Formulation and Evaluation of an Injectable Dosage Form

 

Sneha Thomas, R. Selvakumar, Mr. S Mahendran*

Nehru College of Pharmacy, Pampady, Thiruvillwamala, Kerala, India

 

ABSTRACT:

The various initial formulations of the developed and those are examined for drug release profile, bioavailability, and clinical effectiveness and for the pilot plant studies and production scale-up. The drug that we need should be most convenient and in proper form then only it reaches to the desired site of action. This is greatly influenced by which the type of dosage form of the drug. Since, injections include much variety of therapeutic agents. Injections are sterile, pyrogen limited, that is, bacterial endotoxin units limit, preparations intended to be administered parenterally. It is well recognized that the advantages of parenteral injections are immediate systemic drug availability and rapid onset of action.

 

 

 

INTRODUCTION:

The prime function of Research and Developments in pharmaceutical companies is to discover and to develop the new medicines. To achieve these objectives are not easy, in this a small percentage of the synthesized chemical compounds become medicines. In this also most compounds prove, unsuitable for reasons of efficacy, toxicity and potency. When a potential drug, that selected for development should extensively safety. ^[1] A generic drug is the same as a brand name drug in its dosage, safety, strength, how it taken, how it performance, quality and intended use. FDA requires many rigorous test and procedures to assure that the generic drug can be substituted for the brand name drug, before approving a generic drug product^[2].

 

 

The U.S FDA doesn’t provide regulatory formal definition for excipients, and then also, according to guidance on nonclinical safety studies, new excipients are inactive ingredients that added intentionally to the therapeutic and diagnostic products.^[3]Dosage forms are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components that is excipients, in a particular configuration and apportioned into a particular dose. The desired product type must be determined as possible to establish the framework for product development, before formulating a drug substance into a dosage form. ^[4]

 

Before a medicinal agent is formulated into one or more dosage forms, the factors to considered are such therapeutic matters are the nature of illness, in which the manner it is treated (locally or systemic action), age and patient’s anticipated condition.^[4] The drug that we need should be most convenient and in proper form then only it reaches to the desired site of action. This is greatly influenced by which the type of dosage form of the drug.

 

An ideal dosage form should be:

·         It should be safe and easy to administer.

·         It should be easy to handle.

·         It should be easy to produce and manufacture

·         Provide high patient compliance.

·         Should be physically and chemically stable.

·         It should maintain its therapeutic activity throughout the shelf life.^[5]

 

Injectable solution:

Injections include much variety of therapeutic agents. In USP more than 400 injections products are listed. ^[6] If the intravenous administration is preferred then only the dosage form can be solutions or micro emulsions. Or if the administration route is intramuscular or subcutaneous, then the dosage form type is a suspension or other micro particulate drug delivery system. The dosage forms that conveying the drug by means of the injection through skin or the mucous membranes. ^[7] Some medicines cannot be given by oral due chemical action of enzymes. ^[8]

 

The most convenient and simplest form of an injectable product is an isotonic aqueous solution, which have the pH close to that of blood and the body tissues (pH 7.4).^[9]     

 

Figure 1.1: An injectable solution

 

Guiding principles for simple parenteral solutions

Selection of injectable volume

Pharmacopoeias classify the injection into types:

·         Small-volume parenterals

·         Large-volume parenterals

 

According to USP SVPs that containing less than 100 mL and LVPs are having more than 100 mL. SVPs are usually given rapidly in small volume are called as a bolus. In LVPs also they added like 5% dextrose and 0.9 %sodium chloride injection or infusion is administered through IV infusion. Based on the pharmacokinetics of the drug the bolus or infusions are selected.   A bolus administration is preferred for intramuscular or subcutaneous injections. Subcutaneous route is used if the injection volume is less than 1- 1.5 mL and through intramuscular route usually no more than 2 mL.  In the formulation of a solution product, the main step is to select the administration volume and concentration. Example: larger volume or lower concentration is requiring for low solubility, the converse would be true if at higher concentrations the stability is improved.

 

 

pH and Tonicity requirements:

pH considerations:

The generation of pH/stability and pH/ solubility profiles is the main step in the selection of pH in a formulation. For the maximum physiological acceptability, the target pH is approximately pH 7.4.  When the dosing through IV route, a wide pH range can be tolerated and a rapid dilution wit blood also can be achieve. pH value ranging from 2 to 12 can be tolerated in these situations when intramuscular administration is uses the dilution rate is slower and it is further decreases when the subcutaneous route is administered. Tolerability of a formulation depends on its buffering capacity. For Example pH of 0.9%w/v sodium chloride infusion can be low as to pH 4, due to the buffering capacity lack. It symbols it have a negligible effect on the blood pH into which it is infused, when a rapid administration also recommended.

 

Table 1: Buffers used in the approved parenteral products

 

Tonicity consideration:

All parenteral products should be isotonic, especially osmolarities should target between 280 and 290 mOsm/L during a formulation. For LVPs isotonicity is very essential. Either the rapid dilution with blood that will occur after injection or prior to administration the product itself diluted with an LVP, a wider range of osmolarities can be tolerated in SVPs. For hypotonic solutions hypertonic solutions are preferred since the risk of haemolysis associated with the hypotonic solution. By the use of excipients the hypotonic solutions are avoided, since the sodium chloride to raise the osmolality. ^[10] To avoid the tissue damage parenteral formulations should be isotonic with human plasma. ^[11]

 

Choice of excipients:

In pharmaceutical products the formulations should developed by using excipients. In parenteral products the quality, particularly in microbial terms of excipients should be considered necessarily. The injectable grades are usually used for parenteral excipients which have strict bio burden and endotoxin limits. The excipients have pharmacopoeial grade also acceptable. But this is usually to apply In-House microbiological specification limits. ^[10] The integral part of pharmaceutical products development is excipients, to achieve the desired product profile (stability and efficacy). ^[11]

 

General guidance for developing formulations of parenteral drugs:

Pharmacokinetics of the drug:

The absorption rate for routes of administration other than intravenous or intra-arterial, distribution, metabolism and excretion of drugs have effect on route of administration that selected, based on the type of formulation. For example: a drug having a rapid pharmacokinetic profile, there is need of development of modified release dosage formulations. Pharmacokinetics also affects the drug dose and the dosage regimen.  A multiple dosage form developed when a dosage regimen requires frequent injections, if it is feasible also. From the site of injection the drug is distributed very fastly, when the addition of complexing or viscosity agents are added to the formulation to retard the drug transport and dissolution. ^[12]

 

Drug solubility:

The formulation must contain a co-solvent or a solute which sufficiently increases and maintains the drug in solution, if the drug is insufficiently soluble in the water at the dosage required. Solubility is the major factor that gives the concentration in the dosage form. A dispersed system dosage form developed, when simple formulation additives do not result in the solution. ^[12]

 

Drug stability:

If the drug possesses significant degradation problems in the solution, then freeze dried or sterile solid dosage form should be developed. Sometimes drug concentration affects the stability in turn, affect size and the packaging system used also.

 

Example: due to the stability or the solubility limitations if the concentration must be low, then the primary container must be in larger size and also this should preclude the use of syringes, cartridges, and smaller vial sizes. Stability determines the storage conditions since it indicates the drug expiration date. The container used can’t be large if there is need for refrigeration of product and formulation components should be soluble and also stable in colder conditions. The choice of the container size, formulation components and container type are dictated by storage conditions. Compatibility of drugs with potential formulation additives and packaging systems: To ensure the formulation additives the initial preformulation screening studies are necessary. And the solving of one problem should not create any another problem. Buffering agents, antioxidants like stabilizers catalyze the chemical degradation reactions. The one of the reasons for the drug degradation reactions are impurities in excipients. ^[12]

 

Advantages of parenteral products:

These are useful in:

·       Unconscious patients.

·         Uncooperative and unreliable patients.

ü  Onset of action of drugs is faster; hence it is suitable for emergency.

ü  Patients with vomiting and diarrhea.

ü  These are suitable for irritant drugs and drugs with high first pass metabolism.

ü  Drugs are not absorbed orally.

ü  Drugs destroyed by digestive juices.

 

Disadvantages:

·       Parenteral preparations should be sterile and expensive.

·       They require aseptic conditions.

·       Cost

·       They can’t easily self- administrated.

·       Causes local tissue injury to nerves, vessels, etc.

 

Parenteral product formulation depends upon the understanding of several factors that dictate the choice of formulation and dosage form. ^[13]

 

Development of parenteral products:

Based on the requirements of sterility of the finished product parenteral products manufacturing process considered. The products which are preferred should be terminally sterilized and the most of parenterals are filtered through sterilizing grade filters. Sterile products are manufactured in an aseptic specialized area.

 

Figure 1: Production of parenterals

 

Based on the requirements of sterility of the finished product parenteral products manufacturing process considered. The products which are preferred should be terminally sterilized and the most of parenterals are filtered through sterilizing grade filters. Sterile products are manufactured in an aseptic specialized area.

 

Filtration:

If the product is a solution, after its compounding, it should filter. Filtration process is employed for to clarify a solution and removing particulate matter down to 0.2μm in size will eliminate the micro-organisms. It is accomplished by cold sterilization. Any parenteral solution is said to high quality and purity the solution must have high degree of clarity.

Filters mainly functions by:

Sieving or screening:          

The particles are retained on the surface of the filter by sieving

 

Entrapment or impaction:

If the particles smaller than the dimensions of the pore, they impact on the surface of the pore.

 

Electrostatic attraction:

Opposite charged particle to that of the surface of the filter pore to be adsorbed on the surface.

 

Membrane filters are used for parenteral preparations because they have high effective in particle- retention, non-shedding property, non- reactivity and have disposable characteristics also. The most common membranes are made up of cellulose esters, nylon, polycarbonate, PVDF, and Teflon. Membrane filters are disposable type and can be discarded after use. It should clean thoroughly while using. Most pharmaceutical industries that preparing parenterals uses 0.2 μm membrane filter.

 

Filling:

During the filling of product to the containers, should be for the prevention of contamination, especially the product is sterilized by the filtration and will not be sterilized in to the final container. The second one is called as aseptic fill and by using media fills it is validated. The product must be transferred from the bulk container or tank and they subdivided into dose containers during the filling operation. Until it is sealed in to the dose container the operation exposes the sterile product in to the environment, equipment and the manipulative technique of the operators. A liquid is more easily exposed uniformly into the container having the narrow mouth than is used for solid. Liquids which are mobile are easier to transfer and subdivide than viscous or sticky fluids, since these require heavy-duty machinery for the rapid production filling.

 

Liquid:

The filling of liquids into containers with high accuracy involves mainly three methods

·       Volumetric filling

·       Time/pressure filling

·       Net weight filling

 

Volumetric filling machines have pistons or peristaltic pumps. These are most common used method. Time-pressure filling is used for filling of sterile liquids. A filling system is connected by a production tank that equipped with a pressure sensor. The sensor is used for the measurement of pressure and transmits values PLC system that controls the product flow from the tank to the filling manifold. When the tubing is mechanically unpinched then the product flow occurs and it stops tubing is mechanically pinched. The product is driven by using pressure mainly uses nitrogen with no pump mechanism. Time/pressure filling is preferable usually with the proteins that are sensitive to shear forces.

 

The USP requires that containers must be filled with sufficient volume that in excess of the labeled volume to be ensure the withdrawal of the labeled volume. These then provides the suggested fill volumes. Small numbers of containers are filled by using hypodermic syringe and needle. The liquid is drawn into the syringe and then forced through the needle to the container.

 

Sealing:

Ampoules:

To prevent the contents from the contamination by environment, the containers that filled should be sealed as soon as possible. Sealing of ampoules are done by melting of the portion of the glass neck. There are two types of sealing:

·       Pull –seals

·       Tip-seals (bead –seals)

 

Tip seals are employed by melting the glass at the tip of the ampoule neck to form a bead like and close the opening. This is performed in a high temperature gas oxygen flame. Heating of ampoule neck is to evenly on all sides to produce a uniform bead. The flame temperature should properly adjust. The excess heat results in expansion of the gases inside the ampoule that against the soft bead seal, that leads to form bubbles. The ampoule is no longer sealed if the bubble is bursts. Ampoule that sealed incompletely called as leaker.

 

Pull-seals are performed by heat the ampoule neck below the tip. The ampoule to be   seal is rotated in the flame from a single burner. The tip is grasped and then pulled quickly from the ampoule body, when the glass is softens. Pull sealing process is slower one, but the sealing done by this is more secure than that of tip-sealing.  Wide opening ampoules are sealed by pull sealing. Fractures that occur in the ampoule neck during the sealing can occur, if the necks are wetted at the time of filling. The frequency of bubble formation is increased by the wet necks and deposition of the carbon, when the product is organic.

 

Vials and bottles:

By closing the opening using the rubber closure (stopper) the glass or the plastic vials are sealed properly. This should be done by after filling with care, to prevent the contamination of the contents inside. Increased chances for contamination are the large opening in the vials than the ampoules. The open containers must be protected from contamination, especially with the blanket of HEPA filtered laminar airflow. The closure should be correctly fit as not difficulty to introduce into the container mouth. By mechanically the closures are inserted into the vial mouth by an automated process with high speed also.

 

By using the aluminium caps the rubber stoppers are held in appropriate place. The caps cover the stopper and that imped to lip of the vials to hold them in accurately in place. The closure is removed only after the destroying of the aluminium caps. The aluminum caps are structured so that the outer layer of double layered caps, or the single layered caps centre, and this can be removed to visible the centre of the rubber closure. Rubber closures that uses for the intravenous administration have a permanent hole through the closure.

 

Sterilization:

Sterilization of parenteral products should be done after sealing it to the final container that is called as terminal sterilization. It should done within as short time as that possible after the filling and sealing are fully completed. This is accomplished usually by the thermal process. Radiation sterilization also will do to the parenteral finished products in sometimes. The care should be taken in the effect of the elevated temperature on the stability of the products. The elevated temperature that required for the sterilization by thermal process is adversely affects in many products like both pharmaceutical and biological. Non thermal methods are used for the heat-labile products. These non thermal methods include filtration through the bacteria retaining filters. Aseptic conditions should be strictly followed for all operations, and then only the contamination is not introduced into the filtrate.

 

Radiation sterilization is used as an alternative to terminal sterilization method. When the drugs and excipients are exposed to the high energy gamma radiation there are chances of occurring of molecular transformations. In this the successful process is the use of lower energy electron beam (beta particle) radiation. Radiation sterilization is mainly used in the materials like plastic medical devices.

 

Dry-heat sterilization is performed for few dry solids that are not adversely affects by the high temperatures and that require long period of heating. For the sterilization of glassware and metal ware mostly performs the dry-heat sterilization process. After the sterilization process all the equipment will be sterile, dry and pyrogen-free.

 

Autoclaving (saturated steam under pressure) is the most common method used for sterilization process. It is the most effective sterilization method that used for the aqueous liquids or substances, since it can be reached or penetrated by the steam.

Packaging of parenteral products containers:

Types of containers:

A.      Glass containers

B.      Plastic containers

 

Glass containers:

In most of the SVIs glass is used as the material choice for the containers. Principally glass containers are composed of silicon dioxide with varying amounts of various oxides such as potassium, sodium, calcium, magnesium, aluminum, boron, and iron. Silicon oxide tetrahedron forms the basic structural network of glass. Boric oxide will enter into the basic structural network and the other oxides do not enter into this structure. These oxides are present in the network interstices and are loosely bound, relatively free to migrate. During the high reactivity of thermal sterilization these migratory oxides leached into a solution that in contact with glass. To raise the solution pH and catalyze or enter into reactions the oxides that dissolved may hydrolyze.

 

Table 2: USP glass types

Types	General description	General use
I.	Highly resistant borosilicate glass	·  Buffered and unbuffered aqueous solutions ·  All other uses.
II.	Treated soda- lime glass	·  Buffered aqueous solutions with pH below 7.0 ·  Dry powders ·  Oleaginous solutions.
III.	Soda- lime glass	·  Dry powders ·  Oleaginous solutions
NP	General purpose soda-lime glass	·  Not for parenterals. ·  For tablets, oral solutions, ointments, external liquids

 

Plastic containers:

Sterile preparation like large-volume parenterals, ophthalmic solutions and mainly in small volume parenterals uses thermoplastic polymers as packaging materials. The principal advantage of plastic while comparing with glass, it is not breakable easily and reduction in weight also. In large-volume intravenous fluids currently uses the flexible bags of PVC (polyvinyl chloride) or select polyolefin. This having major advantage that there is no requirement of air interchange.

There is some principal problems occur in using these materials:

·       Permeation the molecules and vapors through the wall of the plastic container in either direction.

·       Leaching of constituents may occur from plastic into the product.

·       Absorption or desorption of drug molecules or ions on the plastic material.

 

Rubber closures:

Rubber closures are made up of using milling machines by multiple ingredients plasticized and mixed together at an elevated temperature ^[14].

CONCLUSION:

The most effective route for the delivery of the active pharmaceutical substances is the parenteral rout of administration, prescribed to unconscious patients. The present article describes that design, principles and manufacturing of sterile products. Parenteral preparations are the pyrogen free liquids, which manufactured and stored accordingly to cGMP guidelines. An excellent parenteral product will require proper area, good environmental control and personnel observation, to attain their described therapeutic effect.

 

ACKNOWLEDGEMENT:

Authors wish to thanks the authority of Nehru College of Pharmacy for providing such a facility to carry out this review article.

 

REFERENCES:

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Received on 29.07.2018         Modified on 18.08.2018

Accepted on 07.09.2018       ©A&V Publications All right reserved