Pharmaceutical dosage forms, physical

The critical unit operations that should be monitored and/or optimized are the reaction and fermentation steps for the purpose of increasing API yield and reducing the residual impurity profile. Other critical unit operations that are especially important to the end user (pharmaceutical dosage form operations) include precipitation or crystallization, milling, sizing, and purification operations, which may affect the physical properties (particle size and shape, bulk powder flow, blend uniformity, and compressibility) of the API. 

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. 

Amorphous substances are an important class of pharmaceutical materials that exhibit distinct physical and chemical properties. They are ubiquitous, and may be formed both intentionally and unintentionally during normal pharmaceutical manufacturing operations. The properties of amorphous materials can be exploited to improve the performance (e.g., bioavailability and dissolution rate) of pharmaceutical dosage forms, but these properties can also give rise to unwanted effects (e.g., physical instability) that need to be understood and managed in order for the systems to perform as required. 

Moore, K.L. Physical properties of opadry, coateric, and surelease. In Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms Mcgenity, J.W., Ed. Marcel Dekker New York, 1989 303-316. 

Figure 3.3 Human small intestinal transit time of different pharmaceutical dosage forms measured by y-scintigraphy [40]. The intestinal transit time is fairly fixed and largely independent of the physical properties of the system or food intake.

Polymorphism is defined as the existence of a chemical molecule in different crystal forms or crystal packing arrangements. There is evidence to support the claim that most organic compounds are polymorphic. The existence of two polymorphic forms is also prevalent, and three or more polymorphic forms are not uncommon. Different polymorphs have different physical properties, such as melting point, solubility, density, hardness, and crystal shape. Because of the difference in solubility, a difference in dissolution rates of the polymorphs is expected. Bioavailability in animals or humans may be different, therefore, among the polymorphic forms. This potential difference is an important consideration in pharmaceutical dosage form development. 

A choice of salts can also expand the formulation options for a material. The antimalarial agent a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrene-methanol hydrochloride (Fig. 9) exhibited poor solubility, was delivered as an oral formulation, and required a single dosing of 750 mg (13). Seven salts and the free base were evaluated. The lactate salt was found to be 200 times as soluble as the hydrochloride salt (Table 3). This enhanced solubility would make it possible to reduce the oral dose to achieve the same therapeutic response as well as develop a parenteral formulation for the treatment of malaria. However, the case of lidocaine hydrochloride (Fig. 14) demonstrates that a compound limited to parenteral and topical formulations can be expanded to oral administration by changing to a salt form with acceptable physical properties (16). The hydrochloride salt was hygroscopic, difficult to prepare, and hard to handle. Six salts were evaluated for salt formation, solubility, and hygroscopicity. Other salts, such as phosphate, exhibited properties acceptable for dry pharmaceutical dosage forms. 

When formulating any pharmaceutical dosage form, it is important to remember that there is an equilibrium between the bioavailability of the product, its chemical and physical stability and the technical feasibility of producing it. 

The chemical and physical stability of pure drug substances has been described in Chapters 2 and 3, respectively. The stability of pharmaceutical dosage forms is described in this chapter. 

Fig. 37.1 Physical systems occurring in pharmaceutical dosage forms.

Knapezk, J., Krowezynski, L., Pawhk, B., and Liber, Z. 1984. Pharmaceutical dosage forms with chitosan. In Chitin and Chitosan Sources, Chemistry, Biochemistry, Physical Properties and Applications, Skjak-Braek, G., Anthonsen, T., and Sandford, P. (eds.), London, U.K. Elsevier Applied Science, pp. 665-669. 

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