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Formulation of suspensions

Formulation of suspensions may seem to be simple. After encountering numerous technical problems during pharmaceutical suspension development, the formulator (pharmacist) makes it simple. Some pharmaceutical suspensions are marketed as either prepared form or granular mixtures or dry powders called PFS (powder for suspension) intended for reconstitution.

Pharmaceutical suspension may be formulated for different routes of administration for example oral, topical, ophthalmic, inhalation, otic, rectal, and injection. Examples of some pharmaceutical suspensions: Amoxicillin Oral Suspension, Mebendazole Oral Suspension, Albendazole Oral Suspension, Natamycin Ophthalmic Suspension etc.

Methods for Formulation of Suspensions

Formulation of a suspensions depends on whether the suspension is deflocculated or flocculated. The main methods for formulation of suspensions are [1]

1. Precipitation method

  • Organic solvent precipitation
  • Precipitation by pH
  • Double decomposition

2. Dispersion Method

Precipitation method for Formulation of Suspensions

Three precipitation methods is used for the Formulation of Suspensions.

Organic solvent precipitation

In this method, precipitated is done by dissolving water-insoluble drugs in water-miscible organic solvent and then adding an organic phase to distilled water under suitable conditions. Organic solvents used are methanol, ethanol, polyethylene glycol, and propylene glycol.

Precipitation by pH

In this method, precipitation is done by changing the pH of the medium. This method applies only to those drugs in which solubility is dependent on pH value. For example, Estradiol Suspension and Insulin Suspension are prepared by changing the pH of the medium solution.

Double Decomposition

It is a reaction in which two chemical compounds exchange ions, typically with the precipitation of an insoluble product. For example, Zinc sulfide topical suspension also known as White Lotion (Forming zinc polysulfide by mixing zinc sulfate and Sulfurated potash solutions)[1].

Dispersion Method for Formulation of Suspensions

To ease wetting and dispersion of the solid phase, a vehicle must be formulated in this method. To ensure uniform wetting of hydrophobic solid, the use of surfactant is desirable. In this method, the use of suspending agents such as carboxymethylcellulose and others may be indicated.

Other Methods for Formulation of Suspensions

  1. Use of controlled flocculation:  Controlled flocculation of solid particles is obtained by adding flocculating agents such as Electrolytes, Surfactants, and Polymers.
  2. Use of structured vehicles:  Structured vehicles called also thickening or suspending agents to increase the viscosity of the suspension. They are functioning by entrapping the particle and reducing the sedimentation of particles. Due to difficulty during application by syringe, structured vehicle is not useful for parenteral suspension.
  3. Use of both structured vehicles with flocculating agents.

Ingredients for formulation of suspensions (pharmaceutical)

During the formulation of suspensions selection of excipients are depended on the nature of API (active pharmaceutical ingredients) and the proposed delivery form either prepared pharmaceutical suspension or dry powder for suspension. The core ingredients for a pharmaceutical suspension are active pharmaceutical ingredients, suspending agents, wetting agents, solvents, buffers, antifoaming agents, flocculating agents, preservatives, antioxidants, coloring agents, flavoring agents, sweetening agents etc.

Active pharmaceutical ingredients (API)

These should be finely divided insoluble solid and particle sizes ranging from 0.5 to 5.0 micron for the formulation of suspensions. As with topical products the drug particle size should be usually very fine to micronized (less than 25 microns) [2]. For ophthalmic suspension particle size (diameter) of all suspended or suspendable therapeutic agent is typically at least 0.1 mm to 2.0 mm as well as no greater than 5 mm to 20 mm [3].

Wetting Agents / Surfactants

A wetting agent is a surface-active agent with an HLB value between 7 and 9 and used at a low concentration 0.05 – 0.5%) for the formulation of suspensions to wet the hydrophobic drugs with solvent [4]. Surfactants with higher HLB values such as polysorbates and poloxamers are recommended sometimes. Examples of wetting agents include propylene glycol, sodium lauryl sulphate, polysorbate, docisate sodium, sorbitan fatty acid esters, and glycerin.

Suspending agent / Viscosity modifiers / Thickening agents

These are the main excipients generally effective at a concentration of 1 to 5% for a suspension to reduce sedimentation and for stabilization. These are the vital excipients for formulation of suspensions. Examples include microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxyl propylmethylcellulose (HPMC), xanthan gum, acacia, tragacanth, alginates, guar gum and colloidal silicon dioxide etc.

Solvents/ Vehicles

These are used as a continuous medium in a suspension. Examples include water, alcohol, glycerin, polyethylene glycol, and polypropylene glycol.

Buffers/ Buffering agents

In a pharmaceutical suspension, a buffer is very important to maintain a stable pH so that the API may chemically stable within this suspension. Example include citric acid, anhydrous citric acid (for powder for suspension), carbonates, phosphate, gluconates, succinate, and acetate.

Defoamer/ Antifoaming agents/ Antiflatulent

During reconstituting powder for suspension or manufacturing of suspensions they reduce foam formation. Examples include simethicone commonly as simethicone emulsion (30% aqueous), organic phosphates, stearates, alcohols, paraffin oils, and glycols etc.

Flocculating agents

These are excipients that functioning as wetting and suspending agents in a suspension and facilitate suspended particles to link together in flocs or loose aggregates. These flocs rapidly settle but form large fluffy sediment which is redispersed easily. Examples include electrolytes, surfactants (sodium lauryl sulphate, tweens and span), sodium or potassium chloride, and polymers.

Stabilizer

These helps to stabilize a pharmaceutical suspension by preventing oxidation or microbial contaminations. So, these are the vital excipients for formulation of suspensions. These may be antioxidants and preservatives.

Antioxidants

These excipients prevent oxidation. Examples include ascorbic acid, α-tocopherol, erythorbic acid, glycerol, carotenes, cytosine, acetylcysteine, etc.

Preservatives

These excipients are used for the preservation or the protection of the suspension from microbial contaminations. Examples include methyl hydroxybenzoate (methyl paraben) (concentration 0.2 %) propyl hydroxybenzoate (propyl paraben) (concentration 0.05%), butyl hydroxybenzoate (butyl paraben), propylene glycol (15-30%), benzalkonium chloride (0.004-0.02%), sodium benzoate, benzoic acid (0.1-0.5%).

Organoleptic agents

  • Flavoring Agents

Enhance patient acceptance by producing pleasant flavor. Examples include anise oil, spearmint oil, orange essence, ethyl maltol, eucalyptus oil, adipic acid and almond oil etc. For more: Flavoring agents in pharmaceutical formulations

  • Coloring Agents

Enhance patient acceptance by producing pleasant colorsExamples include caramel, ferric oxide, titanium dioxide, aluminum oxide and FD & C Red #40. For more: Colouring agents in pharmaceuticals

  • Sweetening Agents

Enhance patient acceptance by overcoming the unpleasant taste of the pharmaceutical suspension. Examples include sucrose (up to 80%), sorbitol, mannitol, sodium saccharin, and aspartame etc. For more: Sweetening agents used in pharmaceuticals 

Humectants

These hygroscopic excipients are used to keep pharmaceutical suspension hydrated by preventing the evaporation of aqueous solvents. Examples include propylene glycol, glycerol etc.

Sequestering Agents/ Chelating agents

Chelating agents are added to bind metal ions to prevent the oxidative degradation of drug substance(s) in pharmaceutical suspensions. Examples include ethylenediaminetetraacetic acid (EDTA), malic acid, and oxalic acid.

Osmotic agents

These are used to regulate osmotic pressure especially in parenteral preparation. Examples include sodium chloride, polyethylene glycol (PEG), sorbitol, magnesium citrate and magnesium hydroxide.

Preparation of Suspensions

  1. Dispense the raw materials as per formula or batch manufacturing record (BMR) and sieve them.
  2. Place the portion of solvent, solid sweetener, buffer, surfactants, humectants, and other water-soluble excipients into stainless steel vessel and mix to dissolve.
  3. Add the liquid sweetener, API and other liquid excipients and a portion of solvent into stainless steel vessel and mix.
  4. Mix the suspending agents into a portion of solvent.
  5. Dissolve the preservatives and antioxidants into a portion of solvent.
  6. Mix the coloring agents and flavoring agents into a portion of solvent.
  7. Mix and homogenize all the above steps.
  8. Check the parameter such as description, weight per ml, pH, and viscosity of the sample of bulk product.

Formulation of suspensions pharmaceuticals

Formulation of Cefradine suspension (25mg/ml) (Powder for suspension)

Name of the Ingredients Purpose of Use Quantity/100ml
Cefradine API  2.50 g
Microcrystalline Cellulose and Carboxy Methyl Cellulose Sodium (Avicel) Suspending agents 0.320 g
Sucrose (Sugar) Sweetener  46.365 g
Saccharin Sodium Sweetener 0.005 g
Lactose Sweetener 3.800 g
Propyl Hydroxybenzoate (Propyl Paraben) Preservatives 0.030 g
Methyl Hydroxybenzoate (Methyl Paraben) Preservatives 0.200 g
Sodium Citrate Preservative 0.200 g
Banana Flavor Powder Flavoring agents 0.700 g
Mango Flavor Powder Flavoring agents 0.250 g
Anhydrous Citric Acid Buffer 0.120 g
Colloidal Silicon Dioxide Thickening agents 0.500 g
Pigment Blend (Brown) Coloring agents 0.010 g

Formulation of Sucralfate suspension (Prepared Suspension)

Name of the Ingredient Purpose of Use Quality (g/100 ml)
Sucralfate Active 20 g
Colloidal silicon dioxide Suspending agent 0.20 g
Glycerin 99.5% Humectant 10 g
Microcrystalline Cellulose and Carboxy Methyl Cellulose Sodium (Avicel) Suspending agent 1.25 g
Carboxy Methyl Cellulose Sodium (Sodium CMC) Suspending agent 0.50 g
Xanthan Gum Suspending agent 1.5 g
Methylparaben Preservative 0.20 g
Propylparaben Preservative 0.20 g
Simethicone 30% emulsion USP Antifoaming agent 0.30 g
Flavor such as Peppermint Flavor liquid) Flavoring agent 0.25 g
FD&C Red #40 Coloring Agent 0.015 g
Sorbitol solution  Humectant 20 g
Purified water Solvent q.S to 100 mL
References

1. Lachman, Lieberman, H.A. and Kanig, J.L., The Theory and Practice of Industrial Pharmacy, Lea and Febiger, New York, 15th edition; 2013.

2. Guide to inspections oral solutions and suspensions; oral solutions and suspensions (8/94). USFDA

3. WIPO (PCT), Pharmaceutical Suspension. Patent Number WO 2010/065730 A2, 2010.

4. Remington, Joseph P, and Paul Beringer. Remington: The Science and Practice of Pharmacy. 21st edition. Philadelphia: Lippincott Williams & Wilkins; 2005.

Keywords: Formulation of suspensions, oral suspension formulation, pharmaceutical suspension formulation, dry suspension formulation, Formulation of Sucralfate suspension, Formulation of Cefradine suspension.

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