Excipient physical properties

For any new excipients, APIs or drug products (where new does not necessarily mean novel, but new to the receiving site) there are additional testing criteria, e.g. supplier audits, third-party contract laboratory audits, analytical method transfers, sample management/tracking, etc. For those key excipients, where there is on-site historical experience, it still behoves both parties to check whether the local grade/supplier used by the CMO is equivalent to that used by the supplier (Worsham, 2010). There are many examples of differences in excipient physical properties, e.g. particle size, which have been attributed to different excipient sources that could ultimately impact on the performance of those excipients in formulated products (Frattini and Simioni, 1984 Dansereau and Peck, 1987 Phadke et al., 1994 Lin and Peck, 1994). 

Instability attributable to excipient-mediated water distribution in solids and powders has been explained by excipient physical properties. " Crystalline materials will not uptake moisture until the deliquescent point is reached. In contrast, amorphous excipients will absorb water until their glass transition temperatures fall below the ambient temperature when the mobility of the molecules has increased so much that excipient crystallization will occur to expel the absorbed water from the crystal lattice. Before crystal-... 

The dissolution rate of a dosage form can be impacted by a number of factors during manufacture including the drug substance and excipient physical properties,... 

By choosing the excipient type and concentration, and by varying the spray-drying parameters, control was achieved over the physical properties of the dry chitosan powders. The in vitro release of betamethasone showed a dose-dependent burst followed by a slower release phase that was proportional to the drug concentration in the range 14-44% w/w [200]. 

In the present work, such a systematic approach to the physical characterization of pharmaceutical solids is outlined. Techniques available for the study of physical properties are classified as being associated with the molecular level (properties associated with individual molecules), the particulate level (properties pertaining to individual solid particles), and the bulk level (properties associated with an ensemble of particulates). Acquisition of this range of physical information yields a total profile of the pharmaceutical solid in question, whether it is an active drug, an excipient, or a blend of these. The development of a total profile is a requirement for successful manufacture of any solid dosage form. 

Overdosed and underdosed production samples (B). Properly powdered production samples are supplied with known amounts of the API (overdosing) or a mixture of the excipients (underdosing) in order to obtain the desired range of API concentrations. The amounts of API or excipients added are usually small, so the ensuing changes in the physical properties of the samples are also small and their matrix can be assumed to be essentially identical with that of the production samples. This is an effective, less labor-intensive method than the previous one and allows the required API concentration range to be uniformly spanned. 

Drug products contain both drug substance (sometimes referred to as the Active Pharmaceutical Ingredient [API]) and excipients. The resultant biological, chemical and physical properties of the dmg product are directly dependent on the excipients chosen, their concentration and interactions with the API [1]. 

Preformulation testing provides a basic dossier on the compound and plays a significant role in identifying possible problems and suitable approaches to formulation. Such dossiers already exist for the common excipients. The requirement for aqueous solubility is paramount and preformulation can identify salt forms that are appropriate for further development. Stability and solubility studies wiU indicate the feasibility of various types of formulation such as parenteral liquids and their probable shelf lives. Similar information can be garnered for solid products from the solid physical properties. By performing these studies on a series of candidate compounds, the optimum compound can be identified and further biological and chemical studies guided to provide the best results. 

Finally, knowledge of excipient mechanical and physical properties is essential to creating a robust formulation that manufactures tablets that meet specifications in a time- and material-efficient manner. Excipient selection must also take into consideration API stability and biopharmaceutical performance of the dosage form. Uneducated selection of excipients will likely lead to numerous formulating iterations that require much time and material, which are luxuries that product development scientists do not have in the competitive pharmaceutical environment. 

It is obvious that most of the effects of scale-up are seen in the unit operations that occur before compressing, especially blending, granulation, milling, and drying. These operations impart the important physical properties to the mixture to be compressed. For example, separation of particle sizes in the hopper would be a function of the choice of excipients or the processing steps to get to the final granulation or direct compression mixture. 

Characterization of the physical properties of excipients is also important. This is demonstrated in Table 2 in the light of the example of hydrochlorothiazide. Tablets of greater hardness are obtained if fine instead of coarse Povidone K 90 is taken. To a certain extent, the disintegration and the release are also affected. 

The following physical properties of the drug and excipients are factors in creating a uniform mix or blend ... 

In order to develop a robust formula for a drug product (pharmaceutical dosage form) it is important to understand the chemical and physical properties of the API in conjunction with excipients that may be used to create the most stable product formula in terms of activity and potency. An outline of possible preformulation studies that should be conducted to ensure a proper and complete understanding of the chemical and physical properties of the API is presented in Table 3. 

The presence of amorphous lactose in the excipient may have a negative effect on compactibility and product stability. Direct compression grades of lactose monohydrate are available as granulated/agglomerated particles from multiple vendors. These physical properties are listed in Table 7.4. Commercial products combine the good flowability of coarse lactose crystals and the good compressibility... 

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