Manufacturing Processes of Pharmaceutical Suspension

Abstract

The manufacturing process of Pharmaceutical suspensions can be said to be the large scale or industrial-scale production of pharmaceutical suspensions by pharmaceutical companies. Pharmaceutical suspensions can be defined as liquid dosage forms containing finely divided insoluble materials (the suspensoid) distributed somewhat uniformly throughout the suspending medium (suspending vehicle) in which the drug exhibits a minimum degree of solubility. This dosage form is used for providing a liquid dosage forms for insoluble or poorly soluble drugs, for drugs that are unstable in an aqueous medium for extended periods of time. Such drugs are most frequently supplied as dry powder for reconstitution at the time of dispensing.

Introduction

The manufacturing process of suspensions can be broken down into a series of unit operations which include Milling, granulation, coating, and tablet pressing are all potential parts of the process. The manufacturing processes of suspensions include the steps, tools used and considerations which are undertaken in the process of drug production.
Pharmaceutical suspension describes a dispersion of a solid material (the dispersed phase) in a liquid (the continuous phase) without reference to the particle size of the solid material. However, the particle size of the solid material can affect both its physicochemical behaviour of suspensions. Because of this a distinction is usually made between a colloid or colloidal suspension with a particle size range of up to about 1 micron, and a ‘coarse dispersion’ with larger particles. Pharmaceutical suspensions between colloidal and coarse dispersions, with solid particles generally in the range of 0.1 to 10 micrometre. Suspensions are not optically clear and will appear cloudy unless the size of the particles is within the colloidal range.
In an ideal suspension, insoluble particulate matter or drugs are uniformly suspended in three dimensions throughout the vehicle and remain so even after prolonged periods of time. Here, every dose from the suspension will contain the same amount of drug and will give the same clinical effect to the patient. This, however, is practically not possible because of the thermodynamic instability of suspension. Suspensions as dosage forms can be given orally, intramuscularly subcutaneously, intranasally, inhaled into the lungs, applied to the skin as topical preparations, or used for ophthalmic or otic purposes in the eye or ear, respectively.
Some suspensions are available in a ready-to-use form that is, already distributed through a liquid vehicle with or without stabilizers and other additives while some preparations are available as dry powders intended for reconstitution just before use with an appropriate vehicle ( this is predominantly for drugs that are unstable when kept for a long time in suspension dosage form). Generally, this type of product is a powder mixture containing the drug and suitable suspending and dispersing agents to be diluted and agitated with a specified quantity of vehicle, most often purified water. In addition pharmaceutical suspensions can be used as in-process materials during industrial pharmaceutical manufacturing. For example, tablets are coated with a suspension of insoluble coating materials.
Granules manufactured by wet granulation processes are typically suspended in the air for drying during ﬂuidized bed-drying process. In addition, wet granulation could be carried out on granules suspended in the air in a process called ﬂuid-bed granulation.

The ideal features of Pharmaceutical Suspensions.

An ideal pharmaceutical suspension should contain the following features before it can be deemed a perfect suspension.

The final product should be physically, chemically and microbiologically stable.
It should be aesthetically pleasing and should also have a pleasing odour, and taste.
Suspended particles should be small and uniformly sized in order to give a smooth, elegant product free from a gritty texture.
The suspension must remain sufficiently homogenous for at least the period between shaking the container and removing the required amount.
It must not be too viscous to pour freely from a bottle or to ﬂow through a needle syringe (for injectable suspensions).
All the doses dispensed from a given multi-dose container should have acceptable uniformity of drug content.
It must not recrystallize and/or change its polymorphic form during storage.
The suspended particles should settle slowly and the sediment or creaming produced on storage, if any, should readily redisperse upon gentle shaking of the container.
Parenteral and ophthalmic suspensions should be sterilizable and syringable (for parenteral suspensions).
Parenteral suspensions should be isotonic and non‐irritating.
In the case of an external lotion, the product must be fluid enough to spread easily over the affected area but not so ﬂuid that it runs off the surface too quickly and also must dry quickly and provide an elastic protective film that will not rub off easily.

Classifications of Pharmaceutical Suspension

Classification based on the route of administration (general classes) which includes the oral, parenteral, rectal, otic, ophthalmic, aerosols and topical suspensions
Classification based on the concentration of the dispersed phase which include dilute and concentrated suspensions.
Classification based on electrokinetic nature of solid particles which includes flocculated and deflocculated suspensions.
Classification based on the size of solid particles. It is essentially based on the particle size (diameter) of the dispersed phase and thus can be classified as Coarse suspension (>1 μm), colloidal dispersion (< 1 μm), nanosuspension (10–100 nm).

Materials used for the manufacture of pharmaceutical suspensions.

In the manufacture of Pharmaceutical suspensions there are excipients used and they include

Solvents/ Vehicles: They are the major components which are used as bases in which drugs and other excipients are dissolved or dispersed. The most commonly used vehicle for the formulation of pharmaceutical suspensions is purified water. In a few instances, viscous nonaqueous solvents, such as propylene glycol and polyethylene glycols, are used as vehicles to impart stability to suspended drug particles. The choice of solvent used usually depends on the nature and physicochemical properties of the active pharmaceutical ingredient (API) and the intended use of the formulation.
Buffering agents: They are otherwise known as pH modifiers are agents that are added to suspensions to control potential changes in the pH of formulations. Citrates and phosphates are commonly used buffers in pharmaceutical suspensions. Citrate buffers are used to stabilize suspensions which are in the pH range of 3 – 5, while phosphate buffers are used for the pH range of 7 – 8.
Antioxidants: They are required in certain pharmaceutical suspensions to enhance the chemical stability of the therapeutic agent, where this may be compromised by oxidation. Examples include thiourea, butyl hydroxy toluene (BHT), tocopherols, ascorbic acid, sodium bisulphate, etc.
Preservatives: Preservatives are often added in aqueous suspensions to protect them from microbial contamination. Common preservatives used in pharmaceutical suspensions are parabens, alcohol, glycerin, propylene glycol, and sorbates.
Flocculation modifiers: They are neutral electrolytes that have the capability of preventing caking of suspended solids. Examples of flocculating agents used in pharmaceutical suspension (usually at concentrations 0.01 – 1.00 %) include sodium or potassium chloride, aluminum chloride, calcium salts, citrates, etc.
Suspending agents/ Viscosity-modifiers: These are hydrophilic colloids, such as cellulose derivatives, acacia, and xanthan gum that are added to a suspension to increase viscosity inhibit agglomeration, and decrease sedimentation.
Wetting agents/ surfactants: Wetting agents are used to improve the flow of the liquid vehicle across the particle surface, which in turn improves the homogeneity of distribution of the drug particles throughout the formulation. Examples include polysorbates, sorbitan esters etc.
Antifoaming agents: These are excipients that prevent foam formation during the manufacture of suspensions or when reconstituting powder for suspension. Examples include simethicone, organic phosphates, alcohols, paraffin oils, stearates and glycols
Flavoring agents: Flavours e.g., peppermint, lemon oils, butterscotch, ‘tutti-frutti’ flavour etc., are added to pharmaceutical suspensions for taste-masking purposes.
Humectants: Humectants are added to slow down the rate of evaporation of aqueous vehicle from dosage forms during storage and use. Examples include glycerol, propyleneglycol etc.
Chelating agents: Chelating agents are added to pharmaceutical suspensions to protect drug substance(s) from catalysts that rate of oxidative reaction.
Sweeteners: They are often added to suspensions to reduce any unpleasant taste of the partially dissolved drug and to improve palatability in general. Examples include sorbitol, corn syrup, sucrose, saccharin, acesulfame, and aspartame.
Colorants: These are usually added to provide a more aesthetic appearance to the final product. The choice of colorant is usually tied to the choice of ﬂavour, and their choices are also linked to the patient population, such as age group and geographic region, and the therapeutic need. For example, a red colorant is usually used with strawberry ﬂavour for pediatric formulations.

Manufacturing process of pharmaceutical Suspensions

These processes include the steps taken, the tools used and the considerations which are put in place in the process of manufacture of pharmaceutical suspensions. These includes the following:

Pharmaceutical Manufacturing Steps

The manufacture of pharmaceutical suspensions involves several steps. The first step is to obtain particles of the proper size typically in the micrometer range and then incorporation of the adjuvants to make a suspension. These steps of production can be grouped into the following methods:

Direct Incorporation/ Dispersion Method. This method involves the dissolution of the soluble components in the appropriate volume of diluent (vehicle) and the dispersion of the solid therapeutic agent into the vehicle with the aid of mixing, prior to correction for volume. When the dispersion method is used for suspension preparation, the vehicle must be formulated so that the solid phase is easily wetted and dispersed. Wetting agents and suspending agents may be used to achieve that. The mixing rate employed during the dispersion of the solid therapeutic agent is an important determinant in the manufacture of the formulation. If the suspension is flocculated, high-speed mixing may be employed as the flow properties of the system are pseudoplastic. However, if the formulation has been poorly designed and has poor flocculation properties, high-speed mixing will result in an increase in the viscosity of the product (termed dilatant flow).
Precipitation method: The preparation of suspensions by precipitation method includes dissolving the drug in the vehicle (or a portion of the available volume), prior to precipitation following the addition of a counterion; the salt formed is insoluble.The excipients are then dissolved in the vehicle, or dissolved in a portion of the vehicle, which is then added to the suspension of drug.At this stage, the formulation may be exposed to high shearing rates to ensure homogeneity. The volume of the formulation is then corrected by adding the required mass of diluent to get the required volume of suspension needed. The potential problem with this method of suspension formulation is the production of ionic by-products from the precipitation interaction. If the concentration of these ionic byproducts is too high, then there is need to wash the precipitated therapeutic agent with an aqueous solvent.
Controlled flocculation: This type of flocculation imparts structure to suspensions with virtually no increase in viscosity. The preparation of suspensions by controlled flocculation includes dissolving the wetting agent in approximately half the final volume of the aqueous vehicle.The drug is micronized and is uniformly spread over the surface of the vehicle at the desired concentration and allowed to be wetted undisturbed and the wet slurry thus formed is passed through a fine wire sieve or a colloid mill to remove poorly wetted powder.The slurry concentrate of the drug is agitated and the flocculating agent is added till flocculation endpoint is reached. To determine the endpoint, small samples are transferred to a graduated cylinder, an equal amount of vehicle is added and the cylinder is gently shaken and allowed to stand undisturbed. The sample with the highest ratio of sediment to total suspension volume, exhibiting a clear supernate and good drainage characteristic, is considered to be at the appropriate endpoint. Then the remaining formulation adjuvants (preservatives, colorant, flavor, buffer etc.) are added and the slurry is brought to final volume with liquid vehicle.

In continuous manufacturing, raw materials and energy are fed into the system at a constant rate, and at the same time, a continual extraction of output products is achieved. The process performance is heavily dependent on the stability of the material flowrate. For powder-based continuous processes, it is essential to feed powders consistently and accurately into the successive processes in the line, as feeding is characteristically the first step in manufacturing. Feeders are designed to achieve performance reliability, feed rate accuracy, and minimal interruptions. With pharmaceutical manufacturing, a wide range of non-active ingredients may be blended with the active pharmaceutical ingredient or ingredients to create the final blend used for the solid dosage form. During the manufacturing process, milling is often obligatory to reduce the average particle size in a drug powder. There are several reasons for this, including increasing homogeneity and dosage uniformity and increasing the solubility of the drug compound. Sometimes repeated powder blending followed by milling occurs to improve the manufacturability of the blends. Granulation can also be employed in which small particles are connected to form larger particles called granules. Granulation is used to prevents the “demixing” of components in the mixture, by creating a granule which contains all of the ingredients in their required proportions, which improves flow characteristics of powders and increases compaction properties for tablet formation. Solid and liquid ingredients are mixed in compounding equipments to produce suspensions.

Pharmaceutical Manufacturing Tools

This involves the precise requirements for manufacturing in pharmaceutical industries and the equipments which are employed. These equipments includes: capsule filling machines, x-ray inspection systems, tablet punches, and spray drying accessories and Millers which are used for particle size reduction of hard or coarse particles. Almost every process can be automated to ensure precise manufacturing and formulation development. Contained process equipment and transfer systems should be used in the compounding of highly hazardous materials like buffering agents, detergents, and antiseptics which may be dangerous to workers. Eyewashes and safety showers help minimize injuries if workers accidentally contact corrosive or irritating substances. Because of the wet surfaces in compounding areas, workers need to be protected from electrical hazards of equipment and utilities. Burns and falls are prevented by the installation of insulation on hot surfaces and maintaining dry non-slip floors. Safety equipment is just as essential to the drug manufacturing process.

Pharmaceutical Manufacturing Considerations

Manufacturing operations pose many health and safety hazards to workers which include moving machine parts, pressurised equipment and pipes, and the heavy manual handling of materials and equipment. More potential risks are steam, hot liquids, heated surfaces, hot workplace environments, confined spaces, hazardous energy sources, and high noise levels can all be dangerous. Exposure to hazardous chemicals during manufacturing operations may result in chronic health risks for workers. Chemicals with severe health effects can damage the eyes and skin, be corrosive or irritating to body tissues or cause suffocation or oxygen deficiency. Chemicals with chronic health effects can cause cancer or damage the liver, kidneys, lungs, or other organ systems if mishandled. The implementation of appropriate control measures e.g. process modifications, engineering controls, administrative practices, personal and respiratory protective equipment helps to limit health and safety hazards.
Organic synthesis reactions may create significant safety risks from highly hazardous materials, fire, explosion, or uncontrolled chemical reactions that impact the public around the plant. Process safety can be very complex with organic synthesis but examining the dynamics of chemical reactions, along with the properties of highly hazardous materials, helps with safety. The training of operating and engineering staff in their response to emergency and risk is also helpful. It is essential to employ companies that specialize in process hazard analysis to reduce the risks of chemical synthesis operations. It’s essential to take every precaution to ensure workers’ health and safety when manufacturing pharmaceuticals.

Conclusion

Large scale manufacturing process has more benefits both to the consumer ( more availability of drugs) and the manufacturing companies. It is therefore important to understanding of pharmaceutical manufacturing processes and risks which are involved in large scale manufacture of pharmaceutical products and how best to manage them.

References

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