Excipient active ingredients

Cosmetic formulations are composed of active ingredients and excipients. Active ingredients are compounds directly related with the efficacy of the cosmetic product. Excipients can have different functions such as to facilitate the preparation of the formulation, to achieve the required physicochemical properties, to improve the efficacy or to provide stability to the finished product. On the other hand, active ingredients in some cosmetic formulations can act as auxiliary ingredients in other formulations. 

To remove the excipient, the tablet was ground to a powder and a weighed portion treated with a known volume of a mixture of 5% glacial acetic acid in methanol. The slurry was well stirred to ensure all the active ingredients were dissolved and the mixture was filtered. 

The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy, in which case additional safety and efficacy data are required. The same qualitative and quantitative composition only applies to the active ingredients. Differences in excipients will be accepted unless there is concern that they may substantially alter the safety or efficacy. The same pharmaceutical form must take into account both the form in which it is presented and the form in which it is administered. Various immediate-release oral forms, which would include tablets, capsules, oral solutions and suspensions, shall be considered the same pharmaceutical form for this purpose. 

Medicinal products and bulk pharmaceutical chemicals are produced mainly in batch processes. Controlling these products and chemicals at the end of their manufacturing processes is not in line with the general principle of quality assurance, which is that quality should be built into the product. It is then necessary to ensure that appropriate good manufacturing practices are adhered to throughout the manufacture of both bulk pharmaceutical chemicals (active ingredients as well as excipients) and medicinal products. 

Non-specific absolute assay methods, e.g. volumetric titration, can be applied to avoid the establishment of a reference substance. This is only appropriate, however, when the monograph describes a separation test for related substances. This approach is certainly valid for the determination of the content of pharmaceutical raw materials but less acceptable for the assay of content of pharmaceutical preparations where the employment of specific assay methods is recommended (ICH Guideline 1994) to take account of decomposition of the active ingredient during the shelf life of the product and to avoid possible interference from excipients. 

The dose of the drug and its solubility are important considerations in the design of the formulation. The amount and type of active ingredient influences capsule size and the nature and amount of excipients to be used in the formulation. Larger-dose drugs that must be granulated to produce tablets may be more easily direct-filled into hard shell capsules with proper choice of excipients. 

In general, aqueous ophthalmic solutions are manufactured by methods that call for the dissolution of the active ingredient and all or a portion of the excipients into all or a portion of the water and the sterilization of this solution by heat or by sterilizing filtration through sterile depth or membrane filter media into a sterile receptacle. If incomplete at this point, this sterile solution is then mixed with the additional required sterile components, such as previously sterilized solutions of viscosity-imparting agents, preservatives, and so on, and the batch is brought to final volume with additional sterile water. 

When an ophthalmic ointment is manufactured, all raw material components must be rendered sterile before compounding unless the ointment contains an aqueous fraction that can be sterilized by heat, filtration, or ionizing radiation. The ointment base is sterilized by heat and appropriately filtered while molten to remove extraneous foreign particulate matter. It is then placed into a sterile steam-jacketed kettle to maintain the ointment in a molten state under aseptic conditions, and the previously sterilized active ingredients) and excipients are added aseptically. While still molten, the entire ointment may be passed through a previously sterilized colloid mill for adequate dispersion of the insoluble components. 

Development pharmaceutics information is intended to cover a number of aspects related to the active ingredient(s), excipients, container-closure system, and the finished (drug) product. These aspects will be considered individually below. 

The compatibility of the active ingredient with other active ingredients and excipients should be demonstrated. Preformulation study reports often provide useful relevant information. Preliminary stability study reports may be used as supporting data. 

Antioxidants should be used only when it can be shown that their incorporation cannot be avoided by appropriate manufacturing methods or packaging. Their intended performance in the product should be clearly stated—e.g., whether for the benefit of the active ingredient or an excipient. Their efficacy can depend on their nature, their concentration (subject to safety considerations), when they are incorporated in the manufacture of the finished product, the container, and the formulation (particularly their compatibility with other constituents). All of these issues should be addressed. Their activity should also be determined in the finished product under conditions simulating the use of the product. The extent of degradation should be determined with and without the antioxidant. 

Factors affecting the mix of active ingredients and excipients should be discussed. These should include particle size and shape, rugosity, charge, flow properties, and water content. Since the dose delivery for these products is dependent on air flow characteristics, an attempt should be made to establish an in vivo-in vitro correlation. 

The formulation of this type of product usually employs a small number of ingredients and sometimes only the active ingredient. Particle size and particle size distribution, rugosity, and particle charge should be considered for all ingredients, and the specific grade of excipients should be stated. The excipients should be sourced from a single supplier (with data to demonstrate the suitability of different batches of material), but if multiple sources are used, additional data will be required to establish the suitability of different batches from each supplier. 

The possibility of container-closure interactions should be considered, taking into account any admixture and dilution of products. Sorption of active ingredients and excipients should be considered as should leaching of container-closure components over the shelf life. Studies should extend to simulation of use. Pack components, administration devices (e.g., giving sets), and label adhesives should be considered. 

Upper and lower acceptance limits are expected for all ingredients—these would normally be nominal 5% for active ingredients and nominal 10% for excipients, with wider ranges being individually justified. Where factorization is used, the details should be included, together with information on total mass adjustment if necessary. Overages need to be stated and justified in the development pharmaceutics section. 

Justifications for the use of nonstandard (i.e., nonpreferred or nonpharmacopeial) methods of sterilization may include the heat instability of the active ingredient or an essential excipient. The choice of a method based on filtration through a microbial retentive filter and/or aseptic assembly should be justified, and the appropriate in process controls (including bioburden controls on active ingredients, excipients, bulk solutions, process time constraints etc) discussed in detail in the application. Commercial considerations should not form part of the argument for the application of a nonstandard sterilization process. The highest possible sterility assurance level should be achieved. 

Where there are existing pharmacopeial specifications for active ingredients in the Ph Eur or the pharmacopeia of a member state, these will be expected to apply. Other pharmacopeial specifications or in-house specifications may be used in other cases. The same is true for excipients where harmonized specifications are mentioned. Particular quality requirements related to a particular application are discussed, e.g., particle size control requirements. 

Compatibility of the excipients and active ingredient is addressed (but often with little detail). Formulation optimization and excipient ranges may be included in the discussion. The inclusion of antioxidants in the formulation is discussed as appropriate. 

Issues similar to those discussed above for other dosage form types arise from the active ingredients and excipients proposed for use. 

There are two EPARs for eyedrops. Specific issues considered for these include container composition and tamper evidence, the optimization of the formulation and manufacture, preservative and preservation issues, and justification for the use of nonterminal sterilization processes. Many of the points concerning active ingredients and excipients are similar to those discussed above. Changes in formulation during the development process (e.g., for carbomers or surfactants) are mentioned. Particle size controls for suspension products are discussed. 

A number of oral solution or suspension products are included in the EPARs. Apart from the usual points of consideration for active ingredients and excipients, particular mention is made of possible precipitation of active ingredient when a solution is in use, the inclusion of excipients having a major impact on bioavailability, the need for flavoring to mask the taste of the active ingredient, relative potency compared with other routes of administration, preservation issues, dosing devices and the precision and accuracy of the dose delivered, and bioequivalence where formulations have been modified during the development process. 

Another excipient used in feed additive premixes is a diluent used to dilute or standardize activity. Diluents are similar in composition to grain carriers, except the particle size is generally smaller. No attempt is made to absorb the active drug to the individual particles of the diluents. If a liquid is used it is mainly for dust control. A diluent is considered for use when the level of the active ingredient components in the premix approaches or exceeds 50% of the product or when two or more active components vary greatly from one another in density [13]. Examples of diluent materials are ground limestone, sodium sulfate, kaolin, corn cob flour, and ground oyster shells. 

Many drugs, including many biopharmaceuticals, are administered to localized areas within the body by, for example, s.c. or i.m. injection. Local toxicity tests appraise whether there is any associated toxicity at/surrounding the site of injection. Predictably, these are generally carried out by s.c. or i.m. injection of product to test animals, followed by observation of the site of injection. The exact cause of any adverse response noted (i.e. active ingredient or excipient) is usually determined by their separate subsequent administration. 

Addition of various excipients (substances other than the active ingredient(s) which, for example, stabilize the final product or enhance the characteristics of the final product in some other way). 

Streptokinase is a 48 kDa extracellular bacterial protein produced by several strains of Streptococcus haemolyticus group C. Its ability to induce lysis of blood clots was first demonstrated in 1933. Early therapeutic preparations administered to patients often caused immunological and other complications, usually prompted by impurities present in these products. Chromatographic purification (particularly using gel filtration and ion-exchange columns) overcame many of these initial difficulties. Modern chromatographically pure streptokinase preparations are usually supplied in freeze-dried form. These preparations (still obtained by non-recombinant means) often contain albumin as an excipient. The albumin prevents flocculation of the active ingredient upon its reconstitution. 

Another potential benefit of UHPLC is its capability of solving the most challenging separation tasks in pharmaceutical analysis. Figure 9.4 shows a UPLC method developed to analyze pharmaceutical formulations used to treat the common cold. Cold products often contain multiple active ingredients to treat different symptoms and can contain decongestants, antihistamines, pain relievers, cough suppressants, expectorants, and numerous excipients of various polarities. The analysis of a total of 20 components was achieved within 10 min. 

In 21 CFR Section 210.3(b)(8)(2), an inactive ingredient means any component other than an active ingredient. According to the CFR, the term inactive ingredient includes materials in addition to excipients. 21 CFR Section 201.117 states... 

A pharmacopeia is a collection of recommended specifications and other information for therapeutic products, including drug substances (active ingredients), excipients, dosage forms (also called preparations), and other articles. One function of a pharmacopeia is to provide a uniform and public basis on... 

An antidepressant in 10,20, and 40 mg doses Active ingredient Fluoxethine hydrochloride Excipients Starch, gelatin, silicone, titanium dioxide, iron oxide, etc. 

Pharmaceuticals, for the purpose of this book, means chemical compounds that are used in pharmaceutical production. This can comprise the active ingredient, which is also called active pharmaceutical ingredient (API) or drug substance or drug product and the inert pharmaceutical ingredients (excipients) that are used to formulate a drug product in the form of tablets, capsules, ointments, creams, lotions, parenterals, inhalers, and a variety of drug delivery systems. 

Figure 8 shows a typical F4PLC chromatogram of the tablet extract illustrating the complexity of the sample, which contains numerous natural components, excipients and additives. During the SP method development, it was found that extraction with a neutral aqueous buffer was problematic due the loss of one of the active ingredients by hydrolysis. The use of the PTFE filter was also important because this hydrolysis product, which is highly hydrophobic, was absorbed by nylon filters under the filtration conditions. 

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