Formulation Development and Evaluation of Calcium and Vitamin C Effervescent Tablet

Medicines are not only a science; it is also an art. Solid dosage forms, especially tablets, are the most popular among all administrated medicaments. Tablets contain quantity of drug which is given as a single unit and they are collectively known as solid unit dosage forms. About 70% of the total medicines are dispensed in the form of tablets.^(1,2)

1.1 Tablets:

A tablet is a solid oral dosage form used in pharmaceuticals. According to the Indian Pharmacopoeia, it is a compact unit created by compressing one or more drugs, with or without diluents. Tablets can vary widely in shape, size, and weight, depending on the medicinal content and the intended method of administration. Different types of tablets available in market are conventional tablet, repeat action tablet, delayed release tablet, sugar coated tablet, film coated tablet, chewable tablet, buccal tablet, sublingual tablet and effervescent tablet. It is simple for administration, lower price of production, and elegance. Tablets contain one or more active ingredients. They have contained excipients such as diluents, binders, disintegrating agents, glidants, lubricants, flavours and sweeteners^.(3,4)

1.1.1 General properties of Tablets:

1. It is a refined product with a distinct identity, designed to be flawless and free from imperfections like chips, cracks, discoloration, or contamination.⁽⁴⁾
2. It maintains both physical and chemical stability, ensuring its properties remain consistent over time.
3. It is strong and tough, able to handle mechanical shocks during making, packing, shipping, dispensing, and use.
4. Tablets are uniform in weight and in drug content.⁽⁵⁾

1.1.2 Advantages of Tablets:

• • Accuracy in dose
  • Enhanced biological activity, along with maintained physical and chemical stability.
  • Easy to administered.
  • Cost-effective manufacturing on a large scale.
  • Lighter and compact.
  • They are easiest and cheapest to package and strip.⁽⁶⁾
  • Sustained release product is possible by enteric coating.

1.1.3 Disadvantages of Tablets:

• • Challenging to swallow in case of children and geriatric patients.
  • Drugs that absorb moisture easily are not suitable for compressed tablets.
  • Oxygen sensitive drug require special coating.
  • Some medicines show gastric irritation while administered in tablet form.
  • Low density and amorphous APIs are difficult to compress in tablet press.
  • Possibility of bioavailability problems resulting from slow disintegration and dissolution.⁽⁷⁾

1.3 Introduction to effervescent tablets:

Effervescent tablets are specially formulated to dissolve in water, releasing carbon dioxide to create a fizzy solution. They are produced by compressing powdered ingredients into solid tablets, which are then stored in blister packs or airtight containers with desiccants to prevent moisture exposure. When dropped into water, they quickly dissolve, forming a drinkable solution. These formulations can also be found as effervescent powders or granules, often undergoing granulation before being shaped into tablets. Their popularity is rising in industries such as pharmaceuticals and dietary supplements due to their ease of consumption. Designed to dissolve instantly in liquids like water or juice, they offer a convenient and enjoyable intake method.^(8,9) Effervescent tablets are widely favored by individuals using them for medicinal purposes or as dietary supplements. The reaction between citric acid and sodium bicarbonate, as well as tartaric acid and sodium bicarbonate, leads to the release of carbon dioxide, as demonstrated below.

C6H8O7.H2O+3NaHCO3 _(Aq) → Na3C6H5O7 + 4H2O + 3CO2 (g) ↑

Citric acid + Sodium bicarbonate → Sodium citrate + Water + Carbon dioxide

C4H6O6 + 2 NaHCO3→ Na2C4H4O6 + 2H2O + 2CO2 (g) ↑

Tartaric acid + Sodium bicarbonate → Sodium tartrate + Water + Carbon dioxide

Fig. 1.1 Effervescent tablets in water

1.3.1 Benefits of effervescent tablets: 

• • Quick absorption and effect. 
  • No need for swallowing. 
  • Gentle on the stomach and intestines. 
  • Convenient to carry.⁽¹⁰⁾

1.3.2 Drawbacks of effervescent tablets: 

• • Some active ingredients may have an unpleasant taste. 
  • Larger tablet size necessitates specialized packaging. 
  • Production costs are higher due to the need for various excipients and specialized facilities. 
  • A clear solution is generally preferred for consumption, though fine dispersion is widely accepted.^(11,12)

1.3.3 Effect of water on effervescent formulations:

Even a small amount of water can trigger the reaction. Since water is also produced during the process, it speeds up the reaction. To ensure stability, effervescent products are manufactured and stored with minimal exposure to water.^(12,13)

1.3.4 Drugs that can be manufactured in effervescent products:

Medications that meet the mentioned criteria can be formulated as effervescent products. This delivery method offers several advantages and can be particularly useful in pain management therapies.^(13–14)ulcers,allergies^(14,15), osteoporosis, arthritis, inflammation, antimicrobial infections and many other conditions. aspirin, paracetamol, Ibuprofen,  and other vitamins, cal. carbonate, and other antacids like ranitidine, famotidine, etc. are examples of this.^(16,17,18)

1.3.5 Preparation of effervescent tablets:

An effervescent tablet consists of three main components -

• Active component
• Acid source
• Alkaline compound (mainly carbonate or bicarbonate)

The acid and alkali are essential elements that enable the tablet to effervesce and dissolve upon contact with water. Citric acid, available in both hydrated and anhydrous forms, is the most commonly used acidic component. However, other edible acids like tartaric acid, fumaric acid, adipic acid, and malic acid can also be utilized .

The carbonate, which generates carbon dioxide for effervescence, is typically a water-soluble alkaline compound. Its selection is crucial, as it not only facilitates effervescence but also impacts tablet stability. Due to its affordability and high solubility, sodium bicarbonate is one of the most commonly used options. Other suitable alkaline or alkaline earth metal carbonates include potassium carbonate or bicarbonate, calcium carbonate or bicarbonate, sodium carbonate, and sodium glycine. Additional components such as buffering agents, ligands, sweeteners, and coloring agents may also be included.^(19,20)

1.3.5.1 Acid source:

Food acids, acid anhydrides, and acid salts are the three main acid sources.

A. Food acids:

Food acids are the most widely used since they occur naturally and are ingestible.

1. Citric acid -

Citric acid is the most commonly used food acid because it is abundant, relatively inexpensive, has good solubility, and has a pleasing flavour. Citric acid comes in both monohydrate and unhydrate forms. It is sold as colourless, transparent crystals or as white crystalline powder. Citric acid is widely accessible in fine granular, free-flowing powder forms with various particle sizes such as coarse, medium, fine, and so on. It has no odour and a harsh acidic flavour. It is soluble in both water and alcohol. It creates solutions with a citrus flavour. Because it is highly hygroscopic, efforts must be taken to avoid exposure during manufacturing and storage^.(18,19) The monohydrate form is more hygroscopic than the anhydrous form. When stored at humidity levels above 70% RH, the anhydrous form has a tendency to cake. Citric acid monohydrate absorbs insignificant amounts of moisture between 65 and 75% relative humidity, but significant amounts are absorbed above these humidity levels, whereas citric acid unhydrate absorbs insignificant amounts of moisture between 25 and 50% RH and significant amounts between 50 and 75% RH, with the formation of monohydrate form. The monohydrate melts at 100°C and releases crystallization water at 75°C, making it suitable for use as a binder source in hot melt granulation.(18,19,20)

b) Tartaric acid-

Effervescent tablets frequently contain tartaric acid because it is an easily available commercial substance. With 1 part acid to less than 1 part water, it is more soluble than citric acid. It is offered as either white crystalline powder or colourless monoclinic crystals. It has no smell and a rather sour flavour. Additionally, it is more hygroscopic than citric acid and becomes deliquescent at RH levels above 75%. It is just as potent as citric acid, but because it is diprotic as opposed to triprotic, bigger doses must be required to reach equal acid concentrations in the effervescent process. Tartaric acid is similar to citric acid in terms of compressibility^.(21,22)

c) Ascorbic acid-

Ascorbic acid is a white to light yellow, crystalline powder that has no fragrance and a harsh acidic taste. It is readily soluble in both alcohol and water (1 in 3.5). Ascorbic acid and anhydrous citric acid responded similarly when it came to the production of carbon dioxide from effervescent tablets based on these acids, ascorbic acid, tartaric acid, and sodium bicarbonate. The majority of carbon dioxide was produced by tartaric acid, although it took longer to disintegrate. The ascorbic acid gradually darkens when exposed to light. Since ascorbic acid is less hygroscopic than tartaric and citric acid, making effervescent tablets is made easier. Ascorbic acid usage reduces the necessity for strict air and temperature controls during manufacturing. ^(22,23)

d) Fumaric acid -

Fumaric acid is found as a crystalline powder or white, odourless or virtually odourless granules. It is a potent acid that is essentially non-hygroscopic and very cost-effective. It’s extremely low water solubility (about 1 in 33 at 20°C) creates a challenge in the manufacturing of effervescent tablets. Salts with higher water solubility, like monosodium or potassium fumarate, can be utilized to make fumaric acid. Some formulations make use of fumaric acids lubricating characteristics to reduce the need for additional lubricants^.(24,25)

e) Malic acid -

Malic acid is sold as a crystalline white powder. It tastes very acidic and has a faint aroma. Additionally, it is easily soluble and hygroscopic. When mixed with a carbonate source, it has an acid strength that is lower than citric acid but strong enough to generate enough effervescence. Malic acid is more expensive than citric acid but can be employed in effervescent recipes for a smoother aftertaste.⁽²⁶⁾

f) Adipic acid

Adipic acid is sold as a white crystalline powder and is almost completely non hygroscopic, but it also dissolves in water much less readily than citric acid. Additionally, it cost less and is less readily available. It has been claimed that this acid is having lubricating qualities. ^(27,28)

g) Succinic acid

Succinic acid comes as shiny, odourless, white crystals or powder. It is also used as a flavouring agent. It is also dissolved in water but less readily than citric acid. ⁽²⁹⁾

B. Anhydrides of Acid

When acid anhydrides and water are combined, the corresponding acid is hydrolyzed. They can provide prolonged high-volume effervescence due to ongoing acid generation if the rate of hydrolysis is controlled. Commonly utilized anhydrides include succinic and citric anhydrides.(46) A denture soak formula has been created using succinic anhydride. Additionally, they function as internal desiccants, which lessens a tendency for caking. Although glutamic anhydride has been employed, there were issues due to the taste of glutamic acid. Because it will result in an earlier conversion of acid anhydride to acid, water cannot be employed in the production of products containing acid anhydrides^.(30,31)

C. Salts of Acid

The following are examples of commonly used acid salts:

1. Monosodium phosphate (sodium dihydrogen phosphate)

Both granular and powdered versions are offered. It dissolves easily in water. It easily combines with carbonates and bicarbonates to produce effervescence after dissolving in water.

b) Disodium dihydrogen pyrophosphate (sodium acid pyrophosphate)

This acid salt is similarly easily accessible, soluble in water, and has been employed in the manufacture of effervescent tablets.^(32,33)

c) Salts of acid citrate

Both disodium hydrogen citrate and sodium dihydrogen citrate easily dissolve in water and yield acidic solutions. Both of them were utilized in effervescent tablets.

d) Hydrochlorides of amino acid

Amino acid hydrochlorides quickly release acid in solution, and this reaction has been employed in effervescent electrolyte replacements to prevent unfavorable electrolyte concentrations. These materials are both costly and hygroscopic^.(33,34)

e) Sodium acid sulphite

Although sodium acid sulphite or sodium bi sulphite forms an acid solution, it is not safe to consume. It can also be employed in effervescent formulations for various purposes, such as toilet cleaners. Because it is a strong reducing agent, it is incompatible with oxidising agents.(35,36)

1.3.5.2 Alkaline compound:

The alkaline substance is a crucial component of effervescent reactions in addition to the acidic source. Effervescence is provided by dry, solid carbonate and bicarbonate salts in most effervescent tablets. Bicarbonates are more reactive than carbonates and are utilized more frequently.⁽³⁷⁾

a) Sodium bicarbonate:

Sodium bicarbonate has a saline, slightly alkaline taste and is an odourless, white crystalline powder. It comes in five different grades of particle size, ranging from tiny powders to freely flowing granules. At 20°C, it dissolves in water 1 in 11 parts. It is abundant, cheap, and non-hygroscopic. ^(38,39) Of all the sources of bicarbonate, it is the one that is utilised the most. It can be consumed and is frequently combined with other substances to act as an antacid. By weight, it produces around 52% carbon dioxide. With a pH of 8.3 in an aqueous solution with a 0.85% concentration, it is the least acidic of all alkalies. Due to its lack of elasticity, it causes issues when compressed. Spray drying technology was employed in the manufacturing process to help sodium bicarbonate overcome its poor flowability and low compressibility. There is also immediately compressible sodium bicarbonate that has been spray-dried and contains additives like silicon oil and polyvinyl pyrrolidone. This product has good stability and compressibility^.(38)

If any moisture is present, normal sodium bicarbonate products, which are very unstable, will react with the acid component of an effervescent formulation. As a result, the manufacturing company faces a problem since it must handle, produce, and package the product in a humidity-controlled environment to reduce the risk of early effervescent reaction and ruination. The sodium bicarbonate must frequently be pre dried before use in order to remove extra moisture and prevent reactivity. Many of these issues can be prevented by using Effer-Soda Sodium Bicarbonate^.(39) Effer-Soda It becomes a more stable form of sodium bicarbonate when it is dried and partially desiccated to boost its stability. It has a core of sodium bicarbonate and sodium carbonate as "desiccant skin" that has been added during manufacturing. In terms of  bulk, this "desiccant skin" accounts for 8–12% of Effer-Soda. By absorbing moisture to create a hydrated salt (sodium sesquicarbonate), which is stable up to 70°C, this sodium carbonate outer layer creates a barrier that safeguards the sodium bicarbonate core. The sodium carbonate outer layer dissolves when a lot of moisture is added to a glass of water by an effervescent tablet or powder, releasing the sodium bicarbonate for interaction with the acid component^.(40)

b) Sodium carbonate:

In effervescent tablets, sodium carbonate, commonly referred to as soda ash, can serve as a source of carbon dioxide. Due to its high pH of 11.5 in an aqueous solution of 1% concentration, it is also employed as an alkalizing agent. It is very soluble in water. Commercially, sodium carbonate is offered in anhydrous, monohydrate, and di carbohydrate forms. It is present in colourless, white crystals^.(49) Due to its capacity to absorb moisture and stop the start of an effervescent reaction, an anhydrous form is chosen. It also functions as a stabilising agent and is more effervescent response resistant.⁽³⁹⁾

c) Potassium bicarbonate and potassium carbonate:

Although more expensive than their sodium counterparts, potassium bicarbonate and carbonate are more soluble than their sodium counterparts. They are employed when sodium ion is unwanted or needs to be restricted, such as in antacids where dosing is based on the recommended daily intake of salt. While potassium carbonate is hygroscopic at RH above 2% and deliquescent at more than 40%RH, potassium bicarbonate absorbs significant amounts of water above 80% RH. There are also few commercially available forms. According to reports, potassium carbonate (2% in an effervescent dosage form) acts as a desiccant and may withstand total moisture levels of up to 0.4% w/w while still preventing the degradation of the effervescent base^.(40,41)

d) Sodium sesquicarbonate:

Equimolar quantities of sodium carbonate and sodium bicarbonate are combined with twice as much water to form sodium sesqui-carbonate^.(17) It has a pH of 10.1 in a 2% solution and is soluble in water. The laundry sector is where it is largely used. However, sodium sesquicarbonate is not favoured over sodium bicarbonate and sodium carbonate mixes, and its dihydrate form also has stability issues.

e) Sodium glycine carbonate:

Glycine and sodium carbonate are combined to form sodium glycine carbonate. It has less alkalinity and is more water-soluble. It is stable, heat-resistant, and non- hygroscopic. Its limited production of carbon dioxide only around 18% by weight is a drawback. While sodium glycine carbonate only produces about 95 ml of carbon dioxide per gram, sodium bicarbonate releases about 270 ml per gram. Since sodium bicarbonate is one of the raw materials used in the production of sodium glycine carbonate, it is also significantly less expensive than sodium glycine carbonate. It was discovered that using a combination of specific acids, such as fumaric acid and malic acid with sodium glycine carbonate, enables the direct compression of effervescent tablets in a typical environment^.(40) with great carbonation that are highly pleasant and free of sodium ions.^(41,42)

1.3.5.3 Other excipients:

a. Diluents:

In effervescent goods, diluents are typically not required. Typically, sufficient amounts of the effervescent components themselves are present to provide the appropriate tablet mass. Sodium bicarbonate is the preferred ingredient if a denser tablet is needed due to its low cost, lack of impact on pH change, and enhanced effervescent reaction. Other easily soluble materials, such as sodium chloride and sodium sulphate, can be employed. They display good compatibility with the components of the effervescent reaction and are high-density crystalline powders. The diluents employed must have high water solubility, particle sizes that are comparable to those of other effervescent components, and good compressibility. Diluents can also be chosen from sorbitol, mannitol, or combinations of these, and spray-dried lactose is another popular option. Spray-dried lactose is especially preferred as a diluent because it makes the blend flowable and enhances the formulation's compressibility and tablet ability.⁽⁴³⁾

b. Binders:

Binders are included in traditional tablets to help create a granulation that is appropriate for tablet compression. Binders are typically added to tablets to slow down the tablet's quick-dissolving. If a binder is employed, it must also be entirely soluble in water and leave no trace of an insoluble substance. Additionally, it must have little remaining moisture. Given their low water solubility or high residual water content, binders like gelatine, starch paste, and natural and cellulose gums are not very effective. Effervescent tablet binders such as polyvinyl pyrrolidonework well. You can add it as a dry powder or a wet aqueous, alcoholic, or hydroalcoholic solution. It is excellent for effervescent formulation because it is also effective at low percentages. Malitol was also discovered to be an effective binder for Vitamin C effervescent tablets, which functioned by crystal bridge creation. Another application for polyethylene glycol 6000 is as a lubricant and a binder. ⁽⁴⁴⁾

c. Disintegrants-

As it is preferred that the tablet should generate a clear solution within a few minutes after addition to a glass of cold water, disintegrants are typically not utilized in effervescent tablets. As disintegrants, dextrose and/or sucrose have been employed in aspirin-effervescent tablets.

d. Lubricants-

Effervescent tablets naturally tend to stick and usually have rougher surfaces than regular tablets. Using the right lubricants helps reduce sticking, and tablets made with tartaric acid stick less to equipment compared to those with citric acid.A great lubricant needs to be water soluble, tasteless, and non-toxic. Due to the nature of the raw components and the requirement for quick tablet disintegration, effervescent granulations are challenging to lubricate.^(44,45)

e. Glidants:

Due to the size of the tablet and the free-flowing granulations, glidants are typically not required. The right physical forms for direct compression are chosen for the ingredients of effervescent medicines.

f. Anti-adherents:

By utilizing polytetrafluoroethylene or polyurethane glued to the punch surfaces, the adhesion of the granulation mixture to the surfaces can be minimized.

g. Sweeteners:

In an effervescent product, natural water-soluble sweeteners such as sucrose, lactose, xylitol, D-glucose, sorbitol, or mannitol may be included. You may also use artificial sweeteners that are allowed by health standards, such as saccharin or its calcium or sodium salt, aspartame, Acesulfame K or cyclamates

h. Flavours:

Sweeteners alone are insufficient for taste masking; thus, water-soluble flavours may be added to make the formulation more appealing. Fruity flavours in dry forms, such as orange, lemon, and pineapple, are typically favoured to increase organoleptic characteristics.

i. Colours:

Improving the look and recognizing the preparation.

j. Surfactant:

Surfactants are used to improve medication wetting and dissolving. However, they may pose issues owing to foam development.

k. Antifoaming agents:

Antifoaming agents are substances designed to reduce or prevent foam formation. Common examples include certain alcohols like cetostearyl alcohol, insoluble oils such as castor oil, stearates, polydimethylsiloxanes, various silicone derivatives, ethers, and glycols. These agents work by breaking down foam or inhibiting its formation in different applications.  ^(41,42,43)

1.3.6 Reason for selection of Effervescent tablets:

1. No need to swallow tablet:

Orally disintegrating effervescent tablets provide a convenient option for individuals who have difficulty swallowing, including elderly patients, stroke survivors, and bedridden individuals. They are also beneficial for patients who must avoid swallowing, such as those with renal failure, and for those who refuse to swallow, such as pediatric, geriatric, or psychiatric patients. These tablets dissolve quickly in the mouth without the need for water, making administration easier.

2.Accurate dosing:

Studies suggest that effervescent tablets improve the absorption of a significant number of active ingredients compared to traditional formulations. This enhancement is attributed to the carbon dioxide released during the effervescent reaction, which can increase the permeability of active ingredients by modifying the paracellular pathway. The paracellular pathway primarily facilitates the absorption of hydrophilic compounds, allowing solutes to pass through the intercellular spaces between epithelial cells. It is believed that carbon dioxide expands these spaces, leading to greater uptake of both hydrophilic and hydrophobic active ingredients. Additionally, the improved absorption of hydrophobic compounds may result from non-polar carbon dioxide molecules integrating into cell membranes, creating a more hydrophobic environment that supports their absorption^{.  (45)}

3. Improved palatability:

Effervescent-based drug formulations offer a superior taste compared to traditional liquids, mixtures, and suspensions. Their enhanced taste-masking ability results from minimizing unpleasant flavors and incorporating complementary ingredients like flavors and fragrances. These tablets are designed to dissolve in water, creating a fizzy solution that is generally more palatable than a simple mixture of non-effervescent powder in water. Additionally, their effervescent nature can make them more appealing to consumers compared to conventional dosage forms.

1.3.7 Manufacturing of effervescent tablets:

The manufacturing procedure for effervescent tablets is largely the same as that for normal tablets, but controlled environmental conditions are required. As a result, controlling humidity and temperature in the production environment is a crucial stage in the production of these tablets. Due to the hygroscopic nature of the raw materials employed in its production and the potential for the commencement of an effervescent reaction as a result of moisture absorption by these components, a regulated environment is necessary Maintaining low relative humidity (maximum 25% or less) and moderate to cool temperatures (25°C) in manufacturing areas is essential to prevent granules or tablets from adhering to machinery and absorbing moisture, which could lead to product degradation. Granulation remains the most widely used method for producing tablets with optimal properties. Various granulation techniques exist, including one-step granulation using water or organic solvents and two-step granulation, where acid and alkali phases are processed separately.^(47,48)

1.3.7.1 Wet granulation:

Despite its complexities, wet granulation continues to be the favored approach for effervescent granulation. This method ensures consistent tablet weight and even distribution of active ingredients while forming uniform granules that are well-suited for compression .

1. Two-step granulation technique:

Before incorporating the tablet lubricant, the acidic and basic components undergo separate granulation, followed by dry mixing. This can be achieved using a fluid bed spray granulator, a single pot system, or a high-shear granulator with subsequent drying. The process requires standard equipment, which can also be utilized for drying and granulating other materials. An alternative approach involves granulating only one of the effervescent components while adding the other as a powder during the final blending stage. This mixture is combined with additional ingredients such as flavors and lubricants. By eliminating the need for full granulation, this method enhances efficiency and reduces production costs.⁽⁴⁸⁾

2. One-step granulation technique:

The one-step granulation method rapidly generates dry effervescent granules by combining acidic and alkaline components. A minimal amount of water initiates and controls the effervescent reaction, promoting granule formation. Granulation can also be achieved using organic solvents such as alcohol (diluted with water), isopropanol, or other binder-containing solvents. The effervescent ingredients and other formulation components must remain insoluble in the chosen organic solvent.

3. Fluidized bed granulation:

Effervescent components are granulated in a single step using fluid-bed granulator-dryer technology. In this process, a dry mixture of an acid source and a carbonate source is suspended in a heated air stream, forming a fluidized bed. When a small amount of water—typically used as the granulating fluid is introduced, a brief reaction occurs before the water evaporates. The reaction ceases once spraying stops and warm, dry air completes the drying phase.

Alternatively, a rotor fluid-bed spray granulator can be employed to produce effervescent granules, minimizing direct contact between the reactive components. This method follows a continuous two- or three-step process. Initially, alkaline components undergo granulation in the rotary fluid bed. Subsequently, an acidic powder and granulating solution are sprayed onto the alkaline spheres, forming an outer acidic layer separated by a neutral binder layer. Once agglomeration is complete, the drying phase begins.^(47,48).

4. High shear granulation:

High shear granulator-dryer technology enables a rapid transition from granulation to drying by generating a vacuum within the bowl. This lowers the boiling point of water, allowing the bowl to heat up and provide the necessary energy for evaporation. Within seconds, surface water is eliminated from the wet granules, halting the effervescent reaction. Additionally, a combination of microwave radiation and vacuum can be employed to dry effervescent granules and prevent further reaction. TOPO granulation is another approach where vacuum application effectively stops the process.

1.3.7.2 Dry granulation:

Wet granulation may initiate an effervescent reaction, potentially causing substance degradation. To mitigate this, alternative techniques have been introduced. One such method is dry granulation through slugging, where large tablets or slugs are formed using roller compactors or direct compression. These approaches are regarded as more efficient than wet granulation.

i. Slugging:

The production of slugs or large tablets requires high-capacity tableting equipment. One such machine, the roller compactor also called a chilsonator compresses premixed powders between two counter-rotating rollers under significant pressure. The material formed varies depending on the roller setup, resulting in ribbons, sheets, or fragmented pieces. These slugs are then reduced to the appropriate size for tablet granulation. Lubrication may be necessary during the slug formation process. This method facilitates the dry granulation of acidic and basic components, either separately or together.It is especially helpful for materials that need pre compression to boost density or get rid of trapped air owing to porosity but cannot be compressed using conventional wet granulation procedures. This method has the benefits of being straightforward, inexpensive, increasing product throughput, requiring fewer operators and less space, and requiring less air ventilation. The technique's main disadvantage,

However, is the usage of pricey excipients, which limits its applicability to small-batch manufacturing of effervescent tablets.

ii. Direct compression:

Direct compression has emerged as an effective alternative to dry granulation for manufacturing effervescent tablets with acetylsalicylic acid. This approach enhances process stability and operational efficiency. However, its widespread application is restricted, as it requires carefully formulated raw materials to ensure proper compressibility, free-flowing properties, and uniform distribution without segregation. As a result, direct compression is best suited for highly controlled manufacturing environments rather than widespread industrial use.

iii. Granulation by heating:

Heated dry granulation serves as an alternative to wet granulation. In this process, hydrated citric acid is heated to around 100°C, causing it to release its hydration water, which then functions as the granulating liquid, promoting particle agglomeration in the powder mixer. The formed granules are subsequently cooled to attain the required mechanical strength and stability.

Two key approaches to dry granulation include hot melt granulation and surface hot melt granulation. In surface hot melt granulation, all components are mixed, dried in an oven, and water is released from citric acid and other ingredients to form granules. However, using a static bed dryer presents challenges, leading to lower reproducibility. Hot melt granulation, conducted in a high-shear granulator-dryer, involves heating the bowl to release citric acid’s hydration water, sometimes triggering an effervescent reaction that produces additional binding liquid.

Low-melting polymers, such as PEGs, have been employed as binding agents in fluid bed spray granulation. Furthermore, a unique hot melt extrusion method necessitates a binder capable of hot-melt extrusion, like PEGs with molecular weights between 1000 and 8000 Da. This technique utilizes extruders featuring solid conveying zones, several temperature-controlled heating areas, and an extrusion die for effective processing.

1.3.8 Evaluation tests of effervescent granules:

1.3.8.1 Angle of repose:

 One way to measure the angle of repose is by allowing effervescent granules to flow through a funnel onto a flat surface, forming a conical pile. The height and radius of the pile are then measured, enabling the calculation of the angle using a designated formula. Alternatively, digital or mechanical testers can be used to determine the angle automatically based on the pile’s dimensions.

Tan Θ = h/r

Where,

Θ is the angle of repose,

h is the pile's height, and

r is the radius of the pile's base.

1.3.8.2 Bulked density:

Bulk density is calculated by dividing the mass of the powder by its total volume, including the gaps between particles. This factor is essential in the development of effervescent dosage forms, as it affects flow properties, compressibility, and dissolution rate. Precise bulk density measurements ensure uniform dosing and enhance packaging efficiency.

Bulk density = Mass of Sample (M)/ Volume of granules (V)

1.3.8.3 Tapped density:

Tapped density represents the density of a powder after it has been subjected to tapping or compression, mimicking how it settles during storage or transport. It provides a more precise assessment of powder packing behavior than bulk density and is crucial for formulating effervescent dosage forms, as it impacts uniformity and dissolution rate. The calculation involves dividing the granule mass by the tapped volume of the powder. Reliable measurements require a calibrated tapping instrument, adhering to standardized guidelines established by the USP or EP.

Tapped density = Mass of sample (M) / Tapped volume of Granules (V)

1.3.8.4 Carr’s index:

Carr's Index, also referred to as the compressibility index, is an indirect measure of powder flow based on bulk density. Developed by Carr, this index determines the percentage compressibility of a powder, indicating its strength and stability in forming bridges or arches. The calculation involves comparing poured bulk density with tapped density using a specific formula: subtracting tapped density from poured density, dividing the result by poured density, and multiplying by 100 to express compressibility as a percentage.

% Compressibility = Tapped density – Bulk density / Tapped density × 100

1.3.8.5 Hausner’s ratio:

Hausner's ratio is an important parameter for assessing powder flowability, calculated as the ratio of tapped density to bulk density. Tapped density is determined after the powder undergoes standardized tapping, whereas bulk density is measured by dividing the powder's mass by its recorded volume.

Hausner ratio = Tapped density / Bulk density

1.3.9 Evaluation tests of effervescent tablets:

The pharmacopeial evaluation of effervescent tablets closely mirrors that of conventional tablets, with special emphasis on the disintegration test. Various factors are assessed, including effervescence duration, disintegration time, dissolution rate, weight uniformity, content consistency, solution pH, hardness, friability, water activity, sensory characteristics, and carbon dioxide concentration. These evaluations help ensure the tablets meet required quality standards.

1.3.9.1 Organoleptic properties:

Effervescent tablets undergo organoleptic evaluation to ensure they meet quality standards and provide a pleasant sensory experience. This assessment includes visual inspection to check for color, shape, and uniformity, odor analysis to detect the characteristic scent of active ingredients, and taste testing to evaluate the effervescent reaction and overall palatability. These procedures help confirm that the tablets are both effective and appealing to consumers.

1.3.9.2 Weight variation:

The weight variation test is used to confirm that each batch of effervescent tablets meets the specified weight range. During this process, individual tablets from a sample are weighed and compared to the overall batch weight. Acceptable weight limits are determined based on the percentage deviation from the average. If all tablets fall within this range, the batch passes the test. However, if any tablets exceed the acceptable limits, further analysis is conducted to identify the cause of the variation and implement necessary corrective measures.

1.3.9.3 Content of uniformity:

To assess uniformity in a single-dose formulation, analyze the active ingredient levels in 10 units. Each unit's composition should range between 85% and 115% of the average. The test becomes invalid if any unit falls beyond this range or outside 75% to 125%. If one unit is between 75% and 125% but outside the 85% to 115% range, examine 20 additional units. The test is deemed acceptable if, among all 30 units tested, no more than one falls outside the 85% to 115% range, and none exceed 75% to 125%.^(42,45,46)

1.3.9.4 Disintegration time/ effervescent time:

According to IP guidelines, tablet disintegration is tested by placing one tablet in a beaker containing 250 ml of water maintained between 20°C and 30°C. The release of CO2 bubbles is observed as the tablet dissolves. It should completely disintegrate within five minutes without leaving clumps or undissolved particles. This process is repeated with five additional tablets. The test is deemed successful if all six tablets fully disintegrate within the specified time unless specific tablet requirements indicate otherwise.

1.3.9.5 Friability test:

For tablets with an average weight of 0.65 g or less, a sample consisting of 6.5 g of whole tablets is collected for testing. If the average tablet weight is 0.65 g or more, a set of 10 intact tablets is taken instead. The tablets are carefully dedusted, then precisely weighed before being placed in a drum and rotated 100 times. After rotation, any loose dust is removed, and the tablets are weighed again. The test is conducted once, but if the weight loss exceeds the allowable limit of 1.0%, it is repeated twice, and the average of the three trials is calculated. If tablets in the sample show visible cracks, chipping, or breakage after testing, the sample is considered to have failed.^(49,51)

1.3.9.6 Dissolution test:

During an effervescent tablet dissolution test, the tablet is immersed in a fixed volume of water maintained at a specific temperature using dissolution equipment. The apparatus, equipped with either a paddle or a basket, rotates to create agitation. At set intervals, the drug concentration in the water is analyzed using a spectrophotometer or another appropriate method.

1.3.9.7 PH of the solution:

Maintaining the correct pH in an effervescent tablet solution is crucial for quality control. Consistent pH levels across batches indicate uniformity in raw materials, whereas significant variations may point to granulation or weighing inconsistencies. The tablet's taste is also influenced by pH—citrus and berry-flavored antacids tend to work best in an acidic environment, whereas mint flavors are typically formed at a neutral to slightly alkaline pH. Since the pH of effervescent tablets shifts over time due to carbonic acid degradation and the presence of slowly dissolving components, it is essential to measure it accurately using a pH meter at a specified time.^(41,42)

1.3.9.8 Water activity:

Water activity (aW) is essential for food safety as it determines the amount of unbound water available for microbial growth. Two primary methods for measuring aW are capacitance sensors and chilled-mirror dewpoint systems. Capacitance sensors use hygroscopic polymer membranes, while chilled-mirror systems employ dewpoint sensors and infrared thermometers. Both techniques have their advantages and limitations but provide accurate and reliable measurements.^(49,50)

1.3.9.9 Hardness and thickness:

Effervescent tablets need to be durable enough to prevent chipping or breaking. Using suitable tools, such as those with bevelled edges, can help minimize these problems. A 1:1 ratio between tablet thickness and hardness is recommended for strength, but it may complicate packaging due to increased thickness. Tablet height also plays a role in packaging, influencing how tightly the tablets fit. Hardness can be measured using standard testers like Monsanto’s or Pfizer’s hardness testers, Strong Cobb, or Schleuengir, while thickness can be assessed with a Vernier caliper.^(17,35,48)

1.3.10 Innovations in effervescent tablet technology :

Effervescent tablets have traditionally been recognized for their ability to generate carbon dioxide through the reaction of acidic sources with alkaline carbonates. However, recent innovations have introduced the production of hydrogen gas and oxygen bubbles, expanding their potential for topical drug delivery by integrating both mechanical and physiological effects. Advancements in effervescent buccal and denture tablets have also highlighted their effectiveness in oral hygiene and antimicrobial applications. These tablets offer versatility in delivering oral medications, as well as herbal and nutraceutical formulations. Additionally, effervescent technology has progressed in cosmeceutical applications, including pedicures, manicures, and bath bombs. Moreover, its potential in pulmonary drug delivery makes it a promising avenue for future development.

5. AIM AND OBJECTIVES

5.1 AIM: Formulation, Development and Evaluation of Calcium and Vitamin C Effervescent Tablets

5.2 OBJECTIVE -

• To procure API and excipients and to perform compatibility studies
• To formulate effervescent tablets containing Calcium and Vit C by suitable method
• To carry out evaluation test for effervescent tablet formulations.
• To conduct short-term stability studies for optimized batches

6. RATIONALE

Enhanced Calcium Absorption: One of the primary benefits of combining calcium with Vitamin C in an effervescent tablet is that Vitamin C helps enhance the absorption of calcium. Vitamin C creates a more acidic environment in the stomach, which aids in the solubility of calcium salts, allowing for better absorption into the bloodstream. This is particularly important for people who may struggle with calcium absorption or have a risk of calcium deficiency.

Bone Health Support: Calcium is essential for maintaining strong bones and teeth, and Vitamin C plays a supporting role in bone health. Vitamin C is critical for collagen synthesis, which is necessary for the structural integrity of bones. By combining calcium with Vitamin C, the tablet not only helps supply calcium for bone strength but also supports the collagen framework, improving bone flexibility and repair.

Convenient Delivery: The effervescent form of the tablet allows for quick dissolution in water, ensuring that the active ingredients are readily available for absorption. The fizzing action makes the tablet more palatable, especially for those who may find traditional calcium supplements hard to swallow or taste unpleasant

RESULT AND DISCUSSION

PREFORMULATION STUDIES:

Organoleptic Properties:    

The given sample of Calcium lactate gluconate and Calcium Carbonate powder was found to be white toWhite off in color and Vitamin C powder was found to be  white in color. The results were shown in Table No. 9.1

Table No. 9.1  : Organoleptic properties of Calcium lactate gluconate ,Calcium Carbonate & Vitamin C

The melting point ofCalcium lactate gluconate ,Calcium Carbonate & Vitamin Cis given in Table No. 9.2. The melting point of the drug matches with the values found in literature.

Table No.9.2: Melting Point of Calcium lactate gluconate ,Calcium Carbonate & Vitamin C

Solubility Analysis:

Solubility of Calcium lactate gluconate, calcium carbonate, Vitamin C was determined in different solvents. The results were shown in Table No. 9.3.

Titrimetric Analysis -

Procedure -

Weigh and Crush 10 Tablet in mortar pestle upto Homogenous blend weigh quantity of powder containing of 60mg of calcium in conical flask add 100 ml of purified water and neutralize the solution using Accurate volume of 30 ml 1M sodium hydroxide shake and sonicate for 5 min add pinch of calcon indicator again shake add 20gm sodium chloride shake and sonicate for 2 min titrate with 0.1 M disodium EDTA blue colour is end point

                                  4 gm à 253 mg

                          0.9486 gm à 60 mg

 Calculation –

B.R× 4.008 × 0.1 M Disodium EDTA molarities × Avg weight of Tablet

Sample Weight × 0.1 M Disodium EDTA

14.6 × 4.008 × 0.1002 × 4

0.9486 × 0.1

23.45

0.0948

247.36 mg

Limit- 227 to 278 mg

Assay of Vitamin C -

Procedure- Dissolve 0.15 gm mix of 10 ml of dilute sulphuric acid and 80 ml of purified water add 1ml of starch solution titrate with 0.05 M Iodine until persistant violet colour obtained.

4 gm à 100 mg

0.600 gm à 150 mg

B.R × 4.008 × exact normality of 0.05 Iodine × 8.81 ×  Avg weight of Tablet

Weight Taken in mg × 0.05

15.8× 0.05284 × 8.81 × 4

0.600 × 0.05

29.42

0.03

=   980 mg

Limit- 900 to1100 mg

Assay of Calcium  and Vit C  Effervescent tablet

Procedure – For Calcium lactate gluconate, Calcium carbonate

Weigh and Crush 10 Tablet in mortar pestle upto Homogenous blend weigh quantity of powder containing of 60mg of calcium in conical flask add 100 ml of purified water and neutralize the solution using Accurate volume of 30 ml 1M sodium hydroxide shake and sonicate for 5 min add pinch of calcon indicator again shake add 20gm sodium chloride shake and sonicate for 2 min titrate with 0.1 M disodium EDTA blue colour is end point

                                  4 gm à 253 mg

                          0.9486 gm à 60 mg

 Calculation –

B.R× 4.008 × 0.1 M Disodium EDTA molarities × Avg weight of Tablet

Sample Weight × 0.1 M Disodium EDTA

14.6 × 4.008 × 0.1002 × 4

0.9486 × 0.1

23.45

0.0948

247.36 mg

Limit- 227 to 278 mg

Result-   In 4gm of Calcium and Vit C Effervescent tablet 247.36 elemental calcium present

Procedure-For Vitamin C

Dissolve 0.15 gm mix of 10 ml of dilute sulphuric acid and 80 ml of purified water add 1ml of starch solution titrate with 0.05 M Iodine until persistant violet colour obtained.

4 gm à 100 mg

0.600 gm à 150 mg

B.R × 4.008 × exact normality of 0.05 Iodine × 8.81 ×  Avg weight of Tablet

Weight Taken in mg × 0.05

15.8× 0.05284 × 8.81 × 4

0.600 × 0.05

29.42

0.03

=   980 mg

Limit- 900 to1100 mg

Result – In 4 gm of Calcium and Vit C Effervescent tablet  980 mg of Vitamin C is present.

Fourier Transform Infra-Red Spectroscopy (FTIR):

The compatibility study was performed via the usage of Fourier Transform Infrared Spectrophotometer (Agilent Technologies). Infrared absorption spectrum of Calcium lactate gluconate, Calcium Carbonate, Vit C was recorded using Fourier Transform Infra-Red Spectrometer

DRUG-DRUG AND DRUG-EXCIPIENT COMPATIBILITY STUDY -

10.1.5 Identification of pure drug using FTIR: Calcium lactate gluconate

The FTIR spectra of the tested sample, which was identified as Calcium lactate gluconate , are shown below:

Figure 1: FTIR standard spectra of Calcium lactate gluconate

Table no   : Interpretation of FTIR spectra of pure drug Calcium Carbonate

10.1.7 Identification of pure drug using FTIR: Vitamin C

Table no  : Interpretation of FTIR spectra of pure drug Vitamin C

10.1.7 Active + Citric acid (Initial) 

Active+ Citric acid (Final) –

  Active+ Sodium Bicarbonate (Final)

10.1.11 Active + Simethicone (Final) –

10.1.13 Active + Sucralose  (Final) -

10.1.15 Active + Orange Capsil (Final)

10.1.19 Active + Sodium Benzoate (Final)

The accelerated stability studies of the pure drug, Calcium lactate gluconate , calcium carbonate,Vit C were conducted using a stability chamber set at a temperature of 40°C and relative humidity of 75%. The analysis of the samples was performed using FTIR analysis. The correlation of FTIR spectra includes the initial spectrum labelled as " Active + Excipent Initial " and the final spectrum denoted as " Active + Excipent Final " obtained after stability studies.

Evaluation of Pre-compression characteristics of powder blend:

The experimental results obtained for formulations F1 to F7 are presented in the following Table. The properties analysed include the angle of repose, bulk density, tapped density, Carr's index, Hausner's ratio, and acid-neutralizing capacity. The values obtained for each formulation are compared to the standard values or accepted ranges in order to evaluate their performance

Results of pre-compression characteristics of powder blend

Carr's index values for the formulations ranged from 13.13 % to 18.74 %. Carr's index is a measure of the compressibility of a powder, with lower values indicating better flow properties.

As per the standard categorization, Carr's index values in the range of 5-15% are considered excellent, indicating excellent flowability. The obtained Carr's index values for all the formulations fall within the 'Good' flowability category.

Hausner's ratio values for the formulations ranged from 1.266 to 1.143 Hausner's ratio is a measure of the bulk density and tapped density of a powder, with lower values indicating better flow properties. According to the standard categorization, Hausner's ratio values in the range of 1.14-1.20 are considered good, indicating good flowability. All the formulations exhibited 'Good' flowability based on their Hausner's ratio values falling within this range.

The bulk density and tapped density were determined for the formulations. The bulk density values ranged from 0.666 g/ml to 0.690 g/ml, while the tapped density values ranged from 0.768 g/ml to 0.789 g/ml. These values provide insights into the packing and compaction properties of the formulations

Evaluation of Post compression characteristics of formulation batches:

The experimental results obtained for post-compression characteristics of formulations F1 to F7 are presented in the following Table. The properties analysed include the diameter, thickness, hardness, disintegration time and pH of the solution. The values obtained for each formulation are compared to the standard values or accepted ranges in order to evaluate their performance.

Result of Post compression characteristics of formulation batches