Parenterals Product requiring sterile packaging: General formulation, vehicles and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Parenterals Product requiring sterile packaging: General formulation, vehicles and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Formulation Principles: Parenteral drugs are formulated as solutions, suspensions, emulsions, liposomes, microspheres, nanosystems, and powders to be reconstituted as solutions. This section describes the components commonly used in parenteral formulations, focusing on solutions and freeze-dried products. General guidance is provided on appropriate selection of the finished sterile dosage form and initial approaches used to develop the optimal parenteral formulation.

Vehicles:

1. Water – Since most liquid injections are quite dilute, the component present in the highest proportion is the vehicle. The vehicle of  greatest importance for parenteral products is water. Water of suitable quality for compounding and rinsing product contact surfaces, to meet United States Pharmacopeia (USP) and other compendia specifications for Water for Injection (WFI), may be prepared either by distillation or by reverse osmosis. Only by these two methods is it possible to separate various liquid, gas, and solid contaminating substances from water. With the possible exception of freeze-drying, there is no unit operation more important and none more costly to install and operate than that for the preparation of WFI.
2. Water-miscible vehicles – A number of solvents that are miscible with water have been used as a portion of the vehicle in the formulation of parenterals. These solvents are used to solubilize certain drugs in an aqueous vehicle and to reduce hydrolysis. The most important solvents in this group are ethyl alcohol, liquid polyethylene glycol, and propylene glycol. Ethyl alcohol is used in the preparation of solutions of cardiac glycosides and the glycols in solutions of barbiturates, certain alkaloids, and certain antibiotics. Such preparations are given intramuscularly.

3.Non-aqueous vehicles – The most important group of non-aqueous vehicles is the fixed oils. The USP provides specifications for such vehicles, indicating that the fixed oils must be of vegetable origin so they will metabolize, will be liquid at room temperature, and will not become rancid readily. The USP also specifies limits for the free fatty acid content, iodine value, and saponification value (oil heated with alkali to produce soap, i.e., alcohol plus acid salt). The oils most commonly used are corn oil, cottonseed oil, peanut oil, and sesame oil. Fixed oils are used as vehicles for certain hormone (e.g., progesterone, testosterone, deoxycorticosterone) and vitamin (e.g., Vitamin K, Vitamin E) preparations. The label must state the name of the vehicle, so the user may beware in case of known sensitivity or other reactions to it.

Added substances: The USP includes in this category all substances added to a preparation to improve or safeguard its quality. An added substance may:

  • Increase and maintain drug solubility. Examples include complexing agents and surface active agents. The most commonly used complexing agents are the cyclodextrins, including Captisol. The most commonly used surface active agents are polyoxyethylene sorbitan monolaurate (Tween 20) and polyoxyethylene sorbitan monooleate (Tween 80).
  • Provide patient comfort by reducing pain and tissue irritation, as do substances added to make a solution isotonic or near physiological pH. Common tonicity adjusters are sodium chloride, dextrose, and glycerin.
  • Enhance the chemical stability of a solution, as do antioxidants, inert gases, chelating agents, and buffers.
  • Enhance the chemical and physical stability of a freeze dried product, as do cryoprotectants and lyoprotectants. Common protectants include sugars, such as sucrose and trehalose, and amino acids, such as glycine.
  • Enhance the physical stability of proteins by minimizing self-aggregation or interfacial induced aggregation. Surface active agents serve nicely in this capacity.
  • Minimize protein interaction with inert surfaces, such as glass and rubber and plastic. Competitive binders, such as albumin, and surface active agents are the best examples.
  • Protect a preparation against the growth of microorganisms. The term ‘preservative’ is sometimes applied only to those substances that prevent the growth of microorganisms in a preparation. However, such limited use is inappropriate, being better used for all substances that act to retard or prevent the chemical, physical, or biological degradation of a preparation.
  • Although not covered in this chapter, other reasons for adding solutes to parenteral formulations include sustaining and/or controlling drug release (polymers), maintaining the drug in a suspension dosage form (suspending agents, usually polymers and surface active agents), establishing emulsified dosage forms (emulsifying agents, usually amphiphilic polymers and surface active agents), and preparation of liposomes (hydrated phospholipids).

Antimicrobial agents: The USP states that antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple-dose containers. The USP provides a test for Antimicrobial Preservative Effectiveness to determine that an antimicrobial substance or combination adequately inhibits the growth of microorganisms in a parenteral product. Because antimicrobials may have inherent toxicity for the patient, the USP prescribes maximum volume and concentration limits for those commonly used in parenteral products (e.g., phenylmercuric nitrate and thimerosal 0.01%, benzethonium chloride and benzalkonium chloride 0.01%, phenol or cresol 0.5%, and chlorobutanol 0.5%). Benzyl alcohol, phenol, and the parabens are the most widely used antimicrobial preservative agents used in injectable products.

Buffers: Buffers are used to stabilize a solution against chemical degradation or, especially for proteins, physical degradation (i.e., aggregation and precipitation) which might occur if the pH changes appreciably. Buffer systems should have as low a buffering capacity as feasible, so as not to significantly disturb the body’s buffering systems when injected. In addition, the buffer type and concentration on the activity of the active ingredient must be evaluated carefully. Buffer components are known to catalyze degradation of drugs. The acid salts most frequently employed as buffers are citrates, acetates, and phosphates. Amino acid buffers, especially histidine, have become buffer systems of choice for controlling solution pH of monoclonal antibody solutions.

Anitoxidants: Antioxidant’s are frequently required to preserve products, due to the ease with which many drugs, including proteins with methionine or cysteine amino acids conformationally exposed, are oxidized. Sodium bisulfite and other sulfurous acid salts are used most frequently. Ascorbic acid and its salts are also good antioxidants. The sodium salt of ethylenediaminetetraacetic acid (EDTA) has been found to enhance the activity of antioxidants, in some cases, by chelating metallic ions that would otherwise catalyze the oxidation reaction.

Tonicity Agents: Tonicity Agents are used in many parenteral and ophthalmic products to adjust the tonicity of the solution. Although it is the goal for every injectable product to be isotonic with physiologic fluids, this is not an essential requirement for small volume injectables administered intravenously. However, products administered by all other routes, especially into the eye or spinal fluid, must be isotonic. Injections into the subcutaneous tissue and muscles should also be isotonic to minimize pain and tissue irritation. The agents most commonly used are electrolytes and mono- or disaccharides.

Cryoprotectants and Lyoprotectants: Cryoprotectants and Lyoprotectants are additives that serve to protect biopharmaceuticals from adverse effects, due to freezing and/or drying of the product during freeze-dry processing. Sugars (non-reducing), such as sucrose or trehalose, amino acids, such as glycine or lysine, polymers, such as liquid polyethylene glycol or dextran, and polyols, such as mannitol or sorbitol, all are possible cryo- or lyoprotectants. Several theories exist to explain why these additives work to protect proteins against freezing and/or drying effects. Excipients that are preferentially excluded from the surface of the protein are the best cryoprotectants, and excipients that remain amorphous during and after freeze drying serve best as lyoprotectants.

General guidance for developing formulations of Parenteral Drugs: The final formulation of a parenteral drug product depends on understanding the following factors that dictate the choice of formulation and dosage form.

1. Route of administration—Injections may be administered by such routes as intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intralesional, and intrathecal. The type of dosage form (solution, suspension, etc.) determines the particular route of administration employed. Conversely, the desired route of administration places requirements on the formulation. For example, suspensions would not be administered directly into the bloodstream, due to the danger of insoluble particles blocking capillaries. Solutions administered subcutaneously require strict attention to tonicity adjustment, otherwise irritation of the plentiful supply of nerve endings in this anatomical area would give rise to pronounced pain. Injections intended for intraocular, intraspinal, intracisternal, and intrathecal administration require stricter standards of such properties as formulation tonicity, component purity, and limit of endotoxins, due to the sensitivity of tissues encountered to irritant and toxic substances.

2. If the route of administration must be intravenous, then only solutions or microemulsions can be the dosage form. If the route of administration is subcutaneous or intramuscular, then the likely type of dosage form is a suspension or other microparticulate delivery system.

3. Pharmacokinetics of the drug—Rates of absorption (for routes of administration other than intravenous or intraarterial), distribution, metabolism, and excretion for a drug have some effect on the selected route of administration and, accordingly, the type of formulation. For example, if the pharmacokinetic profile of a drug is very rapid, modified release dosage formulations may need developed. The dose of drug and the dosage regimen are affected by pharmacokinetics, so the size (i.e., concentration) of the dose will also influence the type of formulation and amounts of other ingredients in the formulation. If the dosage regimen requires frequent injections, then a multiple dose formulation must be developed, if feasible. If the drug is distributed quickly from the site injection, complexing agents or viscosity inducing agents may be added to the formulation to retard drug dissolution and transport.

4. Drug solubility—If the drug is insufficiently soluble in water at the required dosage, then the formulation must contain a co-solvent or a solute that sufficiently increases and maintains the drug in solution. If relatively simple formulation additives do not result in a solution, then a dispersed system dosage form must be developed. Solubility also dictates the concentration of drug in the dosage form.

5. Drug stability—If the drug has significant degradation problems in solution, then a freeze-dried or other sterile solid dosage form must be developed. Stability is sometimes affected by drug concentration that, in turn, might affect size and type of packaging system used. For
example, if concentration must be low, due to stability and/or solubility limitations, then the size of primary container must be larger, and this might preclude the use of syringes, cartridges, and/or smaller vial sizes. Obviously, stability dictates the expiration date of the product that, in turn, determines the storage conditions. Storage conditions might dictate choice of container size, formulation components, and type of container. If a product must be refrigerated, then the container cannot be too large, and formulation components must be soluble and stable at colder conditions.

6. Compatibility of drug with potential formulation additives and packaging systems—It is well-known that drug-excipient incompatibilities frequently exist. Initial preformulation screening studies are essential to ensure that formulation additives, although possibly solving one problem, will not create another. Stabilizers, such as buffers and antioxidants, although chemically stabilizing the drug in one way, may also catalyze other chemical degradation reactions. Excipients and certain drugs can form insoluble complexes. Impurities in excipients can cause drug degradation reactions. Peroxide impurities in polymers may catalyze oxidative degradation reactions with drugs, including proteins, which are oxygen sensitive.

7. The use of silicone to lubricate vial rubber closures, syringe rubber plungers to coat the inner surface of glass syringes, and cartridges potentially can induce protein aggregation. Therefore, compatibility studies need to be designed to determine the potential for a new biopharmaceutical drug adversely affected by the presence of silicone applied to certain packaging surfaces. The increased popularity of laminated rubber closures and plungers has been due to the elimination of the need for applying silicone to these materials. Silicone coating is still required for glass syringes and cartridges, which provide new opportunities for the use of plastic syringes with biopharmaceuticals that further minimize the potential for incompatibilities between biopharmaceuticals and packaging systems.

8. Desired type of packaging—Selection of packaging (i.e., type, size, shape, color of rubber closure, label, and aluminum cap) is often based on marketing preferences and competition. Knowing the type of final package early in the development process aids the formulation scientist in being sure the product formulation will be compatible and elegant in that packaging system.

Table 1 – Main steps involved in the formulation of a new Parenteral Drug Product

1.      Obtain physical properties of active drug substance

a. Structure, molecular weight

b. “Practical” solubility in water at room temperature

c. Effect of pH on solubility

d. Solubility in certain other solvents

e. Unusual solubility properties

f. Isoelectric point for a protein or peptide

g. Hygroscopicity

h. Potential for water or other solvent loss

i. Aggregation potential for protein or peptide

2.      Obtain chemical properties of active drug substance

a.       Must have a ‘validatable’ analytical method for potency

and purity

b.      Time for 10% degradation at room temperature in aqueous solution in the pH range of anticipated use

c. Time for 10% degradation at 5°C

d. pH stability profile

e. Sensitivity to oxygen

f. Sensitivity to light

g. Major routes of degradation and degradation products

3.      Initial formulation approaches

a. Know timeline(s) for drug product

b. Know how drug product will be used in the clinic

i. Single dose vs multiple dose

ii. If multiple dose, will preservative agent be part of drug

solution/powder or part of diluent?

iii. Shelf life goals

iv. Combination with other products, diluents

c.       From knowledge of solubility and stability properties and

information from anticipated clinical use, formulate drug

with components and solution properties known to be

successful at dealing with these issues, then perform

accelerated stability studies.

i. High temperature storage

ii. Temperature cycling

iii. Light and/or oxygen exposure

iv. For powders, expose to high humidities

d. May need to perform several short-term stability studies
as excipient types and combinations are eliminated

e. Selection of primary container and closure

i. Be aware of potential for tubing glass to be subject to

glass delamination (glass lamellae); work with glass

supplier to select type of glass

ii. Most rubber closure formulations are coated rubber to

minimize leachables and do not require siliconization

f. Design and implement an initial manufacturing method of

the product

g. Finalize formulation

i. need for tonicity adjusting agent

ii. need for antimicrobial preservative

h. Approach to obtain sterile product

i. Terminal sterilization

ii. Sterile filtration and aseptic processing

Multiple choice questions:

1.Parenteral drugs are formulated as

a) liposomes

b)microspheres

c)nanosystems

d)all of these

2.Vehicles used for parenteral formulation are

a)Water

b)Water-miscible vehicles

c)Non-aqueous vehicles

d)All of these

3.Water of suitable quality for compounding and rinsing product contact surfaces, to meet United States Pharmacopeia (USP) and other compendia specifications for Water for Injection (WFI), may be prepared by

a)distillation

b)reverse osmosis

c)both of these

d)none of these

4.The most important Water-miscible vehicles used in parenteral formulation are

a)ethyl alcohol

b)liquid polyethylene glycol

c)propylene glycol

d)all of these

5.Which of the following is used in the preparation of solutions of cardiac glycosides?

a)ethyl alcohol

b)liquid polyethylene glycol

c)propylene glycol

d)all of these

6.Glycols are used in the formulation of

a)barbiturates

b)certain alkaloids

c)certain antibiotics

d)all of these

7.The most important group of non-aqueous vehicles is

a)mineral oils

b)volatile oils

c)fixed oils

d)all of these

8.The oils most commonly used as Non-aqueous vehicles for parenterals are

a)corn oil

b)cottonseed oil

c)peanut oil

d)all of these

9.Fixed oils are used as vehicles for

a)Vitamin K

b)Vitamin E

c)Progesterone

d)All of these

10.The most commonly used complexing agents in parenterals is/are

a)cyclodextrins

b) sodium chloride

c)dextrose

d)glycerin

11.Benzalkonium chloride should be used in what concentration in parenterals?

a)0.01%

b)0.5%

c)0.005%

d)0.2%

12.The most commonly used tonicity agents in parenterals are

a)electrolytes

b)mono saccharides

c)disaccharides

d)all of these

13.Sodium bisulfite is

a)antioxidant

b)tonicity adjuster

c)buffer

d)cryoprotectant

14.The acid salts most frequently employed as buffers are

a)citrates

b)acetates

c)phosphates

d)all of these

15.Additives that serve to protect biopharmaceuticals from adverse effects, due to freezing and/or drying of the product during freeze-dry processing are called

a)Cryoprotectants

b)Lyoprotectants

c)Buffers

d)a and b

Solutions:

  1. d)all of these
  2. d)All of these
  3. c)both of these
  4. d)all of these
  5. a)ethyl alcohol
  6. d)all of these
  7. c)fixed oils
  8. d)all of these
  9. d)All of these
  10. a)cyclodextrins
  11. a)0.01%
  12. d)all of these
  13. a)antioxidant
  14. d)all of these
  15. d)a and b

References:

  1. Remington Essential of Pharmaceutics, 1st edition 2013, page no. 496-499.
  2. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th edition, page no. 514-522.

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