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Compared with oral administration, the use of solubilizers in the delivery of injected drugs is more restricted. Accordingly, the injection form must hold highly strict standards to meet the requirements of the Pharmacopoeia. Solubilizing agent characterization and qualification are also of worry.
Parenteral solubilizing agents must be safe, pure, sterile, pyrogen-free, free of particulate matter, compatible with the active ingredient as well as other excipients and compatible with the packaging components. Consequently, careful consideration should be given while picking a solubilizing agent.
Additionally, the supplier is in authority to make sure that solubilizing agents meet pharmacopoeia specifications, only if the solubilizing agent manufacturer makes such a representation in specifications, labeling, contractual agreement, a Drug Master File (DMF), or a Certificate of Suitability to the European Pharmacopeia (CEP).
Physical characterization and identification tests of a solubilizing agent should be considered carefully. A positive identification test uniquely applicable to the solubilizing agent is required. Many analytical techniques can be used to characterize and identify the pharmaceutical solubilizing agent, such as:
If a solubilizing agent is present in pharmacopoeia, the monograph specifications are generally acceptable in the registration file.
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For solubilizing agents not defined in any pharmacopoeia, specifications should comprise physical characterization, identification tests, purity tests, assay, and impurity tests. A certification must be included to approve that solubilizing agents are of non-animal.
The Handbook of Excipients is an outstanding reference on the safety and adverse reactions to numerous solubilizing agents.
When selecting a solubilizing agent, the formulator should guarantee that any considered solubilizing agent is officially approved for use by the FDA. New solubilizing agents can be utilized, but in order to prove safety, they will require extensive toxicological evaluation.
The FDA provides an inert ingredient database that lists excipients and the ranges of their use in approved product. Any product with an injection volume of more than 5 mL should not use added substances unless it is clearly proven that they contain reasonable and safe concentrations. Just because the excipient is listed as GRAS (Generally Recognized As Safe), does not mean that it can be utilized in parenteral preparations.
Furthermore, the degradation products are considered much more toxic than the parent molecule. The Pharmacopoeia requires three different chromatographic systems to be tested for organic impurities. In addition to local toxicity, there are many other potential adverse reactions involving excipients. Many of these pose little threat provided the amounts of excipients are constrained to certain levels. Excessive amounts, conversely, can cause problems, particularly for patients who cannot tolerate even moderate levels.
For example, too much absorption of glycine solutions, when utilized as irrigants during transurethral resections, can lead to hyponatremia, hypertension, and confusion.
The control of elemental impurities in pharmaceutical materials is currently transitioning from control based on the concentration of pharmaceutical ingredients to control based on allowable daily exposure of drugs. The manufacturing process should be properly controlled so that impurities do not exceed the prescribed standards.
Careful investigation of the impurity profile of the excipient and its potential influence on formulation stability must be carefully checked. It is important that manufacturers identify and set appropriate limits for impurities. These limits should be based upon appropriate toxicological data, or the limits described in national compendial requirements. Many pharmacopoeial monographs do not include an impurity profile, therefore, meeting the requirements of the pharmacopoeia is not sufficient to fully characterize the excipient.
Any traces of metal ions, salts, organic reagents, or other impurities can impair particle production and/or affect stability. Therefore, the determined specifications and the raw material test plan of excipients should be part of the overall control strategy of the suspension production process. These requirements impose restrictions on the choice of excipients, except for the prerequisites for acceptable use in injectable pharmaceutical products. Heavy metal contamination of excipients is a problem, especially for sugars, phosphates, and citrates.
Similarly, the USP and FDA limit the aluminum content of all high-dose parenterals used in total parenteral nutrition to 25 g per liter. In addition, it is also required to indicate on the label of the container for immediate use the maximum content of aluminum in the SVP to be added to the LVP and drug bulk packaging on the expiration date. Impurities in excipients can have a significant impact on the safety, efficacy, or stability of the drug. The monomers or metal catalysts used in the polymerization process are toxic, and if they are present in trace amounts, they can also damage the stability of the drug product.
The development of parenteral drug formulations is more than just deciding on the excipients to be used with a given drug. The development of sterile products requires consideration and evaluation of specific key quality attributes, regardless of the type of product, whether it is intravenous, intramuscular, subcutaneous, intrathecal, intraarticular, ophthalmic, or inhaled products.
It is generally believed that microbial properties are mainly applicable to sterile medicines. However, the main focus of the application of controlled drugs is the safety of the product. Related to the safety of non-sterile products is the potential microbial burden caused by raw materials and/or processing environments.
The U.S. Food and Drug Administration (FDA) pointed out in its microbiological inspection guidelines that each company is expected to develop microbiological specifications for non-sterile products. In order to promote strict requirements for non-sterile drugs, the Therapeutic Goods Administration has released the results of studies on the microbiological quality of non-sterile drugs. Attempts are currently being made to align the proposed USP non-sterile product testing standards with those for the European Pharmacopoeia.
The microbial burden of non-sterile products is particularly important for patients with weakened immune function, and some people believe that the restrictions on oral products must be stricter than those imposed on products that do not affect immunity. The United States and the European Union clearly define the quality expectations of sterile products [98]. A strategy for controlling endotoxins in excipients must also be developed, with appropriate restrictions, depending on the route and schedule of administration of sterile products.
In this section, we will calculate the Allowable Daily Exposure (ADE) of impurities for a hypothetical solubilizing agent and present the results in a table.
The ADE is calculated using the following formula:
ADE (µg/day) = (PDE x BW) / (1 - F)
Where:
For our calculation, let's assume:
| Impurity | Limit (µg/g) | Actual Content (µg/g) |
|---|---|---|
| Impurity A | 10 | 5 |
| Impurity B | 5 | 3 |
| Impurity C | 15 | 12 |
The table above shows the impurity profile of our hypothetical solubilizing agent. The calculated ADE for this agent is µg/day.
The endotoxin limit of a product is the concentration of endotoxin that must not be reached or exceeded when the product is released for sale. The limits of endotoxins in the Pharmacopoeia are expressed in units of APIs. However, this restriction must apply to the entire finished product, including excipients and container closure systems.
It is not clearly stated in the pharmacopoeia or any regulatory documents or guidelines. However, the final dosage form only meets the specifications and can be used safely when the total endotoxin contributed by all the components of the product is less than the endotoxin limit. The bioburden and endotoxin limit of excipients used in the manufacture of sterile medical products should be stated. If the bioburden and endotoxin test of the solution are checked before sterilization, the excipients may not be tested separately.
If excipients or other ingredients are used in multiple products, it is very likely that a different endotoxin limit will be determined for each formulation containing this substance. In that case, the most stringent of those restrictions should be selected as the restriction of the material so that the ingredient can be used in any formulation.
Particulate matter is a key indicator of the quality of injectable drug products. In the United States Pharmacopoeia (USP), undissolved particles other than bubbles that are unintentionally present in a drug product solution are defined as foreign particles. Particles are considered to be a broad category of substances inherent or external to pharmaceutical products, which may be caused by the manufacturing process.
Concerns for patient safety were recognized relative to particulates in parenteral drug products. Furthermore, the used solubilizing agent should meet the allowed limit of particulate matters.
The physical and chemical compatibility of excipients with the drug is a key consideration before formulation to ensure that the selected excipients will not compromise the stability and safety of the drug. Excipients are usually designed to be inert. Direct chemical reactions between excipient molecules and drug molecules are relatively rare. The more common cause of drug-excipient interactions involves impurities derived from the drug, excipient, or packaging materials.
During the pre-formulation and formulation stages of parenteral dosage forms, the physicochemical properties and the compatibility of the solubilizer with the active ingredients should be thoroughly evaluated. The test method requirements are similar to the oral dosage form. The adequate characterization of the key quality attributes of the selected excipients is critical to the formulation development process. Through compatibility studies to identify key physical and chemical properties, methods can be developed to control the aspects of excipients that are critical to product performance.
Compatibility with the drug must be demonstrated as part of the reason for use. In addition, excipients must be selected to meet specific needs. Compatibility studies that only mix one or two excipients with the drug substance can provide excellent information about the interaction of excipients with the drug. The content of excipients should be kept within the functional concentration range to reflect their concentration in the formulation. Then conduct follow-up studies to prove that the final selected level is appropriate by exploring concentrations above and below the recommended concentration.
Even though excipients are generally considered inert, they can interact with packaging ingredients, so careful consideration of the main packaging ingredients is essential. Glass and plastic containers have a tendency to infiltrate formulations. The glass container contains oxides of calcium, magnesium, boron, potassium and calcium, iron, and magnesium, which may interact with the preparation and cause leaching. Rubber is another ingredient that may exhibit some undesirable interactions. Therefore, it is necessary to study the compatibility between the solubilizer used and the selected packaging material.
Parenteral formulations are sterile, pyrogen-free; free of particulate matter and bypass the body's natural defense mechanisms. Functional uses of excipients include improving solubility and stability, safety and efficacy, as bulking agents in lyophilized formulations, tonicity agents, and aiding in controlled or prolonged drug delivery. Numerous parenteral preparations need solubilizing agents to increase or maintain solubility of the active substance in the solution. The basic methods of solubilizing parenteral drugs include: salt formation, pH adjustment, co-solvents, surfactants, complexing agents, and changing the formulation from solution to dispersion. The criteria for choosing a solubilizing agent depend on many factors, including the type of drug and the route of injection. Solubilizing agents used in injectable preparations must meet some stringent requirements. Parenteral solubilizing agents must be safe, pure, sterile, pyrogen-free, free of particulate matter, compatible with the active ingredient as well as other excipients, and compatible with the packaging components.
Characterization and Qualification of Solubilizing Agents. (2024, Jan 16). Retrieved from https://studymoose.com/document/characterization-and-qualification-of-solubilizing-agents
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