disintegration in the upper gastrointestinal system, according to in vitro research. The medication was released because the coat was vulnerable to enzymatic assault in the colon.

Inulin is a naturally occurring carbohydrate found in a variety of plants, including chicory, artichokes, onions, and garlic. According to B.P., inulin is a polysaccharide that is extracted from the tubers of Aclianthus tuberosus, Dehlia rariabilis, and other species of the compositea family [65]. When it is hydrolyzed, it mostly produces fructose. It is made up of a variety of polymers and oligomers with two to sixty or more D-fructose molecules joined by β (2-1) bonds. Inulin's resistance to hydrolysis and digestion in the upper gastrointestinal tract is widely acknowledged. It is fermented in the colon by the colonic microbiota, particularly by Bacteroids and Bifidobacteria. A potential biodegradable coating for colonic medication administration was assessed using inulin HP (high degree of polymerization) integrated into Eudragit RS film. An initial investigation into the production and properties of inulin hydrogels as a colonic drug delivery vehicle was conducted [66].

Chondroitin sulphate: The majority of mammalian cartilaginous tissues contain chondroitin sulfate, a high viscosity mucopolysaccharide that is used as a substrate by the bacteroides that live in the large intestine, primarily Bacteroides thetaiotamicron and Bacteroides ovatus. It is made up of N-acetyl-D-galactosamide and D glucoronic acid. In the human colon, eating meat and slouched epithelial cells are thought to be the natural sources of chondroitin sulfate. It has been reported that a colon-specific medication delivery system based on chondroitin sulfate and cross-linked chondroitin sulphate.

1.6.9. EVALUATION OF COLON SPECIFIC DRUG DELIVERY SYSTEMS:

A colon-specific medication delivery system that releases the drug in the colon while remaining intact in the stomach and small intestine is considered effective. To assess the colonic medication delivery system, several in vitro and in vivo techniques are employed [67].  

IN VITRO METHODS:

Drug release studies in 0.1N HCL for two hours (mean gastric emptying time) and in pH 7.4 Sorensen's phosphate buffer for three hours (mean small intestine transit time) using USP dissolution rate test apparatus or flow through dissolution apparatus are typically used to evaluate the coats'/carriers' capacity to withstand the physiological conditions of the stomach and small intestine. When using this procedure to examine tablets with pectin compression coatings, it was discovered that the medication was not released during the testing time. By incubating the medication in a buffer media with either enzyme or rat, guinea pig, or rabbit faecal material present, the delivery system's capacity to release the drug in the colon is evaluated in vitro.

1.6.10. IN VIVO METHODS:

1. Animal models:

To assess the in vivo efficacy of colon-specific drug delivery systems, various animal models are employed. A glucoside prodrug of dexamethasone was utilized to test colon-specific drug delivery in guinea pigs. Rats and pigs are two more animal models that are employed for the in vivo assessment of colon-specific drug delivery systems. Methods for tracking how human colon-specific delivery devices behave in vivo: The in vivo behaviour of the oral dose form is monitored using a number of methods, including (a) string technique, (b) endoscopy, (c) radiotelemetry, (d) roentgenography, and (e) gamma scintigraphy [68,69].

1.A. String technique:

The patient in this research swallowed a pill that was fastened to a length of thread, leaving the free end of the string hanging from his lips. By removing the thread and manually inspecting the tablet for indications of breakdown, the tablet was removed from the stomach at different intervals. A vomiting response was used in several experiments to recover the pills. The GI tract's motility and physicochemical environment may change if a foreign item, such a string, is present. The GI tract's motility is further impacted by the psychological strain and worry that come with this approach.

1. B. Endoscopic technique:

This optical method uses a fiber scope (gastroscope) to immediately observe how the dose behaves after consumption. To make it easier to swallow the endoscopic tube, a slight sedative must be administered. The sedative itself may change GI motility and stomach emptying. The GI tract's altered motility is also influenced by psychological variables.

1.C. Radio telemetry:

This method entails administering a capsule that contains a tiny pH probe interfaced with a tiny radio transmitter that can broadcast a signal indicating the pH of the surrounding environment to an external antenna that is fastened to the subject's body. The behaviour of the dosage form under study may therefore be impacted by the physical attachment of the dosage form to the capsule. Additionally, a sizable quantity of buffer salt must be included in the dosage form. When this salt is released, the pH of the gastrointestinal tract changes, which the pH capsule detects as a result of the dosage form change. This makes it impossible to evaluate commercially available products without buffer salt.

1. D. Roentgenography:

An X-ray can be used to see a solid dosage form when a radio-opaque substance is added to it. When barium sulfate is added to pharmaceutical dosage forms, it becomes feasible to monitor the dosage form's movement, position, and integrity following oral administration by putting the person under a fluoroscope and obtaining a series of X-rays at different intervals. Using barium sulfate as a radio-opaque substance, this method was utilized to assess a capsule dosage form coated with Eudragit S® to carry oral ingested medications to the colon. Because several photos must be taken, using an X-ray exposes the patient to a rather high radiation exposure. Continuous information gathering is not possible.

1. E. Gamma scintigraphy:

External scintigraphy, often known as gamma scintigraphy, is now the most effective method for assessing the in vivo behavior of dose forms in both people and animals. In order to track the in vivo behavior of dose forms, work in this field started in the 1970s by altering conventional nuclear medicine techniques. For gamma scintigraphy to work, the dose form must contain a γ-emitting radioactive isotope that an external gamma camera can detect in vivo. Neutron activation techniques or traditional labeling techniques can be used to radiomark the dose form. Gamma scintigraphy is the most popular non-invasive approach among all of these methods for examining how oral dose forms behave in vivo under typical physiological settings. Gamma scintigraphy has the following advantages over previous techniques: (a) it exposes participants to very little radiation, unlike reontgenography (X-rays); (b) it provides both qualitative and quantitative results, which other techniques cannot; (c) it is completely non-invasive; and (d) it enables in vivo evaluation of dosage forms under typical physiological conditions.

2. AIM AND OBJECTIVE

AIM: The aim of the present study is to formulate a pharmaceutically stable and quality improved formulation of Prednisolone enteric coated for treating against bacterial infections.

OBJECTIVE:

• Prednisolone dosage form design and formulation for targeted colon administration.
• Design and assessment of a dosage form that is reliant on time.
• The creation of core and enteric press-coated tablet formulations.
• In order to do this, a number of prototype formulation experiments will be conducted and assessed in relation to several quality control tests, including assay and dissolution.
• The invitro dissolution parameters will be used to finalize the recipe.
• In order to treat some colonic disorders including ulcerative colitis and irritable bowel syndrome, it is important to reduce the impact of the stomach emptying time on medication release and ensure that the tablet may pass through the small intestine undamaged.

3. MATERIALS AND METHODS

3.1. Materials

Table 3: List of materials

3.2. EQUIPMENT’S

Table 4: List of equipment’s

3.3. METHODS:

3.3.1. PREFORMULATION STUDIES

The physical and chemical characteristics of a drug ingredient, both by itself and in combination with additional compounds like excipients, are examined through pre-formulation research. It is the initial phase in the logical creation of dosage forms [79].

Objective: The main goal of pre-formulation testing is to produce data that will be useful in creating a stable and bioavailable dosage form that can be mixed with excipients.

Scope: Using pre-formulation criteria increases the likelihood of creating a product that is acceptable, safe, effective, and stable while also serving as the foundation for improving the quality of the medicinal product.

Determination of λ_max of Prednisolone

Standard Stock Solution: 100 milli litters of pH 6.8 phosphate buffer (1000 μg/ml) were used to dissolve 100 milligrams of prednisolone.

Scanning: A UV scan was performed between 200 and 400 nm using the stock solution, which contained 10μg/ml of methanol. For the further analytical investigations, the absorption maximum, which was determined to be 243 nm, was utilized.

Prednisolone calibration curve in 0.1N HCl

To obtain concentrations of 2, 4, 6, 8, and 10 μg/ml, the relevant aliquots from the standard stock solution (1000 μg/ml) were transferred to a series of 10 ml volumetric flasks and brought up to 10 ml with 0.1 N HCl. At 243 nm, the solution's absorbance was measured. To validate the calibration curve, this process was carried out in triplicate. Figure No. displays a displayed calibration graph [80].

Making a phosphate buffer at 6.8 pH

In enough water to make 1000 milli-litters, dissolve 28.80 grams of disodium hydrogen phosphate and 11.45 grams of potassium di hydrogen phosphate.

To obtain concentrations of 2, 4, 6, 8, and 10 μg/ml, the relevant aliquots from the standard stock solution (1000 μg/ml) were transferred to a series of 10 ml volumetric flasks and made up to 10 ml with 6.8pH phosphate buffer. At 243 nm, the solution's absorbance was measured. To validate the calibration curve, this process was carried out in triplicate. Figure No. displays a displayed calibration graph [81].

Compatibility studies

The medicine and one or more excipients are in close contact with coated tablets, which may have an impact on the drug's stability. Therefore, choosing the right excipients requires an understanding of how drugs interact with excipients. Drug-excipient compatibility studies and Fourier transform infrared spectrophotometry (FT-IR) were used to investigate this.

FLOW PROPERTIES

Angle of Repose:

The Angle of Repose was measured in order to ascertain the flow property. The angle of repose was calculated to ascertain the flow property. It is the greatest angle that may be formed between a powder heap's free-standing surface and the horizontal [82].

Angle of repose= tan-¹ (h/r)

where, 

h = height of a pile (2 cm)

r = radius of pile base.

Procedure:

• 20 grams of the material were extracted.
• To create a heap, the sample was gradually moved through the funnel.
• The height of the resulting powder pile was measured.
• Using a pencil, the produced circumference was sketched on the graph paper.
• The angle of repose was calculated by measuring the radius. For a sample, this was done three times.

Bulk density:

The ratio of a powder's mass to its bulk volume is called its bulk density. By measuring the volume of a known mass powder sample that was fed through a screen into a graduated cylinder or via a volume measuring device into a cup, the bulk density was ascertained.

Bulk density = M / V0

Where M= mass of the powder;

           V0=bulk volume of the powder.

Limits:

It has been said that excellent packing is indicated by bulk density values less than 1.2 g/cm3, whereas bad packing is indicated by values larger than 1.5 g/cm3.

Tapped density:

Volume V₀ was recorded after a known amount of powder was transferred to a graduated cylinder, which was then fixed to a device for determining density. The cylinder was tapped 500 times before the reading was recorded. The density is determined by mechanically tapping the cylinder with a measuring cylinder that contains the powder sample. Following the observation of the initial volume, the cylinder is mechanically tapped, and volume readings are taken until minimal additional volume changes are observed [83].

Tap density = M / Vr

Where M = mass of the powder, 

            Vr = final tapping volume of the powder.

Compressibility index and Hausner ratio:

The following formula may be used to get the compressibility index and hausner ratio using the observed values of bulk density and tapped density:

Compressibility index = 100 × tapped density / bulk density

Hausner ratio = tapped density / bulk density

Flow properties and corresponding Angle of repose, Compressibility index and Hausner ratio:

Table 5: Acceptance Criteria of Flow Properties

Angle of repose:

The funnel technique was used to calculate the powder blend's angle of repose. A funnel was used to collect the precisely weighed powder. The funnel's height was modified such that its tip just brushed the top of the powder pile. The powder cone's diameter was measured, and the equation was used to determine its angle of repose [83]. 

Tan θ = h/r

Where h and r are the height of pile and radius of the base of pile.

Different ranges of flowability in terms of angle of repose are given below in the table

Table 6: Relationship between Angle of Repose (θ) and flow properties

FORMULATION DEVELOPMENT OF PREDNISOLONE ENTERIC COATED TABLETS

Table 7: Compilation of Prednisolone core Tablets

FORMULATION FOR ENTERIC PRESS COAT

Table 8: Composition table

PREDNISOLONE CORE TABLETS

Wet granulation was used to create enteric-coated prednisolone pills.

1. Pass half of the disintegrant and prednisolone through sieve #30 mesh.

2. Pass MCC through a sieve with a mesh of #30 mesh.

3. Sift the materials from Steps 1 and 2 through #30 mesh.

4. Fill the blender with the ingredients from step three and blend for half an hour.

5. Use the binder solution (starch + water) to granulate the aforesaid mix. The resulting granules were then dried and sieved.

6. Half of the disintegrants were combined with dried granules.

7. Fill the blender with the materials from step 5 and blend for five minutes.

8. Use 9mm round punches to compress the mixture into tablets.

Formulation of mixed blend for barrier layer:

Using the direct compression method, the varied formulations including ethylcellulose and HPMC in various compositions were weighed, dry mixed, and employed as press-coating material to create press-coated tablets, accordingly, after around ten minutes [84].

Preparation of press-coated tablets:

As shown in the table, 200 mg of the blended mixture was press-coated onto the core tablets.  After weighing and transferring 100 mg of barrier layer material onto a 12 mm die, the core tablet was manually positioned in the middle.  Using a KBr hydraulic press, the remaining 100 mg of the barrier layer material was put into the die and squeezed for three minutes at a pressure of five tons.

Preparation of enteric coating solution:

Polymer solution was prepared with HPMC phthalate, myvacet and colour in ethanol as solvent.

EVALUATION OF TABLETS:

The quantitative examination and assessment of a tablet’s chemical, physical and bioavailability qualities are vital in the design of tablets and to monitor product quality. Regarding the quality of pharmaceutical tablets, different pharmacopoeias have established different requirements. The diameter, size, form, thickness, weight, hardness, and dissolution and disintegration characteristics are among them [85].

1. Physical Appearance:

Consumer acceptability, lot-to-lot consistency, and tablet-to-tablet uniformity are all dependent on a tablet's overall look, identity, and elegance. Measurements of size, form, colour, odour, taste, and other characteristics are all part of the regulation of overall appearance.

2. Size & Shape:

It is controllable and dimensionally characterized. A tablet's thickness is only a variable. A micrometer or another tool can be used to measure the thickness of tablets. The thickness of tablets should be kept within a standard deviation of ± 5%.

3. Weight variation test:

These weight variation tests are specified by various pharmacopoeia and are an in-process quality control test to make sure the manufacturers control the variation in the weight of the compressed tablets. Comparing the weight of each pill in a sample with an upper and lower percentage limit of the observed sample average is the main basis for these tests. The average weight of compressed, uncoated tablets has been set by the USP. These are relevant when the tablet contains 50mg or more of the drug substance or when the latter comprises 50% or more, by weight of the dosage form.

Method:

After calculating the average weight of twenty tablets, the weights of the individual tablets were compared to the average weight; no tablet's average weight should differ by more than twice the relevant percentage, and no two tablets' average weights should differ by more than the percentages specified in the USP.

Table9: Limits for Tablet Weight Variation Test

4. Content Uniformity:

The purpose of the content uniformity test is to make sure that each tablet in a batch has the same quantity of the medicinal component. The content uniformity test has been incorporated into the monographs of all coated and uncoated tablets as well as all capsules meant for oral administration, when the available dosage form sizes vary from 50 mg or smaller, as a result of heightened awareness of physiological availability.

Method:

Choose 30 pills at random. Ten of these were tested separately. If nine out of ten tablets have at least 85% and no more than 115% of the drug's listed content, and the tenth tablet has at least 75% and no more than 125% of the declared content, the tablet passes the test. The remaining 20 pills will be analyzed separately if these requirements are not fulfilled, and none of them may fall beyond the 85–115% range.

5. Thickness and diameter:

Using vernier callipers, the diameter and thickness of ten tablets were measured as they were being compressed.

6. Hardness:

Determinations of hardness, or more accurately, crushing strength, are made during tablet manufacturing and are used to assess if the tablet machine needs to have its pressure adjusted. If the tablet is too soft, it might not be able to survive handling during later processing, including coating or packaging and shipping operations; if it is too hard, it might not dissolve in the time needed to fulfil the dissolving requirements. The kilos represent the force needed to shatter the tablet. When the force produced by a coil spring is applied diametrically to the tablet, the compact and portable hardness tester calculates the force necessary to shatter the tablet [85].

7. Friability:

Tablets most frequently chip, cap, or shatter due to friction and stress. The friability test, which assesses the tablet's resistance to abrasion during handling, shipping, and packing, is closely linked to tablet hardness. The Roche friabilator is typically used to measure it.

Method:

After being weighed, many tablets are put into the device, where they are subjected to rolling and repeated shocks while falling six inches each time. The pills are weighed after 100 rotations or four minutes of therapy, and the weight is compared to the starting weight. One indicator of tablet friability is the amount lost as a result of abrasion. A percentage is used to express the value. Any broken or shattered tablets are not chosen, and a weight loss of no more than 1% of the weight of the tablets undergoing the friability test is deemed typically acceptable.

The percentage friability was determined by the formula:

% Friability = (W1-W2) / W1 X 100

W1 = Weight of tablets before test

W2 = Weight of tablets after test

8. Disintegration test (RRCT):

After oral administration, a medication must first be in solution in order to be absorbed from a solid dosage form. Disintegration, or the breaking up of the tablet, is often the first crucial step toward this state. The disintegration test calculates how long it will take for a batch of pills to break up into particles that can fit through a 10-mesh screen under specific circumstances. For traditional dosage forms, the test is often helpful as a quality assurance tool [86].

Method:

Six glass tubes with an open top and a 10-mesh screen at the bottom are used in the U.S.P. apparatus to evaluate disintegration. One tablet per tube is used to test the disintegration time, and the basket rack is set up in a 1-L beaker of water, simulated gastric fluid, or simulated intestinal fluid at 37 ± 20C so that the tablet stays 2.5 cm below the liquid's surface when it moves upward and stays no closer than 2.5 cm from the beaker's bottom when it moves downward. At a rate of 28 to 32 cycles per minute, move the basket with the tablets up and down a distance of 5 to 6 cm. Putting perforated plastic discs on each pill will stop them from floating. The test requires that the tablet break up and that every particle flow through the 10-mesh screen within the allotted time. Any residue that is left over ought to have a soft bulk. Twelve pills are used for the test if one or two do not dissolve.

Disintegration time: Uncoated tablet: 5-30 minutes.

Coated tablet: 1-2 hours

9. In-vitro release studies for RRCTs

The LABINDIA TS 8000 USP dissolving test device was set up to run at 50 rpm for one hour after the tablet was placed in its basket. Five millilitres of sample were taken out every five minutes and refilled with pH6.8 phosphate buffer solutions. Using buffer solution as a blank, the extracted samples were examined for the presence of medication at 243 nm using a UV spectrophotometer [87].

Dissolution parameters for RRCTs:

Apparatus -- USP-II, Paddle Method

Dissolution Medium -- pH6.8 Phosphate buffer

RPM -- 50

Sampling intervals (min) -- 5, 10, 15, 20, 30, 45, 60 min.

Temperature -- 37 + 0.5°C

In-vitro Dissolution methods for Enteric press-coated tablets

The traditional paddle technique of press-coated tablets was used for in vitro dissolution investigations of colon targeted drug delivery systems. The tablets were made at 37 ± 0.5 °C with 0.1N HCL in the USP II paddle method at 50 rpm for the first two hours, and then pH6.8 phosphate buffer was added. At prearranged intervals, 5 ml of the filtered aliquot was manually removed and replaced with 5 ml of brand-new buffer solution that was kept at the same temperature [88]. The samples were examined using a UV spectrophotometer set at 243 nm. Each formulation's lag time and % release were calculated.

Dissolution parameters for enteric press coated tablets:

Apparatus -- USP-II, Paddle Method

Dissolution Medium – first 2 hours 0.1 N HCl

pH6.8 Phosphate buffer

RPM -- 50

Sampling intervals (min) -- 5, 10, 15, 20, 30, 45, 60 min.

Temperature -- 37 + 0.5°C

Stability Studies:

In accordance with ICH requirements, the formulations' stability research was conducted for three months at 40 ± 2o C/75 ± 5% RH while the samples were kept in a stability chamber (Lab-care, Mumbai).  Stability tests are used to demonstrate the quality of a drug substance or drug product and how it changes over time in response to various environmental factors (heat, humidity, light, air, etc.). The finished mixture was packaged appropriately, such as in blister and strip packs, and will be stored at various temperatures and humidity levels while the samples' physical and chemical characteristics are examined.

STABILITY STUDIES STORAGE CONDITIONS

Table 10: Stability studies Storage conditions

4. RESULTS AND DISCUSSION

4.1. Analytical methods

Table 11: Calibration curve plot in 0.1N HCl

Figure 10:  Calibration curve plot of Prednisolone in 0.1 N HCl

Table 12: Calibration curve plot in pH6.8 Phosphate buffer

Figure 11: Calibration curve plot of Prednisolone in pH6.8 Phosphate buffer

4.2. Pre-Compression Characteristics

4.2.1. Evaluation of blend characteristics:

Wet granulation was used to create prednisolone pills. Pre-compression properties such as Hausner's Ratio, bulk density, tapped density, compressibility index, and angle of repose were assessed for the granules.

4.2.2 Blend properties of different formulations 

Table 13: Blend properties of different formulations

Angle of repose:

The flow property was determined to be satisfactory, and the angle of repose values for batches F1 through F9 lie between 25 and 30.

Bulk and Tapped Density:

The formulated blend's bulk density value was found to be within the range of 0.3 gm/ml, while the tapped density was determined to be within the range of about 0.4 gm/ml.

Compressibility index:

For batches F1–F9, the flow property was determined to be excellent, and the percentage compressibility was found to be within the range of 15.

Hausner’s ratio:

For batches F1 through F9, the Hausner's ratio value is between 1.14 and 1.16, indicating good flow properties.

4.3. Post Compression Studies:

Table 14: Post Compression Studies

Hardness:

For batches F1 through F9, the hardness was kept between 4.1 and 4.8 kg/cm2. 

Percentage friability:

For the formulated batches F1 through F9, the percentage friability was determined to be within the range of NMT 1% w/w.

Assay:

The assay value for the entire formed batch from F1–F9 was determined to be between 90 and 110 percent.

Weight variation:

All of the formed batches F1 through F9 had weight variation values that fell within the allowed 5% range.

Disintegration time:

By altering the disintegrant's concentration, the disintegration times for the formed batches F1–F9 utilizing various super disintegrants range from 2 minutes 48 seconds to 1 minute 10 seconds.

4.4. Dissolution profile of different formulations

Table 16: Dissolution profile of different formulations

Figure 12: Comparison of dissolution curves of all the formulated batches

Crospovidone XL's concentration was optimized in the F7 formulation, which was shown to have good flow properties and release 99.5% of the medication after 30 minutes.

4.5. EVALUATION PARAMETERS FOR ENTERIC PRESS COATED TABLETS

DISSOLUTION STUDY FOR ENTERIC PRESS COATED TABLET

Table 17: Dissolution profile for Prednisolone tablets