Drug substance suspensions

Many dry solid parenteral products, such as the cephalosporins, are prepared by sterile crystallization techniques. Control of the crystallization process to obtain a consistent and uniform crystal form, habit, density, and size distribution is particularly critical for drug substances to be utilized in sterile suspensions. For example, when the crystallization process for sterile ceftazidime pentahydrate was modified to increase the density and reduce the volume of the fill dose, the rate of dissolution increased significantly. 

Sustained release from disperse systems such as emulsions and suspensions can be achieved by the adsorption of appropriate mesogenic molecules at the interface. The drug substance, which forms the inner phase or is included in the dispersed phase, cannot pass the liquid ciystals at the interface easily and thus diffuses slowly into the continuous phase and from there into the organism via the site of application. This sustained drug release is especially pronounced in the case of multilamellar liquid crystals at the interface. 

Residual solvents are considered a subset of organic impurities. Solvents used to create a solution or suspension during the manufacturing process may not be completely eliminated in the course of manufacture. Solvents used later in the synthesis are more likely to be present in the drug substance, although solvents that have low volatility may persist from earlier steps. 

Das and Haider described a simultaneous spectrophotometrie method for the analysis of binary dosage form mixtures of diloxanide furoate with metronidazole or with tinidazole [19], Powdered tablets or suspension, equivalent to 50 mg of the drug substances, were dissolved in 50 mL of dimethylformamide with shaking. After 15 minutes, the solution was diluted to 100 mL with water and filtered. A 1 mL portion of the filtrate was diluted to 50 mL with water, and the absorbance of the resulting solution measured at 320 and 262 nm for metronidazole and diloxanide furoate simultaneously. Alternatively, readings were taken at 318 and 262 nm for the simultaneous determination of tinidazole and diloxanide furoate. Recoveries were reported to be quantitative. 

The physical characteristics, particularly the particle size of the drug substance, are very important for suspensions. As with topical products in which the drug is suspended, particles are usually very fine to micronized (to <25 microns). For syrup, elixir, or solution dosage forms in which there is nothing suspended, particle size and physical characteristics of raw materials are not that important. However, they can affect the rate of dissolution of such raw materials in the manufacturing process. Raw materials of a finer particle size may dissolve faster than those of a larger particle size when the product is compounded. 

Examples of a few oral suspensions in which a specific and well-defined particle-size specification for the drug substance is important include phenytoin suspension, car-bamazepine suspension, trimethoprim and sulfamethoxazole suspension, and hydrocortisone suspension. It is therefore a good idea to indicate particle size in the raw material specification, even though it is meant for dissolving in the processing, to better validate the manufacturing process while avoiding scale-up problems. 

It is essential to understand how and when the polymorphs of drug substance in oral liquid dosage forms and suspensions can be controlled. One approach to study this phenomenon is to seed the formulation with a small amount of a known polymorphic crystal (other than what is used for the product), which is a common practice to rapidly determine what effect this may have on long-term storage. From these types of studies, the appropriate excipients can be used to preserve the specific polymorphic form desired. However, even when the drug in its crystalline form is studied extensively, there are cases when a previously unknown polymorph may be formed in solution and lead to precipitation (14). 

Change in particle size distribution of the drug substance, if the drug is in suspension. 

Any qualitative and quantitative changes in an excipient beyond the ranges noted in level 2 change Change in crystalline form of the drug substance, if the drug is in suspension... 

It is important to characterize the physicochemical properties of the suspensions well, so that the PK data can be interpreted appropriately. Typical characterization of the drug substance includes purity, residual solvents, aqueous solubility pro Lie (pH 2, FaSSIF), crystallinity (XRPD/DSC), particle size, pl and logP. For solution formulations at various stages of discovery studies, dose analysis is essential, and for efLcacy assessment and toxicology studies, chemical stability for the... 

Historically, the administration of crystalline APIs has mainly found use in parenteral applications associated with intramuscular and subcutaneous injections as well as topical applications of suspensions containing micronized APIs. Commercially marketed pharmaceuticals categorized as suspensions for parenteral administration are illustrated in Table 17.3. Many of these products utilize drug substance size reduction in order to promote dissolution following administration. The degree... 

Table 3 Proposed Maximum Stress Conditions for Solutions or Suspensions of Drug Substances...

From a pharmacokinetic perspective, BA data for a given formulation provide an estimate of the relative fraction of the orally administered dose that is absorbed into the systemic circulation when compared with the BA data for a solution, suspension, or intravenous dosage form [21 CFR 320.25(d)(2) and (3)]. In addition, BA studies provide other useful pharmacokinetic information related to distribution, elimination, the effects of nutrients on absorption of the drug, dose proportionality, linearity in pharmacokinetics of the active moieties, and, where appropriate, inactive moieties. BA data may also provide information indirectly about the properties of a drug substance before entry into the systemic circulation, such as permeability and the influence of presystemic enzymes and/or transporters (e.g., p-glycoprotein). 

The use of gelatine capsules filled with the bulk drug substance can be applied for large animals, especially dogs. Another method is the intra-oesophageal administration of the dissolved drug or the drug as a suspension by means of a rubber hose. 

The stability of the drug substance needs to be determined prior to the beginning of the study. In case of application of suspensions, the homogenous distribution... 

Dispersed systems are dosage forms composed of two or more phases, where one phase is distributed in another [2], If a dispersed system is formed by liquid phases, then it is known as an emulsion. In contrast, the dispersed system is named a suspension when the liquid dosage form is accomplished by the distribution of a solid phase suspended in a liquid matrix. The solid phase of a suspension is usually the drug substance, which is insoluble or very poorly soluble in the matrix [12],... 

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