Introduction

Granulation is a process of forming or crystalizing powders into grains. It is a process in which primary powder particles are compressed to bind and form multi-particle entities that are known as granules. In the process of granulation, particles are collected together by compressing the particles and this causes them to form bonds between each particle. The bonds may also be formed with the use of a binding agent. (Aulton, M & Taylor, K, (2013), Aulton’s pharmaceutics: the design and manufacture of medicines, Page 419)

The actual granulation of powders occurs after the necessary dry mixing of all the powdered ingredients, ensuring a uniform distribution of each ingredient throughout the mix. Once granules are formed, the final product is either packaged on its own, if they are large granules that may be administered as a dosage form on its own, or the granules, when smaller (0.2-0.4mm) may be mixed with excipients and compressed into an effervescent tablet or they may be contained within a capsule. (Aulton, M & Taylor, K, (2013), Aulton’s pharmaceutics: the design and manufacture of medicines, Page 419)

Reasons for Granulation

• Granulation prevents the segregation of ingredients within a powder mix
• It improves the powder flow properties of a powder mix
• It enhances a powder mix’s ability to be compacted ‘ in the case of formulating an effervescent tablet
• It reduces the toxicity of a toxic powder ingredient
• It reduces the formation of a cake, as the granules are able to absorb moisture, without disrupting powder flow.
• Granules are denser than the initial powder, therefore it has a lower volume per weight, making it easier to store and transport

Types of Granulation

There are 3 types of granulation:

(i) Wet Granulation

Granules formed by adding a granulation liquid, that contains a volatile solvent, to a powder mix that contains a high shear granulator. (Dhenge, Ranjit M.; Washino, Kimiaki; Cartwright, James J.; Hounslow, Michael J.; Salman, Agba D. (2012). “Twin screw granulation using conveying screws: Effects of viscosity of granulation liquids and flow of powders”. Powder Technology)

(ii) Dry Granulation

Granules formed without the addition of any liquid, as the powder mix may be moisture sensitive. Instead, particles are aggregated to form granules by applying high pressure that compacts and densifies the powder mix. (Dhenge, Ranjit M.; Washino, Kimiaki; Cartwright, James J. Michael J. Salman, Agba D. (2012). “Twin screw granulation using conveying screws: Effects of viscosity of granulation liquids and flow of powders”. Powder Technology)

(iii) Fusion Granulation

Aim

Formulations of granules from a powder mix by methods of wet and dry granulation and evaluate the different methods of granulation.

Methodology

Calculations for Dry Granulation

1. C6H8O2.H2O + 3NaHCO3 ‘ Na3C6H5O7 + 4H2O + 3CO2 ‘

Citric Acid Sodium Sodium

Bicarbonate Citrate

2. C4H6O6 + 2NaHCO3 ‘ Na2C4H4O6 + 2H2O + 2CO2’

Tartaric Acid Sodium

Titrate

Calculation 1

Citric Acid: Sodium Bicarbonate

1:3

MWCitric Acid = 192.124g.mol-1

MWSodium Bicarb = 84.007g.mol-1

n=m/M

=4g/192.12g.mol-1

=0.02082mol (Citric Acid)

1:3

0.02082: x

x = 3 x 0.02082

=0.0625mol (Sodium Bicarb)

m= nM

= (0.0625) (84.007)

= 5.24g (Sodium Bicarb)

Calculation 2

Tartaric Acid: Sodium Bicarbonate

1:2

MWTartaric Acid = 150.087g.mol-1

n = m/M

= (8)/ (150.087)

=0.0533mol (Tartaric Acid)

1:2

0.0533 : x

x = 2 x 0.0533

=0.1066mol (Sodium Bicarb)

m = nM

= (0.1066) (84.007)

=8.96g (Sodium Bicarb)

Final Calculation for Dry Granulation

Total Weight of Sodium Bicarb to add: 5.24g + 8.96g
=14.20g

Calculations for Wet Granulation

Working Formula(WF) = 50/100

=0.5

Amount of Lactose Powder to add: 50-32-0.05-2.5-2-1/2

=12.95g

Method of Dry Granulation

1. Placed a water bath on a tripod stand and placed above an active Bunsen burner.
2. Heated up the porcelain evaporating dish by placing it in the water bath.
3. Weighed out the Citric Acid (4g), the Sodium Bicarbonate (14.20g), the Tartaric Acid (8g) and the Sucrose (0.5g).
4. Mixed all the above ingredients.
5. Sieved the powder mix to ensure uniform particle size.
6. Added the powder mix to the heated up porcelain evaporating dish.
7. Pressed the powder mix continuously with a metal spatula, formulating a cake.
8. Removed the porcelain evaporating dish from the water bath and transferred the granules to an appropriate container.
9. Labelled the container with complete instructions, including Store in a cool, dry place.

Method of Wet Granulation

1. Weighed out the Methyl Cellulose (32g), Sodium Saccharin (0.05g), Vanillin (2.5g), Acacia (2g) and Lactose (12.95g).
2. Measured out the Amaranth (1ml).
3. Added the ingredients to a mortar in increasing bulk, and mixed with a pestle after each addition.
4. Added adequate water to form a cohesive mass of powder.
5. Placed the mass in a 2mm sieve that was above a 710”m sieve.
6. Pressed the powder mass through the 2mm sieve and observed the granules of equal size fall on the 710”m sieve. Smaller granules were sieved through the 710”m sieve and discarded as waste.
7. Transferred the granules from the sieve to a watch glass and placed it in the oven set at 60’C until dry.
8. Transferred granules from the watch glass into an appropriate container.
9. Labelled the container with the correct instructions, including ‘Store in a cool, dry place.’

Results and discussion

Effervescent granules

• Colour: white effervescent granules
• Texture: rough, grainy and hard
• Appearance: larger than original powder

The gas formed in effervescent granules is due to the reaction between tartaric and citric acids and sodium bicarbonate (the acids and bases respectively). The mixed powders were heated in a porcelain dish. With time the particle size of each granule increased slightly and there was less cohesion between the powder particles. They were formed into granules due to their new particle size. When compressed the granules formed a cake however they were easily redispersed upon scattering. Samples were tested for their potential to work and placed in water. This was confirmed by the effervescing granules. The granules were thereafter placed in a seal tight jar and labelled. The granules could be used as antacids, urinary alkalinises and the management of mild urinary tract infections due to the presence of sodium bicarbonate. They could be used in the initial stages of uricosuric therapy in chronic gout as it alkalinises the uric acid deposits in the joints.

Ingredients

Ingredient Use

• Citric acid Acidifying agent. Anti-oxidant, buffering agent, chelating agent, flavour enhancer
• Tartaric acid Acidifying agent, flavouring agent
• Sucrose Coating agent, sweetening agent
• Sodium bicarbonate (active ingredient) Alkalizing agent, therapeutic agent (used for a variety of purposes including metabolic acidosis, alkalinisation of urine and antacid).

Label

Questions:

1. Name and explain the use of two similar granulated products on the market?

• Zantac: works by reducing the amount of acid your stomach produces. It is used to treat and prevent ulcers in the stomach and intestines.
• Citro Soda: a gastric antacid and alkalinising agent. It is used in the maintenance of pH and to treat mild urinary tract infections.

2. Can sodium bicarbonate granules be used for gout?

Gout is an inflammatory condition caused by defective uric acid metabolism. This leads to uric acid being deposited into the bloodstream, joints, tendons etc. sodium bicarbonate may prevent the development of uric acid renal calculi in the initial stages of uricosuric therapy. Since sodium bicarbonate is a base and gout is uric acid built up i.e. it is acidic, the sodium bicarbonate will neutralise the acid thus reducing the effects of gout.

3. Can sodium bicarbonate be used to treat urinary tract infections (UTI’s)?

Urinary tract infections are caused by bacteria invading the urinary tract. Bladder infections are the most common, followed by more serious kidney infections. A urinary tract infection will cause painful urination, intense urgency to urinate, fever and lower abdominal pain. Sodium bicarbonate is an effective way of treating UTI’s. Sodium bicarbonate works by alkalinising urine and relieving discomfort in mild urinary tract infections and dysuria in patients with cystitis in whom there is no definite clinical evidence of bacterial infection. The sodium bicarbonate regulates the acid base balance of the acidic urine hence neutralises the acidity of urine, and in turn relieves the burning sensation caused by UTI’s.

Methylcellulose granules

• Colour: light pink, slightly fluffy and glassy granules
• Size: small but significantly larger than previous powder

Methylcellulose granules are bulk forming laxatives and are used in the treatment of constipation. It works by drawing water into the gastrointestinal tract, thereby softening and increasing the volume of faeces. It can also be used in the treatment of diarrhoea due to its water retaining properties. Care should be taken when dispensing methylcellulose granules to hypertensive patients as it may cause an increase in water retention, which may lead to an increase in blood pressure. It is highly recommended to increase fluid intake when taking these granules in order to prevent intestinal compaction.

The formation of methylcellulose granules is one that requires a relatively good amount of accuracy, as these granules are formed via the wet granulation method, and the drop wise addition of water plays a crucial part in its resulting texture. Addition of too little water will result in leaving most of the formulation in powder phase, while too much water will cause particles to become wet and stringy which will be unable to pass through the sieve. The right amount of water was therefore added to form the granules, which then dried in the oven in order for the moisture to be removed. After approximately twenty minutes in the oven the granules were somewhat dry but still fluffy, indicating that the drying process was not yet complete. This was due to limited time in the lab as well as the constant opening of the oven by other students in the lab.

Ingredients

Ingredient Use

• Methyl cellulose Bulk forming laxative. Used in the treatment of constipation and diarrhoea. Absorbs moisture and acts as an emulsifying agent
  Amaranth Colouring agent
• Sodium saccharin Sweetening agent
• Vanillin Flavouring agent
• Acacia Suspending and emulsifying agent as well as binder
• Lactose Used as diluent

Label

Questions

1 Can methylcellulose granules be safely used in patients with hypertension?

Methylcellulose should be used with caution in hypertensive patients due to its strong water absorbing properties. Fluid retention in the body is usually accompanied with an increased blood pressure due to there being an increase in blood volume.

2 What advice should we give to patients taking methylcellulose granules?

Methylcellulose is a bulk forming laxative and as such, it should be taken with plenty of fluid (water) in order to prevent vomiting due to material swelling in the throat. It is also a laxative and should not be taken for more than seven days unless indicated by a doctor. The granules should not be taken before going to bed as it may cause a blockage in the bowel. It should be noted that methylcellulose granules should be taken at least three hours before or after taking other medication so that no interactions occur and the medication does not get excreted too quickly. If a dose of methylcellulose is missed, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once

3 Discuss the efficacy of methylcellulose as a slimming agent?

Methylcellulose granules are used in the treatment of constipation. Since it is able to absorb water and increase bowel activity it may be useful as a slimming agent, although its use as an appetite suppressant in obesity is not conclusive. It is however not indicated for use as slimming agent as it may lead to dehydration and other complications associated with weight loss.

Conclusion

The aim of this practical was achieved. Methylcellulose granules as well as effervescent granules were produced. Two methods of granulation were explored mainly the fusion method and the wet gum method (effervescent granules and methylcellulose granules were formulated respectively). The spontaneous dissolution as well as the expansion of the methylcellulose granules in water indicated that the formulations were prepared correctly. The effervescent granules were not completely granulated. This could a result of water bath temperature not being high enough. The methylcellulose were somewhat dry but still fluffy, indicating that the drying process was not yet complete. This was due to limited time in the lab as well as the constant opening of the oven by other students in the lab.

Granulated formulations have widespread use in the health sector and help with conditions such as acid reflux and diarrhoea and constipation. From a pharmaceutical point of view packing, filling and transport processes are able to be carried out efficiently. It also improves dissolution rates, increases chemical stability, improves flow properties and leads to quicker absorption, proving that granulation is an effective technique that can be used to form for therapeutic indications.

References

• SAMF 10th Edition, (2012), South Africa: Health and Medical Publishing Group of the South African Medical Association
• MIMS Volume 51, Number 10 (October 2011), South Africa: Magazine publishers Association of South Africa
• British Pharmacopoeia. 2016, from www.pharmacopoeia.com.innopac.wits.ac.za
• Aulton, M & Taylor, K, (2013), Aulton’s pharmaceutics: the design and manufacture of medicines, Page 419
• Dhenge, Ranjit M.; Washino, Kimiaki; Cartwright, James J. Michael J. Salman, Agba D. (2012). “Twin screw granulation using conveying screws: Effects of viscosity of granulation liquids and flow of powders”. Powder Technology

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