Potency uniformity

Active ingredient solubility and particle size are generally important ingredient characteristics that need to be controlled to ensure potency uniformity in many topical drug products such as emulsions, creams, and ointments. Crystalline form is also important where the active ingredient is dispersed as a solid phase in either the oil or water phase of an emulsion, cream, or ointment. 

It is important that active ingredient solubility in the carrier vehicle be known and quantified at the manufacturing step in which the ingredient is added to the liquid phase. The development data should adequately demonstrate such solubility and its validation. 

Substances that are very soluble, as is frequently the case with ointments, would be expected to present less of a problem than if the drug substance were to be suspended, as is the case with creams. If the drug substance is soluble, then potency uniformity would be based largely on adequate distribution of the component throughout the mix. 

Production controls should be implemented that account for the solubility characteristics of the drug substance inadequate controls can adversely affect product potency, efficacy, and safety. For example, in one instance, residual water remaining in the manufacturing vessel, used to produce an ophthalmic ointment, resulted in partial solubilization and subsequent recrystallization of the drug substance the substance recrystallized in a larger particle 

In addition to ingredient solubility and particle size, other physical characteristics and specifications for both ingredients and finished products are important. 

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Solubility The soluble active ingredient should be added to the liquid phase that will be its carrier vehicle. Data of solubility have to be determined as part of the process validation. Potency uniformity has to be tested by demonstrating satisfactory distribution in the emulsified mix [20],... 

Pesticides. Many pesticides are highly concentrated and are in a physical form requiring further treatment to permit effective appHcation. Typically carriers or diluents are used (see Insectcontroltechnology). Although these materials are usually considered inert, they have a vital bearing on the potency and efficiency of the dust or spray because the carrier may consist of up to 99% of the final formulation. The physical properties of the carrier or diluent are of great importance in the uniform dispersion, the retention of pesticide by the plant, and in the preservation of the toxicity of the pesticide. The carrier must not, for example, serve as a catalyst for any reaction of the pesticide that would alter its potency. 

Thyroid hormones used in medicine include both the natural and synthetic hormones. The synthetic hormones are generally preferred because they are more uniform in potency than are the natural hormones obtained from animals. Thyroid hormones are listed in the Summary Drug Table Thyroid and Antithyroid Dragp. 

Thyroid hormones are used as replacement therapy when the patient is hypothyroid. By supplementing the decreased endogenous thyroid production and secretion with exogenous thyroid hormones, an attempt is made to create a euthyroid (normal thyroid) state Levotliyroxine (Synthroid) is the drug of choice for hypothyroidism because it is relatively inexpensive, requires once-a-day dosages, and lias a more uniform potency than do other thyroid hormone replacement drugs. 

Traditionally, apart from tests such as those for appearance and weight, most tests used for the evaluation of final product are destructive in nature. Thus, for determination of such important attributes as potency or content uniformity the present conventional approach is to test a small sample of product, which hopefully is representative of the batch. Clearly it would be highly desirable if such attributes could be measured on every unit or a more representative number of units of product. Use of near-infrared offers this possibility for many if not all drugs. 

Studies involving instrumented compaction equipment can be extremely useful in the development of dosage forms, especially when the amount of drug substance is limited in quantity. Marshall has described a program in which dynamic studies of powder compaction can be used at all stages of the development process to acquire formulation information [63]. The initial experiments include a determination of the intrinsic compactability of the compound. In subsequent work, simple tablets are prepared, and tested for dissolution, potency, and content uniformity. Through studies of the compaction mechanism, it becomes possible to deduce means to improve the formulation under study. 

Levothyroxine (L-thyroxine, T4) is the drug of choice for thyroid hormone replacement and suppressive therapy because it is chemically stable, relatively inexpensive, free of antigenicity, and has uniform potency however, any of the commercially available thyroid preparations can be used. Once a particular product is selected, therapeutic interchange is discouraged. 

Liothyronine (synthetic T3) has uniform potency but has a higher incidence of cardiac adverse effects, higher cost, and difficulty in monitoring with conventional laboratory tests. 

Several in vitro tests are currently employed to assure drug product quality. These include purity, potency, assay, content uniformity, and dissolution specifications. For a pharmaceutical product to be consistently effective, it must meet all of its quality test criteria. When used as a QC test, the in vitro dissolution test provides information for marketing authorization. The dissolution test forms the basis for setting specifications (test, methodology, acceptance criteria) to allow batch release into the market place. Dissolution tests also provides a useful check on a number of physical characteristics, including particle size distribution, crystal form, etc., which may be influenced by the manufacturing procedure. In vitro dissolution tests and QC specifications should be based on the in vitro performance of the test batches used in in vivo studies or on suitable compendial specifications. For conventional-release products, a single-point dissolution... 

Different production batches of the same pharmaceutical preparation can have very similar concentrations of API (+5% around the nominal value) and excipients close to the nominal value. It is difficult to obtain a set of production samples of the target product spanning the concentration range required to develop a calibration model that will allow the pharmacopoeial recommendations to be met and different enough values ( 20% around the nominal one) of potency, content uniformity, etc., accommodated. 

Despite the uncertainties in HOP for the toxins, there is reason to suspect that their mouse intraperitoneal potencies (MIP), the ri for the standard mouse bioassay system, do not bear a uniform relationship to them. Early pharmacological work ( ) on the paralytic shellfish toxins was conducted with shellfish extracts. 

The physical properties of pellets have been widely used to determine an acceptable yield of pellets. These include shape indices, size and size distribution, densities, pore volume and distribution, flow properties, and friability. Of course, drug release from the pellets is a critical parameter to be monitored in order to ensure potency and uniformity of drug distribution. 

Many of the FDA s post-approval, pre-marketing inspections result in citations because validation (and consistency) of the full-scale batches could not be established due to problems with product dissolution, content uniformity, and potency. Validation reports on batch scale-ups may also reflect selective reporting of data. 

The only effective treatment is replacement therapy with thyroid hormones. Levothyroxine, a synthetic levoisomer of thyroxine (T4), is the drug of choice since it is stable, relatively inexpensive, free of antigenicity, and of uniform potency. It results in a pool of thyroid hormone that is rapidly converted into the more potent T3. Levothyroxine can be administered orally or... 

Tablet weight, hardness, thickness, content uniformity, friability, dissolution, disintegration, Assay/ potency...

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